Biointerface membranes incorporating bioactive agents

Abstract

A biointerface membrane for an implantable device including a nonresorbable solid portion with a plurality of interconnected cavities therein adapted to support tissue ingrowth in vivo, and a bioactive agent incorporated into the biointerface membrane and adapted to modify the tissue response is provided. The bioactive agents can be chosen to induce vascularization and/or prevent barrier cell layer formation in vivo, and are advantageous when used with implantable devices wherein solutes are transported across the device-tissue interface.

1 . An implantable device, the device comprising a sensing region for sensing an analyte and a biointerface membrane adjacent to the sensing region, wherein the membrane is configured to modify an in vivo tissue response by a porous architecture and by incorporation of a bioactive agent in the membrane.  
     
     
         2 . The implantable device of  claim 1 , wherein the biointerface membrane supports tissue ingrowth and interferes with barrier-cell layer formation, and wherein the biointerface membrane comprises cavities of from about 90 μm to about 370 μm in at least one dimension.  
     
     
         3 . The implantable device of  claim 1 , wherein the biointerface membrane supports tissue ingrowth and interferes with barrier-cell layer formation, and wherein the biointerface membrane comprises cavities of from about 0.6 μm to about 20 μm in at least one dimension.  
     
     
         4 . The implantable device of  claim 1 , wherein the biointerface membrane supports tissue ingrowth and interferes with barrier-cell layer formation, and wherein the biointerface membrane comprises cavities, wherein the biointerface membrane comprises a micro-architecture situated within at least some of the cavities of a macro-architecture, wherein the macro-architecture comprises a frame comprising a plurality of elongated strands of a material, wherein the strands are less than about 6 μm in all but the longest dimension.  
     
     
         5 . The implantable device of  claim 1 , wherein the biointerface membrane comprises a material selected from the group consisting of silicone, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene, polyvinyl alcohol, polyvinylchloride, polyvinylidene fluoride, polybutylene terephthalate, polymethylmethacrylate, polyether ether ketone, polyurethanes, cellulosic polymers, polysulfones, block copolymers thereof, and mixtures thereof.  
     
     
         6 . The implantable device of  claim 1 , wherein the biointerface membrane comprises silicone.  
     
     
         7 . The implantable device of  claim 1 , wherein the bioactive agent is selected from the group consisting of anti-inflammatory agents, anti-infective agents, anesthetics, inflammatory agents, growth factors, angiogenic factors, growth factors, immunosuppressive agents, antiplatelet agents, anticoagulants, ACE inhibitors, cytotoxic agents, anti-sense molecules, and mixtures thereof.  
     
     
         8 . The implantable device of  claim 1 , wherein the bioactive agent is selected from the group consisting of Sphingosine-1-phosphate, monobutyrin, Cyclosporin A, Anti-thrombospondin-2, Rapamycin, Dexamethasone, and mixtures thereof.  
     
     
         9 . The implantable device of  claim 1 , wherein the bioactive agent comprises an anti-barrier cell agent that employs a mechanism configured to speed up a host infiltration of the porous architecture by inhibiting at least one of foreign body giant cells and occlusive cell layers.  
     
     
         10 . The implantable device of  claim 9 , wherein the anti-barrier cell agent comprises Super Oxide Dismutase Mimetic.  
     
     
         11 . The implantable device of  claim 9 , wherein the anti-barrier cell agent employs an anti-inflammatory mechanism or an immunosuppressive mechanism configured to modify a wound healing of a host tissue.  
     
     
         12 . The implantable device of  claim 9 , wherein the anti-barrier cell agent is selected from the group consisting of cyclosporine, Dexamethasone, and Rapamycin.  
     
     
         13 . The implantable device of  claim 1 , wherein the bioactive agent comprises a non-heparin based synthetic coating configured to improve a performance of a blood-contacting surface.  
     
     
         14 . The implantable device of  claim 1 , wherein the bioactive agent comprises a vascularization agent.  
     
     
         15 . The implantable device of  claim 14 , wherein the vascularization agent is selected from the group consisting of an angiogenic agent configured for stimulating a neovascularization, Sphingosine-1-Phosphate, Monobutyrin, an anti-sense molecule, Basic Fibroblast Growth Factor, Acidic Fibroblast Growth Factor, Vascular Endothelial Growth Factor, Platelet Derived Endothelial Cell Growth Factor BB, Angiopoietin-1, Transforming Growth Factor Beta, Transforming Growth Factor Alpha, Hepatocyte Growth Factor, Tumor Necrosis Factor-Alpha, Angiogenin, Interleukin-8, Hypoxia Inducible Factor-I, Angiotensin-Converting Enzyme Inhibitor Quinaprilat, Angiotropin, Thrombospondin, Peptide KGHK, Low Oxygen Tension, Lactic Acid, Insulin, Growth Hormone, and mixtures thereof.  
     
     
         16 . The implantable device of  claim 14 , wherein the vascularization agent comprises a pro-inflammatory agent configured for promoting an inflammation response or an immune response.  
     
     
         17 . The implantable device of  claim 16 , wherein the pro-inflammatory agent is selected from the group consisting of a xenogenic carrier, a Lipopolysaccharide, and a protein.  
     
     
         18 . The implantable device of  claim 1 , wherein the bioactive agent is incorporated into the biointerface membrane via a carrier matrix.  
     
     
         19 . The implantable device of  claim 18 , wherein the carrier matrix is selected from the group consisting of collagen, a particulate matrix, a non-resorbable matrix, resorbable matrix, a controlled-release matrix, a gel, and mixtures thereof.  
     
     
         20 . The implantable device of  claim 1 , wherein the bioactive agent is cross-linked with a material that forms the biointerface membrane.  
     
