US2008063693A1PendingUtilityA1

Antimicrobial coating for inhibition of bacterial adhesion and biofilm formation

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Assignee: BACTERIN INCPriority: Apr 29, 2004Filed: Jul 15, 2004Published: Mar 13, 2008
Est. expiryApr 29, 2024(expired)· nominal 20-yr term from priority
Inventors:Guy S. CookMatt Trebella
A61L 27/54A01N 25/10A01N 59/16A61L 29/085A61L 31/10A61L 2300/606B05D 3/104B05D 3/142A61L 2300/406A61L 29/16A61L 27/34A61L 31/16C09D 5/14A61L 2300/104
40
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Claims

Abstract

The present invention provides antimicrobial coatings for coating substrate surfaces, particularly medical devices, for preventing bacterial adhesion and biofilm formation by inhibiting microbial growth and proliferation on the coating surface. The antimicrobial coatings are composed of a hydrogel and a bioactive agent including a substantially water-insoluble antimicrobial metallic material that is solubilized within the coating. Antimicrobial coating formulations for obtaining such coatings, and coating methods are also described.

Claims

exact text as granted — not AI-modified
1 . An antimicrobial coating for inhibiting microbial adhesion comprising:
 a hydrogel layer comprising a three-dimensional hydrophilic polymer network; and   a bioactive agent comprising at least one substantially water-insoluble antimicrobial metallic material that is solubilized within the hydrogel layer.   
     
     
         2 . The antimicrobial coating of  claim 1 , wherein the hydrogel layer is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyethyleneimine, polyacrylic acid, polyhydroxyethylmethacrylate, polyvinyl alcohol-glycine co-polymer, polyvinyl alcohol-lysine co-polymer, and combinations and copolymers thereof. 
     
     
         3 . The antimicrobial coating of  claim 1  wherein the hydrogel layer comprises a polyvinyl alcohol. 
     
     
         4 . The antimicrobial coating of  claim 1  wherein the bioactive agent comprises a synthetic or naturally occurring antibiotic, an antibacterial compound, or combinations thereof. 
     
     
         5 . The antimicrobial coating of  claim 1 , wherein the substantially water-insoluble antimicrobial metallic material comprises a metal, a metal alloy, a metal salt, a metal complex, or combinations thereof. 
     
     
         6 . The antimicrobial coating of  claim 1 , wherein the substantially water-insoluble antimicrobial metallic material is selected from the group consisting of silver halides, silver sulfazines, silver sulfadiazines silver sulfonamides silver sulfonylureas and combinations thereof. 
     
     
         7 . The antimicrobial coating of  claim 5  wherein the substantially water-insoluble antimicrobial metallic material comprises silver sulfadiazine. 
     
     
         8 . The antimicrobial coating of  claim 1  further comprising a stabilizing agent selected from the group consisting of antioxidants, photostabilizers, free-radical scavengers and combinations thereof. 
     
     
         9 . The antimicrobial coating of  claim 8  wherein the stabilizing agent comprises an antioxidant. 
     
     
         10 . The antimicrobial coating of  claim 8 , wherein the stabilizing agent comprises a photostabilizer. 
     
     
         11 . The antimicrobial coating of  claim 8 , wherein the antioxidant is selected from the groups consisting of a lactone, phenolic, phosphite, thioester, hindered amine, hindered benozoate benzoate,hindered phenolic, and combinations thereof. 
     
     
         12 . The antimicrobial coating of  claim 8 , wherein the antioxidant is selected from the group consisting of:
 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)-1,3,5-thiazine-2,4,6-(1H,3H,5H)-trione; poly[(6-morpholino-s-thiazine-2,4-diyl)[2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]]; 3,5-di-t-butyl-4-hydroxybenzoic acid hexadecyl ester; alpha-tocopherol; alpha-tocopherol polyetheylene glycol succinate; alpha-lipoic acid; butylated hydroxy toluene, sodium ascorbate, and combinations thereof.   
     
     
         13 . The antimicrobial coating of  claim 8 , wherein the photostabilizer comprises a benzoate, benzophenone, benzotriazole, cyanoacrylate, organo nickel or organo zinc. 
     
