US 20110232838Al (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0232838 A1 Stopek et al. (43) Pub. Date: Sep. 29, 201 1

54 THERAPEUTIC IMPLANT P u bl'lcatlon ' Cl assl'? cation' (76) Inventors.. Joshua Stopek, Guilford,- CT (US),, ( 51) Int. Cl. Amin Elachchabi, Hamden, CT 2;; gill)‘; (38828? (US); Daniel Broom, Branford, CT ( ' ) (US); Garrett Ebersole, B05D 5/00 (200601) Southington, CT (US) (52) US. Cl...... 156/242; 156/60; 427/224 (21) Appl. No.: 13/051,333

(22) Filed: Mar. 18, 2011 (57) ABSTRACT Related US- Application Data Surgical implants of the present disclosed include a ?lm (62) Division of application NO 13/051 261 ?led on Mar comprising a ?rst therapeutic agent and a mesh comprising a 18 201 1 ' ’ ’ ' second therapeutic agent. The surgical implant includes a ?lm ’ ' in direct contact With a mesh. The ?rst therapeutic agent may (60) Provisional application No, 61/316,898, ?led on Mar, be released at a ?rst rate and the second therapeutic agent may 24, 2010. be released at a second rate. Patent Application Publication Sep. 29, 2011 Sheet 1 0f 4 US 2011/0232838 A1

FIG. 1

20 10A 20A

20B 108 FIG. 2A Patent Application Publication Sep. 29, 2011 Sheet 2 0f 4 US 2011/0232838 A1

100

FIG. 3

100 100 / 122 I 120

120A ‘ "w v '

110 FIG. 4A 4 FIG. 4B Patent Application Publication Sep. 29, 2011 Sheet 3 0f 4 US 2011/0232838 A1

230 Patent Application Publication Sep. 29, 2011 Sheet 4 0f 4 US 2011/0232838 A1

15 + g :1: 1°- . 2 ~ [I] Mesh/Film Alone (no drug) 5’, 5 5_ E Mesh/Film (0.3 mg/cm2) .5 T1 I Mesh/Film (1 mgi'cm2) gain- 0 I MeshiFilm (3 mg/cm2) 1 uS - '5 I l l I A N L N k b ca 11me Post-Surgery (h)

Figure 7. Incisional injury-induced hypersensitivity for CMC/giyceroI/bupivacaine HCI films.

%HCIbupivacaine released(isem)

c I . : : . 0 10 20 48 Time (h) Figure 8. In Vivo bupivacaine HCI release from CMC/glycerol films of various payloads (0.3 to 3 mglcm2). US 2011/0232838 A1 Sep. 29, 2011

THERAPEUTIC IMPLANT [0010] The ?rst therapeutic agent may be released in situ from about less than 24 hours after implantation, and in CROSS-REFERENCE TO RELATED certain embodiments, from about less than one hour after APPLICATIONS implantation. The second therapeutic agent may be released [0001] This application is a divisional of US. patent appli in situ from about more than 24 hours, and in certain embodi cation Ser. No. 13/051,261 ?led Mar. 18, 2011, Which claims ments, from about 24 hours to about fourteen days. The ?rst the bene?t of and priority to US. Provisional Patent Appli therapeutic agent may be the same as or different than the cation No. 61/316,898, ?led Mar. 24, 2010, the entire disclo second therapeutic agent. sure of Which is incorporated by reference herein. [0011] The ?rst or second therapeutic agent may include anti-in?ammatory agents, analgesic agents, anesthetic TECHNICAL FIELD agents, antibiotic agents, angiogenic agents, antispasmodic [0002] The present application relates to a biocompatible agents, groWth factors, gene-based therapies, proteins, pep composite soft tissue repair surgical implant Which comprises tides, nucleic acids, polymers drugs, and combinations at least one therapeutic agent for use in repair of hernias, for thereof. In alternate embodiments, the ?rst or the second example, and methods of making such surgical implants. therapeutic agent may include bupivacaine hydrochloride, bupivacaine, or capsaicin. BACKGROUND OF RELATED ART [0012] A method of treating tissue is disclosed, the method comprising the steps of implanting in the tissue a surgical [0003] A hernia is basically a defect resulting in the protru implant, the surgical implant comprising a ?lm including a sion of part of an organ, tissue or structure through the Wall of ?rst therapeutic agent and a mesh including a second thera a body cavity Within Which it is normally contained. peutic agent; the ?lm releasing the ?rst therapeutic agent to [0004] Meshes may be applied subcutaneously (e.g., under the tissue; and the mesh releasing the second therapeutic the skin) internally or externally of the abdominal Wall and agent to the tissue. may be either absorbable or nonabsorbable depending on the [0013] A method of manufacturing a surgical implant is nature and severity of the particular defect or hernia being also disclosed, including providing, in a ?lm, a ?rst therapeu treated. tic agent; providing, in a mesh, a second therapeutic agent and [0005] Both laparoscopic and open procedures have been applying the ?lm to the mesh. An alternate method of manu preferred for the treatment of hernias With meshes. It is desir facturing is provided comprising the steps of: providing, in a able to treat hernias, as When carrying out any surgery, With as polymer solution, a ?rst therapeutic agent; providing, in a little trauma to the patient as possible, reducing the post mesh, a second therapeutic agent; applying the polymer solu operative pain for the patient. Thus, improvements to meshes, tion to the mesh. including reducing post-operative pain remain desirable.

SUMMARY BRIEF DESCRIPTION OF DRAWINGS [0006] The present disclosure is directed to a surgical [0014] The accompanying draWings, Which are incorpo implant including a ?lm for releasing a ?rst therapeutic agent, rated in and constitute a part of this speci?cation, illustrate and a mesh for releasing a second therapeutic agent. The ?lm embodiments of the disclosure and, together With a general covers at least a portion of the mesh. In certain embodiments, description of the disclosure given above, and the detailed the mesh is at least partially embedded Within the ?lm, alter description of the embodiment(s) given beloW, serve to natively, the ?lm may be positioned adjacent a ?rst surface of explain the principles of the disclosure, Wherein: the mesh. The ?rst therapeutic agent is released at a ?rst rate [0015] FIG. 1 illustrates one embodiment of an implant and the second therapeutic agent is released at a second rate. according to the present disclosure; [0007] In some embodiments, the ?lm comprises a Water soluble polymer. The ?lm may also be rapidly degrading, [0016] FIG. 2A illustrates a cross-sectional vieW of the Wherein the ?lm degrades from about less than 24 hours after implant of FIG. 1; implantation, and in certain embodiments, from about less [0017] FIG. 2B illustrates a schematic cross-sectional vieW than one hour after implantation. of the implant of FIG. 2A; [0008] Materials Which may comprise the ?lm include [0018] FIG. 3 illustrates a plan vieW of another embodi polyesters, polysaccharides, proteins, peptides, hydrophilic ment of an implant according to the present disclosure; vinyls, polyamides, polyamines, polyalkylene oxalates, poly [0019] FIG. 4A illustrates a cross-sectional vieW of the (anhydrides), polyamidoesters, copoly(ether-esters), poly implant of FIG. 3; (carbonates), poly(hydroxyalkanoates), polyimide carbon [0020] FIG. 4B illustrates a schematic cross-sectional vieW ates, poly(imino carbonates), polyorthoesters, polyoxaesters, ofthe implant of FIG. 3; polyphosphaZenes, poly (propylene fumarates), polyure thanes, polymer drugs and combinations thereof. The ?lm [0021] FIG. 5 illustrates a perspective vieW of one embodi may also comprise glycerol or carboxymethyl cellulose. ment of a mold for making implants of the present disclosure; [0009] Materials Which may comprise the mesh include [0022] FIG. 6 illustrates a sectional vieW of a portion of the polyole?ns, polyesters, proteins, polysaccharides, and com mold of FIG. 5, binations thereof. The mesh may further include a coating, [0023] FIG. 7 illustrates incisional injury-induced hyper Which optionally includes the second therapeutic agent. sensitivity for implants according to the present disclosure; Alternatively, the mesh may have at least one degradable and ?lament, the degradable ?lament optionally containing the [0024] FIG. 8 illustrates in vivo bupivacaine HCl release second therapeutic agent. from implants according to the present disclosure. US 2011/0232838 A1 Sep. 29, 2011

