US 2006001.3853A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0013853 A1 Richard (43) Pub. Date: Jan. 19, 2006

(54) MEDICAL DEVICES HAVING CONDUCTIVE Publication Classification SUBSTRATE AND COVALENTLY BONDED COATING LAYER (51) Int. Cl. A6IF 2100 (2006.01) (76) Inventor: Robert E. Richard, Wrentham, MA (52) U.S. Cl...... 424/423 (US) (57) ABSTRACT Correspondence Address: MAYER, FORTKORT & WILLIAMS, PC The present invention provides a medical device comprising 251 NORTHAVENUE WEST an electrically conductive Substrate and a coating layer that 2ND FLOOR covers at least a portion of the electrically conductive WESTFIELD, NJ 07090 (US) Substrate, wherein the coating layer comprises a polymer that is made by a process that comprises (a) electrochemi cally linking a initiator to a Surface of the electrically (21) Appl. No.: 10/894,391 conductive Substrate and (b) conducting a free radical poly merization reaction in the presence of one or more free (22) Filed: Jul. 19, 2004 radical polymerizable monomers. Patent Application Publication Jan. 19, 2006 Sheet 1 of 2 US 2006/0013853 A1

O E. O d

s O On 8 S. C ATRP of styrene

PS-1a(C

FIG 1 Patent Application Publication Jan. 19, 2006 Sheet 2 of 2 US 2006/0013853 A1

US 2006/OO13853 A1 Jan. 19, 2006

MEDICAL DEVICES HAVING CONDUCTIVE they may lack mechanical integrity Since they envelop the SUBSTRATE AND COVALENTLY BONDED device, but do not necessarily chemically adhere to it. COATING LAYER Another potential drawback is that Spray coatings and dip coatings are physical, rather than chemical, coatings. FIELD OF THE INVENTION Because they rely upon the Spray or dip equipment and not 0001. The present invention relates generally to medical upon chemical interactions at a molecular level for control devices which contain polymeric Surface coatings. The ling the coating process, precision in terms of thickneSS and present invention also relates to methods for producing conformity with the substrate surface has been difficult to covalently bonded polymeric coatings for medical devices, achieve with these techniques. particularly for insertable or implantable medical devices. 0006 Attempts have been made to address the poor adhesion problem, including first coating the metal Surface BACKGROUND OF THE INVENTION with one or more “primer layers,” followed by application of the polymeric coating of interest. One obvious disadvantage 0002) Numerous polymer-based medical devices have of Such a primer is that it introduces another layer which been developed for the delivery of therapeutic agents to the does not aid, and may even hinder, the drug delivery body. In accordance with Some typical delivery Strategies, a functions of the polymeric coating. In addition, the polymers therapeutic agent is provided within a polymeric carrier or materials Suitable for use as a primer layer may not layer and/or beneath a polymeric barrier layer that is asso necessarily possess the desired mechanical or biocompatible ciated with a medical device. Once the medical device is characteristics, and thus the range of materials that may be placed at the desired location within a patient, the therapeu utilized as part of a coating System for a medical device may tic agent is released from the medical device at a rate that is dependent upon the nature of the polymeric carrier and/or be limited. barrier layer. 0007. In view of the above, it would be advantageous to provide coatings that have desirable biostability and/or 0003. Materials which are suitable for use in making biocompatibility properties, while also having improved implantable or insertable medical devices typically exhibit one or more of the qualities of exceptional biocompatibility, mechanical properties. It would also be desirable to provide extrudability, elasticity, moldability, good fiber forming tenacious coatings which exhibit improved adhesion to the properties, tensile Strength, durability, and the like. More Surfaces of common medical device Substrates. over, the physical and chemical characteristics of the device materials can play an important role in determining the final SUMMARY OF THE INVENTION release rate of the therapeutic agent. 0008. These and other challenges of the prior art are 0004. As a specific example, block copolymers of poly addressed by the present invention which provides a medical isobutylene and polystyrene, for example, polystyrene-poly device comprising an electrically conductive Substrate and a isobutylene-polystyrene triblock copolymers (SIBS copoly coating layer that covers at least a portion of the electrically mers), which are described in U.S. Pat. No. 6,545,097 to conductive Substrate. The coating layer comprises a poly Pinchuk et al., hereby incorporated by reference in its mer, which is made by a process that comprises (a) electro entirety, have proven valuable as release polymers in chemically linking a free radical polymerization initiator to implantable or insertable drug-releasing medical devices. AS a Surface of the electrically conductive Substrate and (b) described in Pinchuk et al., the release profile characteristics conducting a free radical polymerization reaction in the of therapeutic agents Such as paclitaxel from SIBS copoly presence of one or more free radical polymerizable mono mer Systems demonstrate that these copolymers are effective CS. drug delivery Systems for providing therapeutic agents to 0009. The present invention is advantageous in that Sites in Vivo. These copolymers are particularly useful for coated medical devices are provided in which the coating is medical device applications because of their excellent covalently bonded to the surface of the medical device, Strength, biostability and biocompatibility, particularly thereby providing a strong, conformal coating. within the vasculature. For example, SIBS copolymers exhibit high tensile Strength, which frequently ranges from 0010 Another advantage of the present invention is that 2,000 to 4,000 psi or more, and resist cracking and other implantable or insertable medical devices are provided, forms of degradation under typical in Vivo conditions. which result in controlled release of a therapeutic agent. Biocompatibility, including vascular compatibility, of these 0011 Yet another advantage of the present invention is materials has been demonstrated by their tendency to pro that methods of coating medical devices are provided which voke minimal adverse tissue reactions (e.g., as measured by avoid various limitations of Standard dip and Spray coating reduced macrophage activity). In addition, these polymers proceSSeS. are generally hemocompatible as demonstrated by their ability to minimize thrombotic occlusion of small vessels 0012. These and other embodiments and advantages of when applied as a coating on coronary Stents. the present invention will become immediately apparent to those of ordinary skill in the art upon review of the Detailed 0005 Currently, technologies used to prepare coatings on Description and claims to follow. medical devices having metal Surfaces, which are typical of coronary Stents and many other medical devices, include BRIEF DESCRIPTION OF THE DRAWINGS Spray and dip coating. While these processes are capable of producing effective coatings, there is a need for a more 0013 FIG. 1 schematically illustrates a two-step process efficient and precise coating method. One major drawback of for the grafting of polystyrene to an electrically conducting the coatings produced using these prior art methods is that Substrate. US 2006/OO13853 A1 Jan. 19, 2006

