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.