Clinical islet transplantation (CIT), the infusion of allogeneic islets into the liver, has shown significant promise in the long-term treatment of Type diabetes by providing a cell-based means to mimic the normal physiological response to glucose. While promising, it is dampened by the impaired function and loss of islets following implantation. This loss is attributed to strong inflammatory and immunological responses to the transplant, primarily instigated by cell surface proteins and antigens. In this application, we see to minimize detrimental host responses that lead to islet engraftment failure by encapsulating the islets in novel ultrathin polymeric layers. Ultrathin coatings are generated through the covalent layer-by-layer assembly of biomaterials functionalized with bioorthogonal chemical handles. Through the controlled, covalent linking of polymers layers on the islet cell cluster surface, resulting stable capsules are on the order of 500-fold smaller than standard practices;thus, void volumes are dramatically reduced and nutritional transport and glucose sensing are unaffected. Further, the composition, structure, thickness, and function of these layers can be intricately controlled on the nanometer scale. Once fabricated, these ultrathin layers serve as ideal platforms for cell surface engineering, whereby bioactive motifs capable of dynamically interacting with implant-host interface can be tethered. As such, the inert biomaterial layer can be converted to a bioactive surface capable of actively altering the localized implant environment. We hypothesize that covalently stabilized, ultrathin coatings, generated via covalent layer-by-layer assembly, will enhance islet engraftment and functional duration by masking host recognition of surface antigens and proteins, without imparting limitations on nutrient or insulin diffusion. In addition, the tethering of bioactive agents capable of instructin immune responses will further enhance long-term survival of the transplanted islets. To test this hypothesis, biostable, covalently-linked, ultrathin coatings will be generated on the islet surface using biocompatible polymers capable of masking surface antigens and inflammatory proteins (Aim 1). Additionally, the surface of ultrathin coatings will be functionalized with immunomodulatory agents capable of directing host innate and adaptive immune responses at the transplant interface (Aim 2).
Aims will be evaluated both in vitro and in diabetic murine models. The design of effective strategies to build tailored nano-thin layers on the islet surface capable of expressing active immunomodulatory agents could significantly improve the efficacy and long-term stability of islet transplants in the absence of chronic, systemic immunosuppression.
The development of treatment options for insulin-dependent diabetics with islet cells, which provide physiological regulation of glucose, could result in dramatic improvements in quality of life, as well as a substantial decrease in disease management complications. Herein, we seek to develop a novel encapsulation approach that serves to minimize or eliminate the need for anti-rejection therapy following an islet cell transplant. As such, we believe this platform will serve to significantly enhance treatment options for insulin- dependent diabetics by minimizing the immuno-therapeutic drug load and enhancing long-term efficacy. We believe these studies are highly relevant to the mission of the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) and are designed to result in a significant impact on public health.
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