0.014 FIG. 2 is an SEM image of polystyrene grafted to more polymers and is made by a process that includes (a) a Steel Substrate Surface. electrochemically linking an initiator to a Surface of the electrically conductive Substrate and (b) conducting a free DETAILED DESCRIPTION OF THE radical polymerization reaction in the presence of a free INVENTION radical polymerizable monomer, or two or more free radical polymerizable comonomers. 0.015 The present invention relates to medical devices having polymeric coating layers wherein covalent bonds 0019. The technology for linking the initiator to the exist at the interfaces between the coating layers and the electrically conductive Surface, for example, a StainleSS Steel substrates on which they are formed, and to methods for Surface, includes electrografting processes Such as those producing Such coating layers. Specifically, the present disclosed by Claes et al., Polymer Coating of Steel by a invention relates to processes for chemically linking (e.g., Combination of Electrografiing and Atom-Transfer Radical covalently bonding) a polymer to a Substrate Such as an Polymerization, Macromolecules, Web release No. electrically conductive Substrate (e.g., a metal Surface) by 0217130, published Jul. 19, 2003, the contents of which are electrochemically attaching an initiator Species to the Sub hereby incorporated by reference in their entirety. Strate followed by a monomer polymerization reaction Such 0020. The usually weak and short-term adhesion between as atom-transfer radical polymerization (ATRP). The pro organic polymers and radically different materials. Such as ceSSes of the present invention can be used for a number of metals, glass, and carbon have presented Special challenges purposes, including the preparation of passive device coat in formulating Suitable coatings. For example, proper adhe ings, hydrophilic device coatings, and device coatings that Sion of the polymer to a medical device having a metallic can be loaded with one or more therapeutic agents for in Situ Surface (e.g., a coronary Stent) can often be one of the most delivery of the agent after implantation within a patient. important factors in the Successful implementation of a 0016 For purposes of clarity, as used herein, polymers medical device. are molecules containing one or more chains, which contain 0021. The electrografting method overcomes this and multiple copies of one or more constitutional units. An other challenges by forming a tenacious chemical link example of a common polymer is polystyrene between a functional group of an initiator and the metal atoms of a Substrate Such as Stainless Steel. The electrograft ing processes comprises applying an electric potential to the electrically conductive Substrate in the presence of the -the-h- initiator, with the ensuing reaction, for example, a reduction reaction, creating a link between the initiator and the Sub strate. Such a link establishes a covalent bond at the Sub Strate Surface Such that a strong adhesion is established between the resulting polymeric coating and the Substrate Surface. The final polymer coating may be formed by where n is an integer, typically an integer of 10 or more, polymerization according to various known polymerization more typically on the order of 10's, 100's, 1000's or even methods, including atom-transfer radical polymerization more, in which the constitutional units in the chain corre (ATRP), among others. spond to Styrene monomers: 0022. Examples of some suitable substrates for the prac tice of the present invention include but is not limited to, electrically conductive Substrates comprising an elemental transition metal or alloy, including metals. Such as copper, nickel, tantalum, Silver, gold, platinum, palladium, iridium, oSmium, rhodium, titanium, tungsten, ruthenium and metal alloys Such as iron-chromium alloys (e.g., stainless Steel, which typically contains at least 50% iron and at least 11.5% chromium), nickel-titanium alloys, nickel-chromium alloys (e.g., INCONEL(R) alloys), cobalt chromium alloys, plati num-enriched Stainless Steel or combinations of two or more (i.e., they originate from, or have the appearance of origi metals or metal alloys. nating from, the polymerization of Styrene monomers in this case, the addition polymerization of Styrene monomers). AS 0023 Not all of the electrically conductive substrate used herein, copolymers are polymers that contain at least needs to be conductive, but rather only those portions to two dissimilar constitutional units. which it is desired to attach the initiator. Hence, the con ductive Substrate can be, for example, a Solid metal Sub 0.017. As used herein, a polymer “block” is a grouping of Strate, a non-conductive Substrate having a metallic coating, 10 or more constitutional units, commonly 20 or more, 50 or and so forth. more, 100 or more, 200 or more, 500 or more, or even 1000 0024. In general, the initiator will have at least one or more units. A “chain” is a linear (unbranched) grouping functionality that is conducive to electrografting and at least of 10 or more constitutional units (i.e., a linear block). one functionality that is able to initiate free radical poly 0.018. In one aspect, the invention provides a medical merization (e.g., an activated halide functionality, which is device that comprises a Substrate, preferably an electrically able to initiate ATRP polymerization of, for example, vinyl conductive Substrate, and a coating layer that covers at least monomers). One specific example is 2-chloropropionate a portion of the Substrate. The coating layer contains one or ethyl acrylate (cPEA). US 2006/OO13853 A1 Jan. 19, 2006

0.025 In some embodiments, the initiator is a polymeric variety of functional groups (e.g., alcohol, amine, carboxy macro-initiator, e.g., a polymeric macro-initiator containing lic, acid, Sulfonate), a combination of electrografting with at least one functionality that is conducive to electrografting Subsequent ATRP is preferred in many embodiments. ATRP and at least one further functionality that is able to initiate and the other polymerization methods described herein are free radical polymerization such as ATRP. In some embodi well-detailed in the literature and are described, for example, ments, the initiator comprises an electrochemically linkable in an article by Pyun and Matyjaszewski, “Synthesis of group comprising any alkyl halide with one or more acti Nanocomposite Organic/Inorganic Hybrid Materials. Using vating groups on the C. carbon (Such as aryl, carbonyl, allyl, Controlled/“Living” Radical Polymerization,” Chem. Mater, and the like). Also, the initiator may comprise a polyhalo 13:3436-3448 (2001), the contents of which are incorpo genated compound or compounds with a weak R-Xbond rated by reference in their entirety. such as N-X, S-X, or O-X, where X is a halogen atom, 0030) In polymerizations of a monomer (M, in scheme Such as fluorine, chlorine, bromine, iodine, etc. Examples below) via ATRP, radicals are generated by the redox include polymers of cpA, copolymers of cFEA (e.g., reaction of organic halides Such as alkyl halides (RX, in polycPEA-co-ethyl acrylate), cpEA-terminated poly(alky scheme below) with transition-metal complexes (Met", in lacrylates), and other polymers containing an activated Scheme below). Radicals can then propagate, but are rapidly halide functionality, which are capable of being electro deactivated by the oxidized form of the transition-metal chemically grafted to a conductive Substrate. catalyst. The initiators typically used are haloesters (e.g., 0026. In some embodiments, a difunctional free radical 1-butyl chloropropionate, 2-chloropropionate ethyl acrylate, initiator Such as dimethyl-2,6-heptanedioate is used to ini ethyl 2-boroisobutyrate and methyl 2-bromopropionate), or tiate polymerization (e.g., of a alkyl acrylate monomer Such benzyl halides (e.g., 1-phenylethyl bromide and benzyl as ethyl acrylate), thereby forming a polyacrylate macro bromide). A wide range of transition-metal complexes, Such initiator having a functionality (e.g., an acrylate functional as Ru- (e.g., Grubbs catalyst), Cu-, and Fe-based systems are ity) that can form a covalent bond with a conductive employed in ATRP. For Cu-based systems, ligands such as Substrate Surface. 