Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats

Abstract

Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.

Hydrogel-Composited Laminate for Islet Immune-Isolation to Treat Type 1 Diabetes

“…The semiopen structure of laminates may be further developed to balance the immunoprotection and the nutrient supply to ensure the long-term efficacy of encapsulated islets. On the one hand, host tissues, especially vascular tissues, connected with the circulatory system of the body should be integrated in the devices to sustain the engraftment of the islets. , Prevascularization at the implant sites would be a favorable and practical solution to this problem. ,− Besides, as the concept of local immunomodulation or immunosuppression has drawn growing attention in β-cell therapy, − design of incorporation of functional cells or drugs that could mitigate the immune clearance against β cells in the devices would probably further improve the success of cell therapy in T1D. To this end, when drugs or cells with local immune-suppression function are incorporated and the implant site is prevascularized, the laminate with cell-penetrable edges and gaps in the semiopen structure may favor the in-growth of vascular tissues, which would benefit the long-term engraftment of the islets.…”

Advances in the Use of Biologics and Biomaterials toward the Improvement of Pancreatic Islet Graft Survival in Type 1 Diabetes

“…A recent example is the neovascularized implantable cell homing and encapsulation (NICHE) device, which demonstrated long-term graft survival and diabetes reversal in allogenic subcutaneous transplants using rats and NHPs. [122] The device can be implanted before cell seeding to allow for prevascularization and provides an opportunity for direct subcutaneous injection of therapeutic drugs into the device for local immunomodulation, as demonstrated in the study with an immunosuppressive drug cocktail (CTLA4Ig and rabbit antilymphocyte serum for rats and anti-thymocyte globulin, CTLA4Ig, and anti-CD154 for NHPs). A comprehensive review regarding local immunomodulation for cell therapies can be found in the review article by Nash et al [123] and specifically in the context of islet transplantation in the article by Wang et al [28b] The co-encapsulation of support cells for improved islet function is another innovative approach to improve some of the shortcomings associated with macroencapsulation devices, particularly the issues with lack of vascularization and fibrosis/immune cell infiltration.…”

Current Advances in Immunomodulatory Biomaterials for Cell Therapy and Tissue Engineering

“…Also, they verified PA's suitability as a material for NICHE construction, integration, and vascularization. [ 88 ]…”