     
         14 . The antimicrobial coating of  claim 8 , wherein the stabilizing agent is selected from the group consisting of TiO 2 , WO 3 , magnesium silicate or mixtures thereof. 
     
     
         15 . The antimicrobial coating of  claim 8 , wherein the stabilizing agent comprises TiO 2 . 
     
     
         16 . The antimicrobial coating of  claim 1  wherein the three-dimensional hydrophilic polymer network is a cross-linked matrix comprising ionic or covalent chemical bonds, a cryogel or an interpenetrating polymer network. 
     
     
         17 . The antimicrobial coating of  claim 16  wherein the three-dimensional hydrophilic polymer network has a cross-linked matrix comprising covalent bonds. 
     
     
         18 . The antimicrobial coating of  claim 1  that inhibits biofilm. 
     
     
         19 . A coating composition for providing an antimicrobial coating for inhibiting microbial adhesion comprising:
 a hydrophilic polyfunctional polymer; and   a bioactive agent comprising at least one substantially water-insoluble antimicrobial metallic material that is solubilized in the coating composition.   
     
     
         20 . The coating composition of  claim 19 , wherein the hydrophilic polyfunctional polymer is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyethyleneimine, polyacrylic acid, polyhydroxyethylmethacrylate, polyvinyl alcohol-glycine co-polymer, and polyvinyl alcohol-lysine co-polymer, and combinations and copolymers thereof. 
     
     
         21 . The coating composition of  claim 19 , wherein the hydrophilic polyfunctional polymer comprises a polyvinyl alcohol. 
     
     
         22 . The coating composition of  claim 19 , wherein the bioactive agent is a synthetic or naturally occurring antibiotic, an antibacterial compound, or combinations thereof. 
     
     
         23 . The coating composition of  claim 19 , wherein the water-insoluble antimicrobial metallic material comprises a metal, a metal alloy, a metal salt, a metal complex, or combinations thereof. 
     
     
         24 . The coating composition of  claim 19 , wherein the water-insoluble antimicrobial metallic material is selected from the group consisting of silver halides, silver sulfazines, silver sulfadiazines silver sulfonamides silver sulfonylureas and combinations thereof. 
     
     
         25 . The coating composition of  claim 19 , wherein the water-insoluble antimicrobial metallic material comprises silver sulfadiazine. 
     
     
         26 . The coating composition of  claim 19  further comprising a stabilizing agent. 
     
     
         27 . The coating composition of  claim 26 , wherein the stabilizing agent is selected from the group consisting of antioxidants, free-radical scavengers, and combinations thereof. 
     
     
         28 . The coating composition of  claim 26 , wherein the stabilizing agent comprises an antioxidant. 
     
     
         29 . The coating composition of  claim 26 , wherein the stabilizing agent comprises a photostabilizer. 
     
     
         30 . The coating composition of  claim 28 , wherein the antioxidant is a lactone, phenolic, phosphite, thioester, hindered amine, hindered benzoate, hindered phenolic, and combinations thereof. 
     
     
         31 . The coating composition of  claim 28 , wherein the antioxidant is selected from the group consisting of:
 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione; poly[(6-morpholino-s-triazine-2,4-diyl)[2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]]; 3,5-di-t-butyl-4-hydroxybenzoic acid hexadecyl ester; alpha-tocopherol; alpha-tocopherol polyetheylene glycol succinate; alpha-lipoic acid; butylated hydroxy toluene, sodium ascorbate, and combinations thereof.   
     
     
         32 . The coating composition of  claim 29 , wherein the photostabilizer is selected from the groups consisting of benzoate, benzophenone, benzotriazole, cyanoacrylate, organo nickel, organo zinc, and combinations thereof. 
     
     
         33 . The coating composition of  claim 26 , wherein the stabilizing agent is selected from the group consisting of TiO 2 , WO 3 , magnesium silicate and mixtures thereof. 
     
     
         34 . The coating composition of  claim 26 , wherein the stabilizing agent comprises TiO 2 . 
     
     
         35 . A coating composition for providing an antimicrobial coating for inhibiting biofilm comprising:
 a hydrophilic polyfunctional polymer; and   a bioactive agent comprising at least one substantially water-insoluble antimicrobial metallic material that is solubilized in the coating composition.   
     
