There exists a critical need for new therapeutic approaches to treat ischemic cardiovascular diseases, and neovascularization will likely be a critical component of these therapies While most pre-clinical and clinical efforts to promote neovascularization in cardiovascular diseases have focused on bolus delivery of proangiogenic growth factors, these approaches may be limited by potential side-effects and the inability of single growth factors to promote the formation of a mature and stable vasculature. The hypothesis underlying this proposal is that one may rapidly promote the formation of mature vascular network in an ischemic lower limb by the localized delivery of an appropriate combination of blood-vessel forming cells and growth factors using biodegradable polymer carriers. This hypothesis will be addressed by fabricating three-dimensional porous scaffolds from poly (lactide-co-glycolide) (PLG) that are capable of the localized and sustained delivery of combinations and sequences of angiogenic molecules (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF], and transforming growth factor-beta [TGF-beta). Neovascularization induced from sustained delivery of each factor alone, as contrasted with combination or sequential delivery of the factors will be analyzed in a subcutaneous mouse implant model. Secondly, the ability of differentiated endothelial cells and endothelial cell precursors, both mouse and human-derived, to form new networks of blood vessels and integrate with host vasculature will be evaluated following pre-culture and implantation using the 3-D porous scaffolds. Finally, these cell types will be transplanted into ischemic hind limbs of mice using scaffolds releasing the combination of growth factors found to lead to optimal host vascular cell response. In these last studies, mice that mimic human critical limb ischemia will be utilized. Successful completion of these studies may lead to new approaches in therapeutic angiogenesis (e.g., delivery of combinations of growth factors and blood vessel forming cells). In addition, the systems developed in these studies may provide novel and important model systems to study a variety of developmental processes dependent on the signaling of multiple growth factors.
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