US 2010.0015200A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0015200 A1 McClain et al. (43) Pub. Date: Jan. 21, 2010

(54) DRUG DELIVERY MEDICAL DEVICE A638/19 (2006.01) A638/18 (2006.01) (75) Inventors: James B. McClain, Raleigh, NC A63L/7088 (2006.01) (US); Douglas Taylor, Franklinton, A 6LX 3L/705 (2006.01) NC (US); John Neet, Lawrence, KS A6II 3L/20 (2006.01) (US) A 6LX 3L/75 (2006.01) A6II 35/12 (2006.01) Correspondence Address: A6IR 48/00 (2006.01) WILSON, SONSINI, GOODRICH & ROSATI 650 PAGE MILL ROAD (52) U.S. Cl...... 424/423: 514/12: 424/94.1: 514/8: PALO ALTO, CA 94304-1050 (US) 514/44 R: 514/44 A: 514/558: 514/169: 514/54; 424.793.7 (73) Assignee: MICELL TECHNOLOGIES, INC., Raleigh, NC (US) (57) ABSTRACT (21) Appl. No.: 12/504,597 Provided is a coated implantable medical device, comprising: a Substrate; and a coating disposed on said Substrate, wherein (22) Filed: Jul. 16, 2009 said coating comprises at least one polymer and at least one pharmaceutical agent in a therapeutically desirable morphol Related U.S. Application Data ogy and/or at least one active biological agent and optionally, one or more pharmaceutical carrying agents; wherein Sub (60) Provisional application No. 61/081.691, filed on Jul. stantially all of pharmaceutical agent and/or active biological 17, 2008, provisional application No. 61/212.964, agent remains within said coating and on said Substrate until filed on Apr. 17, 2009. the implantable device is deployed at an intervention site O O inside the body of a subject and wherein upon deplowment of Publication Classification said medical i.e. in E. body of said E. EN of (51) Int. Cl. said pharmaceutical agent and/or active biological agent is A6F 2/02 (2006.01) delivered at said intervention site along with at least a portion A6K 38/17 (2006.01) of said polymer and/ora at least a portion of said pharmaceu A6 IK 38/43 (2006.01) tical carrying agents. US 2010/0015200 A1 Jan. 21, 2010

DRUG DELVERY MEDICAL DEVICE the device is adapted to free greater than 35% of the coating from the Substrate upon a single stimulation of the coating. CROSS-REFERENCE 0010 Provided herein is a medical device comprising a 0001. This application claims the benefit of U.S. Provi Substrate and a coating on at least a portion of said Substrate, sional Application No. 61/081.691, filed Jul. 17, 2008, and wherein said coating comprises an active agent, and wherein U.S. Provisional Application No. 61/212.964, filed Apr. 17. the device is adapted to dissociate greater than 35% of the 2009, which applications are incorporated herein by refer coating from the Substrate upon a single stimulation of the ence in their entirety. coating. 0011 Provided herein is a medical device comprising a BACKGROUND OF THE INVENTION Substrate and a coating on at least a portion of said Substrate, wherein said coating comprises an active agent, and wherein 0002 There is a need for medical device technology that the device is adapted to transfer greater than 35% of the can rapidly, efficiently, reproducibly and safely transfer a coating from the Substrate to an intervention site upon a single Drug Delivery Formulation from the surface of a percutane stimulation of the coating. ous medical device (a coating) onto/into a specific site in the 0012 Provided herein is a medical device comprising a body. Substrate and a coating on at least a portion of said Substrate, wherein said coating comprises an active agent, wherein the SUMMARY OF THE INVENTION coating is patterned, and wherein at least a portion of the 0003 Provided herein is a medical device comprising a coating is adapted to free from the Substrate upon stimulation Substrate and a coating on at least a portion of the Substrate, of the coating. wherein the coating comprises a plurality of layers, wherein 0013 Provided herein is a medical device comprising a at least one layer comprises a pharmaceutical agent that is Substrate and a coating on at least a portion of said Substrate, crystalline, and wherein the device is adapted to free at least wherein said coating comprises an active agent, wherein the a portion of the coating from the Substrate upon stimulation of coating is patterned, and wherein at least a portion of the the coating. coating is adapted to dissociate from the Substrate upon 0004 Provided herein is a medical device comprising a stimulation of the coating. Substrate and a coating on at least a portion of the Substrate, 0014 Provided herein is a medical device comprising a wherein the coating comprises a plurality of layers, wherein Substrate and a coating on at least a portion of said Substrate, at least one layer comprises a pharmaceutical agent that is wherein said coating comprises an active agent, wherein the crystalline, and wherein the device is adapted to dissociate at coating is patterned, and wherein at least a portion of the least a portion of the coating from the Substrate upon stimu coating is adapted to transfer from the Substrate to an inter lation of the coating. vention site upon stimulation of the coating. 0005 Provided herein is a medical device comprising a 0015. In some embodiments, the therapeutically desirable Substrate and a coating on at least a portion of said Substrate, morphology comprises a crystalline form of the pharmaceu wherein the coating comprises a plurality of layers, wherein tical agent that is not a microcapsule. at least one layer comprises a pharmaceutical agent that is 0016. In some embodiments, the single stimulation lasts at crystalline, and wherein the device is adapted to transfer at most 20 seconds. In some embodiments, the device is adapted least a portion of the coating from the Substrate to an inter to free Substantially all of the coating upon the single stimu vention site upon stimulation of the coating. lation of the coating. In some embodiments, the single stimu 0006 Provided herein is a medical device comprising a lation lasts at most 20 seconds. In some embodiments, Sub Substrate and a coating on at least a portion of said Substrate, stantially all of the coating frees from the substrate wherein said coating is at least partially continuous, has at instantaneously upon stimulation of the coating. least one portion conformal to the Substrate, and comprises a 0017. In some embodiments, the patterned coating com pharmaceutical agent that is crystalline, and wherein the prises at least two different shapes. device is adapted to free at least a portion of the coating from 0018 Provided herein is a medical device comprising: a the Substrate upon stimulation of the coating. Substrate; and a coating on at least a portion of said Substrate, 0007 Provided herein is a medical device comprising:a wherein said coating comprises an active agent, and wherein Substrate and a coating on at least a portion of said Substrate, at least a portion of the coating is adapted to transfer from the wherein said coating is at least partially continuous, has at Substrate to an intervention site. In some embodiments, the least one portion conformal to the Substrate, and comprises a portion of the coating is adapted to transfer from the Substrate pharmaceutical agent that is crystalline, and wherein the to the intervention site upon stimulation of the coating. device is adapted to dissociate at least a portion of the coating 0019 Provided herein is a medical device comprising: a from the Substrate upon stimulation of the coating. Substrate; and a coating on at least a portion of said Substrate, 0008 Provided herein is a medical device comprising a wherein said coating comprises an active agent, and wherein Substrate and a coating on at least a portion of said Substrate, at least a portion of the active agent is adapted to transfer from wherein said coating is at least partially continuous, has at the Substrate to an intervention site. In some embodiments, least one portion conformal to the Substrate, and comprises a the portion of the active agent is adapted to transfer from the pharmaceutical agent that is crystalline, and wherein the substrate to the intervention site upon stimulation of the coat device is adapted to transfer at least a portion of the coating ing. from the Substrate to an intervention site upon stimulation of 0020 Provided herein is a medical device comprising: a the coating. Substrate; and a coating on at least a portion of said Substrate, 0009 Provided herein is a medical device comprising a wherein said coating comprises an active agent, and wherein Substrate and a coating on at least a portion of said Substrate, the device is adapted to transfer at least a portion of the wherein said coating comprises an active agent, and wherein coating from the Substrate to an intervention site. In some US 2010/0015200 A1 Jan. 21, 2010

embodiments, the device is adapted to transfer the portion of 0027. In some embodiments of the methods and/or the coating (coating portion) from the Substrate to the inter devices provided herein, the balloon is a compliant balloon. vention site upon stimulation of the coating. In some embodiments, the balloon is a semi-compliant bal 0021 Provided herein is a medical device comprising: a loon. In some embodiments, the balloon is a non-compliant Substrate; and a coating on at least a portion of said Substrate, balloon. In some embodiments, the balloon conforms to a wherein said coating comprises an active agent, and wherein shape of the intervention site. 0028. In some embodiments of the methods and/or the device is adapted to transfer at least a portion of the active devices provided herein, the balloon comprises a cylindrical agent from the Substrate to an intervention site. In some portion. In some embodiments, the balloon comprises a Sub embodiments, the device is adapted to transfer the portion of stantially spherical portion. In some embodiments, the bal the active agent from the substrate to the intervention site loon comprises a complex shape. In some embodiments, the upon stimulation of the coating. complex shape comprises at least one of a double noded 0022 Provided herein is a medical device comprising: a shape, a triple noded shape, a waisted shape, an hourglass Substrate; and a coating on at least a portion of said Substrate, shape, and a ribbed shape. wherein said coating comprises an active agent, wherein the 0029. In some embodiments of the methods and/or device is adapted to free at least a portion of the coating from devices provided herein, the Substrate comprises a cutting the Substrate at an intervention site. In some embodiments, balloon. In some embodiments, the cutting balloon comprises the device is adapted to free the portion of the coating from the at least one tacking element adapted to tack the coating to the Substrate at the intervention site upon stimulation of the coat intervention site. In some embodiments, the tacking element 1ng is adapted to secure the coating to the cutting balloon until 0023 Provided herein is a medical device comprising: a inflation of the cutting balloon. In some embodiments, the Substrate; and a coating on at least a portion of said Substrate, tacking element comprises a wire. In some embodiments, the wherein said coating comprises an active agent, wherein the wire is shaped in the form of an outward pointing wedge. In device is adapted to dissociate at least a portion of the coating Some embodiments, the tacking element does not cut tissue at from the substrate at an intervention site. In some embodi the intervention site. ments, the device is adapted to dissociate the portion of the 0030. In some embodiments of the methods and/or coating from the Substrate at the intervention site upon stimu devices provided herein, the substrate comprises a biomedi lation of the coating. cal implant. In some embodiments, the Substrate comprises a 0024 Provided herein is a medical device comprising: a Surgical tool. Substrate; and a coating on at least a portion of said Substrate, 0031. In some embodiments of the methods and/or wherein said coating comprises an active agent, wherein the devices provided herein, the Substrate comprises at least one device is adapted to dissociate at least a portion of the coating ofa stent, a joint, a screw, a rod, a pin, a plate, a Staple, a shunt, from the substrate and to deliver said portion of the coating to a clamp, a clip, a Suture, a Suture anchor, an electrode, a an intervention site. In some embodiments, the device is catheter, a lead, a graft, a dressing, a pacemaker, a pacemaker adapted to deliver the portion of the coating to the interven housing, a cardioverter, a cardioverterhousing, a defibrillator, tion site upon stimulation of the coating. a defibrillator housing, a prostheses, an ear drainage tube, an 0025. In some embodiments of the methods and/or ophthalmic implant, an orthopedic device, a vertebral disk, a devices provided herein, the substrate comprises a balloon. In bone substitute, ananastomotic device, a perivascular wrap, a Some embodiments, the portion of the balloon having coating colostomy bag attachment device, a hemostatic barrier, a thereon comprises an outer Surface of the balloon. In some vascular implant, a vascular Support, a tissue adhesive, a embodiments, the outer surface is a surface of the balloon tissue sealant, a tissue scaffold, and an intraluminal device. exposed to a coating prior to balloon folding. In some 0032. In some embodiments of the methods and/or embodiments, the outer surface is a surface of the balloon devices provided herein, the Substrate comprises at least a exposed to a coating following balloon folding. In some portion of a tool for delivering to the intervention site a embodiments, the outer surface is a surface of the balloon biomedical implant, wherein the substrate is the biomedical exposed to a coating following balloon crimping. In some implant or wherein the substrate is a portion of the device that embodiments, the coating comprises a material that under is not the biomedical implant. In some embodiments, the goes plastic deformation at pressures provided by inflation of Substrate comprises at least a portion of a tool for performing the balloon. In some embodiments, the coating comprises a a medical procedure. In some embodiments, the tool com material that undergoes plastic deformation at a pressure that prises at least one of a knife, a scalpel, a guidewire, a guiding is less than the rated burst pressure of the balloon. catheter, a introduction catheter, a distracter, a needle, a 0026. In some embodiments of the methods and/or Syringe, a biopsy device, an articulator, a Galotti articulator, a devices provided herein, the coating comprises a material that bone chisel, a bone crusher, a cottle cartilage crusher, a bone undergoes plastic deformation at a pressure that is less than cutter, a bone distractor, an Ilizarov apparatus, an intramed the nominal inflation pressure of the balloon. In some ullary kinetic bone distractor, a bone drill, a bone extender, a embodiments, the coating comprises a material that under bone file, a bone lever, a bone mallet, a bone rasp, a bone saw, goes plastic deformation with at least 8 ATM of pressure. In a bone skid, a bone splint, a bone button, a caliper, a cannula, Some embodiments, the coating comprises a material that a catheter, a cautery, a clamp, a coagulator, a curette, a depres undergoes plastic deformation with at least 6 ATM of pres Sor, a dilator, a dissecting knife, a distractor, a dermatome, Sure. In some embodiments, the coating comprises a material forceps, dissecting forceps, tissue forceps, sponge forceps, that undergoes plastic deformation with at least 4 ATM of bone forceps, Carmalt forceps, Cushing forceps, Dandy for pressure. In some embodiments, the coating comprises a ceps, DeBakey forceps, Doyen intestinal forceps, epilation material that undergoes plastic deformation with at least 2 forceps, Halstead forceps, Kelly forceps, Kocher forceps, ATM of pressure. mosquito forceps, a hemostat, a hook, a nerve hook, an obstet US 2010/0015200 A1 Jan. 21, 2010

rical hook, a skin hook, a hypodermic needle, a lancet, a the liquid is forced between the coating and the substrate. In luxator, a lythotome, a lythotript, a mallet, a partsch mallet, a Some embodiments, the liquid comprises saline. In some mouth prop, a mouth gag, a mammotome, a needle holder, an embodiments, the liquid comprises water. In some embodi occluder, an osteotome, an Epker osteotome, a periosteal ments, the mechanical stimulation comprises a geometric elevator, a Joseph elevator, a Molt periosteal elevator, an configuration of the Substrate that maximizes a shear force on Obweg periosteal elevator, a septum elevator, a Tessier peri the coating. In some embodiments, the mechanical stimula osteal elevator, a probe, a retractor, a Senn retractor, a Gelpi tion comprises a geometric configuration of the Substrate that retractor, a Weitlaner retractor, a USA-Army/Navy retractor, increases a shear force on the coating. In some embodiments, an O'Connor-O’Sullivan retractor, a Deaver retractor, a the mechanical stimulation comprises a geometric configu Bookwalter retractor, a Sweetheart retractor, a Joseph skin ration of the substrate that enhances a shear force on the hook, a Lahey retractor, a Blair (Rollet) retractor, a rigid rake coating. retractor, a flexible rake retractor, a Ragnell retractor, a Linde 0034. In some embodiments of the methods and/or Ragnell retractor, a Davis retractor, a Volkman retractor, a devices provided herein, the coating is freed, dissociated, Mathieu retractor, a Jackson tracheal hook, a Crile retractor, a and/or transferred from the Substrate using a chemical stimu Meyerding finger retractor, a Little retractor, a Love Nerve lation. In some embodiments, the coating is freed from the retractor, a Green retractor, a Goelet retractor, a Cushing vein Substrate using a chemical stimulation. In some embodi retractor, a Langenbeck retractor, a Richardson retractor, a ments, the coating is dissociated from the Substrate using a Richardson-Eastmann retractor, a Kelly retractor, a Parker chemical stimulation. In some embodiments, the coating is retractor, a Parker-Mott retractor, a Roux retractor, a Mayo transferred from the Substrate using a chemical stimulation. Collins retractor, a Ribbon retractor, an Alm retractor, a self In some embodiments, the coating is transferred to the inter retaining retractor, a Weitlaner retractor, a Beckman-Weit vention site using a chemical stimulation. In some embodi laner retractor, a Beckman-Eaton retractor, a Beckman retrac ments, the coating is delivered to the intervention site using a tor, an Adson retractor, a rib spreader, a rongeur, a scalpel, an chemical stimulation. In some embodiments, the chemical ultrasonic scalpel, a laser Scalpel, Scissors, iris Scissors, Kiene stimulation comprises at least one of bulk degradation, inter Scissors, Metzenbaum Scissors, Mayo Scissors, Tenotomy action with a bodily fluid, interaction with a bodily tissue, a Scissors, a spatula, a speculum, a mouth speculum, a rectal chemical interaction with a non-bodily fluid, a chemical inter speculum, Sim's vaginal speculum, Cusco's vaginal specu action with a chemical, an acid-base reaction, an enzymatic lum, a sternal saw, a Suction tube, a Surgical elevator, a Sur reaction, hydrolysis, and combinations thereof. In some gical hook, a Surgical knife, Surgical mesh, a Surgical needle, embodiments, the chemical stimulation comprises bulk deg a Surgical Snare, a Surgical sponge, a Surgical spoon, a Surgical radation of the coating. In some embodiments, the chemical Stapler, a Suture, a Syringe, a tongue depressor, a tonsillotome, stimulation comprises interaction of the coating or a portion a tooth extractor, a towel clamp, towel forceps, Backhaus thereof with a bodily fluid. In some embodiments, the chemi towel forceps, Lorna towel forceps, a tracheotome, a tissue cal stimulation comprises interaction of the coating or a por expander, a Subcutaneus inflatable balloon expander, a tre tion thereof with a bodily tissue. In some embodiments, the phine, a trocar, tweezers, and a venous cliping. chemical stimulation comprises a chemical interaction of the 0033. In some embodiments of the methods and/or coating or a portion thereof with a non-bodily fluid. In some devices provided herein, the coating is freed, dissociated, embodiments, the chemical stimulation comprises a chemical and/or transferred from the Substrate using a mechanical interaction of the coating or a portion thereof with a chemical. stimulation. In some embodiments, the coating is freed from In some embodiments, the chemical stimulation comprises an the Substrate using a mechanical stimulation. In some acid-base reaction. In some embodiments, the chemical embodiments, the coating is dissociated from the Substrate stimulation comprises an enzymatic reaction. In some using a mechanical stimulation. In some embodiments, the embodiments, the chemical stimulation comprises hydroly coating is transferred from the Substrate using a mechanical S1S. stimulation. In some embodiments, the coating is transferred 0035. In some embodiments of the methods and/or to the intervention site using a mechanical stimulation. In devices provided herein, the chemical stimulation is adapted Some embodiments, the coating is delivered to the interven to augment the freeing, dissociation and/or transference of the tion site using a mechanical stimulation. In some embodi coating from the Substrate. In some embodiments, the chemi ments, the mechanical stimulation is adapted to augment the cal stimulation is adapted to initiate the freeing, dissociation freeing, dissociation and/or transference of the coating from and/or transference of the coating from the Substrate. In some the Substrate. In some embodiments, the mechanical stimu embodiments, the chemical stimulation is adapted to cause lation is adapted to initiate the freeing, dissociation and/or the freeing, dissociation and/or transference of the coating transference of the coating from the Substrate. In some from the Substrate. In some embodiments, the coating com embodiments, the mechanical stimulation is adapted to cause prises a material that is adapted to transfer, free, and/or dis the freeing, dissociation and/or transference of the coating sociate from the substrate when at the intervention site in from the Substrate. In some embodiments, the mechanical response to an in-situ enzymatic reaction resulting in a weak stimulation comprises at least one of a compressive force, a bond between the coating and the substrate. shear force, a tensile force, a force exerted on the coating from 0036. In some embodiments of the methods and/or a Substrate side of the coating, a force exerted on the coating devices provided herein, the coating is freed, dissociated, by the Substrate, a force exerted on the coating from an exter and/or transferred from the Substrate using a thermal stimu nal element, a translation, a rotation, a vibration, and a com lation. In some embodiments, the coating is freed from the bination thereof. In some embodiments, the external element Substrate using a thermal stimulation. In some embodiments, is a part of the Subject. In some embodiments, the external the coating is dissociated from the Substrate using a thermal element is not part of the device. In some embodiments, the stimulation. In some embodiments, the coating is transferred external element comprises a liquid. In some embodiments, from the Substrate using a thermal stimulation. In some US 2010/0015200 A1 Jan. 21, 2010

embodiments, the coating is transferred to the intervention and/or transferred from the device by a combination of at least site using a thermal stimulation. In some embodiments, the two of a mechanical stimulation, a chemical stimulation, an coating is delivered to the intervention site using a thermal electromagnetic stimulation, and a Sonic stimulation. stimulation. In some embodiments, the thermal stimulation 0040. In some embodiments of the methods and/or comprises at least one of a hot stimulus and a cold stimulus devices provided herein, the coating is freed, dissociated, adapted to augment the freeing, dissociation and/or transfer and/or transferred from the substrate by extrusion. ence of the coating from the Substrate. In some embodiments, 0041. In some embodiments of the methods and/or the thermal stimulation is adapted to cause the freeing, dis devices provided herein, the device further comprises a Sociation and/or transference of the coating from the Sub release agent. In some embodiments, the release agent is strate. In some embodiments, the thermal stimulation com biocompatible. In some embodiments, the release agent is prises at least one of a hot stimulus and a cold stimulus non-biocompatible. In some embodiments, the release agent adapted to initiate the freeing, dissociation and/or transfer comprises a powder. In some embodiments, the release agent ence of the coating from the Substrate. In some embodiments, comprises a lubricant. In some embodiments, the release the thermal stimulation comprises at least one of a hot stimu agent comprises a Surface modification of the Substrate. lus and a cold stimulus adapted to initiate the freeing, disso 0042. In some embodiments of the methods and/or ciation and/or transference of the coating from the Substrate. devices provided herein, the release agent comprises a physi 0037. In some embodiments of the methods and/or cal characteristic of the coating. In some embodiments, the devices provided herein, the coating is freed, dissociated, physical characteristic of the coating comprises a pattern. In and/or transferred from the device by a electromagnetic Some embodiments, the pattern is a textured surface on the stimulation. In some embodiments, the coating is freed from substrate side of the coating, wherein the substrate side of the the Substrate using a electromagnetic stimulation. In some coating is the part of the coating on the Substrate. In some embodiments, the coating is dissociated from the Substrate embodiments, the pattern is a textured Surface on the inter using a electromagnetic stimulation. In some embodiments, vention site side of the coating, wherein the intervention site the coating is transferred from the Substrate using a electro side of the coating is the part of the coating that is transferred magnetic stimulation. In some embodiments, the coating is to, and/or delivered to, and/or deposited at the intervention transferred to the intervention site using a electromagnetic site. stimulation. In some embodiments, the coating is delivered to 0043. In some embodiments of the methods and/or the intervention site using a electromagnetic stimulation. In devices provided herein, the release agent comprises a vis some embodiments, the electromagnetic stimulation com cous fluid. In some embodiments, the viscous fluid comprises prises an electromagnetic wave comprising at least one of a oil. In some embodiments, the viscous fluid is a fluid that is radio wave, a micro wave, a infrared wave, near infrared Viscous relative to water. In some embodiments, the Viscous wave, a visible light wave, an ultraviolet wave, a X-ray wave, fluid is a fluid that is viscous relative to blood. In some and a gamma wave. In some embodiments, the electromag embodiments, the viscous fluid is a fluid that is viscous rela netic stimulation is adapted to augment the freeing, dissocia tive tourine. In some embodiments, the viscous fluid is a fluid tion and/or transference of the coating from the Substrate. In that is viscous relative to bile. In some embodiments, the Some embodiments, the electromagnetic stimulation is viscous fluid is a fluid that is viscous relative to synovial fluid. adapted to initiate the freeing, dissociation and/or transfer In some embodiments, the viscous fluid is a fluid that is ence of the coating from the Substrate. In some embodiments, Viscous relative to Saline. In some embodiments, the Viscous the electromagnetic stimulation is adapted to cause the free fluid is a fluid that is viscous relative to a bodily fluid at the ing, dissociation and/or transference of the coating from the intervention site. substrate. 0044. In some embodiments of the methods and/or 0038. In some embodiments of the methods and/or devices provided herein, the release agent comprises a gel. devices provided herein, the coating is freed, dissociated, 0045. In some embodiments of the methods and/or and/or transferred from the device by a sonic stimulation. In devices provided herein, the release agent comprises at least Some embodiments, the coating is freed from the Substrate one of the active agent and another active agent. The active using a Sonic stimulation. In some embodiments, the coating agent may be placed on the Substrate prior to the coating in is dissociated from the Substrate using a Sonic stimulation. In order to act as the release agent. The active agent may be a Some embodiments, the coating is transferred from the Sub different active agent than the active agent in the coating. The strate using a Sonic stimulation. In some embodiments, the active agent that is the release agent may provide for a second coating is transferred to the intervention site using a Sonic source of drug to be delivered to the intervention site or stimulation. In some embodiments, the coating is delivered to another location once the coating is released from (or trans the intervention site using a Sonic stimulation. In some ferred from, or freed from, or dissociated from) the substrate. embodiments, the Sonic stimulation comprises a sound wave, 0046. In some embodiments of the methods and/or wherein the Sound wave is at least one of an ultrasound wave, devices provided herein, the release agent comprises a physi an acoustic sound wave, and an infrasound wave. In some cal characteristic of the Substrate. In some embodiments, the embodiments, the Sonic stimulation is adapted to augment the physical characteristic of the Substrate comprises at least one freeing, dissociation and/or transference of the coating from of a patterned coating Surface and a ribbed coating Surface. In the Substrate. In some embodiments, the Sonic stimulation is Some embodiments, the patterned coating Surface comprises adapted to initiate the freeing, dissociation and/or transfer a stent framework. In some embodiments, the ribbed coating ence of the coating from the Substrate. In some embodiments, Surface comprises an undulating Substrate surface. In some the Sonic stimulation is adapted to cause the freeing, disso embodiments, the ribbed coating Surface comprises a Sub ciation and/or transference of the coating from the Substrate. strate surface having bumps thereon. 0039. In some embodiments of the methods and/or 0047. In some embodiments of the methods and/or devices provided herein, the coating is freed, dissociated, devices provided herein, the release agent comprises a prop US 2010/0015200 A1 Jan. 21, 2010

erty that is capable of changing at the intervention site. In 40%, between about 40% and about 45%, at least about 50%, Some embodiments, the property comprises a physical prop at least about 75%, at least about 85%, at least about 90%, at erty. In some embodiments, the property comprises a chemi least about 95%, and/or at least about 99% of the active agent cal property. In some embodiments, the release agent is is adapted to transfer from the substrate to the intervention capable of changing a property when in contact with at least site. In some embodiments, at least about 10% of the active one of a biologic tissue and a biologic fluid. In some embodi agent is adapted to transfer from the Substrate to the interven ments, the release agent is capable of changing a property tion site. In some embodiments, at least about 20% of the when in contact with an aqueous liquid. active agent is adapted to transfer from the Substrate to the 0.048. In some embodiments of the methods and/or intervention site. In some embodiments, at least about 30% of devices provided herein, the release agent is between the the active agent is adapted to transfer from the substrate to the Substrate and the coating. intervention site. In some embodiments, greater than 35% of 0049. In some embodiments of the methods and/or the active agent is adapted to transfer from the substrate to the devices provided herein, substantially all of the coating intervention site. In some embodiments, between about 40% remains on said Substrate until the medical device reaches the and about 45%, of the active agent is adapted to transfer from intervention site. In some embodiments, at least about 10%, at the substrate to the intervention site. In some embodiments, at least about 20%, at least about 30%, greater than 35%, at least least about 50% of the active agent is adapted to transfer from about 40%, between about 40% and about 45%, at least about the substrate to the intervention site. In some embodiments, at 50%, at least about 75%, at least about 85%, at least about least about 75% of the active agent is adapted to transfer from 90%, at least about 95%, and/or at least about 99% of the the substrate to the intervention site. In some embodiments, at coating is adapted to transfer from the Substrate to the inter least about 85% of the active agent is adapted to transfer from vention site. In some embodiments, at least about 10% of the the substrate to the intervention site. In some embodiments, at coating is adapted to transfer from the Substrate to the inter least about 90% of the active agent is adapted to transfer from vention site. In some embodiments, at least about 20% of the the substrate to the intervention site. In some embodiments, at coating is adapted to transfer from the Substrate to the inter least about 95% of the active agent is adapted to transfer from vention site. In some embodiments, at least about 30% of the the substrate to the intervention site. In some embodiments, at coating is adapted to transfer from the Substrate to the inter least about 99% of the active agent is adapted to transfer from vention site. In some embodiments, greater than 35% of the the substrate to the intervention site. As used herein, “about coating is adapted to transfer from the Substrate to the inter when used in reference to a percentage of the active agent can vention site. In some embodiments, between about 40% and mean ranges of 1%-5%, of 5%-I0%, of 10%-20%, and/or of about 45%, of the coating is adapted to transfer from the 10%-50% (as a percent of the percentage of the active agent Substrate to the intervention site. In some embodiments, at transferred, or as a variation of the percentage of the active least about 50% of the coating is adapted to transfer from the agent transferred). Substrate to the intervention site. In some embodiments, at 0052. In some embodiments of the methods and/or least about 75% of the coating is adapted to transfer from the devices provided herein, the active agent portion that is Substrate to the intervention site. In some embodiments, at adapted to transfer upon stimulation is on at least one of a least about 85% of the coating is adapted to transfer from the distal surface of the substrate, a middle surface of the sub Substrate to the intervention site. In some embodiments, at strate, a proximal Surface of the Substrate, and an abluminal least about 90% of the coating is adapted to transfer from the Surface of the Substrate. In some embodiments, the stimula Substrate to the intervention site. In some embodiments, at tion decreases the contact between the coating and the Sub least about 95% of the coating is adapted to transfer from the strate. In some embodiments, the device is adapted to transfer Substrate to the intervention site. In some embodiments, at less than about 1%, less than about 5%, less than about 10%. least about 99% of the coating is adapted to transfer from the less than about 15%, less than about 25%, about 35% or less, substrate to the intervention site. As used herein, “about less than about 40%, less than about 50%, less than about when used in reference to a percentage of the coating can 70%, less than about 80%, and/or less than about 90% of the mean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of active agent absent stimulation of the coating. 10%-50% (as a percent of the percentage of the coating trans 0053. In some embodiments of the methods and/or ferred, or as a variation of the percentage of the coating devices provided herein, the device is adapted to transfer at transferred). least about 10%, at least about 20%, at least about 30%, 0050. In some embodiments of the methods and/or greater than 35%, at least about 40%, between about 40% and devices provided herein, the coating portion that is adapted to about 45%, at least about 50%, at least about 75%, at least transfer upon stimulation is on at least one of a distal Surface about 85%, at least about 90%, at least about 95%, and/or at of the substrate, a middle surface of the substrate, a proximal least about 99% of the coating from the substrate to the surface of the substrate, and an abluminal surface of the intervention site. In some embodiments, the device is adapted Substrate. In some embodiments, the stimulation decreases to transfer at least about 10% of the coating from the substrate the contact between the coating and the Substrate. In some to the intervention site. In some embodiments, the device is embodiments, device is adapted to transfer less than about adapted to transfer at least about 20% of the coating from the 1%, less than about 5%, less than about 10%. less than about substrate to the intervention site. In some embodiments, the 15%, less than about 25%, about 35% or less, less than about device is adapted to transfer at least about 30% of the coating 40%, less than about 50%, less than about 70%, less than from the substrate to the intervention site. In some embodi about 80%, and/or less than about 90% of the coating absent ments, the device is adapted to transfer greater than 35% of stimulation of the coating. the coating from the Substrate to the intervention site. In some 0051. In some embodiments of the methods and/or embodiments, the device is adapted to transfer between about devices provided herein, at least about 10%, at least about 40% and about 45%, of the coating from the substrate to the 20%, at least about 30%, greater than 35%, at least about intervention site. In some embodiments, the device is adapted US 2010/0015200 A1 Jan. 21, 2010

to transfer at least about 50% of the coating from the substrate 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a to the intervention site. In some embodiments, the device is percent of the percentage of the active agent transferred, or as adapted to transfer at least about 75% of the coating from the a variation of the percentage of the active agent transferred). substrate to the intervention site. In some embodiments, the 0056. In some embodiments of the methods and/or device is adapted to transfer at least about 85% of the coating devices provided herein, the coating portion that transfers from the substrate to the intervention site. In some embodi upon stimulation is on at least one of a distal Surface of the ments, the device is adapted to transfer at least about 90% of Substrate, a middle Surface of the Substrate, a proximal Sur the coating from the Substrate to the intervention site. In some face of the substrate, and an abluminal surface of the sub embodiments, the device is adapted to transfer at least about strate. In some embodiments, the stimulation decreases the 95% of the coating from the substrate to the intervention site. contact between the coating and the Substrate. In some In some embodiments, the device is adapted to transfer at embodiments, the device is adapted to transfer less than about least about 99% of the coating from the substrate to the 1%, less than about 5%, less than about 10%. less than about intervention site. As used herein, “about when used in ref 15%, less than about 25%, about 35% or less, less than about erence to a percentage of the coating can mean ranges of 40%, less than about 50%, less than about 70%, less than 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a about 80%, less than about 90% of the active agent absent percent of the percentage of the coating transferred, or as a stimulation of the coating. variation of the percentage of the coating transferred). 0057. In some embodiments of the methods and/or 0054. In some embodiments of the methods and/or devices provided herein, the device is adapted to free at least devices provided herein, the coating portion that transfers about 10%, at least about 20%, at least about 30%, greater upon stimulation is on at least one of a distal Surface of the than 35%, at least about 40%, between about 40% and about Substrate, a middle Surface of the Substrate, a proximal Sur 45%, at least about 50%, at least about 75%, at least about face of the substrate, and an abluminal surface of the sub 85%, at least about 90%, at least about 95%, and/or at least strate. In some embodiments, stimulation decreases the con about 99% of the coating from the substrate. In some embodi tact between the coating and the Substrate. In some ments, the device is adapted to free at least about 10% of the embodiments, the device is adapted to transfer less than about coating from the Substrate to the intervention site. In some 1%, less than about 5%, less than about 10%. less than about embodiments, the device is adapted to free at least about 20% 15%, less than about 25%, about 35% or less, less than about of the coating from the substrate to the intervention site. In 40%, less than about 50%, less than about 70%, less than some embodiments, the device is adapted to free at least about about 80%, and/or less than about 90% of the coating absent 30% of the coating from the substrate to the intervention site. stimulation of the coating. In some embodiments, the device is adapted to free greater 0055. In some embodiments of the methods and/or than 35% of the coating from the substrate. In some embodi devices provided herein, the device is adapted to transfer at ments, the device is adapted to free between about 40% and least about 10%, at least about 20%, at least about 30%, about 45%, of the coating from the substrate. In some greater than 35%, at least about 40%, between about 40% and embodiments, the device is adapted to free at least about 50% about 45%, at least about 50%, at least about 75%, at least of the coating from the substrate to the intervention site. In about 85%, at least about 90%, at least about 95%, and/or at some embodiments, the device is adapted to free at least about least about 99% of the active agent from the substrate to the 75% of the coating from the substrate to the intervention site. intervention site. In some embodiments, the device is adapted In some embodiments, the device is adapted to free at least to transfer at least about 10% of the active agent from the about 85% of the coating from the substrate to the interven substrate to the intervention site. In some embodiments, the tion site. In some embodiments, the device is adapted to free device is adapted to transfer at least about 20% of the active at least about 90% of the coating from the substrate to the agent from the Substrate to the intervention site. In some intervention site. In some embodiments, the device is adapted embodiments, the device is adapted to transfer at least about to free at least about 95% of the coating from the substrate to 30% of the active agent from the substrate to the intervention the intervention site. In some embodiments, the device is site. In some embodiments, the device is adapted to transfer adapted to free at least about 99% of the coating from the greater than 35% of the active agent from the substrate to the substrate to the intervention site. As used herein, “about intervention site. In some embodiments, the device is adapted when used in reference to a percentage of the coating can to transfer between about 40% and about 45%, of the active mean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of agent from the Substrate to the intervention site. In some 10%-50% (as a percent of the percentage of the coating freed, embodiments, the device is adapted to transfer at least about or as a variation of the percentage of the coating freed). 50% of the active agent from the substrate to the intervention 0058. In some embodiments of the methods and/or site. In some embodiments, the device is adapted to transfer at devices provided herein, the coating portion that frees upon least about 75% of the active agent from the substrate to the stimulation is on at least one of a distal Surface of the Sub intervention site. In some embodiments, the device is adapted strate, a middle Surface of the Substrate, a proximal Surface of to transfer at least about 85% of the active agent from the the substrate, and an abluminal surface of the substrate. substrate to the intervention site. In some embodiments, the 0059. In some embodiments of the methods and/or device is adapted to transfer at least about 90% of the active devices provided herein, the stimulation decreases the contact agent from the Substrate to the intervention site. In some between the coating and the Substrate. In some embodiments, embodiments, the device is adapted to transfer at least about the device is adapted to free less than about 1%, less than 95% of the active agent from the substrate to the intervention about 5%, less than about 10%. less than about 15%, less than site. In some embodiments, the device is adapted to transfer at about 25%, about 35% or less, less than about 40%, less than least about 99% of the active agent from the substrate to the about 50%, less than about 70%, less than about 80%, less intervention site. As used herein, “about when used in ref than about 90% of the coating absent stimulation of the coat erence to a percentage of the active agent can mean ranges of 1ng. US 2010/0015200 A1 Jan. 21, 2010

0060. In some embodiments of the methods and/or to deliver between about 40% and about 45%, of the coating devices provided herein, the device is adapted to dissociate at to the intervention site. In some embodiments, the device is least about 10%, at least about 20%, at least about 30%, adapted to deliver at least about 50% of the coating to the greater than 35%, at least about 40%, between about 40% and intervention site. In some embodiments, the device is adapted about 45%, at least about 50%, at least about 75%, at least to deliver at least about 75% of the coating to the intervention about 85%, at least about 90%, at least about 95%, and/or at site. In some embodiments, the device is adapted to deliver at least about 99% of the coating from the substrate. In some least about 85% of the coating to the intervention site. In some embodiments, the device is adapted to dissociate at least embodiments, the device is adapted to deliver at least about about 10% of the coating from the substrate to the interven 90% of the coating to the intervention site. In some embodi tion site. In some embodiments, the device is adapted to ments, the device is adapted to deliver at least about 95% of dissociate at least about 20% of the coating from the substrate the coating to the intervention site. In some embodiments, the to the intervention site. In some embodiments, the device is device is adapted to deliver at least about 99% of the coating adapted to dissociate at least about 30% of the coating from to the intervention site. As used herein, “about when used in the substrate to the intervention site. In some embodiments, reference to a percentage of the coating can mean ranges of the device is adapted to dissociate greater than 35% of the 1%-5%, of 5%-I0%, of 10%-20%, and/or of 10%-50% (as a coating from the Substrate. In some embodiments, the device percent of the percentage of the coating delivered, or as a is adapted to dissociate between about 40% and about 45%, of variation of the percentage of the coating delivered). the coating from the Substrate. In some embodiments, the 0063. In some embodiments of the methods and/or device is adapted to dissociate at least about 50% of the devices provided herein, the coating portion that is delivered coating from the Substrate to the intervention site. In some upon stimulation is on at least one of a distal Surface of the embodiments, the device is adapted to dissociate at least Substrate, a middle Surface of the Substrate, a proximal Sur about 75% of the coating from the substrate to the interven face of the substrate, and an abluminal surface of the sub tion site. In some embodiments, the device is adapted to strate. In some embodiments, the stimulation decreases the dissociate at least about 85% of the coating from the substrate contact between the coating and the Substrate. In some to the intervention site. In some embodiments, the device is embodiments, the device is adapted to deliver less than about adapted to dissociate at least about 90% of the coating from 1%, less than about 5%, less than about 10%. less than about the substrate to the intervention site. In some embodiments, 15%, less than about 25%, about 35% or less, less than about the device is adapted to dissociate at least about 95% of the 40%, less than about 50%, less than about 70%, less than coating from the substrate to the intervention site. In some about 80%, less than about 90% of the coating absent stimu embodiments, the device is adapted to dissociate at least lation of the coating. about 99% of the coating from the substrate to the interven 0064. In some embodiments of the methods and/or tion site. As used herein, “about when used in reference to a devices provided herein, the active agent comprises a phar percentage of the coating can mean ranges of 1%-5%, of maceutical agent. 5%-I0%, of 10%-20%, and/or of 10%-50% (as a percent of 0065. In some embodiments of the methods and/or the percentage of the coating dissociated, or as a variation of devices provided herein, the pharmaceutical agent comprises the percentage of the coating dissociated). a macrollide immunosuppressive drug. In some embodiments 0061. In some embodiments of the methods and/or the macrollide immunosuppressive drug comprises one or devices provided herein, the coating portion that dissociates more of rapamycin, 40-O-(2-Hydroxyethyl)rapamycin upon stimulation is on at least one of a distal Surface of the (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4-Hy Substrate, a middle Surface of the Substrate, a proximal Sur droxymethyl)benzyl-rapamycin, 40-O-4'-(1,2-Dihydroxy face of the substrate, and an abluminal surface of the sub ethyl)benzyl-rapamycin, 40-O-Allyl-rapamycin, 40-O-3 strate. In some embodiments, stimulation decreases the con '-(2,2-Dimethyl-1,3-dioxolan-4-(S)-yl)-prop-2-en-1-yl)-ra tact between the coating and the Substrate. In some pamycin, (2'E,4'S)-40-O-(4',5'-Dihydroxypent-2-en-1-yl)- embodiments, the device is adapted to dissociate less than rapamycin 40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapa about 1%, less than about 5%, less than about 10%. less than mycin, 40-O-(3-Hydroxy)propyl-rapamycin 40-O-(6- about 15%, less than about 25%, about 35% or less, less than Hydroxy)hexyl-rapamycin 40-O-2-(2-Hydroxy)ethoxy about 40%, less than about 50%, less than about 70%, less ethyl-rapamycin 40-O-(3S)-2,2-Dimethyldioxolan-3-yl) than about 80%, less than about 90% of the coating absent methyl-rapamycin, 40-O-(2S)-2,3-Dihydroxyprop-1-yl)- stimulation of the coating. rapamycin, 40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2- 0062. In some embodiments of the methods and/or Nicotinoyloxy)ethyl-rapamycin, 40-O-2-(N-Morpholino) devices provided herein, the device is adapted to deliver at acetoxyethyl-rapamycin 40-O-(2-N-Imidazolylacetoxy) least about 10%, at least about 20%, at least about 30%, ethyl-rapamycin, 40-O-2-(N-Methyl-N'-piperazinyl) greater than 35%, at least about 40%, between about 40% and acetoxyethyl-rapamycin, 39-O-Desmethyl-39.40-O,O- about 45%, at least about 50%, at least about 75%, at least ethylene-rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxy) about 85%, at least about 90%, at least about 95%, and/or at ethyl-rapamycin, 28-O-Methyl-rapamycin, 40-O-(2- least about 99% of the coating to the intervention site. In some Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)- embodiments, the device is adapted to deliver at least about rapamycin 40-O-(2-Nicotinamidoethyl)-rapamycin, 40-O- 10% of the coating to the intervention site. In some embodi (2-(N-Methyl-imidazo-2'-ylcarbethoxamido)ethyl)- ments, the device is adapted to deliver at least about 20% of rapamycin, 40-O-(2-Ethoxycarbonylaminoethyl)- the coating to the intervention site. In some embodiments, the rapamycin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, device is adapted to deliver at least about 30% of the coating 40-O-2-(4',5'-Dicarboethoxy-1'2',3'-triazol-1-yl)-ethyl to the intervention site. In some embodiments, the device is rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), and adapted to deliver greater than 35% of the coating to the 42-3-hydroxy-2-(hydroxymethyl)-2-methylpropanoatera intervention site. In some embodiments, the device is adapted pamycin (temsirolimus). US 2010/0015200 A1 Jan. 21, 2010

0.066. In some embodiments of the methods and/or derivatives, hypothalamus hormones, guanethidine, halofan devices provided herein, the macrollide immunosuppressive trine, haloperidol, heparin (and derivatives), hyaluronic acid, drug is at least 50% crystalline. In some embodiments, the hydralazine, hydrochlorothiazide (and derivatives), salicy macrollide immunosuppressive drug is at least 75% crystal lates, hydroxy Zine, imipramine, indometacin, indoramine, line. In some embodiments, the macrollide immunosuppres insulin, iodine and iodine derivatives, isoconazole, isoprena sive drug is at least 90% crystalline. In some embodiments of line, glucitol and glucitol derivatives, itraconazole, ketopro the methods and/or devices provided herein the macrollide fen, ketotifen, lacidipine, lansoprazole, levodopa, levometha immunosuppressive drug is at least 95% crystalline. In some done, thyroid hormones, lipoic acid (and derivatives), embodiments of the methods and/or devices provided herein lisinopril, lisuride, lofepramine, loperamide, loratadine, the macrollide immunosuppressive drug is at least 97% crys maprotiline, mebendazole, mebeverine, meclozine, mefe talline. In some embodiments of the methods and/or devices namic acid, mefloquine, meloxicam, mepindolol, meprobam provided herein macrollide immunosuppressive drug is at ate, mesalazine, mesuXimide, metamizole, metformin, meth least 98% crystalline. In some embodiments of the methods ylphenidate, metixene, metoprolol, metronidazole, and/or devices provided herein the macrollide immunosup mianserin, miconazole, minoxidil, misoprostol, mizolastine, pressive drug is at least 99% crystalline. moexipril, morphine and morphine derivatives, evening 0067. In some embodiments of the methods and/or primrose, nalbuphine, naloxone, tilidine, naproxen, narco devices provided herein wherein the pharmaceutical agent is tine, natamycin, neostigmine, nicergoline, nicethamide, nife at least 50% crystalline. In some embodiments of the methods dipine, niflumic acid, nimodipine, nimorazole, nimustine, and/or devices provided herein the pharmaceutical agent is at nisoldipine, adrenaline and adrenaline derivatives, novamine least 75% crystalline. In some embodiments of the methods Sulfone, noscapine, nystatin, olanzapine, olsalazine, omepra and/or devices provided herein the pharmaceutical agent is at Zole, omoconazole, oxaceprol, oxiconazole, oxymetazoline, least 90% crystalline. In some embodiments of the methods pantoprazole, paracetamol (acetaminophen), paroxetine, and/or devices provided herein the pharmaceutical agent is at penciclovir, pentazocine, pentifylline, pentoxifylline, per least 95% crystalline. In some embodiments of the methods phenazine, pethidine, plant extracts, phenaZone, phe and/or devices provided herein the pharmaceutical agent is at niramine, barbituric acid derivatives, phenylbutaZone, least 97% crystalline. In some embodiments of the methods pimozide, pindolol, piperazine, piracetam, pirenzepine, pir and/or devices provided herein pharmaceutical agent is at ibedil, piroxicam, pramipexole, pravastatin, prazosin, least 98% crystalline. In some embodiments of the methods procaine, promazine, propiverine, propranolol, propy and/or devices provided herein the pharmaceutical agent is at phenazone, protionamide, proxyphylline, quetiapine, least 99% crystalline. quinapril, quinaprilat, ramipril, ranitidine, reproterol, reser 0068. In some embodiments of the methods and/or pine, ribavirin, risperidone, ritonavir, ropinirole, roXatidine, devices provided herein, the pharmaceutical agent is agent is ruscogenin, rutoside (and derivatives), Sabadilla, Salbutamol. selected form the group consisting of In some embodiments, salmeterol, Scopolamine, Selegiline, Sertaconazole, sertin a pharmaceutical agent is at least one of Acarbose, acetyl dole, Sertralion, silicates, simvastatin, sitosterol, Sotalol, Spa salicylic acid, acyclovir, allopurinol, alprostadil, prostaglan glumic acid, spirapril, spironolactone, stavudine, Streptomy dins, amantadine, ambroXol, amlodipine, S-aminosalicylic cin, Sucralfate, Sufentanil, SulfaSalazine, Sulpiride, Sultiam, acid, amitriptyline, atenolol, azathioprine, balsalazide, Sumatriptan, suxamethonium chloride, tacrine, tacrolimus, beclomethasone, betahistine, beZafibrate, diazepam and diaz taliolol, taurolidine, temazepam, tenoxicam, teraZosin, ter epam derivatives, budesonide, bufeXamac, buprenorphine, binafine, terbutaline, terfenadine, terlipressin, tertatolol. methadone, calcium salts, potassium salts, magnesium salts, tery Zoline, theobromine, butizine, thiamazole, phenothiaz candesartan, carbamazepine, captopril, cetirizine, chenode ines, tiagabine, tiapride, propionic acid derivatives, ticlopi oxycholic acid, theophylline and theophylline derivatives, dine, timolol, tinidazole, tioconazole, tioguanine, tioXolone, trypsins, cimetidine, clobutinol, clonidine, cotrimoxazole, tiropramide, tizanidine, tolazoline, tolbutamide, tolcapone, codeine, caffeine, vitamin D and derivatives of vitamin D, tolnaftate, tolperisone, topotecan, torasemide, tramadol, tra colestyramine, cromoglicic acid, coumarin and coumarin maZoline, trandolapril, tranylcypromine, trapidil, traZodone, derivatives, cysteine, ciclosporin, cyproterone, cytabarine, triamcinolone derivatives, triamterene, trifluperidol, trifluri dapiprazole, desogestrel, desonide, dihydralazine, diltiazem, dine, trimipramine, tripelennamine, triprolidine, trifosfa ergot alkaloids, dimenhydrinate, dimethyl Sulphoxide, mide, tromantadine, trometamol, tropalpin, troXerutine, dimeticone, domperidone and domperidan derivatives, tulobuterol, tyramine, tyrothricin, urapidil, Valaciclovir, Val dopamine, doxazosin, doxylamine, benzodiazepines, proic acid, Vancomycin, vecuronium chloride, Viagra, Ven diclofenac, desipramine, econazole, ACE inhibitors, enala lafaxine, Verapamil, Vidarabine, vigabatrin, Viloazine, Vin pril, ephedrine, epinephrine, epoetin and epoetin derivatives, camine, Vinpocetine, Viduidil, warfarin, Xantinol nicotinate, morphinans, calcium antagonists, modafinil, orlistat, peptide Xipamide, Zafirlukast, Zalcitabine, Zidovudine, Zolmitriptan, antibiotics, phenytoin, riluzoles, risedronate, sildenafil, topi Zolpidem, Zoplicone, Zotipine, amphotericin B, caspofungin, ramate, estrogen, progestogen and progestogen derivatives, Voriconazole, resveratrol, PARP-1 inhibitors (including imi testosterone derivatives, androgen and androgen derivatives, daZoquinolinone, imidazpyridine, and isoquinolindione, tis ethenzamide, etofenamate, etofibrate, fenofibrate, etofylline, Sue plasminogen activator (tPA), melagatran, lanoteplase, famciclovir, famotidine, felodipine, fentanyl, fenticonazole, reteplase, staphylokinase, streptokinase, tenecteplase, uroki gyrase inhibitors, fluconazole, fluarizine, fluoxetine, flurbi nase, abciximab (ReoPro), eptifibatide, tirofiban, prasugrel, profen, ibuprofen, fluvastatin, follitropin, formoterol, fosfo clopidogrel, dipyridamole, cilostazol, VEGF, heparan Sul micin, furosemide, fusidic acid, gallopamil, ganciclovir, fate, chondroitin sulfate, elongated “RGD' peptide binding gemfibrozil, ginkgo, Saint John's wort, glibenclamide, urea domain, CD34 antibodies, cerivastatin, etorvastatin, losartan, derivatives as oral antidiabetics, glucagon, glucosamine and Valartan, erythropoietin, rosiglitaZone, pioglitaZone, mutant glucosamine derivatives, glutathione, glycerol and glycerol protein Apo Al Milano, adiponectin, (NOS) gene therapy, US 2010/0015200 A1 Jan. 21, 2010 glucagon-like peptide 1, atorvastatin, and atrial natriuretic riboprine, Safingol, simtraZene, sparfosate Sodium, Spiromus peptide (ANP), lidocaine, tetracaine, dibucaine, hyssop, gin tine, Spiroplatin, streptonigrin, Sulofenur, tecogalan Sodium, ger, turmeric, Arnica montana, helenalin, cannabichromene, taxotere, tegafur, teloxantrone hydrochloride, temoporfin, rofecoxib, hyaluronidase, and salts, derivatives, isomers, thiamiprine, tirapazamine, trestolone acetate, triciribine racemates, diastereoisomers, prodrugs, hydrate, ester, orana phosphate, trimetrexate glucuronate, tubulozole hydrochlo logs thereof. ride, uracil mustard, uredepa, Verteporfin, vinepidine Sulfate, 0069. In some embodiments of the methods and/or Vinglycinate Sulfate, Vinleurosine Sulfate, vinorelbine tar devices provided herein, the pharmaceutical agent comprises trate, Vinrosidine Sulfate, Zeniplatin, Zinostatin, 20-epi-1,25 hyaluronidase. dihydroxyvitamin D3, 5-ethynyluracil, acylfulvene, ade 0070. In some embodiments of the methods and/or cypenol, ALL-TK antagonists, ambamustine, amidox, ami devices provided herein, the pharmaceutical agent comprises fostine, aminolevulinic acid, amrubicin, anagrelide, ciloStaZol. andrographolide, antagonist D, antagonist G, antarelix, anti 0071. In some embodiments of the methods and/or dorsalizing morphogenetic protein-1, antiandrogen, anties devices provided herein, the pharmaceutical agent comprises trogen, estrogen agonist, apurinic acid, ara-CDP-DL-PTBA, dipyridamole. arginine deaminase, asulacrine, atameStane, atrimustine, axi 0072. In some embodiments of the methods and/or nastatin 1, axinastatin 2, axinastatin 3, aZasetron, azatoxin, devices provided herein, the pharmaceutical agent comprises azatyrosine, baccatin III derivatives, balanol, BCR/ABL an antibiotic agent. antagonists, benzochlorins, benzoylstaurosporine, beta lac 0073. In some embodiments of the methods and/or tam derivatives, beta-alethine, betaclamycin B, betulinic devices provided herein, the pharmaceutical agent comprises acid, bFGF inhibitor, bisaziridinylspermine, bistratene A, a chemotherapeutic agent. breflate, buthionine sulfoximine, calcipotriol, calphostin C, 0.074. In some embodiments of the methods and/or carboxamide-amino-triazole, carboxyamidotriazole, CaRest devices provided herein, the pharmaceutical agent is in a M3, CARN 700, cartilage derived inhibitor, casein kinase therapeutically desirable morphology. inhibitors (ICOS), castanospermine, cecropin B, cetrorelix, 0075. In some embodiments of the methods and/or chloroquinoxaline Sulfonamide, cicaprost, cis-porphyrin, devices provided herein, the active agent comprises a chemo clomifene analogues, clotrimazole, collismycin A, collismy therapeutic agent. In some embodiments of the methods and/ cin B, combretastatin A4, combretastatin analogue, conage or devices provided herein, the pharmaceutical agent com nin, crambescidin 816, cryptophycin 8, cryptophycin A prises a chemotherapeutic agent. In some embodiments, the derivatives, curacin A, cyclopentanthraquinones, cyclo chemotherapeutic agent comprises at least one of an platam, cypemycin, cytolytic factor, cytostatin, dacliximab, angiostatin, DNA topoisomerase, endostatin, genistein, orni dehydrodidemnin B, dexamethasone, dexifosfamide, dexra thine decarboxylase inhibitors, chlormethine, melphalan, Zoxane, dexVerapamil, didemnin B, didox, diethylnorsper pipobroman, triethylene-melamine, triethylenethiophos mine, dihydro-5-azacytidine, dihydrotaxol. 9-, dioxamycin, phoramine, busulfan, carmustine (BCNU), streptozocin, docosanol, dolasetron, dronabinol, duocarmycin SA, 6-mercaptopurine, 6-thioguanine, Deoxyco-formycin, IFN ebselen, ecomustine, edelfosine, edrecolomab, elemene, C. 17C.-ethinylestradiol, diethylstilbestrol, testosterone, pred emitefur, estramustine analogue, filgrastim, flavopiridol, fle nisone, fluoxymesterone, dromostanolone propionate, testo Zelastine, fluasterone, fluorodaunorunicin hydrochloride, for lactone, megestrolacetate, methylprednisolone, methyl fenimex, gadolinium texaphyrin, galocitabine, gelatinase testosterone, prednisolone, triamcinolone, chlorotrianisene, inhibitors, glutathione inhibitors, hepsulfam, heregulin, hex hydroxyprogesterone, estramustine, medroxyprogestero amethylene bisacetamide, hypericin, ibandronic acid, idra neacetate, flutamide, Zoladex, mitotane, hexameth mantone, ilomastat, imatinib (e.g., Gleevec), imiquimod, ylmelamine, indolyl-3-glyoxylic acid derivatives, (e.g., immunostimulant peptides, insulin-like growth factor-1 indibulin), doxorubicin and idarubicin, plicamycin (mithra receptor inhibitor, interferon agonists, interferons, interleu mycin) and mitomycin, mechlorethamine, cyclophospha kins, iobenguane, iododoxorubicin, ipomeanol, 4-, iroplact, mide analogs, traZenes-dacarbazinine (DTIC), pentostatin irsogladine, isobengaZole, isohomohalicondrin B, itasetron, and 2-chlorodeoxyadenosine, letrozole, camptothecin (and jasplakinolide, kahalalide F, lamellarin-N triacetate, leina derivatives), navelbine, erlotinib, capecitabine, acivicin, mycin, lenograstim, lentinan Sulfate, leptolstatin, leukemia acodazole hydrochloride, acronine, adoZelesin, aldesleukin, inhibiting factor, leukocyte alpha interferon, leuprolide--es ambomycin, ametantrone acetate, anthramycin, asperlin, trogen-progesterone, linear polyamine analogue, lipophilic aZacitidine, azetepa, azotomycin, batimastat, benzodepa, disaccharide peptide, lipophilic platinum compounds, lisso bisnafide, bisnafide dimesylate, bizelesin, bropirimine, cac clinamide 7, lobaplatin, lombricine, loxoribine, lurtotecan, tinomycin, calusterone, carbetimer, carubicin hydrochloride, lutetium texaphyrin, lysofylline, lytic peptides, maitansine, carzelesin, cedefingol, celecoxib (COX-2 inhibitor), cirole mannostatin A, marimastat, maspin, matrilysin inhibitors, mycin, crisinatol mesylate, decitabine, dexormaplatin, deza matrix metalloproteinase inhibitors, meterelin, methioni guanine mesylate, diaziquone, duaZomycin, edatrexate, eflo nase, metoclopramide, MIF inhibitor, mifepristone, miltefos mithine, elsamitrucin, enloplatin, empromate, epipropidine, ine, mirimoStim, mitoguaZone, mitotoxin fibroblast growth erbuloZole, etanidazole, etoprine, flurocitabine, fosquidone, factor-Saporin, mofarotene, molgramoStim, ErbituX, human lometrexol, losoxantrone hydrochloride, masoprocol, may chorionic gonadotrophin, monophosphoryl lipid A+myobac tansine, megestrol acetate, melengestrol acetate, metoprine, terium cell wall sk, mustard anticancer agent, mycaperoxide meturedepa, mitindomide, mitocarcin, mitocromin, mitogil B, mycobacterial cell wall extract, myriaporone, N-acetyl lin, mitomalcin, mitosper, mycophenolic acid, nocodazole, dinaline, N-substituted benzamides, nagrestip, naloxone-- nogalamycin, ormaplatin, oxisuran, pegaspargase, peliomy pentazocine, napavin, naphterpin, nartograstim, nedaplatin, cin, pentamustine, perfosfamide, piposulfan, plomestane, nemorubicin, neridronic acid, nisamycin, nitric oxide modu porfimer Sodium, porfiromycin, puromycin, pyrazofurin, lators, nitroxide antioxidant, nitrullyn, oblimersen (Gena US 2010/0015200 A1 Jan. 21, 2010

sense), O'-benzylguanine, okicenone, onapristone, tine, Proter PTT-119, ranimustine, semustine, SmithKline ondansetron, oracin, oral cytokine inducer, paclitaxel ana SK&F-101772, thiotepa, Yakult Honsha SN-22, spiromus logues and derivatives, palauamine, palmitoylrhizoxin, pam tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, idronic acid, panaxytriol, panomifene, parabactin, peldesine, teroxirone, tetraplatin and trimelamol, Taiho 4181-A, aclaru pentosan polysulfate Sodium, pentroZole, perflubron, perillyl bicin, actinomycin D, actinoplanone, Erbamont ADR-456, alcohol, phenazinomycin, phenylacetate, phosphatase inhibi aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto tors, picibanil, pilocarpine hydrochloride, placetin A, placetin AN-3, Nippon Soda anisomycins, anthracycline, azino-my B. plasminogen activator inhibitor, platinum complex, plati cin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers num compounds, platinum-triamine complex, propyl bis-ac BMY-25067, Bristol-Myers BMY-2555 1, Bristol-Myers ridone, prostaglandin J2, proteasome inhibitors, protein BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers A-based immune modulator, protein kinase C inhibitors, BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, microalgal, pyrazoloacridine, pyridoxylated hemoglobin calichemycin, chromoximycin, dactinomycin, daunorubicin, polyoxyethylene conjugate, raf antagonists, raltitrexed, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko ramosetron, ras farnesyl protein transferase inhibitors, ras DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, GAP inhibitor, retelliptine demethylated, rhenium Re 186 ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubi etidronate, ribozymes, RII retinamide, rohitukine, romurtide, cin-fibrinogen, elsamicin-A, epirubicin, erbStatin, esorubi roquinimex, rubiginone B1, ruboxyl, Saintopin, SarCNU, sar cin, esperamicin-A1, esperamicin-A1b, Erbamont FCE cophytol A, Sargramostim, Sdi 1 mimetics, senescence 21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, derived inhibitor 1, signal transduction inhibitors, sizofiran, glidobactin, gregatin-A, grincamycin, herbimycin, idarubi Sobuzoxane, sodium borocaptate, solverol. Somatomedin cin, illudins, kaZusamycin, kesarirhodins, Kyowa Hakko binding protein, Sonermin, sparfosic acid, spicamycin D, KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko splenopentin, spongistatin 1, squalamine, stipiamide, KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, stromelysin inhibitors, sulfinosine, Superactive vasoactive American Cyanamid LL-D49194, Meiji Seika ME 2303, intestinal peptide antagonist, Suradista, Suramin, Swainso menogaril, mitomycin, mitomycin analogues, mitoxantrone, nine, tallimustine, tazarotene, tellurapyrylium, telomerase SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, inhibitors, tetrachlorodecaoxide, tetraZomine, thiocoraline, Nippon Kayaku NKT-01, SRI International NSC-357704, thrombopoietin, thrombopoietin mimetic, thymalfasin, thy oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, mopoietin receptoragonist, thymotrinan, thyroid stimulating porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, hormone, tin ethyl etiopurpurin, titanocene bichloride, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo top sentin, translation inhibitors, tretinoin, triacetyluridine, SM-5887, Snow Brand SN-706, Snow Brand SN-07, Soran tropisetron, turosteride, ubenimex, urogenital sinus-derived gicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS growth inhibitory factor, variolin B. velaresol, Veramine, ver Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, dins, vinxaltine, Vitaxin, Zanoterone, Zilascorb, Zinostatin Sti Steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN malamer, acanthifolic acid, aminothiadiazole, anastrozole, 868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, bicalutamide, brequinar Sodium, capecitabine, carmofur, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Ciba-Geigy CGP-30694, cladribine, cyclopentyl cytosine, Y-25024, Zorubicin, 5-fluorouracil (5-FU), the peroxidate cytarabine phosphate Stearate, cytarabine conjugates, cytara oxidation product of inosine, adenosine, or cytidine with bine ocfosfate, Lilly DATHF, Merrel Dow DDFC, dezagua methanol or ethanol, cytosine arabinoside (also referred to as nine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi Cytarabin, araC, and Cytosar), 5-AZacytidine, 2-Fluoroad DMDC, doxifluridine, Wellcome EHNA, Merck & Co. enosine-5'-phosphate (Fludara, also referred to as FaraA), EX-015, fazarabine, floxuridine, fludarabine, fludarabine 2-Chlorodeoxyadenosine, Abarelix, Abbott A-84861, Abi phosphate, N-(2-furanidyl)-5-fluorouracil, Daiichi Seiyaku raterone acetate, Aminoglutethimide, Asta Medica AN-207, FO-152, 5-FU-fibrinogen, isopropyl pyrrolizine, Lilly Antide, Chugai AG-041R, AVorelin, aseranox, Sensus LY-188011, Lilly LY-264618, methobenzaprim, methotrex B2036-PEG, buserelin, BTG CB-7598, BTG CB-7630, ate, Wellcome MZPES, norspermidine, nolvadex, NCINSC Casodex, cetrolix, clastroban, clodronate disodium, CoSu 127716, NCI NSC-264880, NCI NSC-39661, NCI NSC dex, Rotta Research CR-1505, cytadren, crinone, deslorelin, 612567. Warner-Lambert PALA, pentostatin, piritrexim, droloxifene, dutasteride, Elimina, Laval University EM-800, plicamycin, Asahi Chemical PL-AC, stearate, Takeda TAC Laval University EM-652, epitiostanol, epristeride, 788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, Mediolanum EP-23904, EntreMed 2-ME, exemestane, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, fadrozole, finasteride, formestane, Pharmacia & Upjohn Taiho UFT, uricytin, Shionogi 254-S, aldo-phosphamide ana FCE-24304, ganirelix, goserelin, Shire gonadorelin agonist, logues, altretamine, anaxirone, Boehringer Mannheim BBR GlaxoWellcome GW-5638, Hoechst Marion Roussel Hoe 2207, bestrabucil, budotitane, Wakunaga CA-102, carbopl 766, NCI hCG, idoxifene, isocordoin, Zeneca ICI-182780, atin, carmustine (BiCNU), Chinoin-139, Chinoin-153, Zeneca ICI-1 18630. Tulane University J015X, Schering Ag chlorambucil, cisplatin, cyclophosphamide, American J96, ketanserin, lanreotide, Milkhaus LDI-200, letrozol, leu Cyanamid CL-286558, Sanofi CY-233, cyplatate, dacarba prolide, leuprorelin, liarozole, lisuride hydrogen maleate, zine, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphe loxiglumide, mepitioStane, Ligand Pharmaceuticals nylspiromustine, diplatinum cytostatic, Chugai DWA LG-1127, LG-1447, LG-2293, LG-2527, LG-2716, Bone 2114R, ITI E09, elmustine, Erbamont FCE-24517, Care International LR-103, Lilly LY-326315, Lilly estramustine phosphate sodium, etoposide phosphate, fote LY-353381-HCl, Lilly LY-326391, Lilly LY-353381, Lilly mustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, LY-357489, miproxifene phosphate, Orion Pharma MPV ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, 2213ad, Tulane University MZ-4-71, nafarelin, nilutamide, mycophenolate, Nippon Kayaku NK-121, NCINSC-264395, Snow Brand NKS01, AZko Nobel ORG-31710, AZko Nobel NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimus ORG-31806, orimeten, orimetene, orimetime, ormeloxifene, US 2010/0015200 A1 Jan. 21, 2010

osaterone, Smithkline Beecham SKB-105657, Tokyo Uni nomethionine), SmithKline SK&F-104864, Sumitomo versity OSW-1, Peptech PTL-03001, Pharmacia & Upjohn SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, PNU-156765, quinagolide, ramorelix, Raloxifene, statin, spirocyclopropane derivatives, spirogermanium, Unimed, SS sandostatin LAR, Shionogi S-10364, Novartis SMT-487. Pharmaceutical SS-554, Strypoldinone, Stypoldione, Suntory Somavert, Somatostatin, tamoxifen, tamoxifen methiodide, SUN 0237, Suntory SUN 2071, Sugen SU-101, Sugen teverelix, toremifene, triptorelin, TT-232, vapreotide, Voro SU-5416, SugenSU-6668, Sulindac, sulindac sulfone, super Zole, Yamanouchi YM-116, Yamanouchi YM-511, Yamanou oxide dismutase, Toyama T-506, Toyama T-680, taxol. Teijin chi YM-55208, Yamanouchi YM-53789, Schering AG TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, ZK-1911703, Schering AG ZK-230211, and Zeneca tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, ZD-182780, alpha-carotene, alpha-difluoromethyl-arginine, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amona vinblastine, vinblastine sulfate, Vincristine, Vincristine sul fide, amphethinile, amsacrine, Angiostat, ankinomycin, anti fate, vindesine, Vindesine Sulfate, vinestramide, Vinorelbine, neoplaston A10, antineoplaston A2, antineoplaston A3, anti vintriptol, Vinzolidine, withanolides, Yamanouchi YM-534, neoplaston A5, antineoplaston AS2-1, Henkel APD, Zileuton, urSodeoxycholic acid, Zanosar. aphidicolinglycinate, asparaginase, Avarol, baccharin, batra 0076. In some embodiments of the methods and/or cylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, devices provided herein, the chemotherapeutic agent com bisantrene, Bristo-Myers BMY-40481, Vestarboron-10, bro mofosfamide, Wellcome BW-502, Wellcome BW-773, cal prises Bacillus Calmette-Guerin (BCG). cium carbonate, Calcet, Calci-Chew, Calci-Mix, Roxane cal 0077. In some embodiments of the methods and/or cium carbonate tablets, caracemide, carmethizole devices provided herein, the active agent comprises an anti hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, biotic agent. In some embodiments of the methods and/or Chemes CHX-2053, Chemex CHX-100, Warner-Lambert devices provided herein, the pharmaceutical agent comprises CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, an antibiotic agent. In some embodiments, the antibiotic Warner-Lambert CI-958, clanfenur, claviridenone, ICN com agent comprises at least one of amikacin, amoxicillin, gen pound 1259, ICN compound 4711, Contracan, Cell Pathways tamicin, kanamycin, neomycin, netilmicin, paromomycin, CP-461, Yakult Honsha CPT-11, crisinatol, curaderm, tobramycin, geldanamycin, herbimycin, carbacephem (lora cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS carbef), ertapenem, doripenem, imipenem, cefadroxil, cefa maleate, datelliptinium, DFMO, didemnin-B, dihaematopor Zolin, cefalotin, cephalexin, cefaclor, cefamandole, cefoxitin, phyrin ether, dihydrolenperone dinaline, distamycin, Toyo cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefop Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku eraZone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, DN-9693, docetaxel, Encore Pharmaceuticals E7869, ellip ceftizoxime, ceftriaxone, cefepime, ceftobiprole, clarithro rabin, elliptinium acetate, Tsumura EPMTC, ergotamine, mycin, clavulanic acid, clindamycin, teicoplanin, azithromy etoposide, etretinate, Eulexin, Cell Pathways Exisulind cin, dirithromycin, erythromycin, troleandomycin, tellithro (sulindac sulphone or CP-246), fenretinide, Florical, mycin, aztreonam, amplicillin, azlocillin, bacampicillin, Fujisawa FR-57704, gallium nitrate, gemcitabine, genkw carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, adaphnin, Gerimed, Chugai GLA-43, Glaxo GR-63178, gri meZlocillin, meticillin, nafcillin, norfloxacin, oxacillin, peni folan NMF-5N, hexadecylphosphocholine, Green Cross cillin G, penicillin V, piperacillin, pvampicillin, pivmecilli HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, nam, ticarcillin, bacitracin, colistin, polymyxin B, ciprof ilmofosine, irinotecan, isoglutamine, isotretinoin, Otsuka loxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, JI-36, Ramot K-477, ketoconazole, Otsuak K-76COONa, moxifloxacin, ofloxacin, trovafloxacin, grepafloxacin, spar Kureha Chemical K-AM, MECT Corp KI-8110, American floxacin, afenide, prontosil, Sulfacetamide, Sulfamethizole, Cyanamid L-623, leucovorin, levamisole, leukoregulin, Sulfanilimide, Sulfamethoxazole, Sulfisoxazole, trimethop lonidamine, Lundbeck LU-23-112, Lilly LY-186641, rim, trimethoprim-sulfamethoxazole, demeclocycline, doxy Materna, NCI (US) MAP. marycin, Merrel Dow MDL cycline, oxytetracycline, tetracycline, arsphenamine, 27048, Medco MEDR-340, megestrol, merbarone, merocya chloramphenicol, lincomycin, ethambutol, fosfomycin, fura nine derivatives, methylanilinoacridine, Molecular Genetics Zolidone, isoniazid, lineZolid, mupirocin, nitrofurantoin, MGI-136, minactivin, mitonafide, mitoguidone, Monocal, platensimycin, pyrazinamide, quinupristin?dalfopristin, mopidamol, motretinide, Zenyaku Kogyo MST-16, Mylanta, rifampin, thiamphenicol, rifampicin, minocycline, Sultami N-(retinoyl)amino acids, Nilandron, Nisshin Flour Milling cillin, Sulbactam, Sulphonamides, mitomycin, spectinomy N-021, N-acylated-dehydroalanines, nafazatrom, Taisho cin, spiramycin, roXithromycin, and meropenem. NCU-190, Nephro-Calcitablets, nocodazole derivative, Nor 0078. In some embodiments of the methods and/or mosang, NCI NSC-145813, NCI NSC-361456, NCI NSC devices provided herein, the antibiotic agent comprises eryth 604782, NCI NSC-95580, octreotide, Ono ONO-112, odui romycin. Zanocine, Akzo Org-10172, paclitaxel, pancratistatin, 0079. In some embodiments of the methods and/or pazelliptine, Warner-Lambert PD-11 1707, Warner-Lambert devices provided herein, the active agent comprises an active PD-115934, Warner-Lambert PD-131141, Pierre Fabre biological agent. In some embodiments, the active biological PE-1001, ICRT peptide D, piroxantrone, polyhaematopor agent comprises an active secondary, tertiary or quaternary phyrin, polypreic acid, Efamol porphyrin, probimane, procar structure. In some embodiments, the active biological agent bazine, proglumide, Invitron protease nexin I, Tobishi comprises at least one of growth factors, cytokines, peptides, RA-700, razoxane, retinoids, R-flurbiprofen (Encore Phar proteins, enzymes, glycoproteins, nucleic acids, antisense maceuticals), Sandostatin, Sapporo Breweries RBS, restric nucleic acids, fatty acids, antimicrobials, vitamins, hor tin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, mones, steroids, lipids, polysaccharides, carbohydrates, a Rhone-Poulenc RP-56976, Scherring-Plough SC-57050, hormone, genetherapies, RNA, siRNA, and/or cellular thera Scherring-Plough SC-57068, selenium (selenite and sele pies such as stem cells and/or T-cells. US 2010/0015200 A1 Jan. 21, 2010

