Research Project
10276561
PROJECT SUMMARY/ABSTRACT: Clinical islet transplantation is a promising treatment for insulin-dependent diabetic patients, with the potential to eliminate long-term secondary complications by restoring native insulin signaling. While clinical successes have demonstrated the feasibility of achieving insulin independence through islet replacement therapy, the necessity of a long term immunosuppressive regimen limits the widespread applicability of this procedure, as the substantial risk associated with chronic immunosuppression outweighs the risk of diabetes associated morbidities. As a result, much research has explored the development of macroencapsulation devices to isolate transplanted cells from the recipient immune system. To date, these devices demonstrate limited clinical efficacy, due in large part to limited oxygen delivery to encapsulated cells. In previous work, we demonstrated the use of vasculogenic degradable hydrogels to enhance vascularization, and therefore oxygenation, at the surface of macroencapsulation devices. Despite improved vascularization, non-ideal device geometry limits encapsulated cell viability and function in vivo, as indicated by in silico modeling of device oxygenation. As such, we seek to approach macroencapsulation device design using computational modeling to optimize device oxygen distribution prior to fabrication and testing, and evaluate device oxygenation in vitro and in vivo via a novel, siloxane probe-based magnetic resonance (MR) oximetry technique, originally developed by co-PI Dr. Vikram Kodibagkar for cancer applications. We hypothesize that MR oximetry, via siloxane core probe device labelling, will enable the first precise tracking and evaluation of macroencapsulation device oxygenation in a spatiotemporal manner. We anticipate that MR imaging will validate in silico finite element modeling predictions of oxygen distribution within varied macroencapsulation device designs, and enable non-invasive, real-time tracking of macroencapsulation device oxygenation levels in vivo. These hypotheses will be addressed in the experiments of the following Specific Aims: (1) to validate in silico-optimized macroencapsulation device oxygen gradients via MR oximetry in vitro; (2) to use non-invasive MR oximetry to evaluate in vivo oxygenation of macroencapsulated cell grafts in real time; and (3) use MR oximetry to evaluate macroencapsulation devices scaled to a larger rodent model. We anticipate that this study will enable the design of improved macroencapsulation devices that significantly enhance encapsulated cell survival and function in vivo. This approach to device design, validation, and in vivo evaluation may also facilitate the process of device scale-up, potentially streamlining the process of macroencapsulation device translation to the clinic.
