Title: Islet encapsulation for transplantation: nano- versus micro-encapsulation
Funder: Juvenile Diabetes Research Foundation

Abstract: Despite the potential of islet transplantation to offer a cure for Type 1 diabetes there remain major obstacles to its widespread adoption. For the most part these problems are directly or indirectly related to interactions between the donor islet graft and the immunologically dissimilar host environment. This imposes a clinical requirement for life-long immunosuppression, which is not without clinical risk, and so limits islet transplantation as the treatment of choice to a small sub-set of people with Type 1 diabetes in which the benefits of improved control outweigh the risks of life-long immunosuppression. Widespread adoption of islet transplantation is also currently limited by the scarcity of human donor islet tissue. This could be avoided by xenotransplantation of pig islets but the hyperimmune reaction between pig islets and the human immune system rapidly destroys unprotected islets. These problems could be alleviated by maintaining a biocompatible barrier between the islet graft and the host environment. This project will explore a novel mechanism for generating and maintaining such a barrier. Islet encapsulation strategies to date have mainly focused on large, gel-based capsules. These are effective in hiding the encapsulated islets from the host immune system but the relatively large capsule size causes survival problems for the islets, and places a physical limit on where they can be implanted. For example, their size excludes implanting them in the blood supply to the liver, which is the current route of choice for clinical islet transplantation. We have developed a method for coating islets with very thin (nanometer thick) layers of charged molecules, and of forming intact capsules around the islets by applying multiple layers of the coating (nanoencapsulation). The coating does not affect the survival or function of the islets and they are able to sense change in glucose and to secrete appropriate amounts of insulin. Our initial studies have shown that nanoencapsulated islets can reverse experimental diabetes in a mouse model, and suggest that the nanoencapsulation protects the islets from being rejected by the host immune system. In addition to shielding the islets from the host immune system, the nanocapsules can be modified to deliver drugs or other biological molecules to protect the islets after implantation in the host, and so improve survival of the islet in the important post-transplantation period. Our preliminary experiments demonstrate that incorporating anti-inflammatory molecules into the nanocapsules helps to protect the islets from deleterious stimuli. In this project we will optimize the methods for coating the islets with multiple nanolayers, and for incorporating biologically active molecules into the capsule. We will then test whether nanoencapsulation of human and porcine islets protect them from graft rejection by the host, and from the autoimmune destruction that occurs in Type 1 diabetes.


Research activity codes: 5.4 SURGERY
Health categories: METABOLIC AND ENDOCRINE