Predicting Insulin Secretion Profiles for Immunoisolating Devices with Transplanted Islets

Abstract

Avascular islets or stem cells transplanted under immunoisolating conditions offer considerable hope in overcoming the challenges of islet transplantation; however, because of diffusional limitations, implants face long-term viability and efficiency-of-response problems. To quantitatively characterize the glucose-stimulated insulin release of pancreatic islets, we conducted parallel dynamic perifusion experiments with free and hydrogel encapsulated islets. Perifused human islets secreted less insulin than murine islets per unit mass (IEQ) and had a less pronounced first-phase peak. The data was used to develop a computational model of insulin secretion. Our model couples hormone secretion and nutrient consumption kinetics with diffusive and convective transport, fits well the experimental data, and can be used to predict insulin release profiles for arbitrary geometries and glucose challenges. We found that larger diffusion distances (larger capsules) unavoidably dampen the first-phase insulin response, resulting in a sustained-release type insulin secretion that sluggishly responds to changes in glucose concentration. Hence, bioartificial pancreas devices can provide long-term and physiologically desirable solutions only if immunoisolation and biocompatibility considerations are considered together with optimized nutrient diffusion and insulin release characteristics. Disclosure P. Buchwald: None. A.A. Tomei: Consultant; Self; EyePharma. Research Support; Self; Semma Therapeutics, Inc.. Stock/Shareholder; Self; Converge Biotech Pvt. Ltd.. C.L. Stabler: None.