2,2'-bipyridine and aliphatic amines are typically employed to control both the solubility and activity of various ATRP 0.027 AS previously noted, the initiator is chemically catalysts. A typical ATRP mechanism is illustrated by the linked to an electrochemically conductive Substrate Surface following Scheme: (e.g., a stainless Steel Surface) by electrografting the initiator to the Substrate Surface, thereby forming a covalent bond between the Substrate Surface and the initiator. For example, Initiation R* + Mett (n+1)X in certain preferred embodiments, the initiator is a poly(2- RX -- Met Her chloropropionate ethyl acrylate) macro-initiator, which is Alkyl Synthesized using known methods. In addition to bearing an Halide, Metal M acrylate functional group that is amenable to electrografting, Initiator in the molecule also possesses an activated chloride that is able to initiate the controlled radical polymerization of mono R-MX + Mettm -- R-M + Mett (n+1)X mers such as vinyl monomers by ATRP. An exemplary x M Scheme for the grafting of polystyrene onto an electrically Propagation conductive Substrate, and as published in Claes et al., cited X above, is illustrated in FIG. 1. Upon application of an electric potential, electroreduction of the acrylate occurs at | | the electrically conductive Surface, which Serves in this instance as a cathode, leading to the rapid formation of a film on the same. Poly(2-chloropropionate ethyl acrylate), elec trografted on Steel which is a non-noble metal, forms a 0031. Using these and other techniques described herein, strongly adhering macro-initiator for the ATRP of a mono a variety of polymerS may be chemically bonded to con mer Such as Styrene or other vinyl monomer. ductive medical device Surfaces, depending on the goal to be 0028. Once electrochemically attached, initiators such as achieved. For example, a polymer may be chosen to impart those described above can be used to Synthesize a variety of Specific properties of the medical device, e.g., to render the polymers according to various known methods, including Surface more hydrophilic or hydrophobic, to render the ionic and various radical polymerization methods Such as Surface adhesive or reduce friction during implantation or aZobis(isobutyronitrile)- or peroxide-initiated processes, delivery, to render the Surface biocompatible or passive, to controlled/living radical polymerizations Such as atom make the Surface more resistant to environmental or bio transfer radical polymerization (ATRP), stable free-radical logical attack, to release a therapeutic agent from the Sur polymerization (SFRP), nitroxide-mediated processes face, and So forth. (NMP), and degenerative transfer (e.g., reversible addition 0032. The polymers that may be employed include fragmentation chain transfer (RAFT)) processes. homopolymers or copolymers (such as alternating, random, 0029. In particular, ATRP is a preferred, versatile process Statistical, tapered/gradient and block copolymers), may be by which the chemical architecture of a polymer can be cyclic, linear or branched (e.g., the polymers may have star, controlled very closely, and which proceSS can be used with comb or dendritic architecture), they may be natural or a wide variety of monomers to create polymers having a Synthetic, or they may be thermoplastic or thermosetting. diverse range of chemical characteristics (hydrophobic, 0033. In embodiments where it is desirable to synthesize hydrophilic, ionic, etc.). Because ATRP is tolerant of a polymer blocks having a main chain and a plurality of Side US 2006/OO13853 A1 Jan. 19, 2006 chains, the polymerization can proceed, for example, in the 0038 Conversely, an elevated or “high T. polymer presence of (i) a macro-monomer, which comprises the side block' is a polymer block that displays one or more glass chain and has a free-radical polymerizable end group and (ii) transition temperatures, as measured by any of a number of optionally, a free-radical polymerizable comonomer or a techniques including differential Scanning calorimetry, combination of free-radical polymerizable comonomers. dynamic mechanical analysis, or thermomechanical analy Preferably, the end group of the macro-monomer is termi sis, which is above ambient temperature, more typically nally unsaturated and the polymerizable comonomer is an above 50° C., above 60° C., above 70° C., above 80° C., unsaturated monomer. above 90° C. or even above 100° C. 0034. A "macro-monomer' as the term is used herein is 0039 Hence, copolymers having one or more low T. a macromolecule, commonly a polymer, which has a reac blocks and one or more high T. polymer blocks will typi tive group, often an end-group, which enables it to act as a cally have one or more glass transition temperatures below monomer molecule, contributing a single monomeric unit to ambient temperature and one or more glass transition tem a chain of the final macromolecule. For example, a long peratures above ambient temperature. This typically results chain vinyl polymer or vinyl oligomer (as used herein, an in the formation of rubbery and hard phases within the oligomer is a polymer containing from 2-9 constitutional coating layer at ambient temperatures. units) that has a polymerizable double bond at the end of the chain is a macromonomer. Homopolymerization or copoly 0040) The low and high T. polymer blocks may be merization of a macromonomer yields comb or graft poly present in the copolymers, for example, as interior blockS or CS. as endblocks. The low and high T. polymer blocks may be provided in a variety of configurations, including cyclic, 0.035 Examples of monomers that can be used in the linear and branched configurations. Branched configurations polymerization reactions of the present invention include include Star-shaped configurations (e.g., configurations in unsaturated monomerS Such as alkyl methacrylates, alkyl which three or more chains emanate from a Single branch acrylates, hydroxyalkyl methacrylates, vinyl esters, Vinyl point), comb configurations (e.g., configurations having a aromatics Such as Styrene, C.-methylstyrene, macro-mono main chain and a plurality of branching side chains) and merS having free radical polymerizable end groups, and dendritic configurations (e.g., arborescent and hyper combinations thereof. Examples of macro-monomers branched polymers). The low and high T. polymer blocks include those having a polysiloxane block, a polyisobuty may contain, for example, a repeating Series of units of a lene block, a poly(vinyl aromatic) block Such as a polysty Single type, a series of units of two or more types in a rene block, a polyethylene oxide block, a polyvinylpyrroli repeating (e.g., alternating), random, Statistical or gradient done block, a polymethylmethacrylate block, or a distribution, and so forth. combination thereof, and having a free radical polymeriZ able end group. 