Progenitor endothelial cell capturing with a drug eluting implantable medical device

Abstract

A medical device for implantation into vessels or luminal structures within the body is provided, which stimulates positive blood vessel remodeling. The medical device, such as a stent and a synthetic graft, is provided with a coating with a pharmaceutical composition containing a controlled-release matrix and one or more pharmaceutical substances for direct delivery of drugs to surrounding tissues. The coating on the medical device further comprises one or more barrier layers, and a ligand such as a peptide, an antibody or a small molecule for capturing progenitor endothelial cells in the blood contacting surface of the device for restoring an endothelium at the site of injury. In particular, the drug-coated stents are for use, for example, in balloon angioplasty procedures for preventing or inhibiting restenosis.

What is claimed is: 
     
         1 - 34 . (canceled) 
     
     
         35 . An implantable medical device having an expandable porous support/base structure or scaffold having a lumen, a luminal surface, a tissue-contacting surface, and a coating; said coating comprising:
 (i) one or more covalently bound luminal surface layers of a biocompatible matrix comprising a natural or synthetic polymer or combinations thereof, and   a therapeutically effective amount of a covalently said matrix bound ligand selected from an antibody, an antibody fragment and combinations thereof, configured specifically to bind in vivo to a cell surface antigen or cell membrane molecule comprising CD133, CD45, CD34, CD31, CD14, CDw90, CD117, VEGFR-1, VEGFR-2, Muc-I8 (CD146), CD130, stem cell antigen (Sca-1), stem cell factor 1 (SCF/c-Kit ligand), Tie-2, or MHC -H-2Kk of circulating autologous endothelial progenitor cells in peripheral blood for in vivo capture and proliferation of said endothelial progenitor cells to form a functional endothelial layer on said luminal surface of the implantable medical device, in situ; and   (ii) one or more tissue-contacting biodegradable and biocompatible synthetic polymer matrix layers comprising one or more barrier layers in between one or more therapeutically effective amounts of one or more intimal hyperplasia inhibitory pharmaceutical substances, and one or more pharmaceutically acceptable carriers on said tissue-contacting surface.   
     
     
         36 . The implantable medical device of  claim 35 , wherein the scaffold base comprises biocompatible biodegradable or inert base materials selected from stainless steel, Nitinol, MP35N, gold, tantalum, platinum or platinum iridium, and other biocompatible metals and/or alloys, carbon or carbon fiber, cellulose acetate, cellulose nitrate, silicone, cross-linked polyvinyl acetate (PVA) hydrogel, cross-linked PVA hydrogel foam, polyurethane, polyamide, styrene isobutylene-styrene block copolymer (Kraton), polyethylene teraphthalate, polyurethane, polyamide, polyester, polyorthoester polyanhydride, polyether sulfone, polycarbonate, polypropylene, high molecular weight polyethylene, polytetrafluoroethylene, or other biocompatible polymeric material, or mixture of copolymers thereof polyesters such as, polylactic acid, polyglycolic acid or copolymers thereof, a polyanhydride, polycaprolactone, polyhydroxybutyrate valerate or other biodegradable polymer, or mixtures or copolymers, extracellular matrix components, proteins, collagen, fibrin, and mixtures thereof. 
     
     
         37 . The implantable medical device of  claim 35 , wherein the medical device is a stent. 
     
     
         38 . The implantable medical device of  claim 35 , wherein the biodegradable and biocompatible polymer is selected from the group consisting of polyesters, polycarboxylic acid, polyanhydrides; polyarthoesters; polyamino acids; polyethylene oxide; polyphosphazenes; polylactic acid, polyglycolic acid; polydioxanone; polypropylene fumarate; polydepsipeptides; polycaprolactone, poly(D,L-lactide-co-glyclide), poly(D,L-lactide-co-caprolactone); poly polycaprolactone co-butytacrylate; polyhydroxybutyratee valerate; polycarbonates; calcium phosphates; polyglycosaminoglycans; proteins and polypeptides. 
     
     
         38 . The implantable medical device of  claim 35 , wherein the one or more pharmaceutically acceptable substances comprise cytostatic or cytotoxic agents. 
     
     
         39 . The implantable medical device of  claim 35 , wherein the one or more pharmaceutical substance(s) comprise immunosuppressive agents. 
     
