Crosslinked polymer compositions and methods for their use

Abstract

Crosslinked polymer compositions comprise a first synthetic polymer containing multiple nucleophilic groups covalently bound to a second synthetic polymer containing multiple electrophilic groups. The first synthetic polymer is preferably a synthetic polypeptide or a polyethylene glycol that has been modified to contain multiple nucleophilic groups, such as primary amino (—NH 2 ) or thiol (—SH) groups. The second synthetic polymer may be a hydrophilic or hydrophobic synthetic polymer which contains, or has been derivatized to contain, two or more electrophilic groups, such as succinimidyl groups. The compositions may further comprise other components, such as naturally occurring polysaccharides or proteins (such as glycosaminoglycans or collagen) and/or biologically active agents. Also disclosed are methods for using the crosslinked polymer compositions to effect adhesion between a first surface and a second surface; to effect tissue augmentation; to prevent the formation of surgical adhesions; and to coat a surface of a synthetic implant.

What is claimed is:  
     
         1 . A composition comprising a first synthetic polymer having nucleophilic groups, and a second synthetic polymer having electrophilic groups, wherein said nucleophilic groups and said electrophylic groups are capable of reacting to form covalent bonds between the first synthetic polymer and the second synthetic polymer which results in formation of a three-dimensional matrix.  
     
     
         2 . The composition of  claim 1 , wherein said first synthetic polymer has m nucleophilic groups, and said second synthetic polymer has n nucleophilic groups, wherein m and n are each greater than or equal to 2, and wherein m+n is greater than or equal to 5.  
     
     
         3 . The composition of  claim 2 , wherein m is greater than or equal to two, and n=2.  
     
     
         4 . The composition of  claim 2  wherein m=2, and n is greater than or equal to two.  
     
     
         5 . The composition of  claim 2 , wherein m and n are each greater than or equal to three.  
     
     
         6 . The composition of  claim 1 , wherein the first synthetic polymer is a synthetic polypeptide that contains two or more nucleophilic groups selected from a primary amino group and a thiol group.  
     
     
         7 . The composition of  claim 6 , wherein the first synthetic polymer is a synthetic polypeptide that contains two or more lysine residues.  
     
     
         8 . The composition of  claim 7 , wherein the synthetic polypeptide is a poly(lysine).  
     
     
         9 . The composition of  claim 6 , wherein the first synthetic polymer is a synthetic polypeptide that contains two or more cysteine residues.  
     
     
         10 . The composition of  claim 1 , wherein the first synthetic polymer is a polyethylene glycol that has been modified to contain two or more nucleophilic groups selected from a primary amino group and a thiol group.  
     
     
         11 . The composition of  claim 1 , wherein the second synthetic polymer is a synthetic hydrophilic polymer containing two or more electrophilic groups.  
     
     
         12 . The composition of  claim 10 , wherein the synthetic hydrophilic polymer contains two or more succinimidyl groups.  
     
     
         13 . The composition of  claim 10 , wherein the synthetic hydrophilic polymer is a polyethylene glycol derivative.  
     
     
         14 . The composition of  claim 1 , wherein the second synthetic polymer is a synthetic hydrophobic polymer containing two or more succinimidyl groups.  
     
     
         15 . The composition of  claim 11 , wherein the synthetic hydrophobic polymer is selected from the group consisting of: disuccinimidyl suberate, bis(sulfosuccinimidyl) suberate, dithiobis(succinimidylpropionate), bis(2-succinimidooxycarbonyloxy)ethyl sulfone, 3,3′-dithiobis (sulfosuccinimidylpropionate), and their analogs and derivatives.  
     
     
         16 . The composition of  claim 13 , wherein the synthetic hydrophobic polymer has been chemically derivatized to contain two or more succinimidyl groups.  
     
     
         17 . The composition of  claim 15 , wherein the hydrophobic polymer is a polyacid.  
     
     
         18 . The composition of  claim 16 , wherein the polyacid is selected from the group consisting of: trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid, and hexadecanedioic acid.  
     
     
         19 . The composition of  claim 1  further comprising a polysaccharide or a protein.  
     
     
         20 . The composition of  claim 18 , wherein the polysaccharide is a glycosaminoglycan.  
     
     
         21 . The composition of  claim 19 , wherein the glycosaminoglycan is selected from the group consisting of: hyaluronic acid, chitin, chondroitin sulfate A, chondroitin sulfate B, chondroitin sulfate C, keratin sulfate, keratosulfate, heparin, and derivatives thereof.  
     
     
         22 . The composition of  claim 18 , wherein the protein is collagen or a derivative thereof.  
     
     
         23 . A composition comprising a first polyethylene glycol having primary amino groups, and a second polyethylene glycol having succinimidyl groups.  
     
     
         24 . The composition of  claim 23 , wherein said first polyethylene glycol has m primary amino groups, and said second polyethylene glycol has n succinimidyl groups, wherein m and n are each greater than or equal to 2, and wherein m+n is greater than or equal to 5.  
     
