USOO9066993B2

(12) United States Patent (10) Patent No.: US 9,066,993 B2 Matheny (45) Date of Patent: Jun. 30, 2015

(54) EXTRACELLULAR MATRIX ENCASEMENT A61 K35/22 (2015.01) STRUCTURES AND METHODS A61 K35/38 (2015.01) (52) U.S. Cl. (71) Applicant: Robert G Matheny, Norcross, GA (US) CPC ...... A6L27/36.33 (2013.01); A6.1 F 2/24 (2013.01); A61 K38/005 (2013.01); A61 K35/22 (72) Inventor: Robert G. Matheny, Norcross, GA (US) (2013.01); A61 K35/38 (2013.01); A61K 35/12 (2013.01); A61L 27/3641 (2013.01); A61L (73) Assignee: CORMATRIX CARDIOVASCULAR, 27/3839 (2013.01); A61L 31/005 (2013.01); INC., Roswell, GA (US) A61L 27/3629 (2013.01); A61L 27/3679 (2013.01); A61L 27/3804 (2013.01); A61F 2/02 (*) Notice: Subject to any disclaimer, the term of this (2013.01); A61 K35/28 (2013.01); A61K 38/18 patent is extended or adjusted under 35 (2013.01); A61K 38/1825 (2013.01); A61L U.S.C. 154(b) by 102 days. 27/54 (2013.01) (58) Field of Classification Search (21) Appl. No.: 13/573,566 CPC ...... A61F 2/02: A61F 2/24: A61 K35/12: A61K 35/22: A61K 35/38: A61K 38/005; (22) Filed: Sep. 24, 2012 A61L 27/3633; A61L 27/3679 O O USPC ...... 424/422,490, 572; 427/2.24; 600/16 (65) Prior Publication Data See application file for complete search history. US 2013/OO23721 A1 Jan. 24, 2013 (56) References Cited

U.S. PATENT DOCUMENTS Related U.S. Application Data 2009/0204228 A1* 8, 2009 Hiles (63) Continuation-in-part of application No. 13/328,287. 2010, O262221 A1* 10, 2010 Schafer et al. filed on Dec. 16, 2011. 2012/0100185 A1 * 4, 2012 Wen et al. 2012/0156255 A1* 6/2012 Singh et al. (51) Int. Cl. * cited by examiner A 6LX 35/2 (2015.01) A6DF 3/00 (2006.01) Primary Examiner — Shin Lin Chen A6 IK 9/16 (2006.01) (74) Attorney, Agent, or Firm — Francis Law Group A6IL 33/00 (2006.01) (57) ABSTRACT A6 IN L/362 (2006.01) A6L27/36 (2006.01) A remodelable encasement structure comprising a pouch A6L27/38 (2006.01) formed from at least one sheet of bioremodelable material, A6IL 3L/00 (2006.01) the pouch having an internal region configured to receive a A6F 2/02 (2006.01) device therein, the bioremodelable material comprising al A6 IK35/28 (2015.01) extracellular matrix (ECM) composition that includes al A6 IK38/8 (2006.01) ECM Scaffold component derived from a mammalian source A6IL 27/54 (2006.01) and at least a bioactive component selected from the group A61 F 2/24 (2006.01) consisting of a statin and a chitin derivative. A61 K38/00 (2006.01) 3 Claims, 2 Drawing Sheets U.S. Patent Jun. 30, 2015 Sheet 1 of 2 US 9,066,993 B2

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U.S. Patent Jun. 30, 2015 Sheet 2 of 2 US 9,066,993 B2

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32 FIG. 6 US 9,066,993 B2 1. 2 EXTRACELLULAR MATRIX ENCASEMENT One additional problem that is also often encountered is the STRUCTURES AND METHODS degradation, e.g., corrosion, of medical device leads and, thereby, premature failure of the device after implantation in CROSS-REFERENCES TO RELATED the body. APPLICATIONS Most medical devices are designed to be implanted in the body for an extended period of time. However, when a harsh This application is a continuation-in-part of U.S. applica biological response (or premature failure of the device) is tion Ser. No. 13/328,287, filed on Dec. 16, 2011. encountered after implantation, it is often necessary to remove the device through a secondary Surgical procedure, FIELD OF THE INVENTION 10 which can, and in many instances will, result in undesirable pain and discomfort to the patient, and possibly additional The present invention relates to implantable devices. More trauma to the adjacent tissue. In addition to the pain and particularly, the present invention relates to implantable discomfort, the patient must be subjected to an additional structures and devices; particularly, medical devices encased time consuming and complicated Surgical procedure with the in extracellular matrix (ECM) based pouches and/or include 15 ECM based coatings that effectuate modulated healing of attendant risks of Surgery. damaged tissue and regeneration of new tissue structures with There is thus a need to provide medical devices that are site-specific structural and functional properties. configured for implantation in the body, and Substantially reduce or eliminate the harsh biological responses associated BACKGROUND OF THE INVENTION with conventional implanted medical devices, including inflammation, infection and thrombogenesis. As is well known in the art, treatment of various medical It is therefore an object of the present invention to provide conditions commonly involves implantation of medical encasement structures that are configured to encase a medical devices and/or insertion of medical instruments into a body. device therein and that substantially reduce or eliminate the Illustrative is the implantation or deployment of heart valves 25 harsh biological responses associated with conventional to regulate the flow of blood through cardiovascular vessels, implanted medical devices, including inflammation, infec and pacemakers to control abnormal heart rhythms. tion and thrombogenesis, when implanted in the body. Implantable medical devices; particularly, cardiovascular It is another object of the present invention to provide ECM implants, have unique blood biocompatibility requirements encasement structures that are configured to encase a medical to ensure that the device is not rejected (as in the case of 30 device therein, and effectively improve biological functions natural tissue materials for heart valves and grafts for heart and/or promote modulated healing of adjacent tissue and the transplants) or that adverse thrombogenic (clotting) or hemo growth of new tissue when implanted in the body. dynamic (blood flow) responses are avoided. It is another object of the present invention to provide ECM Several cardiovascular implants, such as heart valves, are encasement structures that are configured to encase a medical formed from natural tissue. Illustrative are the heart valves 35 device therein and administer one or more pharmacological disclosed in U.S. Pat. Nos. 6,719,788 and 5,480,424 to Cox. or therapeutic agents when implanted in the body. The disclosed bioprostheses can, however, be affected by It is yet another object of the present invention to provide gradual calcification, which can, and in many instances will, medical devices that are configured for insertion or implan lead to the eventual stiffening and tearing of the implant. tation in the body and exhibit enhanced biocompatibility and Many non-bioprosthetic implants are, however, fabricated 40 hemocompatibility when inserted or implanted therein. from various metals and polymeric materials, and other exotic materials, such as pyrolytic carbon-coated graphite. SUMMARY OF THE INVENTION For example, pacemakers, defibrillators, leads, and other similar cardiovascular implants are often fabricated from The present invention is directed to extracellular matrix Ni–Co—Cralloy, Co-Cr Mo alloy, titanium, and Ti-6Al 45 (ECM) structures and compositions for encasing devices; 4V alloy, stainless steel, and various biocompatible poly particularly, medical devices. meric materials. Artificial heart valves are often fabricated In some embodiments of the invention, the ECM structures from various combinations of nylon, silicone, titanium, include a pocket or pouch that is configured to receive a TeflonTM, polyacetal, graphite and pyrolytic carbon. device therein. In a preferred embodiment, the device com Artificial hearts and ventricular assist devices are often 50 prises a medical device. fabricated from various combinations of stainless steel, In a preferred embodiment, the pouch comprises (or is cobalt alloy, titanium, Ti-6Al-4V alloy, carbon fiber rein constructed of) an ECM composition that includes at least forced composites, polyurethanes, BiolonTM, HemothaneTM, one ECM material. DacronTM, polysulfone, and other thermoplastics. In other embodiments of the invention, there are provided Finally, catheters and guide wires are often fabricated from 55 medical devices that are configured for insertion or implan Co- Nior stainless steel