Petit Institute for Bioengineering and Bioscience
Georgia Institute of Technology
Engraftment and function of microfluidic PEG-encapsulated islets in a highly vascularized alternative transplant site
Jessica Weaver1, Devon M Headen1, Andres J Garcia1.
1Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States
Type 1 diabetes affects millions worldwide, and treatment is typically limited to exogenous insulin injections, which improves life expectancies and quality of life, but cannot prevent secondary complications of the disease. Islet transplantation is a promising alternative therapy that can potentially restore native insulin signaling, but its widespread application is hindered by a hostile transplant site, and compounded immune and autoimmune responses that result in short graft lives and necessitate life-long systemic immunosuppression. Islet encapsulation aims to modulate the host immune response, reducing or eliminating the need for systemic immunosuppression, by preventing the cell-to-cell contact required to initiate direct antigen recognition.
Encapsulation of allogeneic islets has demonstrated promise by prolonging graft rejection in diabetic rodent models; however, the excess material imparted by traditional alginate microcapsule diameters (600-1000 μm) can produce a diffusional delay of nutrients and insulin through the capsule, and the increased graft volume limits encapsulated islet transplantation to the intraperitoneal (IP) space. These complications, compounded by the limited proximity of islets to vasculature in the IP site, necessitate larger numbers of islet equivalents (IEQ) for diabetes reversal, an additional barrier to the translation of a therapy that already faces pancreatic donor shortages.
We hypothesized that reduced capsule size would allow encapsulated islet delivery to an alternative transplant site, providing greater proximity to vasculature and thereby reducing the required islet loading for diabetes reversal. Additionally, the use of a highly controlled and tunable synthetic hydrogel encapsulation system allows for the optimization of the islet microenvironment for enhanced engraftment and function. To that end, we engineered a microfluidics-based islet encapsulation platform using a defined and highly tunable polyethylene glycol (PEG) hydrogel system to produce smaller capsules than traditional methods (200-400 μm), with minimal impact on islet viability and function, as evaluated by live/dead imaging and metabolic and glucose stimulated insulin response assays. We evaluated the capacity of PEG-encapsulated islets, transplanted in the alternative epididymal fat pad (EFP) site, to restore euglycemia in a diabetic murine model using a single syngeneic pancreatic donor (500-600 IEQ). To deliver islets to the transplant site, unmodified or encapsulated islets were dispersed in a vasculogenic, proteolytically degradable PEG hydrogel and wrapped in the EFP. Blood glucose and body weight was monitored for 100 days, where comparable reversal times were observed in encapsulated (31 ± 11 days) and control groups (40 ± 21 days), and an intraperitoneal glucose tolerance test at 100 days confirmed comparable function in both groups. Histological evaluation of explanted grafts demonstrated minimal inflammatory response to capsules, and both groups exhibit insulin-positive islets with proximal CD31-positive blood vessels at 100 days post-transplant.
This study demonstrates the feasibility of encapsulated islet engraftment and function in a highly vascularized alternative transplant site using a single pancreatic donor. Future studies will explore the ability of this system to prevent or delay graft rejection in an allogeneic model.
Juvenile Diabetes Research Foundation (2-SRA-2014-287-Q-R). National Institute of Health ILET2 Training Grant (T90-DK097787-03).
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 Headen et al. Adv Mater. 2014; 26:3003-8
 Phelps et al. Biomaterials. 2013; 34: 4602-11
11:00 - 12:30
|Cellular Encapsulation||Engraftment and function of microfluidic PEG-encapsulated islets in a highly vascularized alternative transplant site||Room 111-112|