High-yield activation of polymer surfaces for covalent attachment of molecules

Abstract

Polymer surfaces coated with organometallic layers, wherein the organometallic layers and polymer surfaces have functional groups that react to bond the organometallic layer to the polymer surface with organometallic functional groups remaining unreacted for the subsequent covalent attachment of organic overlayers. Coating methods and coated articles are also disclosed.

1 . A coated substrate comprising a polymer surface and an organometallic layer formed thereon, wherein the organometallic layer and polymer surface have functional groups that react to bond the organometallic layer to the polymer surface.  
     
     
         2 . The coated substrate of  claim 1 , wherein said organometallic layer comprises transition metal atoms selected from the group consisting of atoms of Group 4, Group 5 and Group 6 of the Periodic Chart.  
     
     
         3 . The coated substrate of  claim 1 , wherein said organometallic layer comprises alkoxide or dialkylamide groups at least a portion of which react with said functional groups of said polymer surface.  
     
     
         4 . The coated substrate of  claim 1 , wherein said organometallic layer has unreacted functional groups and said coated substrate further comprises an organic overlayer coated on said organometallic layer, said overlayer comprising a compound, polypeptide, oligomer or polymer having functional groups that react with said unreacted organometallic layer functional groups to bond said overlayer to said organometallic layer.  
     
     
         5 . The coated substrate of  claim 4 , wherein said overlayer comprises an organophosphorus, organocarboxylic acid or organocarboxylic acid ester compound covalently bonded to said organometallic layer.  
     
     
         6 . The coated substrate of  claim 5 , wherein the organo group of the organophosphorus, organocarboxylic acid or organocarboxylic acid ester overlayer compound is a saturated or unsaturated, substituted or unsubstituted alkyl group.  
     
     
         7 . The coated substrate of  claim 6 , wherein said aalkyl group is substituted in the omega position and the omega-substituents of the omega-substituted organophosphorus, organocarboxylic acid or organocaroxylic acid ester overlayer compounds are selected from the group consisting of carboxylate, carbamate, hydroxyl, keto, ether, oxy, carbonate, amino, amide and thiol.  
     
     
         8 . The coated substrate of  claim 5 , wherein said overlayer comprises an organo-phosphorus compound selected from the group consisting of phosphoric acids, phosphonic acids and phosphinic acids.  
     
     
         9 . The coated substrate of  claim 8 , wherein said organophosphorus overlayer comprises an organophosphoric acid compound or mixture of compounds of the structure: 
         (RO) x —P(O)—(OR′) y   
       wherein x is 1 or 2, y is 1 or 2 and x+y=3; R is a radical having a total of 1-30 carbons; where R′ is H, a metal or lower alkyl having 1-4 carbons; and, for at least a portion of the organo-phosphorus compounds in the overlayer, R′ is H.  
     
     
         10 . The coated substrate of  claim 8 , wherein said organophosphorus overlayer comprises an organophosphonic acid compound or mixture of compounds of the structure:  
       
         
           
           
               
               
           
         
       
       wherein x is 0 or 1, y is 1, z is 1 or 2 and x+y+z is 3; R and R″ are each independently radicals having a total of 1 to 30 carbons; R′ is H, a metal or lower alkyl having 1-4 carbons, and, for at least a portion of the organophosphorus compounds in the overlayer, R′ is H.  
     
     
         11 . The coated substrate of  claim 8 , wherein said organophosphorus overlayer comprises an organophosphonic acid compound or mixture of compounds of the structure:  
       
         
           
           
               
               
           
         
       
       wherein x is 0, 1 or 2, y is 0, 1 or 2, z is 1 and x+y+z is 3; R and R″ are each independently radicals having a total of 1 to 30 carbons; R′ is H, a metal or lower alkyl and, for at least a portion of the organophosphorus compounds in the overlayer, R′ is H.  
     
     
         12 . The coated substrate of  claim 5 , wherein said overlayer comprises an organo-phosphorus or organocarboxylic acid compound with an organo group containing a C 6  to C 18  hydrocarbon or substituted hydrocarbon group.  
     
     
         13 . The coated substrate of  claim 1 , wherein the substrate is a molded polymer article.  
     
     
         14 . The coated substrate of  claim 1 , wherein the polymer is in the form of a coating.  
     
     
         15 . The coated substrate of  claim 14 , wherein the polymer is a coating on an article made from another material, such as glass, silicon dioxide, metal, or another polymer.  
     
     
         16 . The coated substrate of  claim 1 , wherein the polymer surface has surface functional groups selected from the group consisting of amide, imide, urethane, urea, amine, epoxy, hydroxyl, oxy, keto, acidic C—H, phenol, carboxylic acid, carboxylic acid ester, carboxylic acid anhydride, sulfonic acid, and thiol groups.  
     