wire. In many instances, the wire is tation in the body and include at least one coating of an ECM encased in a polymeric material. composition; the ECM composition similarly including at As is well known in the art, several major problems are least one ECM material. often encountered when a medical device (or other device, According to the invention, the medical devices and asso e.g. tracking apparatus) fabricated from one of the aforemen 60 ciated components can comprise, without limitation, a pace tioned materials is implanted in the body. A major problem maker, defibrillator, synthetic heart valve, ventricular assist that is often encountered after implantation of such a device in device, artificial heart, physiological sensor, catheter, and the the body is inflammation of Surrounding tissue. electrical leads and lines associated therewith. Another major problem is the high incidence of infection. According to the invention, the ECM material can be A further problem that is often encountered after implan 65 derived from various mammalian tissue sources including, tation of the medical device in the body is the formation of without limitation, the Small intestine, large intestine, stom blood clots (thrombogenesis). ach, lung, liver, kidney, pancreas, placenta, heart, bladder, US 9,066,993 B2 3 4 prostate, tissue Surrounding growing enamel, tissue Sur FIG. 6 is a front, partial sectional plan view of the coated rounding growing bone, and any fetal tissue from any mam medical device shown in FIG. 5, in accordance with the malian organ. invention. In some embodiments, the ECM compositions further include one or more additional biologically active compo 5 DETAILED DESCRIPTION OF THE PREFERRED nents to facilitate the treatment of damaged tissue and/or the EMBODIMENT tissue regenerative process. In some embodiments, the ECM compositions thus include Before describing the present invention in detail, it is to be at least one pharmacological agent or composition, which can understood that this invention is not limited to particularly 10 exemplified apparatus, systems, structures or methods as comprise, without limitation, antibiotics orantifungal agents, Such may, of course, vary. Thus, although a number of appa anti-Viral agents, anti-pain agents, anesthetics, analgesics, ratus, systems and methods similar or equivalent to those steroidal anti-inflammatories, non-steroidal anti-inflamma described herein can be used in the practice of the present tories, anti-neoplastics, anti-spasmodics, modulators of cell invention, the preferred apparatus, systems, structures and extracellular matrix interactions, proteins, hormones, 15 methods are described herein. enzymes and enzyme inhibitors, anticoagulants and/or anti It is also to be understood that, although the present inven thrombic agents, DNA, RNA, modified DNA and RNA, tion is described and illustrated in connection with encased NSAIDs, inhibitors of DNA, RNA or protein synthesis, medical devices, the invention is not limited to encased medi polypeptides, oligonucleotides, polynucleotides, nucleopro cal devices. According to the invention, the extracellular teins, compounds modulating cell migration, compounds matrix (ECM) structures and compositions of the invention modulating proliferation and growth of tissue, and vasodilat can also be employed to encase other devices, including, by ing agents. way of example, a tracking device. In some embodiments of the invention, the pharmacologi It is also to be understood that the terminology used herein cal agent specifically comprises an anti-inflammatory agent is for the purpose of describing particular embodiments of the or composition. 25 invention only and is not intended to be limiting. In some embodiments of the invention, the biologically Unless defined otherwise, all technical and scientific terms active component comprises a statin. According to the inven used herein have the same meaning as commonly understood tion, Suitable statins include, without limitation, atorvastatin, by one having ordinary skill in the art to which the invention cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pertains. pravastatin, rosuvastatin, and simvastatin. 30 Further, all publications, patents and patent applications In some embodiments of the invention, the biologically cited herein, whether supra or infra, are hereby incorporated active component comprises chitosan. by reference in their entirety. In some embodiments of the invention, the biologically As used in this specification and the appended claims, the active component comprises a cell. singular forms “a, “an and “the include plural referents In some embodiments of the invention, the biologically 35 unless the content clearly dictates otherwise. Thus, for active component comprises a protein. example, reference to “an active' includes two or more such According to the invention, upon deployment of an actives and the like. encased medical device of the invention, i.e. an ECM encase Further, ranges can be expressed herein as from “about' or ment structure having a medical device therein or a medical “approximately one particular value, and/or to “about' or device (or instrument) coated with an ECM composition of 40 “approximately' another particular value. When such a range the invention, modulated healing and regeneration of tissue is expressed, another embodiment includes from the one par structures with site-specific structural and functional proper ticular value and/or to the other particular value. Similarly, ties are effectuated. when values are expressed as approximations, by use of the antecedent “about' or “approximately, it will be understood BRIEF DESCRIPTION OF THE DRAWINGS 45 that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are Further features and advantages will become apparent significant both in relation to the other endpoint, and inde from the following and more particular description of the pendently of the other endpoint. preferred embodiments of the invention, as illustrated in the It is also understood that there are a number of values accompanying drawings, and in which like referenced char 50 disclosed herein, and that each value is also herein disclosed acters generally refer to the same parts or elements through as “about' or “approximately” that particular value in addi out the views, and in which: tion to the value itself. For example, if the value “10” is FIG. 1 is a perspective view of one embodiment of an ECM disclosed, then “approximately 10” is also disclosed. It is also encasement structure, in accordance with the invention; understood that when a value is disclosed that “less than or FIG. 2 is a perspective, partial sectional view of an ECM 55 equal to the value, “greater than or equal to the value” and encasement structure, illustrating a folded pre-lamination possible ranges between values are also disclosed, as appro configuration of an ECM pouch layer, in accordance with the priately understood by the skilled artisan. For example, if the invention; value “10” is disclosed then “less than or equal to 10” as well FIG. 3 is a front, partial sectional plan view of the ECM as “greater than or equal to 10” is also disclosed. structure shown in FIG. 2, illustrating a laminated ECM 60 Definitions pouch layer end, in accordance with the invention; The term “medical device', as used herein, means and FIG. 4 is a front, partial sectional plan view of another includes any device configured for insertion or implantation embodiment of an ECM structure, in accordance with the in the body of a warm blooded mammal, including humans invention; and primates; avians; domestic household or farm animals, FIG. 5 is a perspective view of one embodiment of a medi 65 Such as cats, dogs, sheep, goats, cattle, horses and pigs; labo cal device having an ECM composition coating thereon, in ratory animals, such as mice, rats and guinea pigs; fish; rep accordance with the invention; and tiles; Zoo and wild animals; and the like. The term “medical US 9,066,993 B2 5 6 device' thus includes, without limitation, a pacemaker, etate, diflumidone sodium, diflunisal, difluprednate, difial defibrillator, synthetic heart valve, ventricular assist device, one, dimethyl sulfoxide, drocinonide, endrysone, enlimo artificial heart, physiological sensor, catheter, and associated mab, enolicam Sodium, epirizole, etodolac, etofenamate, components thereof, including electrical leads and lines asso felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fen ciated therewith. dosal, fenpipalone, fentiazac, flazalone, fluazacort, flufe The terms "extracellular matrix” and “ECM material, are namic acid, flumizole, flunisolide acetate, flunixin, flunixin used interchangeably herein, and mean and include a col meglumine, fluocortin butyl, fluorometholone acetate, flu lagen-rich Substance that is found in between cells in animal quaZone, flurbiprofen, fluretofen, fluticasone propionate, tissue and serves as a structural element in tissues. The ECM furaprofen, furobufen, halcinonide, halobetasol propionate, material typically comprises a complex mixture of polysac 10 halopredone acetate, ibufenac, ibuprofen, ibuprofen alumi charides and proteins secreted by cells. num, ibuprofen piconol, illonidap, indomethacin, indometha According to the invention, the ECM material can be iso cin Sodium, indoprofen, indoxole, intrazole, isoflupredone lated from Small intestine Submucosa, stomach Submucosa, acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydro urinary bladder Submucosa, tissue mucosa, dura mater, liver chloride, lomoxicam, loteprednoletabonate, meclofenamate basement membrane, pericardium or other tissues. Following 15 Sodium, meclofenamic acid, meclorisone dibutyrate, mefe isolation and treatment, it is commonly referred to as extra namic acid, mesalamine, meseclaZone, mesterolone, meth cellular matrix or ECM material. androstenolone, methenolone, methenolone acetate, methyl The terms “pharmacological agent”, “pharmaceutical prednisolone Suleptanate, morniflumate, nabumetone, agent', 'agent”, “active agent”, "drug and “active agent nandrolone, naproxen, naproxen Sodium, naproXol, nima formulation' are used interchangeably herein, and mean and Zone, olsalazine Sodium, orgotein, orpanoxin, oxandrolane, include an agent, drug, compound, composition of matter or oxaprozin, oxyphenbutaZone, oxymetholone, paranyline mixture thereof, including its formulation, which provides hydrochloride, pentosan polysulfate sodium, phenbutaZone some therapeutic, often beneficial, effect. This includes any Sodium glycerate, pirfenidone, piroXicam, piroXicam cin physiologically or pharmacologically active substance that namate, piroxicam olamine, pirprofen, prednazate, prifelone, produces a localized or systemic effect or effects in animals, 25 prodolic acid, produaZone, proxazole, proxazole citrate, including warm blooded mammals, humans and primates; rimexolone, romazarit, Salcolex, Salnacedin, Salsalate, San avians; domestic household or farm animals, such as cats, guinarium chloride, seclaZone, Sermetacin, stanozolol. dogs, sheep, goats, cattle, horses and pigs; laboratory ani Sudoxicam, Sulindac, Suprofen, talmetacin, talniflumate, mals. Such as mice, rats and guinea pigs; fish; reptiles; Zoo and talosalate, tebufelone, tenidap, tenidap Sodium, tenoxicam, wild animals; and the like. 30 tesicam, tesimide, testosterone, testosterone blends, tetry The terms “pharmacological agent”, “pharmaceutical damine, tiopinac, tiXocortol pivalate, tolmetin, tolmetin agent”, “agent”, “active agent”, "drug and “active agent sodium, triclonide, triflumidate, Zidometacin, and Zomepirac formulation' thus mean and include, without limitation, anti Sodium. biotics, anti-viral agents, analgesics, steroidal anti-inflamma The terms 'active agent formulation”, “pharmacological tories, non-steroidal anti-inflammatories, anti-neoplastics, 35 agent formulation' and "agent formulation', are also used anti-spasmodics, modulators of cell-extracellular matrix interchangeably herein, and mean and include an active agent interactions, proteins, hormones, enzymes and enzyme optionally in combination with one or more pharmaceutically inhibitors, anticoagulants and/or antithrombic agents, DNA, acceptable carriers and/or additional inert ingredients. RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, According to the invention, the formulations can be either in RNA or protein synthesis, polypeptides, oligonucleotides, 40 Solution or in Suspension in the carrier. polynucleotides, nucleoproteins, compounds modulating cell The term “pharmacological composition', as used herein, migration, compounds modulating proliferation and growth means and includes a composition comprising a “pharmaco of tissue, and vasodilating agents. logical agent” and/or an "extracellular matrix material” and/ The terms “pharmacological agent”, “pharmaceutical or a “pharmacological agent formulation.” agent', 'agent”, “active agent”, "drug and “active agent 45 The term “therapeutically effective', as used herein, means formulation' also mean and include chitin, chitosan, and that the amount of the “pharmacological composition' and/or derivations thereof. “pharmacological agent' and/or “active agent formulation” The terms “anti-inflammatory” and “anti-inflammatory administered is of Sufficient quantity to ameliorate one or agent” are also used interchangeably herein, and mean and more causes, symptoms, or sequelae of a disease or disorder. include a “pharmacological agent” and/or “active agent for 50 Such amelioration only requires a reduction or alteration, not mulation, which, when a therapeutically effective amount is necessarily elimination, of the cause, symptom, or sequelae administered to a subject, prevents or treats bodily tissue of a disease or disorder. inflammation i.e. the protective tissue response to injury or The terms “prevent and “preventing are used inter destruction of tissues, which serves to destroy, dilute, or wall changeably herein, and mean and include reducing the fre off both the injurious agent and the injured tissues. Anti 55 quency or severity of a disease or condition. The term does not inflammatory agents thus include, without limitation, require an absolute preclusion of the disease or condition. alclofenac, alclometaSone dipropionate, algestone acetonide, Rather, this term includes decreasing the chance for disease alpha amylase, amcinafal, amcinafide, amfenac sodium, ami OCCUCC. prilose hydrochloride, anakinra, anirolac, anitraZafen, apa The terms “treat' and “treatment” are used interchange Zone, balsalazide disodium, bendazac, benoxaprofen, benzy 60 ably herein, and mean and include medical management of a damine hydrochloride, bromelains, broperamole, patient with the intent to cure, ameliorate, stabilize, or prevent budesonide, carprofen, cicloprofen, cintaZone, cliprofen, clo a disease, pathological condition, or disorder. The terms betasol propionate, clobetaSone butyrate, clopirac, clotica include “active treatment’, i.e. treatment directed specifically Sone propionate, cormethasone acetate, cortodoxone, toward the improvement of a disease, pathological condition, decanoate, deflazacort, delatestryl, depo-testosterone, des 65 or disorder, and “causal treatment’, i.e. treatment directed onide, desoximetasone, dexamethasone dipropionate, toward removal of the cause of the associated disease, patho diclofenac potassium, diclofenac sodium, diflorasone diac logical condition, or disorder. US 9,066,993 B2 7 8 The terms “treat' and “treatment' further include “pallia designed) to alter, delay, retard, reduce, and/or detain one or tive treatment’, i.e. treatment designed for the relief of symp more of the phases associated with healing of damaged tissue, toms rather than the curing of the disease, pathological con including, but not limited to, the inflammatory phase (e.g., dition, or disorder, “preventative treatment’, i.e. treatment platelet or fibrin deposition), and the proliferative phase. directed to minimizing or partially or completely inhibiting In some embodiments, “modulated healing refers to the the development of the associated disease, pathological con ability of an ECM composition to alter a substantial inflam dition, or disorder, and 'supportive treatment’, i.e. treatment matory phase (e.g., platelet or fibrin deposition) at the begin employed to Supplement another specific therapy directed ning of the tissue healing process. As used herein, the phrase toward the improvement of the associated disease, pathologi “alter a substantial inflammatory phase' refers to the ability cal condition, or disorder. 