(12) United States Patent (10) Patent No.: US 9,533,072 B2 Matheny (45) Date of Patent: Jan

USO09533072B2

(12) United States Patent (10) Patent No.: US 9,533,072 B2 Matheny (45) Date of Patent: Jan. 3, 2017

(54) REINFORCED VASCULAR PROSTHESES (58) Field of Classification Search CPC ...... A61F 2/07; A61 F 2/24: A61F 2/06; (71) Applicant: CorMatrix Cardiovascular, Inc., A61F 2/86; A61F 2002/046; A61F Roswell, GA (US) 2002/047; A61F 2002/048: A61F (72) Inventor: Robert G Matheny, Norcross, GA 2210/0057; A61F 2002/045; A61F (US) 2250/0067; A61F 2210/0004: A61F 2002/072; A61F 2210/0014; A61L 27/18: (73) Assignee: CORMATRIX CARDIOVASCULAR, A61L 2300/216; A61L 2300/252: A61 L INC., Roswell, GA (US) 2300/40: A61L 2300/41; A61L 2300/414: A61L 2300/416: A61L 2300/434: A61 L (*) Notice: Subject to any disclaimer, the term of this 2300/64; A61L 2430/20: A61L 2430/22: patent is extended or adjusted under 35 A61L 27/34: A61L 27/36; A61L 27/3629; U.S.C. 154(b) by 77 days. A61L 27/3633; A61L 27/38: A61L 27/3834; A61L 27/507; A61L 27/54 (21) Appl. No.: 14/566,155 See application file for complete search history. (22) Filed: Dec. 10, 2014 (56) References Cited (65) Prior Publication Data U.S. PATENT DOCUMENTS US 2015/0094796 A1 Apr. 2, 2015 6,015,432 A 1/2000 Rakos et al. Related U.S. Application Data 7,745,217 B2 6/2010 Patel et al. (63) Continuation-in-part of application No. 14/337,915, (Continued) filed on Jul. 22, 2014, which is a continuation of OTHER PUBLICATIONS (Continued) Sundaram, et al., Small Diameter Vascular Graft Enigneered Using (51) Int. Cl. Human Embryonic Stem Cell-Derived Mesenchymal Cells, Tissue A6IL 27/36 (2006.01) Engineering Part A. vol. 20, pp. 740-750 (2014). A6 IF 2/06 (2013.01) (Continued) Primary Examiner — Christian Sevilla (52) U.S. Cl. Assistant Examiner — Seema Mathew CPC ...... A61L 27/3633 (2013.01); A61F 2/06 (74) Attorney, Agent, or Firm — Francis Law Group (2013.01); A61F 2/07 (2013.01); A61F 2/86 (2013.01); A61L 27/18 (2013.01); A61L 27/34 (57) ABSTRACT (2013.01); A61L 27/3629 (2013.01); A61L Vascular grafts for treating, reconstructing and replacing 27/38 (2013.01); A61L 27/3834 (2013.01); damaged or diseased cardiovascular vessels that are formed A61L 27/507 (2013.01); A61L 27/54 from decellularized extracellular matrix (ECM). The vascu (2013.01); A61 F 2002/072 (2013.01); A61 F lar grafts include outer or outer and inner coatings that 2210/0004 (2013.01); A61 F io et provide structural reinforcement. (Continued) 17 Claims, 2 Drawing Sheets

US 9,533,072 B2 Page 2

Related U.S. Application Data 2006/0136047 A1* 6/2006 Obermiller ...... A61F 2/06 623, 141 application No. 14/031,520, filed on Sep. 19, 2013, 2006/0147433 A1* 7/2006 Hiles ...... A61K 35/37 now abandoned, and a continuation-in-part of appli- 424,93.7 cation No. 14/031423, filed on Sep. 19, 2013. 2006/02574472007/0112411 A1*All 11/20065, 2007 ObermillerHinds et al...... A61F 2/07 623, 1.13 (51) Int. Cl. 2009/0171440 A1* 7/2009 Carlson ...... A61F 2.06 A6F 2/07 (2013.01) 623, 1.15 A6L27/8 (2006.01) 2010/0268321 A1 10, 2010 McDermott et al. A6IL 27/34 (2006.01) 2012/0156255 A1* 6/2012 Singh ...... Also: A6IL 27/38 (2006.01) 2012/0182609 A1* 7, 2012 Borenstein ...... BO1L 3,502707 A6L 27/50 (2006.01) 359,368 A6IL 27/54 (2006.01) 2013/0103079 A1 4/2013 Lau ...... A61L 17/08 A6 IF 2/86 (2013.01) ck 606,229 (52) U.S. Cl. 2013/0116789 A1* 5/2013 Chachques ...... A., CPC ...... A61F 2210/0076 (2013.01); A61F 2013/0325 108 Al 12/2013 Imran et al. 2220/0075 (2013.01); A61F 2250/0067 2014/0066469 A1 3/2014 Robinson ...... A61K 31,4706 (2013.01); A61L 27/36 (2013.01); A61 L ck 514,275 2300/216 (2013.01); A61L 2300/252 2014/0288642 A1* 9, 2014 Yoshida ...... A. s (2013.01); A61 L 2300/40 (2013.01); A61 L 2014/0309726 A1 10/2014 Wang 2300/41 (2013.01); A61 L 2300/414 (2013.01); 2015, 0037293 A1* 2, 2015 Jun ...... A61L 27, 22 A61 L 2300/416 (2013.01); A61L 2300/434 424,93.7 (2013.01); A61 L 2300/64 (2013.01); A61 L 2016/0030496 A1 2/2016 Prakash ...... A6. 2430/20 (2013.01); A61 L 2430/22 (2013.01) 2016/0143729 A1* 5/2016 Matheny ...... A61F 2,203 623/9 (56) References Cited 2016/01995.41 A1* 7/2016 Yang ...... CO8G 63/6852 424/486 U.S. PATENT DOCUMENTS 2016/0256604 A1* 9, 2016 Hanna ...... A61L 27, 18 2016/0302911 A1* 10, 2016 Soletti ...... A61L 27, 18 8,778,012 B2 7/2014 Matheny 2006, OOO9839 A1 1/2006 Tan * cited by examiner U.S. Patent Jan. 3, 2017 Sheet 1 of 2 US 9,533,072 B2

U.S. Patent Jan. 3, 2017 Sheet 2 of 2 US 9,533,072 B2

FIC. 3 E3 US 9,533,072 B2 1. 2 REINFORCED VASCULAR PROSTHESES instances will, break down into large, rigid fragments that can cause obstructions in the interior of the vessel. CROSS-REFERENCES TO RELATED More recently, vascular grafts comprising various remod APPLICATIONS elable materials, such as extracellular matrix sheets, have been developed to treat and reconstruct damaged or diseased This application is a continuation-in-part of U.S. appli cardiovascular vessels. Illustrative are the vascular grafts cation Ser. No. 14/337,915, filed on Jul. 22, 2014, which is disclosed in Applicant's Co-Pending application Ser. No. a continuation-in-part of U.S. application Ser. No. 14/031, 13/573,226. 520, filed on Sep. 19, 2013, which is a continuation-in-part Although such grafts have garnered overwhelming Suc of U.S. application Ser. No. 14/031423, filed on Sep. 19, 10 cess and, hence, gained significant clinical acceptance, there 2013, which claims the benefit of U.S. application Ser. No. are a few drawbacks associated with Such grafts. Among the 61/710,992, filed on Oct. 8, 2012. drawbacks are the construction and, hence, configuration of FIELD OF THE INVENTION the noted vascular grafts. 15 As discussed in detail in Co-Pending application Ser. No. The present invention relates to methods and apparatus 13/573.226, such grafts typically comprise one or more for treating damaged or diseased cardiovascular vessels. sheets of ECM tissue, e.g., Small intestine Submucosa, which More particularly, the present invention relates to reinforced is secured at one edge to form a tubular structure. The vascular grafts or prostheses for treating and/or reconstruct secured edge or seam can, and in many instances will, ing damaged or diseased cardiovascular vessels. disrupt blood flow through the graft. A poorly secured edge also poses a significant risk of thrombosis. BACKGROUND OF THE INVENTION Further, in some instances, wherein the ECM graft com prises two or more sheets, i.e. a multi-sheet laminate. Such As is well known in the art, various vascular grafts or as disclosed in Co-pending application Ser. No. 14/031423, prostheses are often employed to treat and reconstruct 25 the laminate structure is prone to delamination. damaged or diseased cardiovascular vessels. Thus, readily available, versatile vascular grafts that are Currently, the vascular grafts often employed to recon not prone to calcification, thrombosis and intimal hyperpla struct (or replace) damaged or diseased cardiovascular ves sia would fill a substantial and growing clinical need. sels are autologous arteries and veins, e.g., internal mam It is therefore an object of the present invention to provide mary artery or Saphenous vein; particularly, in situations 30 vascular grafts (including "endografts') that Substantially where Small diameter (i.e. 3-4 mm) vessels are required, reduce or eliminate (i) the risk of thrombosis, (ii) intimal such as below the knee and coronary artery bypass grafting. hyperplasia after intervention in a vessel, (iii) the harsh Autologous arteries and veins are, however, often biological responses associated with conventional polymeric unavailable, due to prior harvest, or unsuitable, due to and metal prostheses, and (iv) the formation of biofilm, arterial disease. 35 inflammation and infection. When autologous arteries and veins are unavailable or It is another object of the present invention to provide unsuitable, synthetic polytatrafluoroethylene (PTFE) or vascular grafts that can effectively replace or improve bio Dacron(R) grafts are often employed to reconstruct or replace logical functions or promote the growth of new tissue in a damaged or diseased cardiovascular vessels; particularly, in Subject. situations where large diameter (i.e. >6 mm) vessels are 40 It is another object of the present invention to provide required. vascular grafts that induce host tissue proliferation, biore There are, however, numerous drawbacks and disadvan modeling and regeneration of new tissue and tissue struc tages associated with synthetic grafts. A major drawback is tures with site-specific structural and functional properties. the poor median patency exhibited by Synthetic grafts, due It is another object of the present invention to provide to Stenosis, thromboembolization, calcium deposition and 45 vascular grafts that are capable of administering a pharma infection. Indeed, it has been found that patency is >25% (a) cological agent to host tissue and, thereby produce a desired 3 years using synthetic and cryopreserved grafts in periph biological and/or therapeutic effect. eral and coronary bypass Surgeries, compared to >70% for autologous vascular