期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：37
DOI：10.1073/pnas.2101258118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic β cells and it burdens millions worldwide. T1D patients typically require the life-long administration of insulin or immunosuppressive agents following transplantation. A macroencapsulation device (MED) acts as a bioartificial pancreas and can immunoprotect encapsulated β cells. However, conventional MEDs suffer from limited, cell-loading capacity and slow, glucose-stimulated insulin secretion (GSIS) because of the sole reliance on diffusion. Here, we developed a convection-enhanced MED (ceMED) to afford 3D capsule geometry for maximized cell loading and faster GSIS driven by convection. Overall, we demonstrated that the ceMED significantly improves nutrient exchange that enhances cell viability and GSIS, ultimately leading to a rapid reduction of hyperglycemia.
Islet transplantation for type 1 diabetes treatment has been limited by the need for lifelong immunosuppression regimens. This challenge has prompted the development of macroencapsulation devices (MEDs) to immunoprotect the transplanted islets. While promising, conventional MEDs are faced with insufficient transport of oxygen, glucose, and insulin because of the reliance on passive diffusion. Hence, these devices are constrained to two-dimensional, wafer-like geometries with limited loading capacity to maintain cells within a distance of passive diffusion. We hypothesized that convective nutrient transport could extend the loading capacity while also promoting cell viability, rapid glucose equilibration, and the physiological levels of insulin secretion. Here, we showed that convective transport improves nutrient delivery throughout the device and affords a three-dimensional capsule geometry that encapsulates 9.7-fold-more cells than conventional MEDs. Transplantation of a convection-enhanced MED (ceMED) containing insulin-secreting β cells into immunocompetent, hyperglycemic rats demonstrated a rapid, vascular-independent, and glucose-stimulated insulin response, resulting in early amelioration of hyperglycemia, improved glucose tolerance, and reduced fibrosis. Finally, to address potential translational barriers, we outlined future steps necessary to optimize the ceMED design for long-term efficacy and clinical utility.