10 of an ECM composition to substantially reduce the inflam The terms “patient' and “subject' are used interchange matory response at an injury site. ably herein, and mean and include warm blooded mammals, In Such an instance, a minor amount of inflammation may humans and primates; avians; domestic household or farm ensue in response to tissue injury, but this level of inflamma animals, such as cats, dogs, sheep, goats, cattle, horses and tion response, e.g., platelet and/or fibrin deposition, is Sub pigs; laboratory animals, such as mice, rats and guinea pigs, 15 stantially reduced when compared to inflammation that takes fish; reptiles; Zoo and wild animals; and the like. place in the absence of an ECM composition of the invention. The term “comprise and variations of the term, such as For example, the ECM compositions discussed herein have “comprising and "comprises.” means “including, but not been shown experimentally to delay or alter the inflammatory limited to' and is not intended to exclude, for example, other response associated with damaged tissue, as well as excessive additives, components, integers or steps. formation of connective fibrous tissue following tissue dam The following disclosure is provided to further explain in age or injury. The ECM compositions have also been shown an enabling fashion the best modes of performing one or more experimentally to delay or reduce fibrin deposition and plate embodiments of the present invention. The disclosure is fur let attachment to a blood contact Surface following tissue ther offered to enhance an understanding and appreciation for damage. the inventive principles and advantages thereof, rather than to 25 In some embodiments of the invention, "modulated heal limit in any manner the invention. The invention is defined ing refers to the ability of an ECM composition of the inven solely by the appended claims, including any amendments tion to induce host tissue proliferation, bioremodeling, made during the pendency of this application, and all equiva including neovascularization, e.g., Vasculogenesis, angiogen lents of those claims as issued. esis, and intussusception, and regeneration of tissue struc As stated above, it is understood that, although the present 30 tures with site-specific structural and functional properties. invention is described and illustrated in connection with Accordingly, the ECM compositions discussed herein pro encased medical devices, the invention is not limited to vide an excellent bioabsorbable cellular interface Suitable for encased medical devices. According to the invention, the use with a medical device or Surgical instrument. extracellular matrix (ECM) structures and compositions of As indicated above, in one embodiment of the invention, the invention can also be employed to encase other devices, 35 the ECM encasement structures include an ECM based including, by way of example, a tracking device. pocket or pouch that is configured to receive a medical device As discussed above, in one embodiment, the present inven therein. According to the invention, the encased medical tion is directed to extracellular matrix (ECM) structures and device and associated components can comprise, without compositions for encasing medical devices. limitation, a pacemaker, defibrillator, synthetic heart valve, In one embodiment of the invention, the ECM encasement 40 Ventricular assist device, artificial heart, physiological sensor, structures include an ECM based pocket or pouch that is catheter, and the electrical leads and lines associated there configured to receive a medical device therein. In another with. embodiment of the invention, there is provided a medical According to the invention, the entire medical device or a device (or instrument) that includes at least one coating of an portion thereof can be encased in the ECM based pouch. ECM composition; the ECM composition similarly including 45 Thus, in some embodiments of the invention, the device hous at least one ECM material. ing and a portion of the device leads are encased in an ECM According to the invention, upon deployment of an ECM based pouch. In the noted embodiments, the device leads can encasement structure having a medical device therein or a also be coated with an ECM composition of the invention. medical device (or instrument) coated with an ECM compo In a preferred embodiment, the ECM pouch comprises (or sition of the invention, modulated healing and regeneration of 50 is constructed of) an ECM composition that includes at least tissue structures with site-specific structural and functional one ECM material (hereinafter “ECM pouch'). According to properties are effectuated. the invention, the ECM pouch can comprise various shapes The phrase “modulated healing', as used herein, and vari and sizes to accommodate virtually all shapes and sizes of ants of this language generally refer to the modulation (e.g., medical devices. alteration, delay, retardation, reduction, etc.) of a process 55 As also indicated above, in other embodiments of the involving different cascades or sequences of naturally occur invention, there are provided medical devices that include at ring tissue repair in response to localized tissue damage or least one coating of an ECM composition; the ECM compo injury, Substantially reducing their inflammatory effect. sition similarly including at least one ECM material. Accord Modulated healing, as used herein, includes many different ing to the invention, the medical devices can similarly biologic processes, including epithelial growth, fibrin depo 60 include, without limitation, the aforementioned devices and sition, platelet activation and attachment, inhibition, prolif associated components, as well as Surgical instruments. eration and/or differentiation, connective fibrous tissue pro According to the invention, the ECM material can be duction and function, angiogenesis, and several stages of derived from various mammalian tissue sources and methods acute and/or chronic inflammation, and their interplay with for preparing same, such as disclosed in U.S. Pat. Nos. 7.550, each other. 65 004, 7,244444, 6,379,710, 6,358,284, 6,206,931, 5,733,337 For example, in some embodiments, the ECM composi and 4,902,508 and U.S. application Ser. No. 12/707.427: tions of the invention are specifically formulated (or which are incorporated by reference herein in their entirety. US 9,066,993 B2 10 The mammalian tissue sources include, without limitation, inflammatories, anti-neoplastics, anti-spasmodics, modula the Small intestine, large intestine, stomach, lung, liver, kid tors of cell-extracellular matrix interactions, proteins, hor ney, pancreas, placenta, heart, bladder, prostate, tissue Sur mones, enzymes and enzyme inhibitors, anticoagulants and/ rounding growing enamel, tissue Surrounding growing bone, or antithrombic agents, DNA, RNA, modified DNA and and any fetal tissue from any mammalian organ. RNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, As is also well known in the art, the urinary bladder sub polypeptides, oligonucleotides, polynucleotides, nucleopro mucosa is an extracellular matrix that has the tunica mucosa teins, compounds modulating cell migration, compounds (which includes the transitional epithelial layer and the tunica modulating proliferation and growth of tissue, and vasodilat propria), a Submucosal layer, 3 layers of muscularis, and the ing agents. adventitia (a loose connective tissue layer). This general con 10 According to the invention, the amount of a pharmacologi figuration is true also for Small intestine Submucosa (SIS) and cal agent added to an ECM composition of the invention will, stomach Submucosa (SS). of course, vary from agent to agent. For example, in one Other tissues, such as the liver and pancreas have extracel embodiment, wherein the pharmacological agent comprises lular matrix called