grafts. See Chard, et al., Aorta-Coro SUMMARY OF THE INVENTION nary Bypass Grafting with Polytetrafluoroehtylene Con 50 duits. Early and Late Outcome in Eight Patients, Thorac The present invention is directed to vascular grafts or Cardiovasc Surg, Vol. 94, pp. 312-134 (1987). prostheses for treating, reconstructing or replacing damaged Decellularized bovine internal jugular Xenografts and or diseased cardiovascular vessels. human allograft vessels from cadavers have also employed As discussed in detail herein, in a preferred embodiment, to reconstructor replace damaged or diseased cardiovascular 55 the vascular grafts comprise coated tubular members having vessels. Such grafts are, however, prone to calcification and proximal and distal ends. thrombosis and, thus, have not gained significant clinical In some embodiments of the invention, the tubular mem acceptance. bers comprise a decellularized ECM material derived from Vascular prostheses constructed of various biodegradable a mammalian tissue source, i.e. tubular ECM members. materials. Such as poly (trimethylene carbonate), have also 60 According to the invention, the ECM material can be been developed to reconstruct damaged or diseased cardio derived from various mammalian tissue sources, including, vascular vessels. There are, however, several drawbacks and without limitation, small intestine submucosa (SIS), urinary disadvantages associated with Such prostheses. bladder submucosa (UBS), stomach submucosa (SS), meso One major disadvantage is that the biodegradable mate thelial tissue, placental extracellular matrix, ornomentum rials and, hence, prostheses formed therefrom, often break 65 extracellular matrix, and cardiac extracellular matrix. down at a faster rate than is desirable for the application. A In a preferred embodiment, the mammalian tissue source further disadvantage is that the materials can, and in many comprises an adolescent mammalian tissue source. US 9,533,072 B2 3 4 In some embodiments, the tubular members comprise an BRIEF DESCRIPTION OF THE DRAWINGS ECM/ECM-mimicking biomaterial composition comprising an ECM material and an ECM-mimicking biomaterial, such Further features and advantages will become apparent as poly(glycerol sebacate) (PGS). from the following and more particular description of the In some embodiments of the invention, the tubular mem preferred embodiments of the invention, as illustrated in the ber coating comprises a polymeric composition comprising accompanying drawings, and in which like referenced char a biodegradable polymeric material. Such as poly(e-capro acters generally refer to the same parts or elements through lactone) (PCL). out the views, and in which: In some embodiments of the invention, the tubular mem FIG. 1A is a perspective view of one embodiment of a ber coating comprises an ECM composition comprising at 10 tubular ECM member, in accordance with the invention; least one ECM material. FIG. 1B is a side or edge plan view of the tubular ECM In some embodiments of the invention, the tubular mem member shown in FIG. 1A, in accordance with the inven ber coating comprises an ECM-mimicking biomaterial com tion; position comprising at least one ECM-mimicking biomate FIG. 2A is a perspective view of one embodiment of a rial. 15 coated ECM vascular graft, in accordance with the inven In some embodiments of the invention, the tubular mem tion; bers further comprise an outer reinforcing structure. FIG. 2B is a side or edge plan view of the coated ECM In some embodiments of the invention, the reinforcing vascular graft shown in FIG. 2A, in accordance with the structure comprises a thin member, Such as a strand, that is invention; wound about the outer surface of the tubular member. FIG. 3A is a perspective view of another embodiment of In some embodiments of the invention, the reinforcing a coated ECM vascular graft, in accordance with the inven structure comprises a mesh or woven structure. tion; and In some embodiments of the invention, the reinforcing FIG. 3B is a side or edge plan view of the coated ECM structure comprises an ECM-mimicking biomaterial. Such as vascular graft shown in FIG. 3A, in accordance with the PGS. 25 invention. In some embodiments of the invention, the tubular mem bers and, hence, vascular grafts formed therefrom, further DETAILED DESCRIPTION OF THE comprise at least one additional biologically active agent or PREFERRED EMBODIMENT composition, i.e. an agent that induces or modulates a physiological or biological process, or cellular activity, e.g., 30 Before describing the present invention in detail, it is to induces proliferation, and/or growth and/or regeneration of be understood that this invention is not limited to particu tissue. larly exemplified apparatus, systems, structures or methods In some embodiments, the biologically active agent com as such may, of course, vary. Thus, although a number of prises a cell. Such as, without limitation, a human embryonic apparatus, Systems and methods similar or equivalent to stem cell, fetal cardiomyocyte, myofibroblast, and mesen 35 those described herein can be used in the practice of the chymal stem cell. present invention, the preferred apparatus, Systems, struc In some embodiments, the biologically active agent com tures and methods are described herein. prises a growth factor, such as, without limitation, a trans It is also to be understood that the terminology used herein forming growth factor-alpha (TGF-C.), transforming growth is for the purpose of describing particular embodiments of factor-beta (TGF-B), fibroblast growth factor-2 (FGF-2), 40 the invention only and is not intended to be limiting. basic fibroblast growth factor (bFGF), and vascular epithe Unless defined otherwise, all technical and scientific lial growth factor (VEGF). terms used herein have the same meaning as commonly In some embodiments, the tubular members and, hence, understood by one having ordinary skill in the art to which vascular grafts formed therefrom, further comprise at least the invention pertains. one pharmacological agent or composition (or drug), i.e. an 45 Further, all publications, patents and patent applications agent or composition that is capable of producing a desired cited herein, whether supra or infra, are hereby incorporated biological effect in Vivo, e.g., stimulation or Suppression of by reference in their entirety. apoptosis, stimulation or suppression of an immune As used in this specification and the appended claims, the response, etc. singular forms “a, “an and “the include plural referents Suitable pharmacological agents and compositions 50 unless the content clearly dictates otherwise. Thus, for include, without limitation, antibiotics, anti-viral agents, example, reference to “a pharmacological agent includes analgesics, anti-inflammatories, anti-neoplastics, anti-spas two or more such agents and the like. modics, and anticoagulants and/or antithrombic agents. Further, ranges can be expressed herein as from “about In some embodiments of the invention, the pharmaco or “approximately one particular value, and/or to “about logical agent comprises a statin, i.e. a HMG-CoA reductase 55 or “approximately' another particular value. When such a inhibitor, such as cerivastatin. range is expressed, another embodiment includes from the In some embodiments of the invention, the vascular graft one particular value and/or to the other particular value. and/or coating provides a single-stage agent delivery profile, Similarly, when values are expressed as approximations, by i.e. comprise a single-stage agent delivery vehicle, wherein use of the antecedent “about' or “approximately, it will be a modulated dosage of an aforementioned biologically 60 understood that the particular value forms another embodi active and/or pharmacological agent is provided. ment. It will be further understood that the endpoints of each In some embodiments of the invention, the vascular graft of the ranges are significant both in relation to the other and/or coating provides a multi-stage agent delivery profile, endpoint, and independently of the other endpoint. i.e. comprise a multi-stage delivery vehicle, wherein a It is also understood that there are a number of values plurality of the aforementioned biologically active and/or 65 disclosed herein, and that each value is also herein disclosed pharmacological agents are administered via a modulated as “about' or “approximately” that particular value in addi dosage. tion to the value itself. For example, if the value “10 is US 9,533,072 B2 5 6 disclosed, then “approximately 10” is also disclosed. It is The term “ArtelonTM’, as used herein, means a poly also understood that when a value is disclosed that “less than (urethane urea) material distributed by Artimplant AB in or equal to the value, “greater than or equal to the value' Goteborg, Sweden. and possible ranges between values are also disclosed, as The terms “ECM-mimicking material and “ECM-mim appropriately understood by the skilled artisan. For example, icking biomaterial are used interchangeably herein, and if the value “10” is disclosed then “less than or equal to 10” mean