Abstract
Islet microencapsulation through permselective hydrogels may improve safety and efficacy of transplantation, maintain immunoisolation, and offer metabolic control without chronic and systemic immunosuppression. Impaired transport of glucose/insulin and/or inflammatory responses by the host immune system to the capsules may decrease encapsulated islet functionality. I engineered a platform for immune isolation and modulation of pancreatic islets combining microencapsulation with targeted delivery of immunomodulatory drugs to increase their functionality after transplantation. I performed parallel evaluations of alginate single and double capsules (SC, DC) versus polyethylene glycol (PEG) conformal coating (CC) of human islets. With data obtained in silico and in vivo, I concluded that minimal capsule size is critical for metabolic control and improving the biocompatibility of CC grafts in the site of transplantation using localized and targeted immunomodulation may be beneficial to increase the efficacy of CC grafts. To improve CC biocompatibility, I tested anti-inflammatory dexamethasone (Dex) and cyclosporine A (CsA) loading efficiency and release kinetics in Drug-Integrating Amphiphilic Nanoassemblies (DIANA) and efficacy in decreasing inflammatory cytokine secretion by activated macrophages while maintaining islet functionality in vitro and in vivo. DIANAs loaded Dex increased water solubility by ~15 times and released it within 8 hours. nFIB localize in the site of inflammation when added locally, and nMIC target the graft after IV injection. Local and IV Dex- and CsA-DIANAs decreased inflammation three days post transplantation of CC grafts in mice. This approach can be applied to islet transplantation for improving CC biocompatibility providing optimal metabolic control without chronic systemic immunosuppression.