Avoiding Immunosuppression for Islet Transplantation: Use of Protective Biomaterials

Abstract

Islet transplantation, with the advent of the Edmonton protocol in 2000, has offered a significant alternative for long-lasting treatment of type 1 diabetes. However, the immunosuppression required for transplantation has the cytotoxic effect on pancreatic islets, and thus limiting the long-term efficacy of the transplant. Immediate loss of islets after transplant was also observed because of immediate blood-mediated inflammatory response (IBMIR), which kills islets transplanted in the liver through portal vein. There is also commonly a lack of microvascular blood supply to the transplanted islets. In this chapter, we will review the variety of technologies used to protect transplanted islets against toxicity of immunosuppression, immune rejection, and inflammatory response. We will evaluate the mechanisms of these technologies and their progress in solving the challenges to islet transplantation. The technologies include encapsulation of transplanted islets in various polymers, transplants in sites other than the liver, and creation of new prevascularized transplant site. These technologies offer several mechanisms to prevent immune rejection or immediate contact with cytotoxic inflammatory response, in addition to maintaining islet integrity. New transplant sites are also being developed to support the islets, by allowing establishment of microvasculature and innervation, prior to addition of the islets.

Approaches in Immunotherapy, Regenerative Medicine, and Bioengineering for Type 1 Diabetes

“…There is still much improvement needed for islet encapsulation engineering in order to optimize islet longevity. This includes parameters, such as co-encapsulation, protection against hypoxic stress, prevascularization, and good manufacturing practices ( 135 ). Furthermore, despite successes with encapsulated islet transplantation, it is necessary to continue studying optimal alginate composition as certain mixtures of alginate have been shown to stimulate fibrotic responses eventually leading to nullification of graft effectiveness ( 140 ).…”

“…Islets are highly sensitive cells, requiring a substantial amount of oxygen to function and survive. In order to accommodate this need, researchers have succeeded in transplanting islets into the portal vein ( 145 ) or pre-vascularizing transplant devices ( 135 ). To further improve oxygen supply to encapsulated islets, the angiogenic fibroblast growth factor 1 (FGF-1), was added to capsules to allow for the release of in vitro FGF-1 ( 146 ).…”

“…In another approach seeking to optimize the implantation of encapsulation devices, the subcutaneous region for implantation is prevascularized before transplanting the islets. By enhancing vascularization before transplanting the encapsulated islets first, the increased microvascularization should increase islet cell survival of the encapsulated islets due to their high demand for oxygen ( 135 ). Examples of this approach include the Theracyte device and Sernova Cell Pouch.…”

“…Other toxins that have been found include various other proteins and polyphenols ( 153 ). As a result, this can trigger the immune system against the encapsulated device graft and increased fibrotic overgrowth which prevents nutrient and waste diffusion within the site of the graft ( 135 ). The use of endotoxin-free substrates promotes cell survival, growth, and maturation ( 154 ), suggesting the necessity of using ultra-pure low viscous mannuronate alginate for improved islet transplantation outcomes.…”

High-Throughput Screening of Encapsulated Islets Using Wide-Field Lens-Free On-Chip Imaging

“…The lack of suitable human donor organs also leads to delays in treatment [4][5][6]. In order to overcome some of these issues, islet microencapsulation has been developed [7][8][9][10], which uses a biocompatible semipermeable polymer to encase the islets, forming microcapsules with a typical diameter in the range of a few hundred micrometers to over one millimeter [11]. The semipermeable membrane blocks the immune cells from attacking the implanted islets, while allowing nutrients and insulin to pass through.…”