     
         36 . An antimicrobial coating for inhibiting microbial adhesion on a medical device comprising:
 a hydrogel layer comprising a three-dimensionally cross-linked polyvinyl alcohol network; and   a bioactive agent comprising silver sulfadiazine that is solubilized within the hydrogel layer.   
     
     
         37 . The antimicrobial coating of  claim 36  further comprising a stabilizing agent. 
     
     
         38 . The antimicrobial coating of  claim 37 , wherein the stabilizing agent is selected from the group consisting of antioxidants, photostabilizers, free readical scavengers, and combinations thereof. 
     
     
         39 . The antimicrobial coating of  claim 37 , wherein the stabilizing agent comprises TiO 2 . 
     
     
         40 . An antimicrobial coating for inhibiting biofilm on a medical device comprising:
 a hydrogel layer comprising a three-dimensionally cross-linked polyvinyl alcohol network; and   a bioactive agent comprising silver sulfadiazine that is solubilized within the hydrogel layer.   
     
     
         41 . The antimicrobial coating of  claim 40  further comprising a stabilizing agent. 
     
     
         42 . The antimicrobial coating of  claim 41 , wherein the stabilizing agent is selected from the group consisting of antioxidants, photostabilizers, free readical scavengers, and combinations thereof. 
     
     
         43 . The antimicrobial coating of  claim 41 , wherein the stabilizing agent comprises TiO 2 . 
     
     
         44 . A method for forming an antimicrobial coating for inhibiting microbial adhesion on a substrate material, the method comprising:
 depositing at least one layer of a coating material comprising a hydrophilic polyfunctional polymer and a bioactive agent including at least one antimicrobial substantially water-insoluble metallic compound solubilized therein on a substrate material;   at least partially drying the coating material layer; and   reacting the coating material layer with a cross-linking agent to form a surface immobilized, three-dimensional hydrogel network on the substrate material.   
     
     
         45 . The method of  claim 44  wherein the coating material further comprises a stabilizing agent. 
     
     
         46 . The method of  claim 45 , wherein the stabilizing agent is selected from the group consisting of antioxidants, photostabilizers, free-radical scavengers, and combinations thereof. 
     
     
         47 . The method of  claim 45 , wherein the stabilizing agent comprises TiO 2 . 
     
     
         48 . The method of  claim 44  further comprising pre-treating the substrate material and chemically grafting a hydrophilic polyfunctional material on the substrate material prior to depositing the coating material layer. 
     
     
         49 . A method of inhibiting bacterial adhesion on a substrate material by providing a surface coating comprising:
 a hydrogel layer comprising a three-dimensional hydrophilic polymer network; and   a bioactive agent comprising at least one substantially water-insoluble antimicrobial metallic material that is solubilized within the hydrogel layer.   
     
     
         50 . A method of inhibiting biofilm by providing a surface coating on a substrate material comprising:
 a hydrogel layer comprising a three-dimensional hydrophilic polymer network; and   a bioactive agent comprising at least one substantially water-insoluble antimicrobial metallic material that is solubilized within the hydrogel layer.   
     
     
         51 . The method of  claim 49  or  50 , wherein the substrate material comprises a metallic material, ceramic, glass, or natural or synthetic polymers. 
     
     
         52 . The method of  claim 49  or  50 , wherein the substrate material is part of a medical device or healthcare product. 
     
     
         53 . The method of  claim 52 , wherein the medical device comprises a catheter, wound drain, needle-less connector, stent or a component thereof. 
     
     
         54 . A method of inhibiting bacterial adhesion and biofilm formation on a medical device or healthcare product in a physiological environment by providing a surface coating on a substrate material comprising:
 a hydrogel layer comprising a three-dimensional hydrophilic polymer network; and   a bioactive agent comprising at least one substantially water-insoluble antimicrobial metallic material that is solubilized within the hydrogel layer.   
     
     
         55 . The method of  claim 54 , wherein the substrate material is part of a medical device or healthcare product. 
     
     
         56 . The method of  claim 55 , wherein the medical device comprises a catheter, wound drain, needle-less connector, stent or a component thereof. 
     
