An engineered macroencapsulation membrane releasing FTY720 to precondition pancreatic islet transplantation

• Type of Material: Article
• Authors: Daniel T. Bowers, University of Virginia; Claire E. Olingy, Georgia Institute of Technology and Emory University; Preeti Chhabra, University of Virginia; Linda Langman, University of Virginia; Parker H. Merrill, University of Virginia; Ritu S. Linhart, University of Virginia; Michael L. Tanes, University of Virginia; Dan Lin, University of Virginia; Kenneth L. Brayman, University of Virginia; Edward Botchwey, Emory University
• Language: English
• Date: 2018-02-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/jbm.b.33862
• Title of Journal or Parent Work: Journal of Biomedical Materials Research Part B: Applied Biomaterials
• ISSN: 1552-4973
• Volume: 106
• Issue: 2
• Start Page: 555
• End Page: 568
• Grant/Funding Information: Contract grant sponsor: National Science Foundation; contract grant number: 0933643
• Keywords: islet transplant; regenerative medicine; FTY720; immune modulation; macroencapsulation
• Research Categories: Health Sciences, Medicine and Surgery; Engineering, Biomedical

Abstract

Macroencapsulation is a powerful approach to increase the efficiency of extrahepatic pancreatic islet transplant. FTY720, a small molecule that activates signaling through sphingosine-1-phosphate receptors, is immunomodulatory and pro-angiogenic upon sustained delivery from biomaterials. While FTY720 (fingolimod, Gilenya) has been explored for organ transplantation, in the present work the effect of locally released FTY720 from novel nanofiber-based macroencapsulation membranes is explored for islet transplantation. We screened islet viability during culture with FTY720 and various biodegradable polymers. Islet viability is significantly reduced by the addition of high doses (≥500 ng/mL) of soluble FTY720. Among the polymers screened, islets have the highest viability when cultured with poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). Therefore, PHBV was blended with polycaprolactone (PCL) for mechanical stability and electrospun into nanofibers. Islets had no detectable function ex vivo following 5 days or 12 h of subcutaneous implantation within our engineered device. Subsequently, we explored a preconditioning scheme in which islets are transplanted 2 weeks after FTY720-loaded nanofibers are implanted. This allows FTY720 to orchestrate a local regenerative milieu while preventing premature transplantation into avascular sites that contain high concentrations of FTY720. These results provide a foundation and motivation for further investigation into the use of FTY720 in preconditioning sites for efficacious islet transplantation.