     
         25 . The composition of  claim 24 , wherein m is greater than 3, and n=2.  
     
     
         26 . The composition of  claim 24 , wherein m=2 and n is greater than or equal to 3.  
     
     
         27 . The composition of  claim 24 , wherein m and n are each greater than or equal to 3.  
     
     
         28 . The composition of  claim 23  further comprising a naturally occurring polysaccharide or a naturally occurring protein.  
     
     
         29 . The composition of  claim 28 , wherein the naturally occurring polysaccharide is a glycosaminoglycan.  
     
     
         30 . The composition of  claim 29 , wherein the glycosaminoglycan is selected from the following group: hyaluronic acid, chitin, chondroitin sulfate A, chondroitin sulfate B, chondroitin sulfate C, keratin sulfate, keratosulfate, heparin, and derivatives thereof.  
     
     
         31 . The composition of  claim 28 , wherein the naturally occurring protein is collagen or a derivative thereof.  
     
     
         32 . A method for effecting the nonsurgical attachment of a first surface to a second surface, comprising the steps of: 
 providing a first synthetic polymer containing nucleophilic groups and a second synthetic polymer containing electrophilic groups;    mixing the first synthetic polymer and the second synthetic polymer to initiate crosslinking;    applying the mixture to a first surface before substantial crosslinking has occurred; and    contacting the first surface with a second surface to effect adhesion between the first surface and the second surface.    
     
     
         33 . The method of  claim 32 , wherein said first synthetic polymer has m nucleophilic groups and said second synthetic polymer has n electrophilic groups, wherein m and n are each greater than or equal to 2, and wherein m+n is greater than or equal to 5.  
     
     
         34 . The method of  claim 32 , wherein one of the first and second surfaces is a native tissue surface and the other of the first and second surfaces is selected from a non-native tissue surface and a surface of a synthetic implant.  
     
     
         35 . The method of  claim 32 , wherein both the first and second surfaces are native tissue surfaces.  
     
     
         36 . A method for introducing a crosslinked synthetic polymer composition into a tissue within a body of a mammalian subject, comprising the steps of: 
 providing a first synthetic polymer containing nucleophilic groups and a second synthetic polymer containing electrophilic groups;    administering the first synthetic polymer and the second synthetic polymer simultaneously to the tissue; and    allowing the first synthetic polymer and the second synthetic polymer to crosslink in situ.    
     
     
         37 . The method of  claim 36 , wherein said first synthetic polymer has m nucleophilic groups and said second synthetic polymer has n electrophilic groups, wherein m and n are each greater than or equal to 2, and wherein m+n is greater than or equal to 5.  
     
     
         38 . The method of  claim 36 , wherein the tissue is soft tissue.  
     
     
         39 . The method of  claim 36 , wherein the tissue is hard tissue.  
     
     
         40 . The method of  claim 36 , wherein the first synthetic polymer and the second synthetic polymer are contained within separate barrels of and administered from a dual-compartment syringe.  
     
     
         41 . The method of  claim 36  comprising the additional step of forming a mixture by mixing the first synthetic polymer and the second synthetic polymer before administration, wherein the mixture is administered within 60 seconds of mixing.  
     
     
         42 . A method for preventing the adhesion of a first tissue and a second tissue, comprising the steps of: 
 providing a first synthetic polymer containing nucleophilic groups and a second synthetic polymer containing electrophilic groups;    forming a mixture by mixing the first synthetic polymer and the second synthetic polymer to initiate crosslinking;    applying the mixture to the first tissue before substantial crosslinking has occurred; and    allowing the first synthetic polymer and the second synthetic polymer to continue crosslinking in situ.    
     
     
         43 . The method of  claim 42 , wherein said first synthetic polymer has m nucleophilic groups and said second synthetic polymer has n electrophilic groups, wherein m and n are each greater than or equal to 2, and wherein m+n is greater than or equal to 5.  
     
     
         44 . A method for coating a surface of a synthetic implant, comprising the steps of: 
 providing a first synthetic polymer containing nucleophilic groups and a second synthetic polymer containing electrophilic groups;    forming a mixture by mixing the first synthetic polymer and the second synthetic polymer to initiate crosslinking;    applying the mixture to a surface of a synthetic implant; and    allowing the first synthetic polymer and the second synthetic polymer to crosslink with each other on the surface of the synthetic implant.    
     
     
         45 . The method of  claim 44 , wherein said first synthetic polymer has m nucleophilic groups and said second synthetic polymer has n electrophilic groups, wherein m and n are each greater than or equal to 2, and wherein m+n is greater than or equal to 5.  
     
     
         46 . The method of  claim 44 , wherein the synthetic implant is selected from the group consisting of: artificial blood vessels, artificial heart valves, vascular grafts, vascular stents, vascular stent/graft combinations, surgical membranes, surgical meshes, and breast implants.  
     
