Implantable platform with in-situ vascularization and localized immunosuppression for allogeneic cell transplantation.

Abstract

Allogeneic islet transplantation for diabetes management faces the challenge of preventing immune rejection while maintaining enough graft oxygenation for proper metabolic function. Islet encapsulation within membranes impermeable to immune cells prevents rejection at the expense of optimal graft oxygenation. Conversely, direct vascularization avoids hypoxia but requires systemic administration of toxic immunosuppressive drugs. To overcome this problem, we developed the subcutaneously implantable NICHE platform, which integrates in situ graft vascularization and local immunosuppressant delivery, for long-term islet engraftment. NICHE, 3D-printed in nylon, is comprised of independent drug and cell reservoirs separated by a nanoporous membrane. The membrane allows steady local diffusion of immunosuppressant from the drug reservoir into the cell reservoir. Enhanced NICHE vascularization was assessed using mesenchymal stem cells (MSC) and platelet rich plasma (PRP) in rats and non-human primates (NHP). Tunability of antibody and peptide release from NICHE was tested in vitro. Transplantation of allogeneic islets into prevascularized NICHE with localized co-delivery of anti-lymphocyte serum (ALS) and CTLA4Ig was evaluated in immunocompetent diabetic rats. NICHE loaded with MSC had dense vascularity within the cell reservoir by 4 weeks of subcutaneous implantation in rats and NHP. In vitro drug release was tuned via modification of membrane exchange area and drug concentration loaded. In diabetic rats, localized co-delivery of ALS and CTLA4Ig protected allogeneic islets, resulting in reversal to euglycemic state for at least 60 days. Transplanted rats with NICHE responded to glucose challenge comparable to healthy controls and had significantly higher c-peptide levels than no-implant diabetic controls, demonstrating full graft function. ALS-CLTA4Ig co-delivery via NICHE localized drug at the transplant site with limited accumulation in plasma and peripheral tissues, avoiding potential toxicity. Moreover, circulating lymphocyte population remained intact, indicating rats were not systemically immunosuppressed. NICHE is an effective platform for islet allotransplantation with promising adaptability for use with other cell types and pathologies.