Introduction: Hydrogels have emerged as promising biomaterials for regenerative medicine. We have engineered poly(ethylene glycol) [PEG]-maleimide hydrogels that support improved pancreatic islet and stem cell functionalities, engraftment, vascularization and function in diabetic models.

Methods: For vasculogenic gels, PEG-maleimide was modified with RGD adhesive peptide and VEGF and delivered in situ by crosslinking with a proteolytically degradable peptide [1]. Gels that supported high vascularization were used to deliver either syngeneic islets to immunocompetent diabetic mice or human stem cell-derived islets to diabetic immunodeficient mice. For immunomodulatory materials, hydrogel particles (microgels, 200 μm dia) were fabricated [2]. Biotinylated microgels were functionalized with a chimeric form of Fas ligand (SA-FasL) and used for co-transplantation with islets in allogenic studies. Biotin-functionalized microgels without the chimeric ligand were used as controls. As a prelude to studies with human cells, allogeneic pancreatic islets were co-delivered with SA-FasL-presenting microgels + short rapamycin treatment into diabetic mice or non-human primates.

Results: Two biomaterial strategies have been pursued. We have developed proteolytically degradable synthetic hydrogels, functionalized with vasculogenic factors for localized delivery, engineered to deliver pancreatic islets or human stem cell-islets to extrahepatic transplant sites via in situ gelation. These hydrogels induce differences in vascularization and innate immune responses among transplant sites. This biomaterial-based strategy improves the survival, engraftment, and function of a single pancreatic donor islet mass graft compared to the current clinical intraportal delivery technique. In a second application, we have developed a localized immunomodulation strategy using hydrogels presenting an apoptotic form of Fas ligand (SA-FasL) that results in prolonged survival of allogeneic islet grafts in diabetic mice. Survivors generate normal systemic responses to donor antigens, implying immune privilege of the graft, and have increased T-regulatory cells in the graft. Notably, allogeneic islet grafts exhibited long-term performance in diabetic non-human primates in the absence of systemic immunosuppression. This localized immunomodulatory biomaterial-enabled approach may provide an alternative to chronic immunosuppression for clinical islet transplantation.

Conclusion:  Hydrogel-based strategies to promote islet engraftment and vascularization as well as local immune acceptance in diabetic models have been established. These strategies may significantly impact islet transplantation as a treatment for type 1 diabetes.