     
         21 . The implantable device of  claim 1 , wherein the bioactive agent is configured to be released for a time period of from about one day to about one year.  
     
     
         22 . The implantable device of  claim 1 , wherein the bioactive agent is configured to be released for a time period of from about one week to about four weeks.  
     
     
         23 . An implantable glucose device, the device comprising a nonresorbable biointerface membrane adapted to modify an in vivo tissue response, the membrane comprising a porous membrane architecture and having a bioactive agent incorporated therein.  
     
     
         24 . The implantable device of  claim 23 , wherein the biointerface membrane supports tissue ingrowth and interferes with barrier-cell layer formation, and wherein the biointerface membrane comprises cavities of from about 90 μm to about 370 μm in at least one dimension.  
     
     
         25 . The implantable device of  claim 23 , wherein the biointerface membrane supports tissue ingrowth and interferes with barrier-cell layer formation, and wherein the biointerface membrane comprises cavities of from about 0.6 μm to about 20 μm in at least one dimension.  
     
     
         26 . The implantable device of  claim 23 , wherein the biointerface membrane supports tissue ingrowth and interferes with barrier-cell layer formation, and wherein the biointerface membrane comprises cavities, wherein the biointerface membrane comprises a micro-architecture situated within at least some of the cavities of a macro-architecture, wherein the macro-architecture comprises a frame comprising a plurality of elongated strands of a material, wherein the strands are less than about 6 μm in all but the longest dimension.  
     
     
         27 . The implantable device of  claim 23 , wherein the biointerface membrane comprises a material selected from the group consisting of silicone, polytetrafluoroethylene, expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polyurethanes, polypropylene, polyvinyl alcohol, polyvinylchloride, polyvinylidene fluoride, polybutylene terephthalate, polymethylmethacrylate, polyether ether ketone, polyurethanes, cellulosic polymers, polysulfones, block copolymers thereof, and mixtures thereof.  
     
     
         28 . The implantable device of  claim 23 , wherein the biointerface membrane comprises silicone.  
     
     
         29 . The implantable device of  claim 23 , wherein the bioactive agent is selected from the group consisting of anti-inflammatory agents, anti-infective agents, anesthetics, inflammatory agents, growth factors, angiogenic factors, growth factors, immunosuppressive agents, antiplatelet agents, anticoagulants, ACE inhibitors, cytotoxic agents, anti-sense molecules, and mixtures thereof.  
     
     
         30 . The implantable device of  claim 23 , wherein the bioactive agent is selected from the group consisting of Sphingosine-1-phosphate, monobutyrin, Cyclosporin A, Anti-thrombospondin-2, Rapamycin, Dexamethasone, and mixtures thereof.  
     
     
         31 . The implantable device of  claim 23 , wherein the bioactive agent comprises an anti-barrier cell agent that employs a mechanism configured to speed up a host infiltration of the porous architecture by inhibiting at least one of foreign body giant cells and occlusive cell layers.  
     
     
         32 . The implantable device of  claim 31 , wherein the anti-barrier cell agent comprises Super Oxide Dismutase Mimetic.  
     
     
         33 . The implantable device of  claim 31 , wherein the anti-barrier cell agent employs an anti-inflammatory mechanism or an immunosuppressive mechanism configured to modify a wound healing of a host tissue.  
     
     
         34 . The implantable device of  claim 31 , wherein the anti-barrier cell agent is selected from the group consisting of cyclosporine, Dexamethasone, and Rapamycin.  
     
     
         35 . The implantable device of  claim 23 , wherein the bioactive agent comprises a non-heparin based synthetic coating configured to improve a performance of a blood-contacting surface.  
     
     
         36 . The implantable device of  claim 23 , wherein the bioactive agent comprises a vascularization agent.  
     
     
         37 . The implantable device of  claim 36 , wherein the vascularization agent is selected from the group consisting of an angiogenic agent configured for stimulating a neovascularization, Sphingosine-1-Phosphate, Monobutyrin, an anti-sense molecule, Basic Fibroblast Growth Factor, Acidic Fibroblast Growth Factor, Vascular Endothelial Growth Factor, Platelet Derived Endothelial Cell Growth Factor BB, Angiopoietin-1, Transforming Growth Factor Beta, Transforming Growth Factor Alpha, Hepatocyte Growth Factor, Tumor Necrosis Factor-Alpha, Angiogenin, Interleukin-8, Hypoxia Inducible Factor-I, Angiotensin-Converting Enzyme Inhibitor Quinaprilat, Angiotropin, Thrombospondin, Peptide KGHK, Low Oxygen Tension, Lactic Acid, Insulin, Growth Hormone, and mixtures thereof.  
     
     
         38 . The implantable device of  claim 36 , wherein the vascularization agent comprises a pro-inflammatory agent configured for promoting an inflammation response or an immune response.  
     
     
         39 . The implantable device of  claim 38 , wherein the pro-inflammatory agent is selected from the group consisting of a xenogenic carrier, a Lipopolysaccharide, and a protein.  
     
     
         40 . The implantable device of  claim 23 , wherein the bioactive agent is incorporated into the biointerface membrane via a carrier matrix.  
     
     
         41 . The implantable device of  claim 40 , wherein the carrier matrix is selected from the group consisting of collagen, a particulate matrix, a non-resorbable matrix, resorbable matrix, a controlled-release matrix, a gel, and mixtures thereof.  
     
     
         42 . The implantable device of  claim 23 , wherein the bioactive agent is cross-linked with a material that forms the biointerface membrane.  
     
     
         43 . The implantable device of  claim 23 , wherein the bioactive agent is configured to be released for a time period of from about one day to about one year.  
     
     
         44 . The implantable device of  claim 23 , wherein the bioactive agent is configured to be released for a time period of from about one week to about four weeks.