Hydrogel wound dressing and biomaterials formed in situ and their uses

Abstract

The present invention relates to a method of forming shape-retentive and shape-conforming aggregate wound dressings and biomaterials composed of gel nanoparticles and wound or bodily fluid in which the aggregates are held together by non-covalent bond physical forces such as, without limitation, hydrophobic-hydrophilic interactions and hydrogen bonds. The method comprises introducing a dry powder of gel nanoparticles to a wound site in which the nanoparticles absorb some of the blood or wound exudate and coalesce in situ into the claimed shape-retentive aggregate dressing. The method also comprises introducing the dry nanoparticle powder in or on a wet bodily tissue in vivo to form the claimed shape-retentive biomaterial. In addition, the method also comprises incorporating biomedical agents to produce medicated aggregate dressings or biomaterials for a variety of medical applications. This invention also relates to uses of the method of formation of the shape-retentive aggregates of gel nanoparticles.

1 . A dry powder of polymeric nanoparticles prepared by a method comprising:
 a) polymerizing an effective amount of a monomer or two or more monomers, at least one of which is a 2-alkenoic acid, a hydroxy (2C-4C) alkyl 2-alkenoate, a dihydroxy (2C-4C) alkyl 2-alkenoate, a hydroxy (2C-4C) alkoxy (2C-4C) alkyl 2-alkenoate, a (1C-4C) alkoxy (2C-4C) alkoxy (2C-4C) alkyl 2-alkenoate or a vicinyl epoxy (1C-4C) alkyl 2-alkenoate, in a polar liquid or a mixture of two or more miscible liquids, at least one of which is polar, and an effective amount of a surfactant to produce a suspension of a plurality of polymeric nanoparticles wherein the polymeric nanoparticles have an average diameter of less than 1×10 −6  m; and   b) removing the liquid(s) from the suspension such that the amount of liquid(s) remaining in the dry powder is less than 10% by weight wherein the percentage is based on the total weight of the dry powder.   
     
     
         2 . The dry powder of  claim 1 , wherein the polymeric nanoparticles have an average diameter of from about 1 nanometer to about 1 micrometer. 
     
     
         3 . The dry powder of  claim 1 , wherein the polymeric nanoparticles have an average diameter of from about 20 to about 800 nanometers. 
     
     
         4 . The dry powder of  claim 1 , wherein the polymeric nanoparticles in the suspension exist as clusters when the concentration of polymeric nanoparticles in the suspension is between 5 and 20%. 
     
     
         5 . The dry powder of  claim 1 , wherein the polymeric nanoparticles are about the same average diameter, are formed from one or more monomers and are of a narrow polydispersity. 
     
     
         6 . The dry powder of  claim 1 , wherein the polymeric nanoparticles are of differing average diameter, are formed from one or more monomers and are of a narrow polydispersity. 
     
     
         7 . The dry powder of  claim 1 , wherein the polymeric nanoparticles are formed from one or more monomers and are of a broad polydispersity. 
     
     
         8 . The dry powder of  claim 1 , wherein the step a) further comprises:
 a) adding one or more first working substance(s) in an amount effective to give a first working substance-containing liquid, wherein after polymerization, a portion of the first working substance-containing liquid is occluded by the polymeric nanoparticles;   and step b) further comprises:   adding one or more second working substance(s) in an effective amount to the dry polymeric nanoparticles and dry blending to give a second working substance-containing particulate powder, wherein the first working substance(s) may be the same as or different than the second working substance(s).   
     
     
         9 . The dry powder of  claim 1 , wherein the step a) comprises:
 a) adding from 0.01 to 10 mol percent of a surfactant to a polymerization system comprising a monomer, or two or more different monomers, wherein the monomer or at least one of the two or more monomers comprise(s) one or more hydroxy and/or one or more ester groups, in a polar liquid or mixture of polar liquids, wherein the polar liquid or at least one of the two or more polar liquids comprise(s) one or more hydroxy groups and polymerizing the monomer(s) to form a plurality of polymeric nanoparticles, wherein the addition is in the absence of a cross-linking agent.   
     