0080. In some embodiments of the methods and/or include absorbable and/or resorbable polymers including the devices provided herein, the active biological agent com following, combinations, copolymers and derivatives of the prises siRNA. following: Polylactides (PLA), Polyglycolides (PGA), Poly 0081. In some embodiments of the methods and/or Lactide-co-glycolides (PLGA), Polyanhydrides, Polyorthoe devices provided herein, the coating further comprises a poly sters, Poly(N-(2-hydroxypropyl) methacrylamide), Poly(1- mer. In some embodiments, the active agent comprises a aspartamide), including the derivatives DLPLA poly(dl polymer. In some embodiments, the polymer comprises at lactide); LPLA poly(1-lactide); PDO poly(dioxanone); least one of polyalkyl methacrylates, polyalkylene-co-vinyl PGA-TMC poly(glycolide-co-trimethylene carbonate); acetates, polyalkylenes, polyurethanes, polyanhydrides, ali PGA-LPLA poly(1-lactide-co-glycolide); PGA-DL phatic polycarbonates, polyhydroxyalkanoates, silicone con PLA poly(dl-lactide-co-glycolide); LPLA-DLPLA poly taining polymers, polyalkyl siloxanes, aliphatic polyesters, (1-lactide-co-dl-lactide); and PDO-PGA-TMC poly(gly polyglycolides, polylactides, polylactide-co-glycolides, poly collide-co-trimethylene carbonate-co-dioxanone), and (e-caprolactone)S. polytetrahalooalkylenes, polystyrenes, combinations thereof. poly(phosphaSones), copolymers thereof, and combinations 0084. In some embodiments of the methods and/or thereof. devices provided herein, the polymer has a dry modulus 0082 In some embodiments of the methods and/or between 3,000 and 12,000 KPa. In some embodiments, the devices provided herein, the coating comprises a bioabsorb polymer is capable of becoming soft after implantation. In able polymer. In some embodiments, the active agent com Some embodiments, the polymer is capable of becoming soft prises a bioabsorbable polymer. In some embodiments, the after implantation by hydration, degradation or by a combi bioabsorbable polymer comprises at least one of: Polylac nation of hydration and degradation. In some embodiments, tides (PLA); PLGA (poly(lactide-co-glycolide)); Polyanhy the polymer is adapted to transfer, free, and/or dissociate from drides; Polyorthoesters; Poly(N-(2-hydroxypropyl) meth the substrate when at the intervention site due to hydrolysis of acrylamide); DLPLA poly(dl-lactide); LPLA poly(1- the polymer. lactide); PGA-polyglycolide; PDO poly(dioxanone); 0085. In some embodiments of the methods and/or PGA-TMC poly(glycolide-co-trimethylene carbonate); devices provided herein, the bioabsorbable polymer is PGA-LPLA poly(1-lactide-co-glycolide); PGA-DL capable of resorbtion in at least one of about 1 day, about 3 PLA poly(dl-lactide-co-glycolide); LPLA-DLPLA poly days, about 5 days, about 7 days, about 14 days, about 3 (1-lactide-co-dl-lactide); and PDO-PGA-TMC -poly(gly weeks, about 4 weeks, about 45 days, about 60 days, about 90 collide-co-trimethylene carbonate-co-dioxanone), and days, about 180 days, about 6 months, about 9 months, about combinations, copolymers, and derivatives thereof. In some 1 year, about 1 to about 2 days, about 1 to about 5 days, about embodiments, the bioabsorbable polymer comprises between 1 to about 2 weeks, about 2 to about 4 weeks, about 45 to 1% and 95% glycolic acid content PLGA-based polymer. about 60 days, about 45 to about 90 days, about 30 to about 90 0083. In some embodiments of the methods and/or days, about 60 to about 90 days, about 90 to about 180 days, devices provided herein, the polymer comprises at least one about 60 to about 180 days, about 180 to about 365 days, of polycarboxylic acids, cellulosic polymers, proteins, about 6 months to about 9 months, about 9 months to about 12 polypeptides, polyvinylpyrrolidone, maleic anhydride poly months, about 9 months to about 15 months, and about 1 year mers, polyamides, polyvinyl alcohols, polyethylene oxides, to about 2 years. glycosaminoglycans, polysaccharides, polyesters, aliphatic 0086. In some embodiments of the methods and/or polyesters, polyurethanes, polystyrenes, copolymers, sili devices provided herein, at least a portion of the substrate is cones, silicone containing polymers, polyalkyl siloxanes, bioabsorbable. In some embodiments, the substrate com polyorthoesters, polyanhydrides, copolymers of vinyl mono prises at least one of a bioabsorbable polymer and a bioab mers, polycarbonates, polyethylenes, polypropytenes, poly sorbable metal. In some embodiments, the at least one bio lactic acids, polylactides, polyglycolic acids, polyglycolides, absorbable polymer or bioabsorbable metal is capable of polylactide-co-glycolides, polycaprolactones, poly(e-capro resorbtion in at least one of about 1 day, about 3 days, about lactone)S. polyhydroxybutyrate Valerates, polyacrylamides, 5 days, about 7 days, about 14 days, about 3 weeks, about 4 polyethers, polyurethane dispersions, polyacrylates, acrylic weeks, about 45 days, about 60 days, about 90 days, about latex dispersions, polyacrylic acid, polyalkyl methacrylates, 180 days, about 6 months, about 9 months, about 1 year, about polyalkylene-co-vinyl acetates, polyalkylenes, aliphatic 1 to about 2 days, about 1 to about 5 days, about 1 to about 2 polycarbonates polyhydroxyalkanoates, polytetrahalooalky weeks, about 2 to about 4 weeks, about 45 to about 60 days, lenes, poly(phosphaSones), polytetrahalooalkylenes, poly about 45 to about 90 days, about 30 to about 90 days, about 60 (phosphaSones), and mixtures, combinations, and copoly to about 90 days, about 90 to about 180 days, about 60 to mers thereof. The polymers of the present invention may be about 180 days, about 180 to about 365 days, about 6 months natural or synthetic in origin, including gelatin, chitosan, to about 9 months, about 9 months to about 12 months, about dextrin, cyclodextrin, Poly(urethanes), Poly(siloxanes) or 9 months to about 15 months, and about 1 year to about 2 silicones, Poly(acrylates) such as rhooly(methyl methacry years. late), poly(butyl methacrylate), and Poly(2-hydroxy ethyl 0087. In some embodiments of the methods and/or methacrylate), Poly(vinyl alcohol) Poly(olefins) such as poly devices provided herein, the coating comprises a hydrogel. In (ethylene), rhooly(isoprene), halogenated polymers such as Some embodiments, the hydrogel is adapted to degrade by Poly(tetrafluoroethylene)—and derivatives and copolymers bulk degradation. In some embodiments, the hydrogel is such as those commonly sold as Teflon(R) products, Poly(vi adapted to degrade by Surface degradation. nylidine fluoride), Poly(vinyl acetate), Poly(vinyl pyrroli 0088. In some embodiments of the methods and/or done), Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co devices provided herein, the coating comprises laminated vinyl acetate), Poly(ethylene glycol), Poly(propylene layers that allow direct control of the transfer, freeing, and/or glycol), Poly(methacrylic acid); etc. Suitable polymers also dissociation of the coating from the Substrate. In some US 2010/0015200 A1 Jan. 21, 2010 embodiments, the coating comprises laminated layers that depositing the pharmaceutical agent by an e-RESS, an allow direct control of the transferring, freeing, depositing, e-SEDS, or an e-DPC process. In some embodiments of the tacking, and/or dissociating of the coating from the Substrate, methods and/or devices provided herein, the coating is wherein at least one of the layers comprises the active agent. formed on said Substrate by a process comprising at least one In some embodiments, the coating comprises laminated lay of depositing a polymer by an e-RESS, an e-SEDS, or an ers that allow direct control of the transferring, freeing, e-DPC process, and depositing the active agent by an depositing, tacking, and/or dissociating of the coating from e-RESS, an e-SEDS, or an e-DPC process. In some embodi the substrate, wherein at least one of the layers comprises the ments, the process of forming said coating provides improved pharmaceutical agent. adherence of the coating to the Substrate prior to deployment 0089. In some embodiments of the methods and/or of the device at the intervention site and facilitates dissocia devices provided herein, the coating further comprises at least tion of said coating from said Substrate at the intervention site. one image enhanced polymer. In some embodiments, the In some embodiments, the coating is formed on said substrate image enhanced polymer comprises at least one of EgadMe by a process comprising depositing the active agent by an in which a galactopyranose ring is synthesized to protect a e-RESS, an e-SEDS, or an e-DPC process without electri Gd(III) ion from bulk water; a conjugated polymer MEH cally charging the Substrate. In some embodiments, the coat PPV nanoparticle; bismuth trioxide; a near infrared (NIR) ing is formed on said Substrate by a process comprising fluorochrome; a bioluminescence agent; a SPECT radionu depositing the active agent on the Substrate by an e-RESS, an clide; gadolinium diethylenetriamine pentaacetic acid; Echo e-SEDS, or an e-DPC process without creating an electrical Coat, an ultrasound imaging agent (STS-Biopolymers); and potential between the Substrate and a coating apparatus used barium Sulfate. In some embodiments, the coating comprises to deposit the coating. an imaging agent. In some embodiments, the imaging agent 0094. In some embodiments of the methods and/or comprises at least one of a barium compound and an iodine devices provided herein, the intervention site is in or on the compound. body of a subject. In some embodiments, the intervention site 0090. In some embodiments of the methods and/or is a vascular wall. In some embodiments, the intervention site devices provided herein, the coating comprises a biodegrad is a non-vascular lumen wall. In some embodiments, the able material that is adhered and/or cohered to the substrate intervention site is a vascular cavity wall. prior to implantation, wherein the biodegradable material is 0.095. In some embodiments of the methods and/or capable of degrading over time to lose its cohesion and/or devices provided herein, the intervention site is a wall of a adhesion to the substrate. In some embodiments, the pharma body cavity. In some embodiments, the body cavity is the ceutical agent and/or the active agent is released from the result of a lumpectomy. In some embodiments, the interven coating within at least one of about 1 day, about 3 days, about tion site is a cannulized site within a Subject. 5 days, about 7 days, about 14 days, about 3 weeks, about 4 0096. In some embodiments of the methods and/or weeks, about 45 days, about 60 days, about 90 days, about devices provided herein, the intervention site is a sinus wall. 180 days, about 6 months, about 9 months, about 1 year, about In some embodiments, the intervention site is a sinus cavity 1 to about 2 days, about 1 to about 5 days, about 1 to about 2 wall. In some embodiments, the active agent comprises a weeks, about 2 to about 4 weeks, about 45 to about 60 days, corticosteroid. about 45 to about 90 days, about 30 to about 90 days, about 60 0097. In some embodiments of the methods and/or to about 90 days, about 90 to about 180 days, about 60 to devices provided herein, the intervention site is located in the about 180 days, about 180 to about 365 days, about 6 months reproductive system of a Subject. In some embodiments, the to about 9 months, about 9 months to about 12 months, about device is adapted to aid in fertility. In some embodiments, the 9 months to about 15 months, and about 1 year to about 2 device is adapted to treat a sexually transmitted disease. In years. Some embodiments, the device is adapted to Substantially 0091. In some embodiments of the methods and/or prevent pregnancy. In some embodiments, the active agent devices provided herein, the coating is prepared by a solvent comprises a hormone. In some embodiments, the pharmaceu based coating method. In some embodiments, the coating is tical agent comprises a hormone. In some embodiments, the prepared by a solvent plasma based coating method. device is adapted to Substantially prevent transmission of a 0092. In some embodiments of the methods and/or sexually transmitted disease. In some embodiments, the devices provided herein, the coating comprises a microstruc device is adapted to treat an ailment of the reproductive sys ture. In some embodiments, particles of the active agent are tem sequestered or encapsulated within said microstructure. In 0098. In some embodiments of the methods and/or Some embodiments, the microstructure comprises micro devices provided herein, the intervention site is located in the channels, micropores and/or microcavities. In some embodi urinary system of a subject. In some embodiments, the device ments, the microstructure is selected to allow Sustained is adapted to treat a disease of the urinary system. In some release of the active agent. In some embodiments, the micro embodiments, the active agent comprises a fluoroquinolone. structure is selected to allow controlled release of the active In some embodiments, the pharmaceutical agent comprises agent. fluoroquinolone. 0093. In some embodiments of the methods and/or 0099. In some embodiments of the methods and/or devices provided herein, the coating is formed on said Sub devices provided herein, the intervention site is located at a strate by a process comprising depositing a polymer and/or tumor site. In some embodiments, the tumor site is where a the active agent by an e-RESS, an e-SEDS, or an e-DPC tumor is located. In some embodiments, the tumor site is process. In some embodiments of the methods and/or devices where a tumor was located prior to removal and/or shrinkage provided herein, wherein the coating is formed on said Sub of the tumor. In some embodiments, the active agent com strate by a process comprising at least one of depositing a prises mitomycin C. In some embodiments, the pharmaceu polymer by an e-RESS, an e-SEDS, orane-DPC process, and tical agent comprises mitimycin C. US 2010/0015200 A1 Jan. 21, 2010

0100. In some embodiments of the methods and/or sheath. In some embodiments, the sheath is adapted to expose devices provided herein, the intervention site is located in the the coating to the intervention site upon retraction. ear. In some embodiments, the intervention site is located in 0108. In some embodiments of the methods and/or the esophagus. In some embodiments, the active agent com devices provided herein, the coating comprises a bioadhesive. prises lidocaine. In some embodiments, the pharmaceutical In some embodiments, the active agent comprises a bioadhe agent comprises lidocaine. sive. In some embodiments, the coating closes a vascular 0101. In some embodiments of the methods and/or puncture. In some embodiments, the coating aids in closing a devices provided herein, the intervention site is located in the vascular puncture. larynx. In some embodiments, the intervention site is a loca 0109. In some embodiments of the methods and/or tion of an injury. In some embodiments, the active agent devices provided herein, the coating Substantially prevents comprises CD34 antibodies. adhesion of body tissue. In some embodiments, the coating 0102. In some embodiments of the methods and/or promotes prevention of adhesion of body tissue. In some devices provided herein, the intervention site is an infection embodiments, the coating comprises hyaluronic acid, hyalu site. In some embodiments, the infection site is a site wherein ronate, salts, acids, conjugates, and/or derivatives thereof. In an infection may occur, and wherein the active agent is Some embodiments, the active agent comprises hyaluronic capable of Substantially preventing the infection. In some acid, hyaluronate, salts, acids, conjugates, and/or derivatives embodiments, the infection site is a site wherein an infection thereof. has occurred, and wherein the active agent is capable of 0110. In some embodiments of the methods and/or slowing spread of the infection. In some embodiments, the devices provided herein, the coating comprises a plurality of infection site is a site wherein an infection has occurred, and layers deposited on said Substrate, wherein at least one of the wherein the active agent is capable of treating the infection. In layers comprises the active agent. In some embodiments, at Some embodiments, the active agent comprises an anti-infec least one of the layers comprises a polymer. In some embodi tive agent. In some embodiments, the pharmaceutical agent ments, the polymer is bioabsorbable. In some embodiments, comprises an anti-infective agent. In some embodiments, the the active agent and the polymer are in the same layer, in anti-infective agent comprises clindamycin. separate layers, or form overlapping layers. In some embodi 0103. In some embodiments of the methods and/or ments, the coating comprises a plurality of layers deposited devices provided herein, the intervention site is a Surgery site. on said Substrate, wherein at least one of the layers comprises In some embodiments, the intervention site is an ocular site. the pharmaceutical agent. In some embodiments, the phar 0104. In some embodiments of the methods and/or maceutical agent and the polymer are in the same layer, in devices provided herein, the coating is capable of promoting separate layers, or form overlapping layers. In some embodi healing. In some embodiments, the active agent comprises a ments, the plurality of layers comprise five layers deposited growth factor. In some embodiments, the growth factor com as follows: a first polymer layer, a first active agent layer, a prises at least one of: an epidermal growth factor (EGF), a second polymer layer, a second active agent layer and a third transforming growth factor-alpha (TGF-alpha), a hepatocyte polymer layer. In some embodiments, the plurality of layers growth factor (HGF), a vacscular endothelial growth factor comprise five layers deposited as follows: a first polymer (VEGF), a platelet derived growth factor (PDGF), a fibroblast layer, a first pharmaceutical agent layer, a second polymer growth factor 1 (FGF-1), a fibroblast growth factor 2 (FGF-2), layer, a second pharmaceutical agent layer and a third poly a transforming growth factor-beta (TGF-beta), and a kerati mer layer. In some embodiments, the plurality of layers com nocyte growth factor (KGF). In some embodiments, the prise five layers deposited as follows: a first polymer layer, a active agent comprises a stem cell. first active biological agent layer, a second polymer layer, a 0105. In some embodiments of the methods and/or second active biological agent layer and a third polymer layer. devices provided herein, the coating is capable of at least one 0111. In some embodiments of the methods and/or of retarding healing, delaying healing, and preventing heal devices provided herein, the device provides the coating to ing. In some embodiments, the coating is capable of at least the intervention site over an area of delivery greater than the one of retarding, delaying, and preventing the inflammatory outer Surface contact area of the Substrate. In some embodi phase of healing. In some embodiments, the coating is ments, the area of delivery is at least 1 10% greater than the capable of at least one of retarding, delaying, and preventing outer Surface contact area of the Substrate. In some embodi the proliferative phase of healing. In some embodiments, the ments, the area of delivery is at least 1 10% to 200% greater coating is capable of at least one of retarding, delaying, and than the outer Surface contact area of the Substrate. In some preventing the maturation phase of healing. In some embodi embodiments, the area of delivery is at least 200% greater ments, the coating is capable of at least one of retarding, than the outer Surface contact area of the Substrate. delaying, and preventing the remodeling phase of healing. In 0112 Provided herein is a method comprising providing a Some embodiments, the active agent comprises an anti-angio medical device, wherein the medical device comprises a Sub genic agent. strate and a coating on at least a portion of said Substrate, and 0106. In some embodiments of the methods and/or wherein the coating comprises a plurality of layers, wherein devices provided herein, the coating is a sheath. In some at least one layer comprises a pharmaceutical agent in a embodiments, the sheath is plastically deformable. In some therapeutically desirable morphology, and freeing at least a embodiments, at least a portion of the sheath is capable of portion of the coating from the Substrate upon stimulating the being left at the intervention site upon removal of the sub coating with a stimulation. strate from the intervention site. In some embodiments, the 0113 Provided herein is a method comprising providing a Substrate is capable of mechanically deforming the sheath at medical device, wherein the medical device comprises a Sub the intervention site. strate and a coating on at least a portion of said Substrate, and 0107. In some embodiments of the methods and/or wherein the coating comprises a plurality of layers, wherein devices provided herein, the device comprises a retractable at least one layer comprises a pharmaceutical agent in a US 2010/0015200 A1 Jan. 21, 2010 therapeutically desirable morphology, and dissociating at embodiments, Substantially all of the coating frees, dissoci least a portion of the coating from the Substrate upon stimu ates, and/or transfers from the Substrate instantaneously upon lating the coating with a stimulation. stimulating the coating. 0114 Provided herein is a method comprising providing a I0123 Provided herein is a method comprising providing a medical device, wherein the medical device comprises a Sub medical device, wherein the medical device comprises a Sub strate and a coating on at least a portion of said Substrate, strate and a coating on at least a portion of said Substrate, and wherein said coating comprises an active agent, and wherein wherein the coating comprises a plurality of layers, wherein the coating is patterned, and freeing at least a portion of the at least one layer comprises a pharmaceutical agent in a coating from the Substrate upon stimulating the coating with therapeutically desirable morphology, and transferring at a stimulation. least a portion of the coating from the substrate to the inter 0.124 Provided herein is a method comprising providing a vention site upon stimulating the coating with a stimulation. medical device, wherein the medical device comprises a Sub 0115 Provided herein is a method comprising providing a strate and a coating on at least a portion of said Substrate, medical device, wherein the medical device comprises a Sub wherein said coating comprises an active agent, and wherein strate and a coating on at least a portion of said Substrate, the coating is patterned, and dissociating at least a portion of wherein said coating is at least partially continuous, has at the coating from the Substrate upon stimulating the coating least one portion conformal to the Substrate, and comprises a with a stimulation. pharmaceutical agent in a therapeutically desirable morphol 0.125 Provided herein is a method comprising providing a ogy, and freeing at least a portion of the coating from the medical device, wherein the medical device comprises a Sub Substrate upon stimulating the coating with a stimulation. strate and a coating on at least a portion of said Substrate, 0116 Provided herein is a method comprising providing a wherein said coating comprises an active agent, and wherein medical device, wherein the medical device comprises a Sub the coating is patterned, and transferring at least a portion of strate and a coating on at least a portion of said Substrate, the coating from the Substrate to the intervention site upon wherein said coating is at least partially continuous, has at stimulating the coating with a stimulation. least one portion conformal to the Substrate, and comprises a 0.126 In some embodiments, the patterned coating com pharmaceutical agent in a therapeutically desirable morphol prises at least two different shapes. ogy, and dissociating at least a portion of the coating from the I0127 Provided herein is a method comprising: providing Substrate upon stimulating the coating with a stimulation. a medical device, wherein the medical device comprises a 0117 Provided herein is a method comprising providing a Substrate and a coating on at least a portion of the Substrate, medical device, wherein the medical device comprises a Sub wherein the coating comprises an active agent; and transfer strate and a coating on at least a portion of said Substrate, ring at least a portion of the coating from the Substrate to an wherein said coating is at least partially continuous, has at intervention site. In some embodiments, the transferring the least one portion conformal to the Substrate, and comprises a coating portion (i.e. the portion of the coating) from the pharmaceutical agent in a therapeutically desirable morphol Substrate to the intervention site is upon stimulating the coat ogy, and transferring at least a portion of the coating from the ing with a stimulation. Substrate to the intervention site upon stimulating the coating I0128 Provided herein is a method comprising: providing with a stimulation. a medical device, wherein the medical device comprises a Substrate and a coating on at least a portion of the Substrate, 0118. In some embodiments, the therapeutically desirable wherein the coating comprises an active agent; and transfer morphology comprises a crystalline form of the pharmaceu ring at least a portion of the active agent from the Substrate to tical agent that is not a microcapsule. an intervention site. In some embodiments, the transferring 0119 Provided herein is a method comprising providing a the active agent portion (i.e. the portion of the active agent) medical device, wherein the medical device comprises a Sub from the Substrate to the intervention site is upon stimulating strate and a coating on at least a portion of said Substrate, and the coating with a stimulation. wherein said coating comprises an active agent, and freeing I0129. Provided herein is a method comprising: providing greater than 35% of the coating from the substrate upon a medical device, wherein the medical device comprises a stimulating the coating with a stimulation. Substrate and a coating on at least a portion of the Substrate, 0120 Provided herein is a method comprising providing a wherein the coating comprises an active agent; and freeing at medical device, wherein the medical device comprises a Sub least a portion of the coating from the Substrate at an inter strate and a coating on at least a portion of said Substrate, and vention site. In some embodiments, the freeing the coating wherein said coating comprises an active agent, and dissoci portion (i.e. the portion of the coating) from the Substrate is ating greater than 35% of the coating from the Substrate upon upon stimulating the coating with a stimulation. stimulating the coating with a stimulation. 0.130 Provided herein is a method comprising: providing 0121 Provided herein is a method comprising providing a a medical device, wherein the medical device comprises a medical device, wherein the medical device comprises a Sub Substrate and a coating on at least a portion of the Substrate, strate and a coating on at least a portion of said Substrate, and wherein the coating comprises an active agent; and dissoci wherein said coating comprises an active agent, and transfer ating at least a portion of the coating from the Substrate at an ring greater than 35% of the coating from the substrate to the intervention site. In some embodiments, the dissociating the intervention site upon stimulating the coating with a stimu coating portion (i.e. the portion of the coating) from the lation. Substrate is upon stimulating the coating with a stimulation. 0122. In some embodiments, the single stimulation lasts at I0131 Provided herein is a method comprising: providing most 20 seconds. In some embodiments, the device is adapted a medical device, wherein the medical device comprises a to free, dissociate, and/or transfer substantially all of the Substrate and a coating on at least a portion of the Substrate, coating upon the single stimulation of the coating. In some wherein the coating comprises an active agent; and depositing US 2010/0015200 A1 Jan. 21, 2010

at least a portion of the coating at an intervention site. In some contact between the coating and the Substrate. In some embodiments, the depositing the coating portion (i.e. the embodiments, dissociating dissociates less than about 1%, portion of the coating) at the intervention site is upon stimu less than about 5%, less than about 10%. less than about 15%, lating the coating with a stimulation. less than about 25%, less than about 50%, less than about 0132) Provided herein is a method comprising: providing 70%, less than about 80%, and/or less than about 90% of the a medical device, wherein the medical device comprises a coating absent stimulating at least one of the coating and the Substrate and a coating on at least a portion of the Substrate, substrate. wherein the coating comprises an active agent; and tacking at 0.138. In some embodiments of the methods and/or least a portion of the coating to an intervention site. In some devices provided herein, depositing at least a portion of the embodiments, the tacking the coating portion (i.e. the portion coating comprises depositing at least about 10% at least of the coating) to the intervention site is upon stimulating the about 20%, at least about 30%, at least about 50%, at least coating with a stimulation. about 75%, at least about 85%, at least about 90%, at least 0133. In some embodiments of the methods and/or about 95%, and/or at least about 99% of the coating at the devices provided herein, the transferring, freeing, dissociat intervention site. In some embodiments, stimulating ing, depositing, and/or tacking the coating comprises extrud decreases the contact between the coating and the Substrate. ing the coating from the Substrate. In some embodiments, depositing deposits less than about 0134. In some embodiments of the methods and/or 1%, less than about 5%, less than about 10%. less than about devices provided herein, transferring at least a portion of the 15%, less than about 25%, less than about 50%, less than coating comprises transferring at least about 10%, at least about 70%, less than about 80%, and/or less than about 90% about 20%, at least about 30%, at least about 50%, at least of the coating absent stimulating at least one of the coating about 75%, at least about 85%, at least about 90%, at least and the substrate. about 95%, and/or at least about 99% of the coating from the 0.139. In some embodiments of the methods and/or Substrate. In some embodiments, stimulating decreases the devices provided herein, tacking at least a portion of the contact between the coating and the Substrate. In some coating comprises tacking at least about 10%, at least about embodiments, transferring transfers less than about 1%, less 20%, at least about 30%, at least about 50%, at least about than about 5%, less than about 10%. less than about 15%, less 75%, at least about 85%, at least about 90%, at least about than about 25%, less than about 50%, less than about 70%, 95%, and/or at least about 99% of the coating to the interven less than about 80%, and/or less than about 90% of the coat tion site. In some embodiments, stimulating decreases the ing absent stimulating at least one of the coating and the contact between the coating and the substrate. In some substrate. embodiments, tacking tacks less than about 1%, less than 0135. In some embodiments of the methods and/or about 5%, less than about 10%. less than about 15%, less than devices provided herein, transferring at least a portion of the about 25%, less than about 50%, less than about 70%, less active agent comprises transferring at least about 10% at than about 80%, and/or less than about 90% of the coating least about 20%, at least about 30%, at least about 50%, at absent stimulating at least one of the coating and the Sub least about 75%, at least about 85%, at least about 90%, at Strate. least about 95%, and/or at least about 99% of the active agent 0140 Provided herein is a method of forming a medical from the Substrate. In some embodiments, stimulating device comprising a Substrate and a coating on at least a decreases the contact between the coating and the Substrate. portion of the Substrate, wherein the coating comprises an In some embodiments, transferring transfers less than about active agent, the method comprising: providing the Substrate; 1%, less than about 5%, less than about 10%. less than about and forming the coating on at least a portion of the Substrate 15%, less than about 25%, less than about 50%, less than by depositing the active agent by on the Substrate by at least about 70%, less than about 80%, and/or less than about 90% one of an e-RESS, an e-SEDS, and an e-DPC process, of the active agent absent stimulating at least one of the whereinforming the coating results in at least a portion of the coating and the Substrate. coating being adapted to transfer from the Substrate to an 0136. In some embodiments of the methods and/or intervention site upon stimulating the coating with a stimu devices provided herein, freeing at least a portion of the lation. coating comprises freeing at least about 10%, at least about 0141 Provided herein is a method of forming a medical 20%, at least about 30%, at least about 50%, at least about device comprising a Substrate and a coating on at least a 75%, at least about 85%, at least about 90%, at least about portion of the Substrate, wherein the coating comprises an 95%, and/or at least about 99% of the coating from the sub active agent, the method comprising: providing the Substrate; strate. In some embodiments, stimulating decreases the con and forming the coating on at least a portion of the Substrate tact between the coating and the Substrate. In some embodi by depositing the active agent by on the Substrate by at least ments, freeing frees less than about 1%, less than about 5%, one of an e-RESS, an e-SEDS, and an e-DPC process without less than about 10%. less than about 15%, less than about electrically charging the Substrate, whereinforming the coat 25%, less than about 50%, less than about 70%, less than ing results in at least a portion of the coating being adapted to about 80%, and/or less than about 90% of the coating absent transfer from the Substrate to an intervention site upon stimu stimulating at least one of the coating and the Substrate. lating the coating with a stimulation. 0137 In some embodiments of the methods and/or 0.142 Provided herein is a method of forming a medical devices provided herein, dissociating at least a portion of the device comprising a Substrate and a coating on at least a coating comprises dissociating at least about 10%, at least portion of the Substrate, wherein the coating comprises an about 20%, at least about 30%, at least about 50%, at least active agent, the method comprising: providing the Substrate; about 75%, at least about 85%, at least about 90%, at least and forming the coating on at least a portion of the Substrate about 95%, and/or at least about 99% of the coating from the by depositing the active agent by on the Substrate by at least Substrate. In some embodiments, stimulating decreases the one of an e-RESS, an e-SEDS, and an e-DPC process without US 2010/0015200 A1 Jan. 21, 2010

creating an electrical potential between the Substrate and a 0.148. In some embodiments of the methods and/or coating apparatus used in the at least one e-RESS, an e-SEDS, devices provided herein, forming the coating facilitates trans and an e-DPC process, whereinforming the coating results in fer of the coating to the intervention site. at least a portion of the coating being adapted to transfer from 0149. In some embodiments of the methods and/or the Substrate to an intervention site upon stimulating the devices provided herein, transferring, freeing, dissociating, coating with a stimulation. depositing, and/or tacking step comprises softening the poly merby hydration, degradation or by a combination of hydra 0143 Provided herein is a method of forming a medical tion and degradation. In some embodiments, the transferring, device comprising a Substrate and a coating on at least a freeing, dissociating, depositing, and/or tacking step com portion of the Substrate, wherein the coating comprises an prises softening the polymer by hydrolysis of the polymer. active agent, the method comprising: providing the Substrate; 0150. In some embodiments of the methods and/or and forming the coating on at least a portion of the Substrate devices provided herein, providing the medical device com by depositing the active agent by on the Substrate by at least prises forming the coating out of laminated layers that allow one of a dipping and/or a spraying process, whereinforming direct control of the transferring, freeing, depositing, tacking, the coating results in at least a portion of the coating being and/or dissociating of the coating from the Substrate. In some adapted to transfer from the substrate to an intervention site embodiments, the coating comprises laminated layers that upon stimulating the coating with a stimulation. allow direct control of the transferring, freeing, depositing, 0144 Provided herein is a method of forming a medical tacking, and/or dissociating of the coating from the Substrate, device comprising a Substrate and a coating on at least a wherein at least one of the layers comprises the active agent. portion of the Substrate, wherein the coating comprises an In some embodiments, the coating comprises laminated lay active agent, the method comprising providing the Substrate; ers that allow direct control of the transferring, freeing, and forming the coating on at least a portion of the Substrate depositing, tacking, and/or dissociating of the coating from by depositing the active agent on ths substrate by a dipping the substrate, wherein at least one of the layers comprises the and/or a spraying process, wherein forming the coating pharmaceutical agent. 0151. In some embodiments of the methods and/or results in greater than 35% of the coating being adapted to devices provided herein, the providing step comprises form free from the Substrate upon stimulating the coating with a ing the coating by a solvent based coating method. In some single stimulation. embodiments, the providing step comprises forming the coat 0145. In some embodiments, the single stimulation lasts at ing by a solvent plasma based method. most 20 seconds. In some embodiments, Substantially all of 0152. In some embodiments of the methods and/or the coating is adapted to transfer from the Substrate upon devices provided herein, providing the device comprises stimulating with a single stimulation. In some embodiments, depositing a plurality of layers on said Substrate to form the substantially all of the coating frees from the substrate instan coating, wherein at least one of the layers comprises the active taneously upon stimulating the coating. agent. In some embodiments, at least one of the layers com 0146 In some embodiments of the methods and/or prises a polymer. In some embodiments, the polymer is bio devices provided herein, forming the coating results in the absorbable. In some embodiments, the active agent and the coating adhering to the Substrate prior to the Substrate reach polymer are in the same layer, in separate layers, or form ing the intervention site. overlapping layers. In some embodiments, the plurality of 0147 Some embodiments of the methods and/or devices layers comprise five layers deposited as follows: a first poly provided hereinfurther comprise providing a release agent on mer layer, a first active agent layer, a second polymer layer, a said Substrate. In some embodiments, providing the release second active agent layer and a third polymer layer. agent step is performed prior to the forming the coating step. 0153. In some embodiments of the methods and/or In some embodiments, the release agent comprises at least devices provided herein, the device further comprises a stent. one of a biocompatible release agent, a non-biocompatible In some embodiments, the Substrate is not the stent. release agent, a powder, a lubricant, a surface modification of the Substrate, a viscous fluid, a gel, the active agent, a second Incorporation by Reference active agent, a physical characteristic of the Substrate. In 0154 All publications and patent applications mentioned Some embodiments, the physical characteristic of the Sub in this specification are herein incorporated by reference to strate comprises at least one of a patterned coating Surface of the same extent as if each individual publication or patent the substrate, and a ribbed surface of the substrate. In some application was specifically and individually indicated to be embodiments, the release agent comprises a property that is incorporated by reference. capable of changing at the intervention site. In some embodi ments, the property comprises a physical property. In some DETAILED DESCRIPTION OF THE INVENTION embodiments, the property comprises a chemical property. In Some embodiments, the release agent is capable of changing 0155 The present invention is explained in greater detail a property when in contact with at least one of a biologic below. This description is not intended to be a detailed catalog tissue and a biologic fluid. In some embodiments, the release of all the different ways in which the invention may be imple agent is capable of changing a property when in contact with mented, or all the features that may be added to the instant an aqueous liquid. In some embodiments, the coating results invention. For example, features illustrated with respect to in a coating property that facilitates transfer of the coating to one embodiment may be incorporated into other embodi the intervention site. In some embodiments, the coating prop ments, and features illustrated with respect to a particular erty comprises a physical characteristic of the coating. In embodiment may be deleted from that embodiment. In addi Some embodiments, the physical characteristic comprises a tion, numerous variations and additions to the various pattern. embodiments suggested herein will be apparent to those US 2010/0015200 A1 Jan. 21, 2010

skilled in the artin light of the instant disclosure, which do not and/or devices provided herein, an electrical potential is not depart from the instant invention. Hence, the following speci created between the Substrate and the coating apparatus. fication is intended to illustrate Some particular embodiments 0160 Subjects into which biomedical implants of the of the invention, and not to exhaustively specify all permuta invention may be applied or inserted include both human tions, combinations and variations thereof. Subjects (including male and female Subjects and infant, juve nile, adolescent, adult and geriatric Subjects) as well as ani DEFINITIONS mal Subjects (including but not limited to pig, rabbit, mouse, 0156. As used in the present specification, the following dog, cat, horse, monkey, etc.) for veterinary purposes and/or words and phrases are generally intended to have the mean medical research. ings as set forth below, except to the extent that the context in 0.161. As used herein, a biological implant may include a which they are used indicates otherwise. medical device that is not permanantly implanted. A biologi 0157 “Substrate” as used herein, refers to any surface cal implant in some embodiments may comprise a device upon which it is desirable to deposit a coating. Biomedical which is used in a Subject on a transient basis. For non implants are of particular interest for the present invention; limiting example, the biomedical implant may be a balloon, however the present invention is not intended to be restricted which is used transiently to dilate a lumen and thereafter may to this class of substrates. Those of skill in the art will appre be deflated and/or removed from the subject during the medi ciate alternate substrates that could benefit from the coating cal procedure or thereafter. In some embodiments, the bio process described herein, Such as pharmaceutical tablet cores, logical implant may be temporarily implanted for a limited as part of an assay apparatus or as components in a diagnostic time. Such as during a portion of a medical procedure, or for kit (e.g. a test strip). Examples of substrates that can be coated only a limited time (some time less than permanantly using the methods of the invention include Surgery devices or implanted), or may be transiently implanted and/or momen medical devices, e.g., a catheter, a balloon, a cutting balloon, tarily placed in the subject. In some embodiments, the bio a wire guide, a cannula, tooling, an orthopedic device, a logical implant is not implanted at all, rather it is merely structural implant, stent, Stent-graft, graft, Vena cava filter, a inserted into a Subject during a medical procedure, and Sub heart valve, cerebrospinal fluid shunts, pacemaker electrodes, sequently removed from the subject prior to or at the time the axius coronary shunts, endocardial leads, an artificial heart, medical procedure is completed. In some embodiments, the and the like. biological implant is not permenantly implanted since it com 0158 “Biomedical implant’ as used herein refers to any pletely resorbs into the subject (i.e. is completely resorbed by implant for insertion into the body of a human or animal the subject). In a preferred embodiment the biomedical Subject, including but not limited to stents (e.g., coronary implant is an expandable balloon that can be expanded within stents, vascular stents including peripheral stents and graft a lumen (naturally occuring or non-naturally occurring) hav stents, urinary tract stents, urethral/prostatic stents, rectal ing a coating thereon that is freed (at least in part) from the stent, oesophageal stent, biliary stent, pancreatic stent), elec balloon and left behind in the lumen when the balloon is trodes, catheters, leads, implantable pacemaker, cardioverter removed from the lumen. or defibrillator housings, joints, screws, rods, ophthalmic 0162 “Pharmaceutical agent” as used herein refers to any implants, femoral pins, bone plates, grafts, anastomotic of a variety of drugs orpharmaceutical compounds that can be devices, perivascular wraps, Sutures, staples, shunts for used as active agents to prevent or treat a disease (meaning hydrocephalus, dialysis grafts, colostomy bag attachment any treatment of a disease in a mammal, including preventing devices, ear drainage tubes, leads for pace makers and the disease, i.e. causing the clinical symptoms of the disease implantable cardioverters and defibrillators, vertebral disks, not to develop; inhibiting the disease, i.e. arresting the devel bone pins, Suture anchors, hemostatic barriers, clamps, opment of clinical symptoms; and/or relieving the disease, screws, plates, clips, vascular implants, tissue adhesives and i.e. causing the regression of clinical symptoms). It is possible sealants, tissue scaffolds, various types of dressings (e.g., that the pharmaceutical agents of the invention may also wound dressings), bone Substitutes, intraluminal devices, comprise two or more drugs or pharmaceutical compounds. vascular supports, etc. Pharmaceutical agents include but are not limited to antires 0159. The implants may be formed from any suitable tenotic agents, antidiabetics, analgesics, antiinflammatory material, including but not limited to polymers (including agents, antirheumatics, antihypotensive agents, antihyperten stable or inert polymers, organic polymers, organic-inorganic sive agents, angiogenesis promoters, angiogenesis inhibitors, copolymers, inorganic polymers, and biodegradable poly psychoactive drugs, tranquilizers, antiemetics, muscle relax mers), metals, metal alloys, inorganic materials such as sili ants, glucocorticoids, agents for treating ulcerative colitis or con, and composites thereof, including layered structures Crohn's disease, antiallergics, antibiotics, antiepileptics, anti with a core of one material and one or more coatings of a coagulants, antimycotics, antifungals, antitussives, arterio different material. Substrates made of a conducting material Sclerosis remedies, diuretics, proteins, peptides, enzymes, facilitate electrostatic capture. However, the invention con enzyme inhibitors, gout remedies, hormones and inhibitors templates the use of electrostatic capture, as described herein, thereof, cardiac glycosides, immunotherapeutic agents and in conjunction with Substrate having low conductivity or cytokines, laxatives, lipid-lowering agents, migraine rem which are non-conductive. To enhance electrostatic capture edies, mineral products, otologicals, anti parkinson agents, when a non-conductive Substrate is employed, the Substrate is thyroid therapeutic agents, spasmolytics, plateletaggregation processed for example while maintaining a strong electrical inhibitors, vitamins, cytostatics and metastasis inhibitors, field in the vicinity of the substrate. In some embodiments, phytopharmaceuticals, chemotherapeutic agents and amino however, no electrostatic capture is employed in applying a acids. Examples of Suitable active ingredients are acarbose, coating to the Substrate. In some embodiments of the methods antigens, beta-receptor blockers, non-steroidal antiinflam and/or devices provided herein, the Substrate is not charged in matory drugs NSAIDs, cardiac glycosides, acetylsalicylic the coating process. In some embodiments of the methods acid, alfuZosim, virustatics, aclarubicin, acyclovir, cisplatin, US 2010/0015200 A1 Jan. 21, 2010 actinomycin, alpha- and beta-sympatomimetics, dmeprazole, fylline, perphenazine, pethidine, plant extracts, phenaZone, allopurinol, alprostadil, prostaglandins, amantadine, pheniramine, barbituric acid derivatives, phenylbutaZone, ambroXol, amlodipine, methotrexate, S-aminosalicylic acid, pimozide, pindolol, piperazine, piracetam, pirenzepine, pir amitriptyline, amoxicillin, anastroZole, atenolol, azathio ibedil, piroxicam, pramipexole, pravastatin, prazosin, prine, balsalazide, beclomethasone, betahistine, bezafibrate, procaine, promazine, propiverine, propranolol, propy bicalutamide, diazepam and diazepam derivatives, budes phenaZone, prostaglandins, protionamide, proxyphylline, onide, bufeXamac, buprenorphine, methadone, calcium salts, quetiapine, quinapril, quinaprilat, ramipril, ranitidine, repro potassium salts, magnesium salts, candesartan, carbam terol, reserpine, ribavirin, rifampicin, risperidone, ritonavir, azepine, captopril, cefalosporins, cetirizine, chenodeoxy ropinirole, roXatidine, roXithromycin, ruscogenin, rutoside cholic acid, urSodeoxycholic acid, theophylline and theo and rutoside derivatives, Sabadilla, Salbutamol, salmeterol, phylline derivatives, trypsins, cimetidine, clarithromycin, Scopolamine, selegiline, Sertaconazole, sertindole, Sertralion, clavulanic acid, clindamycin, clobutinol, clonidine, cotri silicates, simvastatin, Sitosterol, Sotalol, spaglumic acid, spar moxazole, codeine, caffeine, Vitamin D and derivatives of floxacin, spectinomycin, spiramycin, spirapril, spironolac Vitamin D, colestyramine, cromoglicic acid, coumarin and tone, stavudine, Streptomycin, Sucralfate, Sufentanil, Sulbac coumarin derivatives, cysteine, cytarabine, cyclophospha tam, Sulphonamides, Sulfasalazine, Sulpiride, Sultamicillin, mide, ciclosporin, cyproterone, cytabarine, dapiprazole, Sultiam, Sumatriptan, suxamethonium chloride, tacrine, tac desogestrel, desonide, dihydralazine, diltiazem, ergot alka rolimus, taliolol, tamoxifen, taurolidine, tazarotene, loids, dimenhydrinate, dimethyl Sulphoxide, dimeticone, temazepam, teniposide, tenoxicam, teraZosin, terbinafine, domperidone and domperidan derivatives, dopamine, dox terbutaline, terfenadine, terlipressin, tertatolol, tetracyclins, aZosin, doxorubizin, doxylamine, benzodiazepines, tery Zoline, theobromine, theophylline, butizine, thiamazole, diclofenac, glycoside antibiotics, desipramine, econazole, phenothiazines, thiotepa, tiagabine, tiapride, propionic acid ACE inhibitors, enalapril, ephedrine, epinephrine, epoetin derivatives, ticlopidine, timolol, tinidazole, tioconazole, and epoetin derivatives, morphinans, calcium antagonists, tioguanine, tioxolone, tiropramide, tizanidine, tolaZoline, irinotecan, modafinil, orlistat, peptide antibiotics, phenytoin, tolbutamide, tolcapone, tolnaftate, tolperisone, topotecan, riluzoles, risedronate, sildenafil, topiramate, macrollide anti torasemide, antioestrogens, tramadol, tramaZoline, trandola biotics, oestrogen and oestrogen derivatives, progestogen and pril, tranylcypromine, trapidil, traZodone, triamcinolone and progestogen derivatives, testosterone and testosterone deriva triamcinolone derivatives, triamterene, trifluperidol, trifluri tives, androgen and androgen derivatives, ethenZamide, dine, trimethoprim, trimipramine, tripelennamine, triproli etofenamate, etofibrate, fenofibrate, etofylline, etoposide, dine, trifosfamide, tromantadine, trometamol, tropalpin, famciclovir, famotidine, felodipine, fenofibrate, fentanyl, troXerutine, tulobuterol, tyramine, tyrothricin, urapidil, fenticonazole, gyrase inhibitors, fluconazole, fludarabine, urSodeoxycholic acid, chenodeoxycholic acid, Valaciclovir, fluiarizine, fluorouracil, fluoxetine, flurbiprofen, ibuprofen, valproic acid, Vancomycin, vecuronium chloride, Viagra, flutamide, fluvastatin, follitropin, formoterol, fosfomicin, Venlafaxine, Verapamil, Vidarabine, vigabatrin, Viloazine, furosemide, fusidic acid, gallopamil, ganciclovir, gemfi vinblastine, Vincamine, Vincristine, Vindesine, Vinorelbine, brozil, gentamicin, ginkgo, Saint John's wort, glibenclamide, Vinpocetine, Vicquidil, warfarin, Xantinol nicotinate, Xipam urea derivatives as oral antidiabetics, glucagon, glucosamine ide, Zafirlukast, Zalcitabine, Zidovudine, Zolmitriptan, Zolpi and glucosamine derivatives, glutathione, glycerol and glyc dem, Zoplicone, Zotipine, clotrimazole, amphotericin B, erol derivatives, hypothalamus hormones, goserelin, gyrase caspofungin, or Voriconazole, resveratrol, PARP-1 inhibitors inhibitors, guanethidine, halofantrine, haloperidol, heparin (including imidazoquinolinone, imidazpyridine, and iso and heparin derivatives, hyaluronic acid, hydralazine, hydro quinolindione, tissue plasminogen activator (tPA), melagat chlorothiazide and hydrochlorothiazide derivatives, salicy ran, lanoteplase, reteplase, Staphylokinase, Streptokinase, lates, hydroxy Zine, idarubicin, ifosfamide, imipramine, tenecteplase, urokinase, and the like. See, e.g., U.S. Pat. No. indometacin, indoramine, insulin, interferons, iodine and 6,897,205; see also U.S. Pat. No. 6,838,528: U.S. Pat. No. iodine derivatives, isoconazole, isoprenaline, glucitol and 6,497,729. glucitol derivatives, itraconazole, ketoconazole, ketoprofen, 0163 Examples of pharmaceutical agents employed in ketotifen, lacidipine, lansoprazole, levodopa, levometha conjunction with the invention include, rapamycin, 40-O-(2- done, thyroid hormones, lipoic acid and lipoic acid deriva Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapa tives, lisinopril, lisuride, lofepramine, lomustine, loperamide, mycin, 40-O-(4-Hydroxymethyl)benzyl-rapamycin, 40-O- loratadine, maprotiline, mebendazole, mebeverine, mecloz 4'-(1,2-Dihydroxyethyl)benzyl-rapamycin, 40-O-Allyl ine, mefenamic acid, mefloquine, meloxicam, mepindolol. rapamycin, 40-O-3 '-(2,2-Dimethyl-1,3-dioxolan-4-(S)-yl)- meprobamate, meropenem, mesalazine, mesuXimide, prop-2-en-1-yl-rapamycin, (2':E,4'S)-40-O-(4',5'- metamizole, metformin, methylphenidate, methylpredniso Dihydroxypent-2-en-1-yl)-rapamycin 40-O-(2-Hydroxy) lone, metixene, metoclopramide, metoprolol, metronidazole, ethoxycarbonylmethyl-rapamycin, 40-O-(3-Hydroxy) mianserin, miconazole, minocycline, minoxidil, misoprostol, propyl-rapamycin 4O—O-(6-Hydroxy)hexyl-rapamycin mitomycin, mizolastine, moexipril, morphine and morphine 40-O-2-(2-Hydroxy)ethoxyethyl-rapamycin 4O O derivatives, evening primrose, nalbuphine, naloxone, tilidine, (3S)-2,2-Dimethyldioxolan-3-yl)methyl-rapamycin, 40-O- naproxen, narcotine, natamycin, neostigmine, nicergoline, (2S)-2,3-Dihydroxyprop-1-yl)-rapamycin, 4O O-(2-Ac nicethamide, nifedipine, niflumic acid, nimodipine, nimora etoxy)ethyl-rapamycin 4O—O-(2-Nicotinoyloxy)ethyl Zole, nimustine, nisoldipine, adrenaline and adrenaline rapamycin, 4O O-2-(N-Morpholino)acetoxyethyl derivatives, norfloxacin, novamine Sulfone, noscapine, nys rapamycin 4O—O-(2-N-Imidazolylacetoxy)ethyl tatin, ofloxacin, olanzapine, olsalazine, omeprazole, omo rapamycin, 40-O-2-(N-Methyl-N'-piperazinyl)acetoxy conazole, ondansetron, oxaceprol, oxacillin, oxiconazole, ethyl-rapamycin, 39-O-Desmethyl-39.40-O,O-ethylene oxymetazoline, pantoprazole, paracetamol, paroxetine, pen rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl ciclovir, oral penicillins, pentazocine, pentifylline, pentoxi rapamycin, 28-O-Methyl-rapamycin, 4O—O-(2- US 2010/0015200 A1 Jan. 21, 2010 20

Aminoethyl)-rapamycin, 4O-O-(2-Acetaminoethyl)-rapa Zine, pethidine, plant extracts, phenaZone, pheniramine, mycin 4O O-(2-Nicotinamidoethyl)-rapamycin, 4O—O- barbituric acid derivatives, phenylbutaZone, pimozide, pin (2-(N-Methyl-imidazo-2'-ylcarbethoxamido)ethyl)- dolol, piperazine, piracetam, pirenzepine, piribedil, piroxi rapamycin, 4O—O-(2-Ethoxycarbonylaminoethyl)- cam, pramipexole, pravastatin, praZosin, procaine, pro rapamycin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, mazine, propiverine, propranolol, propyphenaZone, 40-O-2-(4',5'-Dicarboethoxy-1'2',3'-triazol-1-yl)-ethyl protionamide, proxyphylline, quetiapine, quinapril, quinap rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), and rilat, ramipril, ranitidine, reproterol, reserpine, ribavirin, ris 42-3-hydroxy-2-(hydroxymethyl)-2-methylpropanoatera peridone, ritonavir, ropinirole, roXatidine, ruscogenin, ruto pamycin (temsirolimus). side (and derivatives), Sabadilla, Salbutamol, salmeterol, 0164. In some embodiments, a pharmaceutical agent is at Scopolamine, selegiline, Sertaconazole, sertindole, Sertralion, least one of Acarbose, acetylsalicylic acid, acyclovir, allopu silicates, simvastatin, sitosterol, Sotalol, spaglumic acid, spi rinol, alprostadil, prostaglandins, amantadine, ambroXol. rapril, spironolactone, stavudine, streptomycin, Sucralfate, amlodipine, S-aminosalicylic acid, amitriptyline, atenolol. Sufentanil, Sulfasalazine, Sulpiride, Sultiam, Sumatriptan, SuX azathioprine, balsalazide, beclomethasone, betahistine, amethonium chloride, tacrine, tacrolimus, taliolol, tauroli beZafibrate, diazepam and diazepam derivatives, budesonide, dine, temazepam, tenoxicam, teraZosin, terbinafine, terbuta bufexamac, buprenorphine, methadone, calcium salts, potas line, terfenadine, terlipressin, tertatolol, tery Zoline, sium salts, magnesium salts, candesartan, carbamazepine, theobromine, butizine, thiamazole, phenothiazines, tiagab captopril, cetirizine, chenodeoxycholic acid, theophylline ine, tiapride, propionic acid derivatives, ticlopidine, timolol. and theophylline derivatives, trypsins, cimetidine, clobutinol, tinidazole, tioconazole, tioguanine, tioXolone, tiropramide, clonidine, cotrimoxazole, codeine, caffeine, vitamin D and tizanidine, tolaZoline, tolbutamide, tolcapone, tolnaftate, tol derivatives of vitamin D, colestyramine, cromoglicic acid, perisone, topotecan, torasemide, tramadol, tramazoline, tran coumarin and coumarin derivatives, cysteine, ciclosporin, dollapril, tranylcypromine, trapidil, traZodone, triamcinolone cyproterone, cytabarine, dapiprazole, desogestrel, desonide, derivatives, triamterene, trifluperidol, trifluridine, trimi dihydralazine, diltiazem, ergot alkaloids, dimenhydrinate, pramine, tripelennamine, triprolidine, trifosfamide, troman dimethyl Sulphoxide, dimeticone, domperidone and domp tadine, trometamol, tropalpin, troXerutine, tulobuterol, eridan derivatives, dopamine, doxazosin, doxylamine, ben tyramine, tyrothricin, urapidil, Valaciclovir, Valproic acid, Zodiazepines, diclofenac, desipramine, econazole, ACE Vancomycin, Vecuronium chloride, Viagra, Venlafaxine, Vera inhibitors, enalapril, ephedrine, epinephrine, epoetin and pamil, Vidarabine, vigabatrin, Viloazine, Vincamine, Vinpo epoetin derivatives, morphinans, calcium antagonists, cetine, Viduidil, warfarin, xantinol nicotinate, Xipamide, modafinil, orlistat, peptide antibiotics, phenytoin, riluzoles, Zafirlukast, Zalcitabine, Zidovudine, Zolmitriptan, Zolpidem, risedronate, Sildenafil, topiramate, estrogen, progestogen and Zoplicone, Zotipine, amphotericin B, caspofungin, Voricona progestogen derivatives, testosterone derivatives, androgen Zole, resveratrol, PARP-1 inhibitors (including imidazo and androgen derivatives, ethenZamide, etofenamate, etofi quinolinone, imidazpyridine, and isoquinolindione, tissue brate, fenofibrate, etofylline, famciclovir, famotidine, felo plasminogen activator (tPA), melagatran, lanoteplase, dipine, fentanyl, fenticonazole, gyrase inhibitors, flucona reteplase, staphylokinase, streptokinase, tenecteplase, uroki Zole, fluiarizine, fluoxetine, flurbiprofen, ibuprofen, nase, 40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O- fluvastatin, follitropin, formoterol, fosfomicin, furosemide, Benzyl-rapamycin, 40-O-(4-Hydroxymethyl)benzyl-rapa fusidic acid, gallopamil, ganciclovir, gemfibrozil, ginkgo, mycin, 40-O-4-(1,2-Dihydroxyethyl)benzyl-rapamycin, Saint John's wort, glibenclamide, urea derivatives as oral 40-O-Allyl-rapamycin, 40-O-3'-(2,2-Dimethyl-1,3-diox antidiabetics, glucagon, glucosamine and glucosamine olan-4-(S)-yl)-prop-2-en-1-yl)-rapamycin, (2:E,4'S)-40-O- derivatives, glutathione, glycerol and glycerol derivatives, (4',5'-Dihydroxypent-2-en-1-yl)-rapamycin 40-O-(2-Hy hypothalamus hormones, guanethidine, halofantrine, halo droxy)ethoxycar-bonylmethyl-rapamycin, 40-O-(3- peridol, heparin (and derivatives), hyaluronic acid, hydrala Hydroxy)propyl-rapamycin 4O—O-(6-Hydroxy)hexyl Zine, hydrochlorothiazide (and derivatives), Salicylates, rapamycin 40-O-2-(2-Hydroxy)ethoxyethyl-rapamycin hydroxy Zine, imipramine, indometacin, indoramine, insulin, 4O—O-(3 S)-2,2-Dimethyldioxolan-3-yl)methyl-rapamy iodine and iodine derivatives, isoconazole, isoprenaline, glu cin, 40-O-(2S)-2,3-Dihydroxyprop-1-yl)-rapamycin, citol and glucitol derivatives, itraconazole, ketoprofen, keto 4O—O-(2-Acetoxy)ethyl-rapamycin 4O—O-(2-Nicotinoy tifen, lacidipine, lanSoprazole, levodopa, levomethadone, loxy)ethyl-rapamycin, 4O O-2-(N-Morpholino)acetoxy thyroid hormones, lipoic acid (and derivatives), lisinopril, ethyl-rapamycin 4O—O-(2-N-Imidazolylacetoxy)ethyl-ra lisuride, lofepramine, loperamide, loratadine, maprotiline, pamycin, 40-O-2-(N-Methyl-N'-piperazinyl)acetoxyethyl mebendazole, mebeverine, meclozine, mefenamic acid, rapamycin, 39-O-Desmethyl-39.40-O,O-ethylene mefloquine, meloxicam, mepindolol, meprobamate, mesala rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl Zine, mesuXimide, metamizole, metformin, methylphenidate, rapamycin, 28-O-Methyl-rapamycin, 4O—O-(2- metixene, metoprolol, metronidazole, mianserin, micona Aminoethyl)-rapamycin, 4O—O-(2-Acetaminoethyl)- Zole, minoxidil, misoprostol, mizolastine, moexipril, mor rapamycin 4O—O-(2-Nicotinamidoethyl)-rapamycin, phine and morphine derivatives, evening primrose, nalbu 4O—O-(2-(N-Methyl-imidazo-2-ylcarbethoxamido)ethyl)- phine, naloxone, tilidine, naproxen, narcotine, natamycin, rapamycin, 4O-O-(2-Ethoxycarbonylaminoethyl)-rapamy neostigmine, nicergoline, nicethamide, nifedipine, niflumic cin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, 40-O-2- acid, nimodipine, nimorazole, nimustine, nisoldipine, (4',5'-Dicarboethoxy-1'2',3'-triazol-1-yl)-ethyl-rapamycin, adrenaline and adrenaline derivatives, novamine Sulfone, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), and 42-3-hy noscapine, nystatin, olanzapine, olsalazine, omeprazole, droxy-2-(hydroxymethyl)-2-methylpropanoaterapamycin omoconazole, oxaceprol, oxiconazole, oxymetazoline, pan (temsirolimus), abciximab (ReoPro), eptifibatide, tirofiban, toprazole, paracetamol(acetaminophen), paroxetine, penci prasugrel, clopidogrel, dipyridamole, cilostaZol, VEGF, clovir, pentazocine, pentifylline, pentoxifylline, perphena heparan sulfate, chondroitin sulfate, elongated “RGD' pep US 2010/0015200 A1 Jan. 21, 2010

tide binding domain, CD34 antibodies, cerivastatin, etorvas mitotane, hexamethylmelamine, indolyl-3-glyoxylic acid tatin, losartan, Valartan, erythropoietin, rosiglitaZone, piogli derivatives, (e.g., indibulin), doxorubicin and idarubicin, pli taZone, mutant protein Apo Al Milano, adiponectin, (NOS) camycin (mithramycin) and mitomycin, mechlorethamine, gene therapy, glucagon-like peptide 1, atorvastatin, and atrial cyclophosphamide analogs, traZenes-dacarbazinine (DTIC), natriuretic peptide (ANP), lidocaine, tetracaine, dibucaine, pentostatin and 2-chlorodeoxyadenosine, letrozole, camp hyssop, ginger, turmeric, Arnica montana, helenalin, cannab tothecin (and derivatives), navelbine, erlotinib, capecitabine, ichromene, rofecoxib, and hyaluronidase. acivicin, acodazole hydrochloride, acronine, adoZelesin, 0.165. The pharmaceutical agents may, if desired, also be aldesleukin, ambomycin, ametantrone acetate, anthramycin, used in the form of their pharmaceutically acceptable salts or asperlin, azacitidine, azetepa, azotomycin, batimastat, ben derivatives (meaning salts which retain the biological effec Zodepa, bisnafide, bisnafide dimesylate, bizelesin, bropir tiveness and properties of the compounds of this invention imine, cactinomycin, calusterone, carbetimer, carubicin and which are not biologically or otherwise undesirable), and hydrochloride, carzelesin, cedefingol, celecoxib (COX-2 in the case of chiral active ingredients it is possible to employ inhibitor), cirolemycin, crisinatol mesylate, decitabine, dex both optically active isomers and racemates or mixtures of ormaplatin, dezaguanine mesylate, diaziquone, duaZomycin, diastereoisomers. As well, the pharmaceutical agent may edatrexate, eflomithine, elsamitrucin, enloplatin, empromate, include a prodrug, a hydrate, an ester, a derivative or analogs epipropidine, erbuloZole, etanidazole, etoprine, flurocitabine, of a compound or molecule. fosquidone, lometrexol, losoxantrone hydrochloride, maso 0166 The pharmaceutical agent may be an antibiotic procol, maytansine, megestrol acetate, melengestrol acetate, agent, as described herein. metoprine, meturedepa, mitindomide, mitocarcin, mitocro 0167. The pharmaceutical agent may be a chemotherapeu min, mitogillin, mitomalcin, mitosper, mycophenolic acid, tic agent, as described herein. nocodazole, nogalamycin, ormaplatin, oxisuran, pegaspar 0168 The phamaceutical agent may be an anti-thrombotic gase, peliomycin, pentamustine, perfosfamide, piposulfan, agent, as described herein. plomestane, porfimer Sodium, porfiromycin, puromycin, 0169. The phamaceutical agent may be a statin, as pyrazofurin, riboprine, Safingol, SimtraZene, sparfosate described herein. Sodium, Spiromustine, spiroplatin, Streptonigrin, Sulofenur, 0170 The phamaceutical agent may be an angiogenisis tecogalan Sodium, taxotere, tegafur, teloxantrone hydrochlo promoter, as described herein. ride, temoporfin, thiamiprine, tirapazamine, trestolone 0171 The phamaceutical agent may be a local anesthetic, acetate, triciribine phosphate, trimetrexate glucuronate, tubu as described herein. lozole hydrochloride, uracil mustard, uredepa, verteporfin, 0172 The phamaceutical agent may be an anti-inflamma vinepidine Sulfate, Vinglycinate Sulfate, Vinleurosine Sulfate, tory agent, as described herein. Vinorelbine tartrate, Vinrosidine Sulfate, Zeniplatin, Zinosta 0173 A “pharmaceutically acceptable salt may be pre tin, 20-epi-1.25 dihydroxyvitamin D3, 5-ethynyluracil, acyl pared for any pharmaceutical agent having a functionality fulvene, adecypenol, ALL-TK antagonists, ambamustine, capable of forming a salt, for example an acid or base func amidox, amifostine, aminolevulinic acid, amrubicin, tionality. Pharmaceutically acceptable salts may be derived anagrelide, andrographolide, antagonist D, antagonist G. from organic or inorganic acids and bases. The term “phar antarelix, anti-dorsalizing morphogenetic protein-1, antian maceutically-acceptable salts' in these instances refers to the drogen, antiestrogen, estrogen agonist, apurinic acid, ara relatively non-toxic, inorganic and organic base addition salts CDP-DL-PTBA, arginine deaminase, asulacrine, atames of the pharmaceutical agents. tane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3. 0.174 “Prodrugs are derivative compounds derivatized aZasetron, azatoxin, azatyrosine, baccatin III derivatives, bal by the addition of a group that endows greater solubility to the anol, BCR/ABL antagonists, benzochlorins, benzoylstauro compound desired to be delivered. Once in the body, the sporine, beta lactam derivatives, beta-alethine, betaclamycin prodrug is typically acted upon by an enzyme, e.g., an B, betulinic acid, bFGF inhibitor, bisaziridinylspermine, bis esterase, amidase, orphosphatase, to generate the active com tratene A, breflate, buthionine sulfoximine, calcipotriol, pound. calphostin C, carboxamide-amino-triazole, carboxyamidot 0.175. An “anti-cancer agent”, “anti-tumor agent” or “che riazole, CaRest M3, CARN 700, cartilage derived inhibitor, motherapeutic agent” refers to any agent useful in the treat casein kinase inhibitors (ICOS), castanospermine, cecropin ment of a neoplastic condition. There are many chemothera B, cetrorelix, chloroquinoxaline Sulfonamide, cicaprost, cis peutic agents available in commercial use, in clinical porphyrin, clomifene analogues, clotrimazole, collismycin evaluation and in pre-clinical development that are useful in A, collismycin B, combretastatin A4, combretastatin ana the devices and methods of the present invention for treatment logue, conagenin, crambescidin 816, cryptophycin 8, crypto of cancers. phycin A derivatives, curacin A, cyclopentanthraquinones, 0176). In some embodiments, a chemotherapeutic agent cycloplatam, cypemycin, cytolytic factor, cytostatin, daclix comprises at least one of an angiostatin, DNA topoisomerase, imab, dehydrodidemnin B, dexamethasone, dexifosfamide, endostatin, genistein, ornithine decarboxylase inhibitors, dexraZoxane, dexVerapamil, didemnin B, didox, diethylnor chlormethine, melphalan, pipobroman, triethylene spermine, dihydro-5-azacytidine, dihydrotaxol. 9-, dioxamy melamine, triethylenethiophosphoramine, buSulfan, carmus cin, docosanol, dolasetron, dronabinol, duocarmycin SA, tine (BCNU), Streptozocin, 6-mercaptopurine, 6-thiogua ebselen, ecomustine, edelfosine, edrecolomab, elemene, nine, Deoxyco-formycin, IFN-O, 17O-ethinylestradiol, emitefur, estramustine analogue, filgrastim, flavopiridol, fle diethylstilbestrol, testosterone, prednisone, fluoxymesterone, Zelastine, fluasterone, fluorodaunorunicin hydrochloride, for dromostanolone propionate, testolactone, megestrolacetate, fenimex, gadolinium texaphyrin, galocitabine, gelatinase methylprednisolone, methyl-testosterone, prednisolone, tri inhibitors, glutathione inhibitors, hepsulfam, heregulin, hex amcinolone, chlorotrianisene, hydroxyprogesterone, estra amethylene bisacetamide, hypericin, ibandronic acid, idra mustine, medroxyprogesteroneacetate, flutamide, Zoladex, mantone, ilomastat, imatinib (e.g., Gleevec), imiquimod, US 2010/0015200 A1 Jan. 21, 2010 22 immunostimulant peptides, insulin-like growth factor-1 phosphate, N-(2-furanidyl)-5-fluorouracil, Daiichi Seiyaku receptor inhibitor, interferon agonists, interferons, interleu FO-152, 5-FU-fibrinogen, isopropyl pyrrolizine, Lilly kins, iobenguane, iododoxorubicin, ipomeanol, 4-, iroplact, LY-188011, Lilly LY-264618, methobenzaprim, methotrex irsogladine, isobengaZole, isohomohalicondrin B, itasetron, ate, Wellcome MZPES, norspermidine, nolvadex, NCINSC jasplakinolide, kahalalide F, lamellarin-N triacetate, leina 127716, NCI NSC-264880, NCI NSC-39661, NCI NSC mycin, lenograstim, lentinan Sulfate, leptolstatin, leukemia 612567. Warner-Lambert PALA, pentostatin, piritrexim, inhibiting factor, leukocyte alpha interferon, leuprolide+es plicamycin, Asahi Chemical PL-AC, stearate, Takeda TAC trogen-progesterone, linear polyamine analogue, lipophilic 788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, disaccharide peptide, lipophilic platinum compounds, lisso tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, clinamide 7, lobaplatin, lombricine, loxoribine, lurtotecan, Taiho UFT, uricytin, Shionogi 254-S, aldo-phosphamide ana lutetium texaphyrin, lysofylline, lytic peptides, maitansine, logues, altretamine, anaxirone, Boehringer Mannheim BBR mannostatin A, marimastat, maspin, matrilysin inhibitors, 2207, bestrabucil, budotitane, Wakunaga CA-102, carbopl matrix metalloproteinase inhibitors, meterelin, methioni atin, carmustine (BiCNU), Chinoin-139, Chinoin-153, nase, metoclopramide, MIF inhibitor, mifepristone, miltefos chlorambucil, cisplatin, cyclophosphamide, American ine, mirimoStim, mitoguaZone, mitotoxin fibroblast growth Cyanamid CL-286558, Sanofi CY-233, cyplatate, dacarba factor-Saporin, mofarotene, molgramoStim, ErbituX, human zine, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphe chorionic gonadotrophin, monophosphoryl lipid A+myobac nylspiromustine, diplatinum cytostatic, Chugai DWA terium cell wall sk, mustard anticancer agent, mycaperoxide 2114R, ITI E09, elmustine, Erbamont FCE-24517, B, mycobacterial cell wall extract, myriaporone, N-acetyl estramustine phosphate Sodium, etoposide phosphate, fote dinaline, N-Substituted benzamides, nagrestip, naloxone-- mustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, pentazocine, napavin, naphterpin, nartograstim, nedaplatin, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, nemorubicin, neridronic acid, nisamycin, nitric oxide modu mycophenolate, Nippon Kayaku NK-121, NCINSC-264395, lators, nitroxide antioxidant, nitrullyn, oblimersen (Gena NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimus sense), O'-benzylguanine, okicenone, onapristone, tine, Proter PTT-119, ranimustine, semustine, SmithKline ondansetron, oracin, oral cytokine inducer, paclitaxel ana SK&F-101772, thiotepa, Yakult Honsha SN-22, spiromus logues and derivatives, palauamine, palmitoylrhizoxin, pam tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, idronic acid, panaxytriol, panomifene, parabactin, peldesine, teroxirone, tetraplatin and trimelamol, Taiho 4181-A, aclaru pentosan polysulfate Sodium, pentroZole, perflubron, perillyl bicin, actinomycin D, actinoplanone, Erbamont ADR-456, alcohol, phenazinomycin, phenylacetate, phosphatase inhibi aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto tors, picibanil, pilocarpine hydrochloride, placetin A, placetin AN-3, Nippon Soda anisomycins, anthracycline, azino-my B. plasminogen activator inhibitor, platinum complex, plati cin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers num compounds, platinum-triamine complex, propyl bis-ac BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers ridone, prostaglandin J2, proteasome inhibitors, protein BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers A-based immune modulator, protein kinase C inhibitors, BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, microalgal, pyrazoloacridine, pyridoxylated hemoglobin calichemycin, chromoximycin, dactinomycin, daunorubicin, polyoxyethylene conjugate, raf antagonists, raltitrexed, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko ramosetron, ras farnesyl protein transferase inhibitors, ras DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, GAP inhibitor, retelliptine demethylated, rhenium Re 186 ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubi etidronate, ribozymes, RII retinamide, rohitukine, romurtide, cin-fibrinogen, elsamicin-A, epirubicin, erbStatin, esorubi roquinimex, rubiginone B1, ruboxyl, Saintopin, SarCNU, sar cin, esperamicin-A1, esperamicin-A1b, Erbamont FCE cophytol A, Sargramostim, Sdi 1 mimetics, senescence 21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, derived inhibitor 1, signal transduction inhibitors, sizofiran, glidobactin, gregatin-A, grincamycin, herbimycin, idarubi Sobuzoxane, sodium borocaptate, solverol. Somatomedin cin, illudins, kaZusamycin, kesarirhodins, Kyowa Hakko binding protein, Sonermin, sparfosic acid, spicamycin D, KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko splenopentin, spongistatin 1, squalamine, stipiamide, KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, stromelysin inhibitors, sulfinosine, Superactive vasoactive American Cyanamid LL-D49194, Meiji Seika ME 2303, intestinal peptide antagonist, Suradista, Suramin, Swainso menogaril, mitomycin, mitomycin analogues, mitoxantrone, nine, tallimustine, tazarotene, tellurapyrylium, telomerase SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, inhibitors, tetrachlorodecaoxide, tetraZomine, thiocoraline, Nippon Kayaku NKT-01, SRI International NSC-357704, thrombopoietin, thrombopoietin mimetic, thymalfasin, thy oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, mopoietin receptoragonist, thymotrinan, thyroid stimulating porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, hormone, tin ethyl etiopurpurin, titanocene bichloride, rhizoxin, rodorubicin, Sibanomicin, Siwenmycin, Sumitomo top sentin, translation inhibitors, tretinoin, triacetyluridine, SM-5887, Snow Brand SN-706, Snow Brand SN-07, Soran tropisetron, turosteride, ubenimex, urogenital sinus-derived gicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS growth inhibitory factor, variolin B. velaresol, Veramine, ver Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, dins, vinxaltine, Vitaxin, Zanoterone, Zilascorb, Zinostatin Sti Steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN malamer, acanthifolic acid, aminothiadiazole, anastrozole, 868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, bicalutamide, brequinar Sodium, capecitabine, carmofur, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Ciba-Geigy CGP-30694, cladribine, cyclopentyl cytosine, Y-25024, Zorubicin, 5-fluorouracil (5-FU), the peroxidate cytarabine phosphate Stearate, cytarabine conjugates, cytara oxidation product of inosine, adenosine, or cytidine with bine ocfosfate, Lilly DATHF, Merrel Dow DDFC, dezagua methanol or ethanol, cytosine arabinoside (also referred to as nine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi Cytarabin, araC, and Cytosar), 5-AZacytidine, 2-Fluoroad DMDC, doxifluridine, Wellcome EHNA, Merck & Co. enosine-5'-phosphate (Fludara, also referred to as FaraA), EX-015, fazarabine, floxuridine, fludarabine, fludarabine 2-Chlorodeoxyadenosine, Abarelix, Abbott A-84861, Abi US 2010/0015200 A1 Jan. 21, 2010 raterone acetate, Aminoglutethimide, Asta Medica AN-207, Cyanamid L-623, leucovorin, levamisole, leukoregulin, Antide, Chugai AG-041R, AVorelin, aseranox, Sensus lonidamine, Lundbeck LU-23-112, Lilly LY-186641, B2036-PEG, buserelin, BTG CB-7598, BTG CB-7630, Materna, NCI (US) MAP. marycin, Merrel Dow MDL Casodex, cetrolix, clastroban, clodronate disodium, CoSu 27048, Medco MEDR-340, megestrol, merbarone, merocya dex, Rotta Research CR-1505, cytadren, crinone, deslorelin, nine derivatives, methylanilinoacridine, Molecular Genetics droloxifene, dutasteride, Elimina, Laval University EM-800, MGI-136, minactivin, mitonafide, mitocquidone, Monocal, Laval University EM-652, epitiostanol, epristeride, mopidamol, motretinide, Zenyaku Kogyo MST-16, Mylanta, Mediolanum EP-23904, EntreMed 2-ME, exemestane, N-(retinoyl)amino acids, Nilandron, Nisshin Flour Milling fadrozole, finasteride, formestane, Pharmacia & Upjohn N-021, N-acylated-dehydroalanines, nafazatrom, Taisho FCE-24304, ganirelix, goserelin, Shire gonadorelin agonist, NCU-190, Nephro-Calcitablets, nocodazole derivative, Nor mosang, NCI NSC-145813, NCI NSC-361456, NCI NSC GlaxoWellcome GW-5638, Hoechst Marion Roussel Hoe 604782, NCI NSC-95580, octreotide, Ono ONO-112, odui 766, NCI hCG, idoxifene, isocordoin, Zeneca ICI-182780, Zanocine, Akzo Org-10172, paclitaxel, pancratistatin, Zeneca ICI-118630, Tulane University J015X, Schering Ag pazelliptine, Warner-Lambert PD-11 1707, Warner-Lambert J96, ketanserin, lanreotide, Milkhaus LDI-200, letrozol, leu PD-115934, Warner-Lambert PD-131141, Pierre Fabre prolide, leuprorelin, liarozole, lisuride hydrogen maleate, PE-1001, ICRT peptide D, piroxantrone, polyhaematopor loxiglumide, mepitioStane, Ligand Pharmaceuticals phyrin, polypreic acid, Efamol porphyrin, probimane, procar LG-1127, LG-1447, LG-2293, LG-2527, LG-2716, Bone bazine, proglumide, Invitron protease nexin I, Tobishi Care International LR-103, Lilly LY-326315, Lilly RA-700, razoxane, retinoids, R-flurbiprofen (Encore Phar LY-353381-HCl, Lilly LY-326391, Lilly LY-353381, Lilly maceuticals), Sandostatin, Sapporo Breweries RBS, restric LY-357489, miproxifene phosphate, Orion Pharma MPV tin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, 2213ad, Tulane University MZ-4-71, nafarelin, nilutamide, Rhone-Poulenc RP-56976, Scherring-Plough SC-57050, Snow Brand NKS01, AZko Nobel ORG-31710, AZko Nobel Scherring-Plough SC-57068, selenium (selenite and sele ORG-31806, orimeten, orimetene, orimetime, ormeloxifene, nomethionine), SmithKline SK&F-104864, Sumitomo osaterone, Smithkline Beecham SKB-105657, Tokyo Uni SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, versity OSW-1, Peptech PTL-03001, Pharmacia & Upjohn spirocyclopropane derivatives, spirogermanium, Unimed, SS PNU-156765, quinagolide, ramorelix, Raloxifene, statin, Pharmaceutical SS-554, Strypoldinone, Stypoldione, Suntory sandostatin LAR, Shionogi S-10364, Novartis SMT-487. SUN 0237, Suntory SUN 2071, Sugen SU-101, Sugen Somavert, Somatostatin, tamoxifen, tamoxifen methiodide, SU-5416, SugenSU-6668, Sulindac, sulindac sulfone, super teverelix, toremifene, triptorelin, TT-232, vapreotide, voro oxide dismutase, Toyama T-506, Toyama T-680, taxol. Teijin Zole, Yamanouchi YM-116, Yamanouchi YM-511, Yamanou TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, chi YM-55208, Yamanouchi YM-53789, Schering AG tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, ZK-1911703, Schering AG ZK-230211, and Zeneca ZD-182780, alpha-carotene, alpha-difluoromethyl-arginine, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amona vinblastine, vinblastine sulfate, Vincristine, Vincristine sul fide, amphethinile, amsacrine, Angiostat, ankinomycin, anti fate, vindesine, Vindesine Sulfate, vinestramide, Vinorelbine, neoplaston A10, antineoplaston A2, antineoplaston A3, anti vintriptol, Vinzolidine, withanolides, Yamanouchi YM-534, neoplaston A5, antineoplaston AS2-1, Henkel APD, Zileuton, urSodeoxycholic acid, Zanosar. aphidicolinglycinate, asparaginase, Avarol, baccharin, batra 0177 Chemotherapeutic agents and dosing recommenda cylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, tions for treating specific diseases, are described at length in bisantrene, Bristo-Myers BMY-40481, Vestarboron-10, bro the literature, e.g., in U.S. Pat. No. 6,858,598, “Method of mofosfamide, Wellcome BW-502, Wellcome BW-773, cal Using a Matrix Metalloproteinase Inhibitor and One or More cium carbonate, Calcet, Calci-Chew, Calci-Mix, Roxane cal Antineoplastic Agents as a Combination Therapy in the Treat cium carbonate tablets, caracemide, carmethizole ment of Neoplasia” and U.S. Pat. No. 6,916,800, “Combina hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, tion Therapy Including a Matrix Metalloproteinase Inhibitor Chemes CHX-2053, Chemex CHX-100, Warner-Lambert and an Antineoplastic Agent, both incorporated herein by CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, reference in their entirety. Warner-Lambert CI-958, clanfenur, claviridenone, ICN com 0.178 Methods for the safe and effective administration of pound 1259, ICN compound 4711, Contracan, Cell Pathways chemotherapeutic agents are known to those skilled in the art. CP-461, Yakult Honsha CPT-11, crisinatol, curaderm, In addition, their administration is described in the standard cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS literature. For example, the administration of many chemo maleate, datelliptinium, DFMO, didemnin-B, dihaematopor therapeutic agents is described in the “Physicians’ Desk Ref phyrin ether, dihydrolenperone dinaline, distamycin, Toyo erence” (PDR), e.g., 1996 edition (Medical Economics Com Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku pany, Montvale, N.J.07645-1742, USA), incorporated herein DN-9693, docetaxel, Encore Pharmaceuticals E7869, ellip by reference. rabin, elliptinium acetate, Tsumura EPMTC, ergotamine, 0179 Combinations of two or more agents can be used in etoposide, etretinate, Eulexin, Cell Pathways Exisulind the devices and methods of the invention. Guidance for (sulindac sulphone or CP-246), fenretinide, Florical, selecting drug combinations forgiven indications is provided Fujisawa FR-57704, gallium nitrate, gemcitabine, genkw in the published literature, e.g., in the “Drug Information adaphnin, Gerimed, Chugai GLA-43, Glaxo GR-63178, gri Handbook for Oncology: A Complete Guide to Combination folan NMF-5N, hexadecylphosphocholine, Green Cross Chemotherapy Regimens' (edited by Dominic A. Solimando, HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, Jr., MA BCOP: published by Lexi-Comp, Hudson, Ohio, ilmofosine, irinotecan, isoglutamine, isotretinoin, Otsuka 2007. ISBN 978-1-59195-175-9), as well as in U.S. Pat. No. JI-36, Ramot K-477, ketoconazole, Otsuak K-76COONa, 6,858.598. Specific combinations of chemotherapeutic Kureha Chemical K-AM, MECT Corp KI-8110, American agents having enhanced activity relative to the individual US 2010/0015200 A1 Jan. 21, 2010 24 agents, are described in, e.g., WO 02/40702, “Methods for the Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitox Treatment of Cancer and Other Diseases and Methods of antrone, Levamisole, and Hexamethylmelamine. Developing the Same, incorporated herein by reference in its 0188 Chemotherapeutic agents can also be classified by entirety. WO 02/.40702 reports enhanced activity when treat chemical family, for example, therapeutic agents selected ing cancer using a combination of a platin-based compound from Vinca alkaloids (e.g., vinblastine, Vincristine, and (e.g., cisplatin, oxoplatin), a folate inhibitor (e.g., MTA, Vinorelbine), taxanes (e.g., paclitaxel and docetaxel), indolyl ALIMTA, LY231514), and deoxycytidine or an analogue 3-glyoxylic acid derivatives, (e.g., indibulin), epidipodophyl thereof (e.g., cytarabin, gemcitabine). lotoxins (e.g., etoposide, teniposide), antibiotics (e.g., dacti 0180 Chemotherapeutic agents can be classified into vari nomycin or actinomycin D, daunorubicin, doxorubicin and ous groups, e.g., ACE inhibitors, alkylating agents, angiogen idarubicin), anthracyclines, mitoxantrone, bleomycins, plica esis inhibitors, anthracyclines/DNA intercalators, anti-cancer mycin (mithramycin) and mitomycin, enzymes (L-asparagi antibiotics orantibiotic-type agents, antimetabolites, antime nase which systemically metabolizes L-asparagine and tastatic compounds, asparaginases, bisphosphonates, c0MP deprives cells which do not have the capacity to synthesize phosphodiesterase inhibitors, cyclooxygenase-2 inhibitors their own asparagine); antiplatelet agents; antiproliferative/ DHA derivatives, epipodophylotoxins, hormonal anticancer antimitotic alkylating agents such as nitrogen mustards (e.g., agents, hydrophilic bile acids (URSO), immunomodulators mechlorethamine, ifosphamide, cyclophosphamide and ana or immunological agents, integrin antagonists, interferon logs, melphalan, chlorambucil), ethylenimines and meth antagonists or agents, MMP inhibitors, monoclonal antibod ylmelamines (e.g., hexamethylmelamine and thiotepa), alkyl ies, nitrosoureas, NSAIDs, ornithine decarboxylase inhibi sulfonates (busulfan), nitrosoureas (e.g., carmustine (BCNU) tors, radio/chemo sensitizers/protectors, retinoids, selective and analogs, streptozocin), traZenes-dacarbazinine (DTIC); inhibitors of proliferation and migration of endothelial cells, antiproliferative/antimitotic antimetabolites such as folic Selenium, Stromelysin inhibitors, taxanes, vaccines, and acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., Vinca alkaloids. fluorouracil, floXuridine, and cytarabine), purine analogs and 0181 Alternatively, chemotherapeutic agents can be clas related inhibitors (e.g., mercaptopurine, thioguanine, pen sified by target, e.g., agents can be selected from a tubulin to statin and 2-chlorodeoxyadenosine); aromatase inhibitors binding agent, a kinase inhibitor (e.g., a receptor tyrosine (e.g., anastrozole, exemestane, and letrozole); and platinum kinase inhibitor), an anti-metabolic agent, a DNA synthesis coordination complexes (e.g., cisplatin, carboplatin), procar inhibitor, and a DNA damaging agent. bazine, hydroxyurea, mitotane, aminoglutethimide; hor 0182. Other classes into which chemotherapeutic agents mones (e.g., estrogen) and hormone agonists such as leuti can be divided include: alkylating agents, antimetabolites, nizing hormone releasing hormone (LHRH) agonists (e.g., natural products and their derivatives, hormones and steroids goserelin, leuprolide and triptorelin). (including synthetic analogs), and synthetics. Examples of 0189 Antineoplastic agents are often placed into catego compounds within these classes are given herein. ries, including antimetabolite agents, alkylating agents, anti 0183 Alkylating agents (e.g., nitrogen mustards, ethylen biotic-type agents, hormonal anticancer agents, immunologi imine derivatives, alkyl Sulfonates, nitrosoureas and triaz cal agents, interferon-type agents, and a category of enes) include Uracil mustard, Chlormethine, Cyclophospha miscellaneous antineoplastic agents. Some antineoplastic mide (Cytoxan), Ifosfamide, Melphalan, Chlorambucil, agents operate through multiple or unknown mechanisms and Pipobroman, Triethylene-melamine, Triethylenethiophos can thus be classified into more than one category. phoramine, BuSulfan, Carmustine, Lomustine, Streptozocin, 0190. A first family of antineoplastic agents which may be Dacarbazine, and Temozolomide. used in combination with the present invention consists of 0184 Antimetabolites (e.g., folic acid antagonists, pyri antimetabolite-type antineoplastic agents. Antimetabolites midine analogs, purine analogs and adenosine deaminase are typically reversible or irreversible enzyme inhibitors, or inhibitors) include Methotrexate, 5-Fluorouracil, Floxuri compounds that otherwise interfere with the replication, dine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Flu translation or transcription of nucleic acids. Suitable antime darabine phosphate, Pentostatine, and Gemcitabine. tabolite antineoplastic agents that may be used in the present invention include, but are not limited to acanthifolic acid, 0185 Natural products and their derivatives (e.g., vinca aminothiadiazole, anastrozole, bicalutamide, brequinar alkaloids, antitumor antibiotics, enzymes, lymphokines and sodium, capecitabine, carmofur, Ciba-Geigy CGP-30694, epipodophyllotoxins) include Vinblastine, Vincristine, Vin cladribine, cyclopentyl cytosine, cytarabine phosphate Stear desine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubi ate, cytarabine conjugates, cytarabine ocfosfate, Lilly cin, Epirubicin, Idarubicin, paclitaxel (paclitaxel is commer DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, cially available as Taxol), Mithramycin, Deoxyco-formycin, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Mitomycin-C. L-Asparaginase, Interferons (especially IFN Wellcome EHNA, Merck & Co. EX-015, fazarabine, finas O), Etoposide, and Teniposide. teride, floxuridine, fludarabine, fludarabine phosphate, N-(2'- 0186 Hormones and steroids (e.g., synthetic analogs) furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, fluorou include 17 O.-Ethinylestradiol, Diethylstilbestrol, Testoster racil (5-FU), 5-FU-fibrinogen, isopropyl pyrrolizine, Lilly one, Prednisone, Fluoxymesterone, Dromostanolone propi LY-188011, Lilly LY-264618, methobenzaprim, methotrex onate, Testolactone, Megestrolacetate, Tamoxifen, Methyl ate, Wellcome MZPES, nafarelin, norspermidine, nolvadex, prednisolone, Methyl-testosterone, Prednisolone, NCINSC-127716, NCINSC-264880, NCINSC-39661, NCI Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, NSC-612567, Warner-Lambert PALA, pentostatin, piritr Aminoglutethimide, Estramustine, Medroxyprogesteroneac exim, plicamycin, Asahi Chemical PL-AC, Stearate; Takeda etate, Leuprolide, Flutamide, Toremifene, Zoladex. TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrex 0187 Synthetics (e.g., inorganic complexes such as plati ate, tyrosine kinase inhibitors, tyrosine protein kinase inhibi num coordination complexes) include Cisplatin, Carboplatin, tors, Taiho UFT, toremifene, and uricytin. US 2010/0015200 A1 Jan. 21, 2010