DETAILED DESCRIPTION OF EMBODIMENTS [0030] The mesh component may be formed using any method suitable to forming ?brous structures, including but [0025] The present invention relates to a therapeutic com not limited to knitting, Weaving, knipling, tatting, non-Woven posite surgical implant and methods for making and using techniques, Wet-spinning, electro-spinning, gel-spinning, such a surgical implant. More speci?cally, the implant extrusion, co-extrusion, and the like. Suitable techniques for includes a ?lm comprising at least one layer. The implant making mesh are Within the purvieW of those skilled in the art. further includes a mesh Which may at least partially in contact With or embedded Within the ?lm. In embodiments, the mesh [0031] Implants according to the present disclosure further includes a ?rst release mechanism for releasing a ?rst thera include at least one ?lm, Which in certain embodiments, is peutic agent and the ?lm includes a second release mecha rapidly degrading. In one example, the rapidly degrading nism for releasing a second therapeutic agent. In certain (biodegradable) ?lm covers at least a portion of the mesh. As embodiments, at least one of the therapeutic agents comprises Will be later described, the ?lm may be positioned adjacent at a local anesthetic. least a ?rst and/or second surface of the mesh or, the mesh [0026] According to the present disclosure, implants dis may be at least partially embedded Within the ?lm. Similarly, closed herein include a mesh in combination With a ?lm, each the ?lm may at least partially penetrate into the three dimen comprising any suitable biocompatible material. Suitable sional construct of the mesh. Alternatively, the ?lm may be materials should have su?icient tensile strength to support a present on both the ?rst and second surfaces of the mesh. fascial Wall (on injured tissue site) during repair of a defect, be [0032] Additionally, the ?lm may comprise at least one suf?ciently inert to avoid foreign body reactions When layer, and in some examples, the ?lm may have a multilami retained in the human body for long periods of time and have nar construct. suitably easy handling characteristics for insertion and place [0033] Implants disclosed herein may comprise, for ment in the desired location in the body. example, synthetic materials, natural materials (e. g., biologi [0027] Meshes disclosed herein generally comprise ?la cal) and combinations thereof. Suitable polymers include, ments, major spaces, and pores. The ?laments of the mesh polyole?ns such as polyethylene (including ultra high may be formed by at least tWo strands, the major spaces molecular Weight polyethylene) and polypropylene including formed betWeen the ?laments providing the surgical implant atactic, isotactic, syndiotactic, and blends thereof; polyethyl With the necessary strength, the ?laments arranged (i.e., ene glycols; polyethylene oxides; ultra high molecularWeight Woven or knit) such that pores are formed in the strands polyethylene; copolymers of polyethylene and polypropy themselves. Alternatively, the ?laments may be formed by a lene; polyisobutylene and ethylene-alpha ole?n copolymers; mono?lament ?ber (as opposed to at least tWo strands) that ?uorinated polyole?ns such as ?uoroethylenes, ?uoropropy are arranged to form loops that give rise to the pores. lenes, ?uoroPEGSs, and polytetra?uoroethylene; polya [0028] Suitable meshes for use in the present disclosure mides such as nylon, Nylon 6, Nylon 6,6, Nylon 6,10, Nylon include, for example, a collagen composite mesh such as 1 1, Nylon 12, and polycaprolactam; polyamines; polyimines; PARIETEXTM Composite Mesh (commercially available polyesters such as polyethylene terephthalate, polyethylene from Tyco Healthcare Group LG, d/b/a Covidien). PARI naphthalate, polytrimethylene terephthalate, and polybuty ETEXTM Composite Mesh is a 3-dimensional polyester lene terephthalate; polyethers; polybutester; polytetrameth Weave With a resorbable collagen ?lm bonded on one side. ylene ether glycol; 1,4-butanediol; polyurethanes; acrylic Another suitable mesh includes Parietex ProgripTM self-?x polymers; methacrylics; vinyl halide polymers and copoly ating mesh (also commercially available from Covidien). mers, such as polyvinyl chloride; polyvinyl alcohols; polyvi Parietex ProgripTM is a polyester mesh Which includes poly nyl ethers such as polyvinyl methyl ether; polyvinylidene lactic acid (PLA) microgrips. Other suitable meshes include halides such as polyvinylidene ?uoride and polyvinylidene those sold under the names PARIETENE®, PERMACOLTM, chloride; polychloro?uoroethylene; polyacrylonitrile; pol PARIETEXTM, SURGIPROTM (all commercially available yaryletherketones; polyvinyl ketones; polyvinyl aromatics from Covidien); PROLENETM (commercially available from such as polystyrene; polyvinyl esters such as polyvinyl Ethicon, Inc.); MARLEX®, DULEX®, 3D MAX® mesh, acetate; copolymers of vinyl monomers With each other and PERFIX® plug, VENTRALEX®, and KUGEL® patch (all ole?ns, such as ethylene-methyl methacrylate copolymers; commercially available from C.R. Bard, Inc.); PROLITETM, acrylonitrile-styrene copolymers; ABS resins; ethylene-vinyl PROLITE ULTRATM (all commercially available from acetate copolymers; alkyd resins; polycarbonates; poly Atrium Medical); COMPOSIX®, SEPRAMESH®, and oxymethylenes; polyphosphaZine; polyimides; epoxy resins; VISILEX® (all commercially available from Davol, Inc.); aramids; rayon; rayon-triacetate; spandex; silicones; and and DUALMESH®, MYCROMESH®, and INFINIT® copolymers and combinations thereof. Additionally, non-bio mesh (all commercially available from W.L. Gore). Addition degradable polymers and monomers may be combined With ally, meshes Within the scope and context of this disclosure each other to create a core of a ?ber, for example a ?ber may include biologic materials such as allografts, autografts, possessing a core-sheath con?guration. In certain embodi and xeno grafts. ments, at least the mesh may comprise PET. [0029] According to one embodiment of the present disclo [0034] Other synthetic polymers Which may be utiliZed in sure, Parietex Pro-gripTM Self-?xating mesh may be accordance With the present disclosure include, but are not employed. Pro-gripTM mesh includes a knit comprising a limited to anionic, cationic and neutral monomers and poly mono?lament sheet forming, on one face of the knit, spiked/ mers of vinyl polymers such as polyvinyl alcohol, polyvinyl barbed naps Which protrude perpendicularly With respect to methyl ether, polyvinylpyrrolidone (PVP), poly acrylic acid, said sheet. The naps each have a substantially rectilinearbody styrene sulfonic acid, polyhydroxyethylmethylacrylate and, at the free end of this body, a head of greater Width than (pHEMA) and phospholipid vinyls; acrylic polymers such as that of this body. The barbed naps function as hooks, Which sodium polyacrylate, polyethylacrylate, and polyacrylamide; are capable of being fastened either to another prosthetic polyethylene glycol, polypropylene oxide, and polypropy fabric (belonging to the same prosthesis or not) or directly to lene glycol and homopolymers and copolymers thereof; the biological tissues. In certain embodiments, the fabric or phosphorylcholine functional acrylates and methacrylates; mesh may comprise barbed naps on each surface of the mesh. homopolymers and copolymers thereof. US 2011/0232838 A1 Sep. 29, 2011

