A therapeutic convection–enhanced macroencapsulation device for enhancing β cell viability and insulin secretion

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-09, Vol.118 (37), p.1-12
• Main Authors: Yang, Kisuk, O’Cearbhaill, Eoin D., Liu, Sophie S., Zhou, Angela, Chitnis, Girish D., Hamilos, Allison E., Xu, Jun, Verma, Mohan K. S., Giraldo, Jaime A., Kudo, Yoshimasa, Lee, Eunjee A., Lee, Yuhan, Pop, Ramona, Langer, Robert, Melton, Douglas A., Greiner, Dale L., Karp, Jeffrey M.
• Format: Article
• Language: English
• Subjects: Animals; Beta cells; Biological Sciences; Cell Encapsulation - methods; Cell Survival - drug effects; Cell viability; Convection; Design optimization; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Drug Delivery Systems - instrumentation; Drug Delivery Systems - methods; Fibrosis; Glucose; Glucose tolerance; Glucose transport; Hyperglycemia; Immunological tolerance; Immunosuppression; Insulin; Insulin - metabolism; Insulin secretion; Insulin Secretion - drug effects; Insulin Secretion - physiology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Islet cells; Islets of Langerhans - metabolism; Islets of Langerhans Transplantation - methods; Male; Nutrient transport; Pancreatic islet transplantation; Rats; Transplantation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2101258118

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.