0191 Antimetabolite agents that may be used in the neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT present invention include, but are not limited to, those iden 01, SRI International NSC-357704, oxalysine, oxaunomycin, tified in Table No. 5 of U.S. Pat. No. 6,858,598, incorporated peplomycin, pilatin, pirarubicin, porothramycin, pyrindamy herein by reference. cin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, Siba 0.192 A second family of antineoplastic agents which may nomicin, siwenmycin, Sumitomo SM-5887, Snow Brand be used in combination with the present invention consists of SN-706, Snow Brand SN-07, Sorangicin-A, sparsomycin, SS alkylating-type antineoplastic agents. The alkylating agents Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS are believed to act by alkylating and cross-linking guanine Pharmaceutical SS-9816B, Steffimycin B, Taiho. 4181-2, tali and possibly other bases in DNA, arresting cell division. somycin, Takeda TAN-868A, terpentecin, thrazine, tric Typical alkylating agents include nitrogen mustards, ethyl rozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, eneimine compounds, alkyl Sulfates, cisplatin, and various Fujisawa WF-3405, YoshitomiY-25024 and Zorubicin. nitrosoureas. A disadvantage with these compounds is that they not only attack malignant cells, but also other cells which 0.195 Preferred antibiotic anticancer agents that may be are naturally dividing. Such as those of bone marrow, skin, used in the present invention include, but are not limited to, gastro-intestinal mucosa, and fetal tissue. Suitable alkylating those identified in Table No. 7 of U.S. Pat. No. 6,858,598, type antineoplastic agents that may be used in the present incorporated herein by reference. invention include, but are not limited to, Shionogi 254-S, 0196. A fourth family of antineoplastic agents which may aldo-phosphamide analogues, altretamine, anaxirone, Boe be used in combination with the present invention consists of hiringer Mannheim BBR-2207, bestrabucil, budotitane, synthetic nucleosides. Several synthetic nucleosides have Wakunaga CA-102, carboplatin, carmustine (BiCNU), Chi been identified that exhibit anticancer activity. A well known noin-139, Chinoin-153, chlorambucil, cisplatin, cyclophos nucleoside derivative with strong anticancer activity is phamide, American Cyanamid CL-286558, Sanofi CY-233, 5-fluorouracil (5-FU). 5-Fluorouracil has been used clinically cyplatate, dacarbazine, Degussa D-19-384, Sumimoto in the treatment of malignant tumors, including, for example, DACHP(Myr)2, diphenylspiromustine, diplatinum cyto carcinomas, sarcomas, skin cancer, cancer of the digestive static, Erba distamycin derivatives, Chugai DWA-2114R, ITI organs, and breast cancer. 5-Fluorouracil, however, causes E09, elmustine, Erbamont FCE-24517, estramustine phos phate sodium, etoposide phosphate, fotemustine, Unimed serious adverse reactions such as nausea, alopecia, diarrhea, G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, ipro stomatitis, leukocytic thrombocytopenia, anorexia, pigmen platin, lomustine, mafosfamide, mitolactol, mycophenolate, tation, and edema. Derivatives of 5-fluorouracil with anti Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC cancer activity have been described in U.S. Pat. No. 4,336, 342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter 381. Further 5-FU derivatives have been described in the PTT-119, ranimustine, semustine, SmithKline SK&F- following patents identified in Table No. 8 of U.S. Pat. No. 101772, thiotepa, Yakult Honsha SN-22, spiromus-tine, 6,858.598, incorporated herein by reference. Tanabe Seiyaku TA-077, tauromustine, temozolomide, terox (0197) U.S. Pat. No. 4,000,137 discloses that the peroxi irone, tetraplatin and trimelamol. date oxidation product of inosine, adenosine, or cytidine with 0193 Preferred alkylating agents that may be used in the methanol or ethanol has activity against lymphocytic leuke present invention include, but are not limited to, those iden mia. Cytosine arabinoside (also referred to as Cytarabin, tified in those identified in Table No. 6 of U.S. Pat. No. araC, and Cytosar) is a nucleoside analog of deoxycytidine 6,858,598, incorporated herein by reference. that was first synthesized in 1950 and introduced into clinical 0.194. A third family of antineoplastic agents which may medicine in 1963. It is currently an important drug in the be used in combination with the present invention consists of treatment of acute myeloid leukemia. It is also active against antibiotic-type antineoplastic agents. Suitable antibiotic-type acute lymphocytic leukemia, and to a lesser extent, is useful antineoplastic agents that may be used in the present inven in chronic myelocytic leukemia and non-Hodgkin's lym tion include, but are not limited to Taiho 4181-A, aclarubicin, phoma. The primary action of araC is inhibition of nuclear actinomycin D, actinoplanone, Erbamont ADR-456, aeropl DNA synthesis. Handschumacher, R. and Cheng, Y., “Purine ysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, and Pyrimidine Antimetabolites, Cancer Medicine, Chapter Nippon Soda anisomycins, anthracycline, azino-mycin-A, XV-1, 3rd Edition, Edited by J. Holland, et al., Lea and bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY Febigol, publishers. 25067, Bristol-Myers BMY-25551, Bristol-Myers BMY 0198 5-AZacytidine is a cytidine analog that is primarily 26605, Bristol-Myers BMY-27557, Bristol-Myers BMY used in the treatment of acute myelocytic leukemia and 28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, myelodysplastic syndrome. calichemycin, chromoximycin, dactinomycin, daunorubicin, 0199 2-Fluoroadenosine-5'-phosphate (Fludara, also Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko referred to as Fara.A) is one of the most active agents in the DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, treatment of chronic lymphocytic leukemia. The compound ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubi acts by inhibiting DNA synthesis. Treatment of cells with cin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubi F-araA is associated with the accumulation of cells at the cin, esperamicin-A1, esperamicin-A1b, Erbamont FCE G1/S phase boundary and in S phase; thus, it is a cell cycle S 21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, phase-specific drug. InCorp of the active metabolite, glidobactin, gregatin-A, grincamycin, herbimycin, idarubi F-ara ATP retards DNA chain elongation. F-ara A is also a cin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko potent inhibitor of ribonucleotide reductase, the key enzyme KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko responsible for the formation of dATP 2-Chlorodeoxyad KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, enosine is useful in the treatment of low grade B-cell neo American Cyanamid LL-D49194, Meiji Seika ME 2303, plasms such as chronic lymphocytic leukemia, non menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, Hodgkins' lymphoma, and hairy-cell leukemia. The spectrum US 2010/0015200 A1 Jan. 21, 2010 26 ofactivity is similar to that of Fludara. The compound inhibits CP-461, Yakult Honsha CPT-11, crisinatol, curaderm, DNA synthesis in growing cells and inhibits DNA repair in cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS resting cells. maleate, dacarbazine, datelliptinium, DFMO, didemnin-B, 0200. A fifth family of antineoplastic agents which may be dihaematoporphyrin ether, dihydrolenperone dinaline, dista used in combination with the present invention consists of mycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Dai hormonal agents. Suitable hormonal-type antineoplastic chi Seiyaku DN-9693, docetaxel, Encore Pharmaceuticals agents that may be used in the present invention include, but E7869, elliprabin, elliptinium acetate, Tsumura EPMTC, are not limited to Abarelix; Abbott A-84861; Abiraterone ergotamine, etoposide, etretinate, Eulexin, Cell Pathways acetate; Aminoglutethimide; anastrozole; Asta Medica Exisulind (sulindac sulphone or CP-246), fenretinide, Merck AN-207; Antide; Chugai AG-041R; AVorelin; aseranox: Sen Research Labs Finasteride, Florical, Fujisawa FR-57704, gal sus B2036-PEG. Bicalutamide; buserelin; BTG CB-7598, lium nitrate, gemcitabine, genkwadaphnin, Gerimed, Chugai BTG CB-7630; Casodex; cetrolix; clastroban; clodronate GLA-43, Glaxo GR-63178, grifolan NMF-5N, hexade disodium; Cosudex; Rotta Research CR-1505; cytadren: cylphosphocholine, Green Cross HO-221, homoharringto crinone; deslorelin; droloxifene; dutasteride; Elimina; Laval University EM-800; Laval University EM-652: epitiostanol: nine, hydroxyurea, BTG ICRF-187, ilmofosine, irinotecan, epristeride; Mediolanum EP-23904; EntreMed 2-ME: isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, keto exemestane; fadrozole; finasteride; flutamide; formestane; conazole, Otsuak K-76COONa, Kureha Chemical K-AM, Pharmacia & Upjohn FCE-24304; ganirelix; goserelin; Shire MECT Corp KI-81 10, American Cyanamid L-623, leucov gonadorelin agonist; Glaxo Wellcome GW-5638; Hoechst orin, levamisole, leukoregulin, lonidamine, Lundbeck Marion Roussel Hoe-766; NCI hCG, idoxifene; isocordoin; LU-23-112, Lilly LY-186641, Materna, NCI (US) MAP. Zeneca ICI-182780; Zeneca ICI-118630; Tulane University marycin, Merrel Dow MDL-27048, Medco MEDR-340, JO15X; Schering Ag J96; ketanserin; lanreotide; Milkhaus megestrol, merbarone, merocyanine derivatives, methylanili LDI-200; letrozol; leuprolide; leuprorelin; liarozole; lisuride noacridine, Molecular Genetics MGI-136, minactivin, hydrogen maleate; loxiglumide; mepitioStane; Leuprorelin; mitonafide, mitoquidone, Monocal, mopidamol, motretinide, Ligand Pharmaceuticals LG-1127; LG-1447; LG-2293; Zenyaku Kogyo MST-16, Mylanta, N-(retinoyl)amino acids, LG-2527; LG-2716; Bone Care International LR-103: Lilly Nilandron; Nisshin Flour Milling N-021, N-acylated-dehy LY-326315; Lilly LY-353381-HCl; Lilly LY-326391; Lilly droalanines, nafazatrom, Taisho NCU-190, Nephro-Calci LY-353381; Lilly LY-357489; miproxifene phosphate: Orion tablets, nocodazole derivative, Normosang, NCI NSC Pharma MPV-2213ad; Tulane University MZ-4-71; nafare 145813, NCI NSC-361456, NCI NSC-604782, NCI NSC lin; nilutamide; Snow Brand NKS01; octreotide; Azko Nobel 95580, octreotide, Ono ONO-112, oduizanocine, Akzo Org ORG-31710; Azko Nobel ORG-31806; orimeten; orimetene: 10172, paclitaxel, pancratistatin, pazelliptine, Warner orimetine; ormeloxifene; osaterone; Smithkline Beecham Lambert PD-11 1707, Warner-Lambert PD-115934, Warner SKB-105657; Tokyo University OSW-1: Peptech PTL Lambert PD-131141, Pierre Fabre PE-IO01, ICRT peptide D, 03001: Pharmacia & Upjohn PNU-156765; quinagolide: piroXantrone, polyhaematoporphyrin, polypreic acid, Efamol ramorelix; Raloxifene; statin; Sandostatin LAR; Shionogi porphyrin, probimane, procarbazine, proglumide, Invitron S-10364; Novartis SMT-487; somavert; somatostatin; tamox protease nexin I, Tobishi RA-700, razoxane, retinoids, R-flur ifen; tamoxifen methiodide; teverelix; toremifene; triptore biprofen (Encore Pharmaceuticals), Sandostatin: Sapporo lin; TT-232; vapreotide; Vorozole: Yamanouchi YM-116; Breweries RBS, restrictin-P retelliptine, retinoic acid, Yamanouchi YM-511; Yamanouchi YM-55208; Yamanouchi Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, YM-53789; Schering AG ZK-1911703: Schering AG Scherring-Plough SC-57050, Scherring-Plough SC-57068, ZK-23021 1; and Zeneca ZD-182780. selenium(selenite and selenomethionine), SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, 0201 Preferred hormonal agents that may be used in the SeaPharm SP-10094, spatol, spirocyclopropane derivatives, present invention include, but are not limited to, those iden spirogermanium, Unimed, SS Pharmaceutical SS-554, stry tified in Table No. 9 of U.S. Pat. No. 6,858,598, incorporated poldinone, Stypoldione, Suntory SUN 0237, Suntory SUN herein by reference. 2071, Sugen SU-101, Sugen SU-5416, Sugen SU-6668, 0202) A sixth family of antineoplastic agents which may Sulindac, Sulindac Sulfone; Superoxide dismutase, Toyama be used in combination with the present invention consists of T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, a miscellaneous family of antineoplastic agents including, but thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, not limited to alpha-carotene, alpha-difluoromethyl-arginine, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amona fide, amphethinile, amsacrine, Angiostat, ankinomycin, anti 1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, neoplaston A10, antineoplaston A2, antineoplaston A3, anti Vincristine, Vindesine, vinestramide, Vinorelbine, Vintriptol, neoplaston A5, antineoplaston AS2-1, Henkel APD, Vinzolidine, withanolides, Yamanouchi YM-534, Zileuton, aphidicolinglycinate, asparaginase, Avarol, baccharin, batra urSodeoxycholic acid, and Zanosar. cylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, 0203 Preferred miscellaneous agents that may be used in bisantrene, Bristo-Myers BMY-40481, Vestarboron-10, bro the present invention include, but are not limited to, those mofosfamide, Wellcome BW-502, Wellcome BW-773, cal identified in (the second) Table No. 6 of U.S. Pat. No. 6,858, cium carbonate, Calcet, Calci-Chew, Calci-Mix, Roxane cal 598, incorporated herein by reference. cium carbonate tablets, caracemide, carmethizole 0204] Some additional preferred antineoplastic agents hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, include those described in the individual patents listed in U.S. Chemes CHX-2053, Chemex CHX-100, Warner-Lambert Pat. No. 6,858,598 in (the second) Table No. 7, and are hereby CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, individually incorporated by reference. Warner-Lambert CI-958, clanfenur, claviridenone, ICN com 0205. In embodiments, the agent delivered by the balloon pound 1259, ICN compound 4711, Contracan, Cell Pathways is a radiosensitizer, administered prior to radiation therapy. US 2010/0015200 A1 Jan. 21, 2010 27

Radiosensitizers increase sensitivity to radiation, thereby 0209 For treatment of abcesses, commonly caused by allowing reduction of the radiation dosage. Staphylococcus aureus bacteria, use of an anti-staphylococ 0206. An “antibiotic agent, as used herein, is a substance cus antibiotic Such as flucloxacillin or dicloxacillin is con or compound that kills bacteria (i.e., is bacteriocidal) or inhib templated. With the emergence of community-acquired its the growth of bacteria (i.e., is bacteriostatic). methicillin-resistant staphylococcus aureus MRSA, these tra 0207 Antibiotics that can be used in the devices and meth ditional antibiotics may be ineffective; alternative antibiotics ods of the present invention include, but are not limited to, effective against community-acquired MRSA often include amikacin, amoxicillin, gentamicin, kanamycin, neomycin, clindamycin, trimethoprim-sulfamethoxazole, and doxycy netilmicin, paromomycin, tobramycin, geldanamycin, herbi cline. These antibiotics may also be prescribed to patients mycin, carbacephem (loracarbef), ertapenem, doripenem, with a documented allergy to penicillin. If the condition is imipenem, cefadroxil, cefazolin, cefalotin, cephalexin, cefa thought to be cellulitis rather than abscess, consideration clor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, should be given to possibility of strep species as cause that are cefdinir, cefditoren, cefoperaZone, cefotaxime, cefpodoxime, still sensitive to traditional anti-staphylococcus agents such ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, as dicloxacillin or cephalexin in patients able to tolerate peni ceftobiprole, clarithromycin, clavulanic acid, clindamycin, cillin. teicoplanin, azithromycin, dirithromycin, erythromycin, 0210 Anti-thrombotic agents are contemplated for use in troleandomycin, tellithromycin, aztreonam, ampicillin, the methods of the invention in adjunctive therapy for treat aZlocillin, bacampicillin, carbenicillin, cloxacillin, diclox ment of coronary Stenosis. The use of anti-platelet drugs, e.g., acillin, flucloxacillin, mezlocillin, meticillin, nafcillin, nor to prevent platelet binding to exposed collagen, is contem floxacin, oxacillin, penicillin G, penicillin V, piperacillin, plated for anti-restenotic or anti-thrombotic therapy. Anti pvampicillin, pivmecillinam, ticarcillin, bacitracin, colistin, platelet agents include “GpIIb/IIIa inhibitors” (e.g., abcix polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levof imab, eptifibatide, tirofiban, RheoPro) and ADP receptor loxacin, lomefloxacin, moxifloxacin, ofloxacin, trovafloxa blockers' (prasugrel, clopidogrel, ticlopidine). Particularly cin, grepafloxacin, sparfloxacin, afenide, prontosil, Sulfaceta useful for local therapy are dipyridamole, which has local mide, Sulfamethizole, Sulfanilimide, Sulfamethoxazole, vascular effects that improve endothelial function (e.g., by Sulfisoxazole, trimethoprim, trimethoprim-sulfamethox causing local release of t-PA, that will break up clots or azole, demeclocycline, doxycycline, oxytetracycline, tetra prevent clot formation) and reduce the likelihood of platelets cycline, arsphenamine, chloramphenicol, lincomycin, and inflammatory cells binding to damaged endothelium, and ethambutol, fosfomycin, furazolidone, isoniazid, linezolid, cAMP phosphodiesterase inhibitors, e.g., cilostazol, that mupirocin, nitrofurantoin, platensimycin, pyrazinamide, could bind to receptors on either injured endothelial cells or quinupristin?dalfopristin, rifampin, thiamphenicol, rifampi bound and injured platelets to prevent further platelet bind cin, minocycline, Sultamicillin, Sulbactam, Sulphonamides, 1ng mitomycin, spectinomycin, spiramycin, roXithromycin, and 0211. The methods of the invention are useful for encour meropenem. aging migration and proliferation of endothelial cells from 0208 Antibiotics can also be grouped into classes of adjacent vascular domains to “heal’ the damaged endothe related drugs, for example, aminoglycosides (e.g., amikacin, lium and/or encourage homing and maturation of blood gentamicin, kanamycin, neomycin, netilmicin, paromomy borne endothelial progenitor cells to the site of injury. There cin, Streptomycin, tobramycin), ansamycins (e.g., geldana is evidence that both rapamycin and paclitaxel prevent endot mycin, herbimycin), carbacephem (loracarbef) carbapenems helial cell growth and reduce the colonization and maturation (e.g., ertapenem, doripenem, imipenem, meropenem), first of endothelial progenitor cells (EPCs) making both drugs generation cephalosporins (e.g., cefadroxil, cefazolin, cefa anti-healing. While local delivery of growth factors could lotin, cefalexin), second generation cephalosporins (e.g., accelerate endothelial cell regrowth, virtually all of these cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime), agents are equally effective at accelerating the proliferation of third generation cephalosporins (e.g., cefixime, cefdinir, vascular Smooth muscle cells, which can cause restenosis. cefditoren, cefoperaZone, cefotaxime, cefpodoxime, ceftazi VEGF is also not selective for endothelial cells but can cause dime, ceftibuten, ceftizoxime, ceftriaxone), fourth generation proliferation of smooth muscle cells. To make VEGF more cephalosporins (e.g., cefepime), fifth generation cepha selective for endothelial cells it can be combined with a pro losporins (e.g., ceftobiprole), glycopeptides (e.g., teicopla teoglycan like heparan Sulfate or chondroitin Sulfate or even nin, Vancomycin), macrollides (e.g., azithromycin, clarithro with an elongated “RGD'peptide binding domain. This may mycin, dirithromycin, erythromycin, roXithromycin, sequesterit away from the actual lesion site but still allow it to troleandomycin, tellithromycin, spectinomycin), monobac dissociate and interact with nearby endothelial cells. The use tams (e.g., aztreonam), penicillins (e.g., amoxicillin, ampi of CD34 antibodies and other specific antibodies, which bind cillin, azlocillin, bacampicillin, carbenicillin, cloxacillin, to the surface of blood borne progenitor cells, can be used to dicloxacillin, flucloxacillin, mezlocillin, meticillin, nafcillin, attract endothelial progenitor cells to the vessel wall to poten oxacillin, penicillins G and V, piperacillin, pvampicillin, piv tial accelerate endothelialization. mecillinam, ticarcillin), polypeptides (e.g., bacitracin, colis 0212 Statins (e.g., cerivastatin, etorvastatin), which can tin, polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, have endothelial protective effects and improve progenitor gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nor cell function, are contemplated for use in embodiments of floxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxa methods and/or devices provided herein. Other drugs that cin, trovafloxacin), Sulfonamides (e.g., afenide, prontosil, have demonstrated some evidence to improve EPC coloniza Sulfacetamide, Sulfamethizole, Sulfanilimide, Sulfasalazine, tion, maturation or function and are contemplated for use in Sulfamethoxazole, Sulfisoxazole, trimethoprim, trimethop the methods of the invention are angiotensin converting rim-sulfamethoxazole), tetracyclines (e.g., demeclocycline, enzyme inhibitors (ACE-I, e.g., Captopril, Enalapril, and doxycycline, minocycline, oxytetracycline, tetracycline). Ramipril), Angiotensin II type I receptor blockers (AT-II US 2010/0015200 A1 Jan. 21, 2010 28 blockers, e.g., losartan, Valartan), peroxisome proliferator 0215 “Local anesthetics” are substances which inhibit activated receptor gamma (PPAR-Y) agonists, and erythropoi pain signals in a localized region. Examples of such anesthet etin. The PPAR-Y agonists like the glitazones (e.g., ics include procaine, lidocaine, tetracaine and dibucaine. rosiglitaZone, pioglitaZone) can provide useful vascular Local anesthetics are contemplated for use in embodiments of effects, including the ability to inhibit vascular smooth methods and/or devices provided herein. muscle cell proliferation, and have anti-inflammatory func 0216 “Anti-inflammatory agents' as used herein refer to tions, local antithrombotic properties, local lipid lowing agents used to reduce inflammation. Anti-inflammatory effects, and can inhibit matrix metalloproteinase (MMP) agents useful in the devices and methods of the invention activity So as to stabilize Vulnerable plaque. include, but are not limited to: aspirin, ibuprofen, naproxen, hyssop, ginger, turmeric, helenalin, cannabichromene, rofe 0213 Atherosclerosis is viewed as a systemic disease with coxib, celecoxib, paracetamol (acetaminophen), sirolimus significant local events. Adjunctive local therapy can be used (rapamycin), dexamethasone, dipyridamole, alfuZosin, in addition to systemic therapy to treat particularly vulnerable statins, and glitaZones. Antiinflammatory agents are contem areas of the vascular anatomy. The mutant protein Apo A1 plated for use in embodiments of methods and/or devices Milano has been reported to remove unwanted lipid from a provided herein. blood vessel and can cause regression of atherosclerosis. 0217. Antiinflammatory agents can be classified by Either protein therapy, or gene therapy to provide Sustained action. For example, glucocorticoids are steroids that reduce release of a protein therapy, can be delivered using the meth inflammation or Swelling by binding to cortisol receptors. ods of the invention. Adiponectin, a protein produced by Non-steroidal anti-inflammatory drugs (NSAIDs), alleviate adipocytes, is another protein with anti-atherosclerotic prop pain by acting on the cyclooxygenase (COX) enzyme. COX erties. It prevents inflammatory cell binding and promotes synthesizes prostaglandins, causing inflammation. A cannab generation of nitric oxide (NO). NO has been shown to have inoid, cannabichromene, present in the cannabis plant, has antiatherogenic activity in the vessel wall; it promotes anti been reported to reduce inflammation. Newer COX-inhibi inflammatory and other beneficial effects. The use of agents tors, e.g., rofecoxib and celecoxib, are also antiinflammatory including nitric oxide synthase (NOS) genetherapy that act to agents. Many antiinflammatory agents are also analgesics increase NO levels, are contemplated herein. NOS gene (painkillers), including salicylic acid, paracetamol(acetami therapy is described, e.g., by Channon, et al., 2000, “Nitric nophen), COX-2 inhibitors and NSAIDs. Also included Oxide Synthase in Atherosclerosis and Vascular Injury: among analgesics are, e.g., narcotic drugs such as morphine, Insights from Experimental Gene Therapy.” Arteriosclerosis, and synthetic drugs with narcotic properties such as tramadol. Thrombosis, and Vascular Biology, 2008): 1873-1881. Com 0218. Other antiinflammatory agents useful in the meth pounds for treating NO deficiency are described, e.g., in U.S. ods of the present invention include sirolimus (rapamycin) Pat. No. 7,537,785, “Composition for treating vascular dis and dexamethasone. Stents coated with dexamethasone were eases characterized by nitric oxide insufficiency, incorpo reported to be useful in a particular subset of patients with rated herein by reference in its entirety. “Vulnerable plaque’ exaggerated inflammatory disease evidenced by high plasma occurs in blood vessels where a pool of lipid lies below a thin C-reactive protein levels. Because both restenosis and athero fibrous cap. If the cap ruptures then the highly thrombogenic Sclerosis have such a large inflammatory component, anti lipid leaks into the artery often resulting in abrupt closure of inflammatories remain of interest with regard to local thera the vessel due to rapid clotting. Depending on the location of peutic agents. In particular, the use of agents that have anti the Vulnerable plaque, rupture can lead to sudden death. Both inflammatory activity in addition to other useful statins and glitaZones have been shown to strengthen the pharmacologic actions is contemplated. Examples include fibrous cap covering the plaque and make it less Vulnerable. dipyridamole, statins and glitaZones. Despite an increase in Other agents, e.g., batimastator marimastat, target the MMPS cardiovascular risk and systemic adverse events reported with that can destroy the fibrin cap. use of cyclooxygenase (COX)-inhibitors (e.g., celocoxib), 0214 Angiogenesis promoters can be used for treating these drugs can be useful for short term local therapy. reperfusion injury, which can occur when severely stenotic 0219 “Stability” as used herein in refers to the stability of arteries, particular chronic total occlusions, are opened. the drug in a coating deposited on a Substrate in its final Angiogenesis promoters are contemplated for use in embodi product form (e.g., stability of the drug in a coated Stent). The ments of methods and/or devices provided herein. Myocar term “stability” and/or “stable' in some embodiments is dial cells downstream from a blocked artery will downregu defined by 5% or less degradation of the drug in the final late the pathways normally used to prevent damage from product form. The term stability in some embodiments is oxygen free radicals and other blood borne toxins. A sudden defined by 3% or less degradation of the drug in the final infusion of oxygen can lead to irreversible cell damage and product form. The term stability in some embodiments is death. Drugs developed to prevent this phenomenon can be defined by 2% or less degradation of the drug in the final effective if provided by sustained local delivery. Neurovas product form. The term stability in some embodiments is cular interventions can particularly benefit from this treat defined by 1% or less degradation of the drug in the final ment strategy. Examples of pharmacological agents poten product form. tially useful in preventing reperfusion injury are glucagon 0220. In some embodiments, the pharmaceutical agent is like peptide 1, erythropoietin, atorvastatin, and atrial at least one of 50% crystalline, 75% crystalline, 80% crys natriuretic peptide (ANP). Other angiogenesis promoters talline, 90% crystalline, 95% crystalline, 97% crystalline, and have been described, e.g., in U.S. Pat. No. 6,284,758, “Angio 99% crystalline following sterilization of the device. In some genesis promoters and angiogenesis potentiators. U.S. Pat. embodiments, the pharmaceutical agent crystallinity is stable No. 7.462.593, "Compositions and methods for promoting wherein the crystallinity of the pharmaceutical agent follow angiogenesis,” and US Pat. No. 7,456,151, “Promoting ing sterilization is compared to the crystallinity of the phar angiogenesis with metrinl polypeptides.” maceutical agent at least one of 1 week after sterilization, 2 US 2010/0015200 A1 Jan. 21, 2010 29 weeks after sterilization, 4 weeks after sterilization, 1 month 4 weeks after sterilization, 1 month after sterilization, 2 after sterilization, 2 months after sterilization, 45 days after months after sterilization, 45 days after sterilization, 60 days sterilization, 60 days after sterilization, 90 days after steril after sterilization, 90 days after sterilization, 3 months after ization, 3 months after sterilization, 4 months after steriliza sterilization, 4 months after sterilization, 6 months after ster tion, 6 months after sterilization, 9 months after sterilization, ilization, 9 months after sterilization, 12 months after steril 12 months after sterilization, 18 months after sterilization, ization, 18 months after sterilization, 2 years after steriliza and 2 years after sterilization. In some embodiments, the tion, 3 years after sterilization, 4 years after sterilization, and pharmaceutical agent crystallinity is stable wherein the crys 5 years after sterilization. tallinity of the pharmaceutical agent prior to sterilization is 0225. “Active biological agent” as used herein refers to a compared to the crystallinity of the pharmaceutical agent at Substance, originally produced by living organisms, that can least one of: 1 week after sterilization, 2 weeks after steril be used to preventor treat a disease (meaning any treatment of ization, 4 weeks after sterilization, 1 month after sterilization, a disease in a mammal, including preventing the disease, i.e. 2 months after sterilization, 45 days after sterilization, 60 causing the clinical symptoms of the disease not to develop; days after sterilization, 90 days after sterilization, 3 months inhibiting the disease, i.e. arresting the development of clini after sterilization, 4 months after sterilization, 6 months after cal symptoms; and/or relieving the disease, i.e. causing the sterilization, 9 months after sterilization, 12 months after regression of clinical symptoms). It is possible that the active sterilization, 18 months after sterilization, and 2 years after biological agents of the invention may also comprise two or sterilization. In such embodiments, different devices may be more active biological agents or an active biological agent tested from the same manufacturing lot to determine stability combined with a pharmaceutical agent, a stabilizing agent or of the pharmaceutical agent at the desired time points. chemical or biological entity. Although the active biological 0221. In some embodiments, the pharmaceutical agent agent may have been originally produced by living organ crystallinity is stable at at least one of 1 week after steriliza isms, those of the present invention may also have been Syn tion, 2 weeks after sterilization, 4 weeks after sterilization, 1 thetically prepared, or by methods combining biological iso month after sterilization, 2 months after sterilization, 45 days lation and synthetic modification. By way of a non-limiting after sterilization, 60 days after sterilization, 90 days after example, a nucleic acid could be isolated form from a bio sterilization, 3 months after sterilization, 4 months after ster logical source, or prepared by traditional techniques, known ilization, 6 months after sterilization, 9 months after steriliza to those skilled in the art of nucleic acid synthesis. Further tion, 12 months after sterilization, 18 months after steriliza more, the nucleic acid may be further modified to contain tion, and 2 years after sterilization. non-naturally occurring moieties. Non-limiting examples of 0222. In some embodiments, the pharmaceutical agent active biological agents include growth factors, cytokines, crystallinity on the device tested at a time point after steril peptides, proteins, enzymes, glycoproteins, nucleic acids (in ization does not differ more than 1%, 2%, 3%, 4%, and/or 5% cluding deoxyribonucleotide or ribonucleotide polymers in from the crystallinity tested on a second device manufactured either single or double stranded form, and unless otherwise from the same lot of devices and the same lot of pharmaceu limited, encompasses known analogues of natural nucle tical agent at testing time point before sterilization (i.e. the otides that hybridize to nucleic acids in a manner similar to crystallinity drops no more than from 99 to 94% crystalline, naturally occurring nucleotides), antisense nucleic acids, for example, which is a 5% difference in crystallinity; the fatty acids, antimicrobials, vitamins, hormones, steroids, lip crystallinity drops no more than from 99 to 95% crystalline, ids, polysaccharides, carbohydrates and the like. They further which is a 4% difference in crystallinity; the crystallinity include, but are not limited to, antirestenotic agents, antidia drops no more than from 99 to 96% crystalline, for example, betics, analgesics, antiinflammatory agents, antirheumatics, which is a 3% difference in crystallinity; the crystallinity antihypotensive agents, antihypertensive agents, psychoac drops no more than from 99 to 97% crystalline, for example, tive drugs, tranquilizers, antiemetics, muscle relaxants, glu which is a 2% difference in crystallinity; the crystallinity cocorticoids, agents for treating ulcerative colitis or Crohn's drops no more than from 99 to 98% crystalline, for example, disease, antiallergics, antibiotics, antiepileptics, anticoagu which is a 1% difference in crystallinity; in other examples, lants, antimycotics, antitussives, arteriosclerosis remedies, the starting crystallinity percentage is one of 100%, 98%, diuretics, proteins, peptides, enzymes, enzyme inhibitors, 96%, 97%, 96%, 95%, 90%, 85%, 80%, 75%, 70%, 60%, gout remedies, hormones and inhibitors thereof, cardiac gly 50%, 30%, 25%, and/or anything in between). cosides, immunotherapeutic agents and cytokines, laxatives, 0223) In some embodiments, crystallinity of the pharma lipid-lowering agents, migraine remedies, mineral products, ceutical agent on the device tested at a time point after ster otologicals, anti parkinson agents, thyroid therapeutic agents, ilization does not differ more than 1%, 2%, 3%, 4%, and/or spasmolytics, platelet aggregation inhibitors, vitamins, cyto 5% from the crystallinity of pharmaceutical from the same lot statics and metastasis inhibitors, phytopharmaceuticals and of pharmaceutical agent tested at testing time point before chemotherapeutic agents. Preferably, the active biological sterilization of the pharmaceutical agent. agent is a peptide, protein or enzyme, including derivatives 0224. In some embodiments, crystallinity of the pharma and analogs of natural peptides, proteins and enzymes. The ceutical agent does not drop more than 1%. 2%. 3%, 4%, active biological agent may also be a hormone, gene thera and/or 5% between two testing time points after sterilization pies, RNA, siRNA, and/or cellular therapies (for non-limiting neither of which time point being greater than 2 years after example, stem cells or T-cells). sterilization. In some embodiments, crystallinity of the phar 0226. It is understood that certain agents will fall into maceutical agent does not drop more than 1%. 2%. 3%, 4%, multiple categories of agents, for example, certain antibiotic and/or 5% between two testing time points after sterilization agents are also chemotherapeutic agents, and biological neither of which time point being greater than 5 years after agents can include antibiotic agents, etc. sterilization. In some embodiments, two time points comprise 0227 Specific pharmaceutical agents useful in certain two of 1 week after sterilization, 2 weeks after sterilization, embodiments of devices and/or methods of the invention are US 2010/0015200 A1 Jan. 21, 2010 30 hyaluronidases. Hylenex (Baxter International, Inc.) is a for ery balloon creates a cavity where either none existed or mulation of a human recombinant hyaluronidase, PH-20, that greatly enlarges an existing cavity. For example, a solid tumor is used to facilitate the absorption and dispersion of other can be treated with hyaluronidase and a chemotherapeutic injected drugs or fluids. When injected under the skin or in the agent using a delivery balloon inserted through, e.g., a biopsy muscle, hyaluronidase can digest the hyaluronic acid gel. needle or the like. Vasoactive agents, e.g., TNF-alpha and allowing for temporarily enhanced penetration and disper histamine, also can be used to improve drug distribution sion of other injected drugs or fluids. within the tumor tissue. (See, e.g., Brunstein, et al., 2006, 0228. Hyaluronidase can allow drugs to pass more freely “Histamine, a vasoactive agent with vascular disrupting to target tissues. It has been observed on its own to suppress potential improves tumour response by enhancing local drug tumor growth, and is thus a chemotherapeutic agent. For delivery.” British Journal of Cancer 95:1663-1669). As example, increased drug antitumor activity has been reported another example of treatment of a location lacking a preex by Halozyme Therapeutics (Carlsbad, Calif.), when hyalu isting cavity, dense muscle tissue can be treated locally with ronidase is used in conjunction with another chemotherapeu a slow-release painkiller, using a delivery balloon inserted tic agent to treat an HA-producing tumor (reports available at through a hollow needle. http://www.halozyme.com). A pegylated hyaluronidase 0232 “Active agent as used herein refers to any pharma product (PEGPH2O) is currently being tested as a treatment ceutical agent or active biological agent as described herein. for prostate cancer, and a product containing both hyalu An active agent, in Some embodiments, may comprise a poly ronidase and mitomycin C (Chemophase) is being tested for mer, wherein the polymer provides a desired treatment in the treatment of bladder cancer. body. 0229. In certain embodiments of devices and/or methods 0233 “Activity” as used herein refers to the ability of a provided herein, hyaluronidase is used for treating any HA pharmaceutical or active biological agent to prevent or treat a producing cancer, either alone or in combination with another disease (meaning any treatment of a disease in a mammal, chemotherapeutic agent. In particular embodiments, hyalu including preventing the disease, i.e. causing the clinical ronidase is used in the methods of the invention for treating symptoms of the disease not to develop; inhibiting the dis bladder cancer, e.g., in combination with mitomycin C. In ease, i.e. arresting the development of clinical symptoms; other embodiments, hyaluronidase is used for treating pros and/or relieving the disease, i.e. causing the regression of tate cancer. Cancers potentially treated with hyaluronidase clinical symptoms). Thus the activity of a pharmaceutical or include, but are not limited to, Kaposi's sarcoma, glioma, active biological agent should be of therapeutic or prophylac melanocyte, head and neck Squamous cell carcinoma, breast tic value. cancer, gastrointestinal cancer, and other genitourinary can 0234) “Secondary, tertiary and quaternary structure as cers, e.g., testicular cancer and ovarian cancer. The correla used herein are defined as follows. The active biological tion of HA with various cancers has been described in the agents of the present invention will typically possess some literature, e.g., by Simpson, et al. Front Biosci. 13:5664 degree of secondary, tertiary and/or quaternary structure, 5680. In embodiments, hyaluronidase is used in the devices upon which the activity of the agent depends. As an illustra and methods of the invention to enhance penetration and tive, non-limiting example, proteins possess secondary, ter dispersion of any agents described herein, including, e.g., tiary and quaternary structure. Secondary structure refers to painkillers, antiinflammatory agents, etc., in particular, to the spatial arrangement of amino acid residues that are near tissues that produce HA. one another in the linear sequence. The C-helix and the 0230 Hyaluronidases are described, e.g., in U.S. Pat. App. B-strand are elements of secondary structure. Tertiary struc No. 2005/0260186 and 2006/0104968, both titled “Soluble ture refers to the spatial arrangement of amino acid residues glycosaminoglycanases and methods of preparing and using that are far apart in the linear sequence and to the pattern of soluble glycosaminoglycanases” and incorporated herein by disulfide bonds. Proteins containing more than one polypep reference in their entirety. Bookbinder, et al., 2006, “A recom tide chain exhibit an additional level of structural organiza binant human enzyme for enhanced interstitial transport of tion. Each polypeptide chain in Such a protein is called a therapeutics.” Journal of Controlled Release 1 14:230-241 Subunit. Quaternary structure refers to the spatial arrange reported improved pharmacokinetic profile and absolute bio ment of subunits and the nature of their contacts. For example availability, of peginterferon alpha-2b or the antiinflamma hemoglobin consists of two C. and two B chains. It is well tory agent infliximab, when either one is coinjected with known that protein function arises from its conformation or rHuPH20 (human recombinant hyaluronidase PH-20). They three dimensional arrangement of atoms (a stretched out also reported that an increased Volume of drug could be polypeptide chain is devoid of activity). Thus one aspect of injected Subcutaneously when coinjected with hyaluronidase. the present invention is to manipulate active biological Methods for providing human plasma hyaluronidases, and agents, while being careful to maintain their conformation, so assays for hyaluronidases, are described in, e.g., U.S. Pat. No. as not to lose their therapeutic activity. 7,148,201, “Use of human plasma hyaluronidase in cancer 0235 “Polymer” as used herein, refers to a series of treatment, incorporated herein by reference in its entirety. repeating monomeric units that have been cross-linked or The use of hyaluronidase in the devices and methods of the polymerized. Any suitable polymer can be used to carry out invention is expected to increase the rate and amount of drug the present invention. It is possible that the polymers of the absorbed, providing an added aspect to control over release invention may also comprise two, three, four or more differ rates. ent polymers. In some embodiments of the invention only one 0231 Hyaluronidase co-delivery is also useful when an polymer is used. In certain embodiments a combination of agent is administered using the devices and methods of the two polymers is used. Combinations of polymers can be in invention within a tissue not having a well-defined preexist varying ratios, to provide coatings with differing properties. ing cavity or having a cavity that is Smaller than the inflated Polymers useful in the devices and methods of the present delivery balloon. In these embodiments, inflation of the deliv invention include, for example, stable or inert polymers, US 2010/0015200 A1 Jan. 21, 2010 organic polymers, organic-inorganic copolymers, inorganic dine fluoride), Poly(vinyl acetate), Poly(vinyl pyrrolidone), polymers, bioabsorbable, bioresorbable, resorbable, degrad Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl able, and biodegradable polymers. Those of skill in the art of acetate), Poly(ethylene glycol), Poly(propylene glycol), Poly polymer chemistry will be familiar with the different proper (methacrylic acid), etc. ties of polymeric compounds. 0240 Suitable polymers also include absorbable and/or 0236. In some embodiments, the coating further com resorbable polymers including the following, combinations, prises a polymer. In some embodiments, the active agent copolymers and derivatives of the following: Polylactides comprises a polymer. In some embodiments, the polymer (PLA), Polyglycolides (PGA), PolyLactide-co-glycolides comprises at least one of polyalkyl methacrylates, polyalky (PLGA), Polyanhydrides, Polyorthoesters, Poly(N-(2-hy lene-co-vinyl acetates, polyalkylenes, polyurethanes, poly droxypropyl)methacrylamide), Poly(1-aspartamide), includ anhydrides, aliphatic polycarbonates, polyhydroxyal ing the derivatives DLPLA poly(dl-lactide); LPLA poly kanoates, silicone containing polymers, polyalkyl siloxanes, (1-lactide); PDO poly(dioxanone); PGA-TMC poly aliphatic polyesters, polyglycolides, polylactides, polylac (glycolide-co-trimethylene carbonate); PGA-LPLA poly tide-co-glycolides, poly(e-caprolactone)S. polytetraha (1-lactide-co-glycolide); PGA-DLPLA poly(dl-lactide-co looalkylenes, polystyrenes, poly(phosphaSones), copolymers glycolide); LPLA-DLPLA poly(1-lactide-co-dl-lactide); thereof, and combinations thereof. and PDO-PGA-TMC poly(glycolide-co-trimethylene car 0237. In embodiments, the polymer is capable of becom bonate-co-dioxanone), and combinations thereof. ing soft after implantation, for example, due to hydration, 0241 “Copolymer as used herein refers to a polymer degradation or by a combination of hydration and degrada being composed of two or more different monomers. A tion. In embodiments, the polymer is adapted to transfer, free, copolymer may also and/or alternatively refer to random, and/or dissociate from the substrate when at the intervention block, graft, copolymers known to those of skill in the art. site due to hydrolysis of the polymer. In various embodi 0242. The term “image enhanced polymer or “imaging ments, the device is coated with a bioabsorbable polymer that agent as used herein refer to an agent that can be used with is capable of resorbtion in at least one of about 1 day, about the devices and methods of the invention to view at least one 3 days, about 5 days, about 7 days, about 14 days, about 3 component of the coating, either while the coating is on the weeks, about 4 weeks, about 45 days, about 60 days, about 90 substrate or after it is freed, dissociated and/or transferred. In days, about 180 days, about 6 months, about 9 months, about embodiments, an image enhanced polymer serves as a tracer, 1 year, about 1 to about 2 days, about 1 to about 5 days, about allowing the movement or location of the coated device to be 1 to about 2 weeks, about 2 to about 4 weeks, about 45 to identified, e.g., using an imaging System. In other embodi about 60 days, about 45 to about 90 days, about 30 to about 90 ments, an image enhanced polymer allows the practitioner to days, about 60 to about 90 days, about 90 to about 180 days, monitor the delivery and movement of a coating component. about 60 to about 180 days, about 180 to about 365 days, In embodiments, use of an image enhanced polymer enables about 6 months to about 9 months, about 9 months to about 12 the practitioner to determine the dose of a component of the months, about 9 months to about 15 months, and about 1 year coating (e.g., the active agent) that is freed, dissociated and/or to about 2 years. transferred. Information provided by the image enhanced 0238 Examples of polymers that may be used in the polymer or imaging agent about the amount of coating trans present invention include, but are not limited to polycarboxy ferred to the intervention site can allow the practitioner to lic acids, cellulosic polymers, proteins, polypeptides, polyvi determine the rate at which the coating will be released, nylpyrrolidone, maleic anhydride polymers, polyamides, thereby allowing prediction of dosing over time. Imaging polyvinyl alcohols, polyethylene oxides, glycosaminogly agents may comprise barium compounds Such as, for non cans, polysaccharides, polyesters, aliphatic polyesters, poly limiting example, barium sulfate. Imaging agents may com urethanes, polystyrenes, copolymers, silicones, silicone con prise iodine compounds. Imaging agents may comprise any taining polymers, polyalkyl siloxanes, polyorthoesters, compound that improves radiopacity. polyanhydrides, copolymers of vinyl monomers, polycarbon 0243 In embodiments, an image enhanced polymer is ates, polyethylenes, polypropytenes, polylactic acids, poly used with the device and methods of the invention for a lactides, polyglycolic acids, polyglycolides, polylactide-co purpose including, but not limited to, one or more of the glycolides, polycaprolactones, poly(e-caprolactone)S. following: monitoring the location of the Substrate, e.g., a polyhydroxybutyrate Valerates, polyacrylamides, polyethers, balloon or other device; assessing physiological parameters, polyurethane dispersions, polyacrylates, acrylic latex disper e.g., flow and perfusion; and targeting to a specific molecule. sions, polyacrylic acid, polyalkyl methacrylates, polyalky In embodiments, “smart’ agents that activate only in the lene-co-vinyl acetates, polyalkylenes, aliphatic polycarbon presence of their intended target are used with the device and ates polyhydroxyalkanoates, polytetrahalooalkylenes, poly methods of the invention. (phosphaSones), polytetrahalooalkylenes, poly 0244. In embodiments, imaging agents useful with the (phosphaSones), and mixtures, combinations, and device and methods of the present invention include, for copolymers thereof. example: EgadMe (in which a galactopyranose ring is syn 0239. The polymers of the present invention may be natu thesized to protect a Gd(III) ion from bulk water); conjugated ral or synthetic in origin, including gelatin, chitosan, dextrin, polymer MEH-PPV nanoparticles; bismuth trioxide; near cyclodextrin, Poly(urethanes), Poly(siloxanes) or silicones, infrared (NIR) fluorochromes; bioluminescence agents (e.g., Poly(acrylates) Such as rhooly(methyl methacrylate), poly green fluorescent protein, red fluorescent protein); SPECT (butyl methacrylate), and Poly(2-hydroxy ethyl methacry radionuclides, e.g., 99Tcm (6 h), 111 In (2.8 days), 123I (13.2 late), Poly(vinyl alcohol) Poly(olefins) such as poly(ethyl h) and 125I (59.5 days); PET radionuclides, e.g., 15O (2.07 ene), rhooly(isoprene), halogenated polymers such as Poly min), 13N (10 min), 11C (20.3 min), 18F (1.83 h), 124I (4.2 (tetrafluoroethylene)—and derivatives and copolymers such days) and 94Tcm (53 min); Gd-DTPA (gadolinium diethyl as those commonly sold as Teflon(R) products, Poly(vinyli enetriamine pentaacetic acid); Echo-Coat, an ultrasound US 2010/0015200 A1 Jan. 21, 2010 32 imaging agent (STS-Biopolymers); and barium Sulfate. In degraded sample products are incubated with the GT3TKB embodiments employing nanoparticles, it is important that cells for 48 hours. The results of the assay may be plotted as the particles are small enough to allow renal clearance (e.g. % relative growth vs. concentration of degraded sample in the have a hydrodynamic diameter less than 5.5 nm) and contain tissue-culture well. In addition, polymers and formulations of non-toxic components, and that the material decomposition the present invention may also be evaluated by well-known in products can be eliminated from the body. It is understood Vivo tests, such as Subcutaneous implantations in rats to con that an imaging agent can be conjugated or otherwise attached firm that they do not cause significant levels of irritation or or associated with a compound in the coating according to inflammation at the Subcutaneous implantation sites. methods known to those of skill in the art to form an image 0248. The terms “bioabsorbable.” “biodegradable.” “bio enhanced polymer. erodible.” “bioresorbable.” and “resorbable' are art-recog 0245 Biological imaging agents useful in embodiments nized synonyms. These terms are used herein interchange of the device and methods of the present invention are ably. Bioabsorbable polymers typically differ from non described in, e.g.: U.S. Pat. No. 6,077,880, “Highly radio bioabsorbable polymers in that the former may be absorbed paque polyolefins and method for making the same which (e.g., degraded) during use. In certain embodiments, such use sets forth a highly radiopaque polyolefin; U.S. Pat. No. 7,229. involves in Vivo use. Such as in vivo therapy, and in other 837, “Enhanced photophysics of conjugated polymers.” relat certain embodiments. Such use involves in vitro use. In gen ing to fluorescent ionic conjugated polymers; Dzik-Jurasz, eral, degradation attributable to biodegradability involves the 2003, “Molecular imaging in vivo: an introduction. The degradation of a bioabsorbable polymer into its component British Journal of Radiology, 76: S98-S109, providing an Subunits, or digestion, e.g., by a biochemical process, of the overview of in vivo molecular imaging methods; Von Zur polymer into Smaller, non-polymeric Subunits. In certain Muhlen, et al., 2008, Magnetic Resonance Imaging Contrast embodiments, biodegradation may occur by enzymatic Agent Targeted Toward Activated Platelets Allows In Vivo mediation, degradation in the presence of water (hydrolysis) Detection of Thrombosis and Monitoring of Thrombolysis and/or other chemical species in the body, or both. The bio Circulation. 118:258-267, reporting imaging of activated absorbability of a polymer may be shown in-vitro as platelets using an antibody-containing MRI imaging agent; described herein or by methods known to one of skill in the and Green, et al., “Simple conjugated polymer nanoparticles art. An in-vitro test for bioabsorbability of a polymer does not as biological labels.” Proc. Roy. Soc. A published online 24 require living cells or other biologic materials to show bio Jun. 2009 doi:10.1098/rspa. 2009.0181, describing the use of absorption properties (e.g. degradation, digestion). Thus, nanoparticles of conjugated polymers in biological imaging; resorbtion, resorption, absorption, absorbtion, erosion may all incorporated herein by reference in their entirety. also be used synonymously with the terms “bioabsorbable.” 0246 “Biocompatible' as used herein, refers to any mate “biodegradable.”“bioerodible,” and “bioresorbable.” Mecha rial that does not cause injury or death to the animal or induce nisms of degradation of a bioaborbable polymer may include, an adverse reaction in an animal when placed in intimate but are not limited to, bulk degradation, Surface erosion, and contact with the animal's tissues. Adverse reactions include combinations thereof. for example inflammation, infection, fibrotic tissue forma 0249. As used herein, the term “biodegradation' encom tion, cell death, or thrombosis. The terms “biocompatible passes both general types of biodegradation. The degradation and “biocompatibility” when used herein are art-recognized rate of a biodegradable polymer often depends in part on a and mean that the referent is neither itself toxic to a host (e.g., variety of factors, including the chemical identity of the link an animal or human), nor degrades (if it degrades) at a rate age responsible for any degradation, the molecular weight, that produces byproducts (e.g., monomeric or oligomeric crystallinity, biostability, and degree of cross-linking of Such Subunits or other byproducts) at toxic concentrations, causes polymer, the physical characteristics (e.g., shape and size) of inflammation or irritation, or induces an immune reaction in the implant, and the mode and location of administration. For the host. It is not necessary that any subject composition have example, the greater the molecular weight, the higher the a purity of 100% to be deemed biocompatible. Hence, a degree of crystallinity, and/or the greater the biostability, the subject composition may comprise 99%, 98%, 97%, 96%, biodegradation of any bioabsorbable polymer is usually 95%, 90% 85%, 80%, 75% or even less of biocompatible slower. agents, e.g., including polymers and other materials and 0250 In some embodiments, the coating comprises a bio excipients described herein, and still be biocompatible. degradable material that is adhered and/or cohered to the “Non-biocompatible' as used herein, refers to any material substrate prior to implantation, wherein the biodegradable that may cause injury or death to the animal or induce an material is capable of degrading overtime to lose its cohesion adverse reaction in the animal when placed in intimate con and/or adhesion to the Substrate. In some embodiments, the tact with the animal's tissues. Such adverse reactions are as pharmaceutical agent and/or the active agent is released from noted above, for example. the coating within at least one of about 1 day, about 3 days, 0247 To determine whether a polymer or other material is about 5 days, about 7 days, about 14 days, about 3 weeks, biocompatible, it may be necessary to conduct a toxicity about 4 weeks, about 45 days, about 60 days, about 90 days, analysis. Such assays are well known in the art. One example about 180 days, about 6 months, about 9 months, about 1 year, of such an assay may be performed with live carcinoma cells, about 1 to about 2 days, about 1 to about 5 days, about 1 to such as GT3TKB tumor cells, in the following manner: the about 2 weeks, about 2 about 4 weeks, about 45 to about 60 sample is degraded in 1 M NaOH at 37 degrees C. until days, about 45 to about 90 days, about 30 to about 90 days, complete degradation is observed. The solution is then neu about 60 to about 90 days, about 90 to about 180 days, about tralized with 1 M HC1. About 200 microliters of various 60 to about 180 days, about 180 to about 365 days, about 6 concentrations of the degraded sample products are placed in months to about 9 months, about 9 months to about 12 96-well tissue culture plates and seeded with human gastric months, about 9 months to about 15 months, and about 1 year carcinoma cells (GT3TKB) at 104/well density. The to about 2 years. US 2010/0015200 A1 Jan. 21, 2010

0251 “Hydration” as used herein refers to the absorption least 98% crystalline. In some embodiments of the methods of water by a substance, or the combination of a Substance and/or devices provided herein the pharmaceutical agent is at with water. Hydration of the coating may reduce the coating's least 99% crystalline. cohesive and adhesive binding to the device, thereby facili 0257 "Stabilizing agent” as used herein refers to any sub tating transfer of the coating to the intervention site. stance that maintains or enhances the stability of the biologi 0252 “Hydrolysis” as used herein refers to a chemical cal agent. Ideally these stabilizing agents are classified as Generally Regarded As Safe (GRAS) materials by the US reaction in which water reacts with a compound to produce Food and Drug Administration (FDA). Examples of stabiliz other compounds; involves the splitting of a bond and the ing agents include, but are not limited to carrier proteins. Such addition of the hydrogen cation and the hydroxide anion from as albumin, gelatin, metals or inorganic salts. Pharmaceuti the waterlmage enhanced polymer, imaging agent. cally acceptable excipient that may be present can further be 0253) “Degradation” as used herein refers to the conver found in the relevant literature, for example in the Handbook sion or reduction of a chemical compound to one less com of Pharmaceutical Additives: An International Guide to More plex, e.g., by splitting off one or more groups of atoms. Than 6000 Products by Trade Name, Chemical, Function, and Degradation of the coating may reduce the coating's cohesive Manufacturer; Michael and Irene Ash (Eds.); Gower Publish and adhesive binding to the device, thereby facilitating trans ing Ltd.; Aldershot, Hampshire, England, 1995. fer of the coating to the intervention site. 0258 “Intervention site' as used herein refers to the loca 0254 “Therapeutically desirable morphology” as used tion in the body where the coating is intended to be delivered herein refers to the gross form and structure of the pharma (by transfer from, freeing from, and/or dissociating from the ceutical agent, once deposited on the Substrate, so as to pro substrate). The intervention site can be any substance in the vide for optimal conditions of ex vivo storage, in vivo pres medium Surrounding the device, e.g., tissue, cartilage, a body fluid, etc. The intervention site can be the same as the treat ervation and/or in vivo release. Such optimal conditions may ment site, i.e., the Substance to which the coating is delivered include, but are not limited to increased shelf life (i.e., shelf is the same tissue that requires treatment. Alternatively, the stability), increased in vivo stability, good biocompatibility, intervention site can be separate from the treatment site, good bioavailability or modified release rates. Typically, for requiring Subsequent diffusion or transport of the pharmaceu the present invention, the desired morphology of a pharma tical or other agent away from the intervention site. ceutical agent would be crystalline or semi-crystalline or (0259 “Compressed fluid” as used herein refers to a fluid amorphous, although this may vary widely depending on of appreciable density (e.g., >0.2 g/cc) that is a gas at Standard many factors including, but not limited to, the nature of the temperature and pressure. “Supercritical fluid.” “near-critical pharmaceutical agent, the disease to be treated/prevented, the fluid.” “near-supercritical fluid.” “critical fluid.” “densified intended storage conditions for the Substrate prior to use or fluid, or “densified gas,” as used herein refers to a com the location within the body of any biomedical implant. Pref pressed fluid under conditions wherein the temperature is at erably at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, least 80% of the critical temperature of the fluid and the 90%. 95%, 97%, 98%, 99%, 99.5%, and/or 100% of the pressure is at least 50% of the critical pressure of the fluid, pharmaceutical agent is in crystalline or semi-crystalline and/or a density of +50% of the critical density of the fluid. form. 0260 Examples of substances that demonstrate supercriti 0255. In some embodiments of the methods and/or cal or near critical behavior suitable for the present invention devices provided herein, the macrollide immunosuppressive include, but are not limited to carbon dioxide, isobutylene, drug is at least 50% crystalline. In some embodiments, the ammonia, water, methanol, ethanol, ethane, propane, butane, macrollide immunosuppressive drug is at least 75% crystal pentane, dimethyl ether, Xenon, Sulfur hexafluoride, haloge line. In some embodiments, the macrollide immunosuppres nated and partially halogenated materials such as chlorofluo sive drug is at least 90% crystalline. In some embodiments of rocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, the methods and/or devices provided herein the macrollide perfluorocarbons (such as perfluoromethane and perfluoro immunosuppressive drug is at least 95% crystalline. In some propane, chloroform, trichloro-fluoromethane, dichloro-dif embodiments of the methods and/or devices provided herein luoromethane, dichloro-tetrafluoroethane) and mixtures the macrollide immunosuppressive drug is at least 97% crys thereof. Preferably, the supercritical fluid is hexafluoropro talline. In some embodiments of the methods and/or devices pane (FC-236EA), or 1,1,1,2,3,3-hexafluoropropane. Prefer provided herein macrollide immunosuppressive drug is at ably, the supercritical fluid is hexafluoropropane (FC least 98% crystalline. In some embodiments of the methods 236EA), or 1,1,1,2,3,3-hexafluoropropane for use in PLGA and/or devices provided herein the macrollide immunosup polymer coatings. pressive drug is at least 99% crystalline. 0261 “Sintering as used herein refers to the process by 0256 In some embodiments of the methods and/or which parts of the polymer or the entire polymer becomes devices provided herein wherein the pharmaceutical agent is continuous (e.g., formation of a continuous polymer film). As at least 50% crystalline. In some embodiments of the methods discussed herein, the sintering process is controlled to pro and/or devices provided herein the pharmaceutical agent is at duce a fully conformal continuous polymer (complete sinter least 75% crystalline. In some embodiments of the methods ing) or to produce regions or domains of continuous coating and/or devices provided herein the pharmaceutical agent is at while producing Voids (discontinuities) in the polymer. As least 90% crystalline. In some embodiments of the methods well, the sintering process is controlled Such that some phase and/or devices provided herein the pharmaceutical agent is at separation is obtained or maintained between polymer differ least 95% crystalline. In some embodiments of the methods ent polymers (e.g., polymers A and B) and/or to produce and/or devices provided herein the pharmaceutical agent is at phase separation between discrete polymer particles. least 97% crystalline. In some embodiments of the methods Through the sintering process, the adhesions properties of the and/or devices provided herein pharmaceutical agent is at coating are improved to reduce flaking of detachment of the US 2010/0015200 A1 Jan. 21, 2010 34 coating from the Substrate during manipulation in use. As 0265 “Solution Enhanced Dispersion of Supercritical described herein, in some embodiments, the sintering process Solutions' or “SEDS as used herein involves a spray process is controlled to provide incomplete sintering of the polymer. for the generation of polymer particles, which are formed In embodiments involving incomplete sintering, a polymer is when a compressed fluid (e.g. Supercritical fluid, preferably formed with continuous domains, and Voids, gaps, cavities, supercritical CO) is used as a diluent to a vehicle in which a pores, channels or, interstices that provide space for seques polymer is dissolved (one that can dissolve both the polymer tering a therapeutic agent which is released under controlled and the compressed fluid). The mixing of the compressed conditions. Depending on the nature of the polymer, the size fluid diluent with the polymer-containing Solution may be of polymer particles and/or other polymer properties, a com achieved by encounter of a first stream containing the poly pressed gas, a densified gas, a near critical fluid or a Super mer Solution and a second stream containing the diluent com critical fluid may be employed. In one example, carbon diox pressed fluid, for example, within one spray nozzle or by the ide is used to treat a substrate that has been coated with a use of multiple spray nozzles. The solvent in the polymer polymer and a drug, using dry powder and RESS electrostatic Solution may be one compound or a mixture of two or more coating processes. In another example, isobutylene is ingredients and may be or comprise an alcohol (including employed in the sintering process. In other examples a mix diols, triols, etc.), ether, amine, ketone, carbonate, or alkanes, ture of carbon dioxide and isobutylene is employed. In or hydrocarbon (aliphatic or aromatic) or may be a mixture of another example, 1.1.2.3,3-hexafluoropropane is employed compounds, such as mixtures of alkanes, or mixtures of one in the sintering process. or more alkanes in combination with additional compounds 0262. Whenanamorphous material is heated to a tempera such as one or more alcohols, (e.g., from 0 or 0.1 to 5% of a ture above its glass transition temperature, or when a crystal Cito Cisalcohol, including diols, triols, etc.). See for example line material is heated to a temperature above a phase transi U.S. Pat. No. 6,669,785, incorporated herein by reference in tion temperature, the molecules comprising the material are its entirety. The solvent may optionally contain a Surfactant, more mobile, which in turn means that they are more active as also described in, e.g., U.S. Pat. No. 6,669,785. and thus more prone to reactions such as oxidation. However, 0266. In one embodiment of the SEDS process, a first when an amorphous material is maintained at a temperature stream of fluid comprising a polymer dissolved in a common below its glass transition temperature, its molecules are Sub Solvent is co-sprayed with a second stream of compressed stantially immobilized and thus less prone to reactions. Like fluid. Polymer particles are produced as the second stream wise, when a crystalline material is maintained at a tempera acts as a diluent that weakens the solvent in the polymer ture below its phase transition temperature, its molecules are solution of the first stream. The now combined streams of Substantially immobilized and thus less prone to reactions. fluid, along with the polymer particles, flow out of the nozzle Accordingly, processing drug components at mild conditions, assembly into a collection vessel. Control of particle size, Such as the deposition and sintering conditions described particle size distribution, and morphology is achieved by herein, minimizes cross-reactions and degradation of the drug tailoring the following process variables: temperature, pres component. One type of reaction that is minimized by the sure, solvent composition of the first stream, flow-rate of the processes of the invention relates to the ability to avoid con first stream, flow-rate of the second stream, composition of ventional solvents which in turn minimizes-Oxidation of the second stream (where soluble additives may be added to drug, whether in amorphous, semi-crystalline, or crystalline the compressed gas), and conditions of the capture vessel. form, by reducing exposure thereof to free radicals, residual Typically the capture vessel contains a fluid phase that is at Solvents, protic materials, polar-protic materials, oxidation least five to ten times (5-1Ox) atmospheric pressure. initiators, and autoxidation initiators. 0267 “Electrostatic Dry Powder Coating or “e-DPC” or 0263 “Rapid Expansion of Supercritical Solutions' or "eDPC as used herein refers to Electrostatic Capture as “RESS’’’ as used herein involves the dissolution of a polymer described herein combined with Dry Powder Coating. e-DPC into a compressed fluid, typically a Supercritical fluid, fol deposits material (including, for example, polymer or imper lowed by rapid expansion into a chamber at lower pressure, meable dispersed solid) on the device or other substrate as dry typically near atmospheric conditions. The rapid expansion powder, using electrostatic capture to attract the powder par of the Supercritical fluid solution through a small opening, ticles to the substrate. Dry powder spraying (“Dry Powder with its accompanying decrease in density, reduces the dis Coating or “DPC) is well known in the art, and dry powder Solution capacity of the fluid and results in the nucleation and spraying coupled with electrostatic capture has been growth of polymer particles. The atmosphere of the chamber described, for example in U.S. Pat. Nos: 5,470,603, 6,319, is maintained in an electrically neutral State by maintaining an 541, and 6,372.246, all incorporated herein by reference in isolating “cloud of gas in the chamber. Carbon dioxide, their entirety. Methods for depositing coatings are described, nitrogen, argon, helium, or other appropriate gas is employed e.g., in WO 2008/148013, “Polymer Films for Medical to prevent electrical charge is transferred from the substrate to Device Coating, incorporated herein by reference in its the Surrounding environment. entirety. 0264 “Electrostatic Rapid Expansion of Supercritical 0268 “Dipping Process” and “Spraying Process” as used Solutions or “e-RESS’’’ or “eRESS’’’ as used herein refers to herein refer to methods of coating substrates that have been Electrostatic Capture as described herein combined with described at length in the art. These processes can be used for Rapid Expansion of Supercritical Solutions as described coating medical devices with pharmaceutical agents. Spray herein. In some embodiments, Electrostatic Rapid Expansion coating, described in, e.g., U.S. Pat. No. 7,419,696, “Medical of Supercritical Solutions refers to Electrostatic capture as devices for delivering a therapeutic agent and method of described in the art, e.g., in U.S. Pat. No. 6,756,084, “Elec preparation' and elsewhere herein, can involve spraying or trostatic deposition of particles generated from rapid expan airbrushing a thin layer of Solubilized coating or dry powder sion of supercritical fluid solutions, incorporated herein by coating onto a substrate. Dip coating involves, e.g., dipping a reference in its entirety. Substrate in a liquid, and then removing and drying it. Dip US 2010/0015200 A1 Jan. 21, 2010 coating is described in, e.g., U.S. Pat. No. 5,837.313 “Drug may have contact with material from the pharmaceutical release stent coating process, incorporated herein by refer layer. It is also contemplated that material from the second ence in its entirety. polymer layer may extend through the entire layer largely 0269) “Bulk properties’ properties of a coating including a occupied by pharmaceutical agent and contact material from pharmaceutical or a biological agent that can be enhanced the first polymer layer. through the methods of the invention include for example: 0276. It should be noted however that contact between adhesion, Smoothness, conformality, thickness, and compo material from the second polymer layer (or the first polymer sitional mixing. layer) and material from the pharmaceutical agent layer (e.g.: (0270. “Electrostatically charged” or “electrical potential” a pharmaceutical agent crystal particle or a portion thereof) or “electrostatic capture' as used herein refers to the collec does not necessarily imply formation of a mixture between tion of the spray-produced particles upon a substrate that has the material from the first or second polymer layers and a different electrostatic potential than the sprayed particles. material from the pharmaceutical agent layer. In some Thus, the substrate is at an attractive electronic potential with embodiments, a layer may be defined by the physical three respect to the particles exiting, which results in the capture of dimensional space occupied by crystalline particles of a phar the particles upon the Substrate. i.e. the Substrate and particles maceutical agent (and/or biological agent). It is contemplated are oppositely charged, and the particles transport through the that Such layer may or may not be continuous as phhysical gaseous medium of the capture vessel onto the Surface of the space occupied by the crystal particles of pharmaceutical Substrate is enhanced via electrostatic attraction. This may be agents may be interrupted, for example, by polymer material achieved by charging the particles and grounding the Sub from an adjacent polymer layer. An adjacent polymer layer strate or conversely charging the Substrate and grounding the may be a layer that is in physical proximity to be pharmaceu particles, by charging the particles at one potential (e.g. nega tical agent particles in the pharmaceutical agent layer. Simi tive charge) and charging the Substrate at an opposited poten larly, an adjacent layer may be the layer formed in a process tial (e.g. positive charge), or by some other process, which step right before or right after the process step in which would be easily envisaged by one of skill in the art of elec pharmaceutical agent particles are deposited to form the phar trostatic capture. maceutical agent layer. 0271 “Depositing the active agent by an e-RESS, an 0277 As described herein, material deposition and layer e-SEDS, or an e-DPC process without electrically charging formation provided herein are advantageous in that the phar the substrate' as used herein refers to any of these processes maceutical agent remains largely in crystalline form during as performed without intentionally electrically charging the the entire process. While the polymer particles and the phar substrate. It is understood that the substrate might become maceutical agent particles may be in contact, the layer for electrically charged unintentially during any of these pro mation process is controlled to avoid formation of a mixture CCSSCS. between the pharmaceutical agent particles the polymer par 0272 “Depositing the active agent by an e-RESS, an ticles during formation of a coated device. e-SEDS, or an e-DPC process without creating an electrical 0278. In some embodiments, the coating comprises a plu potential between the Substrate and a coating apparatus’ as rality of layers deposited on said substrate, wherein at least used herein refers to any of these processes as performed one of the layers comprises the active agent. In some embodi without intentionally generating an electrical potential ments, at least one of the layers comprises a polymer. In some between the Substrate and the coating apparatus. It is under embodiments, the polymer is bioabsorbable. In some stood that electrical potential between the substrate and the embodiments, the active agent and the polymer are in the coating apparatus might be generated unintentially during same layer, in separate layers, or form overlapping layers. In any of these processes. Some embodiments, the plurality of layers comprise five lay 0273 “Intimate mixture' as used herein, refers to two or ers deposited as follows: a first polymer layer, a first active more materials, compounds, or Substances that are uniformly agent layer, a second polymer layer, a second active agent distributed or dispersed together. layer and a third polymer layer. 0274 “Layer as used herein refers to a material covering 0279. In some embodiments of the methods and/or a surface or forming an overlying part or segment. Two dif devices provided herein, the coating comprises a plurality of ferent layers may have overlapping portions whereby mate layers deposited on said Substrate, wherein at least one of the rial from one layer may be in contact with material from layers comprises the active agent. In some embodiments, at another layer. Contact between materials of different layers least one of the layers comprises a polymer. In some embodi can be measured by determining a distance between the mate ments, the polymer is bioabsorbable. In some embodiments, rials. For example, Raman spectroscopy may be employed in the active agent and the polymer are in the same layer, in identifying materials from two layers present in close proX separate layers, or form overlapping layers. In some embodi imity to each other. ments, the coating comprises a plurality of layers deposited 0275 While layers defined by uniform thickness and/or on said Substrate, wherein at least one of the layers comprises regular shape are contemplated herein, several embodiments the pharmaceutical agent. In some embodiments, the phar described herein relate to layers having varying thickness maceutical agent and the polymer are in the same layer, in and/or irregular shape. Material of one layer may extend into separate layers, or form overlapping layers. In some embodi the space largely occupied by material of another layer. For ments, the plurality of layers comprise five layers deposited example, in a coating having three layers formed in sequence as follows: a first polymer layer, a first active agent layer, a as a first polymer layer, a pharmaceutical agent layer and a second polymer layer, a second active agent layer and a third second polymer layer, material from the second polymer polymer layer. In some embodiments, the plurality of layers layer which is deposited last in this sequence may extend into comprise five layers deposited as follows: a first polymer the space largely occupied by material of the pharmaceutical layer, a first pharmaceutical agent layer, a second polymer agent layer whereby material from the second polymer layer layer, a second pharmaceutical agent layer and a third poly US 2010/0015200 A1 Jan. 21, 2010 36 mer layer. In some embodiments, the plurality of layers com 97%, and/or at least about 99% percent of the coating that was prise five layers deposited as follows: a first polymer layer, a present on the device prior to use. first active biological agent layer, a second polymer layer, a 0286 “At least a portion of the substrate” as used herein second active biological agent layer and a third polymer layer. refers to an amount and/or percentage of the Substrate. In 0280. In some embodiments, the device provides the coat embodiments of the device and methods of the invention ing to the intervention site over an area of delivery greater wherein a coating is on "at least a portion of the Substrate.” at than the outer Surface contact area of the Substrate. In some least about 10%, at least about 20%, at least about 30%, at embodiments, the area of delivery is at least 110% greater least about 50%, at least about 75%, at least about 85%, at than the outer Surface contact area of the Substrate. In some least about 90%, at least about 95%, and/or at least about 99% of the substrate is coated. In embodiments wherein “at least a embodiments, the area of delivery is at least 110% to 200% portion of the substrate' is bioabsorbable, at least about 10%, greater than the outer Surface contact area of the Substrate. In at least about 20%, at least about 30%, at least about 50%, at some embodiments, the area of delivery is at least 200% least about 75%, at least about 85%, at least about 90%, at greater than the outer Surface contact area of the Substrate. least about 95%, and/or at least about 99% of the substrate is 0281 “Laminate coating as used herein refers to a coat bioabsorbable. ing made up of two or more layers of material. Means for creating a laminate coating as described herein (e.g., a lami 0287. “Transferring at least a portion” as used herein in the nate coating comprising bioabsorbable polymer(s) and phar context of transferring a coating or active agent from the maceutical agent) may include coating the stent with drug and Substrate to an intervention site refers to an amount and/or polymer as described herein (e-RESS, e-DPC, compressed percentage of the coating or active agent that is transferred gas sintering). The process comprises performing multiple from the substrate to an intervention site. In embodiments of and sequential coating steps (with sintering steps for polymer the device and methods of the invention wherein at least a materials) wherein different materials may be deposited in portion of a coating or active agent is transferred from the each step, thus creating a laminated structure with a multitude substrate to an intervention site, at least about 10%, at least of layers (at least 2 layers) including polymer layers and about 20%, at least about 30%, at least about 50%, at least pharmaceutical agent layers to build the final device (e.g.: about 75%, at least about 85%, at least about 90%, at least about 95%, and/or at least about 99% of the coating or active laminate coated Stent). agent is transferred from the substrate to the intervention site. 0282 “Portion of the coating and “portion of the active In some embodiments, at least about 10%, at least about 20%, agent as used herein refer to an amount or percentage of the at least about 30%, at least about 50%, at least about 75%, at coating or active agent that is freed, dissociated, and/or trans least about 85%, at least about 90%, at least about 95%, ferred from the substrate to the intervention site, either at a and/or at least about 99% of the coating is adapted to transfer designated point in delivery, during a certain period of deliv from the substrate to the intervention site. In some embodi ery, or in total throughout the entire delivery process. In ments, at least about 10% of the coating is adapted to transfer embodiments, the device and methods of the invention are from the substrate to the intervention site. In some embodi adapted to free, dissociate, and/or transfera certain amount of ments, at least about 20% of the coating is adapted to transfer the coating and/or active agent. from the substrate to the intervention site. In some embodi 0283 For example, in embodiments, at least about 10%, at ments, at least about 30% of the coating is adapted to transfer least about 20%, at least about 30%, at least about 50%, at from the substrate to the intervention site. In some embodi least about 75%, at least about 85%, at least about 90%, at ments, at least about 50% of the coating is adapted to transfer least about 95%, and/or at least about 99% of the coating is from the substrate to the intervention site. In some embodi adapted to be freed, dissociated, and/or to be transferred from ments, at least about 75% of the coating is adapted to transfer the substrate to the intervention site. In embodiments, at least from the substrate to the intervention site. In some embodi about 10%, at least about 20%, at least about 30%, at least ments, at least about 85% of the coating is adapted to transfer about 50%, at least about 75%, at least about 85%, at least from the substrate to the intervention site. In some embodi about 90%, at least about 95%, and/or at least about 99% of ments, at least about 90% of the coating is adapted to transfer the active agent is adapted to be freed, dissociated, and/or to from the substrate to the intervention site. In some embodi be transferred from the substrate to the intervention site. ments, at least about 95% of the coating is adapted to transfer 0284. The portion of the coating and/or that is freed, dis from the substrate to the intervention site. In some embodi sociated, or transferred from the device substrate is influ ments, at least about 99% of the coating is adapted to transfer enced by any or a combination of, e.g., the size, shape, and from the substrate to the intervention site. As used herein, flexibility of the device substrate, the size, shape, surface "about when used in reference to a percentage of the coating qualities of and conditions (e.g., blood or lymph circulation, can mean ranges of 1%-5% of 5%-10%, of 10%-20%, and/or temperature, etc.) at the intervention site, the composition of of 10%-50% (as a percent of the percentage of the coating the coating, including the particular active agent(s) and spe transferred, or as a variation of the percentage of the coating cific polymer component(s) used in the coating, the relative transferred). proportions of these components, the use of any release agent 0288. In some embodiments, the coating portion that is (s), and Substrate characteristics. Any one or more of these adapted to transfer upon stimulation is on at least one of a and other aspects of the device and methods of the invention distal surface of the substrate, a middle surface of the sub can be adapted to influence the portion of the coating and/or strate, a proximal Surface of the Substrate, and an abluminal active agent freed, dissociated, and/or transferred, as desired Surface of the Substrate. In some embodiments, the stimula to produce the desired clinical outcome. tion decreases the contact between the coating and the Sub 0285 "Substantially all of the coating as used herein strate. In some embodiments, device is adapted to transfer refers to at least about 50%, at least about 75%, at least about less than about 1%, less than about 5%, less than about 10%. 85%, at least about 90%, at least about 95%, at least about less than about 15%, less than about 25%, less than about US 2010/0015200 A1 Jan. 21, 2010 37

