Introduction: Cell-based therapies are a promising option for many chronic conditions however, the need for immunosuppression, invasive surgery, and the inability to monitor, retrieve or replace cells is a major obstacle. We developed a subcutaneously implanted artificial interstitium device that eliminates the need for immunosuppression, advantages a xenogeneic cell source, and permits percutaneous access for loading, reloading, biopsy and graft recovery. The silicone construct-based Cell-Safe (CS) and Cell-Safe Hybrid (CS-h) devices exploit the innate hydrostatic/osmotic gradient to generate autologous ultrafiltrate that brings oxygen and nutrients to transplanted cells and to remove waste products using convective flow. Here we demonstrate the capability of these devices to support porcine islets in nonhuman primates (NHPs) without immunosuppression.

Methods: Proof-of-concept studies in nonhuman primates (NHPs) were performed to evaluate immunoprotection and suitability of ultrafiltrate as a medium to sustain islet viability and function. CS devices were surgically implanted subcutaneously in seven NHPs and percutaneously loaded with variable density porcine islets (30,000-350,000 IEQ) ± hydrogel to resemble an extracellular matrix environment. Serial graft biopsies were performed to characterize ultrafiltrate, assess C-peptide levels, and for histologic evaluation of islets.

Results: Ultrafiltrate is chemically similar to serum with paO2 levels >60mmHg. Pro-inflammatory cytokine levels were stable in ultrafiltrate and periphery. There was no evidence of cellular infiltrate on histological analysis at any timepoint.  In 60% of transplants C-peptide was detectable and positive for 180d with corresponding reduction in HbA1c and biopsied islets were strongly insulin positive.

Conclusion: Artificial interstitium is a novel and easily accessible implant site for cell transplant. The CS and CS-h harnesses convective mechanisms to create a microenvironment with adequate oxygen and nutrients capable of supporting relatively fragile porcine islet cells. This approach prevents systemic inflammation after transplant of xenogeneic cells and there was no evidence of rejection in non-immunosuppressed NHPs.  The CS and CS-h overcome conventional barriers to macroencapsulation, especially removing the requirement for immunosuppression in a xenogeneic setting and enabling easy reloading in the situation of exhausted cells, to dramatically increase the longevity of therapeutic benefit and accessibility of cell-based therapies.