basement membrane. Basement mem diclofilenac (VoltarenR), the amount of diclofilenac included brane generally does not demonstrate the kind of tensile 15 in the ECM composition is preferably in the range of 10 ug-75 strength found in Submucosa. However, other useful proper ng. ties may be opportunistically employed from the extracellular In some embodiments of the invention, the pharmacologi matrices of Such tissues as the liver, pancreas, placenta and cal agent specifically comprises an anti-inflammatory agent. lung tissues; all of which have either basement membrane for According to the invention, Suitable anti-inflammatory agents extracellular matrix or interstitial membrane (as with the include, without limitation, alclofenac, alclometasone dipro lung). For example, the pancreatic extracellular membrane pionate, algestone acetonide, alpha amylase, amcinafal, Supports beta islet cells that are critical to pancreatic function. amcinafide, amfenac sodium, amiprilose hydrochloride, Also, for example, the liver is one tissue known to be able to anakinra, anirolac, anitraZafen, apaZone, balsalazide diso regenerate itself and therefore special qualities may be dium, bendazac, benoxaprofen, benzydamine hydrochloride, present in the liver basement membrane that help facilitate 25 bromelains, broperamole, budesonide, carprofen, ciclopro that process. fen, cintaZone, cliprofen, clobetasol propionate, clobetaSone The extracellular matrices Surrounding developing tooth butyrate, clopirac, cloticasone propionate, cormethasone enamel and developing bone also have particular advantages acetate, cortodoxone, decanoate, deflazacort, delatestry1. over other matrices in that they support the growth and dif depo-testosterone, desonide, desoximetaSone, dexametha ferentiation of the hard tissues of bone and enamel. 30 Sone dipropionate, diclofenac potassium, diclofenac sodium, According to the invention, matrices can be used in whole diflorasone diacetate, diflumidone sodium, diflunisal, diflu or in part, so that, for example, an extracellular matrix can prednate, diftalone, dimethyl sulfoxide, drocinonide, end contain just the basement membrane (or transitional epithe rysone, enlimomab, enolicam Sodium, epirizole, etodolac, lial layer) with the Subadjacent tunica propria, the tunica etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fen Submucosa, tunica muscularis, and tunica serosa. The extra 35 clorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, cellular matrix component of the composition can contain flufenamic acid, flumizole, flunisolide acetate, flunixin, any or all of these layers, and thus could conceivably contain flunixin meglumine, fluocortin butyl, fluorometholone only the basement membrane portion, excluding the Submu acetate, fluguaZone, flurbiprofen, fluretofen, fluticaSone pro cosa. However, generally, and especially since the Submucosa pionate, furaprofen, furobufen, halcinonide, halobetasol pro is thought to contain and Support the active growth factors, 40 pionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen cytokines and other proteins necessary for in Vivo tissue aluminum, ibuprofen piconol, illonidap, indomethacin, regeneration, the matrix composition from any given Source indomethacin Sodium, indoprofen, indoxole, intrazole, isof will contain the active extracellular matrix portions that Sup lupredone acetate, isoxepac, isoxicam, ketoprofen, lofemi port cell development and differentiation and tissue regenera Zole hydrochloride, lomoxicam, loteprednol etabonate, tion. 45 meclofenamate Sodium, meclofenamic acid, meclorisone For purposes of this invention, the extracellular matrix dibutyrate, mefenamic acid, mesalamine, meseclaZone, mes from any of the mammalian tissue consists of several basi terolone, methandrostenolone, methenolone, methenolone cally inseparable layers broadly termed extracellular matrix. acetate, methylprednisolone Suleptanate, morniflumate, For example, where it is thought that separating a basement nabumetone, nandrolone, naproxen, naproxen Sodium, membrane from the submucosa is considered to be very dif 50 naproXol, nimaZone, olSalazine sodium, orgotein, orpanoxin, ficult, if not impossible, because the layers are thin and it is Oxandrolane, Oxaprozin, oxyphenbutaZone, oxymetholone, not possible to delaminate them from each other, the extra paranyline hydrochloride, pentosan polysulfate Sodium, cellular matrix from that particular layer will probably nec phenbutaZone sodium glycerate, pirfenidone, piroxicam, essarily contain some basement membrane with the Submu piroXicam cinnamate, piroxicam olamine, pirprofen, pred COSa. 55 nazate, prifelone, prodolic acid, produaZone, proxazole, As stated above, in some embodiments of the invention, the proxazole citrate, rimexolone, romazarit, Salcolex, Salnace ECM structure (or material thereof) includes at least one din, Salsalate, sanguinarium chloride, seclaZone, Sermetacin, bioactive component. In some embodiments, the bioactive stanozolol, Sudoxicam, Sulindac, Suprofen, talmetacin, talni component comprises a pharmacological agent or composi flumate, talosalate, tebufelone, tenidap, tenidap Sodium, tion, i.e. an agent that is capable of producing a desired 60 tenoxicam, tesicam, tesimide, testosterone, testosterone biological effect in Vivo, Such as stimulation or Suppression of blends, tetrydamine, tiopinac, tiXocortol pivalate, tolmetin, cell division, stimulation or Suppression of apoptosis, stimu tolmetin Sodium, triclonide, triflumidate, Zidometacin, and lation or Suppression of an immune response, anti-bacterial Zomepirac sodium. activity, etc. According to the invention, the amount of an anti-inflam Suitable pharmacological agents (and/or compositions) 65 matory added to an ECM composition of the invention can include, without limitation, antibiotics, anti-viral agents, similarly vary from anti-inflammatory to anti-inflammatory. analgesics, steroidal anti-inflammatories, non-steroidal anti For example, in one embodiment of the invention, wherein US 9,066,993 B2 11 12 the pharmacological agent comprises ibuprofen (AdvilR), Statins facilitate the reduction of inflammatory factors by the amount of ibuprofen included in the ECM composition is inhibiting the Fc-receptor present on Type I (M1) mac preferably in the range of 100 ug-200 mg. ropages, which results in reduced production of MMPs. Low In some embodiments of the invention, the pharmacologi ered MMPs also results in a lowered presence of thrombi, as cal agent comprises a statin, i.e. a HMG-CoA reductase the MMPs attach to ECM present in thrombi or damaged inhibitor. According to the invention, Suitable statins include, ECM at wound sites. without limitation, atorvastatin (LIPITORR), cerivastatin, Macrophage growth reduction also results in lowered pres fluvastatin (LescolR), lovastatin (Mevacor R. Altocor R. Alto ence of tissue factor (TF); a protein necessary for the initia prev(R), mevastatin, pitavastatin (Livalo(R), PitavaR), pravas tion of thrombinformation. A lowered presence of TF results 10 in a lowered presence of thrombi; particularly, in the cardio tatin (PravacholR), Selektine(R), Lipostat(R), rosuvastatin vascular system, especially in conjunction with reduced (Crestor(R), and simvastatin (Zocor R, LipexR). Several MMPS actives comprising a combination of a statin and another Plaque Stabilizing Properties/Actions agent, such as eZetimbe/simvastatin (VytorinR), are also Suit Reduced MMPs and reduced TF also results in increased able. 15 plaque stability, which can help to prevent stroke or myocar Applicant has found that statins exhibit numerous benefi dial infarction by reducing the probability of plaque breaking cial properties that provide several beneficial biochemical off and becoming lodged within a smaller vessel. Plaque actions or activities. The properties and beneficial actions stability further aids in reduction of atherosclerosis. resulting therefrom are discussed in detail below. Fibrinolysis Properties/Actions Anticholesterolemic Properties/Actions Blocking RhoA activation also affects the presence of tis As is well known in the art, statins are a class of drugs that Sue plasminogen activators (t-PA) and plasminogen activator primarily function to lower levels of cholesterol production in inhibitor Type 1 (PAI-1). T-PA is a protein involved in the the liver. Lower levels of cholesterol are achieved by virtue of breakdown of blood clots. As an enzyme, it catalyzes the the statins limiting the production of mevalonate in the conversion of plasminogen to plasmin, the major enzyme cholestrol biosynthetic pathway. Statins competitively inhibit 25 responsible for clot breakdown (fibrinolysis). HMG-CoA reductase, which, because the molecules are so PAI-1 is a protein that functions as the principal inhibitor similar, results in the statins actually taking the place of the oft-PA and, hence, is the principal inhibitor of fibrinolysis. HMG-CoA reductase in the cholesterol biosynthetic pathway With t-PA presence raised and PAI-1 diminished by blocking and reducing the rate at which the mevalonate is produced; RhoA activation caused by statins, a reduced thrombotic Subsequently lowering the rate at which cholesterol is pro 30 effect is realized due to the reduced opportunity for fibrin to duced in the liver. form the polymeric mesh of a hemostatic plug. The reduced Anti-Inflammatory Properties/Actions MMPs and TF that result from the presence of a statin work in Statins also have numerous additional favorable effects on concert with the increased t-PA and reduced PAI-1 to further cellular structures and processes. One specific example is that reduce the potential for thrombii. statins can, and in many instances will, aid in the reduction of 35 NO Regulation Properties/Actions thromboxane A2 (TXA), which then lowers platelet activa Blocking RhoA activation also affects the presence of tion. Nitric Oxide (NO). As is well known in the art, the endothe TXA is also known as a vasoconstrictor and is especially lium uses NO to signal the Surrounding Smooth muscles to important during tissue injury and inflammation due to its relax, resulting invasodialation and increased blood flow. NO impact on platelet activation and aggregation, as well as its 40 contributes to vessel homeostasis by, among other things, ability to augment the expression of adhesion molecules and inhibiting vascular Smooth muscle function, platelet aggre chemokines. This allows statins to aid in the reduction of gation, and leukocyte adhesion to the endothelium. These inflammation by the reduction of TXA, which results in less factors are what allow NO to aid in the reduction of endothe Vascoconstriction, less platelet activation and aggregation, as lial dysfunction when modulated with a statin. The reduction well as reduced augmentation of adhesion molecules and 45 of leukocyte adhesion is a specific example of how the NO chemokines. production associated with a statin aids in the reduction of Statins further impact cellular structures and processes by inflammation. blocking rashomilog gene family, member A (RhoA) activa RhoA Activation Blocking Properties/Actions tion. Blocking RhoA activation impacts numerous systems, The administration of statins can also affect the presence of Such as macrophage growth, tissue plasminogen activators 50 endothelins and agiotensin receptors. Endothelins are pro (t-PA), plasminogen activator inhibitor type 1 (PAI-1), teins that constrict blood vessels and raise blood pressure. smooth muscle cell (SMC) proliferation, nitric oxide (NO) There are three isoforms of endothelins; ET-1, ET-2, and production, endothelins, and angiotensin receptors. As dis ET-3, with ET-1 being the isoform primarily affected by cussed below, when statins block RhoA activation, the result statins and RhoA activation blocking. Secretion of ET-1 from ant impact can be seen in many physiological structures and 55 the endothelium signals vasoconstriction and influences local processes, including inflammation, Smooth muscle cell pro cellular growth and survival. ET-1 has been implicated in the duction and size, and Vasconstriction. development and progression of vascular disorders, such as Blocking RhoA activation reduces macrophage growth atherosclerosis and hypertension. The decrease in the pres and, thereby, matrix metalloprotinases (MMPs), i.e. a family ence of ET-1 associated with statins and RhoA activation of zinc-dependent proteases that play a role in cellular behav 60 blocking results in decreased vasoconstriction and progres ior (i.e. proliferation, migration, apoptosis, differentiation, sion of the aforementioned disorders. ECM modulation, immune response, etc., and tissue factors Angiotensin receptors are protein coupled receptors that (TF). A reduction in MMPs and TF limit the reduction of are responsible for the signal transduction of the vasocon ECM proteins. stricting stimulus of the main effector hormone angiotensin MMPs are produced by activated neutrophils and mac 65 II. Angiotensin Receptor II Type I (AT-1) is the angiotensin rophages (inflammatory cells) and play on important part in receptor primarily affected by statin administration and wound healing and inflammation. RhoA activation blocking. AT-1 mediates, among other US 9,066,993 B2 13 14 things, vasocontraction, cardiac hypertrophy, and Vascular hand, the amount of D units in chitosan Samples is high smooth muscle cell proliferation. The reduction in AT-1 that enough to allow the polymer to dissolve in acidic aqueous accompanies statin administration and RhoA activation media. Some authors consider chitosan to be the polymer blocking results in reduced vasoconstriction. with at least 60% of Dunits. SeeS. Aiba, Studies on Chitosan. C-Reactive Protein Reduction Properties/Actions 5 4. Lysozymic Hydrolysis of Partially N-Acetylated Chitosans, C-Reactive Proteins (CRP) are also influenced by statin J. Biol. Macromol. Vol. 14(4), pp. 225-228 (1992). administration. CRP are found in the blood; the levels of Chitin is the second most abundant natural polymer in which deviate in response to varying levels of inflammation. nature after cellulose and it is found in the structure of a wide CRP levels diminish in response to statin administration and, number of invertebrates (crustaceans’ exoskeleton, insects thereby, the reduction in inflammation. 10 cuticles) and the cell walls of fungi, among others. On the Adhesion Molecule Reduction Properties/Actions other hand, chitosan only occurs naturally in Some fungi Adhesion molecules are proteins that are located on the cell (Mucoraceae). Surface and impact inflammation and thrombin formation in Chitosan is prepared by hydrolysis of acetamide groups of endothelial cells. With a higher incidence of inflammation chitin. This is normally conducted by severe alkaline hydroly comes a higher incidence of cell adhesion molecules. Statins 15 sis treatment due to the resistance of such groups imposed by reduce the presence of adhesion molecules on the endothe the trans arrangement of the C-C substituents in the Sugar lium. This helps to reduce inflammation by removing the r1ng. attachment mechanism for leukocytes and Subsequent plaque As stated and discussed in detail below, chitosan exhibits a buildup, the result being a lowered probability of atheroscle wide range of favorable biochemical properties that make it rosis. an outstanding agent for use in the medical field. Rac-1 Reduction Properties/Actions Biodegradability Properties/Actions Rac-1 is also a protein found in human cells. Rac-1 plays a Although chitosan is absent from mammals, chitosan can central role in endothelial cell migration, tubulogenesis, be readily degraded in vivo by several proteases (lysozyme, adhesion, and permeability. The expression of Rac-1 can, and papain, pepsin, etc.). It has also been found that the biodeg in many instances will, be reduced by the administration of a 25 radation of chitosan leads to the release of non-toxic oligosac statin. The decrease in the presence of Rac-1 also results in the charides of variable length, which can be subsequently incor decrease of reactive oxygen species (ROS). i.e. chemically porated to glycosaminoglycans and glycoproteins, to reactive molecules that have important roles in cell signaling metabolic pathways or be excreted. See Pangburn, et al., and homeostasis. Lysozyme Degradation of Partially Deacetylated Chitin, its Systemic administration of a statin typically ranges from 30 Films and Hydrogels, Vol. 3(2), pp. 105-108 (1982). 