title: Injectable and inherently vