Shenshen Cai

Release of basic fibroblast growth factor from a crosslinked glycosaminoglycan hydrogel promotes wound healing

We describe synthetic extracellular matrix (sECM) hydrogel films composed of co‐crosslinked thiolated derivatives of chondroitin 6‐sulfate (CS) and heparin (HP) for controlled‐release delivery of basic fibroblast growth factor (bFGF) to full‐thickness wounds in genetically diabetic (db/db) mice. In this model for chronic wound repair, full‐thickness wounds were treated with CS, CS‐bFGF, or CS‐HP‐bFGF films. At 2 and 4 weeks postinjury, wound closure and formation of the new epidermis and dermis were determined. Both CS and CS‐HP hydrogel films accelerated wound repair, even without bFGF. Addition of bFGF to CS films showed partial dose‐dependent acceleration of wound repair. Importantly, addition of bFGF to co‐crosslinked CS‐HP sECM films showed a dramatic bFGF dose‐dependent acceleration of wound healing, as well as improved dermis formation and vascularization. Compared with 27% wound closure in 2 weeks in the controls, 89% wound closure was observed for mice treated with the CS‐HP‐bFGF films. The synthetic CS‐HP sECM films mimic the chemistry and biology of heparan sulfate proteoglycans, and may have clinical potential for topical delivery of growth factors to patients with compromised wound healing.

Injectable synthetic extracellular matrices for tissue engineering and repair.

The development of novel biointeractive hydrogels for tissue engineering1, 2, 3, tissue repair, and release of drugs4 and growth factors5 has attracted considerable attention over the past decade. Our attention has focused on hydrogels based on the extracellular matrix (ECM), a heterogeneous collection of covalent and noncovalent molecular interactions comprised primary of proteins and glycosaminoglycans (GAGs)6. In the ECM, covalent interactions connect chondroitin sulfate (CS), heparan sulfate (HS) and other sulfated GAGs to core proteins forming proteoglycans (PGs). Noncovalent interactions include binding of link modules of PGs to hyaluronan (HA), electrostatic associations with ions, hydration of the polysaccharide chains, and triple helix formation to generate collagen fibrils.

Effect of Gelatin on Heparin Regulation of Cytokine Release from Hyaluronan-Based Hydrogels

The hypothesis that incorporation of small amounts (0.3% w/w) of modified heparin in thiol-modified hyaluronan or HA and gelatin hydrogels would regulate release of cytokine growth factors (GFs) from those gels has been investigated in vitro. In addition, the physiologic response to gel implantation has been evaluated in vivo. Tests were performed with 6 GFs: basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), keratinocyte growth factor, platelet-derived growth factor-AA (PDGF), and transforming growth factor-β 1. Release profiles for all 6 over several weeks were well fit by first order exponential kinetics (R2 > 0.9 for all cases). The most remarkable result of the experiment was a dramatic variation in the total mass ultimately released, which varied from as much as 90.2% of the initial load for bFGF to as little as 1.8% for PDGF, a 45-fold difference. Furthermore, gels containing either VEGF of Ang-1 produced twice the vascularization response in vivo as gels not containing a growth factor. Thus, those GFs maintained strong physiologic effectiveness.