0041) Specific examples of low T. polymer blocks from which the low T. polymer blocks of the present invention 0036). In some specific embodiments, the polymer formed can be Selected include homopolymer blocks and copolymer comprises a low T. polymer block or a high T. polymer blocks formed from (or having the appearance of being block. In other specific embodiments, the polymer formed is formed from) one or more of the following: acrylic mono a copolymer that comprises (i) a low T. polymer block and mers, methacrylic monomers, Vinyl ether monomers, cyclic (ii) a high T. polymer block, for example, wherein the ether monomers, ester monomers, unsaturated hydrocarbon macro-initiator comprises a free radical terminated low T. monomers, including alkene monomers, halogenated alkene polymer block (or a free radical terminated high T. polymer monomers, halogenated unsaturated hydrocarbon mono block). In still other specific embodiments, the polymer is a mers, and Siloxane monomers. Numerous specific examples copolymer that further comprises a low T. block and a graft are listed below. The T values are published values for copolymer block comprising a main chain and a plurality of homopolymers of the listed monomeric unit. Side chains, wherein the macro-initiator comprises a free radical terminated low T. polymer block and wherein the 0042 Specific acrylic monomers include: (a) alkyl acry radical polymerization reaction is conducted in the presence lates such as methyl acrylate (T 10° C), ethyl acrylate (T. of a macro-monomer comprising the Side chain and a free -24° C), propyl acrylate, isopropyl acrylate (T -11° C., radical polymerizable end group. isotactic), butyl acrylate (T-54° C), Sec-butyl acrylate (T. -26°C.), isobutyl acrylate (T-24°C.), cyclohexyl acrylate 0037 A“low T. polymer block” is a polymer block that (T, 19° C), 2-ethylhexyl acrylate (T-50° C), dodecyl displays one or more glass transition temperatures (T,), as acrylate (T. -3°C.) and hexadecyl acrylate (T., 35° C), (b) measured by any of a number of techniques including arylalkyl acrylates Such as benzyl acrylate (T. 6° C), (c) differential Scanning calorimetry (DSC), dynamic mechani alkoxyalkyl acrylates Such as 2-ethoxyethyl acrylate (T. cal analysis (DMA), or dielectric analysis (DEA), that is -50° C) and 2-methoxyethyl acrylate (T-50° C), (d) below ambient temperature, more typically below 25 C., halo-alkyl acrylates Such as 2.2.2-trifluoroethyl acrylate (T. below 0° C., below -25 C., or even below -50° C. -10°C.) and (e) cyano-alkyl acrylates Such as 2-cyanoethyl “Ambient temperature” is typically 25 C-45 C., more typically body temperature (e.g., 35 C.-40°C.). As a result acrylate (T. 4°C). of their low glass transition temperature, low T. polymer 0043 Specific methacrylic monomers include (a) alkyl blocks are typically elastomeric at ambient temperature. methacrylates such as butyl methacrylate (T20° C), hexyl Homopolymers of Some low T. polymer blocks, such as methacrylate (T -5° C), 2-ethylhexyl methacrylate (T. linear or branched silicone (e.g. polydimethylsiloxane), are -10° C), octyl methacrylate (T. -20° C), dodecyl meth Viscous liquids or millable gums at room temperature and acrylate (T-65 C.), hexadecyl methacrylate (T. 15° C.) become elastomeric upon covalent cross-linking. and octadecyl methacrylate (T -100° C) and (b) ami US 2006/OO13853 A1 Jan. 19, 2006 noalkyl methacrylates Such as diethylaminoethyl methacry (T,118° C) and 4-fluorostyrene (T 95° C) and (iv) ester late (T 20° C) and 2-tert-butyl-aminoethyl methacrylate Substituted vinyl aromatics Such as 4-acetoxystyrene (T. (T. 33° C). 116° C). 0044) Specific vinyl ether monomers include (a) alkyl 0.052 Other specific vinyl monomers include: (a) vinyl vinyl ethers such as methyl vinyl ether (T-31° C), ethyl alcohol (T. 85° C); (b) vinyl esters such as vinyl benzoate vinyl ether (T-43° C), propyl vinyl ether (T-49° C), (T, 71° C), vinyl 4-tert-butylbenzoate (T 101° C), vinyl butyl vinyl ether (T-55° C), isobutyl vinyl ether (T-19 cyclohexanoate (T, 76° C), vinyl pivalate (T, 86° C), vinyl C.), 2-ethylhexyl vinyl ether (T-66° C) and dodecyl vinyl trifluoroacetate (T. 46° C), vinyl butyral (T. 49° C), (c) ether (T-62°C). vinyl amines such as 2-vinyl pyridine (T 104° C), 4-vinyl pyridine (T 142° C), and vinyl carbazole (T. 227° C), (d) 0.045 Specific cyclic ether monomers include tetrahydro vinyl halides such as vinyl chloride (T, 81° C) and vinyl furan (T-84° C), trimethylene oxide (T-78° C), ethyl fluoride (T40° C); (e) alkyl vinyl ethers such as tert-butyl ene oxide (T, -66° C), propylene oxide (T, -75° C), vinyl ether (T. 88° C) and cyclohexyl vinyl ether (T. 81 methylglycidyl ether (T-62°C.), butylglycidyl ether (T. C.), and (f) other vinyl compounds Such as 1-vinyl-2- -79° C), allylglycidyl ether (T-78° C), epibromohydrin pyrrolidone (T. 54 C.) and vinyl ferrocene (T, 189° C.). (T-14°C), epichlorohydrin (T-22°C.), 1.2-epoxybutane (T-70° C), 1.2-epoxyoctane (T-67° C) and 1.2-epoxy 0053 Specific aromatic monomers, other than vinyl aro decane (T-70° C.). matics, include: acenaphthalene (T214°C) and indene (T. 85° C). 0046) Specific ester monomers (other than acrylates and 0054) Specific methacrylic monomers include (a) meth methacrylates) include ethylene malonate (T, -29° C), acrylic acid (T. 228° C), (b) methacrylic acid salts such as vinyl acetate (T. 30° C), and vinyl propionate (T 10° C). sodium methacrylate (T. 310° C), (c) methacrylic acid 0047 Specific alkene monomers include ethylene, pro anhydride (T. 159° C), (d) methacrylic acid esters (meth pylene (T -8 to -13° C), isobutylene (T -73° C), acrylates) including (i) alkyl methacrylates Such as atactic 1-butene (T-24°C.), trans-butadiene (T-58° C), 4-me methyl methacrylate (T 105-120° C), syndiotactic methyl thyl pentene (T. 29° C), 1-octene (T-63° C) and other methacrylate (T. 115° C), ethyl methacrylate (T. 65° C), C-olefins, cis-isoprene (T-63° C), and trans-isoprene (T. isopropyl methacrylate (T, 81° C), isobutyl methacrylate -66° C). (T. 53° C), t-butyl methacrylate (T,118° C) and cyclohexyl methacrylate (T 92° C), (ii) aromatic methacrylates such as 0.048 Specific halogenated alkene monomers include phenyl methacrylate (T 110° C) and including aromatic vinylidene chloride (T -18° C), vinylidene fluoride (T. alkyl methacrylates Such as benzyl methacrylate (T54 C.), –40° C), cis-chlorobutadiene (T. -20° C), and trans-chlo (iii) hydroxyalkyl methacrylates Such as 2-hydroxyethyl robutadiene (T-40°C). methacrylate (T57° C) and 2-hydroxypropyl methacrylate (T, 76° C), (iv) additional methacrylates including 0049 Specific siloxane monomers include dimethylsi isobornyl methacrylate (T. 110° C) and trimethylsilyl meth loxane (T-127° C), diethylsiloxane, methylethylsiloxane, acrylate (T. 68° C), and (e) other methacrylic-acid deriva methylphenylsiloxane (T-86° C), and diphenylsiloxane. tives including methacrylonitrile (T 120° C). 