and include a biodegradable material that induces neovascularization and bioremodeling of tissue in Vivo, i.e. as well as “greater than or equal to 10” is also disclosed. when disposed proximate damaged biological tissue. The DEFINITIONS terms “ECM-mimicking material and “ECM-mimicking 10 biomaterial' thus include, without limitation, ECM-mimick The terms 'graft' and “endograft are used interchange ing polymeric biomaterials; specifically, poly(glycerol seba ably herein, and mean and include a structure that is con cate) (PGS). figured for implantation in a cardiovascular structure, e.g., a The terms “biologically active agent” and “biologically cardiovascular vessel. active composition' are used interchangeably herein, and 15 mean and include agent that induces or modulates a physi The terms “extracellular matrix” and “ECM are used ological or biological process, or cellular activity, e.g., interchangeably herein, and mean and include a collagen induces proliferation, and/or growth and/or regeneration of rich Substance that is found in between cells in mammalian tissue. tissue, and any material processed therefrom, e.g. decellu The terms “biologically active agent” and “biologically larized ECM. According to the invention, the ECM material active composition' thus mean and include, without limita can be derived from various mammalian tissue sources tion, the following growth factors: platelet derived growth including, without limitation, the Small intestine, large intes factor (PDGF), epidermal growth factor (EGF), transform tine, stomach, lung, liver, kidney, pancreas, placenta, heart, ing growth factor alpha (TGF-alpha), transforming growth bladder, prostate, tissue Surrounding growing enamel, tissue factor beta (TGF-beta), fibroblast growth factor-2 (FGF-2), Surrounding growing bone, and any fetal tissue from any 25 basic fibroblast growth factor (bFGF), vascular epithelial mammalian organ. growth factor (VEGF), hepatocyte growth factor (HGF), The ECM material can thus comprise, without limitation, insulin-like growth factor (IGF), nerve growth factor (NGF), small intestine submucosa (SIS), urinary bladder submucosa platlet derived growth factor (PDGF), tumor necrosis factor (UBS), stomach submucosa (SS), central nervous system alpha (TNA-alpha), and placental growth factor (PLGF). tissue, dermal extracellular matrix, Subcutaneous extracel 30 The terms “biologically active agent” and “biologically lular matrix, gastrointestinal extracellular matrix, i.e. large active composition' also mean and include, without limita and Small intestines, tissue Surrounding growing bone, pla tion, human embryonic stem cells, fetal cardiomyocytes, cental extracellular matrix, ornomentum extracellular myofibroblasts, mesenchymal stem cells, autotransplated matrix, epithelium of mesodermal origin, i.e. mesothelial expanded cardiomyocytes, adipocytes, totipotent cells, tissue, cardiac extracellular matrix, e.g., pericardium and/or 35 pluripotent cells, blood stem cells, myoblasts, adult stem myocardium, kidney extracellular matrix, pancreas extracel cells, bone marrow cells, mesenchymal cells, embryonic lular matrix, lung extracellular matrix, and combinations stem cells, parenchymal cells, epithelial cells, endothelial thereof. The ECM material can also comprise collagen from cells, mesothelial cells, fibroblasts, osteoblasts, chondro mammalian sources. cytes, exogenous cells, endogenous cells, stem cells, The terms “urinary bladder submucosa (UBS)”, “small 40 hematopoietic stem cells, bone-marrow derived progenitor intestine submucosa (SIS) and “stomach submucosa (SS)” cells, myocardial cells, skeletal cells, fetal cells, undifferen also mean and include any UBS and/or SIS and/or SS tiated cells, multi-potent progenitor cells, unipotent progeni material that includes the tunica mucosa (which includes the tor cells, monocytes, cardiac myoblasts, skeletal myoblasts, transitional epithelial layer and the tunica propria), Submu macrophages, capillary endothelial cells, Xenogenic cells, cosal layer, one or more layers of muscularis, and adventitia 45 allogenic cells, and post-natal stem cells. (a loose connective tissue layer) associated therewith. The terms “biologically active agent” and “biologically The ECM material can also be derived from basement active composition' also mean and include, without limita membrane of mammalian tissue/organs, including, without tion, the following biologically active agents (referred to limitation, urinary basement membrane (UBM), liver base interchangeably herein as a “protein', 'peptide' and “poly ment membrane (LBM), and amnion, chorion, allograft 50 peptide'): collagen (types I-V), proteoglycans, gly pericardium, allograft acellular dermis, amniotic membrane, cosaminoglycans (GAGS), glycoproteins, growth factors, Wharton's jelly, and combinations thereof. cytokines, cell-surface associated proteins, cell adhesion Additional Sources of mammalian basement membrane molecules (CAM), angiogenic growth factors, endothelial include, without limitation, spleen, lymph nodes, salivary ligands, matrikines, cadherins, immuoglobins, fibril colla glands, prostate, pancreas and other secreting glands. 55 gens, non-fibrallar collagens, basement membrane colla The ECM material can also be derived from other sources, gens, multiplexins, Small-leucine rich proteoglycans, deco including, without limitation, collagen from plant sources rins, biglycans, fibromodulins, keratocans, lumicans, and synthesized extracellular matrices, i.e. cell cultures. epiphycans, heparin Sulfate proteoglycans, perlecans, agrins, The term “angiogenesis', as used herein, means a physi testicans, Syndecans, glypicans, serglycins, selectins, lecti ologic process involving the growth of new blood vessels 60 cans, aggrecans, Versicans, neurocans, brevicans, cytoplas from pre-existing blood vessels. mic domain-44 (CD-44), macrophage stimulating factors, The term “neovascularization', as used herein, means and amyloid precursor proteins, heparins, chondroitin Sulfate B includes the formation of functional vascular networks that (dermatan Sulfate), chondroitin Sulfate A, heparin Sulfates, can be perfused by blood or blood components. Neovascu hyaluronic acids, fibronectins, tenascins, elastins, fibrillins, larization includes angiogenesis, budding angiogenesis, 65 laminins, nidogen/enactins, fibulin I, fibulin II, integrins, intus Suceptive angiogenesis, Sprouting angiogenesis, thera transmembrane molecules, thrombospondins, ostepontins, peutic angiogenesis and Vasculogenesis. and angiotensin converting enzymes (ACE). US 9,533,072 B2 7 8 The terms “pharmacological agent”, “active agent'. aZolides, metronidazole, penicillins, tetracyclines, 'drug and “active agent formulation” are used interchange trimethoprim-sulfamethoxazole and Vancomycin. ably herein, and mean and include an agent, drug, com The terms “pharmacological agent”, “active agent'. pound, composition of matter or mixture thereof, including “drug and “active agent formulation’ further include, with its formulation, which provides some therapeutic, often 5 out limitation, the following steroids: andranes (e.g., testos beneficial, effect. This includes any physiologically or phar terone), cholestanes, cholic acids, corticosteroids (e.g., dex macologically active Substance that produces a localized or amethasone), estraenes (e.g., estradiol) and pregnanes (e.g., systemic effect or effects in animals, including warm progesterone). blooded mammals, humans and primates; avians; domestic The terms “pharmacological agent”, “active agent'. 10 “drug and “active agent formulation' can further include household or farm animals, such as cats, dogs, sheep, goats, one or more classes of narcotic analgesics, including, with cattle, horses and pigs; laboratory animals, such as mice, rats out limitation, morphine, codeine, heroin, hydromorphone, and guinea pigs; fish; reptiles; Zoo and wild animals; and the levorphanol, meperidine, methadone, oxycodone, propoxy like. phene, fentanyl, methadone, naloxone, buprenorphine, The terms “pharmacological agent”, “active agent'. 