Project Summary Type 1 diabetes (T1D) is an autoimmune disease that, in the U.S., affects 1.6 million people, amasses $16 billion in annual healthcare expenses, and annually rises in prevalence by 64,000 new diagnoses. Clinical islet transplantation (CIT), which is infusion of islets through the hepatic portal vein, has shown promise as a T1D treatment. However, only 50% of recipients maintain insulin independence at five years and the procedure is currently limited to a marginal subset of T1D patients, in part due to two major limitations: instant blood- mediated inflammatory reaction and delayed vascularization of islets (>14 days). A significant loss of delivered islets – 60-80% – occurs within hours to days following transplantation in the intrahepatic site. Therefore, there is a significant need to establish an alternative transplant site that avoids instant blood- mediated inflammatory reaction and supports the long-term engraftment of islets. The subcutaneous site is an attractive extrahepatic site with high clinical potential in terms of accessibility, convenience, ability to re-dose (if necessary), ease of monitoring, and ease of retrieval (if necessary). However, the unmodified subcutaneous site is clinically limited due to inadequate vascular perfusion and, as a result, inadequate metabolic kinetics and low oxygenation. An elegant, facile strategy to promote neovascularization is the biomaterial- mediated delivery of proangiogenic factors such as vascular endothelial growth factor (VEGF). VEGF promotes the growth of endothelial cells and is a major regulator of native islet vascularization and development. The objective of this project is to engineer injectable VEGF-delivering synthetic poly(ethylene glycol) [PEG] hydrogels that promote islet vascularization, engraftment, and function in the subcutaneous space. We have previously engineered VEGF-containing hydrogels that promote islet survival, vascularization, and function in the rodent gonadal fat pad and omentum, sites with high inherent vascularization. My central hypothesis is that the VEGF-delivering gel can be further optimized to promote islet vascularization, engraftment, and function in the subcutaneous space, a site with high clinical potential. My preliminary data support this hypothesis and provide strong scientific premise and feasibility for this application. The overall objective will be accomplished across three specific aims: 1) Identify VEGF-PEG hydrogel formulations that optimally support islet vascularization using a vascularized islet-on-a-chip platform; 2) Evaluate the ability of VEGF-PEG hydrogels to promote allogeneic islet vascularization, engraftment, and function in diabetic rats; and 3) Examine the ability of VEGF-hydrogels to promote allogeneic islet vascularization and engraftment in the subcutaneous space of non-diabetic pigs. Expected outcomes for this project include: 1) An injectable delivery vehicle for islets that promotes islet vascularization, en...