10 mg-80 mg daily. However, it is well known in the art that, Biocompatibility Properties/Actions in some instances, the dosage of a statin that is required to Chitosan also exhibits very good compatibility; particu reach a therapeutically effective local level can result in vari larly, cytocompatibility. ous toxicities within different organ systems, such as the liver The enhanced cytocompatibility of chitosan has been and musculature. However, due to the direct nature of the 35 proven in vitro with myocardial, endothelial and epithelial administration of statins when incorporated in or provided in cells, fibroblast, hepatocytes, condrocytes and keratinocytes. contact with an ECM material or composition of the inven See Chatelet, et al., Influence of the Degree of Acetylation on tion, therapeutically effective dosages can be much smaller, Some Biological Properties of Chitosan Films, Biomaterials, thereby, substantially reducing the possibility of systemic vol. 22(3), pp. 261-268 (2001). toxicities. 40 Analgesic Properties/Actions According to the invention, the amount of a statin added to It has been reported that chitosan exhibits very favorable a pharmacological composition of the invention is preferably analgesic properties (or effects). Okamoto, et al. specifically less than 20 mg, more preferably, less than approximately 10 studied the analgesic effect of chitosan on inflammatory pain ng. due to intraperitoneal administration of acetic acid. See Oka In some embodiments of the invention, the ECM material 45 moto, et al., Analgesic Effects of Chitin and Chitosan, Carbo includes 100 ug-5 mg of a statin. In some embodiments of the hyd. Poly, vol. 49, pp. 249-252 (2002). invention, the ECM material includes 500 ug-2 mg of a statin. Okamoto, et al. found that, due to its polycationic nature, In some embodiments of the invention, the bioactive com the free primary amino groups of chitosan can protonate in the ponent comprises chitosan or a derivative thereof. presence of protonions and, thereby, reduce the pH, which is Chitosan exhibits a wide range of favorable biochemical 50 a primary cause of the analgesic properties. From experimen properties that make it an outstanding agent for use in the tal data, it was also concluded that the analgesic effect was medical field. The biochemical properties of chitosan, which due primarily to the absorption of bradykinin, one of the main are discussed below, include biocompatibility, biodegradabil components (or Substances) related to pain. ity and non-toxicity. Additional properties, such as analgesic, Haemostatic Properties/Actions hemostatic, antimicrobial, and antioxidant have also been 55 It has also been reported that chitosan, as well as Sulphated reported. See Aranaz, et al., Functional Characterization of chitosan oligomers, exhibit anticoagulant activity tested in Chitin and Chitosan, Current Chemical Biology, Vol. 3, pp. vitro. The anticoagulant activity of chitosan is deemed to be 203-230 (2009); and Kumar MNVR, A Review of Chitin and related to its positive charge, since red blood cells mem Chitosan Applications, React. Funct. Polm. Vol. 46, pp. 1-27 branes are negatively charged. See Rao, et al., Use of Chito (2000). 60 san as Biomaterial. Studies on its Safety and Hemostatic As is well known in the art, chitinandchitosan are typically Potential, J. Biomed. Mat. Res., Vol. 34, pp. 21-28 (1997). described as a family of linear polysaccharides consisting of Permeation Enhancing Properties/Actions varying amounts f (1-4) linked residues of N-acetyl-2 amino It has also been reported that chitosan acts as a permeation 2-deoxy-D-glucose and 2-amino-2-deoxy-Dglucose residues enhancer by opening epithelial tight junctions. The mecha (“D' units or residues). 65 nism underlying this behavior is deemed to be based on the Chitin samples have a low amount of Dunits and hence the interaction of positively charged chitosan and the cell mem polymer is insoluble in acidic aqueous media. On the other brane resulting in a reorganization of the tight junction-asso US 9,066,993 B2 15 16 ciated proteins. See Smith, et al., Effect of Chitosan on Epi In some embodiments of the invention, the bioactive com thelial Cell Tight Junctions, Pharm. Res., vol. 21 (1), pp. ponent comprises a protein. According to the invention, the 43-49 (2004). protein can comprise, without limitation, a growth factor, Antimicrobial Properties/Actions collagen, proteoglycan, glycosaminoglycan (GAG) chain, The antimicrobial activity of chitin, chitosan, and their glycoprotein, cytokine, cell-surface associated protein, cell derivatives against different groups of microorganisms. Such adhesion molecule (CAM), angiogenic growth factor, endot as bacteria, yeast, and fungi, has also received considerable helial ligand, matrikine, matrix metalloprotease, cadherin, attention in recent years. Two main mechanisms have been immunoglobin, fibril collagen, non-fibrillar collagen, base suggested as the cause of the inhibition of microbial cells by ment membrane collagen, multiplexin, Small-leucine rich 10 proteoglycan, decorin, biglycan, fibromodulin, keratocan, chitosan. lumican, epiphycan, heparan Sulfate proteoglycan, perlecan, The first mechanism comprises the interaction with anionic agrin, testican, Syndecan, glypican, Serglycin, selectin, lecti groups on the cell Surface, due to chitosan’s polycationic can, aggrecan, Versican, nuerocan, brevican, cytoplasmic nature, causes the formation of an impermeable layer around domain-44 (CD44), macrophage stimulating factor, amyloid the cell, which prevents the transport of essential solutes. 15 precursor protein, heparin, chondroitin Sulfate B (dermatan The second mechanism involves the inhibition of the RNA Sulfate), chondroitin Sulfate A, heparan Sulfate, hyaluronic and protein synthesis by permeation into the cell nucleus. See acid, fibronectin (Fn), tenascin, elastin, fibrillin, laminin, Liu et al., Antibacterial Action of Chitosan and Carboxy nidogen?entactin, fibulin I, fibulin II, integrin, a transmem mathylated Chitosan, J. Appl. Polym. Sci., vol. 79(7), pp. brane molecule, platelet derived growth factor (PDGF), epi 1324-1335 (2001). dermal growth factor (EGF), transforming growth factor Antioxidative Properties/Actions alpha (TGF-alpha), transforming growth factor beta (TGF Chitosan has also shown a significant Scavenging capacity beta), fibroblast growth factor-2 (FGF-2) (also called basic against different radical species; the results being comparable fibroblast growth factor (bFGF)), thrombospondin, osteopon to those obtained with commercial antioxidants. See Park, et tin, angiotensin converting enzyme (ACE), and vascular epi al., Free Radical Scavenging Activities of Differently 25 thelial growth factor (VEGF). Deacetylated Chitosans, Carbohyd. Polym. Vol. 55(1), pp. According to the invention, the bioactive components ref 17-22 (2004). erenced above can comprise any form. In some embodiments Tissue Repair Properties/Actions of the invention, the bioactive component or components, e.g. By virtue of the above discussed properties of chitosan, simvastatin and/or chitosan, comprise microcapsules that chitosan can and in most instances will, enhance the repair of 30 provide delayed delivery of the agent contained therein. damaged tissue. Indeed, it has been found that chitosan acti Additional Suitable pharmacological compositions that vates immunocytes and inflammatory cells, such as PMN, can be delivered within the scope of the invention are dis macrophage, fibroblasts and angioendothelial cells. See closed in Pat. Pub. Nos. 20070014874, 20070014873, Ueno, et al., Topical Formulations and Wound Healing Appli 20070014872, 20070014871, 20070014870, 20070014869, cations of Chitosan, Adv. Drug Del. Res., vol. 52, pp. 105-115 35 and 20070014868; which are expressly incorporated by ref (2001). erence herein in its entirety. Chitosan oligomers have also exhibited tissue repair prop As indicated above, upon deployment of an ECM encase erties. It has been suggested that the tissue repair properties ment structure or a medical device (or instrument) coated are due to their ability to stimulate fibroblast production by with an ECM composition of the invention, modulated heal affecting the fibroblast growth factor. Subsequent collagen 40 ing and regeneration of tissue structures with site-specific production further facilitates the formation of connective tis structural and functional properties is effectuated. SC. Referring now to FIG.1, there is shown one embodiment of According to the invention, the amount of chitosan added an ECM encasement structure 10. Enclosed within the ECM to a pharmacological composition of the invention is prefer structure 10 is a medical instrument 20 and at least a portion ably less than 50 ml, more preferably, less than approximately 45 of the leads 22a, 22b, associated therewith. 