[0035] Additionally, biodegradable synthetic or natural [0040] In certain embodiments, the ?lm may comprise a materials may be employed. As used herein, the term “biode polysaccharide such as CMC While the mesh portion com gradable” includes both bioabsorbable and bioresorbable prises polyester or polypropylene. materials. By biodegradable, it is meant that the materials [0041] Additionally, the surgical implant may comprise decompose, or lose structural integrity under body conditions any or all of emulsifying agents, solubiliZing agents, Wetting (e. g., enzymatic degradation, hydrolysis) or are broken doWn agents, taste modifying agents, plasticiZers, active agents, (physically or chemically) under physiologic conditions in Water soluble inert ?llers, preservatives, buffering agents, the body (e. g., dissolution) such that the degradation products coloring agents, and stabiliZers. Addition of a plasticiZer to are excretable or absorbable by the body. the formulation can improve ?exibility. The plasticiZer or [0036] Suitable bioabsorbable polymers may comprise mixture of plasticiZers may be polyethylene glycol, glycerol, implants of the present disclosure including, but are not lim sorbitol, sucrose, corn syrup, fructose, dioctyl-sodium sulfo ited to polymers selected from the group consisting of ali succinate, triethyl citrate, tributyl citrate, 1,2-propylenglycol, phatic polyesters; polyamides; polyamines; polyalkylene mono-, di- or triacetates of glycerol, or natural gums. oxalates; poly(anhydrides); polyamidoesters; copoly(ether [0042] Turning noW to FIG. 1, one embodiment of an esters); poly(carbonates) including tyrosine derived carbon implant 2 according to the present disclosure is illustrated ates; poly(hydroxyalkanoates) such as poly(hydroxybutyric including a ?lm 10, Which surrounds or encapsulates a mesh acid), poly(hydroxyvaleric acid), andpoly(hydroxybutyrate); 20. As illustrated, the ?lm 10 is present on a ?rst and second polyimide carbonates; poly(imino carbonates) such as poly surface (20a, 20b) of the mesh 20. More speci?cally, the ?lm (bisphenol A-iminocarbonate and the like); polyorthoesters; 10 comprises a Water soluble polymer, Which may be pro vided as a laminate ?lm or sheet. The ?lm 10 may be smooth polyoxaesters including those containing amine groups; or rough in surface texture. Further, as shoWn in FIG. 2A, at polyphosphaZenes; poly (propylene fumarates); polyure least tWo ?lms (10a and 10b) may be in contact With the mesh thanes; polymer drugs such as polydi?unisol, polyaspirin, 20. It is further envisioned that more than one layer of mesh 20 and protein therapeutics; biologically modi?ed (e.g., protein, may also be present in the implant 2. peptide)bioabsorbable polymers; and copolymers, block [0043] The ?lms may comprise a single, laminate layer, or copolymers, homopolymers, blends, and combinations conversely, the ?lms may comprise several layers, creating a thereof. multi-laminate ?lm. Multi-laminate ?lms may comprise [0037] More speci?cally, for the purpose of this invention, similar or different materials. The multi-laminate ?lms may aliphatic polyesters include, but are not limited to, homopoly also comprise different polymer chain orientations, i.e., they mers and copolymers of lactide (including lactic acid, D-,L may have anisotropic properties, Which When combined (op and meso lactide); glycolide (including glycolic acid); epsi tionally at various orientations relative to one another) create lon-caprolactone, p-dioxanone (1,4-dioxan-2-one); trimeth a stronger implant. Additionally, ?lms disclosed herein may ylene carbonate (1,3-dioxan-2-one); alkyl derivatives of tri be continuous or discontinuous. methylene carbonate; A-valerolactone; [3-butyrolactone; [0044] The ?lm 10 is positioned adjacent the mesh 20 and y-butyrolactone; e-decalactone; hydroxybutyrate; hydroxy as illustrated in FIGS. 2A and 2B, the ?lm 10a, 10b is present valerate; 1,4-dioxepan-2-one (including its dimer 1,5,8,12 of a ?rst and second surface (20a, 20b) of the mesh 20, tetraoxacyclotetradecane-7,14-dione); 1,5-dioxepan-2-one; encapsulating the mesh 20 therein. The mesh 20 is illustrated 6,6-dimethyl-1,4-dioxan-2-one; 2,5-diketomorpholine; piv as a mono?lament mesh 20; hoWever, implants comprising alolactone; 0t,0t diethylpropiolactone; ethylene carbonate; multi?lament mesh are Within the scope of the present dis ethylene oxalate; 3-methyl-1,4-dioxane-2,5-dione; 3,3-di closure. The mono?lament mesh 20 includes spaces and/or ethyl-1,4-dioxan-2,5-dione; 6,8-dioxabicycloctane-7-one; pores Which may be formed by the intersection of at least tWo and polymer blends and copolymers thereof. In certain ?laments. The ?lm 10 may also penetrate Within the pores or embodiments, the mesh may comprise an aliphatic polyester. spaces Within or betWeen the mesh 20, interlocking thereWith. [0038] Other suitable biodegradable polymers include, but [0045] Another embodiment of an implant according to the present disclosure is illustrated in FIGS. 3, 4A, and 4B. An are not limited to, poly(amino acids) including proteins such implant 100 comprises a rapidly degrading ?lm 110 in direct as collagen (I, II and III), elastin, ?brin, ?brinogen, silk, and contact With a mesh 120. The mesh 120 comprises mono?la albumin; peptides including sequences for laminin and ment threads 122 (illustrated in the cross-sectional vieW, FIG. ?bronectin (RGD); polysaccharides such as hyaluronic acid 4). The rapidly degrading ?lm 110 is in direct contact With a (HA), dextran, alginate, chitin, chitosan, and cellulose; gly ?rst side 12011 of the mesh. The mono?lament mesh 120 may cosaminoglycan; gut; and combinations thereof. Collagen as include spaces and/or pores Which, in embodiments, may be used herein includes natural collagen such as animal derived penetrable by the ?lm 110. In other embodiments, one layer collagen, gelatiniZed collagen, or synthetic collagen such as of the ?lm 110 may be in direct contact With the mesh 120, human or bacterial recombinant collagen. covering at least a portion of the ?rst surface 120a thereof. In [0039] Additionally, synthetically modi?ed natural poly some embodiments, the ?lm 110 may penetrate pores of the mers such as cellulose and polysaccharide derivatives, mesh knit or Weave 120. including alkyl celluloses, hydroxyalkyl celluloses, cellulose [0046] In general, the ?lm covers at least a portion of the ethers, cellulose esters, nitrocelluloses, and chitosan may be mesh. The ?lm may be positioned adjacent to at least a ?rst utiliZed. Examples of suitable cellulose derivatives include surface of the mesh and in certain embodiments, the ?lm at methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, least partially penetrates into a ?rst surface of the mesh. In yet hydroxypropyl methyl cellulose, hydroxybutyl methyl cellu alternate embodiments, the ?lm may be embedded at least lose, cellulose acetate, cellulose propionate, cellulose acetate partially or entirely Within the mesh construct (2 -dimensional butyrate, cellulose acetate phthalate, carboxymethyl cellu or 3-dimensional), penetrating into the pores and/ or inter lose (CMC), cellulose triacetate, and cellulose sulfate sodium stices of the mesh. It should be understood that above salt. These may be collectively referred to herein, in embodi examples are non-limiting and other constructs are envi ments, as “celluloses.” sioned Which comprise the combination of a ?lm and a mesh. US 2011/0232838 A1 Sep. 29, 2011