50%, less than about 70%, less than about 80%, and/or less adapted to transfer at least about 95% of the coating from the than about 90% of the coating absent stimulation of the coat substrate to the intervention site. In some embodiments, the ing device is adapted to transfer at least about 99% of the coating 0289. In some embodiments, at least about 10%, at least from the substrate to the intervention site. As used herein, about 20%, at least about 30%, at least about 50%, at least "about when used in reference to a percentage of the coating about 75%, at least about 85%, at least about 90%, at least can mean ranges of 1%-5% of 5%-10%, of 10%-20%, and/or about 95%, and/or at least about 99% of the active agent is of 10%-50% (as a percent of the percentage of the coating adapted to transfer from the substrate to the intervention site. transferred, or as a variation of the percentage of the coating In some embodiments, at least about 10% of the active agent transferred). is adapted to transfer from the substrate to the intervention 0292. In some embodiments, the coating portion that site. In some embodiments, at least about 20% of the active transfers upon stimulation is on at least one of a distal Surface agent is adapted to transfer from the Substrate to the interven of the substrate, a middle surface of the substrate, a proximal tion site. In some embodiments, at least about 30% of the surface of the substrate, and an abluminal surface of the active agent is adapted to transfer from the Substrate to the Substrate. In some embodiments, stimulation decreases the intervention site. In some embodiments, at least about 50% of contact between the coating and the Substrate. In some the active agent is adapted to transfer from the substrate to the embodiments, the device is adapted to transfer less than about intervention site. In some embodiments, at least about 75% of 1%, less than about 5%, less than about 10%. less than about the active agent is adapted to transfer from the substrate to the 15%, less than about 25%, less than about 50%, less than intervention site. In some embodiments, at least about 85% of about 70%, less than about 80%, and/or less than about 90% the active agent is adapted to transfer from the substrate to the of the coating absent stimulation of the coating. intervention site. In some embodiments, at least about 90% of 0293. In some embodiments, the device is adapted to the active agent is adapted to transfer from the substrate to the transfer at least about 10%, at least about 20%, at least about intervention site. In some embodiments, at least about 95% of 30%, at least about 50%, at least about 75%, at least about the active agent is adapted to transfer from the substrate to the 85%, at least about 90%, at least about 95%, and/or at least intervention site. In some embodiments, at least about 99% of about 99% of the active agent from the substrate to the inter the active agent is adapted to transfer from the substrate to the vention site. In some embodiments, the device is adapted to intervention site. As used herein, “about when used in ref transfer at least about 10% of the active agent from the sub erence to a percentage of the active agent can mean ranges of strate to the intervention site. In some embodiments, the 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a device is adapted to transfer at least about 20% of the active percent of the percentage of the active agent transferred, or as agent from the Substrate to the intervention site. In some a variation of the percentage of the active agent transferred). embodiments, the device is adapted to transfer at least about 0290. In some embodiments, the active agent portion that 30% of the active agent from the substrate to the intervention is adapted to transfer upon stimulation is on at least one of a site. In some embodiments, the device is adapted to transfer at distal surface of the substrate, a middle surface of the sub least about 50% of the active agent from the substrate to the strate, a proximal Surface of the Substrate, and an abluminal intervention site. In some embodiments, the device is adapted Surface of the Substrate. In some embodiments, the stimula to transfer at least about 75% of the active agent from the tion decreases the contact between the coating and the Sub substrate to the intervention site. In some embodiments, the strate. In some embodiments, the device is adapted to transfer device is adapted to transfer at least about 85% of the active less than about 1%, less than about 5%, less than about 10%. agent from the Substrate to the intervention site. In some less than about 15%, less than about 25%, less than about embodiments, the device is adapted to transfer at least about 50%, less than about 70%, less than about 80%, and/or less 90% of the active agent from the substrate to the intervention than about 90% of the active agent absent stimulation of the site. In some embodiments, the device is adapted to transfer at coating. least about 95% of the active agent from the substrate to the 0291. In some embodiments, the device is adapted to intervention site. In some embodiments, the device is adapted transfer at least about 10%, at least about 20%, at least about to transfer at least about 99% of the active agent from the 30%, at least about 50%, at least about 75%, at least about substrate to the intervention site. As used herein, “about 85%, at least about 90%, at least about 95%, and/or at least when used in reference to a percentage of the active agent can about 99% of the coating from the substrate to the interven mean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of tion site. In some embodiments, the device is adapted to 10%-50% (as a percent of the percentage of the active agent transfer at least about 10% of the coating from the substrate to transferred, or as a variation of the percentage of the active the intervention site. In some embodiments, the device is agent transferred). adapted to transfer at least about 20% of the coating from the 0294. In some embodiments, the coating portion that substrate to the intervention site. In some embodiments, the transfers upon stimulation is on at least one of a distal Surface device is adapted to transfer at least about 30% of the coating of the substrate, a middle surface of the substrate, a proximal from the substrate to the intervention site. In some embodi surface of the substrate, and an abluminal surface of the ments, the device is adapted to transfer at least about 50% of Substrate. In some embodiments, the stimulation decreases the coating from the Substrate to the intervention site. In some the contact between the coating and the Substrate. In some embodiments, the device is adapted to transfer at least about embodiments, the device is adapted to transfer less than about 75% of the coating from the substrate to the intervention site. 1%, less than about 5%, less than about 10%. less than about In some embodiments, the device is adapted to transfer at 15%, less than about 25%, less than about 50%, less than least about 85% of the coating from the substrate to the about 70%, less than about 80%, less than about 90% of the intervention site. In some embodiments, the device is adapted active agent absent stimulation of the coating. to transfer at least about 90% of the coating from the substrate 0295) “Freeing at least a portion as used herein in the to the intervention site. In some embodiments, the device is context of freeing a coating and/or active agent from the US 2010/0015200 A1 Jan. 21, 2010

Substrate at an intervention site refers to an amount and/or 0299. In some embodiments, the device is adapted to dis percentage of a coating or active agent that is freed from the sociate at least about 10%, at least about 20%, at least about substrate at an intervention site. In embodiments of the device 30%, at least about 50%, at least about 75%, at least about and methods of the invention wherein at least a portion of a 85%, at least about 90%, at least about 95%, and/or at least coating or active agent is freed from the Substrate at an inter about 99% of the coating from the substrate. In some embodi vention site, at least about 10%, at least about 20%, at least ments, the device is adapted to dissociate at least about 10% about 30%, at least about 50%, at least about 75%, at least of the coating from the substrate to the intervention site. In about 85%, at least about 90%, at least about 95%, and/or at Some embodiments, the device is adapted to dissociate at least least about 99% of the coating or active agentis freed from the about 20% of the coating from the substrate to the interven tion site. In some embodiments, the device is adapted to substrate at the intervention site. In some embodiments, the dissociate at least about 30% of the coating from the substrate device is adapted to free at least about 10%, at least about to the intervention site. In some embodiments, the device is 20%, at least about 30%, at least about 50%, at least about adapted to dissociate at least about 50% of the coating from 75%, at least about 85%, at least about 90%, at least about the substrate to the intervention site. In some embodiments, 95%, and/or at least about 99% of the coating from the sub the device is adapted to dissociate at least about 75% of the strate. In some embodiments, the device is adapted to free at coating from the Substrate to the intervention site. In some least about 10% of the coating from the substrate to the embodiments, the device is adapted to dissociate at least intervention site. In some embodiments, the device is adapted about 85% of the coating from the substrate to the interven to free at least about 20% of the coating from the substrate to tion site. In some embodiments, the device is adapted to the intervention site. In some embodiments, the device is dissociate at least about 90% of the coating from the substrate adapted to free at least about 30% of the coating from the to the intervention site. In some embodiments, the device is substrate to the intervention site. In some embodiments, the adapted to dissociate at least about 95% of the coating from device is adapted to free at least about 50% of the coating the substrate to the intervention site. In some embodiments, from the substrate to the intervention site. In some embodi the device is adapted to dissociate at least about 99% of the ments, the device is adapted to free at least about 75% of the coating from the Substrate to the intervention site. As used coating from the Substrate to the intervention site. In some herein, “about when used in reference to a percentage of the embodiments, the device is adapted to free at least about 85% coating can mean ranges of 1%-5%, of 5%-10%, of 10%- of the coating from the substrate to the intervention site. In 20%, and/or of 10%-50% (as a percent of the percentage of some embodiments, the device is adapted to free at least about the coating dissociated, or as a variation of the percentage of 90% of the coating from the substrate to the intervention site. the coating dissociated). In some embodiments, the device is adapted to free at least 0300. In some embodiments, the coating portion that dis about 95% of the coating from the substrate to the interven Sociates upon stimulation is on at least one of a distal Surface tion site. In some embodiments, the device is adapted to free of the substrate, a middle surface of the substrate, a proximal at least about 99% of the coating from the substrate to the surface of the substrate, and an abluminal surface of the intervention site. As used herein, “about when used in ref Substrate. In some embodiments, stimulation decreases the erence to a percentage of the coating can mean ranges of contact between the coating and the Substrate. In some 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a embodiments, the device is adapted to dissociate less than percent of the percentage of the coating freed, or as a variation about 1%, less than about 5%, less than about 10%. less than of the percentage of the coating freed). about 15%, less than about 25%, less than about 50%, less 0296. In some embodiments, the coating portion that frees than about 70%, less than about 80%, less than about 90% of upon stimulation is on at least one of a distal Surface of the the coating absent stimulation of the coating. Substrate, a middle Surface of the Substrate, a proximal Sur 0301 “Depositing at least a portion' as used herein in the face of the substrate, and an abluminal surface of the sub context of a coating and/or active agent at an intervention site Strate. refers to an amount and/or percentage of a coating and/or 0297. In some embodiments, the stimulation decreases the active agent that is deposited at an intervention site. In contact between the coating and the Substrate. In some embodiments of the device and methods of the invention embodiments, the device is adapted to free less than about wherein at least a portion of a coating and/or active agent is 1%, less than about 5%, less than about 10%. less than about deposited at an intervention site, at least about 10%, at least 15%, less than about 25%, less than about 50%, less than about 20%, at least about 30%, at least about 50%, at least about 70%, less than about 80%, less than about 90% of the about 75%, at least about 85%, at least about 90%, at least coating absent stimulation of the coating. about 95%, and/or at least about 99% of the coating and/or 0298 “Dissociating at least a portion” as used herein in the active agent is deposited at the intervention site. In some context of dissociating a coating and/or active agent from the embodiments, stimulating decreases the contact between the Substrate at an intervention site refers to an amount and/or coating and the Substrate. In some embodiments, depositing percentage of a coating and/or active agent that is dissociated deposits less than about 1%, less than about 5%, less than from the substrate at an intervention site. In embodiments of about 10%. less than about 15%, less than about 25%, less the device and methods of the invention wherein at least a than about 50%, less than about 70%, less than about 80%, portion of a coating and/or active agentis dissociated from the and/or less than about 90% of the coating absent stimulating substrate at an intervention site, at least about 10%, at least at least one of the coating and the Substrate. about 20%, at least about 30%, at least about 50%, at least 0302 “Delivering at least a portion” as used herein in the about 75%, at least about 85%, at least about 90%, at least context of a coating and/or active agent at an intervention site about 95%, and/or at least about 99% of the coating and/or refers to an amount and/or percentage of a coating and/or active agent is dissociated from the Substrate at the interven active agent that is delivered to an intervention site. In tion site. embodiments of the device and methods of the invention US 2010/0015200 A1 Jan. 21, 2010 39 wherein at least a portion of a coating and/or active agent is about 75%, at least about 85%, at least about 90%, at least delivered to an intervention site, at least about 10%, at least about 95%, and/or at least about 99% of the coating and/or about 20%, at least about 30%, at least about 50%, at least active agentistacked at the intervention site. In some embodi about 75%, at least about 85%, at least about 90%, at least ments, stimulating decreases the contact between the coating about 95%, and/or at least about 99% of the coating and/or and the Substrate. In some embodiments, tacking tacks less active agent is delivered to the intervention site. than about 1%, less than about 5%, less than about 10%. less 0303. In some embodiments, the device is adapted to than about 15%, less than about 25%, less than about 50%, deliver at least about 10%, at least about 20%, at least about less than about 70%, less than about 80%, and/or less than 30%, at least about 50%, at least about 75%, at least about about 90% of the coating absent stimulating at least one of the 85%, at least about 90%, at least about 95%, and/or at least coating and the Substrate. In some embodiments, the device about 99% of the coating to the intervention site. In some comprises a tacking element that cooperates with the stimu embodiments, the device is adapted to deliver at least about lation to tack the coating to the intervention site. In some 10% of the coating to the intervention site. In some embodi embodiments, the device comprises a tacking element that ments, the device is adapted to deliver at least about 20% of tacks the coating to the Substrate until stimulating with a the coating to the intervention site. In some embodiments, the stimulation. device is adapted to deliver at least about 30% of the coating 0307 “Adhere.” “adherence.” “adhered,” “cohere.” to the intervention site. In some embodiments, the device is “coherence.” “cohered, and related terms, as used herein in adapted to deliver at least about 50% of the coating to the the context of adherence or coherence of the substrate to the intervention site. In some embodiments, the device is adapted coating refer to an interaction between the Substrate and the to deliver at least about 75% of the coating to the intervention coating that is sufficiently strong to maintain the association site. In some embodiments, the device is adapted to deliver at of the coating with the substrate for an amount of time prior to least about 85% of the coating to the intervention site. In some the stimulation, e.g., mechanical, chemical, thermal, electro embodiments, the device is adapted to deliver at least about magnetic, or Sonic stimulation, that is intended to cause the 90% of the coating to the intervention site. In some embodi coating to be freed, dissociated, and/or transferred. These ments, the device is adapted to deliver at least about 95% of same terms, as used in the context of an interaction between the coating to the intervention site. In some embodiments, the the coating and the target tissue area and/or intervention site device is adapted to deliver at least about 99% of the coating refer to an interaction between the coating and the target to the intervention site. As used herein, “about when used in tissue area and/or intervention site that is sufficient to keep the reference to a percentage of the coating can mean ranges of coating associated with the target tissue area and/or interven 1%-5%, of 5%-I0%, of 10%-20%, and/or of 10%-50% (as a tion site for an amount of time as desired for treatment, e.g., percent of the percentage of the coating delivered, or as a at least about 12 hours, about 1 day, about 3 days, about 5 variation of the percentage of the coating delivered). days, about 7 days, about 14 days, about 3 weeks, about 4 0304. In some embodiments, the coating portion that is weeks, about 45 days, about 60 days, about 90 days, about delivered upon stimulation is on at least one of a distal Surface 180 days, about 6 months, about 9 months, about 1 year, about of the substrate, a middle surface of the substrate, a proximal 1 to about 2 days, about 1 to about 5 days, about 1 to about 2 surface of the substrate, and an abluminal surface of the weeks, about 2 to about 4 weeks, about 45 to about 60 days, Substrate. In some embodiments, the stimulation decreases about 45 to about 90 days, about 30 to about 90 days, about 60 the contact between the coating and the Substrate. In some to about 90 days, about 90 to about 180 days, about 60 to embodiments, the device is adapted to deliver less than about about 180 days, about 180 to about 365 days, about 6 months 1%, less than about 5%, less than about 10%. less than about to about 9 months, about 9 months to about 12 months, about 15%, less than about 25%, less than about 50%, less than 9 months to about 15 months, and about 1 year to about 2 about 70%, less than about 80%, less than about 90% of the years. coating absent stimulation of the coating. 0308 “Balloon as used herein refers to a flexible sac that 0305. In some embodiments, depositing at least a portion can be inflated within a natural or non-natural body lumen or of the coating comprises depositing at least about 10%, at cavity, or used to create a cavity, or used to enlarge an existing least about 20%, at least about 30%, at least about 50%, at cavity. The balloon can be used transiently to dilate alumen or least about 75%, at least about 85%, at least about 90%, at cavity and thereafter may be deflated and/or removed from least about 95%, and/or at least about 99% of the coating at the subject during the medical procedure or thereafter. In the intervention site. In some embodiments, stimulating embodiments, the balloon can be expanded within the body decreases the contact between the coating and the Substrate. and has a coating thereon that is freed (at least in part) from In some embodiments, depositing deposits less than about the balloon and left behind in the lumen or cavity when the 1%, less than about 5%, less than about 10%. less than about balloon is removed. A coating can be applied to a balloon 15%, less than about 25%, less than about 50%, less than either after the balloon has been compacted for insertion, about 70%, less than about 80%, and/or less than about 90% resulting in a coating that partially covers the Surface of the of the coating absent stimulating at least one of the coating balloon, or it can be applied prior to or during compaction. In and the substrate. embodiments, a coating is applied to the balloon both prior to 0306 “Tacking at least a portion” as used herein in the and after compaction of the balloon. In embodiments, the context of tacking at least a portion of the coating to an balloon is compacted by, e.g., crimping or folding. Methods intervention site refers to an amount and/or percentage of a of compacting balloons have been described, e.g., in U.S. Pat. coating and/or active agent that is tacked at an intervention No. 7.308,748, “Method for compressing an intraluminal site. In embodiments of the device and methods of the inven device,” and U.S. Pat. No. 7,152,452, “Assembly for crimp tion wherein at least a portion of a coating and/or active agent ing an intraluminal device and method of use.” relating to is tacked at an intervention site, at least about 10%, at least uniformly crimping a balloon onto a catheter or other intralu about 20%, at least about 30%, at least about 50%, at least minal device, and U.S. Pat. No. 5,350,361 “Tri-fold balloon US 2010/0015200 A1 Jan. 21, 2010 40 for dilatation catheter and related method.” relating to balloon the compliance of a balloon is dependent on the dimensions folding methods and devices, all incorporated herein by ref and/or characteristics of the cavity and/or lumen walls, not erence in their entirety. In some embodiments the balloon is only the expandability of the balloon. delivered to the intervention site by a delivery device. In some 0312 “Cutting balloon” as used herein refers to a balloon embodiments, the delivery device comprises catheter. In commonly used in angioplasty having a special balloon tip Some embodiments, the balloon is an angioplasty balloon. with cutting elements, e.g., Small blades, wires, etc. The cut Balloons can be delivered, removed, and visualized during ting elements can be activated when the balloon is inflated. In delivery and removal by methods known in the art, e.g., for angioplasty procedures, Small blades can be used score the inserting angioplasty balloons, stents, and other medical plaque and the balloon used to compress the fatty matter devices. Methods for visualizing a treatment area and plan against the vessel wall. A cutting balloon might have tacks or ning instrument insertion are described, e.g., in U.S. Pat. No. other wire elements which in some embodiments aid in free 7,171,255, "Virtual reality 3D visualization for surgical pro ing the coating from the balloon, and in some embodiments, cedures” and U.S. Pat. No. 6,610,013, “3D ultrasound-guided may promote adherence or partial adherence of the coating to intraoperative prostate brachytherapy, incorporated herein the target tissue area, or some combination thereof. In some by reference in their entirety. embodiments, the cutting balloon cutting elements also score 0309 “Compliant balloon” as used herein refers to a bal the target tissue to promote the coating's introduction into the loon which conforms to the intervention site relatively more target tissue. In some embodiments, the cutting elements do than a semi-compliant balloon and still more so than a non not cut tissue at the intervention site. In some embodiments, compliant balloon. Compliant balloons expand and stretch the cutting balloon comprises tacking elements as the cutting with increasing pressure within the balloon, and are made elements. from Such materials as polyethylene or polyolefin copoly 0313 “Inflation pressure' as used herein refers to the pres mers. There is in the art a general classification of balloons sure at which a balloon is inflated. As used herein the nominal based on their expandability or “compliance' relative to each inflation pressure refers to the pressure at which a balloon is other, as described e.g., in U.S. Pat. No. 5,556,383, “Block inflated in order to achieve a particular balloon dimension, copolymer elastomer catheter balloons.” Generally, “non usually a diameter of the balloon as designed. The “rated burst compliant' balloons are the least elastic, increasing in diam pressure' or “RBP as used herein refers to the maximum eter about 2-7%, typically about 5%, as the balloon is pres statistically guaranteed pressure to which a balloon can be Surized from an inflation pressure of about 6 atm to a pressure inflated without failing. For PTCA and PTA catheters, the of about 12 atm, that is, they have a “distension” over that rated burst pressure is based on the results of invitro testing ot pressure range of about 5%. “Semi-compliant' balloons have the PTCA and/or PTA catheters, and normally means that at Somewhat greater distensions, generally 7-16% and typically least 99.9% of the balloons tested (with 95% confidence) will 10-12% over the same pressurization range. “Compliant” not burst at or below this pressure. balloons are still more distensible, having distensions gener 0314 "Tacking element as used herein refers to an ele ally in the range of 16-40% and typically about 21% over the ment on the substrate surface that is used to influence transfer same pressure range. Maximum distensions, i.e. distension of the coating to the intervention site. For example, the tack from nominal diameter to burst, of various balloon materials ing element can comprise a projection, e.g., a bump or a spike, may be significantly higher than the distension percentages on the Surface of the Substrate. In embodiments, the tacking discussed above because wall strengths, and thus burst pres element is adapted to secure the coating to the cutting balloon sures, vary widely between balloon materials. These disten until inflation of the cutting balloon. In some embodiments, sion ranges are intended to provide general guidance, as one tacking element can comprise a wire, and the wire can be of skill in the art will be aware that the compliance of a shaped in the form of an outward pointing wedge. In certain balloon is dependent on the dimensions and/or characteristics embodiments, the tacking element does not cut tissue at the of the cavity and/or lumenwalls, not only the expandability of intervention site. the balloon. 0315. As used herein, a “surgical tool refers to any tool 0310. A compliant balloon may be used in the vasculature used in a Surgical procedure. Examples of Surgical tools of a Subject. A compliant balloon might also be used in any include, but are not limited to: As used herein, a 'surgical tube or hole outside the vasculature (whether naturally occur tool” refers to any tool used in a Surgical procedure. Examples ring or or man-made, or created during an injury). For a of Surgical tools include, but are not limited to: a knife, a non-limiting example, a compliant balloon might be used in a Scalpel, a guidewire, a guiding catheter, a introduction cath lumpectomy to put a coating at the site where a tumor was eter, a distracter, a needle, a syringe, a biopsy device, an removed, to: treat an abscess, treat an infection, prevent an articulator, a Galotti articulator, a bone chisel, a bone crusher, infection, aid healing, promote healing, or for a combination a cottle cartilage crusher, a bone cutter, a bone distractor, an of any of these purposes. The coating in this embodiment may Ilizarov apparatus, an intramedullary kinetic bone distractor, comprise a growth factor. a bone drill, a bone extender, a bone file, a bone lever, a bone 0311. “Non-Compliant balloon” as used herein refers to a mallet, a bone rasp, a bone saw, a bone skid, a bone splint, a balloon that does not conform to the intervention site, but bone button, a caliper, a cannula, a catheter, a cautery, a rather, tends to cause the intervention site to conform to the clamp, a coagulator, a curette, a depressor, a dilator, a dissect balloon shape. Non-compliant balloons, commonly made ing knife, a distractor, a dermatome, forceps, dissecting for from such materials as polyethylene terephthalate (PET) or ceps, tissue forceps, sponge forceps, bone forceps, Carmalt polyamides, remain at a preselected diameter as the internal forceps, Cushing forceps, Dandy forceps, DeBakey forceps, balloon pressure increases beyond that required to fully Doyen intestinal forceps, epilation forceps, Halstead forceps, inflate the balloon. Non-compliant balloons are often used to Kelly forceps, Kocher forceps, mosquito forceps, a hemostat, dilate spaces, e.g., vascular lumens. As noted with respect to a hook, a nerve hook, an obstetrical hook, a skin hook, a a compliant balloon, one of skill in the art will be aware that hypodermic needle, a lancet, a luxator, a lythotome, a lythot US 2010/0015200 A1 Jan. 21, 2010 ript, a mallet, a partsch mallet, a mouth prop, a mouth gag, a embodiments, PID is treated by local delivery to the fallopian mammotome, a needle holder, an occluder, an osteotome, an tubes and/or ovaries. In other embodiments, STDs such as Epker osteotome, a periosteal elevator, a Joseph elevator, a chlamydia and gonorrhoea are treated via a similar adminis Molt periosteal elevator, an Obweg periosteal elevator, a sep tration route. A dosage of clindamycin for the systemic treat tum elevator, a Tessier periosteal elevator, a probe, a retractor, ment of pelvic inflammatory disease is, e.g., 900 mg IV q8h a Senn retractor, a Gelpi retractor, a Weitlaner retractor, a (in combination with gentamicin) administered for 14 days. USA-Army/Navy retractor, an O'Connor-O'Sullivan retrac Treatment of PID is described by, e.g., Mollen, et al., 2006, tor, a Deaver retractor, a Bookwalter retractor, a Sweetheart “Prevalence of tubo-ovarian abcess in adolescents diagnosed retractor, a Joseph skin hook, a Lahey retractor, a Blair with pelvic inflammatory disease in a pediatric emergency (Rollet) retractor, a rigid rake retractor, a flexible rake retrac department. Pediatr Emerg Care 22(9): 621-625; Hartmann, tor, a Ragnell retractor, a Linde-Ragnell retractor, a Davis et al., 2009, “Tubo-ovarian abscess in virginal adolescents: retractor, a Volkman retractor, a Mathieu retractor, a Jackson exposure of the underlying etiology. J Pediatr Adolesc tracheal hook, a Crile retractor, a Meyerding finger retractor, Gynecol 22(3):e 13-16; Lehmann, et al., 2001, “Drug treat a Little retractor, a Love Nerve retractor, a Green retractor, a ment of nonviral sexually transmitted diseases: specific issues Goelet retractor, a Cushing vein retractor, a Langenbeck in adolescents. Paediatr Drugs 3(7):481-494. Reproductive retractor, a Richardson retractor, a Richardson-Eastmann organs include not only the gonads and/or ovaries, but any retractor, a Kelly retractor, a Parker retractor, a Parker-Mott tissue in the reproductive system of a male or a female Sub retractor, a Roux retractor, a Mayo-Collins retractor, a Ribbon ject. retractor, an Alm retractor, a self retaining retractor, a Weit 0317 Intravaginal and transvaginal treatment of infec laner retractor, a Beckman-Weitlaner retractor, a Beckman tions are also contemplated in certain embodiments of the Eaton retractor, a Beckman retractor, an Adson retractor, a rib methods and/or devices of the invention. Formulations of spreader, a rongeur, a scalpel, an ultrasonic scalpel, a laser drugs for these indications are described in, e.g., U.S. Pat. No. Scalpel, Scissors, iris Scissors, Kiene Scissors, Metzenbaum 6,416.779, “Device and method for intravaginal or transvagi Scissors, Mayo Scissors, Tenotomy Scissors, a spatula, a nal treatment of fungal, bacterial, viral or parasitic infec speculum, a mouth speculum, a rectal speculum, Sim's vagi tions, incorporated herein by reference in its entirety. Fun nal speculum, Cusco's vaginal speculum, a sternal saw, a gal, bacterial, viral and parasitic infections and conditions, Suction tube, a Surgical elevator, a Surgical hook, a Surgical can be treated by methods comprising inserting into the knife, Surgical mesh, a Surgical needle, a Surgical Snare, a vagina a device of the invention coated with a drug formulated Surgical sponge, a Surgical spoon, a Surgical Stapler, a Suture, for treatment of these conditions, with, e.g., a mucoadhesive a syringe, a tongue depressor, a tonsillotome, a tooth extrac agent to promote adherence of the drug to the vaginal wall. tor, a towel clamp, towel forceps, Backhaus towel forceps, The mucoadhesive agent can be a polymer Such as an algi Lorna towel forceps, a tracheotome, a tissue expander, a nate, pectin, or a cellulose derivative such as hydroxypropyl Subcutaneus inflatable balloon expander, a trephine, a trocar, methylcellulose. Mucoadhesive formulations are described, tweezers, and a venous cliping. In some embodiments, a e.g., by Edsman, et al., 2005, “Pharmaceutical applications of Surgical tool may also and/or alternatively be referred to as a mucoadhesion for the non-oral routes. J. Pharm. Pharmacol. tool for performing a medical procedure. In some embodi 57(1):3-22. The drug may be therapeutically active topically ments, a Surgical tool may also and/or alternatively be a tool by acting directly on vaginal epithelium or mucosa or it may for delivering to the intervention site a biomedical implant. be transported transvaginally into the uterus, cervix and even 0316 “Reproductive care” as used herein refers to care of into the general circulation. U.S. Pat. No. 6,416,779 describes a Subject's reproductive system. Active agents are contem dosages of agents for intravaginal and transvaginal formula plated for use in embodiments of methods and/or devices tions for treating various diseases, e.g., as follows: in general, provided herein for Reproductive care. Devices and methods the dosage comprises from about 10 to about 2000 mg of the provided herein are contemplated for use in Reproductive antibiotic per daily dose to be delivered transvaginally to the care. The Subject may be male or female, the care may be cervix. The transvaginal formulation can comprise a penetra preventative, or to treat a condition, ailment, or disease. As tion enhancer and/or sorption promoter and/or mucoadhesive used herein, the terms “condition' and “ailment” are inter agent. The antibiotic dose depends on the antibiotic anti changeable. For example, Reproductive care of a subject's infective activity. For treatment of chlamydia, the dosage is reproductive system may include, in Some embodiments, hor typically within 100-2000 mg/day dose administered for at mone delivery to reproductive organs, whether for birth con least seven days, unless otherwise indicated. For transvaginal trol or reproductive assistance or for another purpose, fertility treatment of gonorrhea, lumefloxacin (400 mg), norfloxacin treatment, whether to reduce fertility or to increase fertility, (800 mg), afloxam (400 mg), ciproflaxin (500mg), azitromy infection treatment, such as treatment of yeast infections or cin (1000mg), ceflitoxime (400 mg) and doxicycline (100 mg) other infections, and treatment and/or prevention of sexually twice a day/7 days can be administered in doses as needed to transmitted diseases (STDs) Such as bacterial vaginosis, alleviate the symptoms and to effectively eliminate gonococ chancroid, donovanosis, gonorrhea, lymphogranuloma cus from the individual organism in daily doses from about Venereum, chlamydia, non-gonococcal urethritis, staphylo 400 mg to about 3000 mg. The formulation may, additionally, coccal infection, syphillis, tinea cruris, adenovirus, viral contain about 500-1000 mg of probenecid. For local treat hepatitus, herpes symplex, HIV/AIDS, HTLV 1.2, genital ment of herpes simplex, antiviral drugs such as acyclovir warts, human papillomavirus HPV, molluscum contagiosum, (200-1200 mg/day) or famciclovir (100-1200 mg/day), are mononucleosis, kaposi's sarcoma (Herpes 8), and/or tri administered for at least 7 days in a combination of transvagi chomoniasis. In embodiments, the devices and methods of the nal and intravaginal formulation. When using the devices and invention are used to treat pelvic inflammatory disease (PID), methods of the present invention, it is understood that the including, e.g., infection and/or inflammation of the fallopian amount of agent transferred via a coating to an intervention tube, ovary, endometrium, and other pelvic infections. In site can be varied depending on the rate of release of the active US 2010/0015200 A1 Jan. 21, 2010 42 agent from the coating after transfer, to achieve dosages com as used herein. The male reproductive organs include the parable to those used with other local treatment methods. prostate, penis and testes (testicles). 0318 Hormones that can be delivered locally using the 0321 Urologic conditions and ailments include sexual devices and methods of the invention include, e.g.: delivery of dysfunction and fertility issues, as well as general urology 20 micrograms/day ethinyl estradiol to hypoestrogenic Sub issues. Conditions include, for example, urinary Stones, uri jects for peak bone mass acquisition during adolescence; 200 nary incontinence, cancers of the urologic tract (e.g., bladder cancer, kidney cancer, and cancer of the urethra), cancers of micrograms/day of 17f-estradiol to relieve severe post the male reproductive tracts (e.g., testicular cancer, prostate menopausal symptoms; 400 micrograms/day of the GNRH cancer), Benign Prostate Hyperplasia (BPH), hypogonadism agonist nafarelin for 4 weeks in the initial treatment of (Decreased Testosterone), erectile dysfunction, premature endometriosis, followed by half-dose therapy (200 micro ejaculation, Peyronie's Disease, prostatitis, seminal vesiculi grams/day) for 20 weeks; and estradiol release of 100 mg/day tis, prostatic abscess, bladder neck hypertrophy and adrenal of estradiol, as its 3-acetate ester can maintain a circulating tumors. Urologic care also encompasses vasectomy and plasma concentration of 300 pmol/L of the drug, to treat reversal of vasectomy. vaginal atrophy or for hormone replacement therapy (HRT). 0322 BPH, including chronic prostatitis and chronic pel In general, estradiol can be administered intravaginally in a vic pain syndrome (CP/CPPS) is a common disorder affect dosage amount of 25 about 10 to about 50 ug, preferably ing 50-80% of the aged male population. The cause is attrib about 15 to about 40 g, for example about 25 g, no more than uted to either underlying infection or inflammation and once daily. A Suitable dosage amount of methyltestosterone is treatment and therefore involves antibiotic therapy such as likely to be found in the range of about 0.5 to about 2.5 mg, no fluoroquinolones or ciprofloxacin and anti-inflammatory more than once daily, but greater or lesseramounts can be safe therapy with alpha-adrenergic receptor antagonists such as and effective in particular cases. Other androgens can be alfuZosin. These drugs are typically given systemically usu administered in dosage amounts therapeutically equivalent to ally over the course of two to four months. Localized infec these dosage amounts of methyltestosterone. One of skill in tion and inflammation can be treated much more effectively if the art will understand that amount of hormone (or any other therapy is targeted to the infection site thereby allowing active agent) that can be transferred via a coating to an inter increased local concentrations and reduced systemic toxici vention site will vary depending on the rate of release of the ties. active agent from the coating after transfer. Locally adminis 0323. Using the device and methods of the invention to tered therapies and dosages have been described in, e.g., U.S. apply a drug-releasing coating to the Wall of the prostate, Pat. App. No. 2006/0287611, “Administration of therapeutic treatment agents can be delivered for an extended period (at or diagnostic agents using interlabial pad,” U.S. Pat. No. least two months). Local delivery also reduces the risk of 6,682,757. “Titratable dosage transdermal delivery system.” development of antibiotic resistance. Using a biodegradable WO 03/039553, “Compositions for treatment of postmeno coating matrix, repeat administration can be provided as pausal female sexual dysfunction, all incorporated by refer needed without concerns about build up of polymer. ence herein. 0324 Treatment of BPH and chonic prostatitis are 0319 Pharmaceutical agents useful in these aspects of the described in the literature. See, e.g., Murphy, et al., 2009, invention are active on the vaginal epithelium, mucosa or on "Chronic prostatitis: management strategies, Drugs 69(1): the uterine epithelium or cervix. The pharmaceutical agent is 71-84; Pontari, 2003, “Chronic prostatitis/chronic pelvic pain preferably selected from the group consisting of antifungal, syndrome in elderly men: toward better understanding and antiviral, antibacterial or antiparasitic agents. Examples of treatment. Drugs Aging 20015): 1111-1 115; Mehik, et al., anti-fungal drugs suitable for use in this and other uses of the 2003, Alfuzosin treatment for chronic prostatitis/chronic invention include miconazole, terconazole, isoconazole, fen pelvic pain syndrome: a prospective, randomized, double ticonazole, fluconazole, ketoconazole, clotrimazole, buto blind, placebo-controlled, pilot study. Urology 62(3):425 conazole, econazole, metronidazole, clindamycin, and 429. Wagenlehner, et al., Jun. 3, 2009, “A pollen extract 5-fluoracil. Anti-viral drugs include acyclovir, AZT, famci (Cernilton) in patients with inflammatory chronic prostatitis clovir and vallacyclovir. Antibacterial agents suitable for treat chronic pelvic pain syndrome: a multicentre, randomized, ment of bacterial vaginosis are metronidazole, clindamycin, prospective, double-blind, placebo-controlled phase 3 study.” ampicillin, amoxicillin, tetracycline, doxycycline and other Eur Urol 9 (Epub): Fibbi, et al., Jun. 8, 2009, “Chronic antibiotics. The anti-trichomonas agent Suitable for treatment inflammation in the pathogenesis of benign prostatic hyper of trichomoniasis caused by Trichomonas vaginalis is met plasia.” Int. J. Androl. (Epub). ronidazole. 0325 Stress incontinence, urge incontinence, and pyelitis 0320 “Urologic care” as used herein refers to treatment of pregnancy are common urological conditions in the and prevention of any disease or dysfunction of any part of the female. The most important factor in the production of urge male and female urinary tract and/or the urinary system, and incontinence is infection. Some pathological conditions the male reproductive system. Active agents are contemplated which may be associated with urge incontinence are urethri for use in embodiments of methods and/or devices provided tis, cystitis, urethral stricture, bladder-neck obstruction, ure herein for urologic care. Devices and methods provided thral diverticula, urethral caruncle and the urgency-frequency herein are contemplated for use in Urologic care. The urinary syndrome. Therapy is directed toward the eradication of tract and/or the urinary system consists of the organs involved infection and treatment of the specific lesion. in the production and elimination of liquid waste (urine) from 0326 In embodiments, antiinflammatory or other agents the body: the kidneys, ureters, bladder, and urethra. There are are delivered, e.g., to the posteriorurethra, for treatment of the also two adrenal glands, one on top of each kidney, that pain and inflammation associated with prostatitis/chronic produce important hormones the body needs, which is con pelvic pain syndrome using the devices and methods of the templated to be part of the urinary tract and/or urinary system invention. In embodiments, premature ejaculation caused by US 2010/0015200 A1 Jan. 21, 2010

inflammation is treated in this manner. (See, e.g., A Pontari, are treated by cystoscopic Surgery or in Some cases intravesi M., 2002, “Inflammation and anti-inflammatory therapy in cal drug therapy. In cases where the carcinoma has penetrated chronic prostatis. Urology 60(6Suppl):29-33, and Boneff, the muscular wall of the bladder (i.e. where the cancer has A., 1971, “Topical Treatment of Chronic Prostatitis and Pre progressed to invasive bladder cancer that invades the deeper mature Ejaculation.” International Urology and Nephrology layers of the bladder wall, and possibly nearby organs, such as 4(2): 183-186, describing introduction of a hydrocortisone the uterus, vagina, or prostate gland) metastatic disease is antibiotic mixture into the posterior urethra). likely to occur after Surgery. Additional chemotherapy, either 0327. In embodiments, the devices and methods of the systemic or local, is thus needed. Response to treatment of invention are useful for local delivery of agents including bladder transitional cell carcinoma appears to be related to mitomycin C and BCG for treatment of urinary tract transi drug concentration and duration of exposure, therefore the tional cell carcinoma (TCC). Transitional cell carcinoma capability of the devices and methods of the invention to (TCC, also urothelial cell carcinoma or UCC) is a type of deliver a concentrated dose of agent directly to the treatment cancer that typically occurs in the urinary system: the kidney, site is advantageous for this indication. urinary bladder, and accessory organs. It is the most common 0332 Methods of treatment and agents used in treating type of bladder cancer and cancer of the ureter, urethra, and bladder and urinary tract cancers are described in, e.g., U.S. urachus, and it is the second most common type of kidney Pat. No. 7,326,734, “Treatment of bladder and urinary tract cancer. TCC arises from the transitional epithelium, a tissue cancers,” and U.S. Pat. No. 6,355,691, “Urushiol therapy of lining the inner surface of these hollow organs. Bacillus Cal transitional cell carcinoma of the bladder.” (describing intra mette-Guerin (BCG) therapy and CpG-Oligodeoxynucle vesical administration of urushiol) both incorporated herein otides (CpG-ODN), a synthetic agent, have been used to by reference in their entirety. prevent the recurrence of urinary tract transitional cell carci 0333) A variety of agents have been reported to have sig noma (TCC). Both CpG-ODN and BCG likely work by nificant activity in transitional cell carcinoma of the bladder, stimulating a potent immunological response. They are cur including cisplatin-based regimens such as MVAC (methotr rently infused into the urinary tract through a catheter at exate, vinblastine, doxorubicin, and cisplatin), which has weekly intervals under local anesthesia. This procedure is become standard for patients with metastatic urothelial car unpleasant, cumbersome and expensive. In embodiments, a cinoma. A drawback of MVAC is toxicity and poor patient single, topical application of the an appropriate agent (e.g., tolerance. Local administration of MVAC using the devices BCG, CpG-ODN, and/or mitomycin C) is applied directly to and methods of the invention could allow lower dosages to be the wall of the urethra, particularly near the original lesion administered, resulting in better tolerance. Other agents use site, using, e.g., a foley-type catheter. ful for treating TCC of the bladder are paclitaxel and doc 0328. The use of a bioresorbable polymer with the phar etaxel, gemcitabine, thiotepa, valrubicin, epirubicin, inter maceutical agent can increase the concentration of the agent feron alpha 2b, ifosfamide, and the methotrexate analogues, delivered to the target tissue, retaining it locally, thereby trimetrexate and piritrexim. increasing effectiveness and reducing overall bladder irrita 0334 Bladder cancer is frequently treated by an initial tion. It can also reduce the threat of spread of BCG to sexual instillation of drug, e.g., within 6 hours of tumor resection, partners. Use of a polymer that can provide for controlled followed by a 4-8 week induction treatment, followed by drug delivery over the course of 6-8 weeks can negate the about one year or more of a maintenance regimen. Intravesi need for repeat application procedures. cal combination chemotherapies for administration to 0329. Either alone or in combination with BCG therapy, patients having bladder cancer are described, e.g., by Witjes, the application of mitomycin C can also reduce Subsequent et al., 2008 Jan, “Intravesical pharmacotherapy for non inflammation and promote healing after endoscopic Surgery. muscle-invasive bladder cancer: a critical analysis of cur Local treatment of TCC using BCG, CpG-ODN, and/or mito rently available drugs, treatment schedules, and long-term mycin C is described in the literature, e.g., by: Thalmann, et results. Eur Urol. 53(1):45-52, and Lamm, et al., Ser. No. al., 2002, “Long-term experience with bacillus Calmette 10/26/2005, “Bladder Cancer: Current Optimal Intravesical Guerin therapy of upper urinary tract transitional cell carci Treatment: Pharmacologic Treatment. Urologic Nursing noma in patients not eligible for surgery. JUrol. 168(4 Pt 1): 25(5):323-6, 331-2. 1381-1385; Olbert, et al., 2009, “In vitro and in vivo effects of 0335 Chemotherapy can be administered at or near the CpG-Oligodeoxynucleotides (CpG-ODN) on murine transi time of tumor resection, to prevent tumor recurrence. Immu tional cell carcinoma and on the native murine urinary blad notherapy (e.g., BCG), has been shown to reduce recurrence der wall.” Anticancer Res. 29(6):2067-2076; Melonakos, et when given as maintenance therapy rather than at the time of al., “Treatment of low-grade bulbar transitional cell carci resection. In general, immunotherapy is seen as more effec noma with urethral instillation of mitomycin C, Oct. 28 2008, tive against high-grade carcinoma, and chemotherapy as Adv Urol. 173694 Epub: Di Stasi, et al., 2005, “Percutaneous more effective against low-grade carcinoma. sequential bacillus Calmette-Guerin and mitomycin C for 0336 Chemotherapy agent dosing: The standard intrave panurothelial carcinomatosis. CanJ Urol 12(6):2895-2898. Sicular dosage of thiotepa is 30 mg in 15 cc sterile water. 0330. In specific embodiments, the devices and methods When given as a single instillation at the time of tumor resec of the invention are used for intravesical drug therapy of tion, an exposure of 30 minutes is used. When not given in bladder cancer. In bladder cancer, cancer cells invade the wall conjunction with tumor resection, doses of 30 mg to 60 mg of the bladder. The wall of the bladder consists of several are used in 15 cc to 30 cc of sterile water and held for 2 hours. layers and the treatment modalities used to treat bladder can Treatment is given weekly for 4 to 8 weeks, depending on cer are typically selected on the basis of how far the cancer has volume of residual disease. When repeated treatments are penetrated into the layers of the bladder wall. used, blood counts should be obtained, since thiotepa has a 0331. The majority of superficial tumors (e.g., those that molecular weight of 188 and drugs with molecular weight are confined to the mucosa and lamina propria of the bladder) less than 300 are more readily absorbed from the bladder. US 2010/0015200 A1 Jan. 21, 2010 44

0337 The standard dosage of mitomycin C is 40 mg in 20 bacillus Calmette-Guerin alone previously failed.” Journal of cc sterile water. Mitomycin C should not be given if bladder Urology, 166(4): 1300-1304), about 60% of patients who fail perforation is Suspected. In a randomized study, recurrence to respond to BCG can be rescued with BCG plus interferon was reportedly nearly cut in halfby using an optimized sched alpha. The standard dose is 50 mg to 81 mg of BCG plus 50 ule: 40 mg/20 cc (compared with 20 mg/20 cc), overnight million units of interferon alpha 2b. Treatments are given dehydration, ultrasound-confirmed complete bladder empty weekly for 6 weeks, with maintenance using up to 3 weekly ing, alkalinization using 1.3 g of sodium bicarbonate the night instillations at 3 or 6 months, and then every 6 to 12 months. before, morning of, and 30 minutes prior to treatment. Mito The dose of BCG is reduced to /3, /10, /100 as needed to mycin C is inactivated by acid urine (Au, et al. 2001, “Meth prevent increased side effects. ods to improve efficacy of intravesical mitomycin C: Results 0344. In embodiments, urinary tract cancers are treated of a randomized phase III trial’ Journal of the National Can with radiolabeled or cytotoxic GRP analogs using the devices cer Institute, 93(8), 597-604). It has been reported that that and methods of the invention. High levels of vascular gastrin local hyperthermia, which can be obtained with a microwave releasing peptide (GRP) receptors have been reported in uri applicator inserted into the bladder with a special catheter can nary tract cancers, making these cancers particularly Suitable enhance the efficacy of mitomycin C, albeit with a significant for therapies that target the tumor vascular bed. (See, e.g., increase in Systemic absorption. Fleischmann, et al., Jun 2009, Endocr. Relat. Cancer, 16(2): 0338. The standard dosage of doxorubicin is 50 mg in 25 623-33.) cc of sterile water. Doxorubicin should not be given if bladder (0345 “Gastrointestinal care” or “GI care” as used herein perforation is suspected. Optimal response occurs when refers to the treatment and prevention of diseases and/or ail given as a single instillation at the time of tumor resection. An ments of gastrointestinal system (GI system) and/or the gas exposure of 30 minutes is used when given at the time of trointestional tract (GI tract), which can include treatment and Surgery. When given to treat existing disease rather than pre prevention of diseases and/or ailments of the esophagus, vent recurrence, treatment is held for 2 hours, and given stomach, first, second and third part of the duodenum, weekly for 4 to 8 weeks, depending on volume of residual jejunum, ileum, the ileo-cecal complex, large intestine (as disease. cending, transverse and descending colon) sigmoid colon and 0339. The standard dosage of epirubicin is 80 mg in 40 cc rectum. Active agents are contemplated for use in embodi sterile water. Like doxorubicin, mitomycin C, and valrubicin, ments of methods and/or devices provided herein for gas epirubicin is a vesicant and will result in necrosis with trointestinal care. Devices and methods provided herein are extravasation. Best results occur with immediate postopera contemplated for use in Gastrointestinal care. tive instillation, but instillation should not be done if bladder 0346 Upper gastrointestinal disease includes disease of perforation or any risk for extravasation is present, since this the oral cavity, esophagus, and stomach. Intestinal disease would put the patient at risk for peritonitis. includes disease of the Small intestine, large intestine, disease 0340 Valrubicin was specifically approved for BCG-re that affect both the large and small intestine, and disease of fractory carcinoma in situ of the bladder. The standard dose is the rectum and anus. Disease of the accessory digestive 800 mg in 75 mL normal saline weekly for 6 weeks. glands includes liver, pancreas, gall bladder and bile duct 0341 Immunotherapy agent dosing: Immunotherapies disease. Other gastrointestinal diseases include, e.g., hernia, (also called adjuvant therapies) include not only bacillus Cal peritoneal disease, and gastrointestinal bleeding. mette-Guerin (BCG), as described above, but also Interferon 0347 Diseases of the upper gastrointestinal tract include, Alpha2b. The standard intravesicular dose of BCG is 81 mg e.g., esophagitis, which can becaused by candidiasis, rupture for TheraCys(R) and 50 mg for TICE.R. both in 50 cc physi (Boerhaave syndrome, Mallory-Weiss syndrome), UES (Ze ologic Saline. Treatment should be postponed for at least 1 to nker's diverticulum), LES (Barrett's esophagus), esoph 2 weeks following tumor resection or bladder biopsy. Treat ageal cancers, bacterial infections, viral infections, esoph ments are typically repeated weekly for 6 weeks, with dose ageal motility disorder (Nutcracker esophagus, Achalasia, reductions to /3, /10, /30, or /100 as needed to prevent increas Diffuse esophageal spasm, GERD), esophageal stricture, ing or severe symptoms of bladder irritation. Additional megaesophagus, gastritis (atrophic, Menetrier's disease, gas instillations can be given at 3 months (6 weeks after comple troenteritis), peptic (gastric), ulcer (Cushing ulcer, Dieu tion of the initial 6-week course). Maintenance BCG can be lafoy's lesion), dyspepsia, pyloric Stenosis, achlorhydria, gas provided using up to 3 weekly instillations in disease-free troparesis, gastroptosis, portal hypertensive gastropathy, patients given at 3, 6, 12, 18, 24, 30, and 36 months, and at gastric antral vascular ectasia, gastric dumping syndrome, years (counting from the start of treatment) 4, 5, 6, 8, 10, and and gastric Volvulus. 12 for patients with CIS or high-grade disease. 0348 Diseases of the intestine include, e.g., enteritis 0342 Interferon Alpha2b, which is relatively non-toxic, (duodenitis, jeunitis, ileitis), Peptic (duodenal) ulcer, Curl has been given intravesically in doses as high as 1 billion units ing's ulcer, malabsorption diseases (e.g., coeliac, tropical without dose-limiting side effects. The standard dose is 50 to sprue, blind loop syndrome, Whipple's, short bowel syn 100 million units weekly for 6 weeks. Additional mainte drome, Steatorrhea), cancers, bacterial infections, viral infec nance treatments can be beneficial. tions, appendicitis, colitis (pseudomembranous, ulcerative, 0343 BCG immunotherapy can be combined with chemo ischemic, microscopic, collagenous, lymphocytic), func therapy, e.g., mitomycin C. Combination chemotherapy can tional colonic disease (IBS, intestinal pseudoobstruction/ be used in patients with metastatic transitional cell carci Ogilvie syndrome), megacolon/toxic megacolon, diverticuli noma. Combination immunotherapy, specifically the use of tis? diverticulosis, enterocolitis, IBD, Crohn's disease, BCG plus interferon alpha2b, can be effective. According to vascular diseases (e.g., abdominal angina, mesenteric O'Donnell, et al., 2001, “Salvage intravesical therapy with ischemia, angiodysplasia), bowel obstruction (due to, e.g., interferon-alpha2b plus low dose bacillus Calmette-Guerin is illeus, intussusception, Volvulus), fecal impaction, and diar effective in patients with superficial bladder cancer in whom rhea. US 2010/0015200 A1 Jan. 21, 2010

