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Supporting islet transplant using polymer nanofiber scaffolds loaded with proangiogenic and immune suppressive compounds

Daniel Bowers², Preeti Chhabra¹, Linda Langman¹, Edward Botchwey², Kenneth Brayman¹

¹Department of Surgery; ²Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States

Alternate islet transplant sites must be pre-vascularized or very quickly vascularized following transplant in order to prevent hypoxia induced islet necrosis. The local release of the S1P analog pro-drug FTY720 (fingolimod), can induce microvascular remodeling. We are investigating the ability of nanofiber scaffolds loaded with FTY720 to modulate the process of angiogenesis and inflammation as well as provide physical cues that mimic the extracellular matrix. Nanofibers are electrospun from polymer solutions of PLAGA or PLAGA/PCL with and without FTY720. Islets are assessed for viability (Propidium Iodide and Fluorescein Diacetate staining) and function (response to 28mM and 2.8mM glucose). Microvascular remodeling is assessed by automated image analysis of intravital light microscopy images obtained from dorsal skinfold window chambers.

Image analysis of repeated measures of microvessel metrics show significant differences between diabetic and non-diabetic animals within 7 days of implant in response to FTY720 local release (p<0.05). Islets cultured with nanofibers for 48 hours show a reduced viability (45% fibers verses 70% for controls), however the addition of FTY720 improves the viability to at least that of untreated islets (76%). No significant differences in Stimulation Index have been found (1.85 controls verses 2.0 fibers). Preliminary data from in vivo studies suggest that local release of FTY720 may reduce the rejection process in allotransplant models and that the pocket does not interfere with insulin secretion.

A polymer nanofiber pocket provides a device in which islets can be transplanted in alternate sites. The porous nature of the nanofibers allow blood vessels to penetrate the pocket to reform the important intraislet vasculature. The local release of factors, such as FTY720, from the biodegradable polymers provides a way to guide the healing and inflammatory process where a strict immune barrier may not be required. Further animal studies, including xenogenic transplants are planned.