[0047] As discussed hereinabove, the ?lm may comprise a released at the same rate. Similarly, the ?rst and second thera multi-laminar or multilayer construct. The multi-laminar peutic agents may have the same release rate, hoWever, the construct may provide for different release rates and kinetics. ?rst therapeutic agent may be released over less or more The ?rst therapeutic agent may be disposed therein at least hours/days/Weeks as compared to the second therapeutic one layer of the multi-laminar ?lm. In one embodiment, the agent (longer or shorter persistence). For example, at 37° C., multi-laminar ?lm includes a ?lm having at least one barrier a ?rst therapeutic agent such as bupivacaine hydrochloride layer disposed thereon. The barrier layer may or may not may have a release rate of 7.5 mg/hour for a total of 10 hours include a bioactive agent. Additionally, the multi-laminar (releasing 75 mg), While the second therapeutic agent such as construct may utiliZe different polymers and different crystal bupivacaine (free base) may have a release rate of 7.5 structures of varying polymers to optimiZe drug delivery/ mg/hour for a total of 72 hours (releasing 540 mg). release into the surrounding environment. [0052] The ?rst therapeutic agent may be released in situ [0048] Films of the present disclosure may be rapidly from about less than 24 hours after implantation, in certain degrading or rapidly absorbing. The rapidly degrading ?lm at embodiments, from less than about 1 hour after implantation. least partially degrades from about less than 24 hours after The second therapeutic agent may be released in situ from implantation. The rapidly degrading ?lm may entirely about greater than 24 hours, and in certain embodiments, degrade from about less than 24 hours folloWing implanta from about 3 days (72 hours) to about 14 days after implan tion. In certain embodiments, the rapidly degrading ?lm tation. In certain embodiments, the second therapeutic agent degrades from about less than one hour after implantation. may begin releasing in situ less than about 24 hours and The rapid degradation of the ?lm may enable a faster delivery continue to release for about 14 days folloWing implantation. of the ?rst therapeutic agent to the patient. In one non-limiting [0053] More speci?cally, When the ?rst and second thera example, bupivacaine hydrochloride is combined With a peutic agents comprise bupivacaine hydrochloride, the ?rst CMC ?lm (in solution using standard mixing techniques). therapeutic agent may have a delivery of 7.5-10 milligrams/ Once implanted, the CMC ?lm may hydrolyZe in less than hour for a total time period of less than 24 hours, While the one hour in situ, delivering a predetermined payload of bupi second therapeutic agent may have a delivery of 7.5 milli vacaine hydrochloride to the patient in less than one hour. grams/hour, for a total time period of greater than 24 hours. [0049] Surgical implants include therapeutic agents Which [0054] In certain embodiments, at least the ?rst therapeutic are delivered or carried to the tissue site and released over a agent comprises bupivacaine hydrochloride. In other embodi speci?ed time period. More speci?cally, the ?rst therapeutic ments, at least the second therapeutic agent comprises bupi agent is delivered or carried to the implant/tissue site by the vacaine (free base). ?lm component. The ?lm serves as the delivery vehicle for [0055] In certain embodiments, at least the ?rst therapeutic transporting the ?rst therapeutic agent into the body. The ?rst agent comprises capsaicin. In other embodiments, at least the therapeutic agent may be contained on or Within the ?lm second therapeutic agent comprises capsaicin. utiliZing a variety of methods, for example, the ?rst therapeu [0056] In other embodiments, the therapeutic agents have tic agent may be contained Within micro/nanospheres, lipo different release rates. The term rate as used herein should be somes, carbon nanotubes, micro/nanoparticles, drug mac understood to relate to a therapeutic payload/unit time. For romers, polymer drugs, prodrugs, other nano structures, and example, the second release rate may be sloWer compared to the like, and using various salt forms, incorporated in the ?lm. the ?rst release rate. Upon implantation, both the ?rst and The ?rst therapeutic agent may also be impregnated Within second therapeutic agents may begin to elute into the sur the ?lm in the form of a particulate suspension or emulsion. rounding tissue. The ?rst therapeutic agent is released into [0050] The second therapeutic agent is delivered or carried tissue immediately upon implantation (bolus release), While to the implant/tissue site by the mesh component. The mesh the second therapeutic agent is delivered at a sloWer rate, serves as the delivery vehicle for transporting the second Which may be through a sustained or controlled release over therapeutic agent. The second therapeutic agent may be con the folloWing days/Weeks. tained on or Within the mesh. For example, the mesh may [0057] Conversely, in other embodiments, the ?rst thera comprise a coating Which includes the second therapeutic peutic agent may have a sloWer release rate as compared to the agent. In another non-limiting example, the second therapeu second therapeutic agent. tic agent may be compounded Within the polymer resin, com [0058] As previously stated, in certain embodiments, the prising at least one ?lament of the mesh. In another example, ?rst and second therapeutic agents are released over time the therapeutic agent may be disposed around or Within inter periods ranging from minutes to Weeks. For example, the ?rst stices of the mesh. In yet an alternate example, at least one therapeutic agent may comprise a local anesthetic, to assist in ?lament of the mesh may comprise a polymer drug, Wherein providing local pain relief during surgery, the ?rst therapeutic upon degradation of the ?lament, the polymer drug is hydro agent having a persistence of less than 6 hours. The second lyZed and released into the surrounding tissue in either mono therapeutic agent may comprise an analgesic to relieve longer mer or polymer form. In alternate embodiments, the second term pain associated With healing or in?ammation. The sec therapeutic agent may be contained Within microspheres or ond therapeutic agent may have a persistence of from about a microparticles. Similar to the ?rst therapeutic agent, the sec feW hours (or immediately folloWing surgery), to several ond therapeutic agent may also be impregnated Within a coat Weeks post operation. In certain embodiments, the second ing in the form of a particulate suspension or emulsion. therapeutic agent may have a persistence of from about 24 [0051] Therapeutic agents of the present disclosure are hours to about 7 days folloWing surgery. released into the surrounding tissue at various elution or [0059] In one embodiment, Where the ?lm comprises a fast release rates (dose/unit time). More speci?cally, the ?rst degrading ?lm, due to fast hydrolysis or degradation of the therapeutic agent may be released at a ?rst rate and the second ?lm component, the ?rst therapeutic agent may have a faster therapeutic agent may be released at a second rate. In other release rate, such as a bolus release compared to the second embodiments, the ?rst and second therapeutic agents may be agent disposed on or Within the mesh. In certain embodi US 2011/0232838 A1 Sep. 29, 2011

