(57b) Long Term Glycemic Control Using Polymer Encapsulated, Human Stem-Cell Derived β-Cells in Immune Competent Rodents

Introduction: Host recognition and subsequent foreign body responses are a series of immune-mediated reaction that impacts the performance of implanted biomedical devices. Immune cell recognition of biomaterial surfaces initiate a cascade of inflammatory events that result in the fibrous and collagenous encapsulation of foreign materials. This encapsulation, over time, can lead to device failure and discomfort for the recipient. These adverse outcomes emphasize the critical need for biomaterials that do not elicit foreign body responses to overcome this key challenge to long-term biomedical device function. We have developed rapid, combinatorial methods for covalent chemical modification and in vivo evaluation of superbiocompatible alginate based hydrogels for prolonged protection and immunoisolation of transplanted cells/tissue. One prime example for the utility of this technology is for the development of a bioartificial pancreas for the treatment of patients suffering from diabetes.

Diabetes is a global epidemic afflicting over 300 million people. While a rigorous regimen of blood glucose monitoring coupled with daily injections of exogenous insulin remains the leading treatment for type-1 diabetics, patients still suffer ill effects due to the challenges associated with daily compliance. The transplantation of donor tissue, either in the form of a pancreas transplantation or infusion of cadaveric islets, are currently implemented clinically as one strategy to achieve insulin independence for type 1 diabetics. This approach has been limited due to two major drawbacks: 1) the limited supply of available donor tissue, and 2) the adverse effects associated with a lifetime of immunosuppression. Recently, the in vitro differentiation of human pluripotent stem cells (hPSCs) into functional pancreatic β-cells has been reported, providing for the first time a path to produce an unlimited supply of human insulin-producing tissue. The immunoisolation of insulin-producing cells with porous biomaterials to provide an immune-barrier is one strategy to overcome the need for immunosuppression. However, clinical implementation has been challenging due to host immune responses to implant materials. Here, we report the first long term glycemic correction of a diabetic, immune-competent animal model with human SC-β cells encapsulated using a novel superbiocompatible chemically modified alginate formulation.

Materials and Methods:  Using a combinatorial synthesis and high-throughput screening strategies we evaluated a large library of chemically modified alginate hydrogel formulation for in vivo biocompatibility. Lead formulations was used for encapsulate SC-β cells and further evaluated for ability to provide long-term glycemic correction and glucose-responsiveness in immune competent diabetic mice. To ensure proper biocompatibility assessment in our studies we used an immunocompetent streptozotocin-induced diabetic C57BL/6 mouse model for our study, because this strain is known to produce a strong fibrotic and foreign body response similar to observations made in human patients

Results and Discussion: Here, we develop rapid, combinatorial methods for covalent chemical modification and in vivo evaluation of one of alginate based hydrogels. SC-β cells were encapsulated with novel, alginate-derivatives capable of mitigating foreign body responses in vivo. Devices implanted into the intraperitoneal (IP) space induced glycemic correction in streptozotocin-treated (STZ) C57BL/6J mice until removal at 174 days without any immunosuppression. Human c-peptide and in vivo glucose responsiveness demonstrate therapeutically-relevant glycemic control. Retrieved implants revealed viable insulin-producing cells after 174 days in immune-competent mice. 

Conclusions:  The combinatorial synthesis and screening strategy presented here provide a potential roadmap for the identification of next generation biomaterials, which can mitigate the foreign body response and improve the long-term fidelity of implanted devices. Using our lead hydrogel formulation we have shown that encapsulated SC-β cells can achieve glucose-responsive, long-term glycemic correction (174 days with the mice still euglycemic at the end of the experiment) in an immune-competent diabetic animal with no immunosuppression. This formulation provided sufficient immunoprotection to enable long-term glycemic correction, in spite of the xenogeneic stimulation that these human cells manifest in an immunocompetent rodent recipient. We believe that encapsulated human SC-β cells have the potential to provide for insulin independence for patients suffering from type 1 diabetes.