     
         47 . The method of  claim 44 , wherein the mixture has a net neutral charge.  
     
     
         48 . A method for preparing a negatively charged compound-containing matrix useful for delivery of a negatively charged compound to a mammalian subject, comprising the steps of: 
 providing a first synthetic polymer containing nucleophilic groups and a second synthetic polymer containing electrophilic groups;    forming a mixture by mixing the first synthetic polymer and the second synthetic polymer to initiate crosslinking, wherein the first synthetic polymer is present in the mixture in molar excess compared to the second synthetic polymer,    allowing the first synthetic polymer and the second synthetic polymer to continue crosslinking to form a positively charged crosslinked synthetic polymer matrix; and    reacting the matrix with the negatively charged compound.    
     
     
         49 . The method of  claim 48 , wherein said first synthetic polymer has m nucleophilic groups and said second synthetic polymer has n electrophilic groups, wherein m and n are each greater than or equal to 2, and wherein m+n is greater than or equal to 5.  
     
     
         50 . The method of  claim 48 , wherein the first synthetic polymer is a polyethylene glycol, and wherein the nucleophilic groups are selected from a primary amino group and a thiol group.  
     
     
         51 . The method of  claim 48 , wherein the second synthetic polymer is a polyethylene glycol derivative, and wherein the electrophilic groups are succinimidyl groups.  
     
     
         52 . The method of  claim 48 , wherein the negatively charged compound is succinylated collagen.  
     
     
         53 . The method of  claim 48 , wherein the negatively charged compound is a negatively charged glycosaminoglycan derivative selected from the group consisting of: sodium hyaluronate, keratan sulfate, keratosulfate, sodium chondroitin sulfate A, sodium dermatan sulfate B, sodium chondroitin sulfate C, heparin, esterified chondroitin sulfate C, esterified heparin, and combinations thereof.  
     
     
         54 . A method for preparing a positively charged compound-containing matrix useful for delivery of a positively charged compound to a mammalian subject, comprising the steps of: 
 providing a first synthetic polymer containing nucleophilic groups and a second synthetic polymer containing electrophilic groups;    forming a mixture by mixing the first synthetic polymer and the second synthetic polymer to initiate crosslinking, wherein the second synthetic polymer is present in the mixture in molar excess compared to the second synthetic polymer;    allowing the first synthetic polymer and the second synthetic polymer to continue crosslinking to form a negatively charged crosslinked synthetic polymer matrix; and    reacting the matrix with the positively charged compound.    
     
     
         55 . The method of  claim 54 , wherein said first synthetic polymer has m nucleophilic groups and said second synthetic polymer has n electrophilic groups, wherein m and n are each greater than or equal to 2, and wherein m+n is greater than or equal to 5.  
     
     
         56 . The method of  claim 54 , wherein the first synthetic polymer is a polyethylene glycol, and wherein the nucleophilic groups are selected from a primary amino group and a thiol group.  
     
     
         57 . The method of  claim 54 , wherein the second synthetic polymer is a polyethylene glycol, and wherein the electrophilic groups are succinimidyl groups.  
     
     
         58 . The method of  claim 54 , wherein the positively charged compound is methylated collagen.  
     
     
         59 . The method of  claim 54 , wherein the positively charged compound is a glycosaminoglycan derivative selected from the group consisting of: esterified deacetylated hyaluronic acid, esterified deacetylated desulfated chondroitin sulfate A, esterified deacetylated desulfated chondroitin sulfate C, deacetylated desulfated keratan sulfate, deacetylated desulfated keratosulfate, esterified desulfated heparin, chitosan, and combinations thereof.  
     
     
         60 . A method for making a synthetic lenticule, comprising the steps of: 
 providing a first synthetic polymer containing nucleophilic groups and a second synthetic polymer containing electrophilic groups;    forming a mixture by mixing the first synthetic polymer and the second synthetic polymer to initiate crosslinking;    placing said mixture into a lenticular shaped mold or onto a surface of an eye; and    allowing the first synthetic polymer and the second synthetic polymer to continue crosslinking to form a clear lenticule.    
     
     
         61 . The method of  claim 60 , wherein said first synthetic polymer has m nucleophilic groups and said second synthetic polymer has n electrophilic groups, wherein m and n are each greater than or equal to 2, and wherein m+n is greater than or equal to 5.  
     
     
         62 . The method of  claim 60 , wherein the first synthetic polymer is a polyethylene glycol, and wherein the nucleophilic groups are selected from a primary amino group and a thiol group.  
     
     
         63 . The method of  claim 60 , wherein the second synthetic polymer is a polyethylene glycol derivative, and wherein the electrophilic groups are succinimidyl groups.  
     
     
         64 . The method of  claim 60  further comprising a protein.  
     
     
         65 . The method of  claim 64  wherein said protein is collagen or a derivative thereof.