ments, the ?lm component may at least partially degrade Within interstices or pores in the mesh, compounded into the before the second therapeutic agent is eluted into the sur resin or otherWise incorporated therein. The second therapeu rounding environment. In other Words, the ?rst therapeutic tic agent may also comprise suspensions or emulsions, micro agent may shield, protect or otherWise provide a barrier to the particles, ?bers and the like, Which may be combined or release of the second therapeutic agent. It is also envisioned otherWise incorporated into the Woven or knit mesh. For that the release of the ?rst therapeutic agent may trigger example, the controlled release of the second therapeutic environmental changes (e.g., pH and ionicity) Which signal agent may correspond to the degradation of at least one ?la the release of the second therapeutic agent. In yet alternate ment of the mesh. Coating materials may comprise polymers embodiments, the second therapeutic agent may diffuse not limited to those listed herein. through the ?lm, releasing into the surrounding environment. [0066] It should be understood that as described herein, the [0060] Concentrations and doses of therapeutic agents of therapeutic agents are both localiZed methods of drug deliv the present disclosure may vary depending on drug choice or ery, hoWever, the therapeutic agent(s) may also be distributed patient condition. For example, one patient may require more to the surrounding tissues and organs (such as surrounding or less of a speci?c therapeutic agent as compared to another. vasculature) and even dispersed systemically. The dosing rates of different therapeutic agents may vary [0067] Suitable ?rst and second therapeutic agents While e?icacy remains similar. For example, a loWer concen employed in the present disclosure may include analgesics, tration of a ?rst therapeutic agent may be required for a ?rst anesthetics, anti-in?ammatory agents (steroidal and non-ste therapeutic effect, While a higher concentration of a second roidal), antispasmodic agents, groWth factors, gene-based therapeutic agent may be required for a second therapeutic therapeutic agents and combinations thereof. The ?rst thera effect. peutic agent may be the same as or different than the second [0061] The ?rst and second therapeutics may have a bolus therapeutic agent. The therapeutic agents may be the same release or sustained delivery/release into the surrounding class of agents, i.e., both the ?rst and second therapeutics may environment, the release kinetics of Which may correspond to comprise analgesics. Zero order, ?rst order, second order, third order, nth order and [0068] More speci?cally, analgesics such as narcotic anal combinations thereof. Additionally, releases may be diffu gesic therapeutic agents include, but are not limited to: alfen sion, partition, or solubility controlled. tanil, allylprodine, alphaprodine, anileridine, benZylmor [0062] In general, therapeutic agents may be incorporated phine, beZitramide, buprenorphine, butorphanol, clonitaZene, into the implant during manufacture or formation of the codeine, codeine methyl bromide, codeine phosphate, implant, such as by free solution, suspension, liposomal codeine sulfate, desomorphine, dextromoramide, deZocine, delivery, microspheres, etc., or by coating a surface of the diampromide, dihydrocodeine, dihydrocodeinone enol implant, or selective regions thereof, such as by polymer acetate, dihydromorphine, dimenoxadol, dimepheptanol, coating, dry coating, freeZe drying, applying directly to the dimethylthiambutene, dioxaphetyl butyrate, dipipanone, mesh or implant surface; ionically, covalently, or a?inity eptaZocine, ethoheptaZine, ethylmethylthiambutene, ethyl binding to functionaliZe the components of the implant. Thus, morphine, etonitaZene, fentanyl, hydrocodone, hydromor at least one therapeutic agent may be combined With a com phone, hydroxypethidine, isomethadone, ketobemidone, ponent of the implant i.e., the mesh and/or ?lm, to provide levorphanol, lofentanil, meperidine, meptaZinol, metaZocine, release of the therapeutic agent during implantation and in methadone hydrochloride, metopon, morphine, myrophine, some embodiments, release of the therapeutic agent via deg nalbuphine, narceine, nicomorphine, norlevorphanol, radation of the implant. In some embodiments, as the implant normethadone, normorphine, norpipanone, opium, oxyc degrades or hydrolyZes in situ, the therapeutic agents are odone, oxymorphone, papavereturn, pentaZocine, phenadox released. In other embodiments, therapeutic agents may be one, phenaZocine, pheoperidine, piminodine, piritramide, included in the ?lm component (or a selective region(s) proheptaZine, promedol, properidine, propiram, pro thereof) for rapid release of the bioactive agent. poxyphene, rumifentanil, sufentanil, tilidine, and pharma [0063] The delivery mechanism for the ?rst therapeutic ceutically acceptable salts thereof. agent is the ?lm, Which in certain embodiments, is a rapidly [0069] Exemplary non-narcotic analgesic agents that may degrading ?lm. The ?lm may comprise a Water soluble poly be combined With the implants of the invention include, but mer Which, upon implantation, begins dissolution, releasing are not limited to, aceclofenac, acetaminophen, acetaminos the ?rst therapeutic agent. It should be understood, as simi alol, acetanilide, acetylsalicylsalicylic acid (aspirin), larly stated above, that the term degrading includes decom alclofenac, alminoprofen, aloxiprin, aluminum bis(acetyl position, enZymatic degradation, hydrolysis or dissolution, salicylate), aminochlorthenoxaZin, 2-amino-4-picoline, ami Wherein the materials are broken doWn (physically or chemi nopropylon, aminopyrine, ammonium salicylate, amtolmetin cally) under physiologic conditions in the body and the deg guacil, antipyrine, antipyrine salicylate, antrafenine, apa radation products are excretable or absorbable by the body. Zone, benorylate, benoxaprofen, benZpiperylon, benZy [0064] The ?rst therapeutic agent may be formulated into damine, bermoprofen, brofenac, p-bromoacetanilide, 5-bro the polymer ?lm in the form of an emulsion, suspension or mosalicylic acid acetate, bucetin, bufexamac, bumadiZon, other heterogeneous mixture; or mixed in as a homogeneous butacetin, calcium acetylsalicylate, capsaicin, carbam solution prior to, during, or after ?lm formation. Solvents for aZepine, carbiphene, carsalam, celecoxib, chloralantipyrine, use in creating ?lms of the present disclosure include polar, chlorthenoxaZin(e), choline salicylate, cinchophen, cirama non-polar solvents, buffers, and the like. Films may be made dol, clometacin, cropropamide, crotethamide, dexoxadrol, from solutions using methods such as ?lm casting, Which are diclofenac, difenamiZole, di?unisal, dihydroxyaluminum later described. acetylsalicylate, dipyrocetyl, dipyrone, emorfaZone, enfe [0065] The second therapeutic agent is delivered to the namic acid, epiriZole, etersalate, ethenZamide, ethoxaZene, surrounding tissue via the mesh. The second therapeutic etodolac, felbinac, fenoprofen, ?octafenine, ?ufenamic acid, agent may be in the form of a coating on the mesh, trapped ?uoresone, ?upirtine, ?uproquaZone, ?urbiprofen, fosfosal, US 2011/0232838 A1 Sep. 29, 2011