0349 Diseases of the rectum and anus include proctitis, emphysema, allergic rhinitis, the pulmonary sequelae of cys e.g., radiation proctitis, proctalgia fugax, rectal prolapse, anal tic fibrosis, Churg-Strauss syndrome, mycobacterial diseases fissure/anal fistula, anal cancer, and anal abscess. (caused by, e.g., M. tuberculosis, M. avium), severe acute 0350 Diseases of the accessory digestive glands include respiratory syndrome (SARS), and pneumonia. Active agents diseases that affect the liver, e.g., hepatitis, cirrhosis, fatty are contemplated for use in embodiments of methods and/or liver disease, liver cancer, vascular disease (e.g., hepatic devices provided herein for respiratory care. Veno-occlusive disease, portal hypertension, nutmeg liver), alcoholic liver disease, liver failure, liver abscess, hepatorenal 0356. In embodiments, the invention is used for adminis syndrome, peliosis hepatis, hemochromatosis, and Wilson's tering agents prior to or during endotracheal intubation. Use Disease. Additional accessory digestive gland diseases of an endotracheal tube or laryngeal mask can result in sig include pancreatitis (Acute, Chronic, Hereditary), pancreatic nificant postoperative Sore throat, coughing and hoarseness. cancer, pancreatic pseudocyst, exocrine pancreatic insuffi Lidocaine and betamethasone have been applied topically in ciency, and pancreatic fistula. Gall bladder and bile duct gels or sprays to reduce discomfort. Extended, controlled, diseases include cancers, cholecystitis, gallstones/cholecys local delivery controlled local delivery can provide signifi tolithiasis, cholesterolosis, Rokitansky-Aschoff sinuses, cantly greater benefit. For example, the endotracheal tube or postcholecystectomy syndrome, cholangitis (PSC, Ascend laryngeal mask could be coated, fully or partially, with a ing), cholestasis/Mirizzi's syndrome, biliary fistula, haemo bioresorbable matrix betamethasone (0.05%) or another bilia, gallstones/cholelithiasis, choledocholithiasis, and bil appropriate antiinflammatory agent, and/or lidocaine (2.0-4. iary dyskinesia. 0%), or another appropriate anesthetic. Alternately, the coat 0351. Other diseases affecting the GI system include her ing could be delivered to the tissue via a large balloon-type nias, peritonitis, hemoperitoneum, and pneumoperitoneum. catheter prior to insertion of the endotracheal tube or laryn GI bleeding diseases include, hematemesis, melena, and geal mask. hematochezia. Treatment of any GI system disease includes 0357. In related embodiments, compositions can be administration of drugs in association with Surgery or resec applied via a drug/polymer delivery device prior to endo tion, e.g., chemotherapeutic agents, antibiotics, antiinflam scopic procedures, or applied to the endoscope itself. Topical matory agents, or combinations thereof. administration of local anesthetic agents can reduce a rise in 0352. In certain embodiments, Ankaferd blood stopper, a blood pressure, decrease the time before a patient can drive or medicinal plant extract, is locally delivered to prevent uncon operate machinery, as well as increase comfort during con trolled bleeding of a passageway such as the rectum using the Scious endoscopic procedures such as gastroendoscopy. The devices and methods of the invention. Nasal passageways can use of antiinflammatory or anesthetic agents has been also be treated in a similar manner. Administration of Ankaf described by, e.g.: Sumathi, et al., 2008, "Controlled com erd blood stopper is described by, e.g., Kurt, et al., 2009, parison between betamethasone gel and lidocaine jelly “Tandem oral, rectal, and nasal administrations of Ankaferd applied over tracheal tube to reduce postoperative Sore throat, Blood Stopper to control profuse bleeding leading to hemo cough, and hoarseness of voice. Br. J. Anaesth. 100(2): 215 dynamic instability. Am. J. Emerg. Med. 27(5):631, e1-2. 218; Kazemi, et al., 2007. “The effect of betamethasone gel in 0353. In other embodiments, tacrolimus is administered reducing Sore throat, cough, and hoarsness after laryngo using the devices and methods of the invention to treat resis tracheal intubation. Middle East J Anesthesiol. 19(1): 197 tant ulcerative proctitis. The effect of tacrolimus ointment in 204; Minoque, et al., 2004, “Laryngotracheal topicalization controlling ulcerative proctitis has been described, e.g., by with lidocaine before intubation decreases the incidence of Lawrance, et al., Nov. 15 2008, "Rectal tacrolimus in the coughing on emergence from general anesthesia. Anesth treatment of resistant ulcerative proctitis.” Aliment. Pharma Analg.99(4): 1253-1257; Xue, et al., 2009, “Spray-as-you-go col. Ther. 28(10): 1214-20. airway topical anesthesia in patients with a difficultairway: a 0354. In embodiments, the devices and methods of the randomized, double-blind comparison of 2% and 4% invention are used to protect mucous membranes. For lidocaine.” Anesth Analg. 108(2): 536-543; Ristikankare, et example, the devices and methods of the invention can be al., 2006, "Sedation, topical pharyngeal anesthesia and car used to deliver topical microbicide, rectally or vaginally, for diorespiratory safety during gastroscopy. J Clin Gastroen prevention of transmission of HIV or other STDs. (See, e.g., terol. 40(10):899-905; and Froehlich, et al., 1995, “Con Hladik, et al., 2008, "Can a topical microbicide prevent rectal scious sedation for gastroscopy: patient tolerance and HIV transmission?”. PLoS Med. 5(8):e167.) cardiorespiratory parameters.” Gastroenterology 0355 "Respiratory care” as used herein refers to the 108(3):697-704. therapy, management, rehabilitation, diagnostic evaluation 0358. In embodiments, the devices and methods of the and care of patients with actual or Suspected diseases, includ invention can be used to prevention tracheal Stenosis in upper ing pathogenic infections, or other conditions or ailments that airway Surgery. Topical application of agents including mito affect the upper and/or lower respiratory system and associ mycin C and heparin have been described to improve healing ated aspects of other system functions. It includes the treat and reduce Scarring following laryngeal/tracheal Surgery. The ment or management of acute and chronic breathing disor methods described do not necessarily provide sufficient ders. Active agents are contemplated for use in embodiments delivery time, or thorough coating of the affected area. The of methods and/or devices provided herein for Respiratory devices and methods of the invention can be used for local care. Devices and methods provided herein are contemplated delivery of a bioresorbable polymer/drug mixture, wherein for use in Respiratory care. Typically, the disease or condition the polymer than can deliver active agent over the course of is a respiratory disease or condition, including, but not limited the normal wound healing period, e.g., one to three months. to, inflammatory airway diseases (e.g., asthma, chronic This extended delivery can significantly reduce the need for obstructive pulmonary disease (COPD), bronchiolitis), bron additional Surgery to treat Scarring and Stenosis of the upper chopulmonary dysplasia, croup, bronchitis, bronchiectasis, airways. Current topical applications known to be safe and US 2010/0015200 A1 Jan. 21, 2010 46 somewhat effective use a concentration of about 0.4-0.5 invention are used to administerpainkillers, antibiotics, botu mg/ml (-0.04-0.05%) of mitomycin C or a concentration of linum toxin, and/or anti-inflammatory agents in Vocal cord heparin of about 5000 U/ml. medialization. 0359. In these embodiments, the delivery device can be 0363. In embodiments, the devices and methods of the similar to an endotracheal catheter having a balloon coated invention are used to administer IGF-1 to protect or repair the with the polymer/drug combination. In further embodiments, neurosensory structures in the inner ear. Cochlear adminis one or more repeat procedures are performed after Surgery, as tration of IGF-1, delivered locally via a hydrogel to the round needed, to ensure adequate delivery of active agent over the window membrane, has been reported to prevent hearing loss caused by noise trauma or ischemia. (See, e.g., Fujiwara, et course of the wound healing process. The use of mitomycin C al., “Insulin-like growth factor 1 treatment via hydrogels res or heparin for reducing Scarring after esophageal or tracheal cues cochlear hair cells from ischemic injury’ 29 Oct. 2008, surgery has been described by, e.g.: Smith, et al., 2009, “Mito NeuroReport 19(16): 1585-1588, and Lee, et al., 2007, mycin C and the endoscopic treatment of laryngotracheal “Novel therapy for hearing loss: delivery of insulin-like Stenosis:are two applications better than one'?” Laryngoscope growth factor 1 to the cochlea using gelatin hydrogel Otol. 119(2):272-283: Sen, et al., Feb. 21 2009, “Topical heparin: A Neurotol. 28(7):976-81.) promising agent for the prevention of tracheal Stenosis in 0364 "Ocular care” as used herein refers to the treatment, airway surgery. J Surg ResEpub ahead of print: Warner, et prevention, and diagnosis of disorders of the eye and tear al., 2008, “Mitomycin C and airway surgery: how well does it duct, including but not limited to injury (e.g., blunt trauma, work?” Ontolaryngol Head Neck Surg. 138(6): 700-709. abrasion, and trauma due to Surgery), bacterial infection, viral 0360 “Ear-Nose-Throat care” or “ENT care” as used infection, diabetic retinopathy, artery occlusion, glaucoma, herein refers to diagnosis, treatment and prevention of disor chemical exposure, Sun damage, keratitis, edema, uveitis, ders, including but not limited to cancers, bacterial infections, cancers, AMD, vision defects, etc. and viral infections, of the ENT system, which can include the 0365 For example, the devices and methods of the inven head and neck region, including the ear, nose, throat and tion can be used to administer agents for treatment of infec paranasal sinuses, as well as disorders of the mouth, salivary tion, e.g., antibiotic or anti-inflammatory agents, between the glands, Vocal cords, larynx, face and neck. ENT disorders Sclera and the eyelid, between the Sclera and the conjunctiva, include, but are not limited to, sinusitis, head and neck cancer, trancsclerally to the retina, or within the vitreous (intravitre skin cancers, disorders or enlargement of the tonsils and ally), using methods known in the art. Glaucoma can be adenoids, sleep disorders, vocal cord disorders, e.g., paraly treated using beta blockers (e.g., levobunolol, timolol, betax sis, hearing loss and vertigo, and hoarseness. Active agents olol, and metipranolol), alpha-agonists (e.g., apraclonidine, are contemplated for use in embodiments of methods and/or brimonidine), carbonic anhydrase inhibitors (e.g., dorZola devices provided herein for ENT care. Devices and methods mide, brinzolamide), prostaglandin-like compounds, e.g., provided herein are contemplated for use in ENT care. latanoprost, bimatoprost, and travoprost, miotic or cholin 0361. In particular embodiments, sinusitis and other sinus ergic agents (e.g., pilocarpine, carbachol), epinephrine com disorders are treated using the methods of the invention. The pounds (e.g., diplivefrin), carbonic anhydrase inhibitors (e.g., sinus system consists of many different pathways, called acetazolamide, methazolamide) or with neuroprotective ducts or ostia, which allow mucus, air and other Substances to drugs, e.g., memantine and brimonidine. As is the case in drain and flow through the system. Inflammation can occur in other uses of the invention, agents typically taken orally can the tissues that make up the ducts and ostia, causing them to be given at much lower doses when administered locally, swell and block the normal flow. Inflammation may becaused reducing the occurrence of adverse side effects. Unwanted by allergies, noxious agents, nasal polyps, and other factors. angiogenesis can be treated using, e.g., angiogenesis inhibi Over time there can be a pathologic increase in inflamed tors including antisense agents (e.g., Macugen), thalidomide, tissue causing permanent disruption in the flow through the and EM-138. U.S. Pat. No. 7,524,865, “Methods and compo sinus system. Obstruction of the narrow ducts and ostia sitions for treating an ocular neovascular disease, incorpo between the paranasal sinuses and nasal cavity develops, rated herein by reference in its entirety, describes ocular dis resulting in a vicious cycle of increased secretions, edema and eases and their treatment using angiogenesis inhibitors. ultimately complete blockage of the sinus pathways. The Accessing the vitreous for drug administration is described, state of chronic sinus inflammation is called sinusitis. Sinusi e.g., in U.S. Pat. No. 7,485,113, “Method for drug delivery tis can both be caused by and can cause a narrowing of the through the vitreous humor, incorporated herein by refer sinus ostia. In some embodiments, the intervention site is a ence in its entirety. sinus cavity wall. In some embodiments, the active agent 0366 “Orthopedic care” as used herein refers to the treat comprises a corticosteroid to treat sinusitis, either alone or in ment, prevention, and diagnosis of orthopedic diseases and conjunction with an antibiotic agent. Methods for accessing conditions, including but not limited to developmental dis sinus ostia or sinus cavities using devices including balloon eases, genetic diseases, injuries, infections, and cancers of the catheters, for dilating the ostia of paranasal sinuses are bones (including the spine and spinal cord), muscles, tendons, described, e.g., in U.S. Pat. Appl. No. 2009/0076446, and joints. Such conditions include diseased, injured, or “Adjustable catheter for dilation in the ear, nose or throat.” abnormal cartilage, bursitis, osteonecrosis, carpal tunnel Syn incorporated herein by reference in its entirety. In some drome, joint pain, and joint injuries, e.g., knee injury. Joint embodiments, the active agent comprises a corticosteroid. pain not due to injury can be caused by inflammation, for 0362. In embodiments, agents including but not limited to example in gout, sacroiliitis, and arthritis. Examples of types chemotherapeutic, antibiotic, orantiinflammatory agents or a ofarthritis that can be treated using the device and methods of combination thereof are administered in the treatment of the invention include osteoarthritis, rheumatoid arthritis, and laryngeal cancer using the devices and methods of the inven infectious arthritis. Infectious arthritis is commonly caused tion. In other embodiments, the devices and methods of the by Staphylococcus aureus, and also can be caused by gonor US 2010/0015200 A1 Jan. 21, 2010 47 rhea or fungi. Developmental orthopedic diseases (DOD) a duration of about 3 months to about 10 years. In embodi include Osteochondritis dissecans, subchondral cystic ments, Sustained release is provided for about 6 months to lesions, physitis, flexural deformities, angular deformities, about 5 years. In certain embodiments, Sustained release of a cuboidal bone disease, and juvenile osteoarthritis. In embodi therapeutically effective compound is provided for about 1 ments, the device and methods of the invention are used to year, 2 years, 3 years, or 4 years, or longer. As a result, the treat arthritis pain and neuropathic pain. In other embodi need for frequent, repeated administrations, such as with ments, the device and methods of the invention are used to injections, is avoided. encourage tissue in-growth following, e.g., injury, Surgery, 0370 “Spinal care” as used herein refers to the treatment, abcess, tumor removal, around orthopedic or cosmetic prevention, and diagnosis of spine and spinal cord diseases implants, etc. For example, agents that can be administered and conditions, including but not limited to developmental include growth hormones, cytokines, e.g., anti-inflammatory and genetic diseases, injuries, infections, and cancers of the agents, stem or regenerative cells, BDNF, fibroblast growth spine and spinal cord, including, e.g., degenerative conditions factors, platelet-derived growth factors, growth differentia (e.g., herniated cervical disc, herniated lumbar disc, spondy tion factors, bone morphogenetic proteins, transforming lolysis, spondylolisthesis, Stenosis, and osteoporosis), anky growth factors, e.g., TGF-betal, cartilage-derived morpho losing spondylitis, Adolescent Idiopathic Scoliosis, spinal genic proteins, vascular endothelial growth factors, epider cord injury, spinal infection; spinal tumor, whiplash. Active mal growth factors, hepatocyte growth factors, insulingrowth agents are contemplated for use in embodiments of methods factors, angiogenic factors, etc. and/or devices provided herein for Spinal care. Devices and 0367. In embodiments, the device and methods of the methods provided herein are contemplated for use in Spinal invention are used to administer therapeutic agents for the Ca treatment of orthopedic diseases and conditions, either alone, 0371. In embodiments, the device and methods of the in conjunction with, or in place of other therapies and/or invention are used to administer therapeutic agents for the Surgery and/or diagnostic procedures, including but not lim treatment of spine and spinal cord diseases and conditions, ited to ACL Surgery and other knee Surgeries, rotator cuff either alone, in conjunction with, or in place of other thera Surgery, joint replacement Surgery, bone grafts, osteotomy, or pies, Surgery, diagnostic procedures, and combinations core decompression. Active agents are contemplated for use thereof, including but not limited to discectomy, fusion, lami in embodiments of methods and/or devices provided herein nectomy or laminotomy, Intradiscal Electrothermal Therapy for Orthopedic care. Devices and methods provided herein (IDET), Percutaneous Vertebral Augmentation (PVA), Arti are contemplated for use in Orthopedic care. ficial Disc Replacement (ADR), vertebroplasty, joint injec 0368. In embodiments, drugs or compounds useful in the tions, epidural injections, laparascopic spine Surgery, and devices and methods of the invention either alone or in com MRI of the spine. bination for treating orthopedic diseases and conditions 0372. In embodiments, the devices and methods of the include, but are not limited to, Steroids, anti-inflammatory invention are used to administer agents for Sustained release drugs, antibiotics, anti-viral agents, cancer-fighting drugs (in in the treatment of degenerative disc disease. Agents useful cluding antioneoplastic, antiproliferative, antimycotic, and for treatment of degenerative disc disease include, e.g., MMP antimetabolite compounds), glucocorticoid anti-inflammato inhibitors. ries (such as dexamethasone, fluocinolone, cortisone, pred 0373. In embodiments, the devices and methods of the nisolone, flumetholone, and derivatives thereof), non-steroi invention are used to provide at least one agent to, e.g., the dal anti-inflammatory drugs (NSAIDs), immune nucleus pulposus of a degenerating disc, the annulus fibroSuS Suppressants, antibiotics, cartilage protectants, disease modi of a degenerating disc, the outer wall of the annulus fibrosus, fying anti-rheumatic drugs (e.g., adalimumab, azathioprine, at a location outside but closely closely adjacent to an outer chloroquine, hydroxychloroquine, cyclosporine, D-penicil wall of the annulus fibrosus and/or at a location outside but lamine, etanercept, gold salts, including sodium aurothioma closely adjacent to an endplate of an adjacent vertebral body. late and auranofin, infliximab, leflunomide, methotrexate, Agents and dosages for Sustained release treatment of degen minocycline, and Sulfasalazine), chondroitin Sulfate, enzyme erative disc disease are described in, e.g., U.S. Pat. No. 7,553, inhibitors, and/or antisense compounds such as antisense oli 827. “Transdiscal administration of cycline compounds, and gonucleotides, and pain relieving agents. Specific agents use U.S. Pat. No. 7,429,378, “Transdiscal administration of high ful in the devices and methods of the invention include, but affinity anti-MMP inhibitors, incorporated herein by refer are not limited to, corticosteroids such as dexamethasone and ence in their entirety. triamcinolone acetonide, angiostatic steroids such as anecor 0374. In embodiments, drugs or compounds useful in the tave acetate, antibiotics including ciprofloxacin, non-steroi devices and methods of the invention either alone or in com dal anti-inflammatory agents such as indomethacin and flur bination for treating spine and spinal cord diseases and con biprofen, co-drugs including low-solubility co-drugs of salts ditions include, but are not limited to, the agents as described or conjugates of synergistic pharmacological agents such as herein with regard to orthopedic care. In additionn, antibiot Suramin/amiloride or 5-FU/THS, Bone Morphogenetic Pro ics useful for treatment of spinal tuberculosis include, e.g., tein (BMP), cell-based therapies (e.g., stem or regenerative combination drug therapy with isoniazid and rifampicin. In cells), imaging agents, and combinations thereof. Drugs and embodiments, the devices and methods of the invention are formulations for treating joint conditions are described, e.g., used to administer analgesics, e.g., morphine, fentanyl, and/ in U.S. Pat. No. 6,936,270 “Device and method for treating or bupivacaine in the epidural space of the spinal cord, for conditions of a joint, incorporated herein by reference in its treatment of pain resulting from Surgery, including but not entirety. limited to spinal or other orthopedic Surgery, gynecological 0369. In embodiments of the devices and methods of the Surgery, abdominal Surgery, and other major Surgical proce invention, joint conditions are treated by providing Sustained dures. Appropriate dosages and administration times for epi release of at least one therapeutically effective compound for durally-administered analgesics have been reported and are US 2010/0015200 A1 Jan. 21, 2010 48 known to those of skill in the art. Continuous epidural admin comprise a shearing force, a compressive force, a force istration offers a safety advantage over intermittent epidural exerted on the coating from a substrate side of the coating, a injections because peak and trough levels of the analgesic force exerted on the coating by the substrate, a force exerted agent are avoided. Furthermore, administration using the on the coating by an external element, a translation, a rotation, devices and methods of the invention avoids complications a vibration, or a combination thereof In embodiments, the associated with the extended use of an epidural catheter. mechanical stimulation comprises balloon expansion, stent 0375 “Cosmetic care” as used herein refers to surgical and expansion, etc. In embodiments, the mechanical stimulation nonsurgical procedures that alter the appearance of body is adapted to augment the freeing, dissociation and/or transfer structures, to improve the patient's appearance and/or for of the coating from the substrate. In embodiments, the reconstructive ortherapeutic purposes. Active agents are con mechanical stimulation is adapted to initiate the freeing, dis templated for use in embodiments of methods and/or devices Sociation and/or transfer of the coating from the Substrate. In provided herein for Cosmetic care. Devices and methods embodiments, the mechanical stimulation can be adapted to provided herein are contemplated for use in Cosmetic care. cause the freeing, dissociation and/or transference of the coat Cosmetic care procedures include, but are not limited to, ing from the Substrate. In embodiments, an external element breast augmentation, breast reduction, breast reshaping, is a part of the subject. In embodiments, the external element body-contouring (e.g., via liposuction or lipectomy), gastric is not part of the device. In embodiments the external element bypass Surgery, stomach stapling, Lap Band Surgery, abdomi comprises a liquid, e.g., Saline or water. In certain embodi noplasty, use of facial fillers, facial implants, neck lift, ble ments the liquid is forced between the coating and the Sub pharoplasty, dacryocystorhynostomy, chemical skin resur strate. In embodiments, the mechanical stimulation com facing, laser skin resurfacing, Sclerotherapy, phlebectomy, prises a geometric configuration of the Substrate that dermabrasion, face lift, lip augmentation and/or restructur maximizes a shear force on the coating. ing, rhinoplasty, ear restructuring, hair replacement, hair 0380 "Chemical Stimulation” as used herein refers to use removal, wound, scar, or lesion treatment (e.g., laser removal of a chemical force to influence the freeing, dissociation, of skin cancertissue), grafting, flap Surgery, micropigmenta and/or transfer of the coating from the substrate. For example, tion, tissue expansion, and the use of coatings on tissue chemical stimulation can comprise bulk degradation, interac expanders, breast implants, and on Solid molded products (for tion with a bodily fluid, interaction with a bodily tissue, a rhinoplasty, chin implants, etc.). Reconstructive procedures chemical interaction with a non-bodily fluid, a chemical inter are intended to repair or alter the appearance of defects or action with a chemical, an acid-base reaction, an enzymatic structural abnormalities caused by, e.g., congenital defects, reaction, hydrolysis, or a combination thereof. In embodi developmental abnormalities, trauma, infection, tumors or ments, the chemical stimulation is adapted to augment the disease, and/or meant to improve body function or a patient's freeing, dissociation and/or transfer of the coating from the health. Many reconstructive care procedures also serve a cos Substrate. In embodiments, the chemical stimulation is metic purpose, for example, breast reconstruction after full or adapted to initiate the freeing, dissociation and/or transfer of partial mastectomy, breast reduction to ease discomfort, the coating from the Substrate. In embodiments, the chemical repair of congenital cleft lip and palate, and blepharoplasty stimulation is adapted to cause the freeing, dissociation and/ (e.g., when dropping eyelids are obscuring a patient's vision). or transfer of the coating from the substrate. In embodiments, 0376 Cosmetic care procedures, particularly reconstruc the chemical stimulation is achieved through the use of a tive procedures performed using the devices and/or methods coating that comprises a material that is adapted to transfer, of the invention, may require the use of biomedical implants, free, and/or dissociate from the substrate when at the inter which are coated with at least one pharmaceutical agent. For vention site in response to an in-situ enzymatic reaction example, the devices and methods of the invention can be resulting in a weak bond between the coating and the Sub used, in conjunction with electroSurgery for tissue ablation, to Strate. treat a Surgery site with agents including but not limited to 0381 “Thermal Stimulation” as used herein refers to use antiinflammatory agents, vasoconstrictors (such as epineph of a thermal stimulus to influence the freeing, dissociation, rine), antibiotics, painkillers, or combinations thereof in both and/or transfer of the coating from the substrate. For example, cosmetic procedures and non-cosmetic therapeutic proce thermal stimulation can comprise at least one of a hot stimu dures. Electrosurgery is described in, e.g., U.S. Pat. No. lus and a cold stimulus. In embodiments, thermal stimulation 7,201,750 “System for treating articular cartilage defects.” comprises at least one of a hot stimulus and a cold stimulus incorporated herein by reference in its entirety. adapted to augment the freeing, dissociation and/or transfer 0377 “Canniluzation' or “Cannulize' or “Cannulizable' ence of the coating from the Substrate. In embodiments, ther as used herein refers to the insertion of a cannula or tube, e.g., mal stimulation comprises at least one of a hot stimulus and a at or near an intervention site. “Cannulizable' as used herein cold stimulus adapted to initiate the freeing, dissociation refers to a location, e.g., a vessel or other lumen or opening, and/or transference of the coating from the Substrate. In into which a cannula can be inserted. embodiments, thermal stimulation comprises at least one of a 0378 “Stimulation' as used herein refers to any mechani hot stimulus and a cold stimulus adapted to cause the freeing, cal stimulation, chemical stimulation, thermal stimulation, dissociation and/or transference of the coating from the Sub electromagnetic stimulation, and/or Sonic stimulation that Strate. influences, causes, initiates, and/or results in the freeing, dis 0382 "Electromagnetic Stimulation' as used herein refers Sociation, and/or the transfer of the coating and/or active to use of an electromagnetic stimulus to influence the freeing, agent from the Substrate. dissociation, and/or transfer of the coating from the Substrate. 0379 “Mechanical Stimulation as used herein refers to For example, the electromagnetic stimulation is an electro use of a mechanical force that influences the freeing, disso magnetic wave comprising at least one of, e.g., a radio wave, ciation, and/or transfer of the coating and/or the active agent a micro wave, a infrared wave, near infrared wave, a visible from the Substrate. For example, mechanical stimulation can light wave, an ultraViolet wave, a X-ray wave, and a gamma US 2010/0015200 A1 Jan. 21, 2010 49 wave. In embodiments, the electromagnetic stimulation is 0385. In some embodiments, the release agent comprises a adapted to augment the freeing, dissociation and/or transfer Viscous fluid. In some embodiments, the viscous fluid com ence of the coating from the Substrate. In embodiments, the prises oil. In some embodiments, the viscous fluid is a fluid electromagnetic stimulation is adapted to initiate the freeing, that is viscous relative to water. In some embodiments, the dissociation and/or transference of the coating from the Sub viscous fluid is a fluid that is viscous relative to blood. In some strate. In embodiments, the electromagnetic stimulation is embodiments, the viscous fluid is a fluid that is viscous rela adapted to cause the freeing, dissociation and/or transference tive tourine. In some embodiments, the viscous fluid is a fluid of the coating from the substrate. that is viscous relative to bile. In some embodiments, the viscous fluid is a fluid that is viscous relative to synovial fluid. 0383 “Sonic Stimulation” as used herein refers to use of a In some embodiments, the viscous fluid is a fluid that is Sonic stimulus to influence the freeing, dissociation, and/or Viscous relative to Saline. In some embodiments, the Viscous transfer of the coating from the Substrate. For example, Sonic fluid is a fluid that is viscous relative to a bodily fluid at the stimulation can comprise a sound wave, wherein the Sound intervention site. wave is at least one of an ultrasound wave, an acoustic Sound 0386. In some embodiments, the release agent comprises a wave, and an infrasound wave. In embodiments, the Sonic physical characteristic of the Substrate. In some embodi stimulation is adapted to augment the freeing, dissociation ments, the physical characteristic of the Substrate comprises and/or transfer of the coating from the substrate. In embodi at least one of a patterned coating Surface and a ribbed coating ments, the Sonic stimulation is adapted to initiate the freeing, Surface. In some embodiments, the patterned coating Surface dissociation and/or transfer of the coating from the Substrate. comprises a stent framework. In some embodiments, the In embodiments, the Sonic stimulation is adapted to cause the ribbed coating Surface comprises an undulating Substrate Sur freeing, dissociation and/or transfer of the coating from the face. In some embodiments, the ribbed coating Surface com substrate. prises an Substrate Surface having bumps thereon. 0384) “Release Agent” as used herein refers to a substance 0387. In some embodiments, the release agent comprises a or Substrate structure that influences the ease, rate, or extent, physical characteristic of the coating. In some embodiments, of release of the coating from the substrate. In certain embodi the physical characteristic of the coating comprises a pattern. ments wherein the device is adapted to transfer a portion of In some embodiments, the pattern is a textured Surface on the the coating and/or active agent from the Substrate to the inter substrate side of the coating, wherein the substrate side of the vention site, the device can be so adapted by, e.g., Substrate coating is the part of the coating on the Substrate. In some attributes and/or surface modification of the substrate (for embodiments, the pattern is a textured surface on the inter non-limiting example: Substrate composition, Substrate mate vention site side of the coating, wherein the intervention site rials, Substrate shape, Substrate deployment attributes. Sub side of the coating is the part of the coating that is transferred strate delivery attributes, substrate pattern, and/or substrate to, and/or delivered to, and/or deposited at the intervention texture), the delivery system of the substrate and coating (for site. non-limiting example: control over the Substrate, control over 0388 “Extrusion' and/or “Extruded and/or to “Extrude' the coating using the delivery system, the type of delivery as used herein refers to the movement of a Substance away system provided, the materials of the delivery system, and/or from another Substance or object, especially upon stimula combinations thereof), coating attributes and/or physical tion, e.g., by a mechanical force. For example, in embodi characteristics of the coating (for non-limiting example: ments of the invention, the coating is extruded from the Sub selection of the active agent and/or the polymer and/or the Strate. polymer-active agent composition, or by the coating having a 0389 Provided herein is a medical device comprising a particular pattern-e.g. a ribbed pattern, a textured Surface, a Substrate and a coating on at least a portion of said Substrate, Smooth Surface, and/or another pattern, coating thickness, wherein said coating comprises an active agent, wherein the coating layers, and/or another physical and/or compositional coating is patterned, and wherein at least a portion of the attribute), release agent attributes (for non-limiting example: coating is adapted to free from the Substrate upon stimulation through the selection a particular release agent and/or the of the coating. manner in which the release agent is employed to transfer the 0390 Provided herein is a medical device comprising a coating and/or the active agent, and/or the amount of the Substrate and a coating on at least a portion of said Substrate, release agent used), and/or a combination thereof. Release wherein said coating comprises an active agent, wherein the agents may include biocompatible release agents, non-bio coating is patterned, and wherein at least a portion of the compatible release agents to aggravate and/or otherwise coating is adapted to dissociate from the Substrate upon induce a healing response or induce inflammation, powder stimulation of the coating. release agents, lubricants (e.g. ePTFE, Sugars, other known 0391 Provided herein is a medical device comprising a lubricants), micronized drugs as the release agent (to create a Substrate and a coating on at least a portion of said Substrate, burst layer after the coating is freed from the substrate, physi wherein said coating comprises an active agent, wherein the cal release agents (patterning of the Substrate to free the coating is patterned, and wherein at least a portion of the coating, others), and/or agents that change properties upon coating is adapted to transfer from the Substrate to an inter insertion (e.g. gels, lipid films, vitamin E, oil, mucosal adhe vention site upon stimulation of the coating. sives, adherent hydrogels, etc.). Methods of patterning a Sub 0392. In some embodiments, the patterned coating com strate are described, e.g., in U.S. Pat. No. 7,537,610, “Method prises at least two different shapes. and system for creating a textured surface on an implantable 0393. “Patterned as used herein in reference to the coat medical device.” In embodiments, more than one release ing refers to a coating having at least two different shapes. The agent is used, for example, the Substrate can be patterned and shapes can be formed by various methods, including for also lubricated. In some embodiments, the release agent com example, etching, masking, electrostatic capture, and/or by prises a viscous fluid. the coating methods described herein. For example the coat US 2010/0015200 A1 Jan. 21, 2010 50 ing may have Voids that are at least partially through the and 'I (59.5 days); PET radionuclides, e.g. 'O (2.07 min), thickness of the coating. In some embodiments, the Voids 'N (10 min), ''C (20.3 min), F (1.83 h), 'I (4.2 days) and extend fully through the coating. The Voids may be in a Tc" (53 min); Gd-DTPA (gadolinium diethylenetriamine regular configuration, or irregular in shape. The Voids may pentaacetic acid); Echo-Coat, an ultrasound imaging agent form a repeating configuration to form the patterned coating. (STS-Biopolymers); and barium sulfate. In embodiments The voids may have been removed from a smooth or solid employing nanoparticles, it is important that the particles are coating to form a patterned coating. The coating may in some Small enough to allow renal clearance (e.g. have a hydrody embodiments be patterned by having a surface that is ribbed, wavy or bumpy. The coating may in Some embodiments be namic diameter less than 5.5 nm) and contain non-toxic com patterned by having been cut and/or etched from a coating ponents, and that the material decomposition products can be sheath and/or sheet in a particular design. The sheath and/or eliminated from the body. It is understood that an imaging sheet in Such embodiments may have been formed using the agent can be conjugated or otherwise attached or associated coating methods for manufacture as described herein. The with a compound in the coating according to methods known pattern design may be chosen to improve the freeing, transfer, to those of skill in the art to forman image enhanced polymer. and/or dissociation from the Substrate. The pattern design 0398 Biological imaging agents useful in embodiments may be chosen to improve the transfer and/or delivery to the of the device and methods of the present invention are intervention site. described in, e.g.: U.S. Pat. No. 6,077,880, “Highly radio 0394 Patterned coatings may be created using the meth paque polyolefins and method for making the same which ods and processes described herein, for non-limiting sets forth a highly radiopaque polyolefin; U.S. Pat. No. 7,229. example, by providing a Substrate having a patterned design 837, “Enhanced photophysics of conjugated polymers.” relat thereon comprising, for example, a material that is chosen to ing to fluorescent ionic conjugated polymers; Dzik-Jurasz, selectively capture the coating particles (whether active 2003, “Molecular imaging in vivo: an introduction. The agent, polymer, or other coating particles) to coat only a British Journal of Radiology, 76: S98-S109, providing an desired portion of the substrate. This portion that is coated overview of in vivo molecular imaging methods; Von Zur may be the patterned design of the Substrate. Muhlen, et al., 2008, Magnetic Resonance Imaging Contrast 0395. The term “image enhanced polymer or “imaging Agent Targeted Toward Activated Platelets Allows In Vivo agent as used herein refer to an agent that can be used with Detection of Thrombosis and Monitoring of Thrombolysis the devices and methods of the invention to view at least one Circulation. 118:258-267, reporting imaging of activated component of the coating, either while the coating is on the platelets using an antibody-containing MRI imaging agent; substrate or after it is freed, dissociated and/or transferred. In and Green, et al., “Simple conjugated polymer nanoparticles embodiments, an image enhanced polymer serves as a tracer, as biological labels. Proc. Roy. Soc. A published online 24 allowing the movement or location of the coated device to be Jun. 2009 doi:10.1098/rspa. 2009.0181, describing the use of identified, e.g., using an imaging system. In other embodi nanoparticles of conjugated polymers in biological imaging; ments, an image enhanced polymer allows the practitioner to all incorporated herein by reference in their entirety. monitor the delivery and movement of a coating component. In embodiments, use of an image enhanced polymer enables Certain Applications of the Technology the practitioner to determine the dose of a component of the coating (e.g., the active agent) that is freed, dissociated and/or 0399 Provided herein is a medical device comprising a transferred. Information provided by the image enhanced Substrate and a coating on at least a portion of the Substrate, polymer or imaging agent about the amount of coating trans wherein the coating comprises a plurality of layers, wherein ferred to the intervention site can allow the practitioner to at least one layer comprises a pharmaceutical agent in a determine the rate at which the coating will be released, therapeutically desirable morphology, and wherein the device thereby allowing prediction of dosing over time. Imaging is adapted to free at least a portion of the coating from the agents may comprise barium compounds such as, for non Substrate upon stimulation of the coating. limiting example, barium sulfate. Imaging agents may com 0400 Provided herein is a medical device comprising a prise iodine compounds. Imaging agents may comprise any Substrate and a coating on at least a portion of the Substrate, compound that improves radiopacity. wherein the coating comprises a plurality of layers, wherein 0396. In embodiments, an image enhanced polymer is at least one layer comprises a pharmaceutical agent in a used with the device and methods of the invention for a therapeutically desirable morphology, and wherein the device purpose including, but not limited to, one or more of the is adapted to dissociate at least a portion of the coating from following: monitoring the location of the Substrate, e.g., a the Substrate upon stimulation of the coating. balloon or other device; assessing physiological parameters, 04.01 Provided herein is a medical device comprising a e.g., flow and perfusion; and targeting to a specific molecule. Substrate and a coating on at least a portion of said Substrate, In embodiments, “smart’ agents that activate only in the wherein the coating comprises a plurality of layers, wherein presence of their intended target are used with the device and at least one layer comprises a pharmaceutical agent in a methods of the invention. therapeutically desirable morphology, and wherein the device 0397. In embodiments, imaging agents useful with the is adapted to transfer at least a portion of the coating from the device and methods of the present invention include, for Substrate to an intervention site upon stimulation of the coat example: EgadMe (in which a galactopyranose ring is syn ing. thesized to protect a Gd(III) ion from bulk water); conjugated 0402 Provided herein is a medical device comprising a polymer MEH-PPV nanoparticles; bismuth trioxide; near Substrate and a coating on at least a portion of said Substrate, infrared (NIR) fluorochromes; bioluminescence agents (e.g., wherein said coating is at least partially continuous, has at green fluorescent protein, red fluorescent protein); SPECT least one portion conformal to the Substrate, and comprises a radionuclides, e.g., 'Tc" (6 h), '''In (2.8 days), 'I (13.2h) pharmaceutical agent in a therapeutically desirable morphol US 2010/0015200 A1 Jan. 21, 2010

ogy, and wherein the device is adapted to free at least a portion the Substrate at an intervention site. In some embodiments, of the coating from the Substrate upon stimulation of the the device is adapted to free the portion of the coating from the coating. Substrate at the intervention site upon stimulation of the coat 0403 Provided herein is a medical device comprising:a ing. Substrate and a coating on at least a portion of said Substrate, 0411 Provided herein is a medical device comprising: a wherein said coating is at least partially continuous, has at Substrate; and a coating on at least a portion of said Substrate, least one portion conformal to the Substrate, and comprises a wherein said coating comprises an active agent, wherein the pharmaceutical agent in a therapeutically desirable morphol device is adapted to dissociate at least a portion of the coating ogy, and wherein the device is adapted to dissociate at least a from the substrate at an intervention site. In some embodi portion of the coating from the Substrate upon stimulation of ments, the device is adapted to dissociate the portion of the the coating. coating from the Substrate at the intervention site upon stimu 0404 Provided herein is a medical device comprising a lation of the coating. Substrate and a coating on at least a portion of said Substrate, 0412 Provided herein is a medical device comprising: a wherein said coating is at least partially continuous, has at Substrate; and a coating on at least a portion of said Substrate, least one portion conformal to the Substrate, and comprises a wherein said coating comprises an active agent, wherein the pharmaceutical agent in a therapeutically desirable morphol device is adapted to dissociate at least a portion of the coating ogy, and wherein the device is adapted to transfer at least a from the substrate and to deliver said portion of the coating to portion of the coating from the Substrate to an intervention an intervention site. In some embodiments, the device is site upon stimulation of the coating. adapted to deliver the portion of the coating to the interven 0405. In some embodiments, the therapeutically desirable tion site upon stimulation of the coating. morphology comprises a crystalline form of the pharmaceu 0413 Provided herein are drug delivery devices and meth tical agent that is not a microcapsule. ods that provide (1) a drug or multiple drugs in the form of for 0406 Provided herein is a medical device comprising: a example, films, Solid solutions, particle mixtures containing Substrate; and a coating on at least a portion of said Substrate, nano, - micro and/or macro particles. The particles may be wherein said coating comprises an active agent, and wherein coated particles, polymerized particles containing one drug at least a portion of the coating is adapted to transfer from the ormultiple drugs optionally mixed with a polymer or multiple Substrate to an intervention site. In some embodiments, the polymers. The polymers may be permanent or bioabsorbable. portion of the coating is adapted to transfer from the Substrate 0414. One embodiment provides a percutaneous medical to the intervention site upon stimulation of the coating. In device with a coating that, upon deployment in the body, Some embodiments, the device is adapted to transfer the por delivers some or all of the coating to a specific therapeutic site tion of the coating from the substrate to the intervention site in the body. The device can be a permanent implant, for upon stimulation of the Substrate. In some embodiments, example a stent, or a transient device, such as a balloon stimulation of the coating is achieved by Stimulation of the catheter. Several other types of devices are contemplated in Substrate. In some embodiments, stimulation of the Substrate the present application. Another embodiment provides translates into a stimulation of the coating to transfer the intraocular drug delivery device. Another embodiment pro coating portion from the Substrate to the intervention site. vides a surgical tool. An illustrative but non-exhaustive list of 04.07 Provided herein is a medical device comprising: a devices contemplated herein is provided herein. Substrate; and a coating on at least a portion of said Substrate, 0415. In one embodiment, delivery of the coating to the wherein said coating comprises an active agent, and wherein tissue at a site inside the body of a subject occurs by a coating at least a portion of the active agent is adapted to transfer from that dissociates from the substrate via: (1) plastic deformation the Substrate to an intervention site. In some embodiments, of the coating by compressive, shear, internally generated the portion of the active agent is adapted to transfer from the and/or externally generated forces, (2) shearing of the coating substrate to the intervention site upon stimulation of the coat from the surface of the device, (3) bulk migration of the ing. coating from the device into the tissue, and/or (4) separation 0408 Provided herein is a medical device comprising: a from the device due to hydrolysis of the polymer, resulting in Substrate; and a coating on at least a portion of said Substrate, a weak bond between the coating and the device. The devices wherein said coating comprises an active agent, and wherein provided herein are for the transfer of some or all of the the device is adapted to transfer at least a portion of the coating from the device to the local tissue to provide a tar coating from the Substrate to an intervention site. In some geted therapeutic effect. In some embodiments (need more embodiments, the device is adapted to transfer the portion of details of dissociation from the “stimulation' and other the coating (coating portion) from the Substrate to the inter ideas in the claims) vention site upon stimulation of the coating. 0416) The devices and method provided herein allow for 04.09 Provided herein is a medical device comprising: a intervention at targeted disease-states that in some embodi Substrate; and a coating on at least a portion of said Substrate, ments are site-specific medical indications, including without wherein said coating comprises an active agent, and wherein limitation lesions, occlusions, infections, tumors, regional the device is adapted to transfer at least a portion of the active sites for tumor therapy Such as intraperitoneal delivery, local agent from the Substrate to an intervention site. In some sites of angiogenesis or inflammation Such as sites within the embodiments, the device is adapted to transfer the portion of eye or retina, gingival delivery for periodontal disease, within the active agent from the substrate to the intervention site the joints in the synovial fluid, in the ventricle to delivery to upon stimulation of the coating. the CNS spinal fluid, and embolic devices that also delivery 0410 Provided herein is a medical device comprising: a drugs. Substrate; and a coating on at least a portion of said Substrate, 0417. The devices and methods provided herein are con wherein said coating comprises an active agent, wherein the templated to be used in the treatment of any disease that device is adapted to free at least a portion of the coating from would benefit from targeted local delivery of a pharmaceuti US 2010/0015200 A1 Jan. 21, 2010 52 cal and/or active biological agent. Examples of diseases allow direct control of the delivering, depositing, and/or tack include without limitation coronary artery disease, peripheral ing of the coating at and/or to the intervention site. In some artery disease (e.g. carotid, femorial, etc), urinary tract embodiments, the coating comprises laminated layers that obstructions and/or infections, biliary tract obstructions and/ allow direct control of the transferring, freeing, depositing, or infections, tumors/cancer, vascular obstructions (e.g. tacking, and/or dissociating of the coating from the Substrate, embolisms, lacunar or embolic stroke, Varicose veins, etc.), wherein at least one of the layers comprises the active agent. neurological disorders, post-operative infections, diseases of In some embodiments, the coating comprises laminated lay the GI tract, diseases of the reproductive system (fallopian ers that allow direct control of the transferring, freeing, tubes), diseases of the Ear-Nose-Throat and any disease asso depositing, tacking, and/or dissociating of the coating from ciated with an impairment of flow through a body tubular the substrate, wherein at least one of the layers comprises the structure (e.g.,dry eye). pharmaceutical agent. The embodiments incorporating a 0418. In one embodiment, the coating comprises one or stent form or framework provide the ability to radiographi more drugs, optionally one or more adjuncts or excipients and cally monitor the stent in deployment. In an alternative one or more polymer compositions. The polymer composi embodiment, the inner-diameter of the stent can be masked tions may be permanent or bioabsorbable; more preferably (e.g. by a non-conductive mandrel). Such masking would bioabsorbable (e.g.: PLGA based w/1-95% glycolic acid con prevent additional layers from being on the interior diameter tent). (abluminal) Surface of the Stent. The resulting configuration 0419. One pervasive challenge to alternative technologies may be desirable to provide preferential elution of the drug to deliver drugs via percutaneous catheter devices is how to toward the vessel wall (luminal surface of the stent) where the insure that the drug-formulation is not shed during position therapeutic effect of anti-restenosis is desired, without pro ing of the device to the therapeutic site. In other words: how viding the same antiproliferative drug(s) on the abluminal to insure that the drug is not washed off during insertion. This Surface, where they may retard healing, which in turn is challenge leads to an advantage of the current invention vs. Suspected to be a cause of late-stage safety problems with prior art because of the specific use of a polymeric formula current DESS. tion in the coating and the method of creating the coating and 0424 One particular advantage provided herein for its formulation. embodiments wherein the device is a stent (coronary, periph 0420 Embodiments provided herein maintain the drug eral, non-vascular etc.) is the ability to deliver the coating to within a mechanically sound polymeric coating (as opposed a much greater area/volume of the arterial wall due to the to coated as particles or formulated in a viscous oil), the spreading of the drug and polymer formulation. This is in coating is much more likely to maintain adhesion to the contrast to a traditional DES that delivers drug solely by device during insertion. In these embodiments, there is little diffusion of the drug out of the coating that permanently or no release of the coating until the device is deployed at the remains on the stent strut. This embodiment may provide therapeutic site. clinical advantages, especially as stent struts advance to thin 0421 For example, and without limitation, the devices and ner and Smaller diameters, of treating more, and more homog methods provided herein may be advantageously employed enously, the entire site of arterial injury caused by deploy in the local treatment of vascular diseases, the local treatment ment of the stent. of internal diseases via providing drug upstream in the vas 0425 Provided herein is a method comprising providing a culature from disease sites for: infection, oncology, etc., the medical device, wherein the medical device comprises a Sub local or regional treatment of tumors, the local treatment strate and a coating on at least a portion of said Substrate, and infections, particularly those that are hard to treat with sys wherein the coating comprises a plurality of layers, wherein temic antibiotics, for example due to poor circulation to the at least one layer comprises a pharmaceutical agent in a infected site (e.g., orthopedic, extremities in diabetics, etc), therapeutically desirable morphology, and freeing at least a the local treatment of neurological disorders such as pain portion of the coating from the Substrate upon stimulating the ailments. coating with a stimulation. 0422. In embodiments involving vascular diseases, the 0426 Provided herein is a method comprising providing a devices and methods provided herein may advantageously medical device, wherein the medical device comprises a Sub employ coating technology to mitigate the formation of free strate and a coating on at least a portion of said Substrate, and particles that could become entrained in the blood stream and wherein the coating comprises a plurality of layers, wherein cause negative complications such as emboli. For example, at least one layer comprises a pharmaceutical agent in a some embodiments are based on the utilization of soft coat therapeutically desirable morphology, and dissociating at ings that undergo facile bulk flow under stress. Other embodi least a portion of the coating from the Substrate upon stimu ments are based on the utilization of biodegradable materials lating the coating with a stimulation. Such as PLGA polymers that are mechanically sound at the 0427 Provided herein is a method comprising providing a time of implant, then over time degrade to lose their cohesion medical device, wherein the medical device comprises a Sub and/or adhesion to the surface of the device. Yet other strate and a coating on at least a portion of said Substrate, and embodiments are based on utilization of layered or laminated wherein the coating comprises a plurality of layers, wherein coatings (laminated layers) to directly control the transfer at least one layer comprises a pharmaceutical agent in a mechanisms of plastic deformation, shear and bulk-migra therapeutically desirable morphology, and transferring at tion. Yet other embodiments use all three aspects described least a portion of the coating from the substrate to the inter above. vention site upon stimulating the coating with a stimulation. 0423 In some embodiments, the coating comprises lami 0428 Provided herein is a method comprising providing a nated layers that allow direct control of the transfer, freeing, medical device, wherein the medical device comprises a Sub and/or dissociation of the coating from the Substrate. In some strate and a coating on at least a portion of said Substrate, embodiments, the coating comprises laminated layers that wherein said coating is at least partially continuous, has at US 2010/0015200 A1 Jan. 21, 2010 least one portion conformal to the Substrate, and comprises a 0438 Provided herein is a method comprising providing a pharmaceutical agent in a therapeutically desirable morphol medical device, wherein the medical device comprises a Sub ogy, and freeing at least a portion of the coating from the strate and a coating on at least a portion of said Substrate, Substrate upon stimulating the coating with a stimulation. wherein said coating comprises an active agent, and wherein 0429 Provided herein is a method comprising providing a the coating is patterned, and transferring at least a portion of medical device, wherein the medical device comprises a Sub the coating from the Substrate to the intervention site upon strate and a coating on at least a portion of said Substrate, stimulating the coating with a stimulation. wherein said coating is at least partially continuous, has at least one portion conformal to the Substrate, and comprises a 0439. In some embodiments, the patterned coating com pharmaceutical agent in a therapeutically desirable morphol prises at least two different shapes. ogy, and dissociating at least a portion of the coating from the 0440 Provided herein is a method comprising: providing Substrate upon stimulating the coating with a stimulation. a medical device, wherein the medical device comprises a 0430 Provided herein is a method comprising providing a Substrate and a coating on at least a portion of the Substrate, medical device, wherein the medical device comprises a Sub wherein the coating comprises an active agent; and transfer strate and a coating on at least a portion of said Substrate, ring at least a portion of the coating from the Substrate to an wherein said coating is at least partially continuous, has at intervention site. In some embodiments, the transferring the least one portion conformal to the Substrate, and comprises a coating portion (i.e. the portion of the coating) from the pharmaceutical agent in a therapeutically desirable morphol Substrate to the intervention site is upon stimulating the coat ogy, and transferring at least a portion of the coating from the ing with a stimulation. In some embodiments, the transferring Substrate to the intervention site upon stimulating the coating the coating portion from the substrate to the intervention site with a stimulation. is upon stimulating the Substrate with a stimulation. In some 0431. In some embodiments, the therapeutically desirable embodiments, stimulating the coating is achieved by stimu morphology comprises a crystalline form of the pharmaceu lating the Substrate. In some embodiments, stimulating the tical agent that is not a microcapsule. Substrate translates into stimulating the coating to transfer the 0432 Provided herein is a method comprising providing a coating portion from the Substrate to the intervention site. medical device, wherein the medical device comprises a Sub strate and a coating on at least a portion of said Substrate, and 0441 Provided herein is a method comprising: providing wherein said coating comprises an active agent, and freeing a medical device, wherein the medical device comprises a greater than 35% of the coating from the substrate upon Substrate and a coating on at least a portion of the Substrate, stimulating the coating with a stimulation. wherein the coating comprises an active agent; and transfer 0433 Provided herein is a method comprising providing a ring at least a portion of the active agent from the Substrate to medical device, wherein the medical device comprises a Sub an intervention site. In some embodiments, the transferring strate and a coating on at least a portion of said Substrate, and the active agent portion (i.e. the portion of the active agent) wherein said coating comprises an active agent, and dissoci from the Substrate to the intervention site is upon stimulating ating greater than 35% of the coating from the Substrate upon the coating with a stimulation. stimulating the coating with a stimulation. 0442 Provided herein is a method comprising: providing 0434 Provided herein is a method comprising providing a a medical device, wherein the medical device comprises a medical device, wherein the medical device comprises a Sub Substrate and a coating on at least a portion of the Substrate, strate and a coating on at least a portion of said Substrate, and wherein the coating comprises an active agent; and freeing at wherein said coating comprises an active agent, and transfer least a portion of the coating from the Substrate at an inter ring greater than 35% of the coating from the substrate to the vention site. In some embodiments, the freeing the coating intervention site upon stimulating the coating with a stimu portion (i.e. the portion of the coating) from the Substrate is lation. upon stimulating the coating with a stimulation. 0435. In some embodiments, the single stimulation lasts at 0443 Provided herein is a method comprising: providing most 20 seconds. In some embodiments, the device is adapted a medical device, wherein the medical device comprises a to free, dissociate, and/or transfer substantially all of the Substrate and a coating on at least a portion of the Substrate, coating upon the single stimulation of the coating. In some wherein the coating comprises an active agent; and dissoci embodiments, Substantially all of the coating frees, dissoci ating at least a portion of the coating from the Substrate at an ates, and/or transfers from the Substrate instantaneously upon intervention site. In some embodiments, the dissociating the stimulating the coating. coating portion (i.e. the portion of the coating) from the 0436 Provided herein is a method comprising providing a Substrate is upon stimulating the coating with a stimulation. medical device, wherein the medical device comprises a Sub 0444 Provided herein is a method comprising: providing strate and a coating on at least a portion of said Substrate, a medical device, wherein the medical device comprises a wherein said coating comprises an active agent, and wherein Substrate and a coating on at least a portion of the Substrate, the coating is patterned, and freeing at least a portion of the wherein the coating comprises an active agent; and depositing coating from the Substrate upon stimulating the coating with at least a portion of the coating at an intervention site. In some a stimulation. embodiments, the depositing the coating portion (i.e. the 0437. Provided herein is a method comprising providing a portion of the coating) at the intervention site is upon stimu medical device, wherein the medical device comprises a Sub lating the coating with a stimulation. strate and a coating on at least a portion of said Substrate, 0445 Provided herein is a method comprising: providing wherein said coating comprises an active agent, and wherein a medical device, wherein the medical device comprises a the coating is patterned, and dissociating at least a portion of Substrate and a coating on at least a portion of the Substrate, the coating from the Substrate upon stimulating the coating wherein the coating comprises an active agent; and tacking at with a stimulation. least a portion of the coating to an intervention site. In some US 2010/0015200 A1 Jan. 21, 2010 54 embodiments, the tacking the coating portion (i.e. the portion delivery of oncology drugs (a) directly to tumors and/or, (b) to of the coating) to the intervention site is upon stimulating the the arteries delivering blood to the tumors for site-specific coating with a stimulation. chemotherapy, and/or (c) to the voids left after the removal of 0446. In some embodiments, the substrate comprises a a tumor (lumpectomy). These oncology (as well as other balloon. In some embodiments, the portion of the balloon non-vascular) applications may not require the cutting having coating thereon comprises an outer Surface of the aspects and could be provided by coatings directly onto the balloon. In some embodiments, the outer Surface is a Surface balloon or onto a sheath over the balloon or according to an of the balloon exposed to a coating prior to balloon folding. In embodiment wherein the coating forms a sheath over the some embodiments, the outer surface is a surface of the bal deflated (pleated) balloon. loon exposed to a coating following balloon folding. In some 0452. A cutting balloon embodiment described herein embodiments, the outer surface is a surface of the balloon provides several advantages. Such embodiment allows for exposed to a coating following balloon crimping. In some concentrating the mechanical force on the coating/wire as the embodiments, the coating comprises a material that under balloon is inflated the wire may serve to concentrate the goes plastic deformation at pressures provided by inflation of point-of-contact-area of the balloon expansion pressure the balloon. In some embodiments, the coating comprises a resulting in a much higher force for plastic deformation of the material that undergoes plastic deformation at a pressure that drug and polymer coating Vs. the non-cutting plain balloon is less than the rated burst pressure of the balloon. which may distribute the pressure over a much larger area 0447. In some embodiments, the coating comprises a (therefore lower force proportional to the ratio of the areas). material that undergoes plastic deformation at a pressure that Embodiments involving a cutting balloon provide for the use is less than the nominal inflation pressure of the balloon. In of polymers that would otherwise be too rigid (higher modu Some embodiments, the coating comprises a material that lus) to deform from a non-cutting balloon. undergoes plastic deformation with at least 8 ATM of pres 0453 Other embodiments provided herein are based on Sure. In some embodiments, the coating comprises a material geometric configurations of the device that optimize both the that undergoes plastic deformation with at least 6 ATM of deformation and the bulk-migration of the coating from the pressure. In some embodiments, the coating comprises a device. In one embodiment wherein the device is a cutting material that undergoes plastic deformation with at least 4 balloon, the (coated) wire of the cutting balloon is shaped like ATM of pressure. In some embodiments, the coating com a wedge, pointed outward. prises a material that undergoes plastic deformation with at 0454. Another embodiment provides catheter-based least 2 ATM of pressure. devices where the drug-delivery formulation is delivered to 0448. In some embodiments, the balloon is a compliant the therapeutic site in the vasculature via inflation of a bal balloon. In some embodiments, the balloon is a semi-compli loon. ant balloon. In some embodiments, the balloon is a non 0455 One embodiment provides coated percutaneous compliant balloon. In some embodiments, the balloon con devices (e.g., balloons, whether cutting balloons or other forms to a shape of the intervention site. balloon types) that, upon deployment at a specific site in the 0449 In some embodiments, the balloon comprises a patient, transfer some or all of the drug-delivery formulation cylindrical portion. In some embodiments, the balloon com (5-10%, 10-25%, 25-50%, 50-90%,90-99%,99-100%) to the prises a Substantially spherical portion. In some embodi site of therapeutic demand. In certain embodiments, the bal ments, the balloon comprises a complex shape. In some loon is at least in part cylindrical as expanded or as formed. In embodiments, the complex shape comprises at least one of a certain embodiments, the balloon is at least in part bulbous as double noded shape, a triple noded shape, a waisted shape, an expanded or as formed. In certain embodiments, the balloon hourglass shape, and a ribbed shape. is at least in part spherical as expanded oras formed. In certain 0450 Some embodiments provide devices that can serve embodiments, the balloon has a complex shape as expanded interventional purposes in addition to delivery of therapeu or as formed (such as a double noded shape, a triple noded tics, such as a cutting balloon. In some embodiments, the shape, has a waist, and/or has an hourglass shape, for non Substrate comprises a cutting balloon. In some embodiments, limiting example). the cutting balloon comprises at least one tacking element 0456. In some embodiments, the substrate comprises a adapted to tack the coating to the intervention site. In some biomedical implant. In some embodiments, the Substrate embodiments, the tacking element is adapted to secure the comprises a Surgical tool. coating to the cutting balloon until inflation of the cutting 0457. In some embodiments, the substrate comprises at balloon. In some embodiments, the tacking element com least one of a stent, a joint, a screw, a rod, a pin, a plate, a prises a wire. In some embodiments, the wire is shaped in the Staple, a shunt, a clamp, a clip, a Suture, a Suture anchor, an form of an outward pointing wedge. In some embodiments, electrode, a catheter, a lead, a graft, a dressing, a pacemaker, the tacking element does not cut tissue at the intervention site. a pacemaker housing, a cardioverter, a cardioverter housing, 0451 One illustration devices provided herein include a a defibrillator, a defibrillator housing, a prostheses, an ear cutting balloon for the treatment of vascular disease (e.g.: drainage tube, an ophthalmic implant, an orthopedic device, a occluded lesions in the coronary or peripheral vasculature). In Vertebral disk, a bone substitute, an anastomotic device, a this embodiment, the coating may be preferentially located on perivascular wrap, a colostomy bag attachment device, a the cutting wire portion of the device. Upon deployment, the hemostatic barrier, a vascular implant, a vascular Support, a wire pushes into the plaque to provide the desired therapeutic tissue adhesive, a tissue sealant, a tissue scaffold, and an cutting action. During this cutting, the polymer and drug intraluminal device. coating is plastically deformed off of the wire by the combi 0458 In some embodiments, the substrate comprises at nation of compressive and shear forces acting on the wire least a portion of a tool for delivering to the intervention site leaving some or all of the coating embedded in the plaque a biomedical implant, wherein the substrate is the biomedical and/or artery wall. A similar approach may be applied to implant or wherein the substrate is a portion of the device that US 2010/0015200 A1 Jan. 21, 2010

is not the biomedical implant. In some embodiments, the ner and Smaller diameters, of treating more, and more homog Substrate comprises at least a portion of a tool for performing enously, the entire site of arterial injury caused by deploy a medical procedure. In some embodiments, the tool com ment of the stent. prises at least one of a knife, a scalpel, a guidewire, a guiding 0460. One embodiment provides coated percutaneous catheter, a introduction catheter, a distracter, a needle, a devices (e.g., balloons, whether cutting balloons or other Syringe, a biopsy device, an articulator, a Galotti articulator, a balloons) that, upon deployment at a specific site in the bone chisel, a bone crusher, a cottle cartilage crusher, a bone patient (intervention site), transfer some or all of the drug cutter, a bone distractor, an Ilizarov apparatus, an intramed delivery formulation (5-10%, 10-25%, 25-50%, 50-90%, ullary kinetic bone distractor, a bone drill, a bone extender, a 90-99%, 99-100%) to the site of therapeutic demand (inter vention site). In certain embodiments, the balloon is at least in bone file, a bone lever, a bone mallet, a bone rasp, a bone saw, part cylindrical as expanded or as formed. In certain embodi a bone skid, a bone splint, a bone button, a caliper, a cannula, ments, the balloon is at least in part bulbous as expanded or as a catheter, a cautery, a clamp, a coagulator, a curette, a depres formed. In certain embodiments, the balloon is at least in part Sor, a dilator, a dissecting knife, a distractor, a dermatome, spherical as expanded or as formed. In certain embodiments, forceps, dissecting forceps, tissue forceps, sponge forceps, the balloon has a complex shape as expanded or as formed bone forceps, Carmalt forceps, Cushing forceps, Dandy for (such as a double noded shape, a triple noded shape, has a ceps, DeBakey forceps, Doyen intestinal forceps, epilation waist, and/or has an hourglass shape, for non-limiting forceps, Halstead forceps, Kelly forceps, Kocher forceps, example). mosquito forceps, a hemostat, a hook, a nerve hook, an obstet 0461 Other embodiments provided herein are based on rical hook, a skin hook, a hypodermic needle, a lancet, a geometric configurations of the device that optimize both the luxator, a lythotome, a lythotript, a mallet, a partsch mallet, a deformation and the bulk-migration of the coating from the mouth prop, a mouth gag, a mammotome, a needle holder, an device. In one embodiment wherein the device is a cutting occluder, an osteotome, an Epker osteotome, a periosteal balloon, the (coated) wire of the cutting balloon is shaped like elevator, a Joseph elevator, a Molt periosteal elevator, an a wedge, pointed outward. Obweg periosteal elevator, a septum elevator, a Tessier peri 0462. In some embodiments, the device comprises a tack osteal elevator, a probe, a retractor, a Senn retractor, a Gelpi ing element that cooperates with the stimulation to tack the retractor, a Weitlaner retractor, a USA-Army/Navy retractor, coating to the intervention site. In some embodiments, the an OxConnor-OxSullivan retractor, a Deaver retractor, a device comprises a tacking element that tacks the coating to Bookwalter retractor, a Sweetheart retractor, a Joseph skin the substrate until the stimulating. hook, a Lahey retractor, a Blair (Rollet) retractor, a rigid rake 0463. In some embodiments, the intervention site is in or retractor, a flexible rake retractor, a Ragnell retractor, a Linde on the body of a subject. In some embodiments, the interven Ragnell retractor, a Davis retractor, a Volkman retractor, a tion site is a vascular wall. In some embodiments, the inter Mathieu retractor, a Jackson tracheal hook, a Crile retractor, a vention site is a non-vascular lumen wall. In some embodi Meyerding finger retractor, a Little retractor, a Love Nerve ments, the intervention site is a vascular cavity wall. 0464. In some embodiments, the intervention site is a wall retractor, a Green retractor, a Goelet retractor, a Cushing vein of a body cavity. In some embodiments, the body cavity is the retractor, a Langenbeck retractor, a Richardson retractor, a result of a lumpectomy. In some embodiments, the interven Richardson-Eastmann retractor, a Kelly retractor, a Parker tion site is a cannulized site within a Subject. retractor, a Parker-Mott retractor, a Roux retractor, a Mayo 0465. In some embodiments, the intervention site is a Collins retractor, a Ribbon retractor, an Alm retractor, a self sinus wall. In some embodiments, the intervention site is a retaining retractor, a Weitlaner retractor, a Beckman-Weit sinus cavity wall. In some embodiments, the active agent laner retractor, a Beckman-Eaton retractor, a Beckman retrac comprises a corticosteroid. tor, an Adson retractor, a rib spreader, a rongeur, a scalpel, an 0466. In some embodiments, the intervention site is ultrasonic scalpel, a laser Scalpel, Scissors, iris Scissors, Kiene located in the reproductive system of a subject. In some Scissors, Metzenbaum Scissors, Mayo Scissors, Tenotomy embodiments, the device is adapted to aid in fertility. In some Scissors, a spatula, a speculum, a mouth speculum, a rectal embodiments, the device is adapted to treat a sexually trans speculum, Sim's vaginal speculum, Cusco's vaginal specu mitted disease. In some embodiments, the device is adapted to lum, a sternal saw, a Suction tube, a Surgical elevator, a Sur Substantially prevent pregnancy. In some embodiments, the gical hook, a Surgical knife, Surgical mesh, a Surgical needle, active agent comprises a hormone. In some embodiments, the a Surgical Snare, a Surgical sponge, a Surgical spoon, a Surgical device is adapted to Substantially prevent transmission of a Stapler, a Suture, a Syringe, a tongue depressor, a tonsillotome, sexually transmitted disease. In some embodiments, the a tooth extractor, a towel clamp, towel forceps, Backhaus device is adapted to treat an ailment of the reproductive sys towel forceps, Lorna towel forceps, a tracheotome, a tissue tem. expander, a Subcutaneus inflatable balloon expander, a tre 0467. In some embodiments, the intervention site is phine, a trocar, tweezers, and a venous cliping. located in the urinary system of a Subject. In some embodi 0459. One particular advantage provided herein for ments, the device is adapted to treat a disease of the urinary embodiments wherein the device is a stent (coronary, periph system. In some embodiments, the active agent comprises eral, non-vascular etc.) is the ability to deliver the coating to fluoroquinolone. In some embodiments, the pharmaceutical a much greater area/volume of the arterial wall due to the agent comprises fluoroquinolone. spreading of the drug and polymer formulation. This is in 0468. In some embodiments, the intervention site is contrast to a traditional DES that delivers drug solely by located at a tumor site. In some embodiments, the tumor site diffusion of the drug out of the coating that permanently is where a tumor is located. In some embodiments, the tumor remains on the stent strut. This embodiment may provide site is where a tumor was located prior to removal and/or clinical advantages, especially as stent Struts advance to thin shrinkage of the tumor. In some embodiments, the active US 2010/0015200 A1 Jan. 21, 2010 56 agent comprises mitomycin C. In some embodiments, the 0476. In some embodiments, the device comprises a pharmaceutical agent comprises mitimycin C. retractable sheath. In some embodiments, the sheath is 0469. In some embodiments, the intervention site is adapted to expose the coating to the intervention site upon located in the ear. In some embodiments, the intervention site retraction. is located in the esophagus. In some embodiments, the active 0477. In some embodiments, the coating comprises a bio agent comprises a lidocaine. In some embodiments, the phar adhesive. In some embodiments, the active agent comprises a maceutical agent comprises a lidocaine. bioadhesive. In some embodiments, the pharmaceutical agent comprises a bioadhesive. In some embodiments, the coating 0470. In some embodiments, the intervention site is is adapted to close a vascular puncture. In some embodi located in the larynx. In some embodiments, the intervention ments, the coating aids in closing a vascular puncture. In site is a location of an injury. In some embodiments, the active Some embodiments, the coating is adapated to close a vascu agent comprises a betamethasone. In some embodiments, the lar puncture. In some embodiments the active agent com pharmaceutical agent comprises a betamethasone. prises a bioadhesive. To close a vascular puncture may 0471. In some embodiments, the intervention site is an include sealing the vascular puncture, and/or providing a seal infection site. In some embodiments, the infection site is a site that closes the vascular puncture. The seal may be the coating wherein an infection may occur, and wherein the active agent of the device. The bioadhesive may comprise an arylates, is capable of Substantially preventing the infection. In some and/or an cryanoacrylates. Bioadhesives may also and/or embodiments, the infection site is a site wherein an infection alternatively be called tissue adhesives. The bioadhesive may has occurred, and wherein the active agent is capable of comprise n-butyl cyanoacrylate, n-butyl-2-cyanoacrylate, slowing spread of the infection. In some embodiments, the 2-octylcyanoacrylate, and Dermabond, and/or variations infection site is a site wherein an infection has occurred, and thereof. wherein the active agent is capable of treating the infection. In 0478 Bioadhesives as used herein refer to, in some embodiments, natural polymeric materials that act as adhe Some embodiments, the active agent comprises an anti-infec sives. The term “bioadhesive' may also and/or alternatively tive agent. In some embodiments, the pharmaceutical agent be used to describe a glue formed synthetically from biologi comprises an anti-infective agent. In some embodiments, the cal monomers such as Sugars, and/or to mean a synthetic anti-infective agent comprises clindamycin. material designed to adhere to biological tissue. Bioadhesives 0472. In some embodiments, the intervention site is a sur may consist of a variety of Substances, for example: proteins gery site. In some embodiments, the intervention site is an and carbohydrates. Proteins such as gelatin and carbohy ocular site. drates such as starch are contemplated herein, as well as 0473. In some embodiments, the coating is capable of syntehtic alternatives to the same. Bioadhesives secreted by promoting healing. In some embodiments, the active agent microbes and by marine molluscs and crustaceans are con comprises a growth factor. In some embodiments, the growth templated herein. factor comprises at least one of an epidermal growth factor 0479. In some embodiments, the coating substantially pre (EGF), a transforming growth factor-alpha (TGF-alpha), a vents adhesion of body tissue. In some embodiments, the hepatocyte growth factor (HGF), a vacscular endothelial coating promotes prevention of adhesion of body tissue. In growth factor (VEGF), a platelet derived growth factor Some embodiments, the coating comprises hyaluronic acid, (PDGF), a fibroblast growth factor 1 (FGF-1), a fibroblast hyaluronate, salts, acids, conjugates, and/or derivatives growth factor 2 (FGF-2), a transforming growth factor-beta thereof. In some embodiments, the active agent comprises (TGF-beta), and a keratinocyte growth factor (KGF). In some hyaluronic acid, hyaluronate, salts, acids, conjugates, and/or embodiments, the active agent comprises a stem cell. derivatives thereof. 0474. In some embodiments, the coating is capable of at 0480. In some embodiments, the device is used to substan least one of retarding healing, delaying healing, and prevent tially prevent tissue adhesion. In some embodiments, the ing healing. In some embodiments, the coating is capable of device is adapted to Substantially prevent tissue adhesion. To at least one of retarding, delaying, and preventing the inflam Substantially prevent tissue adhesion, as used herein, refers to matory phase of healing. In some embodiments, the coating is the ability for the device to, at least in part, block at least a capable of at least one of retarding, delaying, and preventing portion of the biologic process that leads to tissue adhesion. the proliferative phase of healing. In some embodiments, the To Substantially prevent tissue adhesion, as used herein, amy coating is capable of at least one of retarding, delaying, and also and/or alternatively refer to the ability for the device to preventing the maturation phase of healing. In some embodi block at least a portion of fibrin deposition by the body. To ments, the coating is capable of at least one of retarding, Substantially prevent tissue adhesion, as used herein, may delaying, and preventing the remodeling phase of healing. In also and/or alternatively refer to the ability for the device to Some embodiments, the active agent comprises an anti-angio promote dissolving of fibrin. To substantially prevent tissue genic agent. In some embodiments, the coating is capable of adhesion, as used herein, may also and/or alternatively refer releiving pain. In some embodiments, the coating is capable to the ability for the device to promote blood contact with of releiving joint pain. In some embodiments, the coating is injured tissue. In some embodiments, the device comprises a capable of blocking pain. coating comprising hyaluronic to Substantially prevent tissue 0475. In some embodiments, the coating is a sheath. In adhesion. some embodiments, the sheath is plastically deformable. In 0481 “Tissue adhesion” as used herein refers to internal Some embodiments, at least a portion of the sheath is capable Scars that may form after Surgury on or between internal of being left at the intervention site upon removal of the organs and/or body tissue. As used herein, “body tissue' or substrate from the intervention site. In some embodiments, “tissue' refers to any biologic tissue, which includes any the substrate is capable of mechanically deforming the sheath ensemble of cells, not necessarily identical. As used herein, at the intervention site. “body tissue' or “tissue' may also or alternatively refer to any US 2010/0015200 A1 Jan. 21, 2010 57 one of muscle tissue, connective tissue, nervous tissue, epi 0489. “Transfer” or “transference” or “transferring as thelial tissue, and combinations thereof. Tissue between used herein in the context of the coating refers to the convey which adhesions may form can be of the same tissue type, ance of all or any part of the coating from the Substrate to an and/or of different tissue types. intervention site. The coating can beformulated Such that part 0482. When tissue is injured, the area becomes inflamed. or all of it is transferred from the substrate, as desired. Some The body responds by depositing fibrin at the injury site. of the embodiments provided herein are based on transfer of Fibrin can act like glue between the injury site and nearby the coating from the Substrate to the body tissue involving one tissues, causing them to Stick together. Normally, as the body or more of (1) plastic deformation by compressive and/or heals, the fibrin dissolves and is replaced with normal tissue. shear force induced by deployment and/or induced by the In some cases, however, decreased blood flow to the injured native Surrounding tissue and/or induced by the in-growth of tissue prevents the fibrin from dissolving. The result is an new tissue catalyzed by the deployment of the device (2) internal scar, also called an adhesion. Adhesions between shear transfer (wiping off) of the coating from the device tissues can twist and/or pull organs out of their normal posi outward (relative to the device) into the tissue, (3) bulk migra tions within the body. This scar tissue may form as a result of tion, and (4) separation from the device due to hydrolysis of injury to organs and tissues during Surgery. These injuries are the polymer, resulting in a week bond to the device. In some typically caused by Suturing, cauterization, and abrading tis embodiments (need more details of dissociation—from the Sues and organs during Surgery, however, other causes are “stimulation' and other ideas in the claims) envisioned herein. 0490 Similarly, “transferas used herein in the context of 0483. In some embodiments, the device is adapated to the active agent refers to the conveyance of all or any fraction close a vascular puncture. In some embodiments, the coating of an active agent from the Substrate to an intervention site. is adapated to close a vascular puncture. In some embodi 0491. The term “adapted to transfer a specific portion, ments the active agent comprises a bioadhesive. To close a e.g., at least about 10%, at least about 20%, at least about vascular puncture may include sealing the vascular puncture, 30%, greater than 35%, at least about 50%, at least about and/or providing a seal that closes the vascular puncture. The 75%, at least about 85%, at least about 90%, at least about seal may be the coating of the device. The bioadhesive may 95%, and/or at least about 99%, of a coating and/or active include, but not be limited to: arylates, cryanoacrylates. agent from the substrate to the intervention site refers to a device, coating, and/or Substrate that is designed to transfer a 0484 Provided herein is a medical device comprising a certain percentage of its coating to the intervention site. Substrate and a coating on at least a portion of said Substrate, 0492. In some embodiments, the device is adapted to wherein said coating comprises an active agent, and wherein transfer a portion of the coating and/or active agent from the the device is adapted to free greater than 35% of the coating Substrate to the intervention site. For non-limiting example, from the Substrate upon a single stimulation of the coating. the device is so adapted by substrate attributes (for non 0485 Provided herein is a medical device comprising a limiting example: Substrate composition, Substrate materials, Substrate and a coating on at least a portion of said Substrate, shape, substrate deployment attributes, substrate delivery wherein said coating comprises an active agent, and wherein attributes, substrate pattern, and/or substrate texture), the the device is adapted to dissociate greater than 35% of the delivery system of the Substrate and coating (for non-limiting coating from the Substrate upon a single stimulation of the example: control over the Substrate, control over the coating coating. using the delivery system, the type of delivery system pro 0486 Provided herein is a medical device comprising a vided, the materials of the delivery system, and/or combina Substrate and a coating on at least a portion of said Substrate, tions thereof), coating attributes (for non-limiting example: wherein said coating comprises an active agent, and wherein selection of the active agent and/or the polymer and/or the the device is adapted to transfer greater than 35% of the polymer-active agent composition, or by the coating having a coating from the Substrate to an intervention site upon a single particular pattern-e.g. a ribbed pattern, a textured Surface, a stimulation of the coating. Smooth Surface, and/or another pattern, coating thickness, 0487. Provided herein is a method of forming a medical coating layers, and/or another physical and/or compositional device comprising a Substrate and a coating on at least a attribute), release agent attributes (for non-limiting example: portion of the Substrate, wherein the coating comprises an through the selection aparticular release agent and/or how the active agent, the method comprising providing the Substrate; release agent is employed to transfer the coating and/or the and forming the coating on at least a portion of the Substrate active agent, and/or how much of the release agent is used), by depositing the active agent on ths substrate by a dipping and/or a combination thereof. and/or a spraying process, wherein forming the coating 0493. In some embodiments, the substrate is adapted to results in greater than 35% of the coating being adapted to transfer a portion of the coating and/or active agent from the free from the Substrate upon stimulating the coating with a Substrate to the intervention site. For non-limiting example, single stimulation. the substrate is so adapted by selection of the substrate com 0488. In some embodiments of the methods and/or position, Substrate materials, shape, Substrate deployment devices provided herein, the single stimulation lasts at most attributes, substrate delivery attributes, substrate pattern, and/ 20 seconds. In some embodiments of the methods and/or or substrate texture, and/or combinations thereof. For devices provided herein, the device is adapted to free substan example, a balloon can be designed to only partially inflate tially all of the coating upon the single stimulation of the within the confines of the intervention site. Partial inflation coating. In some embodiments, the single stimulation lasts at can prevent a designated portion of coating from being trans most 20 seconds. In some embodiments of the methods and/ ferred. or devices provided herein, substantially all of the coating 0494. In some embodiments, the coating is adapted to frees from the Substrate instantaneously upon stimulation of transfer a portion of the coating and/or active agent from the the coating. Substrate to the intervention site. For non-limiting example US 2010/0015200 A1 Jan. 21, 2010

the coating may be so adapted by selection of the active agent remove any obstruction and/or connection the coating may and/or the polymer and/or the polymer-active agent compo have to the substrate (whether director indirect). sition, or by the coating having a particular pattern-e.g. a 0501. In some embodiments, the device is adapted to free ribbed pattern, a textured Surface, a smooth surface, and/or a portion of the coating and/or active agent from the Substrate. another pattern, coating thickness, coating layers, and/or For non-limiting example, the device is so adapted by Sub another physical and/or compositional attribute. strate attributes (for non-limiting example: Substrate compo 0495. In some embodiments, the substrate is adapted to sition, Substrate materials, shape, Substrate deployment transfer a portion of the coating and/or active agent from the attributes, substrate delivery attributes, substrate pattern, and/ Substrate to the intervention site. For non-limiting example, or substrate texture), the delivery system of the substrate and the substrate is so adapted by selection of the substrate com coating (for non-limiting example: control over the Substrate, position, Substrate materials, shape, Substrate deployment control over the coating using the delivery system, the type of attributes, substrate delivery attributes, substrate pattern, and/ delivery system provided, the materials of the delivery sys or substrate texture, and/or combinations thereof. For tem, and/or combinations thereof), coating attributes (for example, a balloon can be designed to only partially inflate non-limiting example: selection of the active agent and/or the within the confines of the intervention site. Partial inflation polymer and/or the polymer-active agent composition, or by can prevent a designated portion of coating from being trans the coating having a particular pattern—e.g. a ribbed pattern, ferred. a textured surface, a smooth surface, and/or another pattern, 0496. In some embodiments, the coating is adapted to coating thickness, coating layers, and/or another physical transfer a portion of the coating and/or active agent from the and/or compositional attribute), release agent attributes (for Substrate to the intervention site. For non-limiting example non-limiting example: through the selection a particular the coating may be so adapted by selection of the active agent release agent and/or how the release agent is employed to and/or the polymer and/or the polymer-active agent compo transfer the coating and/or the active agent, and/or how much sition, or by the coating having a particular pattern—e.g. a of the release agent is used), and/or a combination thereof. ribbed pattern, a textured Surface, a smooth surface, and/or 0502. In some embodiments, the substrate is adapted to another pattern, coating thickness, coating layers, and/or free a portion of the coating and/or active agent from the another physical and/or compositional attribute. Substrate. For non-limiting example, the Substrate is so 0497. In some embodiments, transferring at least a portion adapted by selection of the Substrate composition, Substrate of the coating comprises transferring at least about 10%, at materials, shape, Substrate deployment attributes, Substrate least about 20%, at least about 30%, greater than 35%, at least delivery attributes, substrate pattern, and/or substrate texture, about 50%, at least about 75%, at least about 85%, at least and/or combinations thereof. For example, a balloon can be about 90%, at least about 95%, and/or at least about 99% of designed to only partially inflate within the confines of the the coating from the Substrate. In some embodiments, stimu intervention site. Partial inflation can prevent a designated lating decreases the contact between the coating and the Sub portion of coating from being freed. strate. In some embodiments, transferring transfers less than 0503. In some embodiments, the coating is adapted to free about 1%, less than about 5%, less than about 10%. less than a portion of the coating and/or active agent from the Substrate. about 15%, less than about 25%, at most about 35%, less than For non-limiting example the coating may be so adapted by about 50%, less than about 70%, less than about 80%, and/or selection of the active agent and/or the polymer and/or the less than about 90% of the coating absent stimulating at least polymer-active agent composition, or by the coating having a one of the coating and the Substrate. particular pattern—e.g. a ribbed pattern, a textured Surface, a 0498. In some embodiments, transferring at least a portion Smooth Surface, and/or another pattern, coating thickness, of the active agent comprises transferring at least about 10% coating layers, and/or another physical and/or compositional at least about 20%, at least about 30%, greater than 35%, at attribute. least about 50%, at least about 75%, at least about 85%, at 0504. In some embodiments, the substrate is adapted to least about 90%, at least about 95%, and/or at least about 99% free a portion of the coating and/or active agent from the of the active agent from the Substrate. In some embodiments, Substrate to the intervention site. For non-limiting example, stimulating decreases the contact between the coating and the the substrate is so adapted by selection of the substrate com Substrate. In some embodiments, transferring transfers less position, Substrate materials, shape, Substrate deployment than about 1%, less than about 5%, less than about 10%. less attributes, substrate delivery attributes, substrate pattern, and/ than about 15%, less than about 25%, at most about 35%, less or substrate texture, and/or combinations thereof. For than about 50%, less than about 70%, less than about 80%, example, a balloon can be designed to only partially inflate and/or less than about 90% of the active agent absent stimu within the confines of the intervention site. Partial inflation lating at least one of the coating and the Substrate. can prevent a designated portion of coating from being freed. 0499. The term “adapted to transfer at least a portion' of 0505. In some embodiments, the coating is adapted to free the coating or active agent to an intervention site refers to a a portion of the coating and/or active agent from the Substrate device that is designed to transfer any portion of the coating or to the intervention site. For non-limiting example the coating active agent to an intervention site. may be so adapted by selection of the active agent and/or the 0500. The term “adapted to free” a portion of a coating polymer and/or the polymer-active agent composition, or by and/or active agent from the Substrate refers to a device, the coating having a particular pattern—e.g. a ribbed pattern, coating, and/or substrate that is designed to free a certain a textured surface, a smooth surface, and/or another pattern, percentage of the coating and/or active agent from the Sub coating thickness, coating layers, and/or another physical strate. As used herein, a device, coating, and/or substrate that and/or compositional attribute. is designed to free a certain percentage of the coating and/or 0506. In some embodiments, freeing at least a portion of active agent from the Substrate is designed to unrestrain the the coating comprises freeing at least about 10% at least coating and/or active agent from the Substrate, and/or to about 20%, at least about 30%, greater than 35%, at least US 2010/0015200 A1 Jan. 21, 2010 59 about 50%, at least about 75%, at least about 85%, at least Surface, a Smooth Surface, and/or another pattern, coating about 90%, at least about 95%, and/or at least about 99% of thickness, coating layers, and/or another physical and/or the coating from the Substrate. In some embodiments, stimu compositional attribute. lating decreases the contact between the coating and the Sub 0511. In some embodiments, the substrate is adapted to strate. In some embodiments, freeing frees less than about free a portion of the coating and/or active agent from the 1%, less than about 5%, less than about 10%. less than about Substrate to the intervention site. For non-limiting example, 15%, less than about 25%, at most about 35%, less than about the substrate is so adapted by selection of the substrate com 50%, less than about 70%, less than about 80%, and/or less position, Substrate materials, shape, Substrate deployment than about 90% of the coating absent stimulating at least one attributes, substrate delivery attributes, substrate pattern, and/ or substrate texture, and/or combinations thereof. For of the coating and the Substrate. example, a balloon can be designed to only partially inflate 0507. The term “adapted to dissociate' a portion of a coat within the confines of the intervention site. Partial inflation ing and/or active agent from the Substrate refers to a device, can prevent a designated portion of coating from being freed. coating, and/or Substrate that is designed to dissociate a cer 0512. In some embodiments, the coating is adapted to tain percentage of the coating and/or active agent from the dissociate a portion of the coating and/or active agent from Substrate. As used herein, a device, coating, and/or substrate the substrate to the intervention site. For non-limiting that is designed to dissociate a certain percentage of the example the coating may be so adapted by selection of the coating and/or active agent from the Substrate is designed to active agent and/or the polymer and/or the polymer-active remove from association between the coating (and/or active agent composition, or by the coating having a particular pat agent) and the Substrate. Also and/or alternatively, as used tern-e.g. a ribbed pattern, a textured Surface, a smooth Sur herein, a device, coating, and/or Substrate that is designed to face, and/or another pattern, coating thickness, coating lay dissociate a certain percentage of the coating and/or active ers, and/or another physical and/or compositional attribute. agent from the Substrate is designed to separate the coating 0513. In some embodiments, dissociating at least a portion (and/or active agent) from the Substrate. This separation may of the coating comprises dissociating at least about 10%, at be reversible in some embodiments. This separation may not least about 20%, at least about 30%, greater than 35%, at least be reversible in some embodiments. about 50%, at least about 75%, at least about 85%, at least 0508. In some embodiments, the device is adapted to dis about 90%, at least about 95%, and/or at least about 99% of Sociate a portion of the coating and/or active agent from the the coating from the Substrate. In some embodiments, stimu Substrate. For non-limiting example, the device is so adapted lating decreases the contact between the coating and the Sub by substrate attributes (for non-limiting example: substrate strate. In some embodiments, dissociating dissociates less composition, Substrate materials, shape, Substrate deploy than about 1%, less than about 5%, less than about 10%. less ment attributes, substrate delivery attributes, substrate pat than about 15%, less than about 25%, at most about 35%, less tern, and/or substrate texture), the delivery system of the than about 50%, less than about 70%, less than about 80%, Substrate and coating (for non-limiting example: control over and/or less than about 90% of the coating absent stimulating the Substrate, control over the coating using the delivery sys at least one of the coating and the Substrate. tem, the type of delivery system provided, the materials of the 0514 “Plastic deformation' as used herein is the change in delivery system, and/or combinations thereof), coating the physical shape of the coating by forces induced on the attributes (for non-limiting example: selection of the active device. Plastic deformation results in increasing the contact agent and/or the polymer and/or the polymer-active agent area of the coating on the tissue and decreasing the contact composition, or by the coating having a particular pattern— area of the coating on the device. This change in contact area e.g. a ribbed pattern, a textured Surface, a Smooth surface, results in Some or all of the coating being preferentially and/or another pattern, coating thickness, coating layers, and/ exposed to the tissue instead of the device. The terms “plastic or another physical and/or compositional attribute), release deformation” and “plastically deform,” as used herein in the agent attributes (for non-limiting example: through the selec context of a coating, are intended to include the expansion of tion a particular release agent and/or how the release agent is the coating material beyond the elastic limit of the material employed to transfer the coating and/or the active agent, such that the material is permanently deformed. “Elastic and/or how much of the release agent is used), and/or a deformation' as used herein refers to a reversible alteration of combination thereof. the form or dimensions of the object under stress or strain, 0509. In some embodiments, the substrate is adapted to e.g., inflation pressure of a balloon Substrate. The terms 'plas dissociate a portion of the coating and/or active agent from tic deformation” and “plastically deform, as used herein in the Substrate. For non-limiting example, the Substrate is so the context of a balloon or other substrate, are intended to adapted by selection of the Substrate composition, Substrate include the expansion of the substrate beyond the elastic limit materials, shape. Substrate deployment attributes, Substrate of the substrate material such that the substrate material is delivery attributes, substrate pattern, and/or substrate texture, permanently deformed. Once plastically deformed, a material and/or combinations thereof. For example, a balloon can be becomes Substantially inelastic and generally will not, on its designed to only partially inflate within the confines of the own, return to its pre-expansion size and shape. “Residual intervention site. Partial inflation can prevent a designated plastic deformation” refers to a deformation capable of portion of coating from being freed. remaining at least partially after removal of the inflation 0510. In some embodiments, the coating is adapted to stress, e.g., when the balloon is deflated. "Elastic deforma dissociate a portion of the coating and/or active agent from tion' as used herein refers to a reversible alteration of the form the Substrate. For non-limiting example the coating may be so or dimensions of the object (whether it is the coating or the adapted by selection of the active agent and/or the polymer Substrate) under stress or strain, e.g., inflation pressure. and/or the polymer-active agent composition, or by the coat 0515 “Shear transferas used herein is the force (or com ing having a particular pattern-e.g. a ribbed pattern, a textured ponent of forces) orthogonal to the device that would drive the US 2010/0015200 A1 Jan. 21, 2010 60 coating away from the device substrate. This could be external element comprises a liquid. In some embodiments, induced on the device by deployment, pressure-response the liquid is forced between the coating and the substrate. In from the Surrounding tissue and/or in-growth of tissue around Some embodiments, the liquid comprises saline. In some the coating. embodiments, the liquid comprises water. In some embodi 0516) “Bulk migration' as used herein is the incorporation ments, the mechanical stimulation comprises a geometric of the coating onto/into the tissue provided by the removal of configuration of the Substrate that maximizes a shear force on the device and/or provided by degradation of the coating over the coating. In some embodiments, the mechanical stimula time and/or provided by hydration of the coating over time. tion comprises a geometric configuration of the Substrate that Degradation and hydration of the coating may reduce the increases a shear force on the coating. In some embodiments, coating's cohesive and adhesive binding to the device, the mechanical stimulation comprises a geometric configu thereby facilitating transfer of the coating to the tissue. ration of the substrate that enhances a shear force on the 0517. One embodiment may described by analogy to con coating. tact printing whereby a biochemically active ink (the poly 0521. In some embodiments, the coating is freed, dissoci mer+drug coating) from a “die” (the device) to the stock (the ated, and/or transferred from the Substrate using a chemical site in the body). stimulation. In some embodiments, the coating is freed from 0518. The devices and methods described in conjunction the Substrate using a chemical stimulation. In some embodi with some of the embodiments provided herein are advanta ments, the coating is dissociated from the Substrate using a geously based on specific properties provided for in the drug chemical stimulation. In some embodiments, the coating is delivery formulation. One such property, especially well transferred from the Substrate using a chemical stimulation. Suited for non-permanent implants such as balloon catheters, In some embodiments, the coating is transferred to the inter cutting balloons, etc. is soft coating that undergoes plastic vention site using a chemical stimulation. In some embodi deformation at pressures provided by the inflation of the ments, the coating is delivered to the intervention site using a balloon (range 2-25 ATM, typically 10-18 ATM). Another chemical stimulation. In some embodiments, the chemical Such property, especially well-suited to permanent implants stimulation comprises at least one of bulk degradation, inter Such as stents is coatings where the polymer becomes soft at action with a bodily fluid, interaction with a bodily tissue, a Some point after implant either by hydration or by degrada chemical interaction with a non-bodily fluid, a chemical inter tion or by combinations of hydration and degradation. action with a chemical, an acid-base reaction, an enzymatic 0519 Some embodiments provide devices that can advan reaction, hydrolysis, and combinations thereof. In some tageously be used in conjunction with methods that can aid/ embodiments, the chemical stimulation comprises bulk deg promote the transfer of the coating. These include introducing radation of the coating. In some embodiments, the chemical stimuli to the coated device once on-site in the body (where stimulation comprises interaction of the coating or a portion the device is delivered either transiently or permanently). thereof with a bodily fluid. In some embodiments, the chemi Such stimuli can be provided to induce a chemical response cal stimulation comprises interaction of the coating or a por (light, heat, radiation, etc.) in the coating or can provide tion thereof with a bodily tissue. In some embodiments, the mechanical forces to augment the transfer of the coating into chemical stimulation comprises a chemical interaction of the the tissue (ultrasound, translation, rotation, vibration and coating or a portion thereof with a non-bodily fluid. In some combinations thereof). embodiments, the chemical stimulation comprises a chemical 0520. In some embodiments, the coating is freed, dissoci interaction of the coating or a portion thereof with a chemical. ated, and/or transferred from the Substrate using a mechanical In some embodiments, the chemical stimulation comprises an stimulation. In some embodiments, the coating is freed from acid-base reaction. In some embodiments, the chemical the Substrate using a mechanical stimulation. In some stimulation comprises an enzymatic reaction. In some embodiments, the coating is dissociated from the Substrate embodiments, the chemical stimulation comprises hydroly using a mechanical stimulation. In some embodiments, the S1S. coating is transferred from the Substrate using a mechanical 0522. In some embodiments, the chemical stimulation is stimulation. In some embodiments, the coating is transferred adapted to augment the freeing, dissociation and/or transfer to the intervention site using a mechanical stimulation. In ence of the coating from the Substrate. In some embodiments, Some embodiments, the coating is delivered to the interven the chemical stimulation is adapted to initiate the freeing, tion site using a mechanical stimulation. In some embodi dissociation and/or transference of the coating from the Sub ments, the mechanical stimulation is adapted to augment the strate. In some embodiments, the chemical stimulation is freeing, dissociation and/or transference of the coating from adapted to cause the freeing, dissociation and/or transference the Substrate. In some embodiments, the mechanical stimu of the coating from the Substrate. In some embodiments, the lation is adapted to initiate the freeing, dissociation and/or coating comprises a material that is adapted to transfer, free, transference of the coating from the Substrate. In some and/or dissociate from the substrate when at the intervention embodiments, the mechanical stimulation is adapted to cause site in response to an in-situ enzymatic reaction resulting in a the freeing, dissociation and/or transference of the coating weak bond between the coating and the substrate. from the Substrate. In some embodiments, the mechanical 0523. In some embodiments, the coating is freed, dissoci stimulation comprises at least one of a compressive force, a ated, and/or transferred from the Substrate using a thermal shear force, a tensile force, a force exerted on the coating from stimulation. In some embodiments, the coating is freed from a Substrate side of the coating, a force exerted on the coating the Substrate using a thermal stimulation. In some embodi by the Substrate, a force exerted on the coating from an exter ments, the coating is dissociated from the Substrate using a nal element, a translation, a rotation, a vibration, and a com thermal stimulation. In some embodiments, the coating is bination thereof. In some embodiments, the external element transferred from the Substrate using a thermal stimulation. In is a part of the Subject. In some embodiments, the external Some embodiments, the coating is transferred to the interven element is not part of the device. In some embodiments, the tion site using a thermal stimulation. In some embodiments, US 2010/0015200 A1 Jan. 21, 2010

