Encapsulated Islet Transplantation: Where Do We Stand?

Abstract

Transplantation of pancreatic islets encapsulated within immuno-protective microcapsules is a strategy that has the potential to overcome graft rejection without the need for toxic immunosuppressive medication. However, despite promising preclinical studies, clinical trials using encapsulated islets have lacked long-term efficacy, and although generally considered clinically safe, have not been encouraging overall. One of the major factors limiting the long-term function of encapsulated islets is the host's immunological reaction to the transplanted graft which is often manifested as pericapsular fibrotic overgrowth (PFO). PFO forms a barrier on the capsule surface that prevents the ingress of oxygen and nutrients leading to islet cell starvation, hypoxia and death. The mechanism of PFO formation is still not elucidated fully and studies using a pig model have tried to understand the host immune response to empty alginate microcapsules. In this review, the varied strategies to overcome or reduce PFO are discussed, including alginate purification, altering microcapsule geometry, modifying alginate chemical composition, co-encapsulation with immunomodulatory cells, administration of pharmacological agents, and alternative transplantation sites. Nanoencapsulation technologies, such as conformal and layer-by-layer coating technologies, as well as nanofiber, thin-film nanoporous devices, and silicone based NanoGland devices are also addressed. Finally, this review outlines recent progress in imaging technologies to track encapsulated cells, as well as promising perspectives concerning the production of insulin-producing cells from stem cells for encapsulation.

The journey of islet cell transplantation and future development

“…47 Macroencapsulation involves encapsulating multiple islets within a device >1mm diameter and is usually placed in an extravascular space. 48 The use of macroencapsulation dates back to the 1950's when Algire, Prehn, and Weaver transplanted thyroid tissue within a device made of lucite rings, membrane filters, and lucite-acetone seal. 49,50 Several studies demonstrate islet cell survival within macroencapsulation devices in mice, but translation to larger animals or humans is often limited by fibroblastic overgrowth around the device.…”

“…Islet Sheet Medical developed a flat sheet device made of ultra-thin biocompatible polymer which showed early promise in small animal models, but failed to be replicated in larger animal studies. 48 The concept of macroencapsulation has been around for several decades, but is still plagued by cell survival challenges as cells are cut off from physiologic gaseous and nutrient exchange. Ongoing studies will help to define the utility of such approaches with the hope that transplants could be conducted without need for chronic immunosuppression.…”

“…57 Alternative microencapsulation materials have been explored, including polyethylene glycol, poly methyl methacrylates, alginate, agarose, or chitosan. 48,58 In one study, Vegas et al maintained normoglycemic for 174 days and suppressed perivascular overgrowth in mice. 59 Human islets have heterogeneous diameters ranging from <50-500mm, and manufacturing a microencapsulation system that accommodates this range has proven to be a challenge.…”

Pig Islet Transplant

“…The capsules have been studied in various materials and sizes. There are three main sizes: macro, micro, and nano [20,21]. The macro-capsule is used to seal islets in centimeter-order devices, which are easy to handle and can be removed and replaced.…”

Conformal Coating of Stem Cell-Derived Islets for β Cell Replacement in Type 1 Diabetes

“…The goal of islet encapsulation is to provide cells with a physical semi-permeable barrier that prevents infiltration of immune cells while allowing smaller molecules such as oxygen, nutrients, glucose, and insulin to diffuse freely through the capsule. Despite efforts so far, encapsulated islets have failed to maintain physiological insulin secretion in vitro (Buchwald et al, 2018) and grant long-term insulin independence in the clinical setting (Calafiore and Basta, 2014;Shimoda and Matsumoto, 2017;Vaithilingam et al, 2017).…”