Purpose: Islet transplantation is a promising therapy for diabetes; however, its success remains limited by poor engraftment efficiency and immune rejection. This study evaluates microporous annealed particle (MAP) gel as a supportive scaffold to enhance engraftment and function of dissociated murine islets in a syngeneic model, with potential applications for stem cell-derived beta-cell therapy.
Methods: Dissociated islet cells from C57BL/6 mice were mixed with MAP gel and transplanted into syngeneic streptozotocin-induced diabetic recipients at the kidney capsule or epididymal fat pad. Blood glucose levels were monitored daily. In additional studies, MAP or nanoporous (NP) gels were implanted with or without Beta TC-6 cells in non-diabetic mice. Cytokine profiles were assessed at days 7 and 14 post-transplantation. A pilot study with human islets (800 or 400 IEQ) was performed at the subcutaneous (SC) site using MAP gel.
Results: In streptozotocin-induced diabetic C57BL/6 mice, transplantation of 100 dissociated islets combined with MAP gel under the kidney capsule restored normoglycemia (BG <200 mg/dL) within 18 days, with glycemic control maintained for at least 40 days. In contrast, dissociated islets transplanted without MAP gel failed to reverse hyperglycemia. In a syngeneic model using the epididymal fat pad as the transplant site, a pilot study with 400 dissociated islets combined with MAP gel resulted in normoglycemia for up to 44 days in two mice, whereas MAP gel alone, whole islets alone, or dissociated islets alone did not restore normoglycemia. In a more recent cohort (n=6), the same transplant strategy led to rapid glycemic control and prolonged islet function for up to 70 days post-transplantation, further supporting MAP gel’s role in enhancing islet engraftment and survival. A pilot xenogeneic study using human islets transplanted at the subcutaneous (SC) site demonstrated MAP gel’s potential across species. Mice receiving 800 IEQ human islets with MAP gel exhibited the most significant glucose reduction, while those receiving 400 IEQ showed a moderate effect. In contrast, control groups remained persistently hyperglycemic. Glucose fluctuations in MAP-supported groups indicated active islet function. Beyond engraftment, MAP gel also displayed immunomodulatory effects. Cytokine profiling at 7 days post-implantation of 1 million Beta TC-6 cells mixed with MAP or nanoporous (NP) gels showed that MAP gel significantly reduced pro-inflammatory cytokines, including IFNγ, IL-6, IL-1α, IL-1β, IL-10, IL-17, and TNFα. Notably, IL-10 levels were significantly decreased in the MAP group, suggesting a shift toward a less inflammatory microenvironment conducive to islet survival.
Conclusions: These results highlight MAP gel as a promising platform for beta-cell replacement therapy, capable of improving transplantation efficiency, modulating local immune responses, and enhancing long-term glycemic control.