15 butorphanol, nalbuphine and pentazocine. “drug and “active agent formulation' thus mean and The terms “pharmacological agent”, “active agent'. include, without limitation, antibiotics, anti-arrhythmic “drug and “active agent formulation' can further include agents, anti-viral agents, analgesics, Steroidal anti-inflam one or more classes of topical or local anesthetics, including, matories, non-steroidal anti-inflammatories, anti-neoplas without limitation, esters, such as benzocaine, chloropro tics, anti-spasmodics, modulators of cell-extracellular caine, cocaine, cyclomethycaine, dimethocaine/larocaine, matrix interactions, proteins, hormones, growth factors, piperocaine, propoxycaine, procaine/novacaine, propara matrix metalloproteinases (MMPS), enzymes and enzyme caine, and tetracaine/amethocaine. Local anesthetics can inhibitors, anticoagulants and/or antithrombic agents, DNA, also include, without limitation, amides. Such as articaine, RNA, modified DNA and RNA, NSAIDs, inhibitors of bupivacaine, cinchocaine/dibucaine, etidocaine, levobupi DNA, RNA or protein synthesis, polypeptides, oligonucle 25 vacaine, lidocaineflignocaine, mepivacaine, prilocaine, ropi otides, polynucleotides, nucleoproteins, compounds modu vacaine, and trimecaine. Local anesthetics can further lating cell migration, compounds modulating proliferation include combinations of the above from either amides or and growth of tissue, and vasodilating agents. esterS. The terms “pharmacological agent”, “active agent'. The terms “anti-inflammatory' and “anti-inflammatory “drug and “active agent formulation' thus include, without 30 agent” are also used interchangeably herein, and mean and limitation, atropine, tropicamide, dexamethasone, dexam include a “pharmacological agent' and/or “active agent ethasone phosphate, betamethasone, betamethasone phos formulation”, which, when a therapeutically effective phate, prednisolone, triamcinolone, triamcinolone amount is administered to a subject, prevents or treats bodily acetonide, fluocinolone acetonide, anecortave acetate, tissue inflammation i.e. the protective tissue response to budesonide, cyclosporine, FK-506, rapamycin, ruboxistau 35 injury or destruction of tissues, which serves to destroy, rin, midostaurin, flurbiprofen, Suprofen, ketoprofen, dilute, or wall off both the injurious agent and the injured diclofenac, ketorolac, nepafenac, lidocaine, neomycin, poly tissues. myxin b, bacitracin, gramicidin, gentamicin, oyXtetracy Anti-inflammatory agents thus include, without limita cline, ciprofloxacin, ofloxacin, tobramycin, amikacin, van tion, alclofenac, alclometaSone dipropionate, algestone comycin, cefazolin, ticarcillin, chloramphenicol, 40 acetonide, alpha amylase, amcinafal, amcinafide, amfenac miconazole, itraconazole, trifluridine, Vidarabine, ganciclo Sodium, amiprilose hydrochloride, anakinra, anirolac, ani Vir, acyclovir, cidofovir, ara-amp, foScarnet, idoxuridine, traZafen, apaZone, balsalazide disodium, bendaZac, benox adefovir dipivoxil, methotrexate, carboplatin, phenyleph aprofen, benzydamine hydrochloride, bromelains, bropera rine, epinephrine, dipivefrin, timolol, 6-hydroxydopamine, mole, budesonide, carprofen, cicloprofen, cintaZone, betaxolol, pilocarpine, carbachol, physostigmine, deme 45 cliprofen, clobetasol propionate, clobetaSone butyrate, carium, dorzolamide, brinzolamide, latanoprost, sodium clopirac, cloticasone propionate, cormethasone acetate, cor hyaluronate, insulin, verteporfin, pegaptainib, ranibizumab, todoxone, decanoate, deflazacort, delatestryl, depo-testos and other antibodies, antineoplastics, anti-VEGFs, ciliary terone, desonide, desoximetaSone, dexamethasone dipropi neurotrophic factor, brain-derived neurotrophic factor, onate, diclofenac potassium, diclofenac sodium, diflorasone bFGF, Caspase-1 inhibitors, Caspase-3 inhibitors, C.-Adre 50 diacetate, diflumidone sodium, diflunisal, difluprednate, noceptors agonists, NMDA antagonists, Glial cell line diftalone, dimethyl sulfoxide, drocinonide, endrysone, enli derived neurotrophic factors (GDNF), pigment epithelium momab, enolicam sodium, epirizole, etodolac, etofenamate, derived factor (PEDF), and NT-3, NT 4, NGF, IGF-2. felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fen The terms “pharmacological agent”, “active agent'. dosal, fenpipalone, fentiazac, flazalone, fluazacort, flufe “drug and “active agent formulation’ further mean and 55 namic acid, flumizole, flunisolide acetate, flunixin, flunixin include the following Class I-Class V antiarrhythmic agents: meglumine, fluocortin butyl, fluorometholone acetate, (Class Ia) quinidine, procainamide and disopyramide: (Class fluquaZone, flurbiprofen, fluretofen, fluticasone propionate, Ib) lidocaine, phenytoin and mexiletine; (Class Ie) flecain furaprofen, furobufen, halcinonide, halobetasol propionate, ide, propafenone and moricizine; (Class II) propranolol. halopredone acetate, ibufenac, ibuprofen, ibuprofen alumi esmolol, timolol, metoprolol and atenolol; (Class III) amio 60 num, ibuprofen piconol, illonidap, indomethacin, indometha darone, Sotalol, ibutilide and dofetilide: (Class IV) Vera cin Sodium, indoprofen, indoxole, intrazole, isoflupredone pamil and diltiazem) and (Class V) adenosine and digoxin. acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydro The terms “pharmacological agent”, “active agent'. chloride, lomoxicam, loteprednoletabonate, meclofenamate “drug and “active agent formulation’ further mean and Sodium, meclofenamic acid, meclorisone dibutyrate, mefe include, without limitation, the following antiobiotics: 65 namic acid, mesalamine, meseclaZone, mesterolone, meth aminoglycosides, cephalosporins, chloramphenicol, clin androstenolone, methenolone, methenolone acetate, meth damycin, erythromycins, fluoroquinolones, macrollides, ylprednisolone Suleptanate, momiflumate, nabumetone, US 9,533,072 B2 9 10 nandrolone, naproxen, naproxen Sodium, naproXol, nima comprising, without limitation, SIS, UBS, SS, central ner Zone, olsalazine Sodium, orgotein, orpanoxin, oxandrolane, Vous system tissue, dermal extracellular matrix, Subcutane oxaprozin, oxyphenbutaZone, oxymetholone, paranyline ous extracellular matrix, gastrointestinal extracellular hydrochloride, pentosan polysulfate Sodium, phenbutaZone matrix, tissue surrounding growing bone, placental extra Sodium glycerate, pirfenidone, piroXicam, piroxicam cinna cellular matrix, omomentum extracellular matrix, mesothe mate, piroxicam olamine, pirprofen, prednazate, prifelone, lial tissue, cardiac extracellular matrix, kidney extracellular prodolic acid, produaZone, proxazole, proxazole citrate, matrix, pancreas extracellular matrix, lung extracellular rimexolone, romazarit, Salcolex, Salnacedin, Salsalate, san matrix, and combinations thereof. guinarium chloride, seclaZone, Sermetacin, stanozolol, Sudo Preferably, the mammalian tissue source comprises an Xicam, Sulindac, Suprofen, talmetacin, talniflumate, 10 adolescent mammalian tissue source, i.e. an adolescent talosalate, tebufelone, tenidap, tenidap Sodium, tenoxicam, mammal. Such as a piglet, which is preferably less than three tesicam, tesimide, testosterone, testosterone blends, tetry (3) years of age. damine, tiopinac, tiXocortol pivalate, tolmetin, tolmetin In a preferred embodiment, the ECM material is decel Sodium, triclonide, triflumidate, Zidometacin, and Zomepirac lularized and, hence, remodelable. Sodium. 15 According to the invention, the ECM material can be The term “pharmacological composition’, as used herein, decellularized by various conventional means. In a preferred means and includes a composition comprising a “pharma embodiment, the ECM material is decellularized via one of cological agent” and/or a “biologically active agent” and/or the unique Novasterilis processes disclosed in U.S. Pat. No. any additional agent or component identified herein. 7,108,832 and U.S. patent applicaiton Ser. No. 13/480,204: The term “therapeutically effective’, as used herein, which are incorporated by reference herein in their entirety. means that the amount of the “pharmacological agent' In some embodiments of the invention, the tubular mem and/or “biologically active agent' and/or “pharmacological bers comprise an ECM/ECM-mimicking biomaterial com composition’ administered is of Sufficient quantity to ame position comprising an ECM material and an ECM-mim liorate one or more causes, symptoms, or sequelae of a icking biomaterial. disease or disorder. Such amelioration only requires a reduc 25 In a preferred embodiment, the ECM-mimicking bioma tion or alteration, not necessarily elimination, of the cause, terial comprises poly(glycerol sebacate) (PGS). symptom, or sequelae of a disease or disorder. As discussed in detail below, Applicant has found that The term "adolescent’, as used herein, means and PGS exhibits numerous beneficial properties that provide includes a mammal that is preferably less than three (3) several beneficial biochemical actions or activities. years of age. 30 PGS Physical Properties The terms “patient' and “subject' are used interchange PGS is a condensate of the non-immunogenic composi ably herein, and mean and include warm blooded mammals, tions glycerol (a simple sugar alcohol) and sebacic acid (a humans and primates; avians; domestic household or farm naturally occurring dicarboxylic acid), wherein, glycerol animals, such as cats, dogs, sheep, goats, cattle, horses and and sebacic acid are readily metabolized when proximate pigs; laboratory animals, such as mice, rats and guinea pigs, 35 mammalian tissue. The non-immunogenic properties Sub fish; reptiles; Zoo and wild animals; and the like. stantially limit the acute inflammatory responses typically The term “comprise' and variations of the term, such as associated with other “biocompatible' polymers, such as “comprising and "comprises.” means “including, but not ePTFE (polytetrafluoroethylene), that are detrimental to limited to' and is not intended to exclude, for example, other bioremodeling and tissue regeneration. additives, components, integers or steps. 