the coating is delivered to the intervention site usingathermal 0527. In some embodiments, the coating is freed, dissoci stimulation. In some embodiments, the thermal stimulation ated, and/or transferred from the substrate by extrusion. comprises at least one of a hot stimulus and a cold stimulus 0528 Provided herein are device geometries that maxi adapted to augment the freeing, dissociation and/or transfer mize the shear forces on the coating. Such geometric design ence of the coating from the Substrate. In some embodiments, of the device provides two advantages: (1) increases (concen trates) the force to plastically deform the drug and polymer the thermal stimulation is adapted to cause the freeing, dis coating (2) decreases the force of adhesion of the coating. For Sociation and/or transference of the coating from the Sub example, a wedge-shape aligns the forces of deformation strate. In some embodiments, the thermal stimulation com along a shear plan as opposed to direct compression. This prises at least one of a hot stimulus and a cold stimulus embodiment provides for: (1) increased efficiency in terms of adapted to initiate the freeing, dissociation and/or transfer % of the coating transferred (2) increased precision in amount ence of the coating from the Substrate. In some embodiments, transferred on a case-by-case basis (3) utilization of harder/ the thermal stimulation comprises at least one of a hot stimu stiffer materials (biopolymers) that would otherwise not lus and a cold stimulus adapted to initiate the freeing, disso deform and/or not bulk-migrate under deployment conditions ciation and/or transference of the coating from the Substrate. (4) minimize the chance of particulate shedding via purpose fully designing the shape and direction of both the deforma 0524. In some embodiments, the coating is freed, dissoci tion and bulk migration. For example for a wedge, particles ated, and/or transferred from the device by a electromagnetic would be less likely because the coating would be pre-dis stimulation. In some embodiments, the coating is freed from posed as a shear from the device in a sheet form with the use the Substrate using a electromagnetic stimulation. In some of soft materials, this may be illustrated as a coating of sili embodiments, the coating is dissociated from the Substrate cone caulk being extruded from the pressure of a rod being using a electromagnetic stimulation. In some embodiments, pushed into a mattress. the coating is transferred from the Substrate using a electro 0529. Another embodiment provide a geometric arrange magnetic stimulation. In some embodiments, the coating is ment of the coating whereby layers, e.g. a laminate structure, transferred to the intervention site using a electromagnetic are provided in the coating to modulate and control the plastic stimulation. In some embodiments, the coating is delivered to deformation, shearing and bulk-migration of the coating into the intervention site using a electromagnetic stimulation. In the tissue. Some embodiments, the electromagnetic stimulation com 0530 One embodiment provides coated substrates that, prises an electromagnetic wave comprising at least one of a upon deploymentata specific site in the patient, transfer some radio wave, a micro wave, a infrared wave, near infrared or all of the coating (5-10%, 10-25%, 25-50%, 50-90%, wave, a visible light wave, an ultraviolet wave, a X-ray wave, 90-99%, 99-100%) to the site of therapeutic demand. and a gamma wave. In some embodiments, the electromag 0531. In some embodiments, the device further comprises a release agent. In some embodiments, the release agent is netic stimulation is adapted to augment the freeing, dissocia biocompatible. In some embodiments, the release agent is tion and/or transference of the coating from the Substrate. In non-biocompatible. In some embodiments, the release agent Some embodiments, the electromagnetic stimulation is comprises a powder. In some embodiments, the release agent adapted to initiate the freeing, dissociation and/or transfer comprises a lubricant. In some embodiments, the release ence of the coating from the Substrate. In some embodiments, agent comprises a Surface modification of the Substrate. the electromagnetic stimulation is adapted to cause the free 0532. In some embodiments, the release agent comprises a ing, dissociation and/or transference of the coating from the physical characteristic of the coating. In some embodiments, substrate. the physical characteristic of the coating comprises a pattern. 0525. In some embodiments, the coating is freed, dissoci In some embodiments, the pattern is a textured Surface on the ated, and/or transferred from the device by a sonic stimula substrate side of the coating, wherein the substrate side of the tion. In some embodiments, the coating is freed from the coating is the part of the coating on the Substrate. In some Substrate using a Sonic stimulation. In some embodiments, embodiments, the pattern is a textured Surface on the inter the coating is dissociated from the Substrate using a Sonic vention site side of the coating, wherein the intervention site stimulation. In some embodiments, the coating is transferred side of the coating is the part of the coating that is transferred from the Substrate using a Sonic stimulation. In some embodi to, and/or delivered to, and/or deposited at the intervention ments, the coating is transferred to the intervention site using site. a Sonic stimulation. In some embodiments, the coating is 0533. In some embodiments, the release agent comprises a delivered to the intervention site using a Sonic stimulation. In Viscous fluid. In some embodiments, the viscous fluid com prises oil. In some embodiments, the viscous fluid is a fluid Some embodiments, the Sonic stimulation comprises a Sound that is viscous relative to water. In some embodiments, the wave, wherein the Sound wave is at least one of an ultrasound viscous fluid is a fluid that is viscous relative to blood. In some wave, an acoustic sound wave, and an infrasound wave. In embodiments, the viscous fluid is a fluid that is viscous rela Some embodiments, the Sonic stimulation is adapted to aug tive tourine. In some embodiments, the viscous fluid is a fluid ment the freeing, dissociation and/or transference of the coat that is viscous relative to bile. In some embodiments, the ing from the Substrate. In some embodiments, the Sonic viscous fluid is a fluid that is viscous relative to synovial fluid. stimulation is adapted to initiate the freeing, dissociation In some embodiments, the viscous fluid is a fluid that is and/or transference of the coating from the Substrate. In some Viscous relative to Saline. In some embodiments, the Viscous embodiments, the Sonic stimulation is adapted to cause the fluid is a fluid that is viscous relative to a bodily fluid at the freeing, dissociation and/or transference of the coating from intervention site. the substrate. 0534. In some embodiments, the release agent comprises a 0526 In some embodiments, the coating is freed, dissoci gel. ated, and/or transferred from the device by a combination of 0535 In some embodiments, the release agent comprises at least two of a mechanical stimulation, a chemical stimula at least one of the active agent and another active agent. The tion, an electromagnetic stimulation, and a Sonic stimulation. active agent may be placed on the Substrate prior to the US 2010/0015200 A1 Jan. 21, 2010 62 coating in order to act as the release agent. The active agent less than about 1%, less than about 5%, less than about 10%. may be a different active agent than the active agent in the less than about 15%, less than about 25%, less than about coating. The active agent that is the release agent may provide 50%, less than about 70%, less than about 80%, and/or less for a second source of drug to be delivered to the intervention than about 90% of the coating absent stimulation of the coat site or another location once the coating is released from (or 1ng transferred from, or freed from, or dissociated from) the sub 0541. In some embodiments, at least about 10%, at least Strate. about 20%, at least about 30%, at least about 50%, at least 0536. In some embodiments, the release agent comprises a about 75%, at least about 85%, at least about 90%, at least physical characteristic of the Substrate. In some embodi about 95%, and/or at least about 99% of the active agent is ments, the physical characteristic of the Substrate comprises adapted to transfer from the substrate to the intervention site. at least one of a patterned coating Surface and a ribbed coating In some embodiments, at least about 10% of the active agent Surface. In some embodiments, the patterned coating Surface is adapted to transfer from the substrate to the intervention comprises a stent framework. In some embodiments, the site. In some embodiments, at least about 20% of the active ribbed coating Surface comprises an undulating Substrate Sur agent is adapted to transfer from the Substrate to the interven face. In some embodiments, the ribbed coating Surface com tion site. In some embodiments, at least about 30% of the prises an Substrate Surface having bumps thereon. active agent is adapted to transfer from the Substrate to the 0537. In some embodiments, the release agent comprises a intervention site. In some embodiments, at least about 50% of property that is capable of changing at the intervention site. In the active agent is adapted to transfer from the substrate to the Some embodiments, the property comprises a physical prop intervention site. In some embodiments, at least about 75% of erty. In some embodiments, the property comprises a chemi the active agent is adapted to transfer from the substrate to the cal property. In some embodiments, the release agent is intervention site. In some embodiments, at least about 85% of capable of changing a property when in contact with at least the active agent is adapted to transfer from the substrate to the one of a biologic tissue and a biologic fluid. In some embodi intervention site. In some embodiments, at least about 90% of ments, the release agent is capable of changing a property the active agent is adapted to transfer from the substrate to the when in contact with an aqueous liquid. intervention site. In some embodiments, at least about 95% of 0538. In some embodiments, the release agent is between the active agent is adapted to transfer from the substrate to the the Substrate and the coating. intervention site. In some embodiments, at least about 99% of 0539. In some embodiments, substantially all of the coat the active agent is adapted to transfer from the substrate to the ing remains on said substrate until the medical device reaches intervention site. As used herein, “about when used in ref the intervention site. In some embodiments, at least about erence to a percentage of the active agent can mean ranges of 10%, at least about 20%, at least about 30%, at least about 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a 50%, at least about 75%, at least about 85%, at least about percent of the percentage of the active agent transferred, or as 90%, at least about 95%, and/or at least about 99% of the a variation of the percentage of the active agent transferred). coating is adapted to transfer from the Substrate to the inter 0542. In some embodiments, the active agent portion that vention site. In some embodiments, at least about 10% of the is adapted to transfer upon stimulation is on at least one of a coating is adapted to transfer from the Substrate to the inter distal surface of the substrate, a middle surface of the sub vention site. In some embodiments, at least about 20% of the strate, a proximal Surface of the Substrate, and an abluminal coating is adapted to transfer from the Substrate to the inter Surface of the Substrate. In some embodiments, the stimula vention site. In some embodiments, at least about 30% of the tion decreases the contact between the coating and the Sub coating is adapted to transfer from the Substrate to the inter strate. In some embodiments, the device is adapted to transfer vention site. In some embodiments, at least about 50% of the less than about 1%, less than about 5%, less than about 10%. coating is adapted to transfer from the Substrate to the inter less than about 15%, less than about 25%, less than about vention site. In some embodiments, at least about 75% of the 50%, less than about 70%, less than about 80%, and/or less coating is adapted to transfer from the Substrate to the inter than about 90% of the active agent absent stimulation of the vention site. In some embodiments, at least about 85% of the coating. coating is adapted to transfer from the Substrate to the inter 0543. In some embodiments, the device is adapted to vention site. In some embodiments, at least about 90% of the transfer at least about 10%, at least about 20%, at least about coating is adapted to transfer from the Substrate to the inter 30%, at least about 50%, at least about 75%, at least about vention site. In some embodiments, at least about 95% of the 85%, at least about 90%, at least about 95%, and/or at least coating is adapted to transfer from the Substrate to the inter about 99% of the coating from the substrate to the interven vention site. In some embodiments, at least about 99% of the tion site. In some embodiments, the device is adapted to coating is adapted to transfer from the Substrate to the inter transfer at least about 10% of the coating from the substrate to vention site. As used herein, “about when used in reference the intervention site. In some embodiments, the device is to a percentage of the coating can mean ranges of 1%-5%, of adapted to transfer at least about 20% of the coating from the 5%-10%, of 10%-20%, and/or of 10%-50% (as a percent of substrate to the intervention site. In some embodiments, the the percentage of the coating transferred, or as a variation of device is adapted to transfer at least about 30% of the coating the percentage of the coating transferred). from the substrate to the intervention site. In some embodi 0540. In some embodiments, the coating portion that is ments, the device is adapted to transfer at least about 50% of adapted to transfer upon stimulation is on at least one of a the coating from the Substrate to the intervention site. In some distal surface of the substrate, a middle surface of the sub embodiments, the device is adapted to transfer at least about strate, a proximal Surface of the Substrate, and an abluminal 75% of the coating from the substrate to the intervention site. Surface of the Substrate. In some embodiments, the stimula In some embodiments, the device is adapted to transfer at tion decreases the contact between the coating and the Sub least about 85% of the coating from the substrate to the strate. In some embodiments, device is adapted to transfer intervention site. In some embodiments, the device is adapted US 2010/0015200 A1 Jan. 21, 2010

to transfer at least about 90% of the coating from the substrate 0547. In some embodiments, the device is adapted to free to the intervention site. In some embodiments, the device is at least about 10%, at least about 20%, at least about 30%, at adapted to transfer at least about 95% of the coating from the least about 50%, at least about 75%, at least about 85%, at substrate to the intervention site. In some embodiments, the least about 90%, at least about 95%, and/or at least about 99% device is adapted to transfer at least about 99% of the coating of the coating from the Substrate. In some embodiments, the from the substrate to the intervention site. As used herein, device is adapted to free at least about 10% of the coating "about when used in reference to a percentage of the coating from the substrate to the intervention site. In some embodi can mean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or ments, the device is adapted to free at least about 20% of the of 10%-50% (as a percent of the percentage of the coating coating from the Substrate to the intervention site. In some transferred, or as a variation of the percentage of the coating embodiments, the device is adapted to free at least about 30% transferred). of the coating from the substrate to the intervention site. In 0544. In some embodiments, the coating portion that some embodiments, the device is adapted to free at least about transfers upon stimulation is on at least one of a distal Surface 50% of the coating from the substrate to the intervention site. of the substrate, a middle surface of the substrate, a proximal In some embodiments, the device is adapted to free at least surface of the substrate, and an abluminal surface of the about 75% of the coating from the substrate to the interven Substrate. In some embodiments, stimulation decreases the tion site. In some embodiments, the device is adapted to free contact between the coating and the Substrate. In some at least about 85% of the coating from the substrate to the embodiments, the device is adapted to transfer less than about intervention site. In some embodiments, the device is adapted 1%, less than about 5%, less than about 10%. less than about to free at least about 90% of the coating from the substrate to 15%, less than about 25%, less than about 50%, less than the intervention site. In some embodiments, the device is about 70%, less than about 80%, and/or less than about 90% adapted to free at least about 95% of the coating from the of the coating absent stimulation of the coating. substrate to the intervention site. In some embodiments, the 0545. In some embodiments, the device is adapted to device is adapted to free at least about 99% of the coating transfer at least about 10%, at least about 20%, at least about from the substrate to the intervention site. As used herein, 30%, at least about 50%, at least about 75%, at least about "about when used in reference to a percentage of the coating 85%, at least about 90%, at least about 95%, and/or at least can mean ranges of 1%-5% of 5%-10%, of 10%-20%, and/or about 99% of the active agent from the substrate to the inter of 10%-50% (as a percent of the percentage of the coating vention site. In some embodiments, the device is adapted to freed, or as a variation of the percentage of the coating freed). transfer at least about 10% of the active agent from the Sub (0548. In some embodiments, the coating portion that frees strate to the intervention site. In some embodiments, the upon stimulation is on at least one of a distal Surface of the device is adapted to transfer at least about 20% of the active Substrate, a middle Surface of the Substrate, a proximal Sur agent from the Substrate to the intervention site. In some face of the substrate, and an abluminal surface of the sub embodiments, the device is adapted to transfer at least about Strate. 30% of the active agent from the substrate to the intervention 0549. In some embodiments, the stimulation decreases the site. In some embodiments, the device is adapted to transfer at contact between the coating and the Substrate. In some least about 50% of the active agent from the substrate to the embodiments, the device is adapted to free less than about intervention site. In some embodiments, the device is adapted 1%, less than about 5%, less than about 10%. less than about to transfer at least about 75% of the active agent from the 15%, less than about 25%, less than about 50%, less than substrate to the intervention site. In some embodiments, the about 70%, less than about 80%, less than about 90% of the device is adapted to transfer at least about 85% of the active coating absent stimulation of the coating. agent from the Substrate to the intervention site. In some 0550. In some embodiments, the device is adapted to dis embodiments, the device is adapted to transfer at least about sociate at least about 10%, at least about 20%, at least about 90% of the active agent from the substrate to the intervention 30%, at least about 50%, at least about 75%, at least about site. In some embodiments, the device is adapted to transfer at 85%, at least about 90%, at least about 95%, and/or at least least about 95% of the active agent from the substrate to the about 99% of the coating from the substrate. In some embodi intervention site. In some embodiments, the device is adapted ments, the device is adapted to dissociate at least about 10% to transfer at least about 99% of the active agent from the of the coating from the substrate to the intervention site. In substrate to the intervention site. As used herein, “about Some embodiments, the device is adapted to dissociate at least when used in reference to a percentage of the active agent can about 20% of the coating from the substrate to the interven mean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of tion site. In some embodiments, the device is adapted to 10%-50% (as a percent of the percentage of the active agent dissociate at least about 30% of the coating from the substrate transferred, or as a variation of the percentage of the active to the intervention site. In some embodiments, the device is agent transferred). adapted to dissociate at least about 50% of the coating from 0546. In some embodiments, the coating portion that the substrate to the intervention site. In some embodiments, transfers upon stimulation is on at least one of a distal Surface the device is adapted to dissociate at least about 75% of the of the substrate, a middle surface of the substrate, a proximal coating from the Substrate to the intervention site. In some surface of the substrate, and an abluminal surface of the embodiments, the device is adapted to dissociate at least Substrate. In some embodiments, the stimulation decreases about 85% of the coating from the substrate to the interven the contact between the coating and the Substrate. In some tion site. In some embodiments, the device is adapted to embodiments, the device is adapted to transfer less than about dissociate at least about 90% of the coating from the substrate 1%, less than about 5%, less than about 10%. less than about to the intervention site. In some embodiments, the device is 15%, less than about 25%, less than about 50%, less than adapted to dissociate at least about 95% of the coating from about 70%, less than about 80%, less than about 90% of the the substrate to the intervention site. In some embodiments, active agent absent stimulation of the coating. the device is adapted to dissociate at least about 99% of the US 2010/0015200 A1 Jan. 21, 2010 64 coating from the Substrate to the intervention site. As used 1'-yl)-rapamycin, (2':E,4'S)-40-O-(4',5'-Dihydroxypent-2'- herein, “about when used in reference to a percentage of the en-1-yl)-rapamycin 40-O-(2-Hydroxy)ethoxycarbonylm coating can mean ranges of 1%-5%, of 5%-10%, of 10%- ethyl-rapamycin, 40-O-(3-Hydroxy)propyl-rapamycin 20%, and/or of 10%-50% (as a percent of the percentage of 4O—O-(6-Hydroxy)hexyl-rapamycin 40-O-2-(2-Hydroxy) the coating dissociated, or as a variation of the percentage of ethoxyethyl-rapamycin 4O—O-(3S)-2,2-Dimethyldiox the coating dissociated). olan-3-yl)methyl-rapamycin, 40-O-(2S)-2,3-Dihydrox 0551. In some embodiments, the coating portion that dis yprop-1-yl-rapamycin, 4O—O-(2-Acetoxy)ethyl Sociates upon stimulation is on at least one of a distal Surface rapamycin 4O—O-(2-Nicotinoyloxy)ethyl-rapamycin, of the substrate, a middle surface of the substrate, a proximal 4O O-2-(N-Morpholino)acetoxyethyl-rapamycin surface of the substrate, and an abluminal surface of the 4O—O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O-2- Substrate. In some embodiments, stimulation decreases the (N-Methyl-N'-piperazinyl)acetoxyethyl-rapamycin, 39-O- contact between the coating and the Substrate. In some Desmethyl-39.40-O.O-ethylene-rapamycin, (26R)-26-Dihy embodiments, the device is adapted to dissociate less than dro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl about 1%, less than about 5%, less than about 10%. less than rapamycin, 4O -O-(2-Aminoethyl)-rapamycin, 4O-O-(2- about 15%, less than about 25%, less than about 50%, less Acetaminoethyl)-rapamycin 4O—O-(2- than about 70%, less than about 80%, less than about 90% of Nicotinamidoethyl)-rapamycin, 4O-O-(2-(N-Methyl the coating absent stimulation of the coating. imidazo-2-ylcarbethoxamido)ethyl)-rapamycin, 4O-O-(2- 0552. In some embodiments, the device is adapted to Ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2'- deliver at least about 10%, at least about 20%, at least about Tolylsulfonamidoethyl)-rapamycin, 40-O-2-(4',5'- 30%, at least about 50%, at least about 75%, at least about Dicarboethoxy-1'2',3'-triazol-1-yl)-ethyl-rapamycin, 85%, at least about 90%, at least about 95%, and/or at least 42-Epi-(tetrazolyl)rapamycin (tacrolimus), and 42-3-hy about 99% of the coating to the intervention site. In some droxy-2-(hydroxymethyl)-2-methylpropanoaterapamycin embodiments, the device is adapted to deliver at least about (temsirolimus). 10% of the coating to the intervention site. In some embodi 0556. In some embodiments of the methods and/or ments, the device is adapted to deliver at least about 20% of devices provided herein, the macrollide immunosuppressive the coating to the intervention site. In some embodiments, the drug is at least 50% crystalline. In some embodiments, the device is adapted to deliver at least about 30% of the coating macrollide immunosuppressive drug is at least 75% crystal to the intervention site. In some embodiments, the device is line. In some embodiments, the macrollide immunosuppres adapted to deliver at least about 50% of the coating to the sive drug is at least 90% crystalline. In some embodiments of intervention site. In some embodiments, the device is adapted the methods and/or devices provided herein the macrollide to deliver at least about 75% of the coating to the intervention immunosuppressive drug is at least 95% crystalline. In some site. In some embodiments, the device is adapted to deliver at embodiments of the methods and/or devices provided herein least about 85% of the coating to the intervention site. In some the macrollide immunosuppressive drug is at least 97% crys embodiments, the device is adapted to deliver at least about talline. In some embodiments of the methods and/or devices 90% of the coating to the intervention site. In some embodi provided herein macrollide immunosuppressive drug is at ments, the device is adapted to deliver at least about 95% of least 98% crystalline. In some embodiments of the methods the coating to the intervention site. In some embodiments, the and/or devices provided herein the macrollide immunosup device is adapted to deliver at least about 99% of the coating pressive drug is at least 99% crystalline. to the intervention site. As used herein, “about when used in 0557. In some embodiments of the methods and/or reference to a percentage of the coating can mean ranges of devices provided herein wherein the pharmaceutical agent is 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a at least 50% crystalline. In some embodiments of the methods percent of the percentage of the coating delivered, or as a and/or devices provided herein the pharmaceutical agent is at variation of the percentage of the coating delivered). least 75% crystalline. In some embodiments of the methods 0553. In some embodiments, the coating portion that is and/or devices provided herein the pharmaceutical agent is at delivered upon stimulation is on at least one of a distal Surface least 90% crystalline. In some embodiments of the methods of the substrate, a middle surface of the substrate, a proximal and/or devices provided herein the pharmaceutical agent is at surface of the substrate, and an abluminal surface of the least 95% crystalline. In some embodiments of the methods Substrate. In some embodiments, the stimulation decreases and/or devices provided herein the pharmaceutical agent is at the contact between the coating and the Substrate. In some least 97% crystalline. In some embodiments of the methods embodiments, the device is adapted to deliver less than about and/or devices provided herein pharmaceutical agent is at 1%, less than about 5%, less than about 10%. less than about least 98% crystalline. In some embodiments of the methods 15%, less than about 25%, less than about 50%, less than and/or devices provided herein the pharmaceutical agent is at about 70%, less than about 80%, less than about 90% of the least 99% crystalline. coating absent stimulation of the coating. 0558. In some embodiments, the pharmaceutical agent is 0554. In some embodiments, the active agent comprises a agent is selected form the group consisting of In some pharmaceutical agent. embodiments, a pharmaceutical agent is at least one of Acar 0555. In some embodiments, the pharmaceutical agent bose, acetylsalicylic acid, acyclovir, allopurinol, alprostadil, comprises a macrollide immunosuppressive drug. In some prostaglandins, amantadine, ambroXol, amlodipine, S-ami embodiments the macrollide immunosuppressive drug com nosalicylic acid, amitriptyline, atenolol, azathioprine, bal prises one or more of rapamycin, 40-O-(2-Hydroxyethyl) Salazide, beclomethasone, betahistine, beZafibrate, diazepam rapamycin (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4- and diazepam derivatives, budesonide, bufeXamac, buprenor Hydroxymethyl)benzyl-rapamycin, 40-O-4-(1,2- phine, methadone, calcium salts, potassium salts, magnesium Dihydroxyethyl)benzyl-rapamycin, 40-O-Allyl-rapamycin, salts, candesartan, carbamazepine, captopril, cetirizine, 40-O-3'-(2,2-Dimethyl-1,3-dioxolan-4-(S)-yl)-prop-2-en chenodeoxycholic acid, theophylline and theophylline US 2010/0015200 A1 Jan. 21, 2010

derivatives, trypsins, cimetidine, clobutinol, clonidine, cotri tiropramide, tizanidine, tolazoline, tolbutamide, tolcapone, moxazole, codeine, caffeine, Vitamin D and derivatives of tolnaftate, tolperisone, topotecan, torasemide, tramadol, tra Vitamin D, colestyramine, cromoglicic acid, coumarin and maZoline, trandolapril, tranylcypromine, trapidil, traZodone, coumarin derivatives, cysteine, ciclosporin, cyproterone, triamcinolone derivatives, triamterene, trifluperidol, trifluri cytabarine, dapiprazole, desogestrel, desonide, dihydrala dine, trimipramine, tripelennamine, triprolidine, trifosfa Zine, diltiazem, ergot alkaloids, dimenhydrinate, dimethyl mide, tromantadine, trometamol, tropalpin, troXerutine, Sulphoxide, dimeticone, domperidone and domperidan tulobuterol, tyramine, tyrothricin, urapidil, Valaciclovir, Val derivatives, dopamine, doxazosin, doxylamine, benzodiaz proic acid, Vancomycin, vecuronium chloride, Viagra, Ven epines, diclofenac, desipramine, econazole, ACE inhibitors, lafaxine, Verapamil, Vidarabine, vigabatrin, Viloazine, Vin enalapril, ephedrine, epinephrine, epoetin and epoetin deriva camine, Vinpocetine, Viduidil, warfarin, Xantinol nicotinate, Xipamide, Zafirlukast, Zalcitabine, Zidovudine, Zolmitriptan, tives, morphinans, calcium antagonists, modafinil, orlistat, Zolpidem, Zoplicone, Zotipine, amphotericin B, caspofungin, peptide antibiotics, phenytoin, riluzoles, risedronate, sildena Voriconazole, resveratrol, PARP-1 inhibitors (including imi fil, topiramate, estrogen, progestogen and progestogen daZoquinolinone, imidazpyridine, and isoquinolindione, tis derivatives, testosterone derivatives, androgen and androgen Sue plasminogen activator (tPA), melagatran, lanoteplase, derivatives, ethenzamide, etofenamate, etofibrate, fenofi reteplase, staphylokinase, streptokinase, tenecteplase, uroki brate, etofylline, famciclovir, famotidine, felodipine, fenta nase, abciximab (ReoPro), eptifibatide, tirofiban, prasugrel, nyl, fenticonazole, gyrase inhibitors, fluconazole, fluiarizine, clopidogrel, dipyridamole, cilostazol, VEGF, heparan Sul fluoxetine, flurbiprofen, ibuprofen, fluvastatin, follitropin, fate, chondroitin sulfate, elongated “RGD' peptide binding formoterol, fosfomicin, furosemide, fusidic acid, gallopamil, domain, CD34 antibodies, cerivastatin, etorvastatin, losartan, ganciclovir, gemfibrozil, ginkgo, Saint John's wort, glib Valartan, erythropoietin, rosiglitaZone, pioglitaZone, mutant enclamide, urea derivatives as oral antidiabetics, glucagon, protein Apo Al Milano, adiponectin, (NOS) gene therapy, glucosamine and glucosamine derivatives, glutathione, glyc glucagon-like peptide 1, atorvastatin, and atrial natriuretic erol and glycerol derivatives, hypothalamus hormones, peptide (ANP), lidocaine, tetracaine, dibucaine, hyssop, gin guanethidine, halofantrine, haloperidol, heparin (and deriva ger, turmeric, Arnica montana, helenalin, cannabichromene, tives), hyaluronic acid, hydralazine, hydrochlorothiazide rofecoxib, hyaluronidase, and salts, derivatives, isomers, (and derivatives), salicylates, hydroxy Zine, imipramine, racemates, diastereoisomers, prodrugs, hydrate, ester, orana indometacin, indoramine, insulin, iodine and iodine deriva logs thereof. tives, isoconazole, isoprenaline, glucitol and glucitol deriva 0559. In some embodiments, the pharmaceutical agent tives, itraconazole, ketoprofen, ketotifen, lacidipine, lanso comprises hyaluronidase. prazole, levodopa, levomethadone, thyroid hormones, lipoic acid (and derivatives), lisinopril, lisuride, lofepramine, lop 0560. In some embodiments, the pharmaceutical agent eramide, loratadine, maprotiline, mebendazole, mebeverine, comprises cilostazol. meclozine, mefenamic acid, mefloquine, meloxicam, mepin 0561. In some embodiments, the pharmaceutical agent dolol, meprobamate, mesalazine, mesuXimide, metamizole, comprises dipyridamole. metformin, methylphenidate, metixene, metoprolol, metron 0562. In some embodiments, the pharmaceutical agent idazole, mianserin, miconazole, minoxidil, misoprostol, comprises an antibiotic agent. mizolastine, moexipril, morphine and morphine derivatives, 0563. In some embodiments, the pharmaceutical agent evening primrose, nalbuphine, naloxone, tilidine, naproxen, comprises a chemotherapeutic agent. narcotine, natamycin, neostigmine, nicergoline, nicethamide, 0564. In some embodiments, the pharmaceutical agent is nifedipine, niflumic acid, nimodipine, nimorazole, nimus in a therapeutically desirable morphology. tine, nisoldipine, adrenaline and adrenaline derivatives, 0565. In certain embodiments, a device of the invention is novamine Sulfone, noscapine, nystatin, olanzapine, olsala used for treatment of cancer. Zine, omeprazole, omoconazole, oxaceprol, oxiconazole, 0566. In certain embodiments, devices and methods of the oxymetazoline, pantoprazole, paracetamol(acetaminophen), invention are used for intraductal treatment of breast cancer. paroxetine, penciclovir, pentazocine, pentifylline, pentoxi In these embodiments, the device is introduced into a breast fylline, perphenazine, pethidine, plant extracts, phenaZone, duct using a delivery tool, e.g., a hollow needle Such as a pheniramine, barbituric acid derivatives, phenylbutaZone, cannula, biopsy needle, or the like into the duct to contact pimozide, pindolol, piperazine, piracetam, pirenzepine, pir target ductal epithelial cells lining the duct. The amount of ibedil, piroxicam, pramipexole, pravastatin, praZosin, agent can vary, but optimally will be an amount Sufficient to procaine, promazine, propiverine, propranolol, propy target all atypical or malignant cells in the duct. Estimates of phenaZone, protionamide, proxyphylline, quetiapine, the quantity of target cells can be made upon the initial iden quinapril, quinaprilat, ramipril, ranitidine, reproterol, reser tification of the target duct, e.g. by cytological evaluation of pine, ribavirin, risperidone, ritonavir, ropinirole, roXatidine, ductal epithelial cells retrieved from the duct. The amount ruscogenin, rutoside (and derivatives), Sabadilla, Salbutamol. may vary depending on the agent's potency and other miti salmeterol, Scopolamine, Selegiline, Sertaconazole, sertin gating factors such as the extent of any time delay of delivery dole, Sertralion, silicates, simvastatin, sitosterol, Sotalol, spa of the agent once inside the duct (e.g. with a time release glumic acid, spirapril, spironolactone, stavudine, Streptomy formulation). cin, Sucralfate, Sufentanil, SulfaSalazine, Sulpiride, Sultiam, 0567. In embodiments, a breast cancer is treated using the Sumatriptan, suxamethonium chloride, tacrine, tacrolimus, devices and methods of the invention to deliver a chemothera taliolol, taurolidine, temazepam, tenoxicam, teraZosin, ter peutic or other appropriate agent as known in the art within binafine, terbutaline, terfenadine, terlipressin, tertatolol. the tumor resective cavity following lumpectomy. In these tery Zoline, theobromine, butizine, thiamazole, phenothiaz embodiments a balloon catheter is inserted into the cavity and ines, tiagabine, tiapride, propionic acid derivatives, ticlopi inflated using methods similar to those used for delivery of dine, timolol, tinidazole, tioconazole, tioguanine, tioXolone, internal radiation therapy using the MammoSite(R) RTS. US 2010/0015200 A1 Jan. 21, 2010 66

0568. The agent delivered can be a therapeutically active thiamiprine, tirapazamine, trestolone acetate, triciribine agent, including e.g., any agent Suitable for treating the breast phosphate, trimetrexate glucuronate, tubulozole hydrochlo condition identified, including e.g., any anti-cancer agents, ride, uracil mustard, uredepa, Verteporfin, vinepidine Sulfate, any prophylactic agents, or any agent for treating any other Vinglycinate Sulfate, Vinleurosine Sulfate, vinorelbine tar breast condition or for prophylaxis against a breast condition. trate, Vinrosidine Sulfate, Zeniplatin, Zinostatin, 20-epi-1,25 Thus, for example, the agent if an anti-cancer agent can dihydroxyvitamin D3, 5-ethynyluracil, acylfulvene, ade include, e.g., an estrogen activity modulator, a cytostatic cypenol, ALL-TK antagonists, ambamustine, amidox, ami agent, or a cytotoxic agent. The agent may also include e.g., fostine, aminolevulinic acid, amrubicin, anagrelide, an antibody, a peptide, a polypeptide, a nucleic acid, a poly andrographolide, antagonist D, antagonist G, antarelix, anti nucleotide, a small organic molecule, a macromolecule, a dorsalizing morphogenetic protein-1, antiandrogen, anties polymer, a carbohydrate, or a lipid. The agent can be formu trogen, estrogen agonist, apurinic acid, ara-CDP-DL-PTBA, lated to be released over time into a breast duct. The agent can arginine deaminase, asulacrine, atameStane, atrimustine, axi be delivered to the lactiferous sinus of the breast duct for nastatin 1, axinastatin 2, axinastatin 3, aZasetron, azatoxin, release into the rest of the ductal system from there, or the azatyrosine, baccatin III derivatives, balanol, BCR/ABL agent may be delivered to any part of the breast duct, e.g., antagonists, benzochlorins, benzoylstaurosporine, beta lac including the ductal lumens of the ductal system and also the tam derivatives, beta-alethine, betaclamycin B, betulinic terminal ductal lobular unit. Methods and devices for intra acid, bFGF inhibitor, bisaziridinylspermine, bistratene A, ductal treatment of breast cancer have been described, e.g., in breflate, buthionine sulfoximine, calcipotriol, calphostin C, U.S. Pat. App. No. 2004/0147904, “Methods and devices for carboxamide-amino-triazole, carboxyamidotriazole, CaRest delivery of agents to breast milk ducts,” and WO 02/078716, M3, CARN 700, cartilage derived inhibitor, casein kinase “Intraductal Treatment Targeting Methylated Promoters in inhibitors (ICOS), castanospermine, cecropin B, cetrorelix, Breast Cancer, both incorporated herein by reference in their chloroquinoxaline Sulfonamide, cicaprost, cis-porphyrin, entirety. clomifene analogues, clotrimazole, collismycin A, collismy 0569. In some embodiments, the active agent comprises a cin B, combretastatin A4, combretastatin analogue, conage chemotherapeutic agent. In some embodiments, the pharma nin, crambescidin 816, cryptophycin 8, cryptophycin A ceutical agent comprises a chemotherapeutic agent. In some derivatives, curacin A, cyclopentanthraquinones, cyclo embodiments, the chemotherapeutic agent comprises at least platam, cypemycin, cytolytic factor, cytostatin, dacliximab, one of an angiostatin, DNA topoisomerase, endostatin, dehydrodidemnin B, dexamethasone, dexifosfamide, dexra genistein, ornithine decarboxylase inhibitors, chlormethine, Zoxane, dexVerapamil, didemnin B, didox, diethylnorsper melphalan, pipobroman, triethylene-melamine, triethyl mine, dihydro-5-azacytidine, dihydrotaxol. 9-, dioxamycin, enethiophosphoramine, busulfan, carmustine (BCNU), strep docosanol, dolasetron, dronabinol, duocarmycin SA, toZocin, 6-mercaptopurine, 6-thioguanine, Deoxyco-formy ebselen, ecomustine, edelfosine, edrecolomab, elemene, cin, IFN-C., 17C.-ethinylestradiol, diethylstilbestrol, emitefur, estramustine analogue, filgrastim, flavopiridol, fle testosterone, prednisone, fluoxymesterone, dromostanolone Zelastine, fluasterone, fluorodaunorunicin hydrochloride, for propionate, testolactone, megestrolacetate, methylpredniso fenimex, gadolinium texaphyrin, galocitabine, gelatinase lone, methyl-testosterone, prednisolone, triamcinolone, chlo inhibitors, glutathione inhibitors, hepsulfam, heregulin, hex rotrianisene, hydroxyprogesterone, estramustine, medroX amethylene bisacetamide, hypericin, ibandronic acid, idra yprogesteroneacetate, flutamide, Zoladex, mitotane, mantone, ilomastat, imatinib (e.g., Gleevec), imiquimod, hexamethylmelamine, indolyl-3-glyoxylic acid derivatives, immunostimulant peptides, insulin-like growth factor-1 (e.g., indibulin), doxorubicin and idarubicin, plicamycin receptor inhibitor, interferon agonists, interferons, interleu (mithramycin) and mitomycin, mechlorethamine, cyclophos kins, iobenguane, iododoxorubicin, ipomeanol, 4-, iroplact, phamide analogs, traZenes-dacarbazinine (DTIC), pentosta irsogladine, isobengaZole, isohomohalicondrin B, itasetron, tin and 2-chlorodeoxyadenosine, letrozole, camptothecin jasplakinolide, kahalalide F, lamellarin-N triacetate, leina (and derivatives), navelbine, erlotinib, capecitabine, acivicin, mycin, lenograstim, lentinan Sulfate, leptolstatin, leukemia acodazole hydrochloride, acronine, adoZelesin, aldesleukin, inhibiting factor, leukocyte alpha interferon, leuprolide--es ambomycin, ametantrone acetate, anthramycin, asperlin, trogen-progesterone, linear polyamine analogue, lipophilic aZacitidine, azetepa, azotomycin, batimastat, benzodepa, disaccharide peptide, lipophilic platinum compounds, lisso bisnafide, bisnafide dimesylate, bizelesin, bropirimine, cac clinamide 7, lobaplatin, lombricine, loxoribine, lurtotecan, tinomycin, calusterone, carbetimer, carubicin hydrochloride, lutetium texaphyrin, lysofylline, lytic peptides, maitansine, carzelesin, cedefingol, celecoxib (COX-2 inhibitor), cirole mannostatin A, marimastat, maspin, matrilysin inhibitors, mycin, crisinatol mesylate, decitabine, dexormaplatin, deza matrix metalloproteinase inhibitors, meterelin, methioni guanine mesylate, diaziquone, duaZomycin, edatrexate, eflo nase, metoclopramide, MIF inhibitor, mifepristone, miltefos mithine, elsamitrucin, enloplatin, empromate, epipropidine, ine, mirimoStim, mitoguaZone, mitotoxin fibroblast growth erbuloZole, etanidazole, etoprine, flurocitabine, fosquidone, factor-Saporin, mofarotene, molgramoStim, ErbituX, human lometrexol, losoxantrone hydrochloride, masoprocol, may chorionic gonadotrophin, monophosphoryl lipid A+myobac tansine, megestrol acetate, melengestrol acetate, metoprine, terium cell wall sk, mustard anticancer agent, mycaperoxide meturedepa, mitindomide, mitocarcin, mitocromin, mitogil B, mycobacterial cell wall extract, myriaporone, N-acetyl lin, mitomalcin, mitosper, mycophenolic acid, nocodazole, dinaline, N-substituted benzamides, nagrestip, naloxone-- nogalamycin, ormaplatin, oxisuran, pegaspargase, peliomy pentazocine, napavin, naphterpin, nartograstim, nedaplatin, cin, pentamustine, perfosfamide, piposulfan, plomestane, nemorubicin, neridronic acid, nisamycin, nitric oxide modu porfimer Sodium, porfiromycin, puromycin, pyrazofurin, lators, nitroxide antioxidant, nitrullyn, oblimersen (Gena riboprine, Safingol, simtraZene, sparfosate Sodium, Spiromus sense), O'-benzylguanine, okicenone, onapristone, tine, Spiroplatin, streptonigrin, Sulofenur, tecogalan Sodium, ondansetron, oracin, oral cytokine inducer, paclitaxel ana taxotere, tegafur, teloxantrone hydrochloride, temoporfin, logues and derivatives, palauamine, palmitoylrhizoxin, pam US 2010/0015200 A1 Jan. 21, 2010 67 idronic acid, panaxytriol, panomifene, parabactin, peldesine, teroxirone, tetraplatin and trimelamol, Taiho 4181-A, aclaru pentosan polysulfate Sodium, pentroZole, perflubron, perillyl bicin, actinomycin D, actinoplanone, Erbamont ADR-456, alcohol, phenazinomycin, phenylacetate, phosphatase inhibi aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto tors, picibanil, pilocarpine hydrochloride, placetin A, placetin AN-3, Nippon Soda anisomycins, anthracycline, azino-my B. plasminogen activator inhibitor, platinum complex, plati cin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers num compounds, platinum-triamine complex, propyl bis-ac BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers ridone, prostaglandin J2, proteasome inhibitors, protein BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers A-based immune modulator, protein kinase C inhibitors, BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, microalgal, pyrazoloacridine, pyridoxylated hemoglobin calichemycin, chromoximycin, dactinomycin, daunorubicin, polyoxyethylene conjugate, raf antagonists, raltitrexed, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko ramosetron, ras farnesyl protein transferase inhibitors, ras DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, GAP inhibitor, retelliptine demethylated, rhenium Re 186 ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubi etidronate, ribozymes, RII retinamide, rohitukine, romurtide, cin-fibrinogen, elsamicin-A, epirubicin, erbStatin, esorubi roquinimex, rubiginone B1, ruboxyl, Saintopin, SarCNU, sar cin, esperamicin-A1, esperamicin-A1b, Erbamont FCE cophytol A, Sargramostim, Sdi 1 mimetics, senescence 21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, derived inhibitor 1, signal transduction inhibitors, sizofiran, glidobactin, gregatin-A, grincamycin, herbimycin, idarubi Sobuzoxane, sodium borocaptate, solverol. Somatomedin cin, illudins, kaZusamycin, kesarirhodins, Kyowa Hakko binding protein, Sonermin, sparfosic acid, spicamycin D, KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko splenopentin, spongistatin 1, squalamine, stipiamide, KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, stromelysin inhibitors, sulfinosine, Superactive vasoactive American Cyanamid LL-D49194, Meiji Seika ME 2303, intestinal peptide antagonist, Suradista, Suramin, Swainso menogaril, mitomycin, mitomycin analogues, mitoxantrone, nine, tallimustine, tazarotene, tellurapyrylium, telomerase SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, inhibitors, tetrachlorodecaoxide, tetraZomine, thiocoraline, Nippon Kayaku NKT-01, SRI International NSC-357704, thrombopoietin, thrombopoietin mimetic, thymalfasin, thy oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, mopoietin receptoragonist, thymotrinan, thyroid stimulating porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, hormone, tin ethyl etiopurpurin, titanocene bichloride, rhizoxin, rodorubicin, Sibanomicin, Siwenmycin, Sumitomo top sentin, translation inhibitors, tretinoin, triacetyluridine, SM-5887, Snow Brand SN-706, Snow Brand SN-07, Soran tropisetron, turosteride, ubenimex, urogenital sinus-derived gicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS growth inhibitory factor, variolin B. velaresol, Veramine, ver Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, dins, vinxaltine, Vitaxin, Zanoterone, Zilascorb, Zinostatin Sti Steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN malamer, acanthifolic acid, aminothiadiazole, anastrozole, 868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, bicalutamide, brequinar Sodium, capecitabine, carmofur, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Ciba-Geigy CGP-30694, cladribine, cyclopentyl cytosine, Y-25024, Zorubicin, 5-fluorouracil (5-FU), the peroxidate cytarabine phosphate Stearate, cytarabine conjugates, cytara oxidation product of inosine, adenosine, or cytidine with bine ocfosfate, Lilly DATHF, Merrel Dow DDFC, dezagua methanol or ethanol, cytosine arabinoside (also referred to as nine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi Cytarabin, araC, and Cytosar), 5-AZacytidine, 2-Fluoroad DMDC, doxifluridine, Wellcome EHNA, Merck & Co. enosine-5'-phosphate (Fludara, also referred to as FaraA), EX-015, fazarabine, floxuridine, fludarabine, fludarabine 2-Chlorodeoxyadenosine, Abarelix, Abbott A-84861, Abi phosphate, N-(2-furanidyl)-5-fluorouracil, Daiichi Seiyaku raterone acetate, Aminoglutethimide, Asta Medica AN-207, FO-152, 5-FU-fibrinogen, isopropyl pyrrolizine, Lilly Antide, Chugai AG-041R, AVorelin, aseranox, Sensus LY-188011, Lilly LY-264618, methobenzaprim, methotrex B2036-PEG, buserelin, BTG CB-7598, BTG CB-7630, ate, Wellcome MZPES, norspermidine, nolvadex, NCINSC Casodex, cetrolix, clastroban, clodronate disodium, CoSu 127716, NCI NSC-264880, NCI NSC-39661, NCI NSC dex, Rotta Research CR-1505, cytadren, crinone, deslorelin, 612567. Warner-Lambert PALA, pentostatin, piritrexim, droloxifene, dutasteride, Elimina, Laval University EM-800, plicamycin, Asahi Chemical PL-AC, stearate, Takeda TAC Laval University EM-652, epitiostanol, epristeride, 788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, Mediolanum EP-23904, EntreMed 2-ME, exemestane, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, fadrozole, finasteride, formestane, Pharmacia & Upjohn Taiho UFT, uricytin, Shionogi 254-S, aldo-phosphamide ana FCE-24304, ganirelix, goserelin, Shire gonadorelin agonist, logues, altretamine, anaxirone, Boehringer Mannheim BBR GlaxoWellcome GW-5638, Hoechst Marion Roussel Hoe 2207, bestrabucil, budotitane, Wakunaga CA-102, carbopl 766, NCI hCG, idoxifene, isocordoin, Zeneca ICI-182780, atin, carmustine (BiCNU), Chinoin-139, Chinoin-153, Zeneca ICI-118630, Tulane University J015X, Schering Ag chlorambucil, cisplatin, cyclophosphamide, American J96, ketanserin, lanreotide, Milkhaus LDI-200, letrozol, leu Cyanamid CL-286558, Sanofi CY-233, cyplatate, dacarba prolide, leuprorelin, liarozole, lisuride hydrogen maleate, zine, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphe loxiglumide, mepitioStane, Ligand Pharmaceuticals nylspiromustine, diplatinum cytostatic, Chugai DWA LG-1127, LG-1447, LG-2293, LG-2527, LG-2716, Bone 2114R, ITI E09, elmustine, Erbamont FCE-24517, Care International LR-103, Lilly LY-326315, Lilly estramustine phosphate sodium, etoposide phosphate, fote LY-353381-HCl, Lilly LY-326391, Lilly LY-353381, Lilly mustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, LY-357489, miproxifene phosphate, Orion Pharma MPV ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, 2213ad, Tulane University MZ-4-71, nafarelin, nilutamide, mycophenolate, Nippon Kayaku NK-121, NCINSC-264395, Snow Brand NKS01, AZko Nobel ORG-31710, AZko Nobel NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimus ORG-31806, orimeten, orimetene, orimetime, ormeloxifene, tine, Proter PTT-119, ranimustine, semustine, SmithKline osaterone, Smithkline Beecham SKB-105657, Tokyo Uni SK&F-101772, thiotepa, Yakult Honsha SN-22, spiromus versity OSW-1, Peptech PTL-03001, Pharmacia & Upjohn tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, PNU-156765, quinagolide, ramorelix, Raloxifene, statin, US 2010/0015200 A1 Jan. 21, 2010

sandostatin LAR, Shionogi S-10364, Novartis SMT-487. Pharmaceutical SS-554, Strypoldinone, Stypoldione, Suntory Somavert, Somatostatin, tamoxifen, tamoxifen methiodide, SUN 0237, Suntory SUN 2071, Sugen SU-101, Sugen teverelix, toremifene, triptorelin, TT-232, vapreotide, Voro SU-5416, SugenSU-6668, Sulindac, sulindac sulfone, super Zole, Yamanouchi YM-116, Yamanouchi YM-511, Yamanou oxide dismutase, Toyama T-506, Toyama T-680, taxol. Teijin chi YM-55208, Yamanouchi YM-53789, Schering AG TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, ZK-1911703, Schering AG ZK-230211, and Zeneca tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, ZD-182780, alpha-carotene, alpha-difluoromethyl-arginine, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine, vinblastine sulfate, Vincristine, Vincristine sul acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amona fate, vindesine, Vindesine Sulfate, vinestramide, Vinorelbine, fide, amphethinile, amsacrine, Angiostat, ankinomycin, anti vintriptol, Vinzolidine, withanolides, Yamanouchi YM-534, neoplaston A10, antineoplaston A2, antineoplaston A3, anti Zileuton, urSodeoxycholic acid, Zanosar. neoplaston A5, antineoplaston AS2-1, Henkel APD, 0570. In some embodiments, the chemotherapeutic agent aphidicolinglycinate, asparaginase, Avarol, baccharin, batra comprises Bacillus Calmette-Guerin (BCG). cylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, 0571. In some embodiments, the active agent comprises bisantrene, Bristo-Myers BMY-40481, Vestarboron-10, bro an antibiotic agent. In some embodiments, the pharmaceuti mofosfamide, Wellcome BW-502, Wellcome BW-773, cal cal agent comprises an antibiotic agent. In some embodi cium carbonate, Calcet, Calci-Chew, Calci-Mix, Roxane cal ments, the antibiotic agent comprises at least one of amika cium carbonate tablets, caracemide, carmethizole cin, amoxicillin, gentamicin, kanamycin, neomycin, hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, netilmicin, paromomycin, tobramycin, geldanamycin, herbi Chemes CHX-2053, Chemex CHX-100, Warner-Lambert mycin, carbacephem (loracarbef), ertapenem, doripenem, CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, imipenem, cefadroxil, cefazolin, cefalotin, cephalexin, cefa Warner-Lambert CI-958, clanfenur, claviridenone, ICN com clor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, pound 1259, ICN compound 4711, Contracan, Cell Pathways cefdinir, cefditoren, cefoperaZone, cefotaxime, cefpodoxime, CP-461, Yakult Honsha CPT-11, crisinatol, curaderm, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS ceftobiprole, clarithromycin, clavulanic acid, clindamycin, maleate, datelliptinium, DFMO, didemnin-B, dihaematopor teicoplanin, azithromycin, dirithromycin, erythromycin, phyrin ether, dihydrolenperone dinaline, distamycin, Toyo troleandomycin, tellithromycin, aztreonam, ampicillin, Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku aZlocillin, bacampicillin, carbenicillin, cloxacillin, diclox DN-9693, docetaxel, Encore Pharmaceuticals E7869, ellip acillin, flucloxacillin, mezlocillin, meticillin, nafcillin, nor rabin, elliptinium acetate, Tsumura EPMTC, ergotamine, floxacin, oxacillin, penicillin G, penicillin V, piperacillin, etoposide, etretinate, Eulexin, Cell Pathways Exisulind pVampicillin, pivmecillinam, ticarcillin, bacitracin, colistin, (sulindac sulphone or CP-246), fenretinide, Florical, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levof Fujisawa FR-57704, gallium nitrate, gemcitabine, genkw loxacin, lomefloxacin, moxifloxacin, ofloxacin, trovafloxa adaphnin, Gerimed, Chugai GLA-43, Glaxo GR-63178, gri cin, grepafloxacin, sparfloxacin, afenide, prontosil, Sulfaceta folan NMF-5N, hexadecylphosphocholine, Green Cross mide, Sulfamethizole, Sulfanilimide, Sulfamethoxazole, HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, Sulfisoxazole, trimethoprim, trimethoprim-sulfamethox ilmofosine, irinotecan, isoglutamine, isotretinoin, Otsuka azole, demeclocycline, doxycycline, Oxytetracycline, tetra JI-36, Ramot K-477, ketoconazole, Otsuak K-76COONa, cycline, arsphenamine, chloramphenicol, lincomycin, Kureha Chemical K-AM, MECT Corp KI-8110, American ethambutol, fosfomycin, furazolidone, isoniazid, lineZolid, Cyanamid L-623, leucovorin, levamisole, leukoregulin, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, quinupristin?dalfopristin, rifampin, thiamphenicol, rifampi Materna, NCI (US) MAP. marycin, Merrel Dow MDL cin, minocycline, Sultamicillin, Sulbactam, Sulphonamides, 27048, Medco MEDR-340, megestrol, merbarone, merocya mitomycin, spectinomycin, spiramycin, roXithromycin, and nine derivatives, methylanilinoacridine, Molecular Genetics meropenem. MGI-136, minactivin, mitonafide, mitoguidone, Monocal, 0572. In some embodiments, the antibiotic agent com mopidamol, motretinide, Zenyaku Kogyo MST-16, Mylanta, prises erythromycin. N-(retinoyl)amino acids, Nilandron, Nisshin Flour Milling 0573. In some embodiments, the active agent comprises N-021, N-acylated-dehydroalanines, nafazatrom, Taisho an active biological agent. In some embodiments, the active NCU-190, Nephro-Calcitablets, nocodazole derivative, Nor biological agent comprises an active secondary, tertiary or mosang, NCI NSC-145813, NCI NSC-361456, NCI NSC quaternary structure. In some embodiments, the active bio 604782, NCI NSC-95580, octreotide, Ono ONO-112, odui logical agent comprises at least one of growth factors, cytok Zanocine, Akzo Org-10172, paclitaxel, pancratistatin, ines, peptides, proteins, enzymes, glycoproteins, nucleic pazelliptine, Warner-Lambert PD-11 1707, Warner-Lambert acids, antisense nucleic acids, fatty acids, antimicrobials, PD-115934, Warner-Lambert PD-131141, Pierre Fabre Vitamins, hormones, steroids, lipids, polysaccharides, carbo PE-1001, ICRT peptide D, piroxantrone, polyhaematopor hydrates, a hormone, gene therapies, RNA, siRNA, and/or phyrin, polypreic acid, Efamol porphyrin, probimane, procar cellular therapies such as stem cells and/or T-cells. bazine, proglumide, Invitron protease nexin I, Tobishi 0574. In some embodiments, the active biological agent RA-700, razoxane, retinoids, R-flurbiprofen (Encore Phar comprises siRNA. maceuticals), Sandostatin, Sapporo Breweries RBS, restric 0575. In some embodiments of the methods and/or tin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, devices provided herein, the device further comprises a stent. Rhone-Poulenc RP-56976, Scherring-Plough SC-57050, In some embodiments, the Substrate is not the stent. Scherring-Plough SC-57068, selenium (selenite and sele nomethionine), SmithKline SK&F-104864, Sumitomo Methods of Manufacturing Generally SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, 0576. In some embodiments, a coating is formed on said spirocyclopropane derivatives, spirogermanium, Unimed, SS Substrate by a process comprising depositing a polymer and/ US 2010/0015200 A1 Jan. 21, 2010 69 or the active agent by an e-RESS, an e-SEDS, or an e-DPC whereinforming the coating results in at least a portion of the process. In some embodiments, the process of forming said coating being adapted to transfer from the Substrate to an coating provides improved adherence of the coating to the intervention site upon stimulating the coating with a stimu substrate prior to deployment of the device at the intervention lation. site and facilitates dissociation of said coating from said 0585 Provided herein is a method of forming a medical substrate at the intervention site. In some embodiments, the device comprising a Substrate and a coating on at least a coating is formed on said Substrate by a process comprising portion of the Substrate, wherein the coating comprises an depositing the active agent by an e-RESS, an e-SEDS, or an active agent, the method comprising: providing the Substrate; e-DPC process without electrically charging the substrate. In and forming the coating on at least a portion of the Substrate Some embodiments, the coating is formed on said Substrate by by depositing the active agent by on the Substrate by at least a process comprising depositing the active agent on the Sub one of an e-RESS, an e-SEDS, and an e-DPC process without strate by an e-RESS, an e-SEDS, orane-DPC process without electrically charging the Substrate, whereinforming the coat creating an electrical potential between the Substrate and a ing results in at least a portion of the coating being adapted to coating apparatus used to deposit the active agent. transfer from the Substrate to an intervention site upon stimu 0577. Means for creating the bioabsorbable polymer(s) lating the coating with a stimulation. +drug (s) coating of the device with or without a Substrate: 0586 Provided herein is a method of forming a medical 0578 Spray coat the coating-form with drug and poly device comprising a Substrate and a coating on at least a meras is done in Micell process (e-RESS, e-DPC, com portion of the Substrate, wherein the coating comprises an pressed-gas sintering). active agent, the method comprising: providing the Substrate; 0579 Perform multiple and sequential coating-sinter and forming the coating on at least a portion of the Substrate ing steps where different materials may be deposited in by depositing the active agent by on the Substrate by at least each step, thus creating a laminated structure with a one of an e-RESS, an e-SEDS, and an e-DPC process without multitude of thin layers of drug(s), polymer(s) or drug-- creating an electrical potential between the Substrate and a polymer that build the final device. coating apparatus used in the at least one e-RESS, an e-SEDS, 0580 Perform the deposition of polymer(s)+drug(s) and an e-DPC process, whereinforming the coating results in laminates with the inclusion of a mask on the inner at least a portion of the coating being adapted to transfer from (luminal) surface of the device. Such a mask could be as the Substrate to an intervention site upon stimulating the simple as a non-conductive mandrel inserted through the coating with a stimulation. internal diameter of the coating form. This masking 0587 Provided herein is a method of forming a medical could take place prior to any layers being added, or be device comprising a Substrate and a coating on at least a purposefully inserted after several layers are deposited portion of the Substrate, wherein the coating comprises an continuously around the entire coating-form. active agent, the method comprising: providing the Substrate; 0581. In some embodiments, the coating comprises a and forming the coating on at least a portion of the Substrate microstructure. In some embodiments, particles of the active by depositing the active agent by on the Substrate by at least agent are sequestered or encapsulated within said microstruc one of a dipping and/or a spraying process, whereinforming ture. In some embodiments, the microstructure comprises the coating results in at least a portion of the coating being microchannels, micropores and/or microcavities. In some adapted to transfer from the substrate to an intervention site embodiments, the microstructure is selected to allow Sus upon stimulating the coating with a stimulation. tained release of the active agent. In some embodiments, the 0588 Provided herein is a method of forming a medical microstructure is selected to allow controlled release of the device comprising a Substrate and a coating on at least a active agent. portion of the Substrate, wherein the coating comprises an 0582. Other methods for preparing the coating include active agent, the method comprising: providing the Substrate; Solvent based coating methods and plasma based coating and forming the coating on at least a portion of the Substrate methods. In some embodiments, the coating is prepared by a by depositing the active agent by on the Substrate by at least Solvent based coating method. In some embodiments, the one of an e-RESS, an e-SEDS, and an e-DPC process, coating is prepared by a solvent plasma based coating whereinforming the coating results in at least a portion of the method. coating being adapted to free from the Substrate upon stimu 0583. Another advantage of the present invention is the lating the coating with a stimulation. ability to create a delivery device with a controlled (dialed-in) 0589 Provided herein is a method of forming a medical drug-elution profile. Via the ability to have different materials device comprising a Substrate and a coating on at least a in each layer of the laminate structure and the ability to portion of the Substrate, wherein the coating comprises an control the location of drug(s) independently in these layers, active agent, the method comprising: providing the Substrate; the method enables a device that could release drugs at very and forming the coating on at least a portion of the Substrate specific elution profiles, programmed sequential and/or par by depositing the active agent by on the Substrate by at least allel elution profiles. Also, the present invention allows con one of a dipping and/or a spraying process, whereinforming trolled elution of one drug without affecting the elution of a the coating results in at least a portion of the coating being second drug (or different doses of the same drug). adapted to free from the Substrate upon stimulating the coat 0584) Provided herein is a method of forming a medical ing with a stimulation. device comprising a Substrate and a coating on at least a 0590 Provided herein is a method of forming a medical portion of the Substrate, wherein the coating comprises an device comprising a Substrate and a coating on at least a active agent, the method comprising: providing the Substrate; portion of the Substrate, wherein the coating comprises an and forming the coating on at least a portion of the Substrate active agent, the method comprising: providing the Substrate; by depositing the active agent by on the Substrate by at least and forming the coating on at least a portion of the Substrate one of an e-RESS, an e-SEDS, and an e-DPC process, by depositing the active agent by on the Substrate by at least US 2010/0015200 A1 Jan. 21, 2010 70 one of an e-RESS, an e-SEDS, and an e-DPC process, when in contact with an aqueous liquid. In some embodi whereinforming the coating results in at least a portion of the ments, the coating results in a coating property that facilitates coating being adapted to dissociate from the Substrate upon transfer of the coating to the intervention site. In some stimulating the coating with a stimulation. embodiments, the coating property comprises a physical 0591 Provided herein is a method of forming a medical characteristic of the coating. In some embodiments, the device comprising a Substrate and a coating on at least a physical characteristic comprises a pattern. portion of the Substrate, wherein the coating comprises an 0597. In some embodiments, forming the coating facili active agent, the method comprising: providing the Substrate; tates transfer of the coating to the intervention site. and forming the coating on at least a portion of the Substrate 0598. In some embodiments, transferring, freeing, disso by depositing the active agent by on the Substrate by at least ciating, depositing, and/or tacking step comprises softening one of a dipping and/or a spraying process, whereinforming the polymer by hydration, degradation or by a combination of the coating results in at least a portion of the coating being hydration and degradation. In some embodiments, the trans adapted to dissociate from the Substrate upon stimulating the ferring, freeing, dissociating, depositing, and/or tacking step coating with a stimulation. comprises softening the polymer by hydrolysis of the poly 0592 Provided herein is a method of forming a medical C. device comprising a Substrate and a coating on at least a 0599. In some embodiments, the providing step comprises portion of the Substrate, wherein the coating comprises an forming the coating by a solvent based coating method. In active agent, the method comprising: providing the Substrate; Some embodiments, the providing step comprises forming the and forming the coating on at least a portion of the Substrate coating by a solvent plasma based method. by depositing the active agent by on the Substrate by at least 0600. In some embodiments, providing the device com one of an e-RESS, an e-SEDS, and an e-DPC process, prises depositing a plurality of layers on said Substrate to form whereinforming the coating results in at least a portion of the the coating, wherein at least one of the layers comprises the coating being adapted to deliver to the intervention site upon active agent. In some embodiments, at least one of the layers stimulating the coating with a stimulation. comprises a polymer. In some embodiments, the polymer is 0593 Provided herein is a method of forming a medical bioabsorbable. In some embodiments, the active agent and device comprising a Substrate and a coating on at least a the polymer are in the same layer, in separate layers, or form portion of the Substrate, wherein the coating comprises an overlapping layers. In some embodiments, the plurality of active agent, the method comprising: providing the Substrate; layers comprise five layers deposited as follows: a first poly and forming the coating on at least a portion of the substrate mer layer, a first active agent layer, a second polymer layer, a by depositing the active agent by on the Substrate by at least second active agent layer and a third polymer layer. one of a dipping and/or a spraying process, whereinforming EXAMPLES the coating results in at least a portion of the coating being adapted to deliver to the intervention site upon stimulating the 0601 The following examples are provided to illustrate selected embodiments. They should not be considered as coating with a stimulation. limiting the scope of the invention, but merely as being illus 0594. In some embodiments, the e-RESS, the e-SEDS, trative and representative thereof. For each example listed and/or the e-DPC process used in forming the coating is herein, multiple analytical techniques may be provided. Any performed without electrically charging the Substrate. In single technique of the multiple techniques listed may be some embodiments, the e-RESS, the e-SEDS, and/or the Sufficient to show the parameter and/or characteristic being e-DPC process used in forming the coating is performed tested, or any combination of techniques may be used to show without creating an electrical potential between the substrate such parameter and/or characteristic. Those skilled in the art and the coating apparatus used in the e-RESS, the e-SEDS, will be familiar with a wide range of analytical techniques for and/or the e-DPC process. the characterization of drug/polymer coatings. Techniques 0595. In some embodiments, forming the coating results presented here, but not limited to, may be used to additionally in the coating adhering to the Substrate prior to the Substrate and/or alternatively characterize specific properties of the reaching the intervention site. coatings with variations and adjustments employed which 0596. Some embodiments further comprise providing a would be obvious to those skilled in the art. release agent on said Substrate. In some embodiments, pro viding the release agent step is performed prior to the forming Sample Preparation the coating step. In some embodiments, the release agent 0602 Generally speaking, coatings on stents, on balloons, comprises at least one of a biocompatible release agent, a on coupons, on other Substrates, or on samples prepared for non-biocompatible release agent, a powder, a lubricant, a in-vivo models are prepared as herein. Nevertheless, modifi Surface modification of the Substrate, a viscous fluid, agel, the cations for a given analytical method are presented within the active agent, a second active agent, a physical characteristic examples shown, and/or would be obvious to one having skill of the Substrate. In some embodiments, the physical charac in the art. Thus, numerous variations, changes, and Substitu teristic of the Substrate comprises at least one of a patterned tions will now occur to those skilled in the art without depart coating surface of the substrate, and a ribbed surface of the ing from the invention. It should be understood that various Substrate. In some embodiments, the release agent comprises alternatives to the embodiments of the invention described a property that is capable of changing at the intervention site. herein and examples provided may be employed in practicing In some embodiments, the property comprises a physical the invention and showing the parameters and/or character property. In some embodiments, the property comprises a istics described. chemical property. In some embodiments, the release agent is capable of changing a property when in contact with at least Coatings on Balloons one of a biologic tissue and a biologic fluid. In some embodi 0603 Coated balloons as described herein and/or made by ments, the release agent is capable of changing a property a method disclosed herein are prepared. In some examples, US 2010/0015200 A1 Jan. 21, 2010

the coated balloons have a targeted coating thickness of ~15 into sections which may be turned 90 degrees and visualized microns (~5 microns of active agent). In some examples, the using the Surface composition techniques presented herein or coating process is PDPDP (Polymer, sinter, Drug, Polymer, other techniques known in the art for Surface composition sinter, Drug, Polymer, sinter) using deposition of drug in dry analysis (or other characteristics, such as crystallinity, for powder form and deposition of polymer particles by RESS example). In this way, what could be an analysis of coating methods and equipment described herein. In the illustrations composition through a depth when the coating is on the bal herein, resulting coated balloons may have a 3-layer coating comprising polymer (for example, PLGA) in the first layer, loon or as removed from the balloon (i.e. a depth from the drug (for example, rapamycin) in a second layer and polymer abluminal surface of the coating to the surface of the removed in the third layer, where a portion of the third layer is sub coating that once contacted the balloon or a portion thereof), stantially drug free (e.g. a Sub-layer within the third layer becomes a surface analysis of the coating which can, for having a thickness equal to a fraction of the thickness of the example, show the layers in the slice of coating, at much third layer). As described layer, the middle layer (or drug higher resolution. Residual coating on an extracted balloon layer) may be overlapping with one or both first (polymer) also can be analyzed and compared to the amount of coating and third (polymer) layer. The overlap between the drug layer on an unused balloon, using, e.g., HPLC, as noted herein. and the polymer layers is defined by extension of polymer Coating removed from the balloon, or analyzed without material into physical space largely occupied by the drug. The removal and/or release from the balloon, may be treated the overlap between the drug and polymer layers may relate to same way, and assayed, visualized, and/or characterized as partial packing of the drug particles during the formation of presented herein using the techniques described and/or other the drug layer. When crystal drug particles are deposited on techniques known to a person of skill in the art. top of the first polymer layer, Voids and or gaps may remain between dry crystal particles. The Voids and gaps are avail Coatings on Stents able to be occupied by particles deposited during the forma tion of the third (polymer) layer. Some of the particles from 0608 Coated stents as described herein and/or made by a the third (polymer) layer may rest in the vicinity of drug method disclosed herein are prepared. In some examples, the particles in the second (drug) layer. When the sintering step is coated Stents have a targeted thickness of ~15 microns (~5 completed for the third (polymer) layer, the third polymer microns of active agent). In some examples, the coating pro layer particles fuse to form a continuous film that forms the cess is PDPDP (Polymer, sinter, Drug, Polymer, sinter, Drug, third (polymer) layer. In some embodiments, the third (poly Polymer, sinter) using deposition of drug in dry powder form mer) layer however will have a portion along the longitudinal and deposition of polymer particles by RESS methods and axis of the stent whereby the portion is free of contacts equipment described herein. In the illustrations herein, result between polymer material and drug particles. The portion of ing coated Stents may have a 3-layer coating comprising the third layer that is substantially of contact with drug par polymer (for example, PLGA) in the first layer, drug (for ticles can be as thin as 1 nanometer. example, rapamycin) in a second layer and polymer in the 0604 Polymer-coated balloons having coatings compris third layer, where a portion of the third layer is substantially ing polymer but no drug are made by a method disclosed drug free (e.g. a Sub-layer within the third layer having a herein and are prepared having a targeted coating thickness thickness equal to a fraction of the thickness of the third of for example, about, about 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, layer). As described, the middle layer (or drug layer) may be 30, 35, 40, 45, or 50 microns, depending in part on whether overlapping with one or both first (polymer) and third (poly the coating expands upon hydration and if so whether it is mer) layer. The overlap between the drug layer and the poly hydrated. In embodiments, the coating thickness is 1-5 mer layers is defined by extension of polymer material into microns. In other embodiments, it is 1-10 microns. . physical space largely occupied by the drug. The overlap 0605 An example coating process is PPP (PLGA, sinter, between the drug and polymer layers may relate to partial PLGA, sinter, PLGA, sinter) using RESS methods and equip packing of the drug particles during the formation of the drug ment described herein. These polymer-coated balloons may layer. When crystal drug particles are deposited on top of the be used as control samples in some of the examples, infra. first polymer layer, Voids and or gaps may remain between 0606. In some examples, the balloons are made of a com dry crystal particles. The Voids and gaps are available to be pliant polymer. In some examples, the balloons are made of a occupied by particles deposited during the formation of the non-compliant polymer. The balloons may be, in some third (polymer) layer. Some of the particles from the third examples, 5 to 50 mm in length, preferably 10-20 mm in (polymer) layer may rest in the vicinity of drug particles in the length. second (drug) layer. When the sintering step is completed for 0607 Balloons can be coated while inflated, and later the third (polymer) layer, the third polymer layer particles compacted, or they can be coated while uninflated. If a bal fuse to form a continuous film that forms the third (polymer) loon is coated while inflated and later folded or otherwise layer. In some embodiments, the third (polymer) layer how compacted, then a portion of the coating can be protected ever will have a portion along the longitudinal axis of the stent during insertion by virtue of being disposed within the por whereby the portion is free of contacts between polymer tion of the balloon that is not exposed until inflation. The material and drug particles. The portion of the third layer that coating can also be protected by using a sheath or other is Substantially of contact with drug particles can be as thin as covering, as described in the art for facilitating insertion of an 1 nanometer. angioplasty balloon. The coating released from a balloon may 0609 Polymer-coated stents having coatings comprising be analyzed (for example, for analysis of a coating band polymer but no drug are made by a method disclosed herein and/or coating a portion of the balloon). Alternatively, in and are prepared having a targeted thickness of, for example, Some examples, the coating is analyzed directly on the bal ~5 microns. An example coating process is PPP (PLGA, loon. This coating, and/or coating and balloon, may be sliced sinter, PLGA, sinter, PLGA, sinter) using RESS methods and US 2010/0015200 A1 Jan. 21, 2010 72 equipment described herein. These polymer-coated Stents taining drug powder of controlled morphology. (WO 2007/ may be used as control samples in some of the examples, 01 1707), the contents of which are herein incorporated by infra. reference in its entirety. 0610. In some examples, the stents are made of a cobalt 0616. A coated coronary stent is prepared as follows: chromium alloy and are 5 to 50 mm in length, preferably 10-20 mm in length, with struts of thickness between 20 and 0.617 3.0x18 mm stainless steel (31.6L) metal stent 100 microns, preferably 50-70 microns, measuring from an (Burpee MaterialsTechnology, LLC: http://www.burpeetech. abluminal Surface to a luminal Surface, or measuring from a com/) is cleaned prior to coating via ultrasonic washing fol side wall to a side wall. In some examples, the stent may be cut lowed by solvent rinse with dichloromethane and hexane. lengthwise and opened to lay flat be visualized and/or assayed 0618. A drug-containing polymer coating is deposited on using the particular analytical technique provided. the stent as follows: 0611. The coating may be removed (for example, for 0619. The metal stent serving as a target substrate for analysis of a coating band and/or coating on a strut, and/or rapamycin coating is placed in a vessel and attached to a high coating on the abluminal Surface of a flattened stent) by voltage electrode. The vessel (V), of approximately 1500 cm3 scraping the coating off using a scalpel, knife or other sharp Volume, is equipped with two separate nozzles through which tool. This coating may be sliced into sections which may be rapamycin or polymers could be selectively introduced into turned 90 degrees and visualized using the Surface composi tion techniques presented herein or other techniques known in the vessel. Both nozzles are grounded. Additionally, the ves the art for Surface composition analysis (or other character sel (V) is equipped with a separate port is available for purg istics, such as crystallinity, for example). In this way, what ing the vessel. Upstream of one nozzle (D) is a small pressure was an analysis of coating composition through a depth when vessel (PV) approximately 5 cm3 in volume with three ports the coating was on the stent or as removed from the Stent (i.e. to be used as inlets and outlets. Each port is equipped with a a depth from the abluminal surface of the coating to the valve which could be actuated opened or closed. One port, Surface of the removed coating that once contacted the strutor port (1) used as an inlet, is an addition port for the dry a portion thereof), becomes a surface analysis of the coating powdered rapamycin. Port (2), also an inlet is used to feed which can, for example, show the layers in the slice of coat pressurized gas, liquid, or supercritical fluid into PV. Port (3), ing, at much higher resolution. Coating removed from the used as an outlet, is used to connect the pressure vessel (PV) stent may be treated the same way, and assayed, visualized, with nozzle (D) contained in the primary vessel (V) with the and/or characterized as presented herein using the techniques target coupon. described and/or other techniques known to a person of skill 0620. 170 micrograms of rapamycin (from Chemwerth in the art. www.chemwerth.com) that is jet-milled to an average (crys Coatings on Coupons talline) particle size of 2 microns; PLGA polymer with 50% 0612. In some examples, samples comprise coupons of glycolic acid content, 0.63 dL/g inherent viscosity (Durect glass, metal, e.g. cobalt-chromium, or another Substance that Corp. http://www.absorbables.com/) is employed. Rapamy are prepared with coatings as described herein, with a plural cin is loaded into (PV) through port (1) then port (1) is ity of layers as described herein, and/or made by a method actuated to the closed position. Gaseous carbon dioxide is disclosed herein. In some examples, the coatings comprise then added to (PV) to a pressure of 400 to 600 psig at 20° C. polymer. In some examples, the coatings comprise polymer through port (2), then port (2) is closed to the Source gas. and active agent. In some examples, the coated coupons are 0621. The second nozzle, nozzle (P), is used to feed pre prepared having a targeted thickness of 10 microns (with 5 cipitated PLGA polymer particles into vessel (V) to coat the microns of active agent), and have coating layers as described stainless steel stent. Nozzle (P) is equipped with a heater and for the coated Stent samples, infra. controller to minimize heat loss due to the expansion of Sample Preparation for In-Vivo Models liquefied gases. Upstream of nozzle (P) is a pressure vessel, 0613 Devices comprising ballons having coatings dis (PV2), with approximately 25-cm3 internal volume. The closed herein are deployed in the porcine coronary arteries of pressure vessel (PV2) is equipped with multiple ports to be pigs (domestic Swine, juvenile farm pigs, or Yucatan minia used for inlets, outlets, thermocouples, and pressure trans ture Swine). Porcine coronary angioplasty is exploited herein ducers. Additionally, (PV2) is equipped with a heater and a since Such model yields results that are comparable to other temperature controller. Each port is connected to the appro investigations assaying neointimal hyperplasia in human Sub priate valves, metering valves, pressure regulators, or plugs to jects. The balloons are expanded to a 1:1.1 balloon:artery ensure adequate control of material into and out of the pres ratio. At multiple time points, animals are euthanized (e.g. t-1 sure vessel (PV2). One outlet from (PV2) is connected to a day, 7 days, 14 days, 21 days, and 28 days), the tissue Sur metering valve through pressure rated tubing which is then rounding the intervention site is extracted, and assayed. connected to nozzle (P) located in vessel (V). The metal stent 0.614 Devices comprising balloons having coatings dis is then charged to 40 kV using a Glassman Series EL high closed herein alternatively are implanted in the common iliac Voltage power source. The following coatings and sintering arteries of New Zealand white rabbits. The balloons are steps are completed: expanded to a 1:1.1 balloon:artery ratio. At multiple time points, animals are euthanized (e.g., t-1 day, 7 days, 14 days, 0622 e-RESS polymer (approx 200 micrograms), 21 days, and 28 days), the tissue Surrounding the intervention 0623 sinter w/compressed gas, site is extracted, and assayed. 0624 e-DPC drug (~85 micrograms, Example 1 0625 e-RESS polymer (-200-250 micrograms), General eDPC and eRESS Deposition Methods and 0626 sinter w/compressed gas, Coating of Stent 0627 e-DPC drug (~85 micrograms), 0615. This example employs equipment and processes 0628 e-RESS polymer (-200-300 micrograms), and described in PCT/US2006/027321, “Polymer coatings con 0629 sinter w/compressed gas. US 2010/0015200 A1 Jan. 21, 2010

