PH Responsive Self-Healing Hydrogels Formed By Boronate-Catechol Complexation

Abstract

Biocompatible hydrogels made from cross-linked catechol-borate ester polymers are disclosed, along with methods of synthesizing and using such hydrogels. The hydrogels of the present invention are prepared by boronic acid-catechol complexation between catechol-containing macromonomers and boronic acid-containing cross-linkers. The resulting hydrogels are pH-responsive and self-healing, and can be used in a number of different biomedical applications, including in surgical implants, in surgical adhesives, and in drug delivery systems is data provides further evidence of the viability of using the disclosed hydrogels for in vivo in biomedical applications.

We claim: 
     
         1 . A biocompatible pH-responsive self-healing hydrogel comprising a cross-linked polymer comprising:
 (a) a plurality of macromonomers comprising at least four terminal catechol moieties and having a molecular weight of 1,000 to 20,000 Daltons; and   (b) one or more cross-linkers comprising two or more terminal boronic acid moieties;   wherein the catechol moieties of the macromonomers are covalently bonded to the boronic acid moieties of the cross linker to form a tetrahedral borate ester, whereby the macromonomers are cross-linked into a polymer.   
     
     
         2 . The hydrogel of  claim 1 , wherein the macromonomers have a molecular weight of 5,000 to 15,000 Daltons. 
     
     
         3 . The hydrogel of  claim 1 , wherein the macromonomers are polyethylene glycols or (dihydroxyphenyl)ethyl methacrylamide copolymers. 
     
     
         4 . The hydrogel of  claim 3 , wherein the polyethylene glycols are 4-arm polyethylene glycols wherein each arm is terminated with a catechol moiety. 
     
     
         5 . The hydrogel of  claim 4 , wherein the 4-arm polyethylene glycols have the structure: 
       
         
           
           
               
               
           
         
       
       wherein each n is independently selected to be from 1 to 200. 
     
     
         6 . The hydrogel of  claim 3 , wherein the (dihydroxyphenyl)ethyl methacrylamide copolymers are comprised of (dihydroxyphenyl)ethyl methacrylamide monomers wherein the phenyl group is nitro substituted. 
     
     
         7 . The hydrogel of  claim 3 , wherein the (dihydroxyphenyl)ethyl methacrylamide copolymers have the structure: 
       
         
           
           
               
               
           
         
       
       wherein each of m, n and a are independently selected to be from 1 to 200. 
     
     
         8 . The hydrogel of  claim 1 , wherein two terminal boronic acid moieties on the cross-linkers are attached to an aromatic ring. 
     
     
         9 . The hydrogel of  claim 8 , wherein the two terminal boronic acid moieties on the cross linkers are either attached to the same aromatic ring or to two different aromatic rings on opposite ends of the cross-linkers. 
     
     
         10 . The hydrogel of  claim 8 , wherein the cross-linkers have the structure: 
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 100. 
     
     
         11 . The hydrogel of  claim 1 , wherein the tetrahedral borate ester group covalently bonding the macromonomers to the cross-linkers has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         12 . A cross-linked polymer made by contacting a plurality of macromonomers comprising at least four terminal catechol moieties and having a molecular weight of between 1,000 and 20,000 Daltons with one or more cross-linkers comprising two terminal boronic acid moieties, whereby the macromonomers are cross-linked into a polymer. 
     
     
         13 . The cross-linked polymer of  claim 12 , wherein the macromonomers have a molecular weight of 5,000 to 15,000 Daltons. 
     
     
         14 . The cross-linked polymer of  claim 12 , wherein the macromonomers are polyethylene glycols or (dihydroxyphenyl)ethyl methacrylamide copolymers. 
     
     
         15 . The cross-linked polymer of  claim 14 , wherein the polyethylene glycols are 4-arm polyethylene glycols wherein each arm is terminated with a catechol moiety. 
     
     
         16 . The cross-linked polymer of  claim 15 , wherein the 4-arm polyethylene glycols have the structure: 
       
         
           
           
               
               
           
         
       
       wherein each n is independently selected to be from 1 to 200. 
     
     
         17 . The cross-linked polymer of  claim 14 , wherein the (dihydroxyphenyl)ethyl methacrylamide copolymers are comprised of (dihydroxyphenyl)ethyl methacrylamide monomers wherein the phenyl group is nitro substituted. 
     
     
         18 . The cross-linked polymer of  claim 14 , wherein the (dihydroxyphenyl)ethyl methacrylamide copolymers have the structure: 
       
         
           
           
               
               
           
         
       
       wherein each of m, n and a are independently selected to be from 1 to 200. 
     
     
         19 . The cross-linked polymer of  claim 12 , wherein two terminal boronic acid moieties on the cross-linkers are attached to an aromatic ring. 
     
     
         20 . The cross-linked polymer of  claim 19 , wherein the two terminal boronic acid moieties on the cross linkers are either attached to the same aromatic ring or to two different aromatic rings on opposite ends of the cross-linkers. 
     
     
         21 . The cross-linked polymer of  claim 20 , wherein the cross-linkers have the structure: 
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 100. 
     
     
         22 . A biocompatible pH-responsive self-healing hydrogel comprising the cross-linked polymer of  claim 12 . 
     
     
         23 . A method of making a pH-responsive self-healing hydrogel comprising cross-linking within an aqueous solution a plurality of macromonomers comprising at least four terminal catechol moieties and having a molecular weight of between 1,000 and 20,000 Daltons by contacting the macromonomers with one or more cross-linkers comprising two terminal boronic acid moieties. 
     
     
         24 . The method of  claim 23 , wherein the macromonomers have a molecular weight of 5,000 to 15,000 Daltons. 
     
     
         25 . The method of  claim 23 , wherein the macromonomers are polyethylene glycols or (dihydroxyphenyl)ethyl methacrylamide copolymers. 
     
     
         26 . The method of  claim 25 , wherein the polyethylene glycols are 4-arm polyethylene glycols wherein each arm is terminated with a catechol moiety. 
     
     
         27 . The method of  claim 26 , wherein the 4-arm polyethylene glycols have the structure: 
       
         
           
           
               
               
           
         
       
       wherein each n is independently selected to be from 1 to 200. 
     
     
         28 . The method of  claim 25 , wherein the (dihydroxyphenyl)ethyl methacrylamide copolymers are comprised of (dihydroxyphenyl)ethyl methacrylamide monomers wherein the phenyl group is nitro substituted. 
     
     
         29 . The method of  claim 25 , wherein the (dihydroxyphenyl)ethyl methacrylamide copolymers have the structure: 
       
         
           
           
               
               
           
         
       
       wherein each of m, n and a are independently selected to be from 1 to 200. 
     
     
         30 . The hydrogel of  claim 23 , wherein two terminal boronic acid moieties on the cross-linkers are attached to an aromatic ring. 
     
     
         31 . The method of  claim 30 , wherein the two terminal boronic acid moieties on the cross linkers are either attached to the same aromatic ring or to two different aromatic rings on opposite ends of the cross-linkers. 
     
     
         32 . The method of  claim 31 , wherein the cross-linkers have the structure: 
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 100. 
     
     
         33 . The method of  claim 23 , wherein the step of contacting the contacting the macromonomers with one or more cross-linkers is performed under basic conditions. 
     
     
         34 . The use of the hydrogel of  claim 1  in the manufacture of a biomedical product. 
     
     
         35 . The use of  claim 34 , wherein the biomedical product is selected from a carrier for the delivery of biomaterials, a tissue implant, a cellular growth scaffold, or a surgical tissue adhesive.