40 The mechanical properties of PGS are substantially simi The following disclosure is provided to further explain in lar to that of biological tissue. Indeed, the value of the an enabling fashion the best modes of performing one or Young's modulus of PGS is between that of a ligament (in more embodiments of the present invention. The disclosure KPa range) and tendon (in GPa range). The strain to failure is further offered to enhance an understanding and appre of PGS is also similar to that of arteries and veins (i.e. over ciation for the inventive principles and advantages thereof, 45 260% elongation). rather than to limit in any manner the invention. The The tensile strength of the PGS is at least 0.28+0.004 invention is defined solely by the appended claims including MPa. The Young's modulus and elongation are at least any amendments made during the pendency of this appli 0.122+0.0003 and at least 237.8+0.64%, respectively. For cation and all equivalents of those claims as issued. applications requiring stronger mechanical properties and a As stated above, the present invention is directed to 50 slower biodegradation rate. PGS can be blended with PCL, vascular grafts or prostheses for treating, reconstructing or i.e. a biodegradable elastomer. replacing damaged or diseased tissue. ECM Mimicking Properties/Actions It is, however, understood that, although the disclosure is It has been established that PGS induces tissue remodel directed to vascular grafts, the invention is also applicable to ing and regeneration when administered proximate to dam coated planar members. 55 aged tissue, thus, mimicking the seminal regenerative prop In a preferred embodiment, the vascular grafts comprise erties of ECM and, hence, an ECM composition formed coated tubular members having proximal and distal ends. therefrom. The mechanism underlying this behavior is In some embodiments of the invention, the tubular mem deemed to be based on the mechanical and biodegradation bers comprise an ECM material derived from a mammalian kinetics of the PGS. See Sant, et al., Effect of Biodegradation tissue source. According to the invention, the mammalian 60 and de novo Matrix Synthesis on the Mechanical Properties tissue sources can include, without limitation, the Small of VIC-seeded PGS-PCL scaffolds, Acta. Biomater, vol. intestine, large intestine, Stomach, lung, liver, kidney, pan 9(4), pp. 5963-73 (2013). creas, placenta, heart, bladder, prostate, tissue Surrounding In some embodiments, the ECM/ECM-mimicking bioma growing enamel, tissue Surrounding growing bone, and any terial composition further comprises PCL, which, according fetal tissue from any mammalian organ. 65 to the invention, modulates the degradation characteristics As discussed in detail herein, in a preferred embodiment, of the composition and, hence, tubular member formed the ECM material comprises ECM selected from the group therewith. US 9,533,072 B2 11 12 In some embodiments, the ECM/ECM-mimicking bioma on Mar. 3, 2013, Ser. No. 14/337,460, filed on Mar. 3, 2013; terial tubular members are formed via a Novasterilis process which are incorporated by reference herein in their entirety. disclosed in U.S. Pat. No. 7,108,832 and U.S. patent appli In some embodiments of the invention, the tubular mem cation Ser. No. 13/480.204, wherein the PGS (and PCL, if ber coating comprises an ECM-mimicking composition employed) is driven into an ECM tubular member. 5 comprising at least one ECM-mimicking biomaterial. In some embodiments, the tubular members comprise a In a preferred embodiment, the ECM-mimicking bioma mesh structure, such as disclosed in U.S. patent application terial comprises PGS. Ser. Nos. 14/554,730, 14/554,795 and 14/554,847, filed on In some embodiments of the invention, the tubular mem Nov. 26, 2014. ber coating comprises an ECM-mimicking composition In some embodiments, the mesh structure is embedded in 10 comprising PGS and PCL. the tubular member. In some embodiments of the invention, the tubular mem In some embodiments, the mesh structure is disposed over ber coating comprises an ECM/ECM-mimicking biomate the luminal surface of the tubular member. rial composition, e.g. 50% ECM/50% PGS. In some embodiments of the invention, the tubular mem In some embodiments, the ECM/ECM-mimicking bioma ber coating comprises a polymeric composition comprising 15 terial composition further comprises PCL. at least one biocompatible polymeric material. In some embodiments, the tubular member coating com According to the invention, the biocompatible polymeric prises a blended plurality of ECM, polymeric, ECM-mim material can comprise, without limitation, polyglycolide icking biomaterial composition, and/or ECM/ECM-mimick (PGA), polylactide (PLA), poly(e-caprolactone) (PCL), ing biomaterial composition coatings. poly dioxanone (a polyether-ester), poly lactide-co-gly In some embodiments, the tubular member coating com collide, polyamide esters, polyalkalene esters, polyvinyl prises a porosity in the range of 10-90%. esters, polyvinyl alcohol, and polyanhydrides, and like poly In some embodiments, the tubular member coating com CS. prises a thickness in the range of 5-100 um, which can vary The biocompatible polymeric material can also comprise, based on the orientation and the size of the vascular grafts. without limitation, natural polymeric materials, including, 25 In some embodiments, the coating thickness is in the range without limitation, polysaccharides (e.g. starch and cellu of 10-20 lum. If multiple coatings are employed, the total lose), proteins (e.g., gelatin, casein, silk, wool, etc.), and coating thickness is preferably in the range of 5-200 um, polyesters (e.g., polyhydroxyalkanoates). more preferably, in the range of 30-80 Lum. In some embodiments of the invention, the coating com According to the invention, the tubular member coating(s) prises a polymeric composition comprising a biocompatible 30 can be applied to the tubular member by various conven polymeric material selected from the group comprising, tional means, including, without limitation, pressure coating without limitation, polyhydroxyalkonates (PHAs), polylac in a vapor chamber, dip coating, and spraying. tides (PLLA) and polyglycolides (PLGA) and their copoly In some embodiments of the invention, the tubular mem mers, for example poly(e-caprolactone-co-glycolide), poly bers further comprise an outer reinforcing structure. Such as anhydrides, and like polymers. 35 disclosed in Co-pending U.S. application Ser. No. 14/337, According to the invention, the polymeric material can 863, filed on Jul. 22, 2014, and Ser. Nos. 14/554,730, also comprise a hydrogel, including, without limitation, 14/554,795 and 14/554,847, filed on Nov. 26, 2014, which polyurethane, poly(ethylene glycol), poly(propylene gly are incorporated by reference herein in their entirety. col), poly(vinylpyrrolidone), Xanthan, methyl cellulose, car According to the invention, the reinforcing structure can boxymethyl cellulose, alginate, hyaluronan, poly(acrylic 40 comprise a wound member or strand configuration, i.e. a thin acid), polyvinyl alcohol, acrylic acid, hydroxypropyl methyl strand wound around the outer surface of the tubular mem cellulose, methacrylic acid, C.B-glycerophosphate, K-carra ber, such as disclosed in Co-Pending application Ser. No. geenan, 2-acrylamido-2-methylpropanesulfonic acid, and 147337,863 or a mesh structure, such as disclosed in Co B-hairpin peptide. Pending application Ser. Nos. 14/554,730, 14/554,795 and In some embodiments, the hydrogel is crosslinked via 45 14/554,847. chemically and/or photocuring, e.g. ultraviolet light. In some embodiments of the invention, the reinforcing In some embodiments, the polymeric material is plasma structure comprises one of the aforementioned ECM mate treated to accommodate hygroscopic agents. rials. In some embodiments of the invention, the tubular mem In some embodiments, the reinforcing structure comprises ber coating comprises an ECM composition comprising at 50 one of the aforementioned polymeric materials. least one of the aforementioned ECM materials. In some embodiments of the invention, the reinforcing Suitable ECM compositions are disclosed in U.S. Pat. structure comprises one of the aforementioned ECM-mim Nos. 8,568,761, 8,753,885, 8,795,728, 8,734,841, 8,642, icking biomaterial compositions. 084, 8,771,737, 8,734,842, 8,784,891, 8,753,886, 8,785,197, In some embodiments of the invention, the reinforcing 8,785,198, 8,735,155 and U.S. patent application Ser. No. 55 structure comprises one of the aforementioned ECM/ECM 13/732,943, filed on Jan. 2, 2013, Ser. No. 1 1/448,351, filed mimicking biomaterial compositions. on Jun. 6, 2006, Ser. No. 14/269,324, filed on May 5, 2014, In some embodiments of the invention, the reinforcing Ser. No. 13/732,558, filed on Jan. 2, 2013, Ser. No. 13/732, structure comprises a biocompatible metal. Such as stainless 731, filed on Jan. 2, 2013, Ser. No. 13/875,017, filed on May steel and NitinolR). 