Fibrin gels engineered with pro-angiogenic growth factors promote engraftment of pancreatic islets in extrahepatic sites in mice

Mejdi Najjar, Vita Manzoli, Maria Abreu, Chiara Villa, Mikaël M. Martino, Ruth Molano, Yvan Torrente, Antonello Pileggi, Luca A Inverardi, Camillo Ricordi, Jeffrey A. Hubbell, Alice Tomei

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

With a view toward reduction of graft loss, we explored pancreatic islet transplantation within fibrin matrices rendered pro-angiogenic by incorporation of minimal doses of vascular endothelial growth factor-A165 and platelet-derived growth factor-BB presented complexed to a fibrin-bound integrin-binding fibronectin domain. Engineered matrices allowed for extended release of pro-angiogenic factors and for their synergistic signaling with extracellular matrix-binding domains in the post-transplant period. Aprotinin addition delayed matrix degradation and prolonged pro-angiogenic factor availability within the graft. Both subcutaneous (SC) and epididymal fat pad (EFP) sites were evaluated. We show that in the SC site, diabetes reversal in mice transplanted with 1,000 IEQ of syngeneic islets was not observed for islets transplanted alone, while engineered matrices resulted in a diabetes median reversal time (MDRT) of 38 days. In the EFP site, the MDRT with 250 IEQ of syngeneic islets within the engineered matrices was 24 days versus 86 days for islets transplanted alone. Improved function of engineered grafts was associated with enhanced and earlier (by day 7) angiogenesis. Our findings show that by engineering the transplant site to promote prompt re-vascularization, engraftment and long-term function of islet grafts can be improved in relevant extrahepatic sites.

Original languageEnglish (US)
Pages (from-to)1916-1926
Number of pages11
JournalBiotechnology and Bioengineering
Volume112
Issue number9
DOIs
StatePublished - Sep 1 2015

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Keywords

  • Angiogenesis
  • Hydrogels
  • Islet transplantation
  • Local release
  • PDGF-BB
  • VEGF-A

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology

Cite this

Najjar, M., Manzoli, V., Abreu, M., Villa, C., Martino, M. M., Molano, R., Torrente, Y., Pileggi, A., Inverardi, L. A., Ricordi, C., Hubbell, J. A., & Tomei, A. (2015). Fibrin gels engineered with pro-angiogenic growth factors promote engraftment of pancreatic islets in extrahepatic sites in mice. Biotechnology and Bioengineering, 112(9), 1916-1926. https://doi.org/10.1002/bit.25589