0050) Specific examples of high T. polymer blocks 0055 Specific acrylic monomers include (a) acrylic acid include homopolymer blocks and copolymer blocks formed (T 105° C), its anhydride and salt forms, such as potassium from (or having the appearance of being formed from) one acrylate (T, 194° C) and sodium acrylate (T. 230° C); (b) or more of the following: Various vinyl aromatic monomers, certain acrylic acid esters such as tert-butyl acrylate (T. other vinyl monomers, other aromatic monomers, meth 43-107° C) (T, 193° C), hexyl acrylate (T. 57° C) and acrylic monomers, and acrylic monomers. Numerous spe isobornyl acrylate (T 94° C); (c) acrylic acid amides such cific examples are listed below. The T values are published as acrylamide (T 165° C), N-isopropylacrylamide (T. values for homopolymers of the listed monomeric unit. 85-130° C) and N,N dimethylacrylamide (T, 89° C); and 0051 Vinyl aromatic monomers are monomers having (d) other acrylic-acid derivatives including acrylonitrile (T. aromatic and Vinyl moieties, including unsubstituted mono 125° C). mers, Vinyl-Substituted monomers and ring-Substituted 0056. In some embodiments, the coating layers of the monomers. Several Specific vinyl aromatic monomers fol present invention are loaded with a therapeutic agent. For low: (a) unsubstituted vinyl aromatics, such as atactic sty example, once an adherent coating has been established via rene (T 100° C), isotactic styrene (T 100° C) and 2-vinyl electrografting and ATRP or another polymerization tech naphthalene (T. 151° C), (b) vinyl substituted aromatics nique, Solvent-based methods may be utilized to introduce a Such as methyl Styrene, (c) ring-Substituted vinyl aromatics therapeutic agent into the polymer coating. including (i) ring-alkylated vinyl aromatics Such as 3-me thylstyrene (T 97° C), 4-methylstyrene (T 97° C), 2,4- 0057 Where solvent-based techniques are used to intro dimethylstyrene (T112° C), 2,5-dimethylstyrene (T 143° duce a therapeutic agent into the coating layer, the Solvent C), 3,5-dimethylstyrene (T 104° C), 2,4,6-trimethylsty System that is Selected will contain one or more Solvent rene (T. 162°C), and 4-tert-butylstyrene (T, 127° C), (ii) Species. The Solvent System preferably is a good Solvent for ring-alkoxylated vinyl aromatics, Such as 4-methoxystyrene the polymer (or polymers) within the coating layer and for (T 113° C) and 4-ethoxystyrene (T 86° C), (iii) ring the therapeutic agent. The particular Solvent species that halogenated vinyl aromatics Such as 2-chlorostyrene (T. make up the Solvent System may also be selected based on 119° C), 3-chlorostyrene (T 90° C), 4-chlorostyrene (T. other characteristics, including drying rate and Surface ten 110° C), 2,6-dichlorostyrene (T. 167° C), 4-bromostyrene SO. US 2006/OO13853 A1 Jan. 19, 2006

0.058 Preferred solvent-based techniques include, but are 0062 Specific examples of medical devices for use in not limited to, Spin coating techniques, web coating tech conjunction with the present invention include vascular niques, Solvent Spraying techniques, dipping techniques, Stents, which deliver therapeutic agent into the vasculature techniques involving coating via mechanical Suspension for the treatment of restenosis. AS used herein, “treatment' including air Suspension, ink jet techniques, electroStatic refers to the prevention of a disease or condition, the techniques, and combinations of these processes. Typically, reduction or elimination of Symptoms associated with a the therapeutic agent is dissolved or dispersed within a disease or condition, or the Substantial or complete elimi Solvent, and the resulting Solution contacted with a previ nation of a disease or condition. Preferred Subjects are ously formed coating layer using, for example, one or more mammalian Subjects and more preferably human Subjects. of these application techniques. 0063 “Therapeutic agents,”“pharmaceutically active 0059. In some embodiments, barrier layers are formed agents,”“pharmaceutically active materials,"drugs,” and over a therapeutic-agent-containing coating layer. For other related terms may be used interchangeably herein and example, Solvent-based techniqueS Such as those discussed include genetic therapeutic agents, non-genetic therapeutic above can be used in which a polymer (or polymers) that agents and cells. Therapeutic agents may be used Singly or comprises the barrier region is (are) first dissolved or in combination. Therapeutic agents may be used singly or in dispersed in a Solvent, and the resulting mixture is Subse combination. Therapeutic agents may be, for example, non quently used to form the barrier layer. In other embodiments, the barrier layer is applied over the therapeutic-agent-con ionic or they may be anionic and/or cationic in nature. taining coating layer using thermoplastic processing tech 0064 Exemplary non-genetic therapeutic agents for use niques. The barrier layer Serves, for example, as a boundary in connection with the present invention include: (a) anti layer to retard diffusion of the therapeutic agent, for thrombotic agents Such as heparin, heparin derivatives, instance, acting to prevent a burst phenomenon whereby urokinase, and PPack (dextrophenylalanine proline arginine much of the therapeutic agent is released immediately upon chloromethylketone); (b) anti-inflammatory agents Such as exposure of the device or a portion of the device to the dexamethasone, prednisolone, corticosterone, budeSonide, implant or insertion Site. estrogen, SulfaSalazine and mesalamine; (c) antineoplastic/ 0060 A wide variety of medical devices are formed in antiproliferative/anti-miotic agents Such as paclitaxel, conjunction with the present invention. Examples of medical 5-fluorouracil, cisplatin, vinblastine, Vincristine, devices include implantable or insertable medical devices, epothilones, endostatin, angiostatin, angiopeptin, mono for example, catheters (e.g., renal or vascular catheters Such clonal antibodies capable of blocking Smooth muscle cell as balloon catheters), guide wires, balloons, filters (e.g., proliferation, and thymidine kinase inhibitors; (d) anesthetic vena cava filters), Stents (including coronary vascular Stents, agents such as lidocaine, bupivacaine and ropivacaine; (e) cerebral, urethral, ureteral, biliary, tracheal, gastrointestinal anti-coagulants Such as D-Phe-Pro-Arg chloromethyl and esophageal stents), Stent grafts, cerebral aneurysm filter ketone, an RGD peptide-containing compound, heparin, coils (including Guglilmi detachable coils and metal coils), hirudin, antithrombin compounds, platelet receptor antago Vascular grafts, myocardial plugs, patches, pacemakers and nists, anti-thrombin antibodies, anti-platelet receptor anti pacemaker leads, heart Valves, biopsy devices, and any bodies, aspirin, prostaglandin inhibitors, platelet inhibitors coated Substrate (which can comprise, for example, glass, and tick antiplatelet peptides, (f) vascular cell growth pro metal, polymer, ceramic and combinations thereof) that is moterS Such as growth factors, transcriptional activators, and implanted or inserted into the body and from which thera translational promoters, (g) Vascular cell growth inhibitors peutic agent is released. Examples of medical devices fur Such as growth factor inhibitors, growth factor receptor ther include patches for delivery of therapeutic agent to antagonists, transcriptional repressors, translational repres intact skin and broken skin (including wounds); Sutures, Sors, replication inhibitors, inhibitory antibodies, antibodies Suture anchors, anastomosis clips and rings, tissue Staples directed against growth factors, bifunctional molecules con and ligating clips at Surgical sites, orthopedic fixation Sisting of a growth factor and a cytotoxin, bifunctional devices Such as interference Screws in the ankle, knee, and molecules consisting of an antibody and a cytotoxin; (h) hand areas, tacks for ligament attachment and meniscal protein kinase and tyrosine kinase inhibitors (e.g., tyr repair, rods and pins for fracture fixation, Screws and plates phostins, genistein, quinoxalines); (ii) prostacyclin analogs, for craniomaxillofacial repair; dental devices Such as void (i) cholesterol-lowering agents; (k) angiopoietins; (1) anti fillers following tooth extraction and guided-tissue-regen microbial agents Such as triclosan, cephalosporins, ami eration membrane films following periodontal Surgery; and noglycosides and nitrofurantoin; (m) cytotoxic agents, cyto tissue engineering Scaffolds for cartilage, bone, Skin and Static agents and cell proliferation affectors, (n) vasodilating other in Vivo tissue regeneration. agents; (O) agents that interfere with endogenous vasoactive mechanisms; (p) inhibitors of leukocyte recruitment, Such as 0061 The medical devices of the present invention monoclonal