gabapentin, gentisic acid, glafenine, ibufenac, ibuprofen, imi nophen, ibuprofen, naproxen sodium, buprenorphine, pro daZole salicylate, indomethacin, indoprofen, isofeZolac, iso poxyphene hydrochloride, propoxyphene nap sylate, meperi ladol, isonixin, ketoprofen, ketorolac, p-lactophenetide, lefe dine hydrochloride, hydromorphone hydrochloide, tamine, loxoprofen, lysine acetylsalicylate, magnesium morphine, oxycodone, codeine, dihydrocodeine bitartrate, acetylsalicylate, methotrimepraZine, metofoline, miroprofen, pentaZocine, hydrocodone bitartrate, levorphanol, di?unisal, moraZone, morpholine salicylate, naproxen, nefopam, trolamine salicylate, nalbuphine hydrochloride, mefenamic nifenaZone, 5' nitro-2' propoxyacetanilide, parsalmide, acid, butorphanol, choline salicylate, butalbital, phenyltolox perisoxal, phenacetin, phenaZopyridine hydrochloride, phe amine citrate, diphenhydramine citrate, methotrimepraZine, nocoll, phenopyraZone, phenyl acetylsalicylate, phenyl sali cinnamedrine hydrochloride, and meprobamate); antiast cylate, phenyramidol, pipebuZone, piperylone, pregabalin, hamatics (e.g., ketotifen and traxanox); antibiotics (e.g., neo prodilidine, propacetamol, propyphenaZone, proXaZole, qui mycin, streptomycin, chloramphenicol, cephalosporin, ampi nine salicylate, ramifenaZone, rimaZolium metilsulfate, sal acetamide, salicin, salicylamide, salicylamide o-acetic acid, cillin, penicillin, tetracycline, and cipro?oxacin); salicylsulfuric acid, salsalte, salverine, simetride, sodium antidepressants (e.g., nefopam, oxypertine, doxepin, amox salicylate, sulfamipyrine, suprofen, talni?umate, tenoxicam, apine, traZodone, amitriptyline, maprotiline, phenelZine, terofenamate, tetradrine, tinoridine, tolfenamic acid, tolpro duloxetine, desipramine, nortriptyline, tranylcypromine, ?u nine, tramadol, TRPAl modulators, TRPM8 modulators, oxetine, doxepin, imipramine, imipramine pamoate, isocar TRPVl modulators, viminol, xenbucin, Zomepirac, and phar boXaZid, trimipramine, and protriptyline); antidiabetics (e.g., maceutically acceptable salts thereof. biguanides and sulfonylurea derivatives); antifungal agents (e.g., griseofulvin, ketoconaZole, itraconiZole, amphotericin [0070] Exemplary local anesthetic therapeutic agents B, nystatin, and candicidin); antihypertensive agents (e.g., include, but are not limited to, ambucaine, amolanone, amy propanolol, propafenone, oxyprenolol, nifedipine, reserpine, localne hydrochloride, benoxinate, benZocaine, betoxycaine, trimethaphan, phenoXybenZamine, pargyline hydrochloride, biphenamine, bupivacaine, butacaine, butaben, butanilicaine, deserpidine, diaZoxide, guanethidine monosulfate, minoxi butethamine, butoxycaine, carticaine, chloroprocaine hydro dil, rescinnamine, sodium nitroprusside, rauWol?a serpen chloride, cocaethylene, cocaine, cyclomethycaine, dibucaine tina, alseroxylon, and phentolamine); anti-in?ammatories hydrochloride, dimethisoquin, dimethocaine, diperadon (e.g., (non-steroidal) indomethacin, ketoprofen, aspirin, hydrochloride, dyclonine, ecgonidine, ecgonine, ethyl chlo diclofenac, ketorolac, ?urbiprofen, naproxen, ibuprofen, ride, beta-eucaine, euprocin, fenalcomine, fomocaine, hexy ramifenaZone, piroxicam, celecoxib, rofecoxib, (steroidal) lcaine hydrochloride, hydroxytetracaine, isobutyl p-ami cortisone, dexamethasone, ?uazacort, hydrocortisone, pred nobenZoate, leucinocaine mesylate, levobupivacaine, nisolone, and prednisone); antineoplastics (e.g., cyclophos levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutox phamide, actinomycin, bleomycin, dactinomycin, daunoru ycaine, methyl chloride, myrtecaine, naepaine, octacaine, bicin, doxorubicin, epirubicin, mitomycin, methotrexate, orthocaine, oXethaZaine, parethoxycaine, phenacaine hydro ?uorouracil, gemcitabine, carboplatin, carmustine (BCNU), chloride, phenol, piperocaine, piridocaine, polidocanol, methyl-CCNU, cisplatin, etoposide, camptothecin and pramoxine, prilocaine, procaine, propanocaine, propara derivatives thereof, phenesterine, paclitaxel and derivatives caine, propipocaine, propoxycaine hydrochloride, pseudoco thereof, docetaxel and derivatives thereof, vinblastine, vinc caine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine ristine, goserelin, leuprolide, tamoxifen, interferon alfa, ret hydrochloride, tolycaine, trimecaine, Zolamine, and pharma inoic acid (ATRA), nitrogen mustard alkylating agents, and ceutically acceptable salts thereof. piposulfan); antianxiety agents (e.g., loraZepam, buspirone, [0071] Other therapeutic agents Which may be utiliZed in praZepam, chlordiaZepoXide, oXaZepam, cloraZepate dipotas accordance With the present disclosure include drugs, amino sium, diaZepam, hydroXyZine pamoate, hydroXyZine hydro acids, peptides, polypeptides, proteins, polysaccharides, chloride, alpraZolam, droperidol, halaZepam, chlormeZa muteins, immunoglobulins, antibodies, cytokines (e.g., lym none, and dantrolene); immunosuppressive agents (e.g., phokines, monokines, chemokines), blood clotting factors, cyclosporine, aZathioprine, miZoribine, and FK506 (tacroli hemopoietic factors, interleukins (1 through 18), interferons mus)); antimigraine agents (e.g., triptans such as sumatriptan, ([3-IFN, ot-IFN and y-IFN), erythropoietin, nucleases, tumor ergotamine, propanolol, isometheptene mucate, and dichlo necrosis factor, colony stimulating factors (e.g., GCSF, GM ralphenaZone); sedatives/hypnotics (e.g., barbiturates such as CSF, MCSF), insulin, anti-tumor agents and tumor suppres sors, blood proteins, ?brin, thrombin, ?brinogen, synthetic pentobarbital, pentobarbital, and secobarbital; and benZodi thrombin, synthetic ?brin, synthetic ?brinogen, gonadotro aZapines such as ?uraZepam hydrochloride, triaZolam, and pins (e.g., FSH, LH, CG, etc.), hormones and hormone ana midaZolam); antianginal agents (e.g., beta-adrenergic block logs (e.g., groWth hormone, luteiniZing hormone releasing ers; calcium channel blockers such as nifedipine, and dilt factor), vaccines (e.g., tumoral, bacterial and viral antigens); iaZem; and nitrates such as nitroglycerin, isosorbide dinitrate, somatostatin; antigens; blood coagulation factors; groWth pentearythritol tetranitrate, and erythrityl tetranitrate); antip factors (e.g., nerve groWth factor, insulin-like groWth factor); sychotic agents (e.g., haloperidol, loxapine succinate, loxap bone morphogenic proteins, TGF-B, protein inhibitors, pro ine hydrochloride, thioridaZine, thioridaZine hydrochloride, tein antagonists, and protein agonists; nucleic acids, such as thiothixene, ?uphenaZine, ?uphenaZine decanoate, ?uphena antisense molecules, DNA, RNA, RNAi, sRNA; oligonucle Zine enanthate, tri?uoperaZine, chlorpromaZine, perphena otides; polynucleotides; cells (including stem cells, adult, Zine, lithium citrate, and prochlorperaZine); antimanic agents embryonic, or induced) viruses, and riboZymes. (e.g., lithium carbonate); antiarrhythmics (e.g., bretylium [0072] In embodiments, the therapeutic agent may include tosylate, esmolol, verapamil, amiodarone, encamide, at least one of the folloWing drugs, including combinations digoxin, digitoxin, mexiletine, disopyramide phosphate, and alternative forms of the drugs such as alternative salt procainamide, quinidine sulfate, quinidine gluconate, quini forms, free acid form, free base forms, pro-drugs and dine polygalacturonate, ?ecamide acetate, tocamide, and hydrates: analgesics/antipyretics (e.g., aspirin, acetami lidocaine); antiarthritic agents (e.g., phenylbutaZone, sulin US 2011/0232838 A1 Sep. 29, 2011