     
         10 . The dry powder of  claim 9 , wherein the monomer(s) are selected from the group consisting of a 2-alkenoic acid, a hydroxy(2C-4C)alkyl 2-alkenoate, a dihydroxy(2C-4C) alkyl 2-alkenoate, a hydroxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkenoate, a (1C-4C)alkoxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkenoate and a vicinyl epoxy(1C-4C)alkyl 2-alkenoate and a combination of two or more thereof. 
     
     
         11 . The dry powder of  claim 10 , wherein the monomer(s) are selected from the group consisting of acrylic acid, methacrylic acid, 2-hydroxyethyl acrylate, 2-hydroxyethylmethacrylate, diethyleneglycol monoacrylate, diethyleneglycol monomethacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methyacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate, dipropylene glycol monoacrylate, dipropylene glycol monomethacrylate, 2,3-dihydroxypropyl methacrylate, glycidyl acrylate, glycidyl methacrylate and a combination of two or more thereof. 
     
     
         12 . The dry powder of  claim 11 , wherein the monomer(s) are selected from the group comprising methacrylic acid, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl methacrylate, glycerol methacrylate and a combination of two or more thereof. 
     
     
         13 . The dry powder of  claim 12 , wherein the liquid(s) are selected from the group consisting of water, a (1C-10C) alcohol, a (2C-8C)polyol, a (1C-4C)alkyl ether of a (2C-8C)polyol, a (1C-4C)acid ester of a (2C-8C)polyol, a hydroxy-terminated polyethylene oxide, a polyalkylene glycol and a hydroxy(2C-4C)alkyl ester of a mono, di- or tricarboxylic acid. 
     
     
         14 . The dry powder of  claim 13 , wherein the liquid(s) are selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 200-600, propylene glycol, dipropylene glycol, 1,4-butanediol, 2,3-butanediol, 1,6-hexanediol, 2,5-hexanediol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, methylcellosolve ether, ethylene glycol monoacetate, propylene glycol monomethyl ether, glycerine, glycerol monoacetate, tri(2-hydroxyethyl)citrate, di(hydroxypropyl)oxalate, glyceryl diacetate, and glyceryl monobutyrate. 
     
     
         15 . The dry powder of  claim 14 , wherein the liquid is water. 
     
     
         16 . The dry powder of  claim 1 , wherein the step a) further comprises adding from about 0.1 to about 15% mol percent of a cross-linking agent. 
     
     
         17 . The dry powder of  claim 16 , wherein the cross-linking agent is selected from the group consisting of ethylene glycol diacrylate, ethylene glycol dimethacrylate, 1,4-dihydroxybutane dimethacrylate, diethylene glycol dimethacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dipropylene glycol dimethacrylate, diethylene glycol diacrylate, dipropylene glycol diacrylate, divinyl benzene, divinyltoluene, diallyl tartrate, diallyl malate, divinyl tartrate, triallyl melamine, N,N′-methylene bisacrylamide, diallyl maleate, divinyl ether, 1,3-diallyl 2-(2-hydroxyethyl) citrate, vinyl allyl citrate, allyl vinyl maleate, diallyl itaconate, di(2-hydroxyethyl) itaconate, divinyl sulfone, hexahydro-1,3,5-triallyltriazine, triallyl phosphite, diallyl benzenephosphonate, triallyl aconitate, divinyl citraconate, trimethylolpropane trimethacrylate and diallyl fumarate. 
     
     
         18 . The dry powder of  claim 17 , wherein the cross-linked polymeric nanoparticles have an average molecular weight of from about 3,000 to about 2,000,000. 
     
     
         19 - 39 . (canceled) 
     
     
         40 . A method of forming a shape-conforming, shape-retentive aggregate dressing or biomaterial in vivo or in situ on a wet wound site, comprising applying the dry powder of  claim 1  to the wet wound site. 
     
     
         41 . (canceled) 
     
     
         42 . A method of treatment of a wound, comprising applying an effective amount of the dry powder of  claim 1 . 
     
     
         43 - 51 . (canceled)