Implantable bioreactor for delivery of paracrine factors

Abstract

An implantable bioreactor containing a barrier which is designed to allow the release of cell-derived biomolecules, but restricts the entry of immunologic and other cells, or the egress of the cells contained within the bioreactor. Two broad classes of implantable bioreactors are envisioned, encompassing devices for both systemic delivery of the bio-products and local delivery at the target tissue. Bioreactors of both classes can be implanted via surgery, through percutaneous techniques, or other techniques which effect implantation.

1 . An implantable bioreactor comprising a housing comprising cells which can produce paracrine factors; wherein the housing comprises a barrier that shields the enclosed cells from immunological attack and permits the transfer of paracrine factors out of the housing. 
     
     
         2 . The implantable bioreactor of  claim 1 , wherein the cells are stem cells. 
     
     
         3 . The implantable bioreactor of  claim 2 , wherein the stem cells are selected from the group consisting of embryonic stem cells, mesenchymal stem cells, whole bone marrow stem cells, adipose-derived stem cells, myocardial derived stem cells and endothelial progenitor stem cells. 
     
     
         4 . The implantable bioreactor of  claim 1 , wherein said housing is selected from the group consisting of a pouch, a semi-permeable membrane, a polymer matrix, a matrix gel and a microfabricated cellular enclosure. 
     
     
         5 . The implantable bioreactor of  claim 1 , wherein said housing is composed of cellulosic and/or synthetic materials. 
     
     
         6 . The implantable bioreactor of  claim 5 , wherein said cellulosic material is cellulose acetate. 
     
     
         7 . The implantable bioreactor of  claim 5 , wherein said synthetic material is selected from the group consisting of polysulfone, polyamide, polacrylonitrile, copolymers thereof, polymethylmetacrylate, polytetrafluroethylene and derivatives thereof, silicon carbide and micro-mechanical porous silicon diaphragms. 
     
     
         8 . The implantable bioreactor of  claim 1 , wherein said bioreactor is a pouch-based bioreactor. 
     
     
         9 . The implantable bioreactor of  claim 8 , wherein the pouch-based bioreactor is mounted on a wire, a catheter or as part of another implantable device. 
     
     
         10 . The implantable bioreactor of  claim 4 , wherein the polymer matrix is selected from the group consisting of polyethylene glycol, hyaluronic acid, chitosan, dextran, collagen and self-assembling oligopeptides. 
     
     
         11 . The implantable bioreactor of  claim 4 , wherein the matrix gel is a cross-linked hydrogel. 
     
     
         12 . The implantable bioreactor of  claim 11 , wherein the cross-linked hydrogel is selected from the group consisting of a N-hydroxysuccinimide ester/amine conjugate, an isocyanate/amine conjugate, an epoxy/amine conjugate, an isothiocyanate/amine conjugate, an alcohol/glutamate conjugate, and a thiol/maleimide conjugate. 
     
     
         13 . The implantable bioreactor of  claim 1 , wherein the bioreactor is adhered to a medical device. 
     
     
         14 . The implantable bioreactor of  claim 4 , wherein the housing is a microfabricated cellular enclosure. 
     
     
         15 . The implantable bioreactor of  claim 14 , wherein the microfabricated cellular enclosure comprises a silicon-permeable membrane. 
     
     
         16 . The implantable bioreactor of  claim 14 , wherein the microfabricated cellular enclosure is adhered to a medical device. 
     
     
         17 . A method of making an implantable bioreactor comprising combining a housing with cells capable of producing paracrine factors. 
     
     
         18 . The method of  claim 17 , wherein the cells are selected from the group consisting of embryonic stem cells, mesenchymal stem cells, adipose-derived stem cells, whole bone marrow stem cells, myocardial derived stem cells and endothelial progenitor stem cells. 
     
     
         19 . The method of  claim 17 , wherein the housing is selected from the group consisting of a pouch, a semi-permeable membrane, a polymer matrix, a matrix gel and a microfabricated cellular enclosure. 
     
     
         20 . The method of  claim 17 , wherein the implantable bioreactor is adhered to a medical device. 
     
     
         21 . A medical device comprising a bioreactor comprising a housing comprising cells which can produce paracrine factors; wherein the housing comprises a barrier that shields the enclosed cells from immunological attack and permits the transfer of paracrine factors out of the housing. 
     
     
         22 . The medical device of  claim 21 , wherein the medical device is a stent, intra-aortic balloon pump, ventricular assist device, prosthetic valve, prosthetic valve clip, prosthetic valve ring, thrombus filter, pacemaker, defibrillator, pacemaker or defibrillator wire, septal occluder, atrial appendage device, pulmonary artery catheter, venous catheter or arterial catheter. 
     
     
         23 . The medical device of  claim 22 , wherein the bioreactor housing is selected from the group consisting of a pouch, a semi-permeable membrane, a polymer matrix, a matrix gel and a microfabricated cellular enclosure. 
     
     
         24 . The medical device of  claim 23 , wherein the matrix gel is a cross-linked hydrogel. 
     
     
         25 . The medical device of  claim 23 , wherein the medical device is a stent and the bioreactor housing is a matrix gel. 
     
     
         26 . The medical device of  claim 25  wherein the matrix gel is a cross-linked hydrogel. 
     
     
         27 . The medical device of  claim 23 , wherein the medical device is a stent and the bioreactor housing is a microfabricated cellular enclosure.