title: Fibrin gels engineered with pro-angiogenic growth factors promote engraftment of pancreatic islets in extrahepatic sites in mice.
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.
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.
authors: Mejdi
authors: M
authors: Najjar
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.|Department of Electronics, Information and Bioengineering, Politecnico di Milano, Italy.
authors: Vita
authors: V
authors: Manzoli
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.
authors: Maria
authors: M
authors: Abreu
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.|Department of Pathophysiology and Transplantation, Universitá degli Studi di Milano, Italy.|Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy.
authors: Chiara
authors: C
authors: Villa
authors: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors: Mikaël M
authors: MM
authors: Martino
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.
authors: R Damaris
authors: RD
authors: Molano
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.|Department of Pathophysiology and Transplantation, Universitá degli Studi di Milano, Italy.|Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy.
authors: Yvan
authors: Y
authors: Torrente
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.|Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.|Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida.|Department of Biomedical Engineering, University of Miami, Miami, Florida.
authors: Antonello
authors: A
authors: Pileggi
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.|Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida.|Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
authors: Luca
authors: L
authors: Inverardi
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.|Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.|Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida.|Department of Biomedical Engineering, University of Miami, Miami, Florida.|Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
authors: Camillo
authors: C
authors: Ricordi
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida.|Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Institute for Molecular Engineering, University of Chicago, Illinois.
authors: Jeffrey A
authors: JA
authors: Hubbell
authors: Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida. atomei@miami.edu.|Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. atomei@miami.edu.|Department of Biomedical Engineering, University of Miami, Miami, Florida. atomei@miami.edu.
authors: Alice A
authors: AA
authors: Tomei
mesh_terms: D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D005337:Fibrin / Q000737:chemistry*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D007515:Islets of Langerhans / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D020574:Proto-Oncogene Proteins c-sis / Q000737:chemistry / Q000172:deficiency / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020100:Hydrogels; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin; D005337:Fibrin
keywords: PDGF-BB; VEGF-A; angiogenesis; hydrogels; islet transplantation; local release