Oxygen-Regulating MEMS Devices for Cell Transplantation to Cure Type 1 Diabetes

Citation

Shang, Kuang-Ming (2024) Oxygen-Regulating MEMS Devices for Cell Transplantation to Cure Type 1 Diabetes. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/xf5z-0p34. https://resolver.caltech.edu/CaltechTHESIS:05212024-231923059

Abstract

Type 1 diabetes is an autoimmune disease in which immune cells specifically attack and destroy the insulin-producing beta cells in the pancreatic islets that regulate blood glucose levels. Traditionally managed with frequent injections of exogenous insulin, beta cell replacement therapy—also known as islet transplantation—has emerged as an alternative clinical option. Recently, the focus has shifted toward subcutaneous islet transplantation, offering a promising and minimally invasive therapy. However, the survival of transplanted islets has been shown to be significantly challenged by hypoxia-induced graft loss stemming from inadequate oxygen supply.

To address this issue, we have developed innovative hollow mesh devices that regulate oxygen. These devices can either bring oxygen from the adjacent oxygen-rich tissue or draw additional oxygen from ambient air to improve oxygen delivery to the hypoxic microenvironment of islet grafts. Fabricated using MEMS techniques and biocompatible materials, these devices feature a network of unobstructed air-containing microchannels. Utilizing the property that oxygen diffuses 10,000 times faster in air than in interstitial fluids, these devices effectively overcome oxygen supply barriers when co-transplanted with islet grafts. By integrating these hollow meshes with the islet grafts, oxygen can be rapidly redistributed throughout the graft, establishing local oxygen balance and regulation. This approach significantly reduces hypoxia-induced graft loss and improves the efficacy of post-transplant blood glucose regulation in recipients.

In this thesis, we first delved into the physiology of oxygen transport within an islet, establishing the critical oxygen threshold necessary for islet cell survival. We developed equivalent circuit models for oxygen diffusion and constructed oxygen-regulating hollow mesh MEMS devices based on these models. We investigated the effects of oxygenation through both computational models and benchtop experiments. Finally, using our device, we demonstrated enhanced survival of islet grafts in diabetic rodent models, successfully achieving a long-term cure for diabetes.

With the preclinical success of this oxygen-regulating hollow mesh in mitigating cellular oxygen deficiency, we also explored and proposed future pathways toward clinical effectiveness. Our device holds significant therapeutic potential to revolutionize clinical outcomes in islet transplantation with the ultimate goal of curing type 1 diabetes.