     
         57 . A method of manufacturing a coating composition for providing an antimicrobial coating for inhibiting microbial adhesion, the method comprising:
 (i) heating an aqueous acidic solution;   (ii) adding a substantially water-insoluble antimicrobial metallic material to the heated aqueous acidic solution so as to completely dissolve the substantially water-insoluble antimicrobial metallic material; and   (iii) adding a hydrophilic polyfunctional polymer to the heated aqueous acidic solution comprising the dissolved substantially water-insoluble antimicrobial metallic material so as to maintain the substantially water-insoluble antimicrobial metallic material in a solubilized form in the coating composition.   
     
     
         58 . The method of  claim 57  wherein the solubilized form of the substantially water-insoluble antimicrobial metallic material in the heated aqueous acidic solution is a homogeneous or substantially homogeneous aqueous phase, wherein the substantially water-insoluble antimicrobial metallic material and the hydrophilic polyfunctional polymer are homogeneously dispersed in the coating composition. 
     
     
         59 . The method of  claim 57 , wherein the hydrophilic polyfunctional polymer is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyethyleneimine, polyacrylic acid, polyhydroxyethylmethacrylate, polyvinyl alcohol-glycine co-polymer, polyvinyl alcohol-lysine co-polymer, and combinations and copolymers thereof. 
     
     
         60 . The method of  claim 57 , wherein the hydrophilic polyfunctional polymer comprises a polyvinyl alcohol. 
     
     
         61 . The method of  claim 57 , wherein the substantially water-insoluble antimicrobial metallic material is a synthetic or naturally occurring antibiotic, an antibacterial compound, or combinations thereof. 
     
     
         62 . The method of  claim 57 , wherein the substantially water-insoluble antimicrobial metallic material comprises a metal, a metal alloy, a metal salt, a metal complex, or combinations thereof. 
     
     
         63 . The method of  claim 57 , wherein the substantially water-insoluble antimicrobial metallic material is selected from the group consisting of silver halides, silver sulfazines, silver sulfadiazines, silver sulfonamides, silver sulfonylureas, and combinations thereof. 
     
     
         64 . The method of  claim 57 , wherein the substantially water-insoluble antimicrobial metallic material comprises silver sulfadiazine. 
     
     
         65 . The method of  claim 57  further comprising adding a stabilizing agent. 
     
     
         66 . The method of  claim 65  wherein the stabilizing agent is dissolved in the coating composition to form a homogeneous phase or is suspended in the coating composition as a microparticulate dispersion. 
     
     
         67 . The method of  claim 65 , wherein the stabilizing agent is selected from the group consisting of antioxidants, photostabilizers, free-radical scavengers, and combinations thereof. 
     
     
         68 . The method of  claim 65 , wherein the stabilizing agent comprises an antioxidant. 
     
     
         69 . The method of  claim 65 , wherein the stabilizing agent comprises a photostabilizer. 
     
     
         70 . The method of  claim 67 , wherein the antioxidant is selected from the groups consisting of lactone, phenolic, phosphite, thioester, hindered amine, hindered benozoate benzoate, hindered phenolic, and combinations thereof. 
     
     
         71 . The method of  claim 68 , wherein the antioxidant is selected from the group consisting of:
 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione; poly[(6-morpholino-s-triazine-2,4-diyl)[2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]]; 3,5-di-t-butyl-4-hydroxybenzoic acid hexadecyl ester; alpha-tocopherol; alpha-tocopherol polyetheylene glycol succinate; alpha-lipoic acid; butylated hydroxy toluene, sodium ascorbate, and combinations thereof.   
     
     
         72 . The method of  claim 69 , wherein the photostabilizer is a benzoate, benzophenone, benzotriazole, cyanoacrylate, organo nickel or organo zinc. 
     
     
         73 . The method of  claim 65 , wherein the stabilizing agent is selected from the group consisting of TiO 2 , WO 3 , magnesium silicate and mixtures thereof. 
     
     
         74 . The method of  claim 65 , wherein the stabilizing agent comprises TiO 2 . 
     
