Our Steps toward Subcutaneous Transplantation of Macro-Encapsulated Islets

Abstract

Background: Diabetes mellitus (DM) can be cured or greatly ameliorated by adequate insulin secretion from a relatively small volume of insulin-producing cells. Cell encapsulation enables allo- and even xeno-geneic cell therapy without immunosuppression. However, micro-encapsulated islets used in recent clinical trials are not fully retrievable after transplantation. By contrast, macro-encapsulated islets can be retrievable. As to the transplantation site, the subcutaneous tissue can be promising, if new strategy could overcome the hypoxic status due to hypovascularity. In this review article, we summarized the development of macro-encapsulated islets and approaches toward subcutaneous transplantation in our laboratory for more than two decades. Our results repeatedly showed that islets and encapsulated islets can be transplanted in various sites including subcutaneous tissue after pretreatment of neovascular induction. As to macro-encapsulation devices, our laboratory firstly developed mesh-reinforced poly-vinyl alcohol (PVA) hydrogel tube and bag and then, agarose-based encapsulation methods followed. After that, PVA macro-encapsulated islets were developed utilizing sol-gel transition of PVA solution through micro-crystallization induced by freezing and thawing. Recently, we took advantage of excellent histocompatibility of ethylene vinyl alcohol co-polymer (EVOH) to fabricate the highly porous EVOH bag. A unique macro-encapsulation device using thermo-sensitive chitosan-based gel in combination with EVOH bag was developed. Most recently, we found that slow release of hepatocyte growth factor (HGF) from the chitosan gel can protect islets against initial hypoxic status and subsequently induce neovascularization in subcutaneous tissue to exert islet function, eliminating the necessity of neovascularization pretreatment. Conclusions: Retrievable and replaceable macro-encapsulated islets that can be transplanted subcutaneously without pretreatment. Although further improvements may be necessary, this method may replace intraportal islet transplantation with immunosuppression in the near future.