Cell Transplantation

IsletsWhole 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.

Cell_1First, 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.

Cell_2A 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.

Stabler CS, Sun XL, Chaikof EL. Surface re-engineering of pancreatic islets with recombinant azido-thrombomodulin. Bioconjugate Chemistry 2007; 18:1713-1715

Wilson J, Cui W, Chaikof EL. Layer-by-layer assembly of a conformal nano-thin PEO coating for intraportal islet transplantation. Nano Letters 2008; 8:1940-48.

Cui W, Wilson JT, Wen J, Angsana J, Qu Z, Stabler C, Haller CA, Chaikof EL. Thrombomodulin improves early outcomes after intraportal islet transplantation. Am J Transplantation 2009; 9:1308-1316.

Wilson JT, Krishnamurthy VR, Qu Z, Cui W, Chaikof EL. Non-covalent cell surface engineering with cationic graft copolymers. J Am Chem Soc 2009; 131:18228–18229

Wilson JT, Haller CA, Qu Z, Cui W, Urlam MK, Chaikof EL. Biomolecular surface engineering of pancreatic islets with thrombomodulin. Acta Biomaterialia 2010; 6:1895-1903

Cui W, Angsana J, Wen J, Chaikof EL. Liposomal formulations of thrombomodulin increase engraftment after intraportal islet transplantation. Cell Transplantation 2010; 19:1359-1367.

Wilson JT, Cui W, Kozlovskaya V, Kharlampieva E, Pan D, Qu Z, Krishnamurthy VR, Mets J, Kumar V, Wen J, Song Y, Tsukruk VV, Chaikof EL. Cell surface engineering with polyelectrolyte multilayer thin films. J Am Chem Soc 2011; 133:7054-64.