Clinical islet transplantation, the intraportal infusion of allogeneic pancreatic islets into a diabetic recipient, is a promising treatment for type 1 diabetes; however, the success of clinical islet transplantation is hindered by the location of the implant site, which is prone to mechanical stresses, inflammatory responses, exposure to high drug and toxin loads, and irretrievability of the transplanted islets. The development of devices to house islets at alternative transplant sites may alleviate many of these issues. Structural support to the islets in the form of a scaffold is critical to reducing pelleting and agglutination of the islets, which results in decreased availability of nutrients to the islets, leading to cell death. In this study, we sought to design and develop a highly porous silicone scaffold with the goals of maximizing nutrient delivery by creating a structure that supports and spatially distributes the islets, as well as promotes vascular infiltration. Macroporous scaffolds were fabricated from highly biocompatible, biostable silicone using the solvent casting and particulate leaching technique (SCPL). Pore size and degree of porosity were individually controlled by varying the particle size and polymer to particle ratio, respectively. Prior to cell loading, scaffolds were steam sterilized and coated in adhesion proteins for enhanced cell adhesion. Preliminary findings in our laboratory evaluated spatial distribution, viability, and function of both rodent, non-human primate, and human islets within the scaffolds. In vivo studies assessed biocompatibility and stability of the silicone scaffolds, as well as vascular infiltration. The results of this study suggest silicone scaffolds represent an opportunity for transplanting islets at extrahepatic sites. Future in vivo studies will evaluate the efficacy of silicone scaffolds at restoring euglycemia in diabetic small animal models.