     
         40 . The implantable medical device of  claim 35 , wherein the one or more pharmaceutical substance(s) is/are selected from the group consisting of antibiotics/antimicrobials, antiproliferative agents, antineoplastic agents, antioxidants, endothelial cell growth factors, smooth muscle cell growth and/or migration inhibitors, thrombin inhibitors, immunosuppressive agents, anti-platelet aggregation agents, collagen synthesis inhibitors, therapeutic antibodies, nitric oxide donors, antisense oligonucleotides, wound healing agents, therapeutic gene transfer constructs, peptides, proteins, extracellular matrix components, vasodialators, thrombolytics, anti-metabolites, growth factor agonists, antimitotics, steroids, steroidal antiinflammatory agents, chemokines, proliferator-activated receptor-gamma agonists, nonsterodial antiinflammatory agents, angiotensin converting enzyme (ACE) inhibitors, free radical scavengers, inhibitors of the CX3CR1 receptor and anti-cancer chemotherapeutic agents. 
     
     
         41 . The implantable medical device of  claim 35 , wherein the one or more pharmaceutical substance(s) is/are selected from the group consisting of cyclosporin A, mycophenolic acid, mycophenolate mofetil acid, rapamycin, rapamycin derivatives, azathioprene, tacrolimus, tranilast, dexamethasone, corticosteroid, everolimus, retinoic acid, vitamin E, rosiglitazone, simvastatins, fluvastatin, estrogen, 17β-estradiol, dihydroepiandrosterone, testosterone, puerarin, platelet factor 4, basic fibroblast growth factor, fibronectin, butyric acid, butyric acid derivatives, paclitaxel, paclitaxel derivatives and probucol. 
     
     
         42 . The medical device of  claim 35 , wherein the one or more pharmaceutical substances comprise rapamycin, rapamycin derivatives, paclitaxel, paclitaxel derivatives, sirolimus, or estradiol. 
     
     
         43 . A stent having scaffold base with a tissue contacting surface, a lumen, a luminal surface, and a coating; said coating comprising:
 a layered matrix comprising a natural or synthetic fiber selected from dextrin, elastin, tropoelastin; cross-linked tropoelastin and combinations thereof,   a therapeutically effective amount of one or more antibody, antibody fragment or combinations thereof, covalently attached to said layered matrix and specifically configured to bind selectively in situ to a cell surface antigen or cell surface membrane molecule, CD34, of circulating autologous endothelial progenitor cells in peripheral blood for capture and proliferation in vivo to form a confluent endothelial cell layer on said luminal surface of the device in less than 72 hours; and   one or more biodegradable barrier layers situated within said layered matrix, said biodegradable barrier layers comprising a therapeutically effective amount of one or more pharmaceutical substances and one or more pharmaceutically acceptable carriers for release to adjacent vascular tissue; and   said scaffold comprising biocompatible biodegradable, inert or undegradable material.   
     
     
         44 . The stent according to  claim 43 , wherein said material is selected from stainless steel, Nitinol, MP35N, gold, tantalum, platinum or platinum iridium, and other biocompatible metals and/or alloys, carbon or carbon fiber, cellulose acetate, cellulose nitrate, silicone, cross-linked polyvinyl acetate (PVA) hydrogel, cross-linked PVA hydrogel foam, polyurethane, polyamide, styrene isobutylene-styrene block copolymer (Kraton), polyethylene teraphthalate, polyurethane, polyamide, polyester, polyorthoester, polyanhydride, polyether sulfone, polycarbonate, polypropylene, high molecular weight polyethylene, polytetrafluoroethylene, or other biocompatible polymeric material, or mixture of copolymers thereof polyesters such as, polylactic acid, polyglycolic acid or copolymers thereof, a polyanhydride, polycaprolactone, polyhydroxybutyrate valerate or other biodegradable polymer, or mixtures or copolymers, extracellular matrix components, proteins, collagen, fibrin, and mixtures thereof. 
     
     
         45 . The stent according to  claim 43 , wherein said biocompatible inert scaffold base is comprises stainless steel, Nitinol, MP35N, gold, tantalum, platinum or platinum iridium. 
     
     
         46 . The stent according to  claim 43 , wherein said biocompatible biodegradable scaffold base comprises polylactic acid, polyglycolic acid or copolymers thereof, a polyanhydride, polycaprolactone, polyhydroxybutyrate valerate or other biodegradable polymer, or mixtures or copolymers, poly(D,L-lactide-co-glycolide), poly(D,L-lactide-co-caprolactone); poly polycaprolactone co-butytacrylate; polyhydroxybutyratee valerate. 
     
     
         47 . The stent according to  claim 43 , wherein biocompatible scaffold base is elected from the group consisting of stainless steel, Nitinol, polylactic acid, poly (L-lactic acid) and poly(D,L-lactide-co-glycolide).