1, 2013, Ser. No. 13/875,043, filed on May 1, 2013, Ser. No. 60 As stated above, in some embodiments of the invention, 13/875,058, filed on May 1, 2013, Ser. No. 14/452,707, filed the tubular members of the invention and, hence, vascular on Aug. 6, 2014, Ser. No. 14/192,973, filed on Jan. 28, 2014, grafts formed therefrom and tubular member coatings fur Ser. No. 14/192,992, filed on Feb. 28, 2014, Ser. No. ther comprise at least one additional biologically active 14/193,008, filed on Feb. 28, 2014, Ser. No. 14/193,030, agent or composition, i.e. an agent that induces or modulates filed on Feb. 28, 2014, Ser. No. 14/193,053, filed on Feb. 28, 65 a physiological or biological process, or cellular activity, 2014, Ser. No. 14/269,414, filed on Mar. 3, 2013, Ser. No. e.g., induces proliferation, and/or growth and/or regenera 14/269,487, filed on Mar. 3, 2013, Ser. No. 14/269,874, filed tion of tissue. US 9,533,072 B2 13 14 In a preferred embodiment, the biologically active agent neoplastics, anti-spasmodics, modulators of cell-extracellu is similarly derived from an adolescent mammal, i.e. a lar matrix interactions, proteins, hormones, enzymes and mammal less than three (3) years of age. enzyme inhibitors, anticoagulants and/or antithrombic Suitable biologically active agents include any of the agents, DNA, RNA, modified DNA and RNA, NSAIDs, aforementioned biologically active agents, including, with inhibitors of DNA, RNA or protein synthesis, polypeptides, out limitation, the aforementioned cells and proteins. oligonucleotides, polynucleotides, nucleoproteins, com In some embodiments of the invention, the biologically pounds modulating cell migration, compounds modulating active agent specifically comprises a growth factor selected proliferation and growth of tissue, and vasodilating agents. from the group comprising transforming growth factor-alpha In some embodiments of the invention, the pharmaco (TGF-C.), transforming growth factor-beta (TGF-B), fibro 10 logical agent comprises one of the aforementioned anti blast growth factor-2 (FGF-2), basic fibroblast growth factor inflammatory agents. (bFGF) and vascular epithelial growth factor (VEGF). According to the invention, upon implanting a tubular In some embodiments of the invention, the pharmaco member and, hence, a vascular graft formed therefrom logical agent comprises a statin, i.e. a HMG-CoA reductase proximate damaged biological tissue of a Subject, the growth 15 inhibitor. According to the invention, Suitable statins factors link to and interact with at least one molecule in the include, without limitation, atorvastatin (Lipitor(R), cerivas tubular member and/or a cell or molecule recruited by the tatin, fluvastatin (Lescol(R), lovastatin (Mevacor(R), Alto ECM and enhances cell and tissue proliferation, bioremod cor(R), Altoprev(R), mevastatin, pitavastatin (LivaloR, eling, and regeneration of new tissue structures. Pitava(R), pravastatin (Pravachol(R), Selektine(R), Lipostat(R), By way of example, according to the invention, when a rosuvastatin (Crestor R), and simvastatin (Zocorr, Lipex.R.). tubular member and, hence, a vascular graft formed there Several actives comprising a combination of a statin and from comprises a growth factor augmented ECM composi another agent, such as eZetimbe/simvastatin (VytorinR), are tion and/or an ECM composition coating comprising ECM also suitable. and an exogenously added growth factor, e.g. bFGF and/or Applicant has found that the noted statins exhibit numer VEGF, and the tubular member is disposed proximate dam 25 ous beneficial properties that provide several beneficial aged biological tissue, the growth factor interacts with the biochemical actions or activities; particularly, when deliv endogenous heparin sulfate present in the ECM and cells ered to damaged tissue with an ECM material. Indeed, recruited by the ECM, wherein the tubular member modu Applicant has found that when a statin is added to ECM lates inflammation and induces tissue proliferation, neovas (wherein a statin augmented ECM composition is formed) cularization, bioremodeling and regeneration of tissue. 30 and the statin augmented ECM composition is administered In some embodiments of the invention, the biologically active agent comprises a protein selected from the group to damaged tissue, the statin interacts with the cells recruited comprising, without limitation, collagen (types I-V), pro by the ECM, wherein the statin augmented ECM composi tion modulates inflammation of the damaged tissue by teoglycans, glycosaminoglycans (GAGS), glycoproteins, modulating several significant inflammatory processes, heparins, chondroitin Sulfate B (dermatan Sulfate), chondroi 35 tin Sulfate A, heparin Sulfates, hyaluronic acids, cytokines, including restricting expression of monocytes chemoattrac cell-surface associated proteins, and cell adhesion molecules tant protein 1 (MCP-1) and chemokine (C-C) motif ligand (CAMs). 2 (CCR2). In some embodiments of the invention, the cytokine is The properties and beneficial actions are further discussed selected from the group comprising a stem cell factor (SCF). 40 in Applicant's Co-Pending application Ser. No. 13/328,287. stromal cell-derived factor-1 (SDF-1), granulocyte macro filed on Dec. 16, 2011, Ser. No. 13/373,569, filed on Sep. 24, phage colony-stimulating factor (GM-CSF), interferon 2012 and Ser. No. 137782,024, filed on Mar. 1, 2013; which gamma (IFN-gamma), interleukin-3, interleukin-4, interleu are incorporated by reference herein in their entirety. kin-8, interleukin-10, interleukin-13, leukemia inhibitory Additional Suitable pharmacological agents and compo factor (LIF), amphiregulin, thrombospondin 1, thrombos 45 sitions that can be employed within the scope of the inven pondin 2, thrombospondin 3, thrombospondin 4, thrombo tion are disclosed in Pat. Pub. Nos. 20070014874, spondin 5, and angiotensin converting enzyme (ACE). 20070014873, 20070014872, 20070014871, 20070014870, According to the invention, when a tubular member and, 20070014869, and 20070014868; which are expressly incor hence, a vascular graft formed therefrom comprises a protein porated by reference herein in its entirety. augmented ECM composition and/or an ECM composition 50 According to the invention, the biologically active and coating comprising ECM and an exogenously added protein, pharmacological agents referenced above can comprise vari e.g., cytokine, the protein similarly interacts with at least one ous forms. molecule in the tubular member and/or a cell or molecule In some embodiments of the invention, the biologically recruited by the ECM and similarly enhances cell and tissue active and pharmacological agents, e.g. simvastatin, com proliferation, bioremodeling, and regeneration of new tissue 55 prise microcapsules that provide delayed delivery of the Structures. agent contained therein. In some embodiments, the tubular members of the inven In some embodiments, the tubular members of the inven tion and, hence, vascular grafts formed therefrom and tubu tion and, hence, vascular grafts formed therefrom comprise lar member coatings further comprise at least one pharma a combination of ECM, polymeric, ECM-mimicking bio cological agent or composition (or drug), i.e. an agent or 60 material composition, and/or ECM/ECM-mimicking bioma composition that is capable of producing a desired biological terial composition coatings having various biologically effect in Vivo, e.g., stimulation or Suppression of apoptosis, active and/or pharmacological agents and/or properties, e.g. stimulation or Suppression of an immune response, etc. a an ECM composition coating comprising a growth factor Suitable pharmacological agents and compositions and an ECM-mimicking biomaterial composition coating include any of the aforementioned agents, including, without 65 comprising a pharmacological agent, e.g. antiinflammatory. limitation, antibiotics, anti-viral agents, analgesics, steroidal In some embodiments, the tubular member coatings com anti-inflammatories, non-steroidal anti-inflammatories, anti prise modulated degradation kinetics, wherein the gradual US 9,533,072 B2 15 16 degradation of the coating provides a controlled release of retard, reduce, and/or detain one or more of the phases biologically active and/or pharmacological agents incorpo associated with healing of damaged tissue, including, but not rated therein. limited to, the inflammatory phase (e.g., platelet or fibrin In some embodiments, the tubular member coatings are deposition), and the proliferative phase when in contact with configured to provide a delivery gradient of various biologi biological tissue. cally active and/or pharmacological agent delivery profiles. In some embodiments, “modulated healing refers to the By way of example, in some embodiments, biologically ability of a tubular member of the invention and, hence, a active and/or pharmacological agents are disposed through vascular graft formed therefrom to restrict the expression of out various depths or thickness ranges of one or more inflammatory components. By way of example, as indicated coatings. 