Introduction By 2045 the number of adults living with type I diabetes is projected to increase to 783 million. Current guidelines recommend exogenous insulin replacement therapy, which entails significant adverse effects and inhibiting cost. Surgical transplantation of insulin-producing pancreatic cells has been proposed as a potential lasting curative treatment for diabetes. Current techniques are fraught with post operative complications and life-long immunosuppression. There is a persistent need for a reliable platform that can facilitate pancreatic tissue transplantation without these limitations. Here, we present our novel Arterio-Venous Graft Rx (AVGRx) which sustains both stem-cell derived beta cells (SCDßCs)and human pancreatic tissue viability and function in vivo in a large animal porcine host without immune suppression.

Methods The AVGRx contains a treatment zone that is shielded from the host immune cells while facilitating contact with the host arterial blood stream for nutrient and hormone exchange. Adult male Yorkshire pigs were obtained for graft implantation. The common carotid artery and distal external jugular vein were surgically exposed, and an end-to-side anastomosis with both graft ends was performed. The AVGRx treatment zone was then injected with either SCDßCs or human pancreatic islets. No immunosuppression was administered. 1-, 2- and 3-weeks post implantation, the porcine host was injected with a 500mg/kg dextrose injection, and blood was collected to measure human insulin using ELISA. To evaluate cell morphology post-explantation, SCDßCs were evaluated using Nkx (beta cell marker), C-peptide (terminal insulin sequence) immunofluorescence. Following explantation, purified human islets were exposed to 2mM and then 20mM glucose solutions. Their supernatant was collected, and human insulin concentrations were measured.

Results Quantification of cellular markers demonstrated unchanged cell count of Nkx (p=0.12) or C-peptide (p=0.13) positive cells between weeks 0, 1 and 2. Compared to baseline insulin secretion, post-explanted human islets demonstrated similar insulin secretion in both low (p=0.68) and high (p=0.31) glucose concentration solutions. Following dextrose bolus, human insulin was detected in vivo each week for three weeks during graft implantation. Conclusion

Conclusion The AVGRx is a novel means to reliably sustain implanted xenograft cells without the need for immunosuppression. SCDßCs and human pancreatic islets were observed to have maintained viability within porcine models for up to 21 days. These findings demonstrate the ability of the AVGRx to interface its payload with a host’s arterial blood supply while also protecting it from a immune response. The AVGRx platform may have a major impact on the future of islet transplant therapy.