dac, penicillanine, salsalate, piroxicam, aZathioprine, nedocromil sodium; metaproterenol sulfate; albuterol; indomethacin, meclofenamate, gold sodium thiomalate, ?unisolide; ?uticasone proprionate; steroidal compounds and ketoprofen, aurano?n, aurothioglucose, and tolmetin hormones (e.g., androgens such as danaZol, testosterone cypi sodium); antigout agents (e.g., colchicine, and allopurinol); onate, ?uoxymesterone, ethyltestosterone, testosterone anticoagulants (e.g., heparin, heparin sodium, and Warfarin enathate, methyltestosterone, ?uoxymesterone, and testoster sodium); thrombolytic agents (e.g., urokinase, streptokinase, one cypionate; estrogens such as estradiol, estropipate, and and alteplase); anti?brinolytic agents (e.g., aminocaproic conjugated estrogens; progestins such as methoxyprogester acid); hemorheologic agents (e.g., pentoxifylline); antiplate one acetate, and norethindrone acetate; corticosteroids such let agents (e.g., aspirin); anticonvulsants (e.g., Valproic acid, as triamcinolone, betamethasone, betamethasone sodium divalproex sodium, phenyloin, phenyloin sodium, clon phosphate, dexamethasone, dexamethasone sodium phos aZepam, primidone, phenobarbitol, carbamaZepine, amobar phate, dexamethasone acetate, prednisone, methylpredniso bital sodium, methsuximide, metharbital, mephobarbital, lone acetate suspension, triamcinolone acetonide, methyl mephenyloin, phensuximide, paramethadione, ethotoin, prednisolone, prednisolone sodium phosphate, phenacemide, secobarbitol sodium, cloraZepate dipotassium, methylprednisolone sodium succinate, hydrocortisone and trimethadione); antiparkinson agents (e.g., ethosuxim sodium succinate, triamcinolone hexacetonide, hydrocorti ide); antihistamines/antipruritics (e.g., hydroXyZine, diphen sone, hydrocortisone cypionate, prednisolone, ?udrocorti hydramine, chlorpheniramine, brompheniramine maleate, sone acetate, paramethasone acetate, prednisolone tebutate, cyproheptadine hydrochloride, terfenadine, clemastine prednisolone acetate, prednisolone sodium phosphate, and fumarate, triprolidine, carbinoxamine, diphenylpyraline, hydrocortisone sodium succinate; and thyroid hormones such phenindamine, aZatadine, tripelennamine, dexchlorphe as levothyroxine sodium); hypoglycemic agents (e.g., human niramine maleate, methdilaZine, and); agents useful for cal insulin, puri?ed beef insulin, puri?ed pork insulin, glyburide, cium regulation (e.g., calcitonin, and parathyroid hormone); chlorpropamide, glipiZide, tolbutamide, and tolaZamide); antibacterial agents (e.g., amikacin sulfate, aZtreonam, hypolipidemic agents (e.g., clo?brate, dextrothyroxine chloramphenicol, chloramphenicol palirtate, cipro?oxacin, sodium, probucol, pravastitin, atorvastatin, loVastatin, and clindamycin, clindamycin palmitate, clindamycin phosphate, niacin); proteins (e.g., DNase, alginase, superoxide dismu metronidaZole, metronidaZole hydrochloride, gentamicin tase, and lipase); nucleic acids (e.g., sense or anti-sense sulfate, lincomycin hydrochloride, tobramycin sulfate, Van nucleic acids encoding any therapeutically useful protein, comycin hydrochloride, polymyxin B sulfate, colistimethate including any of the proteins described herein); agents useful sodium, and colistin sulfate); antiviral agents (e.g., interferon for erythropoiesis stimulation (e.g., erythropoietin); antiul alpha, beta or gamma, ZidoVudine, amantadine hydrochlo cer/antire?ux agents (e.g., famotidine, cimetidine, and raniti ride, ribavirin, and acyclovir); antimicrobials (e.g., cepha dine hydrochloride); antinauseants/antiemetics (e.g., mecliZ losporins such as cefaZolin sodium, cephradine, cefaclor, ine hydrochloride, nabilone, prochlorperaZine, cephapirin sodium, ceftiZoxime sodium, cefoperaZone dimenhydrinate, promethaZine hydrochloride, thiethylpera sodium, cefotetan disodium, cefuroxime e aZotil, cefotaxime Zine, and scopolamine); proton pump inhibitors (e.g., ome sodium, cefadroxil monohydrate, cephalexin, cephalothin praZole); erectile dysfunction therapies (e.g., sildena?l, Vard sodium, cephalexin hydrochloride monohydrate, cefaman ena?l, tadala?l, and alprostadil); as Well as other drugs useful dole nafate, cefoxitin sodium, cefonicid sodium, ceforanide, in the compositions and methods described herein include ceftriaxone sodium, ceftaZidime, cefadroxil, cephradine, and mitotane, halonitrosoureas, anthrocyclines, ellipticine, ceftri cefuroxime sodium; penicillins such as ampicillin, amoxicil axone, ketoconaZole, ceftaZidime, oXaproZin, albuterol, Vala lin, penicillin G benZathine, cyclacillin, ampicillin sodium, cyclovir, urofollitropin, famciclovir, ?utamide, enalapril, penicillin G potassium, penicillin V potassium, piperacillin mefformin, itraconaZole, buspirone, gabapentin, fosinopril, sodium, oxacillin sodium, bacampicillin hydrochloride, clox tramadol, acarbose, loraZepan, follitropin, glipiZide, omepra acillin sodium, ticarcillin disodium, aZlocillin sodium, carbe Zole, ?uoxetine, lisinopril, tramsdol, levo?oxacin, nicillin indanyl sodium, penicillin G procaine, methicillin Za?rlukast, interferon, groWth hormone, interleukin, erythro sodium, and nafcillin sodium; erythromycins such as eryth poietin, granulocyte stimulating factor, niZatidine, bupro romycin ethylsuccinate, erythromycin, erythromycin esto pion, perindopril, erbumine, adenosine, alendronate, alpros late, erythromycin lactobionate, erythromycin stearate, and tadil, benaZepril, betaxolol, bleomycin sulfate, erythromycin ethyl succinate; and tetracyclines such as tetra dexfen?uramine, diltiaZem, fentanyl, ?ecainid, gemcitabine, cycline hydrochloride, doxycycline hyclate, and minocycline glatiramer acetate, grani setron, lamivudine, mangafodipir tri hydrochloride, aZithromycin, clarithromycin); anti-infec sodium, mesalamine, metoprolol fumarate, metronidaZole, tiVes (e.g., GM-CSF); bronchodilators (e.g., sympathomi miglitol, moexipril, monteleukast, octreotide acetate, olo metics such as epinephrine hydrochloride, metaproterenol patadine, paricalcitol, somatropin, sumatriptan succinate, sulfate, terbutaline sulfate, isoetharine, isoetharine mesylate, tacrine, Verapamil, nabumetone, trova?oxacin, dolasetron, isoetharine hydrochloride, albuterol sulfate, albuterol, ZidoVudine, ?nasteride, tobramycin, isradipine, tolcapone, bitolterolmesylate, isoproterenol hydrochloride, terbutaline enoxaparin, ?uconaZole, lansopraZole, terbina?ne, pamidr sulfate, epinephrine bitartrate, metaproterenol sulfate, epi onate, didanosine, diclofenac, cisapride, Venlafaxine, trogli nephrine, and epinephrine bitartrate; anticholinergic agents taZone, ?uvastatin, losartan, imiglucerase, donepeZil, olanZa such as ipratropium bromide; Xanthines such as aminophyl pine, Valsartan, fexofenadine, calcitonin, and ipratropium line, dyphylline, metaproterenol sulfate, and aminophylline; bromide. In some embodiments, the drug may be Water mast cell stabiliZers such as cromolyn sodium; inhalant cor soluble. In some embodiments, the drug may not be Water ticosteroids such as beclomethasone dipropionate (BDP), and soluble. beclomethasone dipropionate monohydrate; salbutamol; [0073] The rate of release of a therapeutic agent can be ipratropium bromide; budesonide; ketotifen; salmeterol; Xin controlled by any means Within the purvieW of one skilled in afoate; terbutaline sulfate; triamcinolone; theophylline; the art. Some examples include, but are not limited to, the US 2011/0232838 A1 Sep. 29, 2011

