Engineering a Translatable, Retrievable Islet Transplant Site with Microporous Scaffolds to Treat Type 1 Diabetes

Abstract

Clinical islet transplantation has long been investigated as a potential cure for type 1 diabetes, yet the standard intrahepatic approach leaves islets prone to an aggressive inflammatory response and necessitates systemic immunosuppression. Herein, we investigated microporous poly(D,L-lactide-co-glycolide) (PLG) scaffolds for extrahepatic islet transplantation in a nonhuman primate (NHP) model. Acellular scaffolds did not elicit an undesirable inflammatory response in the omentum, and in three diabetic NHP transplant recipients we observed signs of islet survival, despite not achieving euglycemia. However, we observed fragility of irradiated scaffolds during seeding and implantation, motivating us to increase the PLG:NaCl ratio used in manufacturing to 1.25:30 w/w. These scaffolds exhibited no differences in porosity or interior geometry between sterilization conditions, and transplants in mice restored glycemic control. We therefore conducted a pilot study of the modified scaffold in a fourth NHP, and although the integrity of the scaffold was improved, there was no improvement in transplant outcomes. Thus, we tested two intermediate PLG:NaCl ratios in mice, finding that a 1.15:30 ratio achieved an optimal balance of mechanical stability and islet compatibility. Overall, this investigation  demonstrates the adaptability of the scaffold for improvement of islet transplant outcomes and future clinical translation.