Cross-linked silk-hyaluronic acid compositions

Abstract

Compositions useful as dermal fillers and methods using such compositions to treat various skin and soft tissue conditions. The dermal fillers can comprise silk attached to hyaluronic acid using for example two cross linkers and can be used to treat of facial imperfections, facial defects, facial augmentations, breast imperfections, breast augmentations or breast reconstructions.

We claim: 
     
         1 . A process for making a dermal filler, the process comprising cross linking a hyaluronic acid and silk using a multiepoxide crosslinker. 
     
     
         2 . The process of  1  wherein the multiepoxide cross linker is 1,4-butanediol diglycidyl ether (BDDE). 
     
     
         3 . A process for making a dermal filler, the process comprising:
 (a) activating a hyaluronic acid using a carbodiimide coupling agent, and   (b) cross linking the activated hyaluronic acid to silk using a mutliamine cross linker.   
     
     
         4 . The process of  claim 3 , wherein the multiamine cross linker is 3-[3-(3-amino propoxy)-2,2-bis(3-amino-propoxymethyl)-propoxy]propylamine (4AA). 
     
     
         5 . The process of  claim 3 , wherein the multiamine cross linker is a diamine cross linker. 
     
     
         6 . The process of  claim 5 , wherein the diamine cross linker is selected from the group consisting of a hexamethylene diamine (HMDA), lysine, lysine methyl ester, and lysine ethyl ester. 
     
     
         7 . The process of  claim 3 , wherein the carboiimide coupling agent is a water soluble carboiimide. 
     
     
         8 . The process of  claim 7 , wherein the water soluble carboiimide coupling agent is 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC). 
     
     
         9 . The process of  claim 3 , further comprising the step of use of an activating agent in conjunction with the carboiimide coupling agent. 
     
     
         10 . The process of  claim 9 , wherein the activating agent is a water soluble activating agent. 
     
     
         11 . The process of  claim 10 , wherein the water soluble coupling agent is a N-hydroxysuccinimide (NHS) or a N-hydroxysulfosuccinimide (sulfoNHS). 
     
     
         12 . The process of  claim 3  wherein the silk is in aqueous solution when cross linked to the hyaluronic acid. 
     
     
         13 . The process of  claim 12 , wherein the silk is a silk fibroin. 
     
     
         14 . The process of  claim 13 , wherein the silk fibroin comprises single stranded silk fibroin. 
     
     
         15 . A process for cross linking a hyaluronic acid to silk, the process comprising the steps of:
 (a) dissolving silk to obtain an aqueous solution of silk fibroin;   (b) mixing a hyaluronic acid with the silk solution in the presence of carbodiimide coupling agent and a mutliamine cross linker at a pH between about 4 to about 7 at a temperature between about 20° C. and about 37° C.   
     
     
         16 . The process of  claim 15 , wherein the multiamine crosslinker is HMDA. 
     
     
         17 . The process of  claim 15 , wherein the multiamine crosslinker is a lysine methyl ester. 
     
     
         18 . A method for treating a soft tissue condition in an individual in need thereof, the method comprising the step of administering the dermal filler of  claim 1  into a skin region of the individual, wherein the administration improves the soft tissue condition. 
     
     
         19 . A method for breast augmentation or breast reconstruction comprising the step of administering the dermal filler of  claim 1  with adipose tissue.