A Harvard Stem Cell Institute (HSCI) led collaboration developed a new macroencapsulation device (MED) that protects the insulin-producing cells of the pancreas and enhances their survival with improved nutrient supply.
More than 40 million people worldwide are affected with Type 1 diabetes (T1D) mellitus, an autoimmune disease in which insulin producing β-cells in the pancreas are destroyed by the immune system. Among the emerging treatment methods are MEDs — compartments designed to house and protect insulin-secreting cells while allowing passage of nutrients. But MEDs have several limitations and scaling up such devices for use in humans has been challenging. As reported in The Proceedings of the National Academy of Sciences, researchers from HSCI, Brigham and Women’s Hospital, and the University of Massachusetts Medical School have designed a convection-enhanced MED (ceMED), which can continuously bathe cells in the nutrients they need and improve cell loading capacity, while increasing cell survival, glucose sensitivity, and timely insulin secretion. In preclinical models, the ceMED rapidly responded to blood sugar levels within two days of being implanted.
“Thanks to recent advances, we’re getting closer and closer to having an unlimited source of β-like cells that can respond to glucose by secreting insulin, but the next challenge is getting those cells into the body in a way that’s minimally invasive and will have longevity with maximal function,” said corresponding author and Harvard Stem Cell Institute (HSCI) Principal Faculty Jeff Karp, PhD, principal investigator and Distinguished Chair in Clinical Anesthesiology, Perioperative and Pain Medicine at Brigham and Women’s Hospital. “Our device demonstrated enhanced cell viability and minimal delay following transplantation. It’s a strong preclinical proof of concept for this system.”
Current MEDs are diffusion dependent — nutrients diffuse across the outer membrane of the device and only a number of cells may receive nutrients and oxygen and, in turn, secrete insulin. The ceMED was designed to provide convective nutrients through a continuous flow of fluid to the encapsulated cells, allowing multiple layers of cells to grow and survive. The team’s prototype features two chambers — an equilibrium chamber (EqC) that collects nutrients from the surroundings and a cell chamber (CC) that houses the protected cells. The EqC is enclosed in polytetrafluoroethylene — a semi-permeable membrane with pores that allow fluids in. An additional inner membrane surrounding the CC selectively allows for nutrient transport and protects against immune responses. Perfused liquids flow through a porous hollow fiber reaching the CC at a similar concentration of nutrients as the tissue surrounding the implant. The hollow fiber allows insulin and glucose to freely pass but does not allow key immune molecules in that could attack the encapsulated cells.
“The application of stem cell-derived islets to treat autoimmune or Type 1 diabetes has now moved to the point of finding a method to protect the cells from immune rejection and maximizing their survival and function following transplantation,” said co-author Doug Melton, PhD, of the Department of Stem Cell and Regenerative Biology and Co-Director of HSCI. “Convection-enhanced macroencapsulation may well be a viable approach to achieve all of these goals.”
The device offers many advantages over conventional insulin pumps and allows cells to secrete insulin on demand and quickly stop secreting insulin as blood glucose levels decline. In rodent models of Type 1 diabetes, the ceMED enhanced the survival and insulin secretions of cells and began to decrease blood glucose level as early as two days post-transplantation.
“Overall, these results highlight significant advantages of ceMED over existing diffusion-based devices including improved cell survival, reduced fibrous encapsulation that can compromise functionality over time, and quicker on and off rates for insulin secretion” said Karp. “This approach has the potential to enhance the success of β cell replacement therapies to help many T1D patients and their families manage this challenging disease.”
Funding: This work was supported by the Juvenile Diabetes Research Foundation (3-SRA-2013-282), and the National Institutes of Health (R01 grant HL095722 and U01DK104218), and the Incheon National University Research Grant in 2021.
Paper cited: Yang K et al. “A Therapeutic Convection Enhanced Macroencapsulation Device for Enhancing β Cell Viability and Insulin Secretion” PNAS DOI: 10.1073/pnas.2101258118