Objective: Islet allotransplantation gains encouraging clinical outcomes using the hepatic portal vein as the standard infusion method. This infusion technique is responsible for significant graft loss due to immediate coagulopathy and long-term immune destruction. Furthermore, shortage of human organ donors limits its application. To solve these problems, we tested a new implantation site, i.e. the retro-peritoneal retro-colic space for the transplantation of encapsulated xenogeneic islets into diabetic mice.

Method: We synthesized an anti-biofouling balanced charged hydrogel combining alginate plus poly-ethylene-imine (PEI), a zwitterionic material, for the encapsulation of either SD rat or wild type neonatal porcine islets (Figure 1). Transplantation was performed into the retroperitoneal retro-colic space of diabetic C57BL/6J mice. Control mice received rat or neonatal pig islets free without encapsulation, or encapsulated islets into the peritoneum. Following transplantation, none of the recipient received any immunosuppression. To allow differentiation of neonatal porcine islets, recipient mice received low dose of insulin injection for 30 days. The biochemical indexes were measured at regular intervals until sacrifice, where transplanted islets were harvested for immunohistochemical staining of insulin, glucagon, TUNEL and cleaved caspase-3.

Result: Mice receiving 400 encapsulated rat islets and 500 encapsulated porcine islets transplanted into the retroperitoneal space maintained normal glycemia for a mean of 267days (range 263-272, n=4) and 133 days (range 123-147, n=4), respectively. In contrast, encapsulated rat islets and porcine islets transplanted into the peritoneum, maintained function for a mean of 66 days (range 58-63, n=4) and 46 days (range 42-53, n=3), respectively. For the transplantation site, P is lower than 0.05 for comparison of rat islets and P is lower than 0.05 for comparison of porcine islet. Xenogeneic islets transplanted free of encapsulation into the retroperitoneal space or the peritoneum lost their function within 3 days after transplantation (P<0.05). Immunohistochemical staining of the harvested islets and surrounding tissue at day 60 showed for rat and porcine islets normal healthy β and α cell (Figure 2). In contrast, free islets harvested after rejection showed death of β cells at the inner part of the islets, marked by the staining of TUNEL and cleaved caspase-3.

Conclusion: Transplantation of encapsulated xenogeneic islets to the retroperitoneal space provides a new implantation strategy for the treatment of type 1 diabetes and should be tested in large animal models.