Enhancing Subcutaneous Islet Transplantation via a Defined Prevascularized Niche within a 3D Bioengineered Platform

Type 1 diabetes (T1D) is a chronic autoimmune disease that in 2022 affected approximately 8.75 million individuals worldwide. T1D is characterized by the loss of pancreatic beta-cells responsible for producing insulin, a fundamental hormone that regulates blood glucose levels. Patients with T1D require lifelong insulin replacement through multiple daily insulin injections or insulin pump therapy. However, these therapies don’t fully restore glycemic control and don’t prevent T1D long-term complications such as neuropathy, retinopathy, kidney disease, stroke, macrovascular problems and foot damage. Pancreatic islet transplantation has emerged as a promising therapy; however, its clinical deployment via portal vein infusion triggers an immediate inflammatory response that hinders its curative potential. The subcutaneous space offers a safer, more accessible alternative, but challenges including hypoxia-driven islet loss and the need for an abundance of cells to achieve efficacy remain, together with the need for systemic immunosuppression. To address these limitations, the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device offers a prevascularized subcutaneous platform designed to support the viability and function of transplanted islets and to offer localized immunosuppressant delivery for islets rejection prophylaxis. This study focuses on optimizing the NICHE device through the integration of a 3D printed rigid space keeper during the prevascularization phase. Temporarily implanted within the device, the space keeper facilitates the formation of a defined cavity by directing vascularized tissue growth around it. This defined space promotes broader distribution of islets and enhances their survival, potentially allowing for effective transplantation with a reduced islet load. The device is fabricated using biocompatible materials that promote tissue integration and allow easy removal of the space keeper without damaging surrounding structures. In vitro studies were conducted to optimize the device design and to evaluate mechanical properties of the different employed materials, while in vivo studies in diabetic rats assessed in-situ vascularization and islet engraftment, achieving T1D reversal. Results showed that prevascularization with the space keeper generates a defined space lined with neovessels, enhancing islet dispersion into a supportive microenvironment. Additionally, blood glucose measurements demonstrated sustained normoglycemia following islet transplantation. Furthermore, analysis of the tissue within the device revealed a reduced infiltration of inflammatory cells following transplantation using the space-keeping design, compared to the previous device in which islets were loaded via simple injection. In parallel, in vitro studies of the adopted materials revealed interesting cell adhesion properties related to their surface roughness. This pre-vascularization strategy addresses key barriers associated with subcutaneous islet transplantation, positioning the NICHE device as a promising platform for more effective cell-based therapies for T1D.