antibodies; (q) cytokines; (r) hormones; and (s) include medical devices that are used for either Systemic inhibitors of HSP90 protein (i.e., Heat Shock Protein, which treatment or for the localized treatment of any mammalian is a molecular chaperone or housekeeping protein and is tissue or organ. Non-limiting examples are tumors, organs needed for the stability and function of other client proteins/ including the heart, coronary and peripheral vascular System Signal transduction proteins responsible for growth and (referred to overall as “the vasculature'), lungs, trachea, Survival of cells) including geldanamycin. esophagus, brain, liver, kidney, bladder, urethra and ureters, eye, intestines, Stomach, pancreas, Vagina, uterus, OVary, and 0065 Preferred non-genetic therapeutic agents include prostate; skeletal muscle, Smooth muscle, breast, dermal paclitaxel, Sirolimus, everolimus, tacrolimus, Epo D, dex tissue, cartilage; and bone. amethasone, estradiol, halofuginone, ciloStazole, geldana US 2006/OO13853 A1 Jan. 19, 2006 mycin, ABT-578 (Abbott Laboratories), trapidil, liprostin, lalkylamines Such as Verapamil, (b) Serotonin pathway Actinomycin D, Resten-NG, Ap-17, abciximab, clopidogrel modulators including: 5-HT antagonists Such as ketanserin and Ridogrel, among others. and naftidrofuryl, as well as 5-HT uptake inhibitors such as 0.066 Exemplary genetic therapeutic agents for use in fluoxetine, (c) cyclic nucleotide pathway agents including connection with the present invention include anti-Sense phosphodiesterase inhibitorS Such as ciloStazole and dipy DNA and RNA as well as DNA coding for the various ridamole, adenylate/Guanylate cyclase Stimulants Such as proteins (as well as the proteins themselves): (a) anti-Sense forskolin, as well as adenosine analogs, (d) catecholamine RNA, (b) tRNA or rRNA to replace defective or deficient modulators including O-antagonists Such as praZOsin and endogenous molecules, (c) angiogenic and other factors bunaZosine, B-antagonists Such as propranolol and C/B- including growth factorS Such as acidic and basic fibroblast antagonists Such as labetalol and carvedilol, (e) endothelin growth factors, vascular endothelial growth factor, endothe receptor antagonists, (f) nitric oxide donors/releasing mol lial mitogenic growth factors, epidermal growth factor, ecules including organic nitrates/nitriteS Such as nitroglyc transforming growth factor C. and B, platelet-derived endot erin, isosorbide dinitrate and amyl nitrite, inorganic nitroSo helial growth factor, platelet-derived growth factor, tumor compounds Such as Sodium nitroprusSide, Sydnonimines necrosis factor C, hepatocyte growth factor and insulin-like Such as molsidomine and linsidomine, nonoates Such as growth factor, (d) cell cycle inhibitors including CD inhibi diazenium diolates and NO adducts of alkanediamines, tors, and (e) thymidine kinase (“TK') and other agents S-nitroSO compounds including low molecular weight com useful for interfering with cell proliferation. Also of interest pounds (e.g., S-nitroso derivatives of captopril, glutathione is DNA encoding for the family of bone morphogenic and N-acetyl penicillamine) and high molecular weight proteins (“BMP’s”), including BMP-2, BMP-3, BMP-4, compounds (e.g., S-nitroso derivatives of proteins, peptides, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, oligosaccharides, polysaccharides, Synthetic polymerS/oli BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, gomers and natural polymerS/oligomers), as well as C-ni and BMP-16. Currently preferred BMP's are any of BMP-2, troSo-compounds, O-nitroSo-compounds, N-nitroSo-com BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric pounds and L-arginine, (g) ACE inhibitors such as cilaZapril, proteins can be provided as homodimers, heterodimers, or fosinopril and enalapril, (h) ATII-receptor antagonists Such combinations thereof, alone or together with other mol as Saralasin and losartin, (i) platelet adhesion inhibitorS Such ecules. Alternatively, or in addition, molecules capable of as albumin and polyethylene oxide, () platelet aggregation inducing an upstream or downstream effect of a BMP can be inhibitors including ciloStazole, aspirin and thienopyridine provided. Such molecules include any of the "hedgehog” (ticlopidine, clopidogrel) and GPIb/IIIa inhibitors such as proteins, or the DNA's encoding them. abciximab, epitifibatide and tirofiban, (k) coagulation path way modulators including heparinoids Such as heparin, low 0067 Vectors for delivery of genetic therapeutic agents molecular weight heparin, dextran Sulfate and B-cyclodex include Viral vectorS Such as adenoviruses, gutted adenovi trin tetradecasulfate, thrombin inhibitorS Such as hirudin, ruses, adeno-associated virus, retroviruses, alpha virus hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylke (Semliki Forest, Sindbis, etc.), lentiviruses, herpes simplex tone) and argatroban, FXa inhibitors Such as antistatin and virus, replication competent viruses (e.g., ONYX-015) and TAP (tick anticoagulant peptide), Vitamin Kinhibitors such hybrid vectors, and non-viral vectorS Such as artificial chro as warfarin, as well as activated protein C, (I) cyclooxyge mosomes and mini-chromosomes, plasmid DNA vectors nase pathway inhibitorS Such as aspirin, ibuprofen, flurbi (e.g., pCOR), cationic polymers (e.g., polyethyleneimine, profen, indomethacin and Sulfinpyrazone, (m) natural and polyethyleneimine (PEI)), graft copolymers (e.g., polyether Synthetic corticosteroids Such as dexamethasone, predniso PEI and polyethylene oxide-PEI), neutral polymers such as lone, methprednisolone and hydrocortisone, (n) lipoxyge polyvinylpyrrolidone (PVP), SP1017 (SUPRATEK), lipids nase pathway inhibitorS Such as nordihydroguairetic acid Such as cationic lipids, liposomes, lipoplexes, nanoparticles, and caffeic acid, (O) leukotriene receptor antagonists, (p) or microparticles, with and without targeting Sequences Such antagonists of E- and P-selectins, (q) inhibitors of VCAM-1 as the protein transduction domain (PTD). and ICAM-1 interactions, (r) prostaglandins and analogs 0068 Cells for use in connection with the present inven thereof including prostaglandins such as PGE1 and PGI2 tion include cells of human origin (autologous or alloge and proStacyclin analogS Such as ciprostene, epoprostenol, neic), including whole bone marrow, bone marrow derived carbacyclin, iloprost and beraprost, (s) macrophage activa mono-nuclear cells, progenitor cells (e.g., endothelial pro tion preventers including bisphosphonates, (t) HMG-CoA genitor cells), Stem cells (e.g., mesenchymal, hematopoietic, reductase inhibitorS Such as lovastatin, pravastatin, fluvas neuronal), pluripotent stem cells, fibroblasts, myoblasts, tatin, Simvastatin and cerivastatin, (u) fish oils and omega Satellite cells, pericytes, cardiomyocytes, Skeletal myocytes 3-fatty acids, (v) free-radical ScavengerS/antioxidants Such or macrophage, or from an animal, bacterial or fungal Source as probucol, Vitamins C and E, ebSelen, trans-retinoic acid (Xenogeneic), which can be genetically engineered, if and SOD mimics, (w) agents affecting various growth factors including FGF pathway agents such as bFGF anti desired, to deliver proteins of interest. bodies and chimeric fusion proteins, PDGF receptor antago 0069. Numerous therapeutic agents, not necessarily nists Such as trapidil, IGF pathway agents including Soma exclusive of those listed above, have been identified as tostatin analogS Such as angiopeptin and ocreotide, TGF-B candidates for vascular treatment regimens, for example, as pathway agents such as polyanionic agents (heparin, fucoi agents targeting restenosis. Such agents are useful for the din), decorin, and TGF-f