     
         17 . The coated substrate of  1 , wherein said polymer surface is a polymer selected from the group consisting of polyamides, polyimides, polyurethanes, polyureas, polyamines, polyepoxides, polyesters containing unreacted hydroxyl or carboxylic acid groups, polysulf-onamides and polysulfides containing unreacted thiol groups.  
     
     
         18 . The coated substrate of  claim 4 , wherein said overlayer comprises a biologically or pharmaceutically active compound covalently bonded to the organometallic coating layer.  
     
     
         19 . The coated substrate of  claim 6 , further comprising a second overlayer of a biologically or pharmaceutically active compound covalently bonded to said functional groups of said organophorphorus, organocarboxylic acid or organocarboxylic acid ester compound overlayer.  
     
     
         20 . The coated substrate of  claim 4 , wherein said overlayer comprises a biologically active ligand compound selected from cell attachment mediators or a substance that enhances or excludes particular varieties of cellular or tissue ingrowth.  
     
     
         21 . The coated substrate of  claim 20 , wherein said biologically active ligand compound is selected from the group consisting of osteo-inductive substances and substances that induce cellular growth and proliferation and integrin cell attachment mediators.  
     
     
         22 . The coated substrate of  claim 21 , wherein said biologically active ligand compound is selected from the group consisting of bone morphogenic proteins (BMP), epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I and II), TGF-  and vascular endothelial growth factor (VEGF).  
     
     
         23 . The coated substrate of  claim 4 , wherein said overlayer comprises a pharmaceutically active compound selected from the group consisting of anti-neoplastic and anti-proliferative agents.  
     
     
         24 . The coated substrate of  claim 4 , wherein said overlayer comprises a active agent selected from the group consisting of acyclovir, cephradine, malphalen, tamoxifen, raloxifene, daunomycin, adriamycin, plumbagin, chlorambucil, ephedrine, atropine, quinine, digoxin, quinidine, biologically active peptides, chlorin e 6 , cephalothin, proline, proline analogues, penicillin V, aspirin, ibuprofen, steroids and nicotinic acid.  
     
     
         25 . A polymer scaffold for tissue engineering comprising the coated substrate of  claim 1 .  
     
     
         26 . A polymer scaffold for tissue engineering comprising the coated substrate of  claim 4 , wherein said overlayer comprises a biologically active ligand for cellular or tissue ingrowth.  
     
     
         27 . The polymer scaffold of  claim 26 , wherein said scaffold is adapted for the re-generation of nervous, musculo-skeletal, cartilaginous, tendenous, hepatic, pancreatic, ocular, integumentary, arterio-venous or urinary tissues or tissues forming solid or hollow organs.  
     
     
         28 . The polymer scaffold of  claim 26 , containing cells selected from the group consisting of cells of the muscular and skeletal systems, parenchymal cells, cells of intestinal origin, exocrine cells, bile duct cells, parathyroid cells, thyroid cells, cells of the adrenal-hypothalmic-pituitary axis, heart muscle cells, kidney epithelial cells, kidney tubular cells, kidney basement membrane cells, nerve cells, blood vessel cells, cells forming bone and cartilage, smooth muscle cells, skeletal muscle cells, ocular cells, integumentary cells, keratinocytes, skin cells and endothelial cells.  
     
     
         29 . The polymer scaffold of  claim 28 , wherein said cells are selected from the group consisting of chondrocytes, fibroblasts, osteocytes, osteoblasts, hepatocytes and pancreatic cells.  
     
     
         30 . The polymer scaffold of  claim 26 , containing cells selected from the group consisting of cells obtained from donors, embryonic stem cells, non-embryonic stem cells, cells from established cell culture lines, cells before genetic engineering and cells after genetic engineering.  
     
     
         31 . The polymer scaffold of  claim 30 , wherein said cells from established cell culture lines comprise cells from embryonic stem cell culture lines and cells from non-embryonic stem cell culture lines.  
     
     
         32 . A method of regulating cellular attachment, migration and proliferation on a polymeric substrate, characterized by contacting living cells, tissues or biological fluids containing living cells with the polymer scaffold of  claim 26 .  
     
     
         33 . An implantable medical device characterized by one or more surfaces comprising the coated substrate of  claim 1 .  
     
     
         34 . The implantable medical device of  claim 33 , characterized in that it is a vascular graft, stent, bone plate, suture, implantable sensor, barrier for surgical adhesion prevention or implantable drug delivery device.