Review
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplant. Mar 24, 2016; 6(1): 69-90
Published online Mar 24, 2016. doi: 10.5500/wjt.v6.i1.69
Survival of encapsulated islets: More than a membrane story
Uriel Barkai, Avi Rotem, Paul de Vos
Uriel Barkai, Avi Rotem, Beta-O2 Technologies, Rosh HaAyin 4809900, Israel
Paul de Vos, Department of Pathology and Medical Biology, Immunoendocrinology, University of Groningen, 9700 RB Groningen, The Netherlands
Author contributions: Barkai U, Rotem U and de Vos P wrote the paper.
Conflict-of-interest statement: Barkai U and Rotem A are employees of Beta-O2 Technologies; de Vos P has no financial conflicts of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Uriel Barkai, PhD, Beta-O2 Technologies, 11 Amal St, POB 11793, Rosh HaAyin 4809900, Israel. u.barkai@beta-o2.com
Telephone: +972-03-9180700 Fax: +972-03-9180701
Received: August 24, 2015
Peer-review started: August 27, 2015
First decision: September 28, 2015
Revised: November 2, 2015
Accepted: December 18, 2015
Article in press: December 20, 2015
Published online: March 24, 2016
Processing time: 206 Days and 22.9 Hours
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.