0630. The process produces a three layer microlaminate seconds to deploy the stent against the tubing wall. Optical construction w/170 micrograms of drug, 600-750 micro microscopy of the stents and of the tubing is performed imme grams of polymer and a total coating thickness 15 microns. diately after retraction of the stent delivery system to show that some of the coating was released from the strut. Calcu Example 2 lations of the amount of coating left on the stent and/or freed General eDPC and eRESS Deposition Methods and from the stent, by means of area measurements, can deter Coating of Stent Using a Release Agent. mine the amount of coating that was freed from, transferred 0631. A coated coronary stent is prepared as described in from, and or dissociated from the stent, and the amount of Example 1, except that prior to coating with the drug-con coating that was deposited at, and/or delivered to the tubing taining polymer, a layer of PTFE release agent is electrostati (i.e., the intervention site). cally deposited on the stent. 0.645. In an alternative embodiment, the stent framework is not comprised of a memory metal, rather is plastically Example 3 deformable and connected to the balloon, such that the stent Example of Coating a Substrate with No Electro shape (e.g. diameter) is defined by and/or controlled by the charging of the Substrate shape (e.g., diameter) of the balloon, and the stent expands and collapses with the balloon. 0632 A coated coronary stent is prepared as described in Example 1, except that the stent is not electrically charged during the coating process. Example 5 Example 4 0646. This example illustrates embodiments that provide a coated coronary stent that frees a coating thereon by a stimu 0633. This example illustrates embodiments that provide a lation. The stimulation in this embodiment is a combination coated coronary stent that frees a coating thereon by a stimu of a mechanical stimulation and a chemical stimulation. lation. The stimulation in this embodiment is expansion of the stent, which frees the coating from the stent, at least in part. 0634. The embodiment comprises a nitinol stent frame Example 6 work over an angioplasty balloon, wherein the nitinol stent memory is set to a collapsed diameter, and the stent is (0647. This example illustrates embodiments that provide a expanded to a deployed diameter by inflation of the angio coated coronary stent that frees a coating thereon by a stimu plasty balloon, which thereafter, upon deflation of the balloon lation. The stimulation in this embodiment is a chemical allows the stent to return to its collapsed diameter and leave stimulation. The balloon of the stent delivery system is con the coating (or a portion thereof), at the intervention site. The structed of a semipermable polymer. The pressurization coating comprises a rapamycin-polymer coating wherein at medium is pH 8 phosphate buffer. The stent (having the least part of rapamycin is in crystalline form and the rapamy balloon thereunder) is positioned at the intervention site. The cin-polymer coating comprises one or more resorbable poly balloon is pressurized to at least to at least 25% below its CS. nominal inflation pressure. Upon pressurization of the bal 0635. In these experiments two different polymers are loon in the diseased artery, at least about 10% to at least about employed: 30% of the coating is released into the intervention site and 0636 Polymer A: -50:50 PLGA-Ester End Group, upon depressurization and removal of the device, this mate MW-19 kD. degradation rate ~1-2 months 0637 Polymer B: -50:50 PLGA-Carboxylate End rial is deposited at the intervention site. Group, MW-10 kD. degradation rate ~28 days 0638. In certain embodiments, stents are coated as fol Example 7 lows: 0639. AS1: Polymer A/Rapamycin/Polymer A/Rapa 0648. This example illustrates embodiments that provide a mycin/Polymer A coated coronary stent that frees a coating thereon by a stimu 0640 AS2: Polymer A/Rapamycin/Polymer A/Rapa lation. The stimulation in this embodiment is athermal stimu mycin/Polymer B lation. (0641 AS1 (B) or AS1 (213): Polymer B/Rapamycin/ Polymer B/Rapamycin/Polymer B Example 8 0642 AS1b: Polymer A/Rapamycin/Polymer A/Rapa mycin/Polymer A In-Vitro Study of Coating Freed From a Stent 0643 AS2b: Polymer A/Rapamycin/Polymer A/Rapa mycin/Polymer B 0649. One sample of the coated stent prepared as 0644. The coated stents stent prepared as described are described in Example 1 was loaded onto a balloon catheter. A loaded onto a balloon catheter. A segment of optically clear segment of optically clear TYGONR B-44-3 Beverage Tub TYGONR) B-44-3 Beverage Tubing with O.D.—0.125", I.D. ing with O.D.—0.125", I.D.—0.0625" (available from McMas =0.0625" (available from McMaster-Carr, Part Number: ter-Carr, Part Number: 5114K11 (www.mcmaster.com) was 5114K11 (www.mcmaster.com) is filled with phosphate filled with phosphate-buffered saline solution and immersed buffered saline solution and immersed in a water bath at 37° in a water bath at 37°C. to mimic physiological conditions of C. to mimic physiological conditions of deployment into a deployment into a coronary artery. The coated Stent was coronary artery. The coated Stents are inserted into the tubing inserted into the tubing and the catheter-balloon was inflated and the catheter-balloon is inflated to 13 ATM for less than 20 to 13 ATM to deploy the stent against the tubing wall. Optical US 2010/0015200 A1 Jan. 21, 2010 74 microscopy was performed immediately after deployment, permanent and/or hard polymers, typically showing 1 to 5% where it was clear that some of the coating was released from the level of efficiency of drug transfer shown here. the strut. Example 11 Example 9 Stent Examples In-Vitro Study of Coating Freed from a Stent Using 0653. In one experiment, a coated coronary stent is pre a Release Agent pared as follows. 3.0x16 mm Co-Cr alloy metal stent (Sky lor stent from Invatec (www.invatec.com)) is coated with a 0650 One sample of the coated stent was prepared as drug-containing coating (170 micrograms of rapamycin from described in Example 2, using about 700 micrograms poly Chemwerth www.chemwerth.com that is jet-milled to an mer and 160 micrograms API, an AS1 formulation (PsDPs average (crystalline) particle size of ~2 microns; PLGA poly DPs), and sintered at 25 psig and 75°C. for 10 minutes, was mer with 50% glycolic acid content, 0.63 dL/g inherent vis loaded onto a balloon catheter. The stent was pre-wetted by cosity (Durect Corp. http://www.absorbables.com/). immersion in an isotonic saline bath at 37° C. for 3 minutes. 0654 Equipment and process similar to those employed in A segment of optically clear TYGONR) B-44-3 Beverage Example 1 are used. Tubing with O.D.—0.125", I.D.—0.0625" (available from 0655 The following coating and sintering steps are car McMaster-Carr Part Number 5114K11; www.mcmaster. ried out: com) was filled with phosphate-buffered saline solution and 0656 e-RESS polymer (approx 100 micrograms), immersed in a water bath at 37° C. to mimic physiological 0657 sinter w/compressed gas, conditions of deployment into a coronary artery. The coated 0658 e-DPC drug (-35 micrograms, stent was inserted into the tubing and the catheter-balloon was 0659 e-RESS polymer (-100-150 micrograms), inflated to 13 ATM to deploy the stent against the tubing wall. 0660 sinter w/compressed gas, Optical microscopy was performed immediately after 0661 e-DPC drug (-35 micrograms), deployment and showed that Some of the coating has been 0662 e-RESS polymer (~100-200 micrograms), and released from the strut. 0663 sinter w/compressed gas 0664. The process produces a coated stent with a three Example 10 layer microlaminate construction w/-70 micrograms of drug. 300-375 micrograms of polymer and a total coating thickness In Vivo Studies of Coating Transfer from a Stent of 6-8 microns. Upon deployment, /10th of the coating is freed from the stent and delivered to the arterial tissue. 0651. Another sample of the coated stent was prepared for 0665. In another experiment, a coated coronary stent is in vivo evaluation in a porcine coronary artery model using prepared as follows. 3.0x16 mm Co-Cr alloy metal stent the Yucatan pig. Subjects were initially given 650 mg acetyl (Skylor stent from Invatec (www.invatec.com)) is coated with salicylic acid and 300 mg Plavix. Maintenance doses of 81 mg a drug-containing coating by spray coating from a solution of acetylsalicylic acid and 75 mg Plavix were administered. The target ACT (activated clotting time) for the procedure was PLGA polymer (Mw-30kg/mol from Durect Corp) and about 250 seconds. Stent oversizing in relation to the artery sirolimus (from Chemwerth www.chemwerth.com). was about 10-20%. The preparation of the sirolimus-coated 0.666 Equipment and process similar to those employed in stent was the same as described in Example 1 and used for the Example 4 are used. in vitro deployment into tubing, except that the device was 0667 Resulting in a coating of -8 um thickness, contain sterilized using ETO prior to implantation into the animal. ing 70 ug of Sirolimus. The histology of the stented artery after 28 days showed 0668. Upon deployment, /sth of the coating is extruded evidence of the extrusion and bulk-migration of the coating from the stent at the intervention site (e.g., the arterial tissue.) into the Surrounding arterial tissue. This extrusion provides treatment of -2.5x greater arterial tissue (area) vs. the ablu Example 12 minal area of the strut itself. Cutting Balloons 0652 The bulk concentration of drug was measured in the arterial tissue Surrounding the implanted Stent at 1, 3, 7, 14. Cutting Balloon (1) Mechanical Stimulation to and 28 days after implant, and provided a quantitative mea Free the Coating sure of the high efficiency of transfer of drug into the thera peutic site using devices and methods of the invention. The 0669 A cutting balloon is coated comprising a polymer amount of drug that was detected in the arterial tissue was as and an active agent. The coated cutting balloon is positioned follows: 1 day after implant, 6 ug. 3 days after implant, ~16 at the intervention site. The balloon is inflated to at least 25% ug; 7 days after implant, 30 g; 14 days after implant, ~30 ug; below its nominal inflation pressure. Upon deflation and 28 days after implant, ~13 Jug. Peak tissue concentration of removal of the cutting balloon from the intervention site, at Sirolimus of ~30 ug at 14 days after implant was representa least about 5% to at least about 30% of the coating is freed tive of approximately /6" of the total drug that had been from the surface of the cutting balloon and is deposited at the loaded on the stent. Note that some drug likely metabolized or intervention site. diffused out of the arterial tissue into other areas of the body. 0670. In some examples, the balloon unfolds during infla These results demonstrate the effectiveness of the devices and tion, causing mechanical shearing forces to at least augment methods of the invention relative to other systems, wherein transfer and/or freeing and/or deposition of the coating from transfer of the coating via bulk migration is inhibited by the balloon to the intervention site. US 2010/0015200 A1 Jan. 21, 2010

0671. In some examples, the balloon twists during infla including but not limited to SEM, TEM, and, where image tion, causing mechanical shearing forces to at least augment enhanced polymers are used, various imaging means capable transfer and/or freeing and/or deposition of the coating from of detecting these enhanced polymers) to detect the percent of the balloon. the coating freed, dissociated and/or transferred from the 0672. In one example, the polymer of the coating is 50:50 substrate and delivered to the intervention site. Again, the PLGA-Ester End Group, MW-19 kD. degradation rate ~1-2 amount of coating known to be on the Substrate based on months or 50:50 PLGA-Carboxylate End Group, MW-10 manufacturing lot characteristics, and/oran assessment of the kD. degradation rate ~28 days. The active agent is a pharma coating remaining on the device following removal of the ceutical agent such as a macrollide immunosuppressive drug. device from the subject (for example, wherein the device is an Equipment and coating process similar to Example 1 is angioplasty catheter and the substrate is the balloon of the employed. The intervention site is a vascular lumen wall. catheter) may be used to determine the percent of coating Upon inflation of the cutting balloon, at least about 50% of the freed, dissociated, and/or transferred from the device. In coating is freed from the device at the intervention site. Some instances, an assessment of the device following the 0673. In another example, a cutting balloon is coated with procedure alone is sufficient to assess the amount freed or a formulation of PLGA+sirolimus with total loading of siroli dissociated from the substrate, without determination of the mus -20 ug with the coating preferentially on the wire of the amount delivered to the intervention site. Additionally, where cutting balloon. Equipment and process similar to Example 1 a determination of improvement and/or disease treatment is is employed. The intervention site is a coronary artery. Upon desired, levels of proinflammatory markers could be tested to inflation of the cutting balloon, about 5% to about 15% of the show improvement and/or treatment of a disease and/or ail coating is freed from the device resulting in delivery of -2.0 ment, for example, by testing high sensitive C-reactive pro ug of drug delivered to the artery. tein (hsCRP), interleukin-6 (IL-6), interleukin-1B (IL-1B), 0674. In another example, the polymer of the coating is and/or monocyte chemoattractant protein-1 (MCP-1). The 50:50PLGA-Ester End Group, MW-19 kD. degradation rate release kinetics of the drug may be shown by plotting the ~1-2 months or 50:50 PLGA-Carboxylate End Group, Sirolimus concentrations at the timepoints noted above. MW-10 kD. degradation rate ~28 days. The active agent is a 0677 For embodiments using different drugs other than chemotherapeutic agent. Equipment and coating process sirolimus, the biomarkers are selected based on the disease to similar to Example 1 is employed. The intervention site is a be treated and the drugs administered during the course of cavity resulting from removal of a tumor. Upon inflation of therapy as determined by one of skill in the art. These biom the cutting balloon, at least about 75% of the coating is arkers may be used to show the treatment results for each transferred from from the device to the intervention site. Subject. 0675. In-vivo testing: A group of 27 New Zealand white 0678. Other in-vivo tests described herein may be used rabbits is prepared for a Seldinger procedure using a cutting instead of this test and/or in addition to this test, adjusted for balloon coated with a formulation of 50:50 PLGA-Ester End the particularities of this device, as would be known to one of Group (MW-19 kD. degradation rate ~1-2 months) and ordinary skill in the art. sirolimus with total loading of sirolimus -20 lug with the 0679. In-vitro testing: One sample of the coated cutting coating preferentially on the wire of the cutting balloon. The balloon prepared in Example 1 is secured to a balloon cath device is placed at a coronary artery intervention site with the eter. A segment of optically clear TYGONR) B-44-3 tubing with O.D.—0.125", I.D.—0.0625" (Available from McMaster assistance of fluoroscopy to aid in positioning the device at Carr Part Number: 5114K11 (www.mcmaster.com)) is filled the same location in each Subject. Six animals are subjected to with phosphate-buffered saline solution and immersed in a the procedure using a coated balloon that does not have siroli water bath at 37° C. to mimic physiological conditions of mus in the coating. After deployment and removal of the deployment into a subject. The coated balloon is inserted into device, 3 control animals are sacrificed at 1 hour post deploy the tubing and the balloon is inflated to at least 25% below the ment and serum and tissue samples are collected. The 3 balloon's nominal pressure to mechanically transfer the coat remaining control animals are sacrificed at 56 days post ing from the balloonto the tubing wall. The balloon is deflated deployment. During the course of the study, serum samples and removed from the tubing. Optical microscopy is per are collected from control and drug-treated animals every five formed on the tubing and/or the balloon (which is inflated to days. The drug treated animals, 3 each, are sacrificed at 1 at least 25% below the balloon's nominal pressure, at least) to hour, 24 hours, 7 days, 14 days, 28 days, 42 days and 56 days determine the presence and amount of coating transferred to post deployment. A serum sample as well as a tissue sample the tubing and/or the amount of coating freed, dissociated, from the deployment site is collected. and/or transferred from the balloon. Other in-vitro tests 0676. The tissue and serum samples may be subjected to described herein may be used instead of this test and/or in analysis for sirolimus concentration. In order to determine the addition to this test, adjusted for the particularities of this amount of coating freed from the device and/or delivered to the intervention site as a percent of the total amount of coating device, as would be known to one of ordinary skill in the art. on the Substrate, the tissue concentration of Sirolimus at the one hour time point (or any time point within the first day Cutting Balloon (2) Mechanical Stimulation to following of the procedure) may be used used along with the Free the Coating total content expected for the coating (based on the total 0680 A cutting balloon is coated using a solution-based content for the manufacturing lot) or along with the content of system (spray or dip coating) comprising a polymer and an coating remaining on the device once removed and the per active agent. The coated cutting balloon is positioned at the centage calculated. This percentage is correlative of the per intervention site. The balloon is inflated to at least 25% below cent of coating freed, dissociated, and/or transferred from the its nominal inflation pressure. At least about 5% to at least device and delivered to the intervention site. Alternatively, the about 30% of the coating is freed from the surface of the tissue may be analyzed by various means (noted herein, cutting balloon and is deposited at the intervention site. US 2010/0015200 A1 Jan. 21, 2010 76

0681. In some examples, the balloon unfolds during infla centage calculated. This percentage is correlative of the per tion, causing mechanical shearing forces to at least augment cent of coating freed, dissociated, and/or transferred from the transfer and/or freeing and/or deposition of the coating from device and delivered to the intervention site. Alternatively, the the balloon to the intervention site. tissue may be analyzed by various means (noted herein, 0682. In some examples, the balloon twists during infla including but not limited to SEM, TEM, and, where image tion, causing mechanical shearing forces to at least augment enhanced polymers are used, various imaging means capable transfer and/or freeing and/or deposition of the coating from of detecting these enhanced polymers) to detect the percent of the balloon. the coating freed, dissociated and/or transferred from the 0683. In one example, the polymer of the coating is 50:50 substrate and delivered to the intervention site. Again, the PLGA-Ester End Group, MW-19kD. degradation rate ~1-2 amount of coating known to be on the Substrate based on months or 50:50 PLGA-Carboxylate End Group, MW-10 manufacturing lot characteristics, and/oran assessment of the kD. degradation rate ~28 days. The active agent is a pharma coating remaining on the device following removal of the ceutical agent such as a macrollide immunosuppressive drug. device from the subject (for example, wherein the device is an Equipment and coating process using a spray and/or dip coat angioplasty catheter and the substrate is the balloon of the ing process is employed. The intervention site is a vascular catheter) may be used to determine the percent of coating lumen wall. Upon inflation of the cutting balloon, at least freed, dissociated, and/or transferred from the device. In about 50% of the coating is freed from the device at the Some instances, an assessment of the device following the intervention site. procedure alone is sufficient to assess the amount freed or 0684. In another example, a cutting balloon is coated with dissociated from the substrate, without determination of the a formulation of PLGA+sirolimus with total loading of siroli amount delivered to the intervention site. Additionally, where mus -20 ug with the coating preferentially on the wire of the a determination of improvement and/or disease treatment is cutting balloon. Equipment and coating process using a spray desired, levels of proinflammatory markers could be tested to and/or dip coating process is employed. The intervention site show improvement and/or treatment of a disease and/or ail is a coronary artery. Upon inflation of the cutting balloon, ment, for example, by testing high sensitive C-reactive pro about 5% to about 15% of the coating is freed from the device tein (hsCRP), interleukin-6 (IL-6), interleukin-1B (IL-1B), resulting in delivery of -2.0 ug of drug delivered to the artery. and/or monocyte chemoattractant protein-1 (MCP-1). The 0685. In another example, the polymer of the coating is release kinetics of the drug may be shown by plotting the 50:50PLGA-Ester End Group, MW-19 kD. degradation rate Sirolimus concentrations at the timepoints noted above. ~1-2 months or 50:50 PLGA-Carboxylate End Group, 0688 For embodiments using different drugs other than MW-10 kD. degradation rate ~28 days. The active agent is a sirolimus, the biomarkers are selected based on the disease to chemotherapeutic agent. Equipment and coating process be treated and the drugs administered during the course of using a spray and/or dip coating process is employed. The therapy as determined by one of skill in the art. These biom intervention site is a cavity resulting from removal of a tumor. arkers may be used to show the treatment results for each Upon inflation of the cutting balloon, at least about 75% of the Subject. 0689. Other in-vivo tests described herein may be used coating is transferred from the device to the intervention site. instead of this test and/or in addition to this test, adjusted for 0686. In-vivo testing: A group of 27 New Zealand white the particularities of this device, as would be known to one of rabbits is prepared for a Seldinger procedure using a cutting ordinary skill in the art. balloon coated with a formulation of 50:50 PLGA-Ester End 0690. In-vitro testing: One sample of the coated cutting Group (MW-19kD. degradation rate ~1-2 months) and siroli balloon prepared in using spray and/or dip coating process is mus with total loading of Sirolimus ~20 Lug with the coating secured to a balloon catheter. A segment of optically clear preferentially on the wire of the cutting balloon. The device is TYGONR) B-44-3 tubing with O.D.—0.125", I.D.-0.0625" placed at a coronary artery intervention site with the assis (Available from McMaster-Carr Part Number: 5114K11 tance of fluoroscopy to aid in positioning the device at the (www.mcmaster.com)) is filled with phosphate-buffered same location in each Subject. Six animals are subjected to the saline solution and immersed in a water bath at 37° C. to procedure using a coated balloon that does not have sirolimus mimic physiological conditions of deployment into a Subject. in the coating. After deployment and removal of the device, 3 The coated balloon is inserted into the tubing and the balloon control animals are sacrificed at 1 hour post deployment and is inflated to at least 25% below the balloon's nominal pres serum and tissue samples are collected. The 3 remaining Sure to mechanically transfer the coating from the balloon to control animals are sacrificed at 56 days post deployment. the tubing wall. The balloon is deflated and removed from the During the course of the study, serum samples are collected tubing. Optical microscopy is performed on the tubing and/or from control and drug-treated animals every five days. The the balloon (which is inflated to at least 25% below the bal drug treated animals, 3 each, are sacrificed at 1 hour, 24 hours, loon's nominal pressure, at least) to determine the presence 7 days, 14 days, 28 days, 42 days and 56 days post deploy and amount of coating transferred to the tubing and/or the ment. amount of coating freed, dissociated, and/or transferred from 0687. The tissue and serum samples may be subjected to the balloon. Other in-vitro tests described herein may be used analysis for sirolimus concentration. In order to determine the instead of this test and/or in addition to this test, adjusted for amount of coating freed from the device and/or delivered to the particularities of this device, as would be known to one of the intervention site as a percent of the total amount of coating ordinary skill in the art. on the Substrate, the tissue concentration of Sirolimus at the one hour time point (or any time point within the first day Cutting Ballon (3)—Mechanical Stimulation to Free following of the procedure) may be used used along with the the Coating total content expected for the coating (based on the total content for the manufacturing lot) or along with the content of 0691. A cutting balloon is coated comprising a release coating remaining on the device once removed and the per agent, a polymer and an active agent. The coated cutting US 2010/0015200 A1 Jan. 21, 2010 77 balloon is positioned at the intervention site. The balloon is percent of the total amount of coating on the Substrate, the inflated to at least 25% below its nominal inflation pressure. tissue concentration of sirolimus at the one hour time point (or At least about 5% to at least about 50% of the coating is freed any time point within the first day following of the procedure) from the surface of the cutting balloon and is deposited at the may be used used along with the total content expected for the intervention site. coating (based on the total content for the manufacturing lot) 0692. In some examples, the balloon unfolds during infla or along with the content of coating remaining on the device tion, causing mechanical shearing forces to at least augment onceremoved and the percentage calculated. This percentage transfer and/or freeing and/or deposition of the coating from is correlative of the percent of coating freed, dissociated, the balloon to the intervention site. and/or transferred from the device and delivered to the inter 0693. In some examples, the balloon twists during infla vention site. Alternatively, the tissue may be analyzed by tion, causing mechanical shearing forces to at least augment transfer and/or freeing and/or deposition of the coating from various means (noted herein, including but not limited to the balloon. SEM, TEM, and, where image enhanced polymers are used, 0694. In one example, the polymer of the coating is 50:50 various imaging means capable of detecting these enhanced PLGA-Ester End Group, MW-19kD. degradation rate ~1-2 polymers) to detect the percent of the coating freed, dissoci months or 50:50 PLGA-Carboxylate End Group, MW-10 ated and/or transferred from the substrate and delivered to the kD. degradation rate ~28 days. The active agent is a pharma intervention site. Again, the amount of coating known to be ceutical agent such as a macrollide immunosuppressive drug. on the Substrate based on manufacturing lot characteristics, Equipment and coating process similar to Example 2 is and/or an assessment of the coating remaining on the device employed. The intervention site is a vascular lumen wall. following removal of the device from the subject (for Upon inflation of the cutting balloon, at least about 50% of the example, wherein the device is an angioplasty catheter and coating is freed from the device at the intervention site. the substrate is the balloon of the catheter) may be used to 0695. In another example, a cutting balloon is coated with determine the percent of coating freed, dissociated, and/or a formulation of PLGA+sirolimus with total loading of siroli transferred from the device. In some instances, an assessment mus -20 ug with the coating preferentially on the wire of the of the device following the procedure alone is sufficient to cutting balloon. Equipment and process similar to Example 2 assess the amount freed or dissociated from the Substrate, is employed. The intervention site is a coronary artery. The without determination of the amount delivered to the inter release agent is ePTFE powder. Upon inflation of the cutting vention site. Additionally, where a determination of improve balloon, about 5% to about 15% of the coating is freed from ment and/or disease treatment is desired, levels of proinflam the device resulting in delivery of -2.0 ug of drug delivered to matory markers could be tested to show improvement and/or the artery. treatment of a disease and/or ailment, for example, by testing 0696. In another example, the polymer of the coating is high sensitive C-reactive protein (hsCRP), interleukin-6 (IL 50:50PLGA-Ester End Group, MW-19 kD. degradation rate 6), interleukin-1B (IL-1B), and/or monocyte chemoattractant ~1-2 months or 50:50 PLGA-Carboxylate End Group, protein-1 (MCP-1). The release kinetics of the drug may be MW-10 kD. degradation rate ~28 days. The active agent is a shown by plotting the sirolimus concentrations at the time chemotherapeutic agent. Equipment and coating process points noted above. similar to Example 2 is employed. The release agent a micronized active agent or another active agent in a micron 0699 For embodiments using different drugs other than ized form. The intervention site is a cavity resulting from sirolimus, the biomarkers are selected based on the disease to removal of a tumor. Upon inflation of the cutting balloon, at be treated and the drugs administered during the course of least about 75% of the coating is transferred from from the therapy as determined by one of skill in the art. These biom device to the intervention site. arkers may be used to show the treatment results for each 0697 In-vivo testing: A group of 27 New Zealand white Subject. rabbits is prepared for a Seldinger procedure using a cutting 0700 Other in-vivo tests described herein may be used balloon coated with a formulation of 50:50 PLGA-Ester End instead of this test and/or in addition to this test, adjusted for Group (MW-19 kD. degradation rate ~1-2 months) and the particularities of this device, as would be known to one of sirolimus with total loading of sirolimus -20 lug with the ordinary skill in the art. coating preferentially on the wire of the cutting balloon. The 0701 In-vitro testing: One sample of the coated cutting device is placed at a coronary artery intervention site with the balloon prepared in Example 2 is secured to a balloon cath assistance of fluoroscopy to aid in positioning the device at eter. A segment of optically clear TYGONR) B-44-3 tubing the same location in each Subject. Six animals are subjected to with O.D.—0.125", I.D.—0.0625" (Available from McMaster the procedure using a coated balloon that does not have siroli Carr Part Number: 5114K11 (www.mcmaster.com)) is filled mus in the coating. After deployment and removal of the with phosphate-buffered saline solution and immersed in a device, 3 control animals are sacrificed at 1 hour post deploy water bath at 37° C. to mimic physiological conditions of ment and serum and tissue samples are collected. The 3 deployment into a subject. The coated balloon is inserted into remaining control animals are sacrificed at 56 days post the tubing and the balloon is inflated to at least 25% below the deployment. During the course of the study, serum samples balloon's nominal pressure to mechanically transfer the coat are collected from control and drug-treated animals every five ing from the balloonto the tubing wall. The balloon is deflated days. The drug treated animals, 3 each, are sacrificed at 1 and removed from the tubing. Optical microscopy is per hour, 24 hours, 7 days, 14 days, 28 days, 42 days and 56 days formed on the tubing and/or the balloon (which is inflated to post deployment. The tissue and serum samples may be Sub at least 25% below the balloon's nominal pressure, at least) to jected to analysis for sirolimus concentration. determine the presence and amount of coating transferred to 0698. In order to determine the amount of coating freed the tubing and/or the amount of coating transferred from the from the device and/or delivered to the intervention site as a balloon. Other in-vitro tests described herein may be used US 2010/0015200 A1 Jan. 21, 2010

instead of this test and/or in addition to this test, adjusted for days. The drug treated animals, 3 each, are sacrificed at 1 the particularities of this device, as would be known to one of hour, 24 hours, 7 days, 14 days, 28 days, 42 days and 56 days ordinary skill in the art. post deployment. 0709. The tissue and serum samples may be subjected to Cutting Balloon (4) Mechanical Stimulation to analysis for sirolimus concentration. In order to determine the Free the Coating amount of coating freed from the device and/or delivered to the intervention site as a percent of the total amount of coating 0702. A cutting balloon is coated comprising a polymer on the Substrate, the tissue concentration of Sirolimus at the and an active agent. The coated cutting balloon is positioned one hour time point (or any time point within the first day at the intervention site. The balloon is inflated to at least 25% following of the procedure) may be used used along with the below its nominal inflation pressure. At least about 10% to at total content expected for the coating (based on the total least about 50% of the coating is freed from the surface of the content for the manufacturing lot) or along with the content of cutting balloon and is deposited at the intervention site. coating remaining on the device once removed and the per centage calculated. This percentage is correlative of the per 0703. In some examples, the balloon unfolds during infla cent of coating freed, dissociated, and/or transferred from the tion, causing mechanical shearing forces to at least augment device and delivered to the intervention site. Alternatively, the transfer and/or freeing and/or deposition of the coating from tissue may be analyzed by various means (noted herein, the balloon to the intervention site. including but not limited to SEM, TEM, and, where image 0704. In some examples, the balloon twists during infla enhanced polymers are used, various imaging means capable tion, causing mechanical shearing forces to at least augment of detecting these enhanced polymers) to detect the percent of transfer and/or freeing and/or deposition of the coating from the coating freed, dissociated and/or transferred from the the balloon. substrate and delivered to the intervention site. Again, the 0705. In one example, the polymer of the coating is 50:50 amount of coating known to be on the Substrate based on PLGA-Ester End Group, MW-19 kD. degradation rate ~1-2 manufacturing lot characteristics, and/oran assessment of the months or 50:50 PLGA-Carboxylate End Group, MW-10 coating remaining on the device following removal of the kD. degradation rate ~28 days. The active agent is a pharma device from the subject (for example, wherein the device is a ceutical agent such as a macrollide immunosuppressive drug. cutting angioplasty catheter and the Substrate is the cutting Equipment and coating process similar to Example 3 is balloon of the catheter) may be used to determine the percent employed. The intervention site is a vascular lumen wall. of coating freed, dissociated, and/or transferred from the Upon inflation of the cutting balloon, at least about 50% of the device. In some instances, an assessment of the device fol coating is freed from the device at the intervention site. lowing the procedure alone is sufficient to assess the amount 0706. In another example, a cutting balloon is coated with freed or dissociated from the substrate, without determination a formulation of PLGA+sirolimus with total loading of siroli of the amount delivered to the intervention site. Additionally, mus -20 ug with the coating preferentially on the wire of the where a determination of improvement and/or disease treat cutting balloon. Equipment and process similar to Example 3 ment is desired, levels of proinflammatory markers could be is employed. The intervention site is a coronary artery. Upon tested to show improvement and/or treatment of a disease inflation of the cutting balloon, about 5% to about 15% of the and/or ailment, for example, by testing high sensitive C-re coating is freed from the device resulting in delivery of -2.0 active protein (hsCRP), interleukin-6 (IL-6), interleukin-1B ug of drug delivered to the artery. (IL-1B), and/or monocyte chemoattractant protein-1 (MCP 0707. In another example, the polymer of the coating is 1). The release kinetics of the drug may be shown by plotting 50:50PLGA-Ester End Group, MW-19 kD. degradation rate the sirolimus concentrations at the timepoints noted above. ~1-2 months or 50:50 PLGA-Carboxylate End Group, 0710 For embodiments using different drugs other than MW-10 kD. degradation rate ~28 days. The active agent is a sirolimus, the biomarkers are selected based on the disease to chemotherapeutic agent. Equipment and coating process be treated and the drugs administered during the course of similar to Example 3 is employed. The intervention site is a therapy as determined by one of skill in the art. These biom cavity resulting from removal of a tumor. Upon inflation of arkers may be used to show the treatment results for each the cutting balloon, at least about 75% of the coating is Subject. transferred from the device to the intervention site. 0711. Other in-vivo tests described herein may be used 0708. In-vivo testing: A group of 27 New Zealand white instead of this test and/or in addition to this test, adjusted for rabbits is prepared for a Seldinger procedure using a cutting the particularities of this device, as would be known to one of balloon coated with a formulation of 50:50 PLGA-Ester End ordinary skill in the art. Group (MW-19 kD. degradation rate ~1-2 months) and 0712. In-vitro testing: One sample of the coated cutting sirolimus with total loading of sirolimus -20 lug with the balloon prepared in Example 3 is secured to a balloon cath coating preferentially on the wire of the cutting balloon. The eter. A segment of optically clear TYGONR) B-44-3 tubing device is placed at a coronary artery intervention site with the with O.D.—0.125", I.D.—0.0625" (Available from McMaster assistance of fluoroscopy to aid in positioning the device at Carr Part Number: 5114K11 (www.mcmaster.com)) is filled the same location in each Subject. Six animals are subjected to with phosphate-buffered saline solution and immersed in a the procedure using a coated balloon that does not have siroli water bath at 37° C. to mimic physiological conditions of mus in the coating. After deployment and removal of the deployment into a subject. The coated balloon is inserted into device, 3 control animals are sacrificed at 1 hour post deploy the tubing and the balloon is inflated to at least 25% below the ment and serum and tissue samples are collected. The 3 balloon's nominal pressure to mechanically transfer the coat remaining control animals are sacrificed at 56 days post ing from the balloonto the tubing wall. The balloon is deflated deployment. During the course of the study, serum samples and removed from the tubing. Optical microscopy is per are collected from control and drug-treated animals every five formed on the tubing and/or the balloon (which is inflated to US 2010/0015200 A1 Jan. 21, 2010 79 at least 25% below the balloon's nominal pressure, at least) to balloon coated with a formulation of 50:50 PLGA-Ester End determine the presence and amount of coating transferred to Group (MW-19 kD. degradation rate ~1-2 months) and the tubing and/or the amount of coating freed, dissociated, sirolimus with total loading of sirolimus ~20 ug with the and/or transferred from the balloon. Other in-vitro tests coating preferentially on the wire of the cutting balloon. The described herein may be used instead of this test and/or in device is placed at a coronary artery intervention site with the addition to this test, adjusted for the particularities of this assistance of fluoroscopy to aid in positioning the device at device, as would be known to one of ordinary skill in the art. the same location in each Subject. Six animals are Subjected to the procedure using a coated balloon that does not have siroli Cutting Balloon (5)—Mechanical and Chemical mus in the coating. After deployment and removal of the Stimulation to Free the Coating device, 3 control animals are sacrificed at 1 hour post deploy ment and serum and tissue samples are collected. The 3 0713. A cutting balloon is coated with a formulation com remaining control animals are sacrificed at 56 days post prising a base layer of methyl acrylate-methacrylic acid deployment. During the course of the study, serum samples copolymer and additional layers of PLGA+paclitaxel with are collected from control and drug-treated animals every five total dose of paclitaxel approx. 0.5 g/mm2 of the wire. The days. The drug treated animals, 3 each, are sacrificed at 1 coating and sintering process is similar to that as described in hour, 24 hours, 7 days, 14 days, 28 days, 42 days and 56 days Example 1. The balloon is constructed of a semipermable post deployment. polymer. The pressurization medium is pH 8 phosphate 0720. The tissue and serum samples may be subjected to buffer. The coated cutting balloon is positioned at the inter analysis for sirolimus concentration. In order to determine the vention site. The balloon is pressurized to at least to at least amount of coating freed from the device and/or delivered to 25% below its nominal inflation pressure. Upon pressuriza the intervention site as a percent of the total amount of coating tion of the cutting balloon in the diseased artery, at least about on the Substrate, the tissue concentration of Sirolimus at the 10% to at least about 30% of the coating is released into the one hour time point (or any time point within the first day intervention site and upon depressurization and removal of following of the procedure) may be used used along with the the device, this material is deposited at the intervention site. total content expected for the coating (based on the total 0714. In some examples, the balloon unfolds during infla content for the manufacturing lot) or along with the content of tion, causing mechanical shearing forces to at least augment coating remaining on the device once removed and the per the pH mediated release of the coating from the balloon to the centage calculated. This percentage is correlative of the per intervention site. cent of coating freed, dissociated, and/or transferred from the 0715. In some examples, the balloon twists during infla device and delivered to the intervention site. Alternatively, the tion, causing mechanical shearing forces to at least augment tissue may be analyzed by various means (noted herein, the pH mediated release of the coating from the balloon. including but not limited to SEM, TEM, and, where image 0716. In one example, a base layer of methyl acrylate enhanced polymers are used, various imaging means capable methacrylic acid copolymer is formed and additional layers of detecting these enhanced polymers) to detect the percent of of the coating is 50:50 PLGA-Ester End Group, MW-19 kD. the coating freed, dissociated and/or transferred from the degradation rate ~1-2 months or 50:50 PLGA-Carboxylate substrate and delivered to the intervention site. Again, the End Group, MW-10 kD. degradation rate ~28 days. The amount of coating known to be on the Substrate based on active agent is a pharmaceutical agent such as a macrollide manufacturing lot characteristics, and/oran assessment of the immunosuppressive drug. Equipment and coating process coating remaining on the device following removal of the similar to Example 1 is employed. The balloon is constructed device from the subject (for example, wherein the device is an ofa semipermable polymer. The pressurization medium is pH cutting angioplasty catheter and the Substrate is the cutting 8 phosphate buffer. The intervention site is a vascular lumen balloon of the catheter) may be used to determine the percent wall. Upon inflation of the cutting balloon, at least about 50% of coating freed, dissociated, and/or transferred from the of the coating is freed from the device at the intervention site. device. In some instances, an assessment of the device fol 0717. In another example, a cutting balloon is coated with lowing the procedure alone is sufficient to assess the amount a base layer of methyl acrylate-methacrylic acid copolymer freed or dissociated from the substrate, without determination and additional layers of PLGA+sirolimus with total loading of the amount delivered to the intervention site. Additionally, of sirolimus ~20LL. Equipment and process similar to Example where a determination of improvement and/or disease treat 1 is employed. The intervention site is a coronary artery. The ment is desired, levels of proinflammatory markers could be balloon is constructed of a semipermable polymer. The pres tested to show improvement and/or treatment of a disease surization medium is pH8 phosphate buffer. Upon inflation of and/or ailment, for example, by testing high sensitive C-re the cutting balloon, about 5% to about 15% of the coating is active protein (hsCRP), interleukin-6 (IL-6), interleukin-1B freed from the device resulting in delivery of -2.0 ug of drug (IL-1B), and/or monocyte chemoattractant protein-1 (MCP delivered to the artery. 1). The release kinetics of the drug may be shown by plotting 0718. In another example, the polymer of the coating is the sirolimus concentrations at the timepoints noted above. 50:50PLGA-Ester End Group, MW-19 kD. degradation rate 0721 For embodiments using different drugs other than ~1-2 months or 50:50 PLGA-Carboxylate End Group, sirolimus, the biomarkers are selected based on the disease to MW-10 kD. degradation rate ~28 days. The active agent is a be treated and the drugs administered during the course of chemotherapeutic agent. Equipment and coating process therapy as determined by one of skill in the art. These biom similar to Example 1 is employed. The intervention site is a arkers may be used to show the treatment results for each cavity resulting from removal of a tumor. Upon inflation of Subject. the cutting balloon, at least about 75% of the coating is 0722. Other in-vivo tests described herein may be used transferred from from the device to the intervention site. instead of this test and/or in addition to this test, adjusted for 0719. In-vivo testing: A group of 27 New Zealand white the particularities of this device, as would be known to one of rabbits is prepared for a Seldinger procedure using a cutting ordinary skill in the art. US 2010/0015200 A1 Jan. 21, 2010

0723 In-vitro testing: One sample of the coated cutting The intervention site is a vascular lumen wall. Upon inflation balloon prepared in Example 1 is secured to a balloon cath of the cutting balloon, at least about 50% of the coating is eter. A segment of optically clear TYGONR) B-44-3 tubing freed from the device at the intervention site. with O.D.—0.125", I.D.—0.0625" (Available from McMaster 0729. In-vivo testing: A group of 27 New Zealand white Carr Part Number: 5114K11 (www.mcmaster.com)) is filled rabbits is prepared for a Seldinger procedure using a cutting with phosphate-buffered saline solution and immersed in a balloon coated with a formulation of Pluronic F127 and water bath at 37° C. to mimic physiological conditions of sirolimus with total loading of sirolimus -20 ug. The device is deployment into a subject. The coated balloon is inserted into placed at a coronary artery intervention site with the assis the tubing and the balloon is inflated to at least 25% below the tance of fluoroscopy to aid in positioning the device at the balloon's nominal pressure to mechanically transfer the coat same location in each Subject. Six animals are subjected to the ing from the balloonto the tubing wall. The balloon is deflated procedure using a coated balloon that does not have sirolimus and removed from the tubing. Optical microscopy is per in the coating. After deployment and removal of the device, 3 formed on the tubing and/or the balloon (which is inflated to control animals are sacrificed at 1 hour post deployment and at least 25% below the balloon's nominal pressure, at least) to serum and tissue samples are collected. The 3 remaining determine the presence and amount of coating transferred to control animals are sacrificed at 56 days post deployment. the tubing and/or the amount of coating freed, dissociated, During the course of the study, serum samples are collected and/or transferred from the balloon. Other in-vitro tests from control and drug-treated animals every five days. The described herein may be used instead of this test and/or in drug treated animals, 3 each, are sacrificed at 1 hour, 24 hours, addition to this test, adjusted for the particularities of this 7 days, 14 days, 28 days, 42 days and 56 days post deploy device, as would be known to one of ordinary skill in the art. ment. 0730. The tissue and serum samples may be subjected to Cutting Balloon (6) Chemical Stimulation to Free analysis for sirolimus concentration. In order to determine the the Coating amount of coating freed from the device and/or delivered to 0724. A cutting balloon is coated with a formulation com the intervention site as a percent of the total amount of coating prising a base layer of methyl acrylate-methacrylic acid on the Substrate, the tissue concentration of Sirolimus at the copolymer and additional layers of PLGA+paclitaxel with one hour time point (or any time point within the first day total dose of paclitaxel approx. 0.5 g/mm2 of the wire. The following of the procedure) may be used used along with the coating and sintering process is similar to that as described in total content expected for the coating (based on the total Example 1. The balloon is constructed of a semipermable content for the manufacturing lot) or along with the content of polymer. The pressurization medium is pH 8 phosphate coating remaining on the device once removed and the per buffer. The coated cutting balloon is positioned at the inter centage calculated. This percentage is correlative of the per vention site. The balloon is pressurized to at least to at least cent of coating freed, dissociated, and/or transferred from the 25% below its nominal inflation pressure. Upon pressuriza device and delivered to the intervention site. Alternatively, the tion of the cutting balloon in the diseased artery, at least about tissue may be analyzed by various means (noted herein, 10% to at least about 30% of the coating is released into the including but not limited to SEM, TEM, and, where image intervention site and upon depressurization and removal of enhanced polymers are used, various imaging means capable the device, this material is deposited at the intervention site. of detecting these enhanced polymers) to detect the percent of In-vivo and/or in-vitro testing as described herein may be the coating freed, dissociated and/or transferred from the used to analyze the coating, the drug, the device, the inter substrate and delivered to the intervention site. Again, the vention site and/or properties thereof. amount of coating known to be on the Substrate based on manufacturing lot characteristics, and/oran assessment of the Cutting Balloon (7). Thermal Stimulation to Free coating remaining on the device following removal of the the Coating device from the subject (for example, wherein the device is a cutting angioplasty catheter and the Substrate is the balloon of 0725. A cutting balloon is coated according to a method the catheter) may be used to determine the percent of coating described herein and the balloon comprises a thermorevers freed, dissociated, and/or transferred from the device. In ible polymer Pluronic F127 and an active agent. The coated Some instances, an assessment of the device following the cutting balloon is positioned at the intervention site. The procedure alone is sufficient to assess the amount freed or balloon is inflated to at least 25% below its nominal inflation dissociated from the substrate, without determination of the pressure. Upon deflation and removal of the cutting balloon amount delivered to the intervention site. Additionally, where from the intervention site, at least about 5% to at least about a determination of improvement and/or disease treatment is 30% of the coating is freed from the surface of the cutting desired, levels of proinflammatory markers could be tested to balloon and is deposited at the intervention site. show improvement and/or treatment of a disease and/or ail 0726. In some examples, the balloon unfolds during infla ment, for example, by testing high sensitive C-reactive pro tion, causing mechanical shearing forces to at least augment tein (hsCRP), interleukin-6 (IL-6), interleukin-1B (IL-1B), transfer and/or freeing and/or deposition of the coating from and/or monocyte chemoattractant protein-1 (MCP-1). The the balloon to the intervention site. release kinetics of the drug may be shown by plotting the 0727. In some examples, the balloon twists during infla Sirolimus concentrations at the timepoints noted above. tion, causing mechanical shearing forces to at least augment 0731. For embodiments using different drugs other than transfer and/or freeing and/or deposition of the coating from sirolimus, the biomarkers are selected based on the disease to the balloon. be treated and the drugs administered during the course of 0728. In one example, the active agent is a pharmaceutical therapy as determined by one of skill in the art. These biom agent Such as a macrollide immunosuppressive drug. Equip arkers may be used to show the treatment results for each ment and coating process similar to Example 1 is employed. Subject. US 2010/0015200 A1 Jan. 21, 2010

0732. Other in-vivo tests described herein may be used 0739. In another example, the polymer of the coating is instead of this test and/or in addition to this test, adjusted for 50:50PLGA-Ester End Group, MW-19 kD. degradation rate the particularities of this device, as would be known to one of ~1-2 months or 50:50 PLGA-Carboxylate End Group, ordinary skill in the art. MW-10 kD. degradation rate ~28 days. The active agent is a 0733. In-vitro testing: One sample of the coated cutting chemotherapeutic agent. Equipment and coating process balloon prepared as in Example 1 is secured to a balloon similar to Example 1 is employed. The intervention site is a catheter. A segment of optically clear TYGON(RB-44-3 tub cavity resulting from removal of a tumor. Upon inflation of ing with O.D.—0.125", I.D.—0.0625" (Available from the cutting balloon and initiation of ultrasonic stimulation, at McMaster-Carr Part Number: 5114K11 (www.mcmaster. com)) is filled with phosphate-buffered saline solution and least about 75% of the coating is transferred from from the immersed in a water bath at 37° C. to mimic physiological device to the intervention site. conditions of deployment into a subject. The coated balloon is 0740. In-vivo testing: A group of 27 New Zealand white inserted into the tubing and the balloon is inflated to at least rabbits is prepared for a Seldinger procedure using a cutting 25% below the balloon's nominal pressure to mechanically balloon coated with a formulation of 50:50 PLGA-Ester End transfer the coating from the balloon to the tubing wall. The Group (MW-19 kD. degradation rate ~1-2 months) and balloon is deflated and removed from the tubing. Optical sirolimus with total loading of sirolimus -20 ug. The device is microscopy is performed on the tubing and/or the balloon placed at a coronary artery intervention site with the assis (which is inflated to at least 25% below the balloon's nominal tance of fluoroscopy to aid in positioning the device at the pressure, at least) to determine the presence and amount of same location in each Subject. Six animals are subjected to the coating transferred to the tubing and/or the amount of coating procedure using a coated balloon that does not have sirolimus transferred from the balloon. Other in-vitro tests described in the coating. After deployment and removal of the device, 3 herein may be used instead of this test and/or in addition to control animals are sacrificed at 1 hour post deployment and this test, adjusted for the particularities of this device, as serum and tissue samples are collected. The 3 remaining would be known to one of ordinary skill in the art. control animals are sacrificed at 56 days post deployment. During the course of the study, serum samples are collected Cutting Balloon (8)—Sonic Stimulation to Free the Coating from control and drug-treated animals every five days. The drug treated animals, 3 each, are sacrificed at 1 hour, 24 hours, 0734. A cutting balloon is coated according to a method as 7 days, 14 days. ~28 days, 42 days and 56 days post deploy described herein and the device comprises a polymer and an ment. The tissue and serum samples may be subjected to active agent. The coated cutting balloon is positioned at the analysis for Sirolimus concentration. intervention site. The balloon is inflated to at least 25% below 0741. In order to determine the amount of coating freed its nominal inflation pressure and Subjected to ultrasonic from the device and/or delivered to the intervention site as a stimulation. Upon deflation and removal of the cutting bal percent of the total amount of coating on the Substrate, the loon from the intervention site, at least about 5% to at least tissue concentration of sirolimus at the one hour time point (or about 30% of the coating is freed from the surface of the any time point within the first day following of the procedure) cutting balloon and is deposited at the intervention site. may be used used along with the total content expected for the 0735. In some examples, the balloon unfolds during infla coating (based on the total content for the manufacturing lot) tion, causing mechanical shearing forces to at least augment or along with the content of coating remaining on the device transfer and/or freeing and/or deposition of the coating from onceremoved and the percentage calculated. This percentage the balloon effected by ultrasonic stimulation to the interven is correlative of the percent of coating freed, dissociated, tion site. and/or transferred from the device and delivered to the inter 0736. In some examples, the balloon twists during infla vention site. Alternatively, the tissue may be analyzed by tion, causing mechanical shearing forces to at least augment various means (noted herein, including but not limited to transfer and/or freeing and/or deposition of the coating from SEM, TEM, and, where image enhanced polymers are used, the balloon effected by ultrasonic stimulation. various imaging means capable of detecting these enhanced 0737. In one example, the polymer of the coating is 50:50 polymers) to detect the percent of the coating freed, dissoci PLGA-Ester End Group, MW-19 kD. degradation rate ~1-2 ated and/or transferred from the substrate and delivered to the months or 50:50 PLGA-Carboxylate End Group, MW-10 intervention site. Again, the amount of coating known to be kD. degradation rate ~28 days. The active agent is a pharma on the Substrate based on manufacturing lot characteristics, ceutical agent such as a macrollide immunosuppressive drug. and/or an assessment of the coating remaining on the device Equipment and coating process similar to Example 1 is following removal of the device from the subject (for employed. The intervention site is a vascular lumen wall. example, wherein the device is a cutting angioplasty catheter Upon inflation of the cutting balloon and initiation of ultra and the substrate is the balloon of the catheter) may be used to sonic stimulation, at least about 50% of the coating is freed determine the percent of coating freed, dissociated, and/or from the device at the intervention site. transferred from the device. In some instances, an assessment 0738. In another example, a cutting balloon is coated with of the device following the procedure alone is sufficient to a formulation of PLGA+sirolimus with total loading of siroli assess the amount freed or dissociated from the Substrate, mus -20 ug with the coating preferentially on the wire of the without determination of the amount delivered to the inter cutting balloon. Equipment and process similar to Example 1 vention site. Additionally, where a determination of improve is employed. The intervention site is a coronary artery. Upon ment and/or disease treatment is desired, levels of proinflam inflation of the cutting balloon and initiation of ultrasonic matory markers could be tested to show improvement and/or stimulation, about 5% to about 15% of the coating is freed treatment of a disease and/or ailment, for example, by testing from the device resulting in delivery of -2.0 ug of drug high sensitive C-reactive protein (hsCRP), interleukin-6 (IL delivered to the artery. 6), interleukin-1B (IL-1B), and/or monocyte chemoattractant US 2010/0015200 A1 Jan. 21, 2010 protein-1 (MCP-1). The release kinetics of the drug may be tromagnetic stimulation, at least about 50% of the coating is shown by plotting the sirolimus concentrations at the time freed from the device at the intervention site. points noted above. 0749. In another example, a cutting balloon is coated with 0742 For embodiments using different drugs other than a formulation of PLGA+sirolimus with total loading of siroli sirolimus, the biomarkers are selected based on the disease to mus -20 ug with the coating preferentially on the wire of the be treated and the drugs administered during the course of cutting balloon. Equipment and process similar to Example 1 therapy as determined by one of skill in the art. These biom is employed. The intervention site is a coronary artery. Upon arkers may be used to show the treatment results for each inflation of the cutting balloon and initiation of electromag Subject. netic stimulation, about 5% to about 15% of the coating is 0743. Other in-vivo tests described herein may be used freed from the device resulting in delivery of -2.0 g of drug instead of this test and/or in addition to this test, adjusted for delivered to the artery. the particularities of this device, as would be known to one of 0750. In another example, the polymer of the coating is ordinary skill in the art. 50:50PLGA-Ester End Group, MW-19 kD. degradation rate 0744. In-vitro testing: One sample of the coated cutting ~1-2 months or 50:50 PLGA-Carboxylate End Group, balloon prepared in Example 1 is secured to a balloon cath MW-10 kD. degradation rate ~28 days. The active agent is a eter. A segment of optically clear TYGONR) B-44-3 tubing chemotherapeutic agent. Equipment and coating process with O.D.—0.125", I.D.—0.0625" (Available from McMaster similar to Example 1 is employed. The intervention site is a Carr Part Number: 5114K11 (www.mcmaster.com)) is filled cavity resulting from removal of a tumor. Upon inflation of with phosphate-buffered saline solution and immersed in a the cutting balloon and initiation of electromagnetic stimula ultrasonic water bath at 37° C. to mimic physiological con tion, at least about 75% of the coating is transferred from from ditions of deployment into a subject. The coated balloon is the device to the intervention site. inserted into the tubing and the balloon is inflated to at least 0751 In-vivo testing: A group of 27 New Zealand white 25% below the balloon's nominal pressure and ultrasonic rabbits is prepared for a Seldinger procedure using a cutting stimulation is iniatiated to mechanically transfer the coating balloon coated with a formulation of 50:50 PLGA-Ester End from the balloon to the tubing wall. The balloon is deflated Group (MW-19 kD. degradation rate ~1-2 months) and and removed from the tubing. Optical microscopy is per sirolimus with total loading of sirolimus -20 ug. The device is formed on the tubing and/or the balloon (which is inflated to placed at a coronary artery intervention site with the assis at least 25% below the balloon's nominal pressure, at least) to tance of fluoroscopy to aid in positioning the device at the determine the presence and amount of coating transferred to same location in each subject. Six animals are subjected to the the tubing and/or the amount of coating freed, dissociated, procedure using a coated balloon that does not have sirolimus and/or transferred from the balloon. Other in-vitro tests in the coating. After deployment and removal of the device, 3 described herein may be used instead of this test and/or in control animals are sacrificed at 1 hour post deployment and addition to this test, adjusted for the particularities of this serum and tissue samples are collected. The 3 remaining device, as would be known to one of ordinary skill in the art. control animals are sacrificed at 56 days post deployment. During the course of the study, serum samples are collected Cutting Balloon (9)—Electromagnetic Stimulation to from control and drug-treated animals every five days. The Free the Coating drug treated animals, 3 each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days. ~28 days, 42 days and 56 days post deploy 0745. A cutting balloon is coated according to a method as ment. The tissue and serum samples may be subjected to described herein and the device comprises a polymer and an analysis for Sirolimus concentration. active agent. The coated cutting balloon is positioned at the 0752. In order to determine the amount of coating freed intervention site. The balloon is inflated to at least 25% below from the device and/or delivered to the intervention site as a its nominal inflation pressure and Subjected to electromag percent of the total amount of coating on the Substrate, the netic stimulation. Upon deflation and removal of the cutting tissue concentration of sirolimus at the one hour time point (or balloon from the intervention site, at least about 5% to at least any time point within the first day following of the procedure) about 30% of the coating is freed from the surface of the may be used used along with the total content expected for the cutting balloon and is deposited at the intervention site. coating (based on the total content for the manufacturing lot) 0746. In some examples, the balloon unfolds during infla or along with the content of coating remaining on the device tion, causing mechanical shearing forces to at least augment onceremoved and the percentage calculated. This percentage transfer and/or freeing and/or deposition of the coating from is correlative of the percent of coating freed, dissociated, the balloon effected by electromagnetic stimulation to the and/or transferred from the device and delivered to the inter intervention site. vention site. Alternatively, the tissue may be analyzed by 0747. In some examples, the balloon twists during infla various means (noted herein, including but not limited to tion, causing mechanical shearing forces to at least augment SEM, TEM, and, where image enhanced polymers are used, transfer and/or freeing and/or deposition of the coating from various imaging means capable of detecting these enhanced the balloon effected by electromagnetic stimulation. polymers) to detect the percent of the coating freed, dissoci 0748. In one example, the polymer of the coating is 50:50 ated and/or transferred from the substrate and delivered to the PLGA-Ester End Group, MW-19 kD. degradation rate ~1-2 intervention site. Again, the amount of coating known to be months or 50:50 PLGA-Carboxylate End Group, MW-10 on the Substrate based on manufacturing lot characteristics, kD. degradation rate ~28 days. The active agent is a pharma and/or an assessment of the coating remaining on the device ceutical agent such as a macrollide immunosuppressive drug. following removal of the device from the subject (for Equipment and coating process similar to Example 1 is example, wherein the device is a cutting angioplasty catheter employed. The intervention site is a vascular lumen wall. and the substrate is the balloon of the catheter) may be used to Upon inflation of the cutting balloon and initiation of elec determine the percent of coating freed, dissociated, and/or US 2010/0015200 A1 Jan. 21, 2010

transferred from the device. In some instances, an assessment 0759. In some examples, the balloon twists during infla of the device following the procedure alone is sufficient to tion, causing mechanical shearing forces to at least augment assess the amount freed or dissociated from the Substrate, transfer and/or freeing and/or deposition of the coating from without determination of the amount delivered to the inter the balloon. vention site. Additionally, where a determination of improve 0760. In one example, the polymer of the coating is 50:50 ment and/or disease treatment is desired, levels of proinflam PLGA-Ester End Group, MW-19 kD. degradation rate ~1-2 matory markers could be tested to show improvement and/or months or 50:50 PLGA-Carboxylate End Group, MW-10 treatment of a disease and/or ailment, for example, by testing kD. degradation rate ~28 days. The active agent is a pharma high sensitive C-reactive protein (hsCRP), interleukin-6 (IL ceutical agent such as a macrollide immunosuppressive drug. 6), interleukin-1B (IL-1B), and/or monocyte chemoattractant Equipment and coating process similar to Example 1 is employed. The intervention site is a vascular lumen wall. protein-1 (MCP-1). The release kinetics of the drug may be Upon inflation of the compliant balloon, at least about 50% of shown by plotting the sirolimus concentrations at the time the coating is freed from the device at the intervention site. points noted above. 0761. In another example, a compliant balloon is coated 0753 For embodiments using different drugs other than with a formulation of PLGA+sirolimus with total loading of sirolimus, the biomarkers are selected based on the disease to Sirolimus ~20 g. Equipment and process similar to Example be treated and the drugs administered during the course of 1 is employed. The intervention site is a coronary artery. Upon therapy as determined by one of skill in the art. These biom inflation of the compliant balloon, about 5% to about 15% of arkers may be used to show the treatment results for each the coating is freed from the device resulting in delivery of Subject. -2.0 ug of drug delivered to the artery. 0754) Other in-vivo tests described herein may be used 0762. In another example, the polymer of the coating is instead of this test and/or in addition to this test, adjusted for 50:50PLGA-Ester End Group, MW-19 kD. degradation rate the particularities of this device, as would be known to one of ~1-2 months or 50:50 PLGA-Carboxylate End Group, ordinary skill in the art. MW-10 kD. degradation rate ~28 days. The active agent is a 0755. In-vitro testing: One sample of the coated cutting chemotherapeutic agent. Equipment and coating process balloon prepared in Example 1 is secured to a balloon cath similar to Example 1 is employed. The intervention site is a eter. A segment of optically clear TYGONR) B-44-3 tubing cavity resulting from removal of a tumor. Upon inflation of with O.D.—0.125", I.D.—0.0625" (Available from McMaster the compliant balloon, at least about 75% of the coating is Carr Part Number: 5114K11 (www.mcmaster.com)) is filled transferred from from the device to the intervention site. with phosphate-buffered saline solution and immersed in a 0763. In-vivo testing: A group of 27 New Zealand white water bath at 37° C. to mimic physiological conditions of rabbits is prepared for a Seldinger procedure using a compli deployment into a subject. The coated balloon is inserted into antballoon coated with a formulation of 50:50 PLGA-Ester the tubing and the balloon is inflated to at least 25% below the End Group (MW-19 kD. degradation rate ~1-2 months) and balloon's nominal pressure and electromagnetic stimulation sirolimus with total loading of sirolimus -20 ug. The device is is initiated to mechanically transfer the coating from the placed at a coronary artery intervention site with the assis balloon to the tubing wall. The balloon is deflated and tance of fluoroscopy to aid in positioning the device at the removed from the tubing. Optical microscopy is performed same location in each Subject. Six animals are subjected to the on the tubing and/or the balloon (which is inflated to at least procedure using a coated balloon that does not have sirolimus 25% below the balloon's nominal pressure, at least) to deter in the coating. After deployment and removal of the device, 3 mine the presence and amount of coating transferred to the control animals are sacrificed at 1 hour post deployment and tubing and/or the amount of coating transferred from the serum and tissue samples are collected. The 3 remaining balloon. Other in-vitro tests described herein may be used control animals are sacrificed at 56 days post deployment. instead of this test and/or in addition to this test, adjusted for During the course of the study, serum samples are collected the particularities of this device, as would be known to one of from control and drug-treated animals every five days. The drug treated animals, 3 each, are sacrificed at 1 hour, 24 hours, ordinary skill in the art. 7 days, 14 days. ~28 days, 42 days and 56 days post deploy ment. The tissue and serum samples may be subjected to Example 13 analysis for Sirolimus concentration. 0764. In order to determine the amount of coating freed Drug-Delivery Balloon Catheters from the device and/or delivered to the intervention site as a percent of the total amount of coating on the Substrate, the 0756) Drug-Delivery Balloon (1) Compliant Balloon tissue concentration of sirolimus at the one hour time point (or 0757. A compliant balloon is coated with a material com any time point within the first day following of the procedure) prising a polymer and an active agent. The coated compliant may be used used along with the total content expected for the balloon is positioned at the intervention site. The balloon is coating (based on the total content for the manufacturing lot) inflated to at least 25% below its nominal inflation pressure. or along with the content of coating remaining on the device Upon deflation and removal of the compliant balloon from the onceremoved and the percentage calculated. This percentage intervention site, at least about 5% to at least about 30% of the is correlative of the percent of coating freed, dissociated, coating is freed from the Surface of the compliant balloon and and/or transferred from the device and delivered to the inter is deposited at the intervention site. vention site. Alternatively, the tissue may be analyzed by 0758. In some examples, the balloon unfolds during infla various means (noted herein, including but not limited to tion, causing mechanical shearing forces to at least augment SEM, TEM, and, where image enhanced polymers are used, transfer and/or freeing and/or deposition of the coating from various imaging means capable of detecting these enhanced the balloon to the intervention site. polymers) to detect the percent of the coating freed, dissoci US 2010/0015200 A1 Jan. 21, 2010

ated and/or transferred from the substrate and delivered to the intervention site. Again, the amount of coating known to be TABLE 1-continued on the Substrate based on manufacturing lot characteristics, and/or an assessment of the coating remaining on the device Time point % Ammonium Acetate Flow Rate following removal of the device from the subject (for (minutes) % Acetonitrile (0.5%), pH 7.4 (mL/min) example, wherein the device is a cutting angioplasty catheter 16.O 100 O 3 and the substrate is the balloon of the catheter) may be used to 17.0 10 90 2 determine the percent of coating freed, dissociated, and/or 2O.O 10 90 O transferred from the device. In some instances, an assessment of the device following the procedure alone is sufficient to 0768. In-vitro Mass Loss test: One sample of the coated assess the amount freed or dissociated from the Substrate, compliant balloon prepared in Example 1 is weighed on a without determination of the amount delivered to the inter microbalance and then secured to a balloon catheter. A seg vention site. Additionally, where a determination of improve ment of optically clear TYGONR) B-44-3 tubing with O.D. ment and/or disease treatment is desired, levels of proinflam =0.125", I.D.—0.0625" (Available from McMaster-Carr Part matory markers could be tested to show improvement and/or Number: 5114K11 (www.mcmaster.com)) is filled with treatment of a disease and/or ailment, for example, by testing phosphate-buffered saline Solution and immersed in a water high sensitive C-reactive protein (hsCRP), interleukin-6 (IL bath at 37° C. to mimic physiological conditions of deploy 6), interleukin-1B (IL-1B), and/or monocyte chemoattractant ment into a subject. The coated balloon is inserted into the protein-1 (MCP-1). The release kinetics of the drug may be tubing and the balloon is inflated to at least 25% below the shown by plotting the sirolimus concentrations at the time balloon's nominal pressure to mechanically transfer the coat points noted above. ing from the balloonto the tubing wall. The balloon is deflated 0765 For embodiments using different drugs other than and removed from the tubing. After drying, the balloon is sirolimus, the biomarkers are selected based on the disease to removed from the guidewire, further dried and weighed on a be treated and the drugs administered during the course of microbalance. Comparison of the pre- and post-deployment therapy as determined by one of skill in the art. These biom weights indicates how much coating is freed, dissociated, arkers may be used to show the treatment results for each and/or transferred from the balloon. This analysis may Subject. instead and/or alternatively include testing of the tubing to 0766. In-vitro testing: One sample of the coated compliant determine the amount of coating freed, dissociated, and/or balloon prepared in Example 1 is secured to a balloon cath transferred from the device during this in-vitro test. eter. A segment of optically clear TYGONR) B-44-3 tubing 0769. In-vitro Coating test: One sample of the coated com with O.D.—0.125", I.D.—0.0625" (Available from McMaster pliant balloon prepared in Example 1 is secured to a balloon Carr Part Number: 5114K11 (www.mcmaster.com)) is filled catheter. A segment of optically clear TYGON(RB-44-3 tub with phosphate-buffered saline solution and immersed in a ing with O.D.—0.125", I.D.—0.0625" (Available from water bath at 37° C. to mimic physiological conditions of McMaster-Carr Part Number: 5114K11 (www.mcmaster. deployment into a subject. The coated balloon is inserted into com)) is filled with phosphate-buffered saline solution and the tubing and the balloon is inflated to at least 25% below the immersed in a water bath at 37° C. to mimic physiological balloon's nominal pressure to mechanically transfer the coat conditions of deployment into a subject. The coated balloon is ing from the balloonto the tubing wall. The balloon is deflated inserted into the tubing and the balloon is inflated to at least and removed from the tubing. Optical microscopy is per 25% below the balloon's nominal pressure to mechanically formed on the tubing and/or the balloon (which is inflated to transfer the coating from the balloon to the tubing wall. The at least 25% below the balloon's nominal pressure, at least) to balloon is deflated and removed from the tubing. The section determine the presence and amount of coating transferred to of tubing exposed to the deployed balloon is cut away from the tubing and/or the amount of coating freed, dissociated, the remainder of the tubing and the interior of the excised and/or transferred from the balloon. tubing rinsed with a small amount of ethanol and an amount 0767 Method for the determination of sirolimus levels: of methylene chloride to make up 25 mL total volume of Media may be assayed for sirolimus content using HPLC. rinsings which are collected in a flask for analysis. Analysis Calibration standards containing known amounts of drug are by HPLC as described above is performed to determine the to determine the amount of drug eluted. The multiple peaks amount of material freed, dissociated, and/or transferred from present for the sirolimus (also present in the calibration stan the balloon. This analysis may instead and/or alternatively dards) are added to give the amount of drug eluted at that time include testing of the substrate itself to determine the amount period (in absolute amount and as a cumulative amount of coating freed, dissociated, and/or transferred from the eluted). HPLC analysis is performed using Waters HPLC device during this in-vitro test. system, set up and run on each sample as provided in the Table 0770. In-vitro testing: One sample of the coated compli 1 below using an injection volume of 100 L. ant balloon prepared in Example 1 is secured to a balloon catheter. A segment of resected coronary artery from Yucatan TABLE 1. miniature swine is positionally fixed and filled with phos Time point % Ammonium Acetate Flow Rate phate-buffered saline solution and immersed in a water bath (minutes) % Acetonitrile (0.5%), pH 7.4 (mL/min) at 37° C. to mimic physiological conditions of deployment into a subject. The coated balloon is inserted into the artery O.OO 10 90 1.2 and the balloon is inflated to at least 25% below the balloon's 1.00 10 90 1.2 12.5 95 5 1.2 nominal pressure to mechanically transfer the coating from 13.5 100 O 1.2 the balloon to the arterial wall. The balloon is deflated and 14.O 100 O 3 removed from the artery. The section of artery exposed to the deployed balloon is cut away from the remainder of the artery US 2010/0015200 A1 Jan. 21, 2010 section, placed into a tissue homogonizer and the homog to mechanically transfer the coating from the balloon to the enized material is extracted with methylene chloride to make tubing wall. The balloon is deflated and removed from the up 25 mL total volume of rinsings which are collected in a tubing. The filter is deployed for 5 minutes after removal of flask for analysis. Analysis by HPLC as described above is the balloon, the flow of saline is halted, the tubing cut adjacent performed to determine the amount of material freed, disso to the epoxy seal, the filter retracted and removed from the ciated, and/or transferred from the balloon. This analysis may tubing. The content of the filter is analyzed. instead and/or alternatively include testing of the substrate 0775 In-vitro testing for distal flow particulates: One itself to determine the amount of coating freed, dissociated, sample of the coated compliant balloon prepared in Example and/or transferred from the device during this in-vitro test. 1 is secured to a guidewire. A segment of optically clear 0771. For embodiments related to non-vascular or non TYGONR) B-44-3 tubing with O.D.-0. 125", I.D.-0.0625" lumenal applications, e.g. a tumor site or other cavity or a (Available from McMaster-Carr Part Number: 5114K11 cannulized site, the same technique is employed with the (www.mcmaster.com)) is filled with phosphate-buffered modification that the tissue to be assayed is resected from the saline solution and immersed in a water bath at 37° C. to tissue adjoining cavity receiving drug treatment. mimic physiological conditions of deployment into a subject 0772 In-vitro testing: One sample of the coated compli and the distal end of the tubing is connected to a turbidity light ant balloon prepared in Example 1 is secured to a balloon scattering detector as described in Analytical Ultracentrifu catheter. A segment of resected coronary artery from Yucatan gation of Polymers and Nanoparticles, W. Machtle and L. miniature swine is positionally fixed and filled with phos Borger, (Springer) 2006, p. 41. The coated balloon is inserted phate-buffered saline solution and immersed in a water bath into the proximal end of the tubing, the proximal end of the at 37° C. to mimic physiological conditions of deployment tubing Surrounding the guidewire sealed with epoxy, and a into a subject. The coated balloon is inserted into the artery hypodermic needle which is attached to an infusion pump and and the balloon is inflated to at least 25% below the balloon's reservoir of 37° C. phosphate-buffered saline solution is nominal pressure to mechanically transfer the coating from inserted into the tubing proximal to the balloon assembly. The the balloon to the arterial wall. The balloon is deflated and flow of saline is commenced, a baseline for light transmission removed from the artery. The section of artery exposed to the through the detector is established and the balloon is inflated deployed balloon is cut away from the remainder of the artery to at least 25% below the balloon's nominal pressure to section and incised lengthwise to lay open the artery. Optical mechanically transfer the coating from the balloon to the microscopy is performed on the interior of artery to determine tubing wall. The balloon is deflated and removed from the the presence and amount of coating transferred to the artery tubing. The flow is maintained for 10 minutes after removal of and/or the amount of coating transferred from the balloon. the balloon, and the flow is analyzed for the presence of The tissue sample is also subjected to TEM-SEM analysis. particles based on detector response. 0773) In-vitro testing of release kinetics: One sample of 0776 Drug-Delivery Balloon (2) Non-Compliant Bal the coated compliant balloon with total loading of sirolimus loon ~201g prepared in Example 1 is secured to a balloon catheter. 0777. A non-compliant balloon is coated with a material A flask containing exactly 25 mL of pH 7.4 aqueous phos comprising a polymer and an active agent. The coated non phate buffer equilibrated to 37° C. equipped for magnetic compliant balloon is positioned at the intervention site. The stirring is prepared. Into this flaskis placed the coated balloon balloon is inflated to at least 25% below its nominal inflation and the catheter portion of the apparatus is secured Such that pressure. Upon deflation and removal of the non-compliant the balloon does not touch the sides of the flask. The balloon balloon from the intervention site, at least about 5% to at least is inflated to 120 psi with sterile water. Aliquots of 100 L are about 30% of the coating is freed from the surface of the removed prior to addition of the balloon, after placement of non-compliant balloon and is deposited at the intervention the balloon but prior to inflation of the balloon, and at regular site. time intervals of 2, 4, 6, 8, 10, 12, and 14 minutes. Upon 0778. In some examples, the balloon unfolds during infla removal of each aliquot an equivalent Volume of aqueous tion, causing mechanical shearing forces to at least augment buffer is added to maintain the volume at 25 mL. The aliquots transfer and/or freeing and/or deposition of the coating from are analyzed by HPLC as described above for the concentra the balloon to the intervention site. tion of Sirolimus. 0779. In some examples, the balloon twists during infla 0774 In-vitro testing for distal flow particulates: One tion, causing mechanical shearing forces to at least augment sample of the coated compliant balloon prepared in Example transfer and/or freeing and/or deposition of the coating from 1 is secured to a guidewire incorporatingaporous filter of 100 the balloon. m pore size, such as the Cordis AngioGuard emboli capture 0780. In one example, the polymer of the coating is 50:50 guidewire. A segment of optically clear TYGONR) B-44-3 PLGA-Ester End Group, MW-19 kD. degradation rate ~1-2 tubing with O.D.—0.125", I.D.—0.0625" (Available from months or 50:50 PLGA-Carboxylate End Group, MW-10 McMaster-Carr Part Number: 5114K11 (www.mcmaster. kD. degradation rate ~28 days. The active agent is a pharma com)) is filled with phosphate-buffered saline solution and ceutical agent such as a macrollide immunosuppressive drug. immersed in a water bath at 37° C. to mimic physiological Equipment and coating process similar to Example 1 is conditions of deployment into a subject. The coated balloon is employed. The intervention site is a vascular lumen wall. inserted into the tubing, the proximal end of the tubing Sur Upon inflation of the non-compliant balloon, at least about rounding the guidewire sealed with epoxy, and a hypodermic 50% of the coating is freed from the device at the intervention needle which is attached to an infusion pump and reservoir of site. 37° C. phosphate-buffered saline solution is inserted into the 0781. In another example, a non-compliant balloon is tubing proximal to the balloon assembly. The flow of saline is coated with a formulation of PLGA+sirolimus with total commenced, the distal filter is deployed and the balloon is loading of Sirolimus ~20 ug. Equipment and process similar inflated to at least 25% below the balloon's nominal pressure to Example 1 is employed. The intervention site is a coronary US 2010/0015200 A1 Jan. 21, 2010 artery. Upon inflation of the non-compliant balloon, about 5% similar to Example 1 is employed. The intervention site is a to about 15% of the coating is freed from the device resulting cavity resulting from removal of a tumor. Upon inflation of in delivery of -2.0 ug of drug delivered to the artery. the balloon, at least about 75% of the coating is transferred 0782. In another example, the polymer of the coating is from from the device to the intervention site. 50:50PLGA-Ester End Group, MW-19 kD. degradation rate 0791 In-vivo and/or in-vitro testing may be performed ~1-2 months or 50:50 PLGA-Carboxylate End Group, according to the methods described herein. MW-10 kD. degradation rate ~28 days. The active agent is a 0792 Drug-Delivery Balloon (4) Chemical Stimulus chemotherapeutic agent. Equipment and coating process 0793. A balloon is coated with a formulation comprising a similar to Example 1 is employed. The intervention site is a base layer of methyl acrylate-methacrylic acid copolymer cavity resulting from removal of a tumor. Upon inflation of and additional layers of PLGA+paclitaxel with total dose of the non-compliant balloon, at least about 75% of the coating paclitaxel approx. 0.5 ug/mm2 of the wire. The coating and is transferred from from the device to the intervention site. sintering process is similar to that as described in Example 1. 0783. In-vivo and/or in-vitro testing may be performed The balloon is constructed of a semipermable polymer. The according to the methods described herein. pressurization medium is pH 8 phosphate buffer. The coated 0784 Drug-Delivery Balloon (3)—Mechanical and balloon is positioned at the intervention site. The balloon is Chemical Stimulus pressurized to at least to at least 25% below its nominal 0785. A balloon is coated with a formulation comprising a inflation pressure. Upon pressurization of the balloon in the base layer of methyl acrylate-methacrylic acid copolymer diseased artery, at least about 10% to at least about 30% of the and additional layers of PLGA+paclitaxel with total dose of coating is released into the intervention site and upon depres paclitaxel approx. 0.5 ug/mm2 of the wire. The coating and Surization and removal of the device, this material is depos sintering process is similar to that as described in Example 1. ited at the intervention site. In-vivo and/or in-vitro testing The balloon is constructed of a semipermable polymer. The may be performed according to the methods described herein. pressurization medium is pH 8 phosphate buffer. The coated 0794) Drug-Delivery Balloon (5) Thermal Stimulus balloon is positioned at the intervention site. The balloon is 0795. A balloon is coated comprising a thermoreversible pressurized to at least to at least 25% below its nominal polymer Pluronic F127 and an active agent. The coated bal inflation pressure. Upon pressurization of the balloon in the loon is positioned at the intervention site. The balloon is diseased artery, at least about 10% to at least about 30% of the inflated to at least 25% below its nominal inflation pressure. coating is released into the intervention site and upon depres Upon deflation and removal of the balloon from the interven surization and removal of the device, this material is depos tion site, at least about 5% to at least about 30% of the coating ited at the intervention site. is freed from the surface of the balloon and is deposited at the 0786. In some examples, the balloon unfolds during infla intervention site. tion, causing mechanical shearing forces to at least augment 0796. In some examples, the balloon unfolds during infla the pH mediated release of the coating from the balloon to the tion, causing mechanical shearing forces to at least augment intervention site. transfer and/or freeing and/or deposition of the coating from 0787. In some examples, the balloon twists during infla the balloon to the intervention site. tion, causing mechanical shearing forces to at least augment 0797. In some examples, the balloon twists during infla the pH mediated release of the coating from the balloon. tion, causing mechanical shearing forces to at least augment 0788. In one example, a base layer of methyl acrylate transfer and/or freeing and/or deposition of the coating from methacrylic acid copolymer is formed and additional layers the balloon. of the coating is 50:50 PLGA-Ester End Group, MW-19 kD. degradation rate ~1-2 months or 50:50 PLGA-Carboxylate 0798. In one example, the active agent is a pharmaceutical End Group, MW-10 kD. degradation rate ~28 days. The agent such as a macrollide immunosuppressive drug. Equip active agent is a pharmaceutical agent such as a macrollide ment and coating process similar to Example 1 is employed. immunosuppressive drug. Equipment and coating process The intervention site is a vascular lumen wall. Upon inflation similar to Example 1 is employed. The balloon is constructed of the balloon, at least about 50% of the coating is freed from ofa semipermable polymer. The pressurization medium is pH the device at the intervention site. 8 phosphate buffer. The intervention site is a vascular lumen 0799. In-vivo and/or in-vitro testing may be performed wall. Upon inflation of the balloon, at least about 50% of the according to the methods described herein. coating is freed from the device at the intervention site. 0800 Drug-Delivery Balloon (6)—Sonic Stimulus 0789. In another example, a balloon is coated with a base 0801. A balloon is coated with a material comprising a layer of methyl acrylate-methacrylic acid copolymer and polymer and an active agent. The coated balloon is positioned additional layers of PLGA+sirolimus with total loading of at the intervention site. The balloon is inflated to at least 25% Sirolimus ~20 g. Equipment and process similar to Example below its nominal inflation pressure and subjected to ultra 1 is employed. The intervention site is a coronary artery. The sonic stimulation. Upon deflation and removal of the balloon balloon is constructed of a semipermable polymer. The pres from the intervention site, at least about 5% to at least about surization medium is pH8 phosphate buffer. Upon inflation of 30% of the coating is freed from the surface of the balloon and the balloon, about 5% to about 15% of the coating is freed is deposited at the intervention site. from the device resulting in delivery of -2.0 ug of drug 0802. In some examples, the balloon unfolds during infla delivered to the artery. tion, causing mechanical shearing forces to at least augment 0790. In another example, the polymer of the coating is transfer and/or freeing and/or deposition of the coating from 50:50PLGA-Ester End Group, MW-19 kD. degradation rate the balloon effected by ultrasonic stimulation to the interven ~1-2 months or 50:50 PLGA-Carboxylate End Group, tion site. MW-10 kD. degradation rate ~28 days. The active agent is a 0803. In some examples, the balloon twists during infla chemotherapeutic agent. Equipment and coating process tion, causing mechanical shearing forces to at least augment US 2010/0015200 A1 Jan. 21, 2010 transfer and/or freeing and/or deposition of the coating from ~20 ug with the coating preferentially on the wire of the the balloon effected by ultrasonic stimulation. balloon. Equipment and process similar to Example 1 is 0804. In one example, the polymer of the coating is 50:50 employed. The intervention site is a coronary artery. Upon PLGA-Ester End Group, MW-19 kD. degradation rate ~1-2 inflation of the balloon and initiation of electromagnetic months or 50:50 PLGA-Carboxylate End Group, MW-10 stimulation, about 5% to about 15% of the coating is freed kD. degradation rate ~28 days. The active agent is a pharma from the device resulting in delivery of -2.0 ug of drug ceutical agent such as a macrollide immunosuppressive drug. delivered to the artery. Equipment and coating process similar to Example 1 is 0814. In another example, the polymer of the coating is employed. The intervention site is a vascular lumen wall. 50:50PLGA-Ester End Group, MW-19 kD. degradation rate Upon inflation of the balloon and initiation of ultrasonic ~1-2 months or 50:50 PLGA-Carboxylate End Group, stimulation, at least about 50% of the coating is freed from the MW-10 kD. degradation rate ~28 days. The active agent is a device at the intervention site. chemotherapeutic agent. Equipment and coating process 0805. In another example, a balloon is coated with a for similar to Example 1 is employed. The intervention site is a mulation of PLGA+sirolimus with total loading of sirolimus cavity resulting from removal of a tumor. Upon inflation of ~20 ug with the coating preferentially on the wire of the the balloon and initiation of electromagnetic stimulation, at balloon. Equipment and process similar to Example 1 is least about 75% of the coating is transferred from from the employed. The intervention site is a coronary artery. Upon device to the intervention site. inflation of the balloon and initiation of ultrasonic stimula 0815. In-vivo and/or in-vitro testing may be performed tion, about 5% to about 15% of the coating is freed from the according to the methods described herein. device resulting in delivery of -2.0 ug of drug delivered to the 0816 Drug-Delivery Balloon (8)—Electrostatically artery. Applied Drug Release Layer 0806. In another example, the polymer of the coating is 0817. A 5x40 mm polyethylene terephthalate (PET) bal 50:50PLGA-Ester End Group, MW-19 kD. degradation rate loon was airbrushed with rapamycin (-5.8 mg from rapamy ~1-2 months or 50:50 PLGA-Carboxylate End Group, cin/acetone solution) as a release agent, then airbrushed with MW-10 kD. degradation rate ~28 days. The active agent is a PLGA (~ 1 mg) and sintered at 67° C. under vacuum for 1 chemotherapeutic agent. Equipment and coating process hour. The balloon was deflated, inserted in the lumen of 3/16" similar to Example 1 is employed. The intervention site is a Tygon tubing, and pressurized to ~245 psig at 37° C. (2 cavity resulting from removal of a tumor. Upon inflation of minutes equilibration time; 1 minute pressurization). Sub the balloon and initiation of ultrasonic stimulation, at least stantial transfer of the coating (a thick layer) to the tubing was about 75% of the coating is transferred from from the device observed. A thin layer of coating remained on the balloon. to the intervention site. 0818. In a related experiment, a 5x40 mm polyethylene 0807. In-vivo and/or in-vitro testing may be performed terephthalate (PET) balloon was electrostatically coated with according to the methods described herein. 240 micrograms of rapamycin as a release agent, then coated 0808 Drug-Delivery Balloon (7)—Electromagnetic with PLGA (1.24 mg) by eRESS and sintered at 68°C. for 1 Stimulus hour. The balloon was deflated, inserted in the lumen of 3/16" 0809. A balloon is coated comprising a polymer and an Tygontubing, and pressurized to 250 psig at 37°C. (2 minutes active agent. The coated balloon is positioned at the interven equilibration time; 1 minute pressurization). Under these tion site. The balloon is inflated to at least 25% below its conditions, no transfer of the PLGA coating to the tubing was nominal inflation pressure and Subjected to electromagnetic observed. stimulation. Upon deflation and removal of the balloon from the intervention site, at least about 5% to at least about 30% of Example 14 the coating is freed from the surface of the balloon and is Balloon Delivery of Weakly Binding Drugs deposited at the intervention site. 0810. In some examples, the balloon unfolds during infla 0819. A compliant balloon was electrostatically coated tion, causing mechanical shearing forces to at least augment with a weakly binding drug, cyrstalline Sirolimus with a transfer and/or freeing and/or deposition of the coating from nominal particle size of 2.4 microns, as part of a bioabsorb the balloon effected by electromagnetic stimulation to the able polymer matrix in dry powder form, and the coating intervention site. sintered at low temperature. Upon introduction of the coated 0811. In some examples, the balloon twists during infla balloon into a model lumen (made from Tygon tubing, as tion, causing mechanical shearing forces to at least augment described herein) and Subsequent inflation, the drug coating transfer and/or freeing and/or deposition of the coating from was shown by cross-sectional analysis to have transferred to the balloon effected by electromagnetic stimulation. the interior of the lumen. This result shows that dry process 0812. In one example, the polymer of the coating is 50:50 ing that isolates a weakly binding drug as particles within a PLGA-Ester End Group, MW-19 kD. degradation rate ~1-2 bioabsorbable polymer matrix can provide the ability to con months or 50:50 PLGA-Carboxylate End Group, MW-10 trol the delivery of weakly binding drugs. kD. degradation rate ~28 days. The active agent is a pharma ceutical agent such as a macrollide immunosuppressive drug. Example 15 Equipment and coating process similar to Example 1 is Drug-Delivery Balloons for Treatment of the Vascu employed. The intervention site is a vascular lumen wall. lature Upon inflation of the balloon and initiation of electromag netic stimulation, at least about 50% of the coating is freed 0820 Drug-Delivery Balloon (1) Treatment of Resteno from the device at the intervention site. sis with Paclitaxel or Sirolimus 0813. In another example, a balloon is coated with a for 0821. A balloon is used to prevent and/or treat restenosis mulation of PLGA+sirolimus with total loading of sirolimus in an artery. A balloon is coated as described herein with US 2010/0015200 A1 Jan. 21, 2010

