Survival of encapsulated islets: More than a membrane story

Abstract

At present, proven clinical treatments but no cures are available for diabetes, a global epidemic with a huge economic burden. Transplantation of islets of Langerhans by their infusion into vascularized organs is an experimental clinical protocol, the first approach to attain cure. However, it is associated with lifelong use of immunosuppressants. To overcome the need for immunosuppression, islets are encapsulated and separated from the host immune system by a permselective membrane. The lead material for this application is alginate which was tested in many animal models and a few clinical trials. This review discusses all aspects related to the function of transplanted encapsulated islets such as the basic requirements from a permselective membrane (e.g., allowable hydrodynamic radii, implications of the thickness of the membrane and relative electrical charge). Another aspect involves adequate oxygen supply, which is essential for survival/performance of transplanted islets, especially when using large retrievable macro-capsules implanted in poorly oxygenated sites like the subcutis. Notably, islets can survive under low oxygen tension and are physiologically active at > 40 Torr. Surprisingly, when densely crowded, islets are fully functional under hyperoxic pressure of up to 500 Torr (> 300% of atmospheric oxygen tension). The review also addresses an additional category of requirements for optimal performance of transplanted islets, named auxiliary technologies. These include control of inflammation, apoptosis, angiogenesis, and the intra-capsular environment. The review highlights that curing diabetes with a functional bio-artificial pancreas requires optimizing all of these aspects, and that significant advances have already been made in many of them.

Keywords: Bio-artificial pancreas, Diabetes, Islets of Langerhans, Encapsulation, Oxygen supply, Permselective membrane, Transplantation

Core tip: Replacing standard insulin therapy for patients with type I diabetics with a cell-based cure is yet to be achieved. Assuming unlimited supply of beta cells, allogeneic or xenogeneic cells should be separated from the host immune system by a permselective membrane that still allows insulin egress. In addition, a mandatory requirement for such a cure in a poorly oxygenated environment includes adequate oxygen supply. In addition, to optimize islet functionality, control over inflammation, cell apoptosis, angiogenesis, and the close environment of the transplanted cells must be accomplished.