depth of the therapeutic agent from the surface of the ?lm, the scopic deployment device, trocar, or other device. The mesh siZe of the therapeutic agent, the hydrophilicity/hydrophobic may be rolled or folded so as to ?t Within the device for ity of the therapeutic agent, and the strength of physical and transfer into the body cavity. physical-chemical interaction betWeen the therapeutic agent, [0079] More broadly, the present disclosure recogniZes that the rapidly degrading ?lm and/or the mesh material. By prop the implant can have any shape that conforms to an anatomi erly controlling some of these factors, a controlled release of cal surface of a human or animal body that may be subject to a therapeutic agent from the implant of the present disclosure a defect to be repaired by the implant. can be achieved. [0080] In another embodiment, the surgical implant of the [0074] Films of the present disclosure may be prepared present disclosure may comprise a backing strip Which may using casting techniques. In some embodiments, implants of releasably attach to the implant. The backing strip may be the present disclosure may be formed using a mold such as formed from a range of materials, including plastics, and may one illustrated in FIGS. 5 and 6. The mold 200 has a base 210 releasably attach using an adhesive. and side Walls 220. Although the base 210 and side Walls 220 [0081] The releasable attachment of a backing strip to the are shoWn generally rectangular in shape, they may comprise implant may provide a more rigid and less ?exible surgical other shapes. The mold 220 includes shims 230 Which are implant, Which may be more easily handled by a surgeon. disposed parallel to each other on an upper surface of the base Following suitable placement of the surgical implant, the 210. The molds may also include a non-stick coating or sur backing strip can be removed from the surgical implant, the face, such as silicone or polyester terephthalate, for ease of surgical implant being retained in the body and the backing manufacturing. It should be noted that any number of shims material being removed by the surgeon. The surgical implant 230 may be employed, as Well as any desired alignment to can therefore bene?t from reduced mass While still providing create implants of various shapes. The mesh may be com characteristics required for surgical handling. bined With a polymer solution or cast ?lm and placed in the mold. In some embodiments, the implant may need to cure or Example 1 dry for a speci?ed amount of time under set temperature, humidity and pressure. The height of the shims and the base [0082] A 2% Weight/volume stock solution is created by may vary so that the mesh can be placed nearer to one surface combining medium viscosity CMC (MWIISO k-400 k or placed a set distance aWay from the implant surface. g/mol) and deioniZed Water using a mechanical stirrer. The CMC solution is then combined With glycerol in a 5:1 ratio [0075] In other embodiments, ?lms may be pre-cast and later combined With the mesh component to create an (CMC: glycerol), and left stirring With a stir bar for about 240 implant. The ?lms may be adhered of otherWise combined minutes. Next, bupivacaine (MW:324.89, from Sigma Ald With the mesh using techniques not limited to solvent Weld rich) is added to the CMC/ glycerol solution using a mechani ing, heat staking, compression ?tting, or the use of adhesives, cal stir bar (at ambient temperature). The concentration of the glues, sealants, epoxies or combinations thereof. For bupivacaine in solution is about 0.25-0.75% Wt/vol. example, the mesh may be coated With a monomer solution [0083] Next, a sheet of polyester mesh is dip coated in a and then placed/pressed adjacent the mesh, creating an bupivacaine solution and dried in the oven overnight at 400 implant of the present. If tWo layers of ?lm are desired, a Celsius and 40% relative humidity. similar technique may be used to apply the second ?lm layer. [0084] The bupivacaine-coated polyester mesh is then [0076] Upon implantation of the implant in vivo, the ?lm placed in a silicone-coated mold, siZed to ?t the mesh. The bupivacaine/ CMC/ glycerol solution is poured over the mesh, solubiliZes in the aqueous environment, releasing the ?rst therapeutic agent. In some embodiments, the ?rst therapeutic creating a uniform ?lm, and then placed in an oven overnight is released from about less than one day, in further embodi at a temperature of about 45° Celsius. ments, from about less than one hour. Sometime thereafter, [0085] A mesh according to the present disclosure can be the second therapeutic agent is released through a second inserted through a small incision (e.g., from about 1 cm to mechanism, and in preferred embodiments, the second thera about 2 cm in length) or tissue puncture With the use of a peutic agent is released from the mesh. The release of the laparoscopic deployment device, such as a needle or trocar. second therapeutic agent is from about more than one day, The mesh may be rolled or folded so as to ?t Within the device and in further embodiments, from about three days to about for transfer into the body cavity. In embodiments utiliZing an fourteen days. absorbable ?lm, the absorbable ?lm may provide suf?cient stiffness to the mesh upon exiting the transfer device, to [0077] Implants of the present disclosure must have su?i re-open the rolled or folded mesh into its original geometric cient structural integrity and physical properties to facilitate shape. the surgeon’s ease of handling in the operating room as Well as positioning in vivo. Materials selection in addition to pro Example 2 cessing/manufacturing constraints can be used to alter/con trol the strength and physical properties of the surgical [0086] Mesh/?lm compositions as prepared in Example 1 implant. Were evaluated for in vivo bupivacaine HCl release and e?i [0078] Desired properties of composite mesh include ?ex cacy using rodent subcutaneous and back incisional acute ible enough, conforming to tissue and being repositionable, postoperative pain preclinical models, respectively. Brie?y, yet stiff enough to be unfolded after insertion, perhaps Sprague-DaWley rats Were anesthetiZed and a 2 cm incision through a laparoscopic port. Additionally, other materials Was made through the skin of the back on midline and a small such as a polymer coating or polymer ?bers may be incorpo pocket created by blunt dissection. Mesh/?lm and/or ?lm and rated into the mesh to increase the mesh stiffness at least for mesh alone test articles Were gently implanted into the inci insertion and implantation. A mesh according to the present sional site using forceps and Were located directly under the disclosure can be inserted through a small incision (e. g., from incision. The incisions Were closed With suture and all rats about 1 cm to about 2 cm in length) With the use of a laparo Were carefully monitored after surgery. Control groups con US 2011/0232838 A1 Sep. 29, 2011

sist of one implant control group and tWo systemic treatment 3. The method according to claim 2, Wherein the ?rst groups. Implant control groups receive mesh/?lms With no providing step comprises providing a ?rst therapeutic agent drug. The systemic controls receive either systemic morphine that is releasable from the ?lm When the ?lm degrades or (3 mg/kg) or saline (2 ml/kg) at the end of surgery and again dissolves. at 47 hr folloWing surgery (1 hr prior to 48 hr testing). In Vivo 4. The method according to claim 1, Wherein the second bupivacaine HCl release Was assessed by evaluating residual providing step comprises providing a second therapeutic bupivacaine at various time points folloWing explantation agent that is releasable from the mesh. (mass balance of remaining bupivacaine HCl) using high 5. The method according to claim 2, Wherein the second pressure liquid chromatography. Behavioral testing Was used providing step comprises providing a coating on a portion of to assess thermal response latency folloWing application of the mesh, Wherein the coating releases the second therapeutic thermal stimulus to incision sites via a diode laser. The ther agent. mal stimulus Was applied to the left side of the incision and 6. The method according to claim 1, Wherein the second the latency (in time, seconds) Was measured as response to providing step comprises providing a mesh including at least distinct tWitching or rippling of the musculature under the one degradable ?lament. skin of the stimulated area. Three response latency readings 7. The method according to claim 1, Wherein the second Were preformed for each subject at each time point. therapeutic agent is of the type that is releasable from the [0087] Results for representative bupivacaine HCl-eluting mesh When the surgical implant is implanted in tissue. CMC/ glycerol mesh integrated ?lms demonstrated the ability 8. The method according to claim 1, Wherein the second to completely prevent injury-induced hypersensitivity in the therapeutic agent is of the type that is releasable from the back incisional model of acute pain and in dose dependant mesh after the ?lm degrades or dissolves. manner. The in vivo release pro?le of bupivacaine HCl cor 9. The method according to claim 1, Wherein at least one of related With behavioral e?icacy at early time points With drug the ?rst and the second therapeutic agent is selected from the release being mostly complete by 8 hrs post-implantation group consisting of bupivacaine hydrochloride, bupivacaine, (FIGS. 7 and 8). and capsaicin. [0088] While several embodiments of the disclosure have 10. A method of manufacturing a surgical implant com been described, it is not intended that the disclosure be limited prising the steps of: thereto, as it is intended that the disclosure be as broad in providing, in a polymer solution, a ?rst therapeutic agent; scope as the art Will alloW and that the speci?cation be read providing, in a mesh, a second therapeutic agent; likeWise. Therefore, the above description should not be con applying the polymer solution to the mesh. strued as limiting, but merely as exempli?cations of embodi 11. The method according to claim 10, Wherein the step of ments of the present disclosure. Various modi?cations and applying further includes casting a ?lm from the polymer variations of the porous substrate and the reinforcement com solution over at least a portion of the surface of the mesh. ponent of the implant Will be apparent to those skilled in the 12. The method according to claim 11, Wherein the ?lm is art from the foregoing detailed description. Such modi?ca degradable or dissolvable. tions and variations are intended to come Within the scope and 13. The method according to claim 11, Wherein the ?rst spirit of the claims appended hereto. therapeutic agent is releasable from the ?lm When the ?lm What is claimed is: degrades or dissolves. 1. A method of manufacturing a surgical implant compris 14. The method according to claim 10, Wherein the second ing the steps of: providing step comprises providing a second therapeutic providing, in a ?lm, a ?rst therapeutic agent; agent that is releasable from the mesh. providing, in a mesh, a second therapeutic agent; 15. The method according to claim 10, Wherein the second applying the ?lm to the mesh. therapeutic agent is of the type that is releasable from the 2. The method according to claim 1, Wherein the ?rst mesh When the surgical implant is implanted in tissue. providing step comprises providing a ?lm that is degradable or dissolvable. * * * * *