10 above, when a tubular member comprises an ECM or In some embodiments, the tubular members of the inven ECM/ECM-mimicking biomaterial composition and/or an tion and, hence, vascular grafts formed therefrom specifi ECM or ECM/ECM-mimicking biomaterial composition cally comprise an ECM composition coating comprising coating comprising a statin and the tubular member is anti-inflammatory growth factors interleukin-10 (IL-10) and disposed proximate damaged biological tissue, the tubular transforming growth factor beta (TGF-B), which will sup 15 member restricts the expression of MCP-1 and CCR2. press the inflammatory reaction leading to a chronic immune In some embodiments, “modulated healing means and response. According to the invention, during a chronic includes the ability of a tubular member of the invention immune response, IL-10 and TGF-B induce the expression and, hence, a vascular graft formed therefrom to alter a of tissue inhibitor of metalloproteinase (TIMP), which Substantial inflammatory phase (e.g., platelet or fibrin depo inhibits matrix metalloproteinases (MMPs) that are respon sition) at the beginning of the tissue healing process. As used sible for ECM degradation during the inflammatory herein, the phrases “alter a substantial inflammatory phase' response. Additionally, IL-10 and TGF-B promote the refers to the ability of a tubular member to substantially recruitment of fibroblasts, which are the seminal cells reduce the inflammatory response at an injury site when in responsible for ECM deposition and bioremodeling. As a contact with biological tissue. result, IL-10, TGF-B, and the TIMPs concomitantly promote 25 In Such an instance, a minor amount of inflammation may ECM deposition and preservation, which thus augments ensue in response to tissue injury, but this level of inflam “modulated healing,” as defined herein. mation response, e.g., platelet and/or fibrin deposition, is In some embodiments, the tubular members of the inven Substantially reduced when compared to inflammation that tion and, hence, vascular grafts formed therefrom specifi takes place in the absence of a tubular member and, hence, cally comprise an ECM composition coating comprising at 30 graft of the invention. least one biologically active or pharmacological agent that The term, “modulated healing also refers to the ability of provides a reinforcing anti-inflammatory effect either a tubular member of the invention and, hence, a vascular through direct reinforcement, i.e. targeting the same inflam graft formed therefrom to induce host tissue proliferation, matory signaling pathway, or indirect reinforcement, i.e. bioremodeling, including neovascularization, e.g., vasculo targeting an alternate inflammatory signaling pathway. An 35 genesis, angiogenesis, and intussusception, and regeneration example of direct reinforcement includes, without limita of tissue structures with site-specific structural and func tion, a combination of IL-10, TGF-B and a glucocorticoid, tional properties. all of which inhibit the expression of seminal inflammatory Thus, in some embodiments, the term “modulated heal cytokine interleukin-1 (IL-1). An example of indirect rein ing also refers to the ability of a tubular member and, forcement includes, without limitation, a combination of 40 hence, a vascular graft formed therefrom to modulate IL-10, TGF-B and an NSAID. (Non-steroidal anti-inflam inflammation and/or induce host tissue proliferation and matory drug) where IL-10 and TGF-B inhibit IL-1, and the remodeling. Again, by way of example, according to the NSAIDs inhibit the activity of both cyclooxygenase-1 invention, when a tubular member comprises an ECM or (COX-1) and cyclooxygenase-2 (COX-2), and thereby, the ECM/ECM-mimicking biomaterial composition and/or an synthesis of prostaglandins and thromboxanes. 45 ECM or ECM/ECM-mimicking biomaterial composition According to the invention and indicated above, upon coating comprising a statin and the tubular member is implanting a tubular member of the invention and, hence, a disposed proximate damaged biological tissue, the statin vascular graft formed therefrom to damaged or diseased interacts with the cells recruited by the ECM, wherein the biological tissue, “modulated healing' is effectuated. The tubular modulates inflammation by, among other actions, tubular member also provides a vessel having a smooth, 50 restricting expression of MCP-1 and CCR2 and induces non-thrombogenic interior Surface. tissue proliferation, bioremodeling and regeneration of tis The term “modulated healing', as used herein, and vari Sue structures with site specific structural and functional ants of this language generally refer to the modulation (e.g., properties. alteration, delay, retardation, reduction, etc.) of a process By way of a further example, according to the invention, involving different cascades or sequences of naturally occur 55 when a tubular member and, hence, a vascular graft formed ring tissue repair in response to localized tissue damage or therefrom comprises a growth factor augmented ECM com injury, Substantially reducing their inflammatory effect. position and/or a coating comprising an ECM composition Modulated healing, as used herein, includes many different comprising ECM and an exogenously added growth factor, biologic processes, including epithelial growth, fibrin depo e.g. TGF-B, is disposed proximate damaged biological tis sition, platelet activation and attachment, inhibition, prolif 60 sue, the growth factor similarly interacts with the ECM and eration and/or differentiation, connective fibrous tissue pro cells recruited by the ECM, wherein the tubular member duction and function, angiogenesis, and several stages of modulates inflammation and induces tissue proliferation, acute and/or chronic inflammation, and their interplay with bioremodeling and regeneration of tissue. each other. In some embodiments, the tubular members of the inven For example, in some embodiments, the tubular members 65 tion and, hence, vascular grafts formed therefrom and/or of the invention and, hence, vascular grafts formed there tubular member coatings provide a single-stage agent deliv from are specifically formulated (or designed) to alter, delay, ery profile, i.e. comprise a single-stage delivery vehicle, US 9,533,072 B2 17 18 wherein a modulated dosage of an aforementioned biologi Referring now to FIGS. 1A and 1B, there is shown one cally active and/or pharmacological agent is provided. embodiment of a tubular member of the invention. As According to the invention, the term "modulated dosage' illustrated in FIG. 1A, the tubular member 12 comprises a as used herein, and variants of this language generally refer continuous member having proximal 14 and distal 16 ends, to the modulation (e.g., alteration, delay, retardation, reduc and a lumen 18 that extends therethrough. tion, etc.) of a process involving different eluting or dispersal As indicated above, in a preferred embodiment of the rates of an agent within biological tissue. invention, the tubular member 12 comprises a decellularized In some embodiments, the single-stage delivery vehicle ECM material. As also indicated above, preferably, the ECM comprises encapsulated particulates of a biologically active material is derived from an adolescent mammal, i.e. a and/or pharmacological agent. 10 mammal less than three (3) years of age. In some embodiments, the encapsulation composition According to the invention, the tubular member 12, and, comprises one of the aforementioned ECM compositions. hence vascular grafts 10a and 10b (discussed below) formed In some embodiments, the encapsulation composition therefrom, can have various diameters, e.g. 3.0 mm, 10.0 comprises a biodegradable polymeric composition compris mm, etc. ing one of the aforementioned polymeric materials. 15 In some embodiments of the invention, the tubular mem In some embodiments, the encapsulation composition ber 12 (or ECM material thereof) further comprises at least comprises one of the aforementioned ECM-mimicking bio one additional biologically active agent or composition, i.e. material compositions. an agent that induces or modulates a physiological or In some embodiments, the encapsulation composition biological process, or cellular activity, e.g., induces prolif comprises one of the aforementioned ECM/ECM-mimick eration, and/or growth and/or regeneration of tissue. ing biomaterial compositions. Suitable biologically active agents include any of the In some embodiments, the encapsulation composition aforementioned biologically active agents, including, with comprises an osmotic fluctuation inducing composition. out limitation, the aforementioned cells, growth factors and According to the invention, Suitable osmotic fluctuation proteins. inducing compositions include, without limitation, polyeth 25 In some embodiments, the tubular member 12 (or ECM ylene glycol, alginate and dextran. material thereof) further comprises at least one pharmaco According to the invention, the term "osmotic fluctua logical agent or composition (or drug), i.e. an agent or tion” as used herein, and variants of this language generally composition that is capable of producing a desired biological refer to the modulation of the osmotic pressure gradient effect in Vivo, e.g., stimulation or Suppression of apoptosis, across a defined barrier. 