Injectable glycosaminoglycan hydrogels for controlled release of human basic fibroblast growth factor.
Synthetic hydrogel mimics of the extracellular matrix (ECM) were created by crosslinking a thiol-modified analog of heparin with thiol-modified hyaluronan (HA) or chondroitin sulfate (CS) with poly(ethylene glycol) diacrylate (PEGDA). The covalently bound heparin provided a crosslinkable analog of a heparan sulfate proteoglycan, thus providing a multivalent biomaterial capable of controlled release of basic fibroblast growth factor (bFGF). Hydrogels contained >97% water and formed rapidly in <10min. With as little as 1% (w/w) covalently bound heparin (relative to total glycosaminoglycan content), the rate of release of bFGF in vitro was substantially reduced. Total bFGF released increased with lower percentages of heparin; essentially quantitative release of bFGF was observed from heparin-free hydrogels. Moreover, the hydrogel-released bFGF retained 55% of its biological activity for up to 28 days as determined by a cell proliferation assay. Finally, when these hydrogels were implanted into subcutaneous pockets in Balb/c mice, neovascularization increased dramatically with HA and CS hydrogels that contained both bFGF and crosslinked heparin. In contrast, hydrogels lacking bFGF or crosslinked heparin showed little increase in neovascularization. Thus, covalently linked, heparin-containing glycosaminoglycan hydrogels that can be injected and crosslinked in situ constitute highly promising new materials for controlled release of heparin-binding growth factors in vivo.
Cai
Shenshen
S
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-125, USA.
Liu
Yanchun
Y
Zheng Shu
Xiao
X
Prestwich
Glenn D
GD
D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D049109:Cell Proliferation; D003432:Cross-Linking Reagents / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D006025:Glycosaminoglycans / Q000737:chemistry*; D006133:Growth Substances; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry; D006493:Heparin / Q000737:chemistry; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007249:Inflammation; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D011092:Polyethylene Glycols / Q000737:chemistry; D012038:Regeneration; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013997:Time Factors; D014945:Wound Healing
D001672:Biocompatible Materials; D003432:Cross-Linking Reagents; D006025:Glycosaminoglycans; D006133:Growth Substances; D019812:Heparan Sulfate Proteoglycans; D020100:Hydrogels; D013438:Sulfhydryl Compounds; C437167:poly(ethylene glycol)diacrylate; D016222:Fibroblast Growth Factor 2; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; D006493:Heparin; D016650:Fluorescein-5-isothiocyanate