title: Controlled Release of Dexamethasone from Organosilicone Constructs for Local Modulation of Inflammation in Islet Transplantation.
abstract: Inflammation is a significant detriment to the engraftment of cells and tissues, particularly for islet transplantation, where a low tolerance for the inflammatory milieu results in significant graft loss. Local treatment with anti-inflammatories, such as glucocorticoids, provides the benefits of site-targeted delivery with minimization of the broad side effects associated with systemic delivery. Polydimethylsiloxane (PDMS) is a flexible platform that is capable of providing sustained delivery of hydrophobic drugs. Here, we evaluated the capacity of PDMS constructs loaded with the anti-inflammatory glucocorticoid dexamethasone (Dex) to locally mitigate inflammation in islet grafts. Dex-PDMS constructs, fabricated in rod or disk geometries, demonstrated prolonged and sustained release at therapeutically relevant levels. In vitro, Dex-PDMS constructs inhibited endotoxin-induced human monocyte and macrophage activation, but they did not impair islet viability or function. Dex-PDMS rods, co-transplanted with islet-seeded scaffolds in a murine model, demonstrated suppression of host inflammatory responses during early- and late-phase engraftment, without significantly altering islet graft potency. The facile nature of these glucocorticoid-doped PDMS constructs allows for the optimization of targeted dose delivery with wide applicability in cell and tissue transplantation.
authors.affiliation: 1 Department of Biomedical Engineering, University of Miami , Miami, Florida.|2 Diabetes Research Institute, University of Miami , Miami, Florida.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Weaver
authors.affiliation: 2 Diabetes Research Institute, University of Miami , Miami, Florida.|3 Department of Molecular and Cellular Pharmacology, University of Miami , Miami, Florida.
authors.forename: Yun
authors.initials: Y
authors.lastname: Song
authors.affiliation: 2 Diabetes Research Institute, University of Miami , Miami, Florida.|4 Department of Biochemistry and Molecular Biology, University of Miami , Miami, Florida.
authors.forename: Ethan Y
authors.initials: EY
authors.lastname: Yang
authors.affiliation: 1 Department of Biomedical Engineering, University of Miami , Miami, Florida.|2 Diabetes Research Institute, University of Miami , Miami, Florida.|5 Department of Surgery, University of Miami , Miami, Florida.|6 Department of Microbiology and Immunology, University of Miami , Miami, Florida.|7 Department of Medicine, University of Miami , Miami, Florida.
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.affiliation: 1 Department of Biomedical Engineering, University of Miami , Miami, Florida.|2 Diabetes Research Institute, University of Miami , Miami, Florida.|5 Department of Surgery, University of Miami , Miami, Florida.|6 Department of Microbiology and Immunology, University of Miami , Miami, Florida.|7 Department of Medicine, University of Miami , Miami, Florida.
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.affiliation: 2 Diabetes Research Institute, University of Miami , Miami, Florida.|3 Department of Molecular and Cellular Pharmacology, University of Miami , Miami, Florida.
authors.forename: Peter
authors.initials: P
authors.lastname: Buchwald
authors.affiliation: 1 Department of Biomedical Engineering, University of Miami , Miami, Florida.|2 Diabetes Research Institute, University of Miami , Miami, Florida.|4 Department of Biochemistry and Molecular Biology, University of Miami , Miami, Florida.|5 Department of Surgery, University of Miami , Miami, Florida.
authors.forename: Cherie L
authors.initials: CL
authors.lastname: Stabler
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003907:Dexamethasone / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004129:Dimethylpolysiloxanes / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice
chemical_list: D003692:Delayed-Action Preparations; D004129:Dimethylpolysiloxanes; D003907:Dexamethasone