title: Proangiogenic hydrogels within macroporous scaffolds enhance islet engraftment in an extrahepatic site.
abstract: The transplantation of allogeneic islets in recent clinical trials has shown substantial promise as a therapy for type 1 diabetes; however, long-term insulin independence remains inadequate. This has been largely attributed to the current intravascular, hepatic transplant site, which exposes islets to mechanical and inflammatory stresses. A highly macroporous scaffold, housed within an alternative transplant site, can support an ideal environment for islet transplantation by providing three-dimensional distribution of islets, while permitting the infiltration of host vasculature. In the present study, we sought to evaluate the synergistic effect of a proangiogenic hydrogel loaded within the void space of a macroporous poly(dimethylsiloxane) (PDMS) scaffold on islet engraftment. The fibrin-based proangiogenic hydrogel tested presents platelet derived growth factor (PDGF-BB), via a fibronectin (FN) fragment containing growth factor and major integrin binding sites in close proximity. The combination of the proangiogenic hydrogel with PDMS scaffolds resulted in a significant decrease in the time to normoglycemia for syngeneic mouse islet transplants. This benefit was associated with an observed increase in competent vessel branching, as well as mature intraislet vessels. Overall, the addition of the proangiogenic factor PDGF-BB, delivered via the FN fragment-functionalized hydrogel, positively influenced the efficiency of engraftment. These characteristics, along with its ease of retrieval, make this combination of a biostable macroporous scaffold and a degradable proangiogenic hydrogel a supportive structure for insulin-producing cells implanted in extrahepatic sites.
authors.affiliation: 1 Diabetes Research Institute, University of Miami , Miami, Florida.
authors.forename: Ann-Christina
authors.initials: AC
authors.lastname: Brady
authors.forename: Mikaël M
authors.initials: MM
authors.lastname: Martino
authors.forename: Eileen
authors.initials: E
authors.lastname: Pedraza
authors.forename: Steve
authors.initials: S
authors.lastname: Sukert
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
authors.forename: Cherie L
authors.initials: CL
authors.lastname: Stabler
mesh_terms: D064591:Allografts; D043925:Angiogenesis Inducing Agents / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D004129:Dimethylpolysiloxanes / Q000737:chemistry / Q000494:pharmacology; D020100:Hydrogels / Q000737:chemistry* / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D009757:Nylons / Q000737:chemistry / Q000494:pharmacology; D016062:Porosity; D020574:Proto-Oncogene Proteins c-sis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D043925:Angiogenesis Inducing Agents; D004129:Dimethylpolysiloxanes; D020100:Hydrogels; D009757:Nylons; D020574:Proto-Oncogene Proteins c-sis; C085707:poly(dimethylsiloxane)-polyamide copolymer; D000077214:Becaplermin