Vascularizing and Degradable Hydrogel for Subcutaneous Islet Transplantation

Kinney, Sean M. (1, 2), Vlahos, Alexander E. (2), Mahou, Redouan (2), Sefton, Michael V. (1, 2) 

(1) Department of Chemical Engineering and Applied Chemistry

(2) Institute of Biomaterials & Biomedical Engineering

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β-cells found in pancreatic islets. Islet transplantation is an improved treatment option for T1D due to the inherent ability of the delivered islets to predict, measure, and respond to changing blood glucose levels in ways that artificial systems can only approximate. Although islet transplantation is a promising option, the invasiveness of transplantation (typically portal vein infusion) and host immune responses result in a significant loss of transplanted islets. Less invasive sites such as the subcutaneous space are more practical, however they do not have the vasculature required to support islet transplants. Methacrylic acid (MAA) based biomaterials have been shown to generate blood vessels and modulate the host’s inflammatory response. We hypothesized that degradable MAA-based hydrogels could be used to deliver islets to the subcutaneous space and allow direct integration into host tissues to rectify diabetes in an immunocompromised SCID beige (SCID/bg) mouse. In this work, MAA-based hydrogels containing rat islets were able to lower the blood glucose levels of diabetic SCID/bg mice with greater efficacy than PEG hydrogel controls. Islets delivered in the degradable MAA gel were subject to the initial host immune response resulting in animals with higher blood glucose levels than those with islets delivered in the non-degradable MAA gel. Although animals in the non-degradable MAA group were normoglycemic, they were unable to resolve an IP glucose tolerance test within two hours. This delayed response is likely due to the diffusion gradient between islets suspended in the gel and the nearest blood vessel. In contrast, islets delivered in the degradable gel that survived the initial immune response were able to integrate into the host vasculature as shown by intra-islet blood vessels. It is expected that slowing the degradation rate such that the MAA-induced effect and physical hydrogel barrier can completely mitigate the initial inflammatory response would increase viability of delivered cells while still allowing integration for improved long-term function. These pilot results show that MAA based hydrogels have the potential to make minimally invasive subcutaneous islet delivery a feasible treatment for T1D.