<p>It is estimated that 1 in 500 Americans are inflicted with type I diabetes (T1D) with approximately 18,000 children and adolescents diagnosed each year. Islet/β cell replacement with long-lasting glucose-sensing and insulin-releasing functions has the potential to eliminate the need for insulin injections and minimize complications for individuals with T1D. However, limitations remain precluding it from widespread clinical use, including i) limited donor supply, ii) significant loss of functional islet mass upon transplantation, iv) limited functional longevity, and v) need for life-long systemic immunosuppression. To restore glucose-responsive insulin-release back to the patient’s body without the need for systemic immunosuppression, our approach involves a subcutaneous injection using a novel fibril-forming biologic, type I oligomeric collagen (Oligomer). Oligomer protects and in situ encapsulates replacement cells beneath the skin by transitioning from a liquid to a stable collagen-fibril scaffold, within seconds, just like those found in the body’s tissues. Preclinical validation studies in streptozotocin-induced diabetic mice show that replacement of islets at a dose of 500 or 800, results in a rapid (within 24 hours) reversal of hyperglycemia. All animals receiving syngeneic islets maintained euglycemia for beyond 90 days, while >80% of animals receiving allogeneic or xenogeneic (rat) islets remained euglycemia for at least 50 days. Histopathological analysis of Oligomer-islet implants showed normal morphology with no apparent evidence of a foreign body response and immune cell infiltrate. To our knowledge, this is the first report of an injectable subQ islet transplant strategy that yields rapid lowering and extended glycemic control without systemic immunosuppression.</p>

<p>Type 1 Diabetes Mellitus (T1D), a chronic disease affecting over 1.5 million Americans, is characterized by the autoimmune destruction of insulin-producing β-cells within pancreatic islets. Islet/β-cell replacement therapies, where replenishable β-cell sources are implanted within protective microenvironments, have the potential to provide a long-term solution for individuals with T1D by restoring glucose-sensitive, insulin release and overall glycemic control. However, most conventional encapsulation materials elicit an immune reaction, known as a foreign body response (FBR), which compromises β-cell health and function. In this dissertation, we designed and evaluated various formulations of a polymerizable collagen, namely type I oligomeric collagen (Oligomer), as encapsulation materials for minimally invasive, subcutaneous delivery of replacement β-cells. Preclinical validation in chemically-induced diabetic mice demonstrated rapid (within 24 hours) reversal of diabetes for beyond 90 days with no signs of rejection or FBR after subcutaneous delivery of both allogeneic and xenogeneic (rat) islets. To further define this uncommon mechanism of protection, the tissue response to Oligomer, in comparison to commercial synthetic and collagen-based materials, was evaluated following subcutaneous implantation within rats, a well-established biocompatibility model. Histological and transcriptomics analyses were used to define the immune response at both cellular and molecular levels. Interestingly, Oligomer showed minimal and transient activation of innate immune cells similar to the sham surgical control, with no evidence of foreign body giant cell formation, inflammatory-mediated bioresorption, or fibrosis. Overall, this work evaluates preclinical efficacy and demonstrates mechanistic understanding of immune tolerance for Oligomer materials for β-cell replacement therapy and other regenerative medicine applications.</p>