antibodies, EGF pathway agents practice of the present invention and include one or more of Such as EGF antibodies, receptor antagonists and chimeric the following: (a) Ca-channel blockers including benzothi fusion proteins, TNF-C. pathway agents Such as thalidomide aZapines Such as diltiazem and clentiazem, dihydropyridines and analogs thereof, Thromboxane A2 (TXA2) pathway Such as nifedipine, amlodipine and nicardapine, and pheny modulatorS Such as Sulotroban, Vapi.prost, daZOXiben and US 2006/OO13853 A1 Jan. 19, 2006 ridogrel, as well as protein tyrosine kinase inhibitorS Such as those of ordinary skill in the art, the ratio may be changed tyrphostin, genistein and quinoxaline derivatives, (x) MMP in a number of ways. For example, in Some embodiments, pathway inhibitorS Such as marimastat, illomastat and met the hydrophilicity of the coating layer can be increased by astat, (y) cell motility inhibitors such as cytochalasin B, (Z) forming polymers using one or more hydrophilic monomers, antiproliferative/antineoplastic agents including antimetabo Such as hydroxyethylmethacrylate or other hydrophilic lites Such as purine analogs (e.g., 6-mercaptopurine or monomers including those numerous examples of hydro cladribine, which is a chlorinated purine nucleoside analog), philic monomers listed above for preparation of low and pyrimidine analogs (e.g., cytarabine and 5-fluorouracil) and high T. polymer blocks. In alternative embodiments, the methotrexate, nitrogen mustards, alkyl Sulfonates, ethylen hydrophobicity of the resulting copolymer is increased by imines, antibiotics (e.g., daunorubicin, doxorubicin), nitroSoureas, cisplatin, agents affecting microtubule dynam forming copolymers with one or more hydrophobic mono ics (e.g., vinblastine, Vincristine, colchicine, Epo D, pacli mers. Any one or more of a number of hydrophobic mono taxel and epothilone), caspase activators, proteasome inhibi mers can be used, Such as methylmethacrylate or other tors, angiogenesis inhibitors (e.g., endostatin, angiostatin hydrophobic monomers, including those numerous and Squalamine), rapamycin, cerivastatin, flavopiridol and examples of hydrophobic monomers listed above for prepa Suramin, (aa) matrix deposition/organization pathway ration of low and high T. polymer blocks. Where the coating inhibitorS Such as halofuginone or other quinazolinone layer comprises a copolymer of hydrophilic and hydropho derivatives and tranilast, (bb) endothelialization facilitators bic units, the ratio of hydrophilic units within the copolymer such as VEGF and RGD peptide, and (cc) blood rheology relative to hydrophobic units can be varied. modulatorS Such as pentoxifylline. 0075. In other embodiments, release is modulated by 0070 Numerous additional therapeutic agents useful for including one or more biodisintegrable polymeric constitu the practice of the present invention are also disclosed in ents in the coating layer, for example, a biodisintegrable U.S. Pat. No. 5,733,925 assigned to NeoRX Corporation, the polymer block. A “biodisintegrable polymer block” is a entire disclosure of which is incorporated by reference. polymer block that undergoes dissolution, degradation, 0071. Therapeutic agents also include ablation agents, resorption and/or other disintegration process upon admin sufficient amounts of which will result in necrosis (death) of istration to a patient. Examples of biodisintegrable polymer undesirable tissue, Such as malignant tissue, prostatic tissue, blocks include the following: (a) polyester blocks, for and So forth. Examples include oSmotic-stress-generating example, polymers and copolymers of hydroxyacids and agents, for example, Salts. Such as Sodium chloride or potas lactones, such as glycolic acid, lactic acid, tartronic acid, sium chloride, organic Solvents, particularly those Such as fumaric acid, hydroxybutyric acid, hydroxyvaleric acid, ethanol, which are toxic in high concentrations, while being dioxanone, caprolactone and Valerolactone, (b) polyanhy well tolerated at lower concentrations, free-radical generat drides, for example, polymers and copolymers of various ing agents, for example, hydrogen peroxide, potassium diacids Such as Sebacic acid and 1,6-bis(p-carboxyphoxy) peroxide or other agents that can form free radicals in tissue; alkanes, for instance, 1,6-bis(p-carboxyphoxy) hexane and basic agents Such as Sodium hydroxide; acidic agents Such as 1,6-bis(p-carboxyphoxy) propane; (c) tyrosine-derived acetic acid and formic acid; enzymes Such as collagenase, polycarbonates, and (d) polyorthoesters. Specific examples hyaluronidase, pronase, and papain, oxidizing agents, Such of biodisintegrable polymer blockS include polyester blockS as Sodium hypochlorite, hydrogen peroxide or potassium Such as poly(glycolic acid) blocks, poly(lactic acid) blocks, peroxide, tissue fixing agents, Such as formaldehyde, acetal poly(lactic acid-co-glycolic acid) blocks, and polycaprolac dehyde or glutaraldehyde; and naturally occurring coagul tone blockS. lants, Such as gengpin. EXAMPLE 0.072 A wide range of therapeutic agent loadings can be used in connection with the dosage forms of the present Polystyrene-Coated Stainless Steel Stent invention, with the pharmaceutically effective amount being readily determined by those of ordinary skill in the art and 0076 Astainless steel stent having a polystyrene coating ultimately depending, for example, upon the condition to be is produced by the electrografting of chlorinated poly(ethyl treated, the nature of the therapeutic agent itself, the tissue acrylate) onto a stainless Steel Stent Surface, followed by into which the dosage form is introduced, and So forth. ATRP with styrene monomer. A 2-chloropropionate ethyl 0073. As will be appreciated by those of ordinary skill in acrylate (cPEA) initiator is synthesized by reaction of 2-hy the art, the release profile associated with the coating layer droxyethyl acrylate with 2-chloroproopionyl chloride in the can be modified, for example, by altering the chemical presence of triethylamine to form (cPEA). The cpEA is dried composition, molecular weight, architecture, and So forth, of over molecular Sieves before electropolymerization, and the the polymer or polymers forming the therapeutic-agent ethyl acrylate monomer is dried over calcium hydride and containing coating layer and/or by providing a barrier layer distilled under reduced pressure. N,N-Dimethylformamide (DMF) is dried over POs and distilled under reduced over the therapeutic-agent-containing coating layer. pressure. Tetraethylammonium perchlorate (TEAP) is 0.074 Hence, in certain embodiments of the present heated in vacuo at 80° C. for 12 hours, prior to use. Styrene invention, the drug release rate of the therapeutic agent is (Aldrich) is dried over CaH and distilled before use. Phe controlled by changing the hydrophilic/hydrophobic ratio of nylethyl bromide (PEBr) (Aldrich) and HMTETA (Aldrich) the polymeric constituents of the coating layer, Such that the are diluted in dried toluene. The Grubbs catalyst (Aldrich) overall hydrophilicity of the coating layer is increased or and NiBr(PPh3). (Aldrich) are used as received and CuCl decreased (or, viewed conversely, the overall hydrophobic (Aldrich) and CuCl2 (Aldrich) are purified by recrystalliza ity is increased or decreased). AS will be appreciated by tion in acetic acid, before use. US 2006/OO13853 A1 Jan. 19, 2006

