Islet transplantation has the potential to be the first real cure for type-1 diabetes. The Edmonton Protocol's success in 2000 excited the community immensely, but follow-up work demonstrating its limitations and failures tempered those feelings. Islets are vulnerable post-isolation and current transplantation methods cause the loss of up to 2/3 of islets within days. This has lead to a massive islet requirement for every recipient. Apoptosis and inadequate revascularization are major contributors to this loss and the effectiveness of a hepatic transplant site has been repeatedly questioned. The aims of this proposal will investigate microporous protein-delivering scaffolds as a novel biomaterials-based approach to extrahepatic islet transplantation and how they can be used to minimize islet loss and maximize transplant success. In distinct contrast with the majority of biomaterials-based approaches to date, which have utilized islet encapsulation, these scaffolds encourage islet engraftment, tissue infiltration and revascularization. They provide a tunable 3D support architecture and most notably, can locally deliver protein factors to the islet microenvironment over time. These scaffolds enable the exploration of a range of islet support architectures and the delivery of several proteins for manipulating the islet microenvironment. In vitro experiments will study the impact of these variables on islet function, survival and apoptosis independent of host tissue effects. In vivo transplantation in a murine model of type-1 diabetes will be used to investigate the effects of scaffold architecture and protein delivery on islet function, survival, apoptosis and revascularization in the context of host tissue, where infiltration and revascularization play important roles to reveal processes limiting, and mechanisms underiying transplant success. Future studies can utilize these findings and optimizations to promote islet transplantation in larger animals or non-human primates, providing the basis for translating this novel approach to the clinic. Type-1 diabetes is a life-long disease with near-inevitable complications that are responsible for significant morbidity and mortality. The shortcomings of current islet transplantation protocols prevent application to the vast majority of diabetes patients. The proposed aims have the potential to significantly improve islet transplantation in two ways;by providing a platform for fundamental studies of the physical and chemical cues important to islets in a transplant setting, and by demonstrating a new extrahepatic transplantation model that minimizes islet loss and maximizes islet function.