20 ml. As illustrated in FIG. 1, the ECM encasement structure 10 In some embodiments of the invention, the chitosan is generally comprises a pocket or pouch 12 having a cavity incorporated in a polymeric network, Such as disclosed in therein 13. The cavity 13 is sized and configured to receive U.S. Pub. Nos. 2008/0254104 and 2009/0062849, which are and contain a medical device 20 therein. incorporated herein in their entirety. 50 In a preferred embodiment of the invention, the pouch 12 In some embodiments of the invention, the bioactive com comprises at least one layer or sheet of encasement material ponent comprises a cell. According to the invention, the cell constructed of an ECM composition of the invention. Accord can comprise, without limitation, a stem cell. Such as, for ing to the invention, the pouch 12 can also include more than example, a human embryonic stem cell, fetal cell, fetal car one layer of encasement material, e.g. two (2), three (3) diomyocyte, myofibroblast, mesenchymal stem cell, 55 encasement layers, etc. The encasement layers can also com autotransplanted expanded cardiomyocyte, adipocyte, totipo prise the same material, i.e. ECM composition, or different tent cell, pluripotent cell, blood stem cell, myoblast, adult materials or compositions. stem cell, bone marrow cell, mesenchymal cell, embryonic As indicated above, in Some embodiments of the invention, stem cell, parenchymal cell, epithelial cell, endothelial cell, the ECM compositions of the invention include one or more mesothelial cell, fibroblast, myofibroblast, osteoblast, chon 60 pharmacological agents or compositions, including, for drocyte, exogenous cell, endogenous cell, stem cell, hemato example, an anti-inflammatory. An encasement layer formed poetic stem cell, pluripotent stem cell, bone marrow-derived from one of the noted ECM compositions will thus also progenitor cell, progenitor cell, myocardial cell, skeletal cell, include any pharmacological agents or compositions added to undifferentiated cell, multi-potent progenitor cell, unipotent the ECM compositions. progenitor cell, monocyte, cardiomyocyte, cardiac myoblast, 65 According to the invention, one or more pharmacological skeletal myoblast, macrophage, capillary endothelial cell, agents and/or compositions, such as a statin, can also be Xenogenic cell, and allogenic cell. deposited on the outer Surface of an outer encasement layer. US 9,066,993 B2 17 18 Referring now to FIG. 2, there is shown a perspective, including inflammation, infection and thrombogenesis, partial sectional view of the ECM encasement structure 10, when implanted in the body. showing a folded pre-lamination configuration of the encase The provision of ECM encasement structures that are con ment layer (denoted '14). As illustrated in FIG. 2, in the figured to encase a medical device therein, and effec 5 tively improve biological functions and/or promote noted embodiment, the encasement layer 14 comprises a modulated healing of adjacent tissue and the growth of single sheet of encasement material. To form the pouch 12, new tissue when implanted in the body. the encasement layer 14 is folded over and laminated on the The provision of ECM encasement structures that are con end 18 (see FIG. 3) and sides 16. figured to encase a medical device therein and adminis Referring now to FIG. 4, in some embodiments of the ter one or more pharmacological ortherapeutic agents to invention, the pouch 12 similarly comprises one encasement 10 a subject when implanted in his/her body. layer 14. However, in the noted embodiments, two (2) sheets The provision of medical devices that are configured for of encasement material or layers 15a, 15b are employed to insertion or implantation in the body and exhibit form the pouch 12. The layers 15a. 15b are laminated on both enhanced biocompatibility and hemocompatibility ends 19a, 19b, as shown in FIG. 4, and sides. when inserted or implanted therein. 15 Without departing from the spirit and scope of this inven According to the invention, the sides and ends of encase tion, one of ordinary skill can make various changes and ment layers of the invention can be laminated by various modifications to the invention to adapt it to various usages and conventional means, such as stitching, including ECM conditions. As such, these changes and modifications are Stitches, stapled, adhesives. The encasement layers can also properly, equitably, and intended to be, within the full range be laminated via microneedles and/or microneedle structures, of equivalence of any subsequently proffered claims. such as disclosed in U.S. Pat. No. 8,778,012. What is claimed is: As indicated above, in other embodiments of the invention, 1. An implantable medical device, comprising: there are provided medical devices that include at least one a pacemaker comprising an outer surface having at least coating of an ECM composition of the invention. According one coating comprising an extracellular matrix (ECM) to the invention, the medical devices can similarly include, 25 without limitation, the aforementioned devices and associ composition disposed thereon, said ECM composition ated components, as well as surgical instruments. coating forming an ECM encasement structure, Referring now to FIGS. 5 and 6, there is shown a medical said ECM composition comprising acellular ECM from a device (preferably, an implantable medical device) 32 having mammalian tissue source, said tissue source being an ECM composition coating 34 disposed thereon. According Selected from the group consisting of small intestine 30 submucosa (SIS), urinary bladder submucosa (UBS) to the invention, various conventional means can be and stomach submucosa (SS), said ECM composition employed to form the coated biocompatible and hemocom further comprising a statin, patable medical device 30, including spray coating, dipping, said coated pacemaker, when implanted in host tissue of a etc. Subject's body, being configured to modulate heart rate As indicated above, upon deployment of an encased medi 35 of said subject and induce modulated healing, said cal device of the invention, i.e. an ECM encasement structure modulated healing comprising modulation of inflamma or the coated medical device of the invention, modulated tion of said host tissue, induced tissue proliferation and healing and regeneration of tissue structures with site-specific bioremodeling of said host tissue. structural and functional properties are effectuated. 2. The encased medical device of claim 1, wherein said As will readily be appreciated by one having ordinary skill 40 in the art, the present invention provides numerous advan statin is selected from the group consisting of atorvastatin, tages compared to prior art vascular endografts. Among the cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, advantages are the following: pravastatin, rosuvastatin and simvastatin. The provision of encasement structures that are configured 3. The medical device of claim 1, wherein said pacemaker to encase a medical device therein and that substantially comprises a plurality of said ECM composition coatings, said reduce or eliminate the harsh biological responses asso 45 plurality of ECM coatings forming a plurality of ECM layers. ciated with conventional implanted medical devices, ck ck ck ck ck