A team of researchers from Brigham and Women’s Hospital, Harvard University, and the University of Massachusetts Medical School has designed a convection-enhanced macroencapsulation device (ceMED) that could significantly improve β cell replacement therapies to help many T1D patients.
The 3D geometry of the capsule enables transplanted, insulin secreting β islet cells encapsulated in the cartridge to continuously bathe in nutrients, improving the number of cells that can be accommodated in each capsule and increasing their survival, glucose sensitivity, and insulin secretion.
The findings are reported in the article, “A Therapeutic Convection Enhanced Macroencapsulation Device for Enhancing β Cell Viability and Insulin Secretion,” published in The Proceedings of the National Academy of Sciences this week.
Burdening millions worldwide, type 1 diabetes involves autoimmune destruction of pancreatic β cells. Patients are typically treated with life-long insulin injections or immunosuppressive agents following transplantation of β cells.
Emerging treatments for type 1 diabetes include macroencapsulation devices (MEDs). MEDs act as a bioartificial pancreas. Like protective armor on a knight, MEDs guard transplanted β cells from the recipient’s immune defenses while allowing the unhindered flow of nutrients.
However, conventional MEDs rely solely on diffusion. This limits the number of cells that can be housed in the capsule and slows glucose-stimulated insulin secretion (GSIS). Scaling up the use of MEDs for humans has been challenging.
The authors of the current study noted, “We demonstrate that the ceMED significantly improves nutrient exchange that enhances cell viability and GSIS, ultimately leading to a rapid reduction of hyperglycemia.” In preclinical models, the authors demonstrate that the ceMED responds 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 Jeffrey Karp, PhD, principal investigator, distinguished chair in clinical anesthesiology, perioperative, and pain medicine, and corresponding author on the paper. “Our device demonstrated enhanced cell viability and minimal delay following transplantation. It’s a strong preclinical proof-of-concept for this system.”
Diffusion allows movement across the outer membrane in current MEDs so that only a limited number of cells receive nutrients and oxygen and, in turn, secrete insulin. The ceMED provides a continuous flow of fluid to the encapsulated cells, allowing multiple layers of cells to grow and survive.
The prototype includes two chambers—an equilibrium chamber that collects nutrients from the surroundings and a cell chamber that houses the protected cells. The equilibrium chamber is enclosed in polytetrafluoroethylene—a semi-permeable membrane with pores that allow fluids in. An additional inner membrane surrounding the cell chamber selectively allows nutrient transport and protects against immune responses.
Porous hollow fibers allow fluids to reach the cell chamber such that the nutrient concentration in the cell chamber matches that in the tissue surrounding the implant. The hollow fibers allow insulin and glucose to pass freely but stop immune molecules that could attack the encapsulated cells.
“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.”
“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 Doug Melton, PhD, co-director of the Harvard Stem Cell Institute and co-author of the paper. “Convection-enhanced macroencapsulation may well be a viable approach to achieve all of these goals.”
The device allows β 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 increased survival and insulin secretion of cells and began to decrease blood glucose levels within two days of transplantation.
“The ceMED device has the potential to be an autonomous system that would not require constant refilling and replacement of insulin cartridges,” said Kisuk Yang, PhD, a former postdoctoral fellow in the Karp Lab and now faculty at the division of bioengineering at Incheon National University in Soul Korea, and who is first author on the paper.
“Due to its responsiveness, this device and novel flow-enhanced approach could be particularly useful for ‘brittle’ diabetics, people whose diabetes results in unpredictable swings in blood sugar levels,” said Eoin O’Cearbhaill, PhD, a co-author who helped develop this concept while working as a postdoctoral fellow in the Karp Lab.
The team noted, that to bring the device to the clinic, the cell loading capacity must be scaled up and the perfusion flow system optimized for human use, in future studies.
Financial support for the work came from the Juvenile Diabetes Research Foundation, the National Institutes of Health, and Incheon National University.