     
         75 . A method of manufacturing a coating composition for providing an antimicrobial coating for inhibiting microbial adhesion, the method comprising:
 (i) heating an aqueous acidic solution;   (ii) adding a substantially water-insoluble antimicrobial metallic material to the heated aqueous acidic solution so as to completely dissolve the substantially water-insoluble antimicrobial metallic material; and   (iii) adding a mixture of a hydrophilic polyfunctional polymer and a stabilizing agent to the heated acidic solution comprising the dissolved substantially water-insoluble antimicrobial metallic material so as to maintain the substantially water-insoluble antimicrobial metallic material in a solubilized form in the coating composition.   
     
     
         76 . The method of  claim 75  wherein the solubilized form of the substantially water-insoluble antimicrobial metallic material in the heated aqueous acidic solution is a homogeneous or substantially homogeneous aqueous phase, wherein the substantially water-insoluble antimicrobial metallic material and the hydrophilic polyfunctional polymer are homogeneously dispersed in the coating solution. 
     
     
         77 . The method of  claim 75 , wherein the hydrophilic polyfunctional polymer is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyethyleneimine, polyacrylic acid, polyhydroxyethylmethacrylate, polyvinyl alcohol-glycine co-polymer, and polyvinyl alcohol-lysine co-polymer, and combinations and copolymers thereof. 
     
     
         78 . The method of  claim 75 , wherein the hydrophilic polyfunctional polymer comprises a polyvinyl alcohol. 
     
     
         79 . The method of  claim 75 , wherein the substantially water-insoluble antimicrobial metallic material is a synthetic or naturally occurring antibiotic, an antibacterial compound, or combinations thereof. 
     
     
         80 . The method of  claim 75 , wherein the substantially water-insoluble antimicrobial metallic material comprises a metal, a metal alloy, a metal salt, a metal complex, or combinations thereof. 
     
     
         81 . The method of  claim 75 , wherein the substantially water-insoluble antimicrobial metallic material is selected from the group consisting of silver halides, silver sulfazines, silver sulfadiazines, silver sulfonamides, silver sulfonylureas, and combinations thereof. 
     
     
         82 . The method of  claim 75 , wherein the substantially water-insoluble antimicrobial metallic material comprises silver sulfadiazine. 
     
     
         83 . The method of  claim 75  wherein the stabilizing agent is dissolved in the coating composition to form a homogeneous phase or is suspended in the coating composition as a microparticulate dispersion. 
     
     
         84 . The method of  claim 75 , wherein the stabilizing agent is selected from the group consisting of antioxidants, photostabilizers, free-radical scavengers, and combinations thereof. 
     
     
         85 . The method of  claim 75 , wherein the stabilizing agent comprises an antioxidant. 
     
     
         86 . The method of  claim 75 , wherein the stabilizing agent comprises a photostabilizer. 
     
     
         87 . The method of  claim 85 , wherein the antioxidant is selected from the group consisting of lactone, phenolic, phosphite, thioester, hindered amine, hindered benozoate, hindered phenolic, and combinations thereof. 
     
     
         88 . The method of  claim 85 , wherein the antioxidant is selected from the group consisting of:
 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione; poly[(6-morpholino-s-triazine-2,4-diyl)[2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]]; 3,5-di-t-butyl-4-hydroxybenzoic acid hexadecyl ester; alpha-tocopherol; alpha-tocopherol polyetheylene glycol succinate; alpha-lipoic acid; butylated hydroxy toluene, sodium ascorbate, and combinations thereof.   
     
     
         89 . The method of  claim 86 , wherein the photostabilizer comprises a benzoate, benzophenone, benzotriazole, cyanoacrylate, organo nickel or organo zinc. 
     
     
         90 . The method of  claim 75 , wherein the stabilizing agent is selected from the group consisting of TiO 2 , WO 3 , magnesium silicate and mixtures thereof. 
     
     
         91 . The method of  claim 75 , wherein the stabilizing agent comprises TiO 2 . 
     
     
         92 . A method of coating a substrate material with an antimicrobial coating for inhibiting microbial adhesion, the method comprising:
 (i) depositing at least one layer of a coating composition comprising a hydrophilic polyfunctional polymer and at least one bioactive agent comprising at least one substantially water-insoluble antimicrobial metallic compound solubilized therein on a substrate material;   (ii) at least partially drying the at least one layer of the coating composition; and   (iii) crosslinking the hydrophilic polyfunctional polymer to form a surface immobilized, three-dimensional hydrogel network on the substrate material.   
     
