Islet dosing and loading density in injection molded macroencapsulation devices

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PROJECT SUMMARY/ABSTRACT: Clinical islet transplantation is a promising alternative therapy for the treatment of type 1 diabetes, with the potential to reduce or eliminate secondary complications and adverse events. The potent immune response to islets remains the greatest challenge to long-term engraftment and function, which necessitates large numbers of islets and typically multiple pancreatic donors to achieve euglycemia, a complication further exacerbated by donor shortages. Methods to eliminate graft rejection in the absence of chronic systemic immunosuppression will vastly expand the eligible patient population and reduce risks associated with cell therapy. Islet encapsulation within a nondegradable biomaterial has long been proposed as a means for reducing immune response to transplanted grafts via a physical barrier to direct antigen recognition by immune cells, with decades of promising research in preclinical studies; however, translation of this technique has been hampered by poor clinical outcomes and safety concerns. As such, macroencapsulation devices for islet encapsulation have been explored in preclinical and clinical studies, and though they confer the safety benefit of a single, retrievable device, functional success of these devices has been limited due in large part to poor oxygen transport. Addressing these specific limitations facing macroencapsulation devices, we use computational modeling-guided device design for improved oxygen transport, and degradable hydrogel-guided enhanced vascularization at the device surface to further maximize oxygen access and mitigate fibrosis. We recently developed a hydrogel injection molding-based method to generate high surface area to volume hydrogel macroencapsulation geometries, a method that enables surgeons to generate encapsulated islets in the clinic upon receipt of cadaveric primary islet isolations. This method is highly reproducible, works with diverse hydrogels, and simple to implement. In this Phase I SBIR application, we will investigate the optimal islet density within macroencapsulation devices in syngeneic studies and identify the optimal allogeneic islet dosage required for diabetes reversal to inform Phase II studies in preclinical large animal allogeneic studies. This will be addressed in the experiments of the following Specific Aims: (1) Syngeneic islet density optimization in a macroencapsulated diabetic rat omentum transplant model, and (2) Allogeneic islet dose optimization in a macroencapsulated diabetic rat omentum transplant model. The expected outcome is that these studies investigating islet density and dosage within high surface area to volume macroencapsulation designs will identify the appropriate configuration to advance to phase II preclinical large animal models.