1. Synthesis of cPEA 2. The device of claim 1, wherein Said electrically con ductive Substrate comprises an elemental transition metal or 0077 cPEA is prepared by reaction of 10 mL of 2-chlo alloy Selected from titanium, platinum, StainleSS Steel, ropropionyl chloride (0.1 mol dissolved in 20 mL of tet nickel-titanium alloy, gold, cobalt-chromium alloy, and rahydrofuran (THF)) with 5.74 mL of 2-hydroxyethyl acry platinum-enriched StainleSS Steel. late (0.05 mol) and 6.97 mL of triethylamine (0.05 mol) 3. The device of claim 1, wherein said initiator is elec dissolved in 60 mL of dried THF. Then, 20 hours later, the trochemically linked to Said electrically conductive Substrate triethylamine hydrochloride byproduct is filtered out and Surface by applying a cathodic electric potential to Said washed with THF. Upon THF evaporation from the filtrate, electrically conductive Substrate in the presence of Said a liquid residue is left, which is extracted by CHCl, washed initiator. three times with water, eluted through a Silica gel column by 4. The device of claim 1, wherein said free radical CHCl, and dried over MgSO. polymerization reaction is an atom-transfer radical polymer 0078. After distillation, cPEA is recovered. ization reaction. 5. The device of claim 1, wherein said initiator comprises 2. Electrografted Stent an electrochemically linkable group Selected from alkyl 0079 Stainless steel stents are electrografted with poly halides with one or more activating groups on an a carbon (cPEA) and poly(cPEA-co-EA) from a DMF solution con of the alkyl halide. taining TEAP (0.05 M) and either cPEA (0.5 M) or a mixture 6. The device of claim 1, wherein said initiator is a of cPEA (0.5 M) and EA (0.5M) by scanning the potential polyhalogenated compound comprising an electrochemi up to the maximum of the first peak and holding this cally linkable group Selected from an -N-X group, an potential until the current decreases dramatically. Complete -S-X group, and an -O-X group, wherein X is a cathodic passivation may require two or more Scans. The halogen atom. substrate is then washed with pure DMF and acetonitrile and 7. The device of claim 1, wherein said initiator comprises dried. an acrylate group and a 2-chloropropionate group. 8. The device of claim 1, wherein the initiator comprises 3. Polymerization of Styrene via ATRP a copolymer of ethyl acrylate and 2-chloropropionate. 0080. The styrene polymerization is performed in closed 9. The device of claim 1, wherein said electrochemically tubes under nitrogen. In a tube is added 68 mg (0.082 mmol linked free radical polymerization initiator is a free radical for a targeted DP=950) of the Grubbs catalyst, together with terminated polymer. the electrografted Stainless Steel Stent. The tube is closed, 10. The device of claim 1, wherein said one or more free evacuated and filled with nitrogen. Then, 2 mL of dry radical polymerizable monomers are Selected from alkyl toluene, 9 mL of styrene (78.5 mmol) and 0.23 mL of PEBr acrylate monomers, hydroxyalkyl acrylate monomers, alkyl (0.082 mmol; targeted DP=950) are then added through a methacrylate monomer, hydroxyalkyl methacrylate mono rubber Septum making the Steel Stent completely immersed. mers, acrylonitrile monomer, methacrylonitrile monomer, a The tube is placed on a magnetic stirrer and heated at 100 Vinyl ester monomers, Styrene monomer, and Substituted C. for 18 hours. After polymerization, the steel stent is Styrene monomers. extensively washed with THF, and the polymer formed in 11. The device of claim 1, wherein said free radical Solution is recovered by precipitation in methanol. polymerizable monomer is an unsaturated monomer. 0081. A representative surface of a typical polystyrene 12. The device of claim 1, wherein said one or more free grafted StainleSS Steel Stent produced according to the meth radical polymerizable monomers comprise a macro-mono ods described above is shown in FIG. 2, which is a scanning mer having a free radical polymerizable group. electron micrograph of a polystyrene-coated Steel plate, 13. The device of claim 12, wherein the macro-monomer published in Claes et al., Polymer Coating of Steel by a comprises a free radical polymerizable group and one or Combination of Electrografiing and Atom-Transfer Radical more of the following blockS: a polysiloxane block, a Polymerization, Macromolecules, Web release No. 0217130 polyalkene block, a poly(halogenated alkene) block, a poly (Jul 19, 2003). ester block, a poly(Vinyl aromatic) block, a polyethylene oxide block, a polyvinylpyrrollidone block, a polyacrylate 0082 Although various embodiments are specifically block, a polymethacrylate block, or a poly(Vinyl ether) illustrated and described herein, it will be appreciated that block. modifications and variations of the present invention are 14. The device of claim 1, wherein said polymer com covered by the above teachings and are within the purview prises (i) a low T. polymer block and (ii) a high T. polymer of the appended claims without departing from the Spirit and block, intended Scope of the invention. 15. The device of claim 14, wherein said initiator com prises a free radical terminated low T. polymer block. 16. The device of claim 14, wherein said low T. block is 1. A medical device comprising an electrically conductive Selected from a polyacrylate block, a polymethacrylate Substrate and a coating layer that covers at least a portion of block, a poly(Vinyl ether) block, a polyester block, a poly Said electrically conductive Substrate, wherein Said coating alkene block, a poly(halogenated alkene) block, and a pol layer comprises a polymer that is made by a process com y(siloxane) block. prising (a) electrochemically linking a free radical polymer 17. The device of claim 14, wherein said high T. block is ization initiator to a Surface of Said electrically conductive Selected from a poly(Vinyl aromatic) block and a polyalky Substrate, and (b) conducting a free radical polymerization l(meth)acrylate block. reaction in the presence of one or more free radical poly 18. The device of claim 1, wherein said polymer com merizable monomers. prises a low T. block and a graft copolymer block compris US 2006/OO13853 A1 Jan. 19, 2006

ing a main chain and a plurality of Side chains, and wherein 22. The device of claim 20, wherein a therapeutic agent is the radical polymerization reaction is conducted in the introduced into the coating layer by (a) providing a Solution presence of a macro-monomer comprising Said Side chain comprising (i) a Solvent System and (ii) said therapeutic and a free radical polymerizable end group. agent; and (b) contacting said Solution with Said coating 19. The device of claim 18, wherein said graft copolymer layer. block comprises a biodisintegrable chain or a high T. polymer chain. 23. The device of claim 1, wherein said medical device is 20. The device of claim 1, wherein said coating layer an implantable or insertable medical device. further comprises a therapeutic agent. 24. The device of claim 23, wherein said implantable or 21. The device of claim 20, wherein Said therapeutic agent insertable medical device is Selected from a catheter, a guide is Selected from one or more of the group consisting of wire, a balloon, a filter, a Stent, a Stent graft, a vascular graft, anti-thrombotic agents, anti-proliferative agents, anti-in a vascular patch and a shunt. flammatory agents, anti-migratory agents, agents affecting 25. The device of claim 23, wherein said implantable or extracellular matrix production and organization, antine insertable medical device is adapted for implantation or oplastic agents, anti-mitotic agents, anesthetic agents, anti insertion into the coronary vasculature, peripheral vascular coagulants, vascular cell growth promoters, vascular cell System, esophagus, trachea, colon, biliary tract, urinary tract, growth inhibitors, cholesterol-lowering agents, vasodilating prostate or brain. agents, and agents that interfere with endogenous vasoactive mechanisms.