The goal of the proposed project is to develop and evaluate novel hyaluronic acid (HA)-based hydrogel films optimized for controlled release of desired peptide growth factors (GFs) while simultaneously providing an advantageous environment for pre-seeded cell growth. Synthetic extracellular matrices (sECMs) fabricated from such biopolymer networks can serve as the foundation for tissue and organ growth both in vitro and in vivo. However, at present the clinical utility of most synthetic matrices is limited by poor regulation of the specific coordinated sequences of GF releases that typically drives tissue maturation in vivo. In the proposed project, an sECM containing small amounts of heparin (Hp), which has been shown to substantially improve control of the time course of release of sequestered GFs, will be fabricated from chemically modified HA, or HA and gelatin (Gtn). Conjugate addition chemistry will be employed to crosslink mixtures of HA-DTPH, Gtn-DTPH and Hp-DTPH, using polyethylene glycol diacrylate (PEGDA) as crosslinking agent. Vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) will be added to the HA-DTPH solution non-covalently prior to crosslinking. The relation between Hp concentration and rate of in vitro GF release from these matrices will be investigated by ELISA. Subsequently, gel samples fabricated with a minimal amount of Hp consistent with sustained GF release will be implanted in a series of mouse ear pinnas, and the angiogenic activity of released GF in vivo quantified by measurement of elicited new microvessel growth. In addition, the potential for controlling tissue phenotypic response at the gene expression level with these imlants will be studied in the same mouse model. Tissue samples will be retrieved at a series of time points post implant, and expression changes due to controlled growth factor release determined by microarray and RT-PCR analysis.
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| Hosack, Luke W; Firpo, Matthew A; Scott, J Anna et al. (2008) Microvascular maturity elicited in tissue treated with cytokine-loaded hyaluronan-based hydrogels. Biomaterials 29:2336-47 |
| Pike, Daniel B; Cai, Shenshen; Pomraning, Kyle R et al. (2006) Heparin-regulated release of growth factors in vitro and angiogenic response in vivo to implanted hyaluronan hydrogels containing VEGF and bFGF. Biomaterials 27:5242-51 |
| Riley, Celeste M; Fuegy, Peter W; Firpo, Matthew A et al. (2006) Stimulation of in vivo angiogenesis using dual growth factor-loaded crosslinked glycosaminoglycan hydrogels. Biomaterials 27:5935-43 |