50:50PLGA-Ester End Group (MW-19 kD. degradation rate balloon is inflated to at least 25% below its nominal inflation ~1-2 months) and paclitaxel or at a loading of 1 g/mm or pressure. The balloon is deflated and removed from the inter sirolimus at a loading of 5 g/mm. The coated balloon is vention site, allowing the coating to be freed from the Surface positioned at the arterial intervention site. The balloon is of the balloon and deposited at the intervention site where it inflated to at least 25% below its nominal inflation pressure. can prevent inflammatory cell binding and promote genera The balloon is deflated and removed from the intervention tion of nitric oxide. The amount of coating transferred upon site, allowing the coating to be freed from the surface of the deployment can be determined using, e.g., test methods as balloon and deposited at the intervention site. The amount of described herein. coating transferred upon deployment can be determined 0830 Drug-Delivery Balloon (6) Treatment of Athero using, e.g., test methods as described herein. Sclerosis Using Batimastat 0822. Drug-Delivery Balloon (2) Treatment of Resteno 0831. A coated balloon is used to prevent and/or treat sis with Cilostazol atherosclerosis in an artery. A balloon is coated as described 0823. A balloon is used to prevent and/or treat restenosis herein with 50:50 PLGA-Ester End Group (MW-19 kD. in an artery. A balloon is coated as described herein with degradation rate ~1-2 months) and batimastat. The coated 50:50PLGA-Ester End Group (MW-19 kD. degradation rate balloon is positioned at the arterial intervention site. The ~1-2 months) and cilostazol. The coated balloon is positioned balloon is inflated to at least 25% below its nominal inflation at the arterial intervention site. The balloon is inflated to at pressure. The balloon is deflated and removed from the inter least 25% below its nominal inflation pressure. The balloon is vention site, allowing the coating to be freed from the Surface deflated and removed from the intervention site, allowing the of the balloon and deposited at the intervention site where it coating to be freed from the surface of the balloon and depos can prevent Vulnerable plaque rupture. The amount of coating ited at the intervention site where it can act to prevent further transferred upon deployment can be determined using, e.g., platelet binding. The amount of coating transferred upon test methods as described herein. deployment can be determined using, e.g., test methods as 0832 Drug-Delivery Balloon (7) Treatment of Reperfu described herein. sion Injury 0824 Drug-Delivery Balloon (3) Promotion of Healing 0833. A coated balloon is used to prevent and/or treat Using CD34 Antibodies reperfusion injury in an artery. A balloon is coated as 0825. A coated balloon is used to promote healing in a described herein with 50:50 PLGA-Ester End Group damaged artery. A balloon is coated as described herein with (MW-19 kD. degradation rate ~1-2 months) and glucagon 50:50PLGA-Ester End Group (MW-19 kD. degradation rate like peptide-1, erythropoietin, atorvastatin, or atrial natri ~1-2 months) and CD34 antibodies. The coated balloon is uretic peptide. The coated balloon is positioned at the arterial positioned at the arterial intervention site. The balloon is intervention site. The balloon is inflated to at least 25% below inflated to at least 25% below its nominal inflation pressure. its nominal inflation pressure. The balloon is deflated and The balloon is deflated and removed from the intervention removed from the intervention site, allowing the coating to be site, allowing the coating to be freed from the surface of the freed from the surface of the balloon and deposited at the balloon and deposited at the intervention site where it can act intervention site. The amount of coating transferred upon to attract progenitor cells to the vessel wall. This can result in deployment can be determined using, e.g., test methods as an acceleration of endothlialization. The amount of coating described herein. transferred upon deployment can be determined using, e.g., 0834 Drug-Delivery Balloon (8)—Promotion of Angio test methods as described herein. genesis 0826 Drug-Delivery Balloon (4) Promotion of Healing 0835. A coated balloon is used to promote angiogenesis. A Using an Agent that Protects Endothelium or Improves EPC balloon is coated as described herein with 50:50PLGA-Ester Function End Group (MW-19 kD. degradation rate ~1-2 months) and 0827. A coated balloon is used to promote healing in a a fibroblast growth factor gene therapy agent (e.g., GenerX, damaged artery. A balloon is coated as described herein with Cardium Therapeutics), or angiopoietin-1. The coated bal 50:50PLGA-Ester End Group (MW-19 kD. degradation rate loon is positioned in a vessel in a tissue bed in need of better ~1-2 months) and a statin (e.g., cerivastatin), an ACE inhibi perfusion. The balloon is inflated to at least 25% below its tor, an angiotensin II type I receptor blocker, a PPAR-gamma nominal inflation pressure. The balloon is deflated and agonist, a glitaZone, or erythropoietin. The coated balloon is removed from the intervention site, allowing the coating to be positioned at the arterial intervention site. The balloon is freed from the surface of the balloon and deposited at the inflated to at least 25% below its nominal inflation pressure. intervention site where it can promote angiogenesis. The The balloon is deflated and removed from the intervention amount of coating transferred upon deployment can be deter site, allowing the coating to be freed from the surface of the mined using, e.g., test methods as described herein. balloon and deposited at the intervention site where it can act 0836 Coated Cutting Balloon (9) Treatment of Throm to protect the endothelium and/or improve EPC colonization, bosis Using Dipyridamole maturation, or function. The amount of coating transferred 0837. A cutting balloon is used to prevent and/or treat upon deployment can be determined using, e.g., test methods thrombosis in an artery. A cutting balloon is coated with 50:50 as described herein. PLGA-Ester End Group (MW-19 kD. degradation rate ~1-2 0828 Drug-Delivery Balloon (5) Treatment of Athero months) and dipyridamole. The coated cutting balloon is Sclerosis Using Adiponectin positioned at the arterial intervention site. The balloon is 0829. A coated balloon is used to prevent and/or treat inflated to at least 25% below its nominal inflation pressure. atherosclerosis in an artery. A balloon is coated as described The balloon is deflated and removed from the intervention herein with 50:50 PLGA-Ester End Group (MW-19 kD. site, allowing the coating to be freed from the surface of the degradation rate ~1-2 months) and adiponectin. The coated balloon and deposited at the intervention site to cause local balloon is positioned at the arterial intervention site. The release oft-PA to breakup clots and/or prevent clotformation. US 2010/0015200 A1 Jan. 21, 2010

The amount of coating transferred upon deployment can be 0845. A coated balloon catheter is used to prevent discom determined using, e.g., test methods as described herein. fort resulting from an endoscopic procedure. Prior to the endoscopic procedure, a compliant balloon is coated with Example 16 50:50PLGA-Ester End Group (MW-19 kD. degradation rate ~1-2 months) and betamethasone (0.05%) or lidocaine (2.0- Drug-Delivery Balloon Catheter for Treatment of the 4.0%), positioned in the endoscopic intervention site and Trachea inflated to at least 25% below its nominal inflation pressure. 0838. Drug-Delivery Balloon (1) Prevention of Dis The balloon is deflated and removed from the intervention comfort from the Use of an Endotracheal Tube Using site, allowing the coating to be freed from the surface of the Betamethasone or Lidocaine balloon and deposited at the intervention site. The amount of 0839. A coated balloon catheter is used to prevent discom coating transferred upon deployment can be determined fort resulting from the use of an endotracheal tube. Prior to using, e.g., test methods as described herein. insertion of the endotracheal tube, procedure, a compliant 0846. Drug-Delivery Balloon (2) Reduction of Discom balloon is coated with 50:50 PLGA-Ester End Group fort Resulting from an Endoscopic Procedure Using (MW-19 kD. degradation rate ~1-2 months) and betametha Betamethasone or Lidocaine sone (0.05%) or lidocaine (2.0-4.0%), positioned in the 0847. A coated balloon catheter is used to reduce discom endotracheal intervention site and inflated to at least 25% fort resulting from an endoscopic procedure. After the endo below its nominal inflation pressure. The balloon is deflated scopic procedure, a compliant balloon is coated with 50:50 and removed from the intervention site, allowing the coating PLGA-Ester End Group (MW-19 kD. degradation rate ~1-2 to be freed from the surface of the balloon and deposited at the months) and betamethasone (0.05%) or lidocaine (2.0-4.0%), intervention site. The amount of coating transferred upon positioned in the endoscopic intervention site and inflated to deployment can be determined using, e.g., test methods as at least 25% below its nominal inflation pressure. The balloon described herein. is deflated and removed from the intervention site, allowing 0840 Drug-Delivery Balloon (2) Reduction of Discom the coating to be freed from the surface of the balloon and fort from the Use of an Endotracheal Tube Using Betametha deposited at the intervention site. The amount of coating Sone or Lidocaine transferred upon deployment can be determined using, e.g., 0841. A coated balloon catheter is used to reduce discom test methods as described herein. fort resulting from the use of an endotracheal tube. After the 0848 Drug-Delivery Balloon (3) Reduction of Inflam endotracheal procedure, a compliant balloon is coated with mation and Promotion of Healing Following Endoscopic Sur 50:50PLGA-Ester End Group (MW-19 kD. degradation rate gery ~1-2 months) and betamethasone (0.05%) or lidocaine (2.0- 0849. A coated balloon catheter is used to reduce inflam 4.0%), positioned in the endotracheal intervention site and mation and promote healing following endoscopic Surgery. inflated to at least 25% below its nominal inflation pressure. After the endoscopic Surgery, a compliant balloon is coated The balloon is deflated and removed from the intervention with 50:50 PLGA-Ester End Group (MW-19 kD. degrada site, allowing the coating to be freed from the surface of the tion rate ~1-2 months) and mitomycin C and/or Bacillus balloon and deposited at the intervention site. The amount of Calmette-Guerin is positioned in the endoscopic intervention coating transferred upon deployment can be determined site and inflated to at least 25% below its nominal inflation using, e.g., test methods as described herein. pressure. The balloon is deflated and removed from the inter 0842 Drug-Delivery Balloon (3) Improved Healing and vention site, allowing the coating to be freed from the Surface Reduction of Scarring Following Laryngeal/Tracheal Sur of the balloon and deposited at the intervention site. The gery amount of coating transferred upon deployment can be deter 0843. A coated balloon catheter is used to improve healing mined using, e.g., test methods as described herein. and reduce Scarring following laryngeal/tracheal Surgery. After the endotracheal procedure, a compliant balloon is Example 18 coated with 50:50 PLGA-Ester End Group (MW-19 kD. degradation rate ~1-2 months) and mitomycin C (0.4-0.5 Drug-Delivery Balloon Catheter for Treatment of a mg/ml or -0.04-0.05%) or heparin (5000 U/ml) positioned in Cancer the endotracheal intervention site and inflated to at least 25% 0850 Drug-Delivery Balloon (1) Treatment of a Blad below its nominal inflation pressure. The balloon is deflated der Transitional Cell Carcinoma and removed from the intervention site, allowing the coating 0851 A coated balloon is used to treat a bladder transi to be freed from the surface of the balloon and deposited at the tional cell carcinoma. The balloon, which is large enough to intervention site. The amount of coating transferred upon contact the bladder walls when inflated, is coated with a deployment can be determined using, e.g., test methods as polymer combined with active agent sufficient to deliver the described herein. The procedure is repeated as necessary to equivalent of either: 1) for administration immediately fol ensure adequate delivery of active agent over the course of the lowing Surgical resection, a combination intravesical treat wound healing process. ment of 1000 mg gemcitabine, or 75 mg docetaxel, or 30 mg thiotepa, followed (sequentially) by 40 mg mitomycin C, then Example 17 the same combination treatment every week for 6 weeks, and Drug-Delivery Balloon Catheter for Treatment of the followed by a maintenance regimen providing the same com Esophagus bination treatment once a month for 12 months; or 2) for administration starting 2 weeks after Surgery, 50 million units 0844 Drug-Delivery Balloon (1) Prevention of Dis Interferon Alpha2b and 81 mg BCG once a week for 6 weeks, comfort Resulting from an Endoscopic Procedure Using with maintenance of up to 3 weekly instillations at 3 or 6 Betamethasone or Lidocaine months, and then once every 6 to 12 months; or 3) for admin US 2010/0015200 A1 Jan. 21, 2010 90 istration as a single instillation at the time of tumor resection, vicinity of a vascular occlusion, which can result in severe 50 mg doxorubicin, then the same dose weekly for 4-8 weeks, bleeding. A balloon is coated with alternating layers of 50:50 then once a month to provide maintenance as desired; or 4) for PLGA-Ester End Group (MW-19 kD. degradation rate ~1-2 administration to treat existing disease, 30 mg thiotepa, then months) and a thrombolytic drug, e.g., tissue plasminogen the same dose weekly for 4 to 8 weeks, depending on Volume activator (tPA), melagatran, lanoteplase, reteplase, staphy of residual disease, then once a month to provide maintenance lokinase, Streptokinase, tenecteplase, urokinase, or any com as desired. In embodiments, the treatment is delivered in more bination thereof. The coated balloon is positioned within the than one procedure, e.g., a second balloon is used to deliver vessel near the site of thrombolysis as desired and inflated to the maintenance regimen. In treatment 2) the dose of BCG is at least 25% below its nominal inflation pressure. The balloon reduced to /3, /10, /100 as needed to prevent increased side is deflated and removed from the intervention site, allowing effects. Treatments 1) through 4) are made to include or not the coating to be freed from the surface of the balloon and include hyaluronidase (rHuPH20, total dose 50-100 U). deposited at the intervention site. The amount of coating 0852. The balloon is inflated to at least 25% below its transferred upon deployment can be determined using, e.g., nominal inflation pressure and left in place for a period of test methods as described herein. time sufficient for transfer of the coating to the bladder walls to take place, e.g., at least about 2 to 30 minutes. The balloon 0858 Drug-Delivery Balloon (2) Treatment with a Neu is deflated and removed from the intervention site, allowing roprotective Agent After Stroke the coating to be freed from the surface of the balloon and 0859. A coated balloon is used to administer a neuropro deposited at the intervention site. The amount of coating tective agent after stroke. A balloon is coated with alternating transferred upon deployment can be determined using, e.g., layers of 50:50 PLGA-Ester End Group (MW-19 kD. deg test methods as described herein. For example, the residual radation rate ~1-2 months) and a neuroprotective drug, e.g., coating on the balloon or the coating within the bladder can be resveratrol, a PARP-1 inhibitor (including imidazoquinoli quantitated. The procedure can be repeated as deemed nec none, imidazpyridine, and isoquinolindione). Resveratrol is essary. an antioxidant that has been shown to preserve mitochondrial 0853. In embodiments of the devices and methods of the function and improve neurological deficits after cerebral invention, the amount of an active agent to be delivered is ischemia that could prove more effective when delivered equal to at least about 35% of that used to coat the balloon. In locally in a controlled fashion than when delivered intrave these embodiments, with regard to intravesical therapy, to nously. The coated balloon is positioned within the vessel deliver a standard dosage of a drug, e.g., 50 mg doxorubicin, near the ischemic site as desired and inflated to at least 25% the coating could comprise 50 mgx(35%)-1, or about 143 mg below its nominal inflation pressure. The balloon is deflated doxorubicin. In related embodiments, layers comprising and removed from the intervention site, allowing the coating about 143 mg doxorubicin are alternated with layers of a to be freed from the surface of the balloon and deposited at the polymer, Such that each doxorubicin layer delivers the appro intervention site. The amount of coating transferred upon priate weekly dose of doxorubicin as dictated by the treat deployment can be determined using, e.g., test methods as ment protocol. Combination treatments are administered, described herein. e.g., by including in the coating layers of additional active 0860 Drug-Delivery Balloon (3) Treatment of Malig agents in the appropriate treatment sequence. nant Glioma 0854 Drug-Delivery Balloon (2) Treatment of a Uri 0861. A coated balloon is used to treat a glioma. Solid nary Tract Transitional Cell Carcinoma paclitaxel, is mixed with polybis(p-carboxyphenoxy) pro 0855. A coated balloon is used to treat a urinary tract pane-sebacic acid copolymer (PCPP-SA) (20:80), synthe transitional cell carcinoma. A balloon is coated with alternat sized, e.g., according to the method of Domb, A. J., and R. ing layers of 50:50 PLGA-Ester End Group (MW-19 kD. Langer (J. Polym. Sci. 25:3373-3386 (1987)), the teachings degradation rate ~1-2 months) and Sufficient active agent to of which are incorporated herein by reference, to give a mix deliver either about 10-40 mg mitomycin C with or without ture containing 0, 20, 30, or 40% paclitaxel by weight. The hyaluronic acid (rHuPH20, total dose 50-100 U), and/or paclitaxel-polymer mixture is dissolved in methylene chlo 10-81 mg bacillus Calmette-Guerin. The coated balloon is ride (Fluka, Switzerland) to give a 10% solution (w:v). The loaded into a Foley-type catheter and the balloon is positioned Solvent is evaporated with a nitrogen stream to yield a dry at a urethral lesion site. The balloon is inflated to at least 25% powder. A compliant or semi-compliant balloon is coated below its nominal inflation pressure. The balloon is deflated with the powder. The coated balloon is inserted into the and removed from the intervention site, allowing the coating glioma using methods known in the art for inserting implants, to be freed from the surface of the balloon and deposited at the e.g., it is inserted following Surgery and resection before the intervention site. The amount of coating transferred upon incision is closed. The balloon is inflated in the space previ deployment can be determined using, e.g., test methods as ously occupied by the tumor, to at least 25% below its nomi described herein. nal inflation pressure. The balloon is deflated and removed from the intervention site, allowing the coating to be freed Example 19 from the surface of the balloon and deposited within the tumor cavity. The amount of coating transferred upon deploy Drug-Delivery Balloon Catheter for Treatment of ment can be determined using, e.g., test methods as described Neurovascular Indications herein. 0856 Drug-Delivery Balloon (1) Treatment of Post 0862 Alternatively, a coated balloon can be inflated Stroke Thrombolysis within a tumor without first performing Surgery. In this case, 0857. A coated balloon is used to treat post-stroke throm a non-compliant or semi-compliant could be used. bolysis. Local delivery of a Sustained treatment can circum 0863 Local delivery of chemotherapeutic agents, and vent the risk associated with infusion of agents in the local polymer selection, are described, e.g., in U.S. Pat. No. 5,626, US 2010/0015200 A1 Jan. 21, 2010

862, “Controlled local delivery of chemotherapeutic agents concentrations of drugs without producing negative side for treating solid tumors, incorporated herein by reference in effects. In a representative example, a balloon is coated with its entirety. alternating layers of 50:50PLGA-Ester End Group (MW-19 0864. The amount of coating transferred upon deployment kD. degradation rate ~1-2 months) and an antibiotic, e.g., can be determined using, e.g., test methods as described erythromycin, TMP-SMX, cephalexin, ciprofloxacin, or herein. nitrofurantoin. The coated balloon is positioned within the 0865 Drug-Delivery Balloon (4) Treatment with a Sta urethra and inflated to at least 25% below its nominal inflation bilizing or Healing Agent After Cerebral Aneurysm pressure. Upon deflation and removal of the balloon from the 0866. A coated balloon is used to administer a stabilizing intervention site, at least about 20% to at least about 40% of or healing agent after cerebral aneurysm, e.g., to prevent the the coating is freed from the surface of the balloon and is vessel from rupturing. A balloon is coated with alternating deposited at the intervention site. The amount of coating layers of 50:50 PLGA-Ester End Group (MW-19 kD. deg transferred upon deployment can be determined using, e.g., radation rate ~1-2 months) and a stabilizing or healing agent, test methods as described herein. In particular examples, the e.g., a polymer matrix (to prevent rupture), doxycyclin (to agent is delivered for at least 3-6 months. accelerate the healing response), or a combination thereof. 0870 For a patient having an indwelling Jureteral stent The coated balloon is positioned at the intervention site and (e.g., triclosan-eluting ureteral stents), a triclosan-eluting inflated to at least 25% below its nominal inflation pressure polymer matrix can be transferred to the stented area, e.g., to The balloon is deflated and removed from the intervention Supplement administration of the triclosan from the Stent. site, allowing the coating to be freed from the surface of the 0871 Treatment and prevention of urinary tract infections balloon and deposited at the intervention site. The amount of has been described in the literature, e.g., by Albert, et al., coating transferred upon deployment can be determined 2004, Antibiotics for preventing recurrent urinary tract using, e.g., test methods as described herein. infection in non-pregnant women. Cochrane Database Syst. 0867 Related information is available in the literature, Rev. 3, CD001209: Borchert, et al., 2008, “Prevention and e.g., in Mocco, et al., March 2009, “Pharos neurovascular treatment of urinary tract infection with probiotics: Review intracranial stent: Elective use for a symptomatic Stenosis and research perspective.” Indian J. Urol. 24(2): 139-144: refractory to medical therapy. Catheter Cardiovasc Interv Salo, et al., 2009, “Biofilm formation by Escherichia coli (Epub): Wang, et al., 2008, “Treatment with melagatran alone isolated from patients with urinary tract infections. Clin or in combination with thrombolytic therapy reduced Nephrol. 71(5): 501-507; Kehinde, et al., 2004, “Bacteriol ischemic braininjury.” Exp Neurol213(1):171-175: Yepes, et ogy of urinary tract infection associated with indwelling J al., 2009, “Tissue-type plasminogen activator in the ischemic ureteral stents. J. Endourol. 18(9):891-896; Cadieux, et al., brain: more than a thrombolytic.” Trends Neurosci 32(1):48 Jun. 19, 2009, “Use of triclosan-eluting ureteral stents in 55; Yousuf, et al., 2009, “Resveratrol exerts its neuroprotec patients with long-term stents. J. Endourol. (Epub). tive effect by modulating mitochondrial dysfunction and 0872 Drug-Delivery Balloon (2) Treatment of a Tubo associated cell death during cerebral ischemia. Brain Res. Ovarian Abcess 1250:242-253; Moroni, et a..., 2009, “Post-ischemic brain 0873. A coated balloon is used to treat a tubo-ovarian damage: targeting PARP-1 within the ischemic neurovascular abcess. A balloon is coated as described herein with alternat units as a realistic avenue to stroke treatment, FEBS J 276 ing layers of 50:50 PLGA-Ester End Group (MW-19 kD. (1):36-45; Eltze, et al., 2008, “Imidazoquinolinone, imida degradation rate ~1-2 months) and an antibiotic agent, e.g., Zopyridine, and isoquinolindione derivatives as novel and clindamycin in combination with gentamycin. The coated potent inhibitors of the poly(ADP-ribose) polymerase balloon is positioned at the intervention site, e.g., within the (PARP): a comparison with standard PARP inhibitors.” Mol fallopian tube, and inflated to at least 25% below its nominal Pharmacol. 74(6):1587-1598: Raganath, et al., Jun. 20, 2009, inflation pressure. The balloon is deflated and removed from “Hydrogel matrix entrapping PLGA-paclitaxel micro the intervention site, allowing the coating to be freed from the spheres: drug delivery with near Zero-order release and surface of the balloon and deposited at the intervention site. implantability advantages for malignant brain tumour.” The amount of coating transferred upon deployment can be Pharm Res (Epub): Kelly, et al., 2008, “Double-balloon trap determined using, e.g., test methods as described herein. The ping technique for embolization of a large wide-necked Supe procedure is repeated as necessary, e.g., to extend treatment rior cerebellar artery aneurysm:case report. NeuroSurgery or to administer a different antibiotic. In an example, the 63(4 Suppl2):291-292. coating is designed to release the agents over a period of at least about two weeks. Example 20 0874 Drug-Delivery Balloon (3) Treatment of Benign Drug-Delivery Device for Urologic and Reproduc Prostatic Hyperplasia tive Care 0875. A coated balloon is used to treat benign prostatic hyperplasia (BPH). A balloon is coated as described herein 0868 Drug-Delivery Balloon (1) Treatment of a Uri with alternating layers of 50:50 PLGA-Ester End Group nary Tract Infection (MW-19 kD. degradation rate ~1-2 months) and an antibiotic 0869. A coated balloon is used to prevent and/or treat a agent combined with an antiinflammatory therapy, e.g., urinary tract infection. Sustained local release of an antibiotic ciprofloxacin and alfuzosin. The coated balloon is inserted agent eliminates the need for systemic treatment that can raise into the prostate tissue through the rectum using a needle and concerns about the development of antibiotic resistance. Fur ultrasound guidance and inflated to at least 25% below its thermore, systemic administration of antibiotic agents is nominal inflation pressure. The balloon is deflated and associated with adverse side effects including gastrointestinal removed from the intervention site, allowing the coating to be upset, and oral and vaginal candidiasis. A drug-releasing freed from the surface of the balloon and deposited at the matrix adhered to the urethral wall could provide high local intervention site. The amount of coating transferred upon US 2010/0015200 A1 Jan. 21, 2010 92 deployment can be determined using, e.g., test methods as release rate. The amount of coating transferred upon deploy described herein. Methods for inserting implants into the ment can be determined using, e.g., test methods as described prostate are known in the art and have been described in, e.g., herein. U.S. Pat. No. 7,442,162, “Method and apparatus for treatment 0884 Response is monitored by methods known to those planning using implanted radioactive seeds. U.S. Pat. No. of skill in the art, e.g., blood estrogen measurement, ultra 7.282,020, “Deflectable implantation device and method of Sound of the ovaries, and measurement of luteinizing hor use.” incorporated herein by reference in their entirety. Meth mone levels. ods for visualizing a treatment area and planning instrument insertion are described, e.g., in U.S. Pat. No. 7,171,255, “Vir Example 21 tual reality3D visualization for surgical procedures” and U.S. Pat. No. 6,610,013, "3D ultrasound-guided intraoperative Drug-Delivery Balloon Catheter for Treatment of prostate brachytherapy, incorporated herein by reference in Infection their entirety. 0876 Drug-Delivery Balloon (4) Hormone Delivery 0885 Drug-Delivery Device—(1) Orthopedic Implant 0877. A coated balloon is used to administer a hormone 0886. A coated balloon is used to treat or prevent staphy vaginally to alleviate the symptoms of menopause. A balloon lococcal infection of an orthopedic implant, either alone or in is coated as described herein with alternating layers of 50:50 conjunction with debridement. A balloon is coated as PLGA-Ester End Group (MW-19 kD. degradation rate ~1-2 described herein with alternating layers of 50:50PLGA-Ester months), and either estrogen (17B-estradiol can be adminis End Group (MW-19 kD. degradation rate ~1-2 months), an tered at about 200 micrograms/day) for administration to a imaging agent, and a combination of the antibiotics ciprof patient not having a uterus, or a combination of estrogen and loxacin and rifampicin. The coated balloon is positioned at progesterone to a patient having an intact uterus. The coated the intervention site, e.g., adjacent to the implant, with or balloon is positioned at the vaginal intervention site and without the aid of imaging guidance, inflated to at least 25% inflated to at least 25% below its nominal inflation pressure. below its nominal inflation pressure, then deflated and The balloon is deflated and removed from the intervention removed. The amount of coating transferred upon deploy site, allowing the coating to be freed from the surface of the ment can be determined using, e.g., test methods as described balloon and deposited at the intervention site. The amount of herein. coating transferred upon deployment can be determined 0887. The procedure is repeated as necessary, e.g., to using, e.g., test methods as described herein. administer multiple treatments around the implant. In an 0878 Drug-Delivery Balloon (5) Contraceptive example, the coating is designed to release the agents over a 0879. A coated balloon is used to administer a hormone period of at least about two weeks. For prophylaxis, the contraceptive. A balloon is coated as described herein with coating is designed to release the agents over a longer period alternating layers of 50:50PLGA-Ester End Group (MW-19 of time, e.g., at least about 1 year and/or longer. When using kD. degradation rate ~1-2 months), and etonogestrelata total the devices and methods of the invention, antibiotic and other dosage sufficient to provide a concentration of about 150 to agents are generally administered to achieve local concentra 900 pg/ml for a period of about 3 years, accounting for the tions comparable to those achieved locally when systemic portion of coating predicted to transfer to the intervention dosages, including IV, SC, or typical oral dosages (e.g., site. rifampicin, 1 coated 450-mg tablet every 12 hours, and cipro 0880. The coated balloon is positioned at the intervention floxacin, 750 mg every 12 hours by mouth) are given. The site, e.g., at a location near or within the reproductive organs, locally-administered dosages are much lower overall than the at an intramuscular location, or at a Subcutaneous location, oral dosages, and better tolerated by patients. inflated to at least 25% below its nominal inflation pressure, 0888 Drug-Delivery Balloon (2) Infection at a Cannu then deflated and removed. In women the drug is adminis lized or Cannulizable Site tered, e.g., at anytime starting on Day 1 of menstrual bleeding 0889. A coated balloon is used to treat or prevent infection and ending on Day 5 or as determined by a physician based on at a cannulized or cannulizable site. A balloon is coated as parameters including release rate. The amount of coating described herein with alternating layers of 50:50PLGA-Ester transferred upon deployment can be determined using, e.g., End Group (MW-19 kD. degradation rate ~1-2 months), an test methods as described herein. Etonogestrel and its use as imaging agent, and an antibiotic, e.g., Vancomycin or cipro a contraceptive via administration to either a male or female floxacin. The coated balloon is deployed through the catheter subject is described, e.g., in U.S. Pat. No. 7.323,454, and positioned within the catheter, with or without the aid of “Etonogestrel esters.” and in the labeling for ImplanonTM imaging guidance, inflated to at least 25% below its nominal etonogestrel implant (Organon USA Inc.). inflation pressure, then deflated and removed. The amount of 0881. Drug-Delivery Balloon (6) Fertility Drug coating transferred upon deployment can be determined 0882. A coated balloon is used to administer a hormone using, e.g., test methods as described herein. contraceptive. A balloon is coated as described herein with 0890. In an example, the coating is designed to release the alternating layers of 50:50PLGA-Ester End Group (MW-19 agents over a period of at least about one week, and/or for as kD. degradation rate ~1-2 months), and clomiphene citrate long as the site is to remain cannulized. In cases where can (Seraphene or Clomid) in an amount sufficient to deliver the nulization time is indefinite, the process can be repeated as equivalent of an oral dosage of 25 milligrams to 150 milli necessary for prevention of new infections, or as new infec grams once a day for five days. tions occur. 0883. The coated balloon is positioned at the intervention site, e.g., at a location near or within the reproductive organs, 0891. In a related example, the devices and methods of the at an intramuscular location, or at a Subcutaneous location, invention are used to percutaneously administer antibiotics at inflated to at least 25% below its nominal inflation pressure, an intervention site within tissue in the vicinity of the infec then deflated and removed. The drug is administered, e.g., tion. early in a woman's menstrual cycle, e.g., days 2 through 6 or 0892 Treatment and prevention of hemodialysis cather as determined by a physician based on parameters including infections is described, e.g., by Saxena, et al., 2005. “Haemo US 2010/0015200 A1 Jan. 21, 2010

dialysis catheter-related bloodstream infections: current tion, characterization of molecular structures, effects of treatment options and strategies for prevention.” Swiss Med bonding, identification of Solid state form, environment and Wkly 135:127-138. stress on a sample. Raman spectra can be collected from a very small volume (<1 um3); these spectra allow the identi Example 22 fication of species present in that volume. Spatially resolved chemical information, by mapping or imaging, terms often Crystallinity of Drug on a Device used interchangeably, can beachieved by Raman microscopy. 0893. The presence and or quantification of the Active 0899 Raman spectroscopy and other analytical tech agent crystallinity can be determined from a number of char niques such as described in Ballss, et al., “Quantitative spatial acterization methods known in the art, but not limited to, distribution of sirolimus and polymers in drug-eluting stents XRPD, vibrational spectroscopy (FTIR, NIR, Raman), polar using confocal Raman microscopy' J. of Biomedical Mate ized optical microscopy, calorimetry, thermal analysis and rials Research Part A, 258-270 (2007), incorporated in its Solid-state NMR. entirety herein by reference, and/or described in Belu et al., X-Ray Diffraction to Determine the Presence and/or Quanti “Three-Dimensional Compositional Analysis of Drug Elut fication of Active Agent Crystallinity ing Stent Coatings. Using Cluster Secondary Ion Mass Spec 0894 Active agent and polymer coated proxy substrates troscopy’ Anal. Chem. 80: 624-632 (2008) incorporated are prepared using 31.6L stainless steel coupons for X-ray herein in its entirety by reference may be used. powder diffraction (XRPD) measurements to determine the 0900 For example, to test a sample using Raman micros presence of crystallinity of the active agent. The coating on copy and in particular confocal Raman microscopy, it is the coupons is equivalent to the coating on the stents understood that to get appropriate Raman high resolution described herein. Coupons of other materials described spectra Sufficient acquisition time, laser power, laser wave herein, such as cobalt-chromium alloys, may be similarly length, sample step size and microscope objective need to be prepared and tested. Likewise, Substrates Such as stents, or optimized. For example a sample (a coated Stent) is prepared other medical devices described herein may be prepared and as described herein. Alternatively, a coated coupon could be tested. Where a coated stent is tested, the stent may be cut tested in this method. Maps are taken on the coating using lengthwise and opened to lay flat in a sample holder. Raman microscopy. A WITec CRM 200 scanning confocal 0895 For example XRPD analyses are performed using Raman microscope using a Nd:YAG laser at 532 nm is an X-ray powder diffractometer (for example, a Bruker D8 applied in the Raman imaging mode. The laser light is Advance X-ray diffractometer) using Cu Ka radiation. Dif focused upon the sample using a 10X dry objective (numerical fractograms are typically collected between 2 and 40 degrees aperture 0.90), and the finely focused laser spot is scanned 2 theta. Where required low background XRPD sample hold into the sample. As the laser scans the sample, over each 0.33 ers are employed to minimize background noise. micron intervala Raman spectrum with high signal to noise is 0896. The diffractograms of the deposited active agent are collected using 0.3 seconds of integration time. Each confo compared with diffractograms of known crystallized active cal cross-sectional image of the coatings displays a region 70 agents, for example micronized crystalline sirolimus in pow um wide by 10 um deep, and results from the gathering of der form. XRPD patterns of crystalline forms show strong 6300 spectra with a total imaging time of 32 min. diffraction peaks whereas amorphous show diffuse and non 0901 Multivariate analysis using reference spectra from distinct patterns. Crystallinity is shown in arbitrary Intensity samples of rapamycin (amorphous and crystalline) and poly units. mer are used to deconvolve the spectral data sets, to provide 0897. A related analytical technique which may also be chemical maps of the distribution. used to provide crystallinity detection is wide angle scattering of radiation (e.g.; Wide Anle X-ray Scattering or WAXS), for Infrared (IR) Spectroscopy for In-Vitro Testing example, as described in F. Unger, et al., “Poly(ethylene (0902 Infrared (IR) Spectroscopy such as FTIR and ATR carbonate): A thermoelastic and biodegradable biomaterial IRare well utilized techniques that can be applied to show, for for drug eluting stent coatings?” Journal of Controlled example, the quantitative drug content, the distribution of the Release, Volume 117, Issue 3,312-321 (2007) for which the drug in the sample coating, the quantitative polymer content technique and variations of the technique specific to a par in the coating, and the distribution of polymer in the coating. ticular sample would be obvious to one of skill in the art. Infrared (IR) Spectroscopy such as FTIR and ATR-IR can similarly be used to show, for example, drug crystallinity. The Raman Spectroscopy following table (Table 2) lists the typical IR materials for 0898 Raman spectroscopy, a vibrational spectroscopy various applications. These IR materials are used for IR win technique, can be useful, for example, in chemical identifica dows, diluents or ATR crystals.

TABLE 2

MATERIAL

NACL KBR CSI AGCL GE ZNSE DIAMOND

Transmission 40,000-625 40,000-400 40,000-200 25,000-360 5,500-625 20,000-454 40,000-2,500 & range (cm-1) 1667-33 Water Sol 35.7 53.5 44.4 Insol. Insol. Insol. Insol. (g 100 g, 25 C.) US 2010/0015200 A1 Jan. 21, 2010

TABLE 2-continued

MATERIAL

NACL KBR CSI AGCL GE ZNSE DIAMOND Attacking Wet Wet Wet Ammonium H2SO4, Acids, K2Cr2Os, materials Solvents Solvents Solvents Salts aqua strong COC. regin alkalies, H2SO4 chlorinated solvents

0903. In one test, a coupon of crystalline ZnSe is coated by 0907. The coating remaining on a device following use of the processes described herein, creating a PDPDP (Polymer, the device may be examined by any of the following test Drug, Polymer, Drug, Polymer) layered coating that is about methods. For example, the coating remaining on a device 10 microns thick. The coated coupon is analyzed using FTIR. following use is an indication of the maximum amount of The resulting spectrum shows crystalline drug as determined coating freed from the device. In an in-vivo or in-vitro by comparison to the spectrum obtained for the crystalline method, an embodiment of the device that is removed from form of a drug standard (i.e. a reference spectrum). the Subject once used is tested for remaining coating (for example, a balloon). Differential Scanning Calorimetry (DSC) Scanning Electron Microscopy (SEM) 0904 DSC can provide qualitative evidence of the crys tallinity of the drug (e.g. rapamycin) using standard DSC (0908 Stents are observed by SEM using a Hitachi S-4800 techniques obvious to one of skilled in the art. Crystalline with an accelerating voltage of 800V. Various magnifications melt can be shown using this analytical method (e.g. rapamy are used to evaluate the integrity, especially at high Strain cin crystalline melting at about 185 decrees C. to 200 regions. SEM can provide top-down and cross-section degrees C., and having a heat of fusion at or about 46.8 J/g). images at various magnifications. Coating uniformity and The heat of fusion decreases with the percent crystallinity. thickness can also be assessed using this analytical technique. Thus, the degree of crystallinity could be determined relative 0909 Pre- and post-expansions stents are observed by to a pure sample, or versus a calibration curve created from a SEM using a Hitachi S-4800 with an accelerating voltage of sample of amorphous drug spiked and tested by DSC with 800V. Various magnifications are used to evaluate the integ known amounts of crystalline drug. Presence (at least) of rity of the layers, especially at high Strain regions. crystalline drug on a stent could be measured by removing Scanning Electron Microscopy (SEM) with Focused Ion (scraping or stripping) Some drug from the stent and testing Beam (FIB) the coating using the DSC equipment for determining the 0910 Stents as described herein, and or produced by melting temperature and the heat of fusion of the sample as methods described herein are visualized using SEM-FIB compared to a known standard and/or standard curve. analysis. Alternatively, a coated coupon could be tested in this method. Focused ion beam FIB is a tool that allows precise Confocal Raman Microscopy site-specific sectioning, milling and depositing of materials. FIB can be used in conjunction with SEM, at ambient or cryo 0905 Confocal Raman Microscopy can provide nonde conditions, to produce in-situ sectioning followed by high structive depth analysis and allows coating specific Raman resolution imaging. Cross-sectional FIB images may be spectral features to be obtained (Bugay et al., “Raman Analy acquired, for example, at 7000x and/or at 20000x magnifica sis of Pharmaceuticals, in “Applications of Vibrational Spec tion. An even coating of consistent thickness is visible. troscopy in Pharmaceutical Research and Development, Ed. Pivonka, D. E., Chalmers, J. M., Griffiths, P. R. (2007) Wiley Optical Microscopy and Sons). In confocal Raman microscopy an aperture is place in a focal place of the collected beam. This limitation 0911. An Optical micrscope may be used to create and defines a shallow portion of the depth of field and thereby inspect the stents and to empirically Survey the coating of the provides definition of the Z-axis spatial resolution for data Substrate (e.g. coating uniformity). Nanoparticles of the drug collection. By adjusting the aperture and moving the focus and/or the polymer can be seen on the surfaces of the substrate within the sample, the sampling position within the sample using this analytical method. Following sintering, the coat moves. Moving the sample focus from the top surface, deeper ings can be see using this method to view the coating confor into the specimen facilitates nondestructive depth analysis. maliy and for evidence of crystallinity of the drug. 0912. In-vitro test: One sample of the coated compliant Example 23 balloon prepared in Example 1 is secured to a balloon cath eter. A segment of optically clear TYGONR) B-44-3 tubing Detection of Coating Remaining on a Device Fol with O.D.—0.125", I.D.—0.0625" (Available from McMaster lowing Use Carr Part Number: 5114K11 (www.mcmaster.com)) is filled with phosphate-buffered saline solution and immersed in a 0906. The ability to uniformly coat a device with con water bath at 37° C. to mimic physiological conditions of trolled composition and thickness using electrostatic capture deployment into a subject. The coated balloon is inserted into in a rapid expansion of supercritical solution (RESS) experi the tubing and the balloon is inflated to at least 25% below the mental series has been demonstrated. balloon's nominal pressure to mechanically transfer the coat US 2010/0015200 A1 Jan. 21, 2010

ing from the balloonto the tubing wall. The balloon is deflated and/or alternatively be used to determine degradation rate of and removed from the tubing. Scanning Electron Microscopy the polymer and/or release rate of the drug from the delivered is performed on the tubing and the balloon (which is inflated coating. to at least 25% below the balloon's nominal pressure, at least) 0920 In-Vivo Test: One sample of the coated compliant to determine the presence and amount of coating transferred balloon prepared in Example 1 is prepared using a coating to the tubing and/or the amount of coating freed, dissociated, comprising a radiolabelled drug. The balloon is secured to a and/or transferred from the balloon. balloon catheter. A segment of optically clear TYGONR) B-44-3 tubing with O.D.—0.125", I.D.—0.0625" (Available Example 24 from McMaster-Carr Part Number: 5114K11 (www.mcmas ter.com)) is filled with phosphate-buffered saline solution and Detection of Coating Freed from a Device Following immersed in a water bath at 37° C. to mimic physiological Use conditions of deployment into a subject. The coated balloon is inserted into the tubing and the balloon is inflated to at least 0913. The ability to uniformly coat a device with con 25% below the balloon's nominal pressure to mechanically trolled composition and thickness using electrostatic capture transfer the coating from the balloon to the tubing wall. The in a rapid expansion of supercritical solution (RESS) experi balloon is deflated and removed from the tubing. The deflated mental series has been demonstrated. balloon is placed into a vial containing Scintillation cocktail, 0914. The amount of coating freed from the device may be inflated to the deployment presure and the amount of radia determined by testing for the amount of coating deposited to tion emitted is determined in a liquid Scintillation counter. the target site. In an in-vivo or in-vitro method, the target site The section of tubing exposed to the balloon is cut away and is tested for coating that is freed from the device, extruded splayed open to expose the interior. The section of tubing is from the device, dissociated from the device, transferred from placed into a vial containing Scintillation cocktail, and the the device, or sheared from the device. amount of radiation emitted is determined in a liquid Scintil Scanning Electron Microscopy (SEM) lation counter. (0915 Stents are observed by SEM using a Hitachi S-4800 Imaging Techniques with an accelerating voltage of 800V. Various magnifications 0921. Use of an imaging agent and/or polymer and/or are used to evaluate the integrity, especially at high Strain coating generally can be employed to monitor amount of regions. SEM can provide top-down and cross-section material freed, dissociated, and/or transferred from the sub images at various magnifications. Coating uniformity and strate, and/or the amount of material transferred to, delivered thickness can also be assessed using this analytical technique. to and/or deposited at the the intervention site. It may also 0916 Pre- and post-expansions stents are observed by and/or alternatively be used to determine degradation rate of SEM using a Hitachi S-4800 with an accelerating voltage of the polymer and/or release rate of the drug from the delivered 800V. Various magnifications are used to evaluate the integ coating. rity of the layers, especially at high Strain regions. 0922. In-Vivo Test: One sample of the coated compliant Scanning Electron Microscopy (SEM) with Focused Ion balloon prepared in Example 1 is prepared using a coating Beam (FIB) comprising a imaging agent Such as barium sulfate. The bal 0917 Stents as described herein, and or produced by loon is secured to a balloon catheter. A segment of optically methods described herein are visualized using SEM-FIB clear TYGONR B-44-3 tubing with O.D.—0.125", I.D.—0. analysis. Alternatively, a coated coupon could be tested in this 0625" (Available from McMaster-Carr Part Number: method. Focused ion beam FIB is a tool that allows precise 5114K11 (www.mcmaster.com)) is filled with phosphate site-specific sectioning, milling and depositing of materials. buffered saline solution and immersed in a water bath at 37° FIB can be used in conjunction with SEM, at ambient or cryo C. to mimic physiological conditions of deployment into a conditions, to produce in-situ sectioning followed by high subject. The coated balloon is inserted into the tubing and the resolution imaging. Cross-sectional FIB images may be balloon is inflated to at least 25% below the balloon's nominal acquired, for example, at 7000x and/or at 20000x magnifica pressure to mechanically transfer the coating from the bal tion. An even coating of consistent thickness is visible. loon to the tubing wall. The balloon is deflated and removed from the tubing. The section of tubing exposed to the balloon Optical Microscopy is cut away and splayed open to expose the interior. The section of tubing is placed into a X-ray fluoroscope, and the 0918. An Optical micrscope may be used to create and amount of coating deposited is determined. inspect the stents and to empirically Survey the coating of the Substrate (e.g. coating uniformity). Nanoparticles of the drug Example 25 and/or the polymer can be seen on the surfaces of the substrate Determination and Detection of Coating Confromal using this analytical method. Following sintering, the coat ity ings can be see using this method to view the coating confor 0923. The ability to uniformly coat devices, e.g., pre- and maliy and for evidence of crystallinity of the drug. post-expansion stents, and balloons, with controlled compo Scintigraphy sition and thickness using electrostatic capture in a rapid expansion of Supercritical solution (RESS) experimental 0919 Use of a radiolabeled drug and/or polymer and/or series has been demonstrated. coating generally can be employed to monitor amount of material freed, dissociated, and/or transferred from the sub Scanning Electron Microscopy (SEM) strate, and/or the amount of material transferred to, delivered 0924 Devices are observed by SEM using a Hitachi to and/or deposited at the the intervention site. It may also S-4800 with an accelerating voltage of 800V. Various mag US 2010/0015200 A1 Jan. 21, 2010 96 nifications are used to evaluate the integrity, especially at high applied in the Raman imaging mode to give X-Z maps. The strain regions. SEM can provide top-down and cross-section sample is placed upon a piezoelectrically driven table, the images at various magnifications. Coating uniformity and laser light is focused upon the sample using a 100x dry thickness can also be assessed using this analytical technique. objective (numerical aperture 0.90), and the finely focused 0925 Pre- and post-inflation balloons, for example, may laser spot is scanned into the sample. As the laser scans the be observed by SEM using a Hitachi S-4800 with an accel sample, over each 0.33 micron interval a Raman spectrum erating voltage of 800V. Various magnifications may be used with high signal to noise is collected using 0.3 Seconds of to evaluate the integrity of the layers, and or of the coating. integration time. Each confocal cross-sectional image of the Scanning Electron Microscopy (SEM) with Focused Ion coatings displays a region 70 um wide by 10 um deep, and Beam (FIB) results from the gathering of 6300 spectra with a total imaging 0926 Devices as described herein, and or produced by time of 32 min. Multivariate analysis using reference spectra methods described herein are visualized using SEM-FIB from Samples of rapamycin and polymer are used to decon analysis. Alternatively, a coated coupon could be tested in this Volve the spectral data sets, to provide chemical maps of the method. Focused ion beam FIB is a tool that allows precise distribution. site-specific sectioning, milling and depositing of materials. 0931. In another test, spectral depth profiles (x-Z maps) of FIB can be used in conjunction with SEM, at ambient or cryo samples are performed with a CRM200 microscope system conditions, to produce in-situ sectioning followed by high from WITec Instruments Corporation (Savoy, Ill.). The resolution imaging. Cross-sectional FIB images may be instrument is equipped with a Nd:YAG frequency doubled acquired, for example, at 7000x and/or at 20000x magnifica laser (532 excitation), a single monochromator (Acton) tion. An even coating of consistent thickness is visible. employing a 600 groove/mm grating and a thermoelectrically cooled 1024 by 128 pixel array CCD camera (Andor Tech Optical Microscopy nology). The microscope is equipped with appropriate col 0927. An optical microscope may be used to create and lection optics that include a holographic laser bandpass rejec inspect the devices and to empirically Survey the coating of tion filter (Kaiser Optical Systems Inc. ) to minimize the Substrate (e.g. coating uniformity). Nanoparticles of the Rayleigh scatter into the monochromator. The Raman scat drug and/or the polymer can be seen on the Surfaces of the tered light are collected with a 50 micron optical fiber. Using Substrate using this analytical method. Following sintering, the "Raman Spectral Imaging” mode of the instrument, spec the coatings can be see using this method to view the coating tral images are obtained by Scanning the sample in the X, Z conformality and for evidence of crystallinity of the drug. direction with a piezo driven xyz scan stage and collecting a spectrum at every pixel. Typical integration times are 0.3 Sper Example 26 pixel. The spectral images are 4800 total spectra correspond ing to a physical scan dimension of 40 by 20 microns. For Visualization of Polymer/Active Agent Layers Coat presentation of the confocal Raman data, images are gener ing a Device Raman Spectroscopy ated based on unique properties of the spectra (i.e. integration 0928. As discussed herein, Raman spectroscopy can be of a Raman band, band height intensity, or band width). The applied to characterize the chemical structure and relative microscope stage is modified with a custom-built sample concentrations of drug and polymer coatings. For example, holder that positioned and rotated the stents around their confocal Raman Spectroscopy/microscopy can be used to primary axis. The X direction is defined as the direction run characterize the relative drug to polymer ratio at the outer ~1 ning parallel to the length of the stent and the Z direction refers um of the coated Surface. In addition confocal Raman X-Z or to the direction penetrating through the coating from the Z (maps or line scans) microscopy can be applied to charac air-coating to the coating-metal interface. Typical laser power terize the relative drug to polymer ratio as a function of depth. is <10 mW on the sample stage. All experiments can be Additionally cross-sectioned samples can be analysed. conducted with a planachromat objective, 100xNA=0.9 (Ni Raman spectroscopy and other analytical techniques such as kon). described in Ballss, et al., “Quantitative spatial distribution of 0932 Samples (n=5) comprising metal substrates made of Sirolimus and polymers in drug-eluting stents using confocal L605 (0.05-0.15% C, 1.00-2.00% Mn, maximum 0.04.0% Si, Raman microscopy' J. of Biomedical Materials Research maximum 0.030% P. maximum 0.3% S, 19.00-21.00% Cr, Part A, 258-270 (2007), incorporated in its entirety herein by 9.00-11.00% Ni, 14.00-16.00% W, 3.00% Fe, and Bal. Co) reference, and/or described in Belu etal, “Three-Dimensional and having coatings as described herein and/or produced by Compositional Analysis of Drug Eluting Stent Coatings methods described herein can be analyzed. For each sample, Using Cluster Secondary Ion Mass Spectroscopy’ Anal. three locations are selected along the Substrate length. The Chem. 80: 624-632 (2008) incorporated herein in its entirety three locations are located within one-third portions of the by reference may be used. substrates so that the entire length of the substrate are repre 0929. A sample (a coated substrate) is prepared as sented in the data. The stent is then rotated 180 degrees described herein. Images are taken on the coating using around the circumference and an additional three locations Raman Spectroscopy. Alternatively, a coated coupon could be are sampled along the length. In each case, the data is col tested in this method. To test a sample using Raman micros lected from the strut portion of the substrate. Six random copy and in particular confocal Raman microscopy, it is spatial locations are also profiled on coated coupon samples understood that to get appropriate Raman high resolution made of L605 and having coatings as described herein and/or spectra Sufficient acquisition time, laser power, laser wave produced by methods described herein. The Raman spectra of length, sample step size and microscope objective need to be each individual component present in the coatings are also optimized. collected for comparison and reference. Using the instrument 0930 For example a WITec CRM 200 scanning confocal Software, the average spectra from the spectral image data are Raman microscope using a Nd:YAG laser at 532 nm is calculated by selecting the spectral image pixels that are US 2010/0015200 A1 Jan. 21, 2010 97 exclusive to each layer. The average spectra are then exported balloon is then pressed into multiple layers of indium foil with into GRAMS/AI v. 7.02 software (Thermo Galactic) and the the outer diameter facing outward. appropriate Raman bands are fit to a Voigt function. The band (0940 TOF-SIMS depth profiling experiments are per areas and shift positions are recorded. formed using an Ion-TOF IV instrument equipped with both 0933. The pure component spectrum for each component Bi and SF5+ primary ion beam cluster sources. Sputter depth of the coating (e.g. drug, polymer) are also collected at 532 profiling is performed in the dual-beam mode, whilst preserv and 785 nm excitation. The 785 nm excitation spectra are ing the chemical integrity of the sample. The analysis source collected with a confocal Raman microscope (WITec Instru is a pulsed, 25-keV bismuth cluster ion source, which bom ments Corp. Savoy, Ill.) equipped with a 785 nm diode laser, barded the surface at an incident angle of 45° to the surface appropriate collection optics, and a back-illuminated thermo normal. The target current is maintained at -0.3 pA (+10%) electriacly cooled 1024x128 pixel array CCD camera opti pulsed current with a raster size of 200 umx200 um for all mized for visible and infrared wavelengths (Andor Technol experiments. Both positive and negative secondary ions are ogy). extracted from the sample into a reflectron-type time-of-flight mass spectrometer. The secondary ions are then detected by a X-ray Photoelectron Spectroscopy (XPS) microchannel plate detector with a post-acceleration energy of 10 kV. A low-energy electron flood gun is utilized for 0934 XPS can be used to quantitatively determine charge neutralization in the analysis mode. elemental species and chemical bonding environments at the 0941 The sputter source used is a 5-keV SF5+ cluster outer 5-10 nm of sample surface. The technique can be oper Source also operated at an incident angle of 45° to the Surface ated in spectroscopy or imaging mode. When combined with normal. For thin model samples on Si, the SF5+ current is a sputtering source XPS can be utilized to give depth profiling maintained at ~2.7 nA with a 750 umx750 um raster. For the chemical characterization. XPS (ESCA) and other analytical thick samples on coupons and for the samples on Stents, the techniques such as described in Belu et al., “Three-Dimen current is maintained at 6nA with a 500umx500um raster. All sional Compositional Analysis of Drug Eluting Stent Coat primary beam currents are measured with a Faraday cup both ings. Using Cluster Secondary Ion Mass Spectroscopy Anal. prior to and after depth profiling. Chem. 80: 624-632 (2008) incorporated herein in its entirety 0942 All depth profiles are acquired in the noninterlaced by reference may be used. mode with a 5-ms pause between sputtering and analysis. 0935 For example, in one test, a sample comprising a stent Each spectrum is averaged over a 7.37 second time period. coated by methods described herein and/or a device as The analysis is immediately followed by 15 seconds of SF5+ described herein is obtained. XPS analysis is performed on a sputtering. For depth profiles of the surface and subsurface sample using a Physical Electronics Quantum 2000 Scanning regions only, the Sputtering time was decreased to 1 second ESCA. The monochromatic Al KC. source is operated at 15 for the 5% active agent sample and 2 seconds for both the 25% kV with a power of 4.5 W. The analysis is done at a 45° take and 50% active agent samples. off angle. Three measurements are taken along the length of 0943 Temperature-controlled depth profiles are obtained each sample with the analysis area ~20 microns in diameter. using a variable-temperature stage with Eurotherm Controls Low energy electron and Arion floods are used for charge temperature controller and IPSG V3.08 software. samples are compensation. first placed into the analysis chamber at room temperature. The samples are brought to the desired temperature under Time of Flight Secondary Ion Mass Spectrometery (TOF ultra high-vacuum conditions and are allowed to stabilize for SIMS) 1 minute prior to analysis. All depth profiling experiments are performed at -100C and 25 C. 0936 TOF-SIMS can be used to determine molecular spe cies (drug and polymer) at the outer 1-2 nm of sample Surface Atomic Force Microscopy (AFM) when operated under static conditions. The technique can be 0944 AFM is a high resolution surface characterization operated in spectroscopy or imaging mode at high spatial technique. AFM is used in the art to provide topographical resolution. Additionally cross-sectioned samples can be imaging, in addition when employed in Tapping ModeM can analysed. When operated under dynamic experimental con image material and or chemical properties of the Surface. ditions, known in the art, depth profiling chemical character Additionally cross-sectioned samples can be analyzed. The ization can be achieved. technique can be used under ambient, Solution, humidified or 0937 For example, to analyze the uppermost surface only, temperature controlled conditions. Other modes of operation static conditions (for example a Tof-SIMS IV (IonToF, Mun are well known and can be readily employed here by those ster)) using a 25KV Bi---- primary ion Source maintained skilled in the art. below 1012 ions per cm2 is used. Where necessary a low 0945. A substrate having a coating as described herein is energy electron flood gun (0.6 nA DC) is used to charge obtained. AFM is used to determine the structure of the drug compensate insulating samples. polymer layers. AFM may be employed as described in 0938 Cluster Secondary Ion Mass Spectrometry, may be Ranade et al., “Physical characterization of controlled release employed for depth profiling as described Belu et al., “Three of paclitaxel from the TAXUS Express2 drug-eluting stent J. Dimensional Compositional Analysis of Drug Eluting Stent Biomed. Mater. Res. 71(4):625-634 (2004) incorporated Coatings Using Cluster Secondary Ion Mass Spectroscopy' herein in its entirety by reference. Anal. Chem. 80: 624-632 (2008) incorporated herein in its 0946 Polymer and drug morphologies, coating composi entirety by reference. tion, at least may be determined using atomic force micros 0939 For example, a ballon coated as described herein is copy (AFM) analysis. A multi-mode AFM (Digital Instru obtained. The balloon is prepared for SIMS analysis by cut ments/Veeco Metrology, Santa Barbara, Calif.) controlled ting it longitudinally and opening it up with tweezers. The with Nanoscope IIIa and NanoScope Extender electronics is US 2010/0015200 A1 Jan. 21, 2010

used. Samples are examined in the dry state using AFM Mixtures but Not in Pure Organic Solvents' J. Am Chem. before elution of the drug (e.g. rapamycin). Samples are also Soc., Vol 118, No. 47, 11695-1 1700 (1996). examined at select time points through a elution period (e.g. 48 hours) by using an AFM probe-tip and flow-through stage Infrared (IR) Spectroscopy for In-Vitro Testing built to permit analysis of wet samples. The wet samples are examined in the presence of the same elution medium used 0951) Infrared spectroscopy, for example FTIR, ATR-IR for in-vitro kinetic drug release analysis (e.g. PBS-Tween20, and micro ATR-IR can be employed to determine secondary or 10 mM Tris, 0.4 wt.% SDS, pH 7.4). Saturation of the structure of a biological Agent. For example fitting of the Solution is prevented by frequent exchanges of the release Amide I, II, of III regions of the infrared spectrum can eluci medium with several Volumes of fresh medium. Tapping date secondary structures (e.g. alpha-helices, beta-sheets). Model M AFM imaging may be used to show topography (a real-space projection of the coating Surface microstructure) Example 28 and phase-angle changes of the AFM over the sample area to contrast differences in the materials properties. The AFM Determination of the Microstructure of a Coating on topography images can be three-dimensionally rendered to a Medical Device Atomic Force Microscopy (AFM) show the surface of a coated stent, which can show holes or Voids of the coating which may occur as the polymer is 0952 AFM is a high resolution surface characterization absorbed and the drug is eluted over time, for example. technique. AFM is used in the art to provide topographical (0947 Scanning Electron Microscopy (SEM) with imaging, in addition when employed in Tapping ModeM can Focused Ion Beam (FIB) Milling Coatings on substrates as image material and or chemical properties of the Surface. described herein, and or produced by methods described Additionally cross-sectioned samples can be analyzed. The herein are visualized using SEM-FIB. Alternatively, a coated technique can be used under ambient, Solution, humidified or coupon could be tested in this method. Focused ion beam FIB temperature controlled conditions. Other modes of operation is a tool that allows precise site-specific sectioning, milling are well known and can be readily employed here by those and depositing of materials. FIB can be used in conjunction skilled in the art. with SEM, at ambient or cryo conditions, to produce in-situ 0953. A device as described herein is obtained. AFM is sectioning followed by high-resolution imaging. FIB -SEM used to determine the microstructure of the coating. A stent as can produce a cross-sectional image of the polymer and drug described herein is obtained. AFM may be employed as layers on the substrate. The image can be used to quantitate described in Ranade et al., “Physical characterization of con the thickness of the layers and uniformity of the layer thick trolled release of paclitaxel from the TAXUS Express2 drug ness at manufacture and at time points after stenting (or after eluting stent” J. Biomed. Mater. Res. 71 (4):625-634 (2004) in-vitro elution at various time points). incorporated herein in its entirety by reference. (0948. A FEI Dual Beam Strata 235 FIB/SEM system is a 0954 For example, polymer and drug morphologies, coat combination of a finely focused Gaion beam (FIB) acceler ing composition, and physical structure may be determined ated by 30 kV with a field emission electron beam in a scan using atomic force microscopy (AFM) analysis. A multi ning electron microscope instrument and is used for imaging mode AFM (Digital Instruments/Veeco Metrology, Santa and sectioning the stents. Both beams focus at the same point Barbara, Calif.) controlled with Nanoscope IIIa and Nano of the sample with a probe diameter less than 10 nm. The FIB Scope Extender electronics is used. Samples are examined in can also produce thinned down sections for TEM analysis. the dry state using AFM before elution of the drug (e.g. 0949. To prevent damaging the surface of the substrate rapamycin). Samples are also examined at select time points with incidentions, a Pt coating is first deposited via electron through a elution period (e.g. 48 hours) by using an AFM beam assisted deposition and ion beam deposition prior to probe-tip and flow-through stage built to permit analysis of FIB sectioning. For FIB sectioning, the Gaion beam is accel wet samples. The wet samples are examined in the presence erated to 30 kV and the sectioning process is about 2 h in of the same elution medium used for in-vitro kinetic drug duration. Completion of the FIB sectioning allows one to release analysis (e.g. PBS-Tween20, or 10 mM Tris, 0.4 wt.% SDS, pH 7.4). Saturation of the solution is prevented by observe and quantify by SEM the thickness of the polymer frequent exchanges of the release medium with severl Vol layers that are, for example, left on the substrate as they are umes of fresh medium. TappingModel M AFM imaging may absorbed. be used to show topography (a real-space projection of the coating Surface microstructure) and phase-angle changes of Example 27 the AFM over the sample area to contrast differences in the materials properties. The AFM topography images can be Determination of Secondary Structures Presence of a three-dimensionally rendered to show the surface of a coated Biological Agent Raman Spectroscopy stent, which can show holes or Voids of the coating which may occuras the polymer is absorbed and the drug is released from 0950 FT-Raman or confocal raman microscopy can be the polymer over time, for example. employed to determine secondary structure of a biological Agent. For example fitting of the Amide I, II, or III regions of Nano X-Ray Computer Tomography the Raman spectrum can elucidate secondary structures (e.g. alpha-helices, beta-sheets). See, for example, Iconomidou, et 0955. Another technique that may be used to view the al., “Secondary Structure of Chorion Proteins of the Teleo physical structure of a device in 3-D is Nano X-Ray Com setan Fish Dentex dentex by ATR FR-IR and FT-Raman Spec puter Tomography (e.g. Such as made by SkyScan), which troscopy”.J. of Structural Biology, 132, 112-122 (2000); Grie could be used in an elution testand/or bioabsorbability test, as benow, et al., “On Protein Denaturation in Aqueous-Organic described herein to show the physical structure of the coating US 2010/0015200 A1 Jan. 21, 2010 99 remaining on Substrates at each time point, as compared to a 3. A medical device comprising: scan prior to elution/bioabsorbtion. a Substrate; and a coating on at least a portion of said Substrate, Example 29 wherein said coating comprises an active agent, and wherein the device is adapted to free greater than 35% of Determination of the Total Content of the Active the coating from the Substrate upon a single stimulation Agent (and/or the Content of Active Agent Remain of the coating. ing on a Device Following an Intervention) 4. A medical device comprising: 0956 Determination of the total content of the active agent a Substrate; and in a coated Substrate may be tested using techniques a coating on at least a portion of said Substrate, described herein as well as other techniques obvious to one of wherein said coating comprises an active agent, skill in the art, for example using GPC and HPLC techniques wherein the coating is patterned, and to extract the drug from the coated substrate and determine wherein at least a portion of the coating is adapted to free the total content of drug in the sample. from the Substrate upon stimulation of the coating. 0957. UV-VIS can be used to quantitatively determine the 5. A medical device comprising: mass of rapamycin (or another active agent) coated onto the a Substrate; and substrates. A UV-Vis spectrum of Rapamycin can be shown a coating on at least a portion of said Substrate, and a Rapamycin calibration curve can be obtained, (e.g. wherein the coating comprises a plurality of layers, (a 277 nm in ethanol). Rapamycin is then dissolved from the wherein at least one layer comprises an active biological coated Substrate in ethanol, and the drug concentration and agent, and mass calculated. wherein the device is adapted to free at least a portion of the 0958. In one test, the total amount of rapamycin (or coating from the Substrate upon stimulation of the coat another active agent) present in units of micrograms per Sub ing. strate is determined by reverse phase high performance liquid 6. The device of any of claims 1-2, wherein the crystalline chromatography with UV detection (RP-HPLC-UV). The pharmaceutical agent is not a microcapsule. analysis is performed with modifications of literature-based 7. The device of any of claims 3, wherein the stimulation HPLC methods for rapamycin (or the other active agent) that lasts at most 20 seconds. would be obvious to a person of skill in the art. The average 8. The device of any claims of 4, wherein the patterned drug content of samples (n=10) from devices comprising coating comprises at least two different shapes. stents and coatings as described herein, and/or methods 9. The device of claim 5, wherein the active biological described herein are tested. agent comprises an active secondary, tertiary or quaternary 0959. The foregoing is illustrative of the present invention, Structure. and is not to be construed as limiting thereof. While embodi 10. The device of claim 5, wherein the active biological ments of the present invention have been shown and agent comprises growth factors, cytokines, peptides, pro described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. teins, enzymes, glycoproteins, nucleic acids, antisense Numerous variations, changes, and Substitutions will now nucleic acids, fatty acids, antimicrobials, vitamins, hor occur to those skilled in the art without departing from the mones, steroids, lipids, polysaccharides, carbohydrates, a invention. It should be understood that various alternatives to hormone, genetherapies, RNA, siRNA, and/or cellular thera the embodiments of the invention described herein may be pies such as stem cells and/or T-cells. employed in practicing the invention. It is intended that the 11. The device of any of claims 1-5, wherein the substrate following claims define the scope of the invention and that comprises a balloon. methods and structures within the scope of these claims and 12. The device of one of claims 1-5, wherein the coating their equivalents be covered thereby. comprises at least one of a non-absorbable polymer and a bioabsorbable polymer. 13. The device of claim 1-2, wherein the pharmaceutical 1. A medical device comprising: agent and a polymer are in the same layer, in separate layers, a Substrate; and or form overlapping layers. a coating on at least a portion of said Substrate, 14. The device of claim 1, wherein the plurality of layers wherein the coating comprises a plurality of layers, comprise five layers deposited as follows: a first polymer wherein at least one layer comprises a pharmaceutical layer, a first pharmaceutical agent layer, a second polymer agent that is crystalline, and layer, a second pharmaceutical agent layer and a third poly wherein the device is adapted to free at least a portion of the mer layer. coating from the Substrate upon stimulation of the coat 15. The device of claim 5, wherein the plurality of layers ing. comprise five layers deposited as follows: a first polymer 2. A medical device comprising: layer, a first active biological agent layer, a second polymer a Substrate; and layer, a second active biological agent layer and a third poly a coating on at least a portion of said Substrate, mer layer. wherein said coating is at least partially continuous, has at 16. A method comprising: least one portion conformal to the Substrate, and com providing a medical device, wherein the medical device prises a pharmaceutical agent that is crystalline, and comprises a Substrate and a coating on at least a portion wherein the device is adapted to free at least a portion of the of said Substrate, and wherein the coating comprises a coating from the Substrate upon stimulation of the coat plurality of layers, wherein at least one layer comprises 1ng. a pharmaceutical agent that is crystalline, and