| Despite recent breakthroughs in the fields of drug delivery and tissue engineering, clinically applicable vascularization therapies for treatment of ischemic tissue or support of engineered tissue implants remain unrealized. Development of such therapies would facilitate the treatment of over 10 million people suffering from peripheral arterial disease and over 100,000 waiting on the organ transplant list in the United States, plus countless others worldwide. Molecular therapies for vascularization have proven ineffective in numerous clinical trials, and cellular therapies, while demonstrating promising potential, share common and, as of yet, unaddressed shortcomings, especially significant apoptosis of transplanted cells. The goal of this project was to test the hypothesis that utilizing molecular therapy to prevent apoptosis and promote cell survival and interaction with the host microenvironment would enhance the therapeutic benefit of cell-based therapeutic vascularization. To do so, a novel growth factor delivery system was developed and optimized for delivery of vascular endothelial growth factor (VEGF), a key molecule in vascular development. When controlled, sustained VEGF delivery was integrated with a previously developed protein gel vehicle for endothelial cell (EC) transplantation, a synergistic effect was observed resulting in increased survival of transplanted EC and improved reperfusion kinetics and functional recovery in a hindlimb ischemia model. The delivery system was further adapted to deliver monocyte chemoattractant protein-1 (MCP-1), a chemokine known to induce recruitment of monocytes and enhance arteriogenic remodeling. Controlled delivery of MCP-1 resulted in improved outcomes for biomaterial vascular grafts in vivo . Further, it was demonstrated that VEGF and MCP-1 could be concurrently delivered from protein gel constructs for EC transplantation, laying the groundwork for a dual delivery system with the potential to both improve survival of - and induce rapid host cell remodeling and interaction with - transplanted EC. The results described herein support the utility of molecular delivery approaches to enhance cell therapy towards an ultimate outcome of improved therapeutic vascularization as both a treatment for ischemia and the basis for the next generation of tissue engineering therapies. |