30 stimulation or Suppression of an immune response, etc. For example, as is well known in the art, alginate is Suitable pharmacological agents and compositions capable of absorbing 200-300 times its weight in water, include any of the aforementioned agents, including, without which substantially increases the osmotic pressure gradient limitation, antibiotics, anti-viral agents, analgesics, and anti of the alginate. The increased osmotic pressure gradient of inflammatories. the alginate results in a rapid dispersal of an agent therefrom. 35 In some embodiments of the invention, the pharmaco In some embodiments of the invention, the tubular mem logical agent comprises a statin, i.e. a HMG-CoA reductase bers of the invention and, hence, vascular grafts formed inhibitor. therefrom and/or tubular member coatings provide a multi Referring now to FIGS. 2A and 2B, there is shown one stage agent delivery profile, i.e. comprise a multi-stage agent embodiment of a vascular graft of the invention. As illus delivery vehicle, wherein a plurality of the aforementioned 40 trated in FIG. 2A, the graft 10a comprises tubular member biologically active and/or pharmacological agents are 12 having proximal 14 and distal 16 ends, and a lumen 18 administered via a modulated dosage. By way of example, that extends therethrough. The tubular member 12 further in Some embodiments, the multi-stage delivery vehicle comprises at least one outer coating 20 disposed on the outer comprises encapsulated particulates comprising an antibi surface 11 of the tubular member 12. otic composition encapsulated in an alginate composition 45 According to the invention, the coating 20 can comprise having a statin incorporated therein, which provides a tiered any of the aforementioned coatings and/or a combination modulated agent delivery. thereof. In some embodiments, the multi-stage agent delivery Referring now to FIGS. 3A and 3B, there is shown vehicle comprises a combination of different biologically another embodiment of a vascular graft of the invention. As active and/or pharmacological agents. By way of example, 50 illustrated in FIG. 3A, the graft 10b similarly comprises in Some embodiments, the multi-stage delivery vehicle tubular member 12 having at least one inner coating outer comprises encapsulated particulates comprising an encap coating 20 disposed on the outer surface 11 of the tubular Sulated growth factor concomitantly administered with an member 12. In this embodiment, the tubular member 12 encapsulated anti-inflammatory. further comprises at least one inner coating 22 disposed on In some embodiments, the multi-stage delivery vehicle 55 the inner surface 13 (or lumen surface) of the tubular comprises a plurality of different biologically active and/or member 12. pharmacological agents encapsulated in different encapsu According to the invention, the inner coating 22 can lation compositions. By way of example, in Some embodi similarly comprise any of the aforementioned coatings and/ ments, the multi-stage delivery vehicle comprises encapsu or a combination thereof. lated particulates comprising a growth factor encapsulated in 60 As will readily be appreciated by one having ordinary alginate composition and a pharmacological agent encapsu skill in the art, the present invention provides numerous lated in a PGS composition. advantages compared to prior art prosthetic valves. Among In some embodiments of the invention, the vascular grafts the advantages are the following: further comprise at least one anchoring mechanism, such as The provision of vascular grafts that substantially reduce disclosed in Co-pending application Ser. Nos. 13/782,024 65 or eliminate (i) the risk of thrombosis, (ii) intimal and 13/686,131; which are incorporated by reference herein hyperplasia after intervention in a vessel, (iii) the harsh in their entirety. biological responses associated with conventional US 9,533,072 B2 19 20 polymeric and metal prostheses, and (iv) the formation (UBS), urinary basement membrane (UBM), liver basement of biofilm, inflammation and infection. membrane (LBM), stomach submucosa (SS), and mesothe The provision of vascular grafts, which can be effectively lial tissue. employed to treat, reconstruct, replace and improve 3. The vascular graft of claim 2, wherein said ECM biological functions or promote the growth of new composition further comprises at least one Supplemental cardiovascular tissue in a cardiovascular structure. biologically active agent. The provision of vascular grafts that induce host tissue 4. The vascular graft of claim 3, wherein said Supplemen proliferation, bioremodeling and regeneration of new tal biologically active agent comprises a cell selected from tissue and tissue structures with site-specific structural the group consisting of a human embryonic stem cell, fetal and functional properties. 10 cardiomyocyte, myofibroblast, and mesenchymal stem cell. The provision of vascular grafts, which are capable of 5. The vascular graft of claim 1, wherein said acellular administering a pharmacological agent to host tissue ECM material comprises adolescent acellular ECM. and, thereby produce a desired biological and/or thera 6. The vascular graft of claim 1, wherein said ECM peutic effect. composition further comprises a pharmacological agent. Without departing from the spirit and scope of this 15 7. The vascular graft of claim 6, wherein said pharmaco invention, one of ordinary skill can make various changes logical agent comprises an agent selected from the group and modifications to the invention to adapt it to various consisting of an antibiotic, anti-viral agent, analgesic, anti usages and conditions. As such, these changes and modifi inflammatory, anti-neoplastic, anti-spasmodic, anticoagulant cations are properly, equitably, and intended to be, within the and antithrombotic agent. full range of equivalence of the following claims. 8. The vascular graft of claim 6, wherein said pharmaco What is claimed is: logical agent comprises a statin selected from the group 1. A vascular graft for treating damaged or diseased tissue consisting of atorvastatin, cerivastatin, fluvastatin, lovasta in cardiovascular vessels, comprising: tin, mevastatin, pitavastatin, pravastatin, rosuvastatin and a biodegradable and remodelable tubular member com simvastatin. prising an extracellular matrix (ECM) composition 25 9. The vascular graft of claim 8, wherein said statin is comprising acellular ECM from a mammalian tissue encapsulated in a second osmotic fluctuation inducing com Source and a growth factor selected from the group position. consisting of a transforming growth factor-alpha (TGF 10. The vascular graft of claim 9, wherein said tubular O), transforming growth factor-beta (TGF-B), fibroblast member comprises a multi-stage delivery vehicle. growth factor-2 (FGF-2), and vascular epithelial 30 11. The vascular graft of claim 1, wherein said first growth factor (VEGF), said tubular member compris reinforcing structure comprises a woven structure. ing an outer surface and a lumen that extends there 12. The vascular graft of claim 1, wherein said first through, said lumen defining a tubular member inner reinforcing structure comprises a second polymeric compo Surface; sition coating comprising a polymeric material selected from said tubular member further comprising at least one 35 the group consisting of poly(e-caprolactone-co-glycolide) biodegradable coating disposed on said tubular mem (PCL), polyhydroxy-alkonate (PHA), polylactide (PLLA) ber outer Surface, said biodegradable coating compris and polyglycolide (PLGA) and its copolymers, and polyan ing an ECM-mimicking biomaterial composition com hydride. prising poly(glycerol sebacate), 13. The vascular graft of claim 1, wherein said tubular said tubular member further comprises a first reinforcing 40 member further comprises a second reinforcing structure. structure disposed proximate the outer Surface, said 14. The vascular graft of claim 13, wherein said second first reinforcing structure comprises poly (glycerol reinforcing structure comprises a mesh structure. Sebacate), 15. The vascular graft of claim 14, wherein said mesh said tubular member being configured to induce modu reinforcing structure comprises Nitinol R. lated healing when disposed proximate damaged car 45 16. The vascular graft of claim 1, wherein said growth diovascular tissue, said modulated healing comprising factor is encapsulated in a first osmotic fluctuation inducing modulation of inflammation of said damaged tissue, composition. and induced host tissue proliferation, bioremodeling of 17. The vascular graft of claim 1, wherein said acellular said damaged tissue, and regeneration of new cardio ECM comprises acellular ECM selected from the group vascular tissue and tissue structures with site specific 50 consisting of Subcutaneous extracellular matrix, large intes structural and functional properties. tine extracellular matrix, placental extracellular matrix, 2. The vascular graft of claim 1, wherein said mammalian omentum extracellular matrix, heart extracellular matrix and tissue source is selected from the group consisting of Small lung extracellular matrix. intestine submucosa (SIS), urinary bladder submucosa k k k k k