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Biotechnol Bioeng. 2015 Sep;112(9):1916-26. doi: 10.1002/bit.25589. Epub 2015 Jul 7.

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

Najjar M1, Manzoli V1,2, Abreu M1, Villa C1,3,4, Martino MM5, Molano RD1, Torrente Y1,3,4, Pileggi A1,6,7,8, Inverardi L1,7,9, Ricordi C1,6,7,8,9, Hubbell JA1,5,10, Tomei AA11,12,13.

Author information

1
Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.
2
Department of Electronics, Information and Bioengineering, Politecnico di Milano, Italy.
3
Department of Pathophysiology and Transplantation, Universitá degli Studi di Milano, Italy.
4
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy.
5
Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
6
Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.
7
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida.
8
Department of Biomedical Engineering, University of Miami, Miami, Florida.
9
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
10
Institute for Molecular Engineering, University of Chicago, Illinois.
11
Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida. atomei@miami.edu.
12
Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. atomei@miami.edu.
13
Department of Biomedical Engineering, University of Miami, Miami, Florida. atomei@miami.edu.

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.

KEYWORDS:

PDGF-BB; VEGF-A; angiogenesis; hydrogels; islet transplantation; local release

PMID:
25786390
DOI:
10.1002/bit.25589
[Indexed for MEDLINE]

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