     
         93 . The method of  claim 92 , wherein the coating composition further comprises a stabilizing agent. 
     
     
         94 . The method of  claim 93 , wherein the stabilizing agent is selected from the group consisting of antioxidants, photostabilizers, free-radical scavengers, and combinations thereof. 
     
     
         95 . The method of  claim 93 , wherein the stabilizing agent comprises an antioxidant. 
     
     
         96 . The method of  claim 93 , wherein the stabilizing agent comprises a photostabilizer. 
     
     
         97 . The method of  claim 95 , wherein the antioxidant selected from the group consisting of lactone, phenolic, phosphite, thioester, hindered amine, hindered benozoate, hindered phenolic, and combinations thereof. 
     
     
         98 . The method of  claim 95 , wherein the antioxidant is selected from the group consisting of:
 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione; poly[(6-morpholino-s-triazine-2,4-diyl)[2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]]; 3,5-di-t-butyl-4-hydroxybenzoic acid hexadecyl ester; alpha-tocopherol; alpha-tocopherol polyetheylene glycol succinate; alpha-lipoic acid; butylated hydroxy toluene, sodium ascorbate, and combinations thereof.   
     
     
         99 . The method of  claim 96 , wherein the photostabilizer is a benzoate, benzophenone, benzotriazole, cyanoacrylate, organo nickel or organo zinc. 
     
     
         100 . The method of  claim 93 , wherein the stabilizing agent is selected from the group consisting of TiO 2 , WO 3 , magnesium silicate and mixtures thereof. 
     
     
         101 . The method of  claim 93 , wherein the stabilizing agent comprises TiO 2 . 
     
     
         102 . A method of coating a substrate material with an antimicrobial coating for inhibiting microbial adhesion, the method comprising:
 (i) pre-treating the surface of a substrate material with a primer layer or a surface oxidant;   (ii) chemically grafting a hydrophilic polyfunctional compound onto the substrate material;   (iii) depositing at least one layer of a coating composition comprising a hydrophilic polyfunctional polymer and at least one bioactive agent comprising at least one substantially water-insoluble antimicrobial metallic compound solubilized therein on a substrate material;   (iv) at least partially drying the at least one layer of coating composition; and   (v) crosslinking the hydrophilic polyfunctional polymer to form a surface immobilized, three-dimensional hydrogel network on the substrate material.   
     
     
         103 . The method of  claim 102  wherein pre-treating the surface of the substrate material comprises coating the surface of the substrate material with the primer layer on which the antimicrobial coating is deposited. 
     
     
         104 . The method of  claim 102  wherein pre-treating the surface of the substrate material with a surface oxidant comprises subjecting the substrate material to an oxidation process that is followed by a chemical grafting reaction rendering the surface hydrophilic, and compatible with the coating. 
     
     
         105 . The method of  claim 102  wherein the surface oxidant comprises plasma. 
     
     
         106 . The method of  claim 102  wherein the hydrophilic polyfunctional compound comprises an aliphatic alcohol. 
     
     
         107 . The method of  claim 102  wherein the hydrophilic polyfunctional polymer is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyethyleneimine, polyacrylic acid, polyhydroxyethylmethacrylate, polyvinyl alcohol-glycine co-polymer, polyvinyl alcohol-lysine co-polymer, and combinations and copolymers thereof. 
     
     
         108 . The method of  claim 102  wherein the hydrophilic polyfunctional polymer comprises polyvinyl alcohol. 
     
     
         109 . The method of  claim 102  wherein the bioactive agent is a synthetic or naturally occurring antibiotic, an antibacterial compound, or combinations thereof. 
     
     
         110 . The method of  claim 102  wherein the substantially water-insoluble antimicrobial metallic compound comprises a metal, a metal alloy, a metal salt, a metal complex, or combinations thereof. 
     
     
         111 . The method of  claim 102  wherein the substantially water-insoluble antimicrobial metallic compound is selected from the group consisting of silver halides, silver sulfazines, silver sulfadiazines, silver sulfonamides, silver sulfonylureas, and combinations thereof. 
     
