Cell Transplantation
Whole organ pancreatic allografts using current immunosuppresive protocols have an expected graft survival as high as 86% at one year and 74% at 5 years after transplantation. Despite these encouraging results, the risk of major perioperative morbidity, the associated complications of chronic immunosuppresion therapy, and the persistent shortage of donor organ tissue remain limitations of this approach. As a consequence, pancreas transplantation continues to have a limited role in the management of diabetes. As an alternative approach, islet transplantation offers several important advantages over whole organ transplantation.
First, islets can be maintained and manipulated more easily than whole organ grafts and may be harvested from donor grafts that otherwise would not be suitable for whole organ transplantation. Second, islet transplantation, in comparison to whole organ grafting, is associated with a considerable reduction in morbidity and mortality, a decrease in intensive care unit utilization, shorter hospital stays, with the promise of achieving major reductions in overall healthcare costs. Significant limitations remain in islet transplantation that can be addressed by innovative strategies at the interface of biology, bioengineering, and biomolecular engineering.
A major obstacle in islet transplantation is the high rate of primary non-function and early islet destruction, which has been observed after intraportal islet infusion, both in animal models and in clinical trials. Substantial evidence now suggests that an acute blood mediated inflammatory injury is largely responsible for the observed functional stunning or destruction of islets and may well amplify subsequent immune reactions. We postulate that molecularly engineered systems, including conformal barriers, anti-thrombotic fusion proteins, and heparan sulfate glycomimetics that limit inflammatory and pro-coagulant responses at the graft-host interface will reduce early islet destruction and, thereby, enhance islet engraftment. In dampening the early innate inflammatory response, a concomitant improvement in long-term islet survival may be attained by modulating the evolution of an adaptive immune response.
