Implantable 3D printed encapsulation system with localized immunomodulation for cell transplantation

Cell-based therapy is increasingly important in modern medicine for the treatment of various diseases including those related to the endocrine system, central nervous system, as well as cancer and cardiovascular disease. Among the treatment options for the aforementioned diseases is organ transplantation, however the number of donors is not sufficient for patients waiting to receive an organ. Moreover, these patients are required to take immunosuppressants for the rest of their lives to prevent rejection. Another possible solution may be hormonal replacement therapies, but even these treatments are not sufficient to restore the metabolic interactions of hormones. Cellular encapsulation systems are one of the leading strategies to recover the function of organs. Stem cells, blood cells, and pancreatic islets are the most used cell types for this purpose. For cells to thrive in a suitable environment, they must receive continuous supply of oxygen and nutrients in order to reduce hypoxic stress on transplanted cell populations, and to support rapid engraftment and long term survival of cells. Another aspect to consider is the cellular source, as it is possible to use transplantation of autologous cells from the patient, harvested from organs, or derived from differentiated stem cells. Alternatively, the use of cells derived from another patient, allotransplantation, or from other species (xenotransplantation), may be beneficial. In this study, the development, characterization and in vivo evaluation of a novel encapsulation system for allotransplantation, named neovascularized implantable cell homing and encapsulation (NICHE), is presented. Fabricated using 3D printing technology, the NICHE supports cell viability and function of transplanted cells through direct vascularization which eliminates graft rejection and by achieving an effective local concentration of immunosuppressant, minimizes systemic drug exposure and the associated adverse effects. Importantly, the proposed system, allows for transcutaneous drug replenishment once the drug reservoir is depleted without requiring the substitution of the implant. Using in vitro analysis of drug release from the NICHE, we demonstrated constant delivery of CTLA4-Ig with retained drug stability and showed that this immunosuppressant did not interfere with cell viability or function. To validate the NICHE as a strategy for cell encapsulation with local immunosuppressant release, we performed subcutaneous implantation of the device followed by minimally invasive drug loading and transcutaneous transplantation of Leydig cells into the cell reservoir in a castrated Sprague Dawley rat model. We assessed device vascularization and engraftment capacity in terms of progesterone secretion and also examined systemic immunosuppressant exposure as well as device retrievability. Overall, we present the NICHE as a strategy for cell transplantation with immense potential for clinical translation.