A Novel Device for Islet Transplantation Providing Immune Protection and Oxygen Supply

Abstract

Islet transplantation as a biological β-cell replacement therapy has emerged as a promising option for achieving restoration of metabolic control in type 1 diabetes patients. However, partial or complete loss of islet graft function occurs in relatively short time (months to few years) after implantation. The high rate of early transplant dysfunction has been attributed to poorly viable and/or functional islets and is mediated by innate inflammatory response at the intravascular (hepatic) transplant site and critical lack of initial nutrient/oxygen supply prior to islet engraftment. In addition, the diabetogenic effect of mandatory immunosuppressive agents, limited control of alloimmunity, and the recurrence of autoimmunity limit the long-term success of islet transplantation. In order to abrogate instant blood-mediated inflammatory reaction and to provide oxygen supply for the islet graft, we have developed an extravascular (subcutaneous) transplant macrochamber (the 'βAir' device). This device contains islets immobilized in alginate, protected from the immune system by a thin hydrophilized teflon membrane impregnated with alginate and supplied with oxygen by daily refueling with oxygen-CO (2) mixture. We have demonstrated successful utilization of the oxygen-refueling macrochamber for sustained islet viability and function as well as immunoprotection after allogeneic subcutaneous transplantation in healthy minipigs. Considering the current limitations of intraportal islet engraftment and the restricted indication for islet transplantation mainly due to necessary immunosuppressive therapy, this work could very likely lead to remarkable improvements in the procedure and moreover opens up further strategies for porcine islet cell xenotransplantation.

Transplantation of bovine adrenocortical cells encapsulated in alginate

“…We compared the transplantation of enBACs alone into immune-competent Wistar rats with the transplantation of BACs in an immune-isolating device that has already been used successfully to transplant pancreatic islets of Langerhans without the use of immunosuppressive drugs. This device has been used both in animal models (5,10,14,23) as well as in a patient suffering from diabetes type 1 (7). enBACs in all groups of adrenalectomized animals were functional, replaced corticosteroids, and rescued the animals from the lethal effect of adrenalectomy.…”

“…Sodium alginate is one of the clinically approved immunoisolating biopolymers; it has already been widely used in a variety of biomedical applications (5)(6)(7)(8)(9)(10). Alginates have several unique structural and chemical parameters, appropriate not only for immune isolation but also for the creation of 3D cellular scaffolds that allow artificial organs to function long term in vitro and in vivo (7,8,11).…”

“…Placing of xenogeneic material inside isolating devices provides additional protection from graft-host interaction. In this study, we used oxygenated immune-isolating devices, which have already undergone successful testing in the transplantation of islets of Langerhans with the goal to treat diabetic patients (5,7,10,14,23). Here, we performed a pilot study to determine the possibility of adapting this device for transplantation of enBACs.…”

Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials

“…Limiting or eliminating the hypoxic period between implantation and the development of a fully functional, intradevice, vascular network would dramatically reduce hypoxia-induced cell death and permit for more clinically translatable devices. Such methods include prevascularization of the transplant site (12), hastening vascularization through the delivery of growth factors (13,14), incorporation of oxygen carriers within biomaterials (15), or the in situ generation of supplemental oxygen (16)(17)(18)(19). In situ oxygen generation is a highly desirable approach, in that it does not require multiple surgeries and provides supplemental oxygen immediately upon implantation.…”

“…In situ oxygen generation is a highly desirable approach, in that it does not require multiple surgeries and provides supplemental oxygen immediately upon implantation. Various agents have been investigated for their oxygen-generating potential, from the electrochemical decomposition of water to the photosynthesis of microalgae to the use of oxygen chambers (18)(19)(20). Although all these agents highlight the potential of in situ oxygen generation to enhance cell viability, most of these complicate the transplant site by increasing the size of the implantable device and/or possibly introducing toxic by-products.…”