     
         112 . The method of  claim 102  wherein the substantially water-insoluble antimicrobial metallic compound comprises silver sulfadiazine. 
     
     
         113 . The method of  claim 102  wherein the coating composition further comprises a stabilizing agent. 
     
     
         114 . The method of  claim 113  wherein the stabilizing agent comprises an antioxidant or a photostabilizer. 
     
     
         115 . The method of  claim 113  wherein the stabilizing agent comprises an antioxidant. 
     
     
         116 . The method of  claim 113  wherein the stabilizing agent comprises a photostabilizer. 
     
     
         117 . The method of  claim 115  wherein the antioxidant is selected from the group consisting of lactone, phenolic, phosphite, thioester, hindered amine, hindered benozoate or hindered phenolic, and combinations thereof. 
     
     
         118 . The method of  claim 115  wherein the antioxidant is selected from the group consisting of:
 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione; poly[(6-morpholino-s-triazine-2,4-diyl)[2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]]; 3,5-di-t-butyl-4-hydroxybenzoic acid hexadecyl ester; alpha-tocopherol; alpha-tocopherol polyetheylene glycol succinate; alpha-lipoic acid; butylated hydroxy toluene, sodium ascorbate, and combinations thereof.   
     
     
         119 . The method of  claim 116  wherein the photostabilizer is selected from the group consisting of benzoate, benzophenone, benzotriazole, cyanoacrylate, organo nickel or organo zinc. 
     
     
         120 . The method of  claim 113  wherein the stabilizing agent is selected from the group consisting of TiO 2 , WO 3 , magnesium silicate and mixtures thereof. 
     
     
         121 . The method of  claim 113  wherein the stabilizing agent comprises TiO 2 . 
     
     
         122 . A method of manufacturing a coating composition for providing an antimicrobial coating for inhibiting microbial adhesion, the method comprising:
 (i) heating an aqueous acidic solution comprising nitric acid;   (ii) adding silver sulfadiazine to the heated aqueous acidic solution so as to completely dissolve the silver sulfadiazine; and   (iii) adding polyvinyl alcohol to the heated aqueous acidic solution comprising the silver sulfadiazine so as to maintain the silver sulfadiazine in a solubilized form in the coating composition.   
     
     
         123 . The method of  claim 122  wherein the aqueous acidic solution comprising nitric acid is heated to a temperature ranging from about 65 to about 70° C. 
     
     
         124 . The method of  claim 122  wherein the aqueous acidic solution comprising nitric acid has a nitric acid concentration of about 70%. 
     
     
         125 . The method of  claim 122  wherein the polyvinyl alcohol has a molecular weight ranging from about 89,000 to about 98,000 daltons. 
     
     
         126 . A method of manufacturing a coating composition for providing an antimicrobial coating for inhibiting microbial adhesion, the method comprising:
 (i) heating an aqueous acidic solution comprising nitric acid;   (ii) adding silver sulfadiazine to the heated aqueous acidic solution so as to completely dissolve the silver sulfadiazine; and   (iii) adding a mixture of a polyvinyl alcohol and micronized titanium dioxide to the heated acidic solution comprising the dissolved silver sulfadiazine so as to maintain the silver sulfadiazine in a solubilized form in the coating composition.   
     
     
         127 . The method of  claim 126  wherein the aqueous acidic solution comprising nitric acid is heated to a temperature ranging from about 65 to about 70° C. 
     
     
         128 . The method of  claim 126  wherein the aqueous acidic solution comprising nitric acid has a nitric acid concentration of about 70%. 
     
     
         129 . The method of  claim 126  wherein the polyvinyl alcohol has a molecular weight ranging from about 89,000 to about 98,000 daltons. 
     
     
         130 . The method of  claim 126  wherein the micronized titanium dioxide has a particle size of about 1 μm. 
     
     
         131 . An antimicrobial coating for inhibiting microbial adhesion comprising:
 a hydrogel layer comprising a three-dimensional polyvinyl alcohol network; and   a bioactive agent comprising silver sulfadiazine that is solubilized within the hydrogel layer.

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