Hyaluronic acid-calcium phosphate composite for growth factor support and method for producing same

Abstract

The present invention relates to a carrier for growth factor related to regeneration of bone tissues that is capable of arbitrarily controlling the delivery rate of growth factors related to bone regeneration and thus especially applicable to a bone void filler in the fields of the dental or orthopedic applications. The carrier for controlling the delivery rate of the growth factor in the present invention is composed of a hyaluronic acid hydrogel having a distribution of interconnected pores and a calcium phosphate microsphere being distributed in the pores of the hyaluronic acid hydrogel. The calcium phosphate microsphere having a porosity suitable for delivery of the growth factor is positioned into the pores of the cross-linked hyaluronic acid hydrogel to complete the carrier.

What is claimed is: 
     
         1 . A hyaluronic acid/calcium phosphate composite for loading a growth factor, comprising:
 a hyaluronic acid hydrogel having a distribution of interconnected pores and being cross-linked in the presence of a cross-linking agent; and   a calcium phosphate microsphere being distributed in the pores of the hyaluronic acid hydrogel and having a size of 45 μm to 75 μm.   
     
     
         2 . The hyaluronic acid/calcium phosphate composite for loading a growth factor as claimed in  claim 1 , wherein the hyaluronic acid has a molecular weight in the range of 1,000,000 to 5,000,000. 
     
     
         3 . The hyaluronic acid/calcium phosphate composite for loading a growth factor as claimed in  claim 1 , wherein the hyaluronic acid has a degree of cross-linking of 40% or less. 
     
     
         4 . The hyaluronic acid/calcium phosphate composite for loading a growth factor as claimed in  claim 1 , wherein the cross-linking agent of the hyaluronic acid is selected from the group consisting of polyoxyethylene bis(glycidyl ether), 1,2,3,4-diepoxybutane, 1,2,7,8-diepoxyoctane, diethylene glycol diglycidyl ether, and 1,4-butanediol diglycidyl ether. 
     
     
         5 . The hyaluronic acid/calcium phosphate composite for loading a growth factor as claimed in  claim 1 , wherein calcium phosphate constituting the calcium phosphate microsphere is selected from the group consisting of monocalcium phosphate (Ca(H 2 PO 4 ) 2 ), dicalcium phosphate (CaHPO 4 ), calcium dihydrogen phosphate (Ca(H 2 PO 4 ) 2 ), tricalcium phosphate (Ca 3 (PO 4 ) 2 ), and octacalcium phosphate (Ca 8 H 2 (PO 4 ) 6 .5H 2 O). 
     
     
         6 . The hyaluronic acid/calcium phosphate composite for loading a growth factor as claimed in  claim 1 , wherein the growth factor is at least one selected from the group consisting of epidermal growth factor (EGF), heparin-binding EGF-like growth factor (HB-EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and bone morphogenetic protein (BMP), including BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, or BMP-18. 
     
     
         7 . A method for preparing a hyaluronic acid/calcium phosphate composite for loading a growth factor, comprising:
 sintering calcium phosphate powder at 1,050° C. to 1,250° C. to obtain a spherical calcium phosphate microsphere having a size of 45 μm to 75 μm; and   mixing the calcium phosphate microsphere with a hyaluronic acid hydrogel cross-linked in the presence of a cross-linking agent to obtain a hyaluronic acid/calcium phosphate composite for loading a growth factor.   
     
     
         8 . The method as claimed in  claim 7 , wherein the hyaluronic acid has a molecular weight in the range of 1,000,000 to 5,000,000. 
     
     
         9 . The method as claimed in  claim 7 , wherein the hyaluronic acid has a degree of cross-linking of 40% or less. 
     
     
         10 . The method as claimed in  claim 7 , wherein the cross-linking agent of the hyaluronic acid is selected from the group consisting of polyoxyethylene bis(glycidyl ether), 1,2,3,4-diepoxybutane, 1,2,7,8-diepoxyoctane, diethylene glycol diglycidyl ether, and 1,4-butanediol diglycidyl ether. 
     
     
         11 . The method as claimed in  claim 7 , wherein calcium phosphate constituting the calcium phosphate microsphere is selected from the group consisting of monocalcium phosphate (Ca(H 2 PO 4 ) 2 ), dicalcium phosphate (CaHPO 4 ), calcium dihydrogen phosphate (Ca(H 2 PO 4 ) 2 ), tricalcium phosphate (Ca 3 (PO 4 ) 2 ), and octacalcium phosphate (Ca 8 H 2 (PO 4 ) 6 .5H 2 O). 
     
     
         12 . The method as claimed in  claim 7 , wherein the growth factor is at least one selected from the group consisting of epidermal growth factor (EGF), heparin-binding EGF-like growth factor (HB-EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and bone morphogenetic protein (BMP), including BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, or BMP-18.