A stepwise funnel selection approach identifying natural polymer-derived hydrogels for long-term islet delivery, restoring normoglycemia in type-1 diabetes

Transplantation of encapsulated islet cells can restore the normal physiological glycemic level in type-1 diabetic patients. However, the clinical rate of success of islet transplantation is limited by robust immune response, inadequate insulin release, and acute hypoxic stress. The physico-biochemical properties of an encapsulating hydrogel play an important role in successful islet transplantation, mitigating the challenges. Herein, we report a comprehensive screening of 20 different commonly available natural polymers based on their various physico-biochemical properties, ease of islet delivery (MIN6), and biological functioning. From the initial screening, the top four leads (alginate, pectin, agarose, and cellulose) were selected based on their long-term degradation, mechanical stability, and insulin release kinetics. Based on further <i>in vitro</i> assessment, pectin was identified as the lead polymer for the <i>in vivo</i> diabetes treatment study. Subcutaneous implantation of MIN6 (mouse beta pancreatic islet) encapsulated pectin hydrogel capsules restored and maintained normoglycemia for 60 days in both C57BL/6 (allogeneic) mice and Wistar rats (xenogeneic) in a streptozotocin-induced diabetic model, without the requirement of any external immunosuppressant. Furthermore, when pectin was used for encapsulation and delivery of isolated primary rat islets to diabetic C57BL/6 mice, it also restored normoglycemia within 3 days of transplantation in the xenogeneic setup and sustained it for 30 days. This study successfully identified a novel natural polymer, pectin, demonstrating potential for maintaining long-term islet viability <i>in vivo</i> and acting as an independent, promising platform for islet delivery in the management of type-1 diabetes.