In Vivo Angiogenesis
Growth factors (GFs) induce neovascularization and microvessel formation in vivowhen delivered in Heprasil® or Extracel-HP® hydrogel films, which allows intact microvessel beds to form with well-defined borders1,2,3. The thiol-modified heparin in the Extracel-HP® mimics heparan sulfate proteoglycans normally present in the extracellular matrix. It also regulates the in vivo GF release so that a functional microvessel network can develop. The model used to study in vivoangiogenesis using Heprasil® or Extracel-HP® involved making hydrogel films impregnated with GFs and implanting them into the ear pinna of Balb/C mice1,2,3. Heprasil® and Extracel-HP® can also be injected subcutaneously as hydrogels.
Growth-Factor Release Rates
Six GFs have been studied for in vitro release from Heprasil®-only and Extracel-HP® hydrogels:
- angiopoietin-1 (Ang-1)1
- vascular endothelial growth factor (VEGF)1,2,3
- keratinocyte growth factor (KGF)2
- basic fibroblast growth factor (bFGF)3,4
- platelet-derived growth factor-AA (PDGF)5
- transforming growth factor β1 (TGF- β1)5
All six GFs are slowly released over several weeks with varying kinetics. The release rates for bFGF and VEGF have been published3,4. Those for Ang-1, KGF, PDGF and TGF-β1 are summarized in Growth-Factor Release.
The Extracel-HP® Hydrogel Kit contains Heprasil® (thiol-modified hyaluronan with thiol-modified heparin), Gelin-S® (thiol-modified gelatin, denatured collagen), and Extralink® (thiol-reactive crosslinking agent). It gels at temperatures from ambient to 37°C at physiological pH, with no low-temperature or low-pH steps in its preparation. The researcher has complete control over gelation time (as short as twenty minutes or as long as several hours), hydrogel stiffness, and hydrogel composition. Extracel-HP® is tested for bacteria growth, lactate dehydrogenase-elevating virus (LDEV), and endotoxins.
- C. M. Riley, P. W. Fuegy, M. A. Firpo, X. Z. Shu, G. D. Prestwich, R.A. Peattie, “Stimulation of in vivo angiogenesis using dual growth factor-loaded crosslinking glycosaminoglycan hydrogels,“ Biomaterials, 27, 5935-5943 (2006).
- R. A. Peattie, E. Rieke, E. Hewett, R. J. Fisher, X. Z. Shu, and G. D. Prestwich, “Dual growth factor-induced angiogenesis in vivo using hyaluronan hydrogel implants,” Biomaterials, 27, 1868-1875 (2006).
- D. B. Pike, S. Cai, K. R. Pomraning, M. A. Firpo, R. J. Fisher, X. Z. Shu, G. D. Prestwich, R. A. Peattie, “Heparin-regulated release of growth factors in vitro and angiogenic response in vivo to implanted hyaluronan hydrogels containing VEGF and bFGF,” Biomaterials, 27, 5242–5251 (2006).
- S. Cai, Y. Liu, X. Z. Shu, G. D. Prestwich, “Injectable glycosaminoglycan hydrogels for controlled release of human basic fibroblast growth factor,”Biomaterials, 26, 6054-6067 (2005).
- Unpublished data from the Rob Peattie lab (Oregon State University) and S. Cai and B. Yu of the Glenn Prestwich (University of Utah) lab.