(68h) Macroporous Polymer Scaffolds for the Transplantation of Embryonic Stem Cell Derived Beta-Cell Progenitors to a Clinically Translatable Site for the Treatment of Type I Diabetes

Type I diabetes mellitus, which affects an estimated 1.5 million Americans, is caused by autoimmune destruction of the pancreatic beta cells that results in the need for life-long insulin therapy. Although insulin therapy has been successful, hypoglycemic events and vascular complications persist. Allogeneic islet transplantation for the treatment of type I diabetes is a therapy in which donor islets are infused intrahepatically, which has led to the transient reversal of diabetes. However, allogenic transplantation has several therapeutic limitations, which include a shortage of donor islets, long-term immunosuppression, and high risk of tissue rejection. All of these limitations have led to the investigation of embryonic or induced pluripotent stem cells as an unlimited source of functional beta-cells. The ability to differentiate embryonic stem cells into pancreatic progenitors in vitro, with subsequent maturation to beta-cells in vivo has been demonstrated; however, these systems are not implemented in a manner that is clinically translatable. Therefore, our group has developed biomaterial scaffolds that support the in vivo maturation of pancreatic progenitors into mature beta-cells at an extrahepatic site that is clinically translatable (omentum). We have previously reported on the ability of microporous poly(lactide-co-glycolide) (PLG) scaffolds to create an environment that supports long-term function of islets at an extrahepatic site, and reversal of diabetes with a minimal islet mass. Herein, we propose to investigate the modification of both PLG scaffolds with extracellular matrix proteins, such as collagen, and the delivery of trophic factors, such as Exendin-4, to promote the in vivo development of human embryonic stem cell (hESC) derived pancreatic progenitors into mature insulin producing beta-cells. Our studies have demonstrated that PLG scaffolds support the differentiation to insulin producing cells, and that sustained exendin-4 delivery significantly increased C-peptide production and improved glycemic control compared to scaffolds without Exendin-4. In conclusion, the goal of this research is to develop a platform on which hESC-derived pancreatic progenitors can be seeded and implanted into a clinically translatable site, such as the omentum, that will allow for efficient maturation of the cells into a population that can reverse diabetes.