? For patients with Type I diabetes mellitus, islet transplantation provides a moment-to-moment fine regulation of insulin that is unachievable by exogenous insulin injection. Islet transplantation has been further improved by using alginate microcapsules for immunoprotection. However, the outcome of multi-institutional trials has shown that insulin-independence success rates vary widely. Thus, in order to better understand the fate of transplanted islets and the relationship among transplanted islet mass, graft function, and overall glucose homeostasis, an accurate and reproducible method of imaging islets in vivo is required. Rather than conventional direct labeling of cells with an magnetic resonance (MR) contrast agent, we propose to label alginate capsules with a clinically approved superparamagnetic iron oxide (SPIO) formulation-allowing for sensitive MR detectability at a single capsule level. Our preliminary data demonstrate that the in vitro viability and insulin secretory response of murine beta-cells and human islets are unaltered by encapsulation with alginate-SPIO as compared to naked islets over a 6-week period. These """"""""magnetocapsules"""""""" (MCs) are also impermeable to proteins greater than 75 kD, enabling immunoprotection of cells by preventing antibody penetration. Furthermore, MC islet cells can restore normoglycemia in vivo in streptozotocin (STZ)-induced diabetic mice for at least 2 months. ? Before initiating human clinical feasibility studies, we propose to apply our transplanted MC islet approach in a large animal model that closely resembles the human condition using clinical MR scanners and imaging parameters with dedicated injection catheters and imaging guidewires. First we will further optimize our MC preparations and test their functionality and MR properties in vivo using diabetic mice (Aims 1 and 2). We will then assess our immunoprotected and MR-trackable islets for functionality in a STZ-induced diabetic swine model (Aim 3). Due to their strong magnetic properties, the MCs enable the use of MR-compatible catheters for image-guided targeted portal vein injections in real time. We hypothesize that the rate of success of insulin-dependence will depend on successful islet delivery and liver engraftment, as well as persistence of capsule integrity, as monitored by MR imaging. As the MCs are composed of clinical grade and FDA-approved materials, this MR-guided approach will be readily translatable to human diabetic clinical trials for further improvements of islet cell transplantation. ? ? ?
