Hydrogel using, as substrate, hyaluronic acid derivative modified with gallol group and use thereof

Abstract

The present invention provides a hydrogel platform using, as a substrate, hyaluronic acid (HA) conjugated to a pyrogallol (PG) moiety. The HA-PG conjugate of the present invention can be rapidly crosslinked by two different methods, in each of which an oxidizing agent is used or a pH is adjusted. The hydrogel of the present invention can not only have excellent biocompatibility, but also can have efficiently controlled physical characteristics such as a crosslinking rate, elasticity, and adhesive strength, depending on each crosslinking method. On the basis of such excellent stability and functionality, the hydrogel of the present invention can be used in various fields including drug delivery, biopharmaceutical materials such as a wound healing agent or anti-adhesive agent, medicines, and cosmetic products.

1 . A method for preparing a hyaluronic acid hydrogel, comprising:
 a step of crosslinking hyaluronic acid derivatives, each of which is modified with a pyrogallol group,   wherein in the hyaluronic acid derivative, hyaluronic acid has been modified with a pyrogallol group.   
     
     
         2 . The method according to  claim 1 ,
 wherein the hyaluronic acid derivative is represented by the following Formula 1:   
       
         
           
           
               
               
           
         
         (in the above Formula 1, R 1  is a hydroxyl group or 
       
       
         
           
           
               
               
           
         
       
       and n is an integer of 1 to 1,000). 
     
     
         3 . The method according to  claim 1  of  2 ,
 wherein in the crosslinking step, crosslinking is carried out by adding an oxidizing agent or a pH adjusting agent. 
 
     
     
         4 . The method according to  claim 3 ,
 wherein the oxidizing agent is any one selected from the group consisting of sodium periodate, hydrogen peroxide, horseradish peroxidase, and tyrosinase.   
     
     
         5 . The method according to  claim 3 ,
 wherein in the crosslinking step carried out by adding the oxidizing agent, crosslinking represented by the following Formula 2 is formed:   
       
         
           
           
               
               
           
         
         (in the above Formula 2, HA' represents hyaluronic acid in which the carboxyl group is substituted with an amide group). 
       
     
     
         6 . The method according to  claim 3 ,
 wherein the pH adjusting agent is any one selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, and barium hydroxide.   
     
     
         7 . The method according to  claim 3 ,
 wherein in the crosslinking step carried out by adding the pH adjusting agent, crosslinking represented by the following Formula 3 is formed:   
       
         
           
           
               
               
           
         
         (in the above Formula 3, HA' represents hyaluronic acid in which the carboxyl group is substituted with an amide group). 
       
     
     
         8 . A hyaluronic acid hydrogel prepared by crosslinking hyaluronic acid derivatives, each of which is represented by the following Formula 1,
 wherein crosslinking represented by the following Formula 2 is formed:   
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         (in the above Formula 1, R 1  is a hydroxyl group or and n is an integer of 1 to 1,000) 
       
       
         
           
           
               
               
           
         
         (in the above Formula 2, HA' represents hyaluronic acid in which the carboxyl group is substituted with an amide group). 
       
     
     
         9 . The hyaluronic acid hydrogel according to  claim 8 ,
 wherein the hyaluronic acid derivative has a molecular weight of 10,000 Da to 2,000,000 Da.   
     
     
         10 . The hyaluronic acid hydrogel according to  claim 8 ,
 wherein the hyaluronic acid derivative has a gallol group substitution rate of 0.1% to 50%.   
     
     
         11 . A hyaluronic acid hydrogel prepared by crosslinking hyaluronic acid derivatives, each of which is represented by the following Formula 1,
 wherein crosslinking represented by the following Formula 3 is formed:   
       
         
           
           
               
               
           
         
         (in the above Formula 1, R 1  is a hydroxyl group or 
       
       
         
           
           
               
               
           
         
       
       and n is an integer of 1 to 1,000) 
       
         
           
           
               
               
           
         
         (in the above Formula 3, HA' represents hyaluronic acid in which the carboxyl group is substituted with an amide group). 
       
     
     
         12 . The hyaluronic acid hydrogel according to  claim 11 ,
 wherein the hyaluronic acid derivative has a molecular weight of 10,000 Da to 2,000,000 Da.   
     
     
         13 . The hyaluronic acid hydrogel according to  claim 11 ,
 wherein the hyaluronic acid derivative has a gallol group substitution rate of 0.1% to 50%.   
     
     
         14 . A scaffold for tissue engineering, comprising:
 the hyaluronic acid hydrogel according to  claim 8 .   
     
     
         15 . A drug delivery carrier, comprising:
 the hyaluronic acid hydrogel according to  claim 8 .   
     
     
         16 . The drug delivery carrier according to  claim 5 ,
 wherein the drug is an antibody, an antibody fragment, a nucleic acid including DNA, RNA, or siRNA, a peptide, a gene, a protein, a stem cell, or a chemical compound.   
     
     
         17 . A filler composition, comprising:
 the hyaluronic acid hydrogel according to  claim 8 .   
     
     
         18 . An adhesion barrier composition, comprising:
 the hyaluronic acid hydrogel according to  claim 8 .   
     
     
         19 . A wound dressing composition, comprising:
 the hyaluronic acid hydrogel according to  claim 8 .   
     
     
         20 . A hyaluronic acid derivative which has the following Formula 1 and is modified with a pyrogallol group: 
       
         
           
           
               
               
           
         
         (in the above Formula 1, R 1  is a hydroxyl group or 
       
       
         
           
           
               
               
           
         
       
       and n is an integer of 1 to 1,000). 
     
     
         21 . A filler composition, comprising:
 a hyaluronic acid derivative modified with a pyrogallol group.   
     
     
         22 . The filler composition according to  claim 21 , wherein the hyaluronic acid derivative is represented by the following Formula I: 
       
         
           
           
               
               
           
         
         (in the above Formula 1, R 1  is a hydroxyl group or 
       
       
         
           
           
               
               
           
         
       
       and n is an integer of 1 to 1,000). 
     
     
         23 . The filler composition according to  claim 22 ,
 wherein the hyaluronic acid derivative has a molecular weight of 10,000 Da to 2,000,000 Da.   
     
     
         24 . The filler composition according to  claim 22 ,
 wherein the hyaluronic acid derivative has a gallol group substitution rate of 1% to 20%.   
     
     
         25 . The filler composition according to  claim 22 ,
 wherein the hyaluronic acid derivative is contained in an amount of 0.1% (w/v) to 10% (w/v) with respect to the entire filler composition.   
     
     
         26 . The filler composition according to  claim 21 ,
 wherein the composition is in a liquid state ex vivo, and forms a gelated state in vivo without a crosslinking agent.   
     
     
         27 . The filler composition according to  claim 21 ,
 wherein the composition is injected into any one site selected from the group consisting of a tear trough region, a glabellar frown line region, an eye-rim region, a forehead region, a nasal bridge region, a nasolabial line region, a marionette line region, and a neck wrinkle region.   
     
     
         28 . The filler composition according to  claim 21 , further comprising:
 any one cell growth factor selected from the group consisting of fibroblast growth factor (FGF), epithelial cell growth factor (EGF), keratinocyte growth factor (KGF), transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β), granulocyte colony stimulating factor (GCSF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), platelet-derived growth factor-BB (PDGF-BB), brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF).   
     
     
         29 . The filler composition of  claim 21 , further comprising:
 any one component selected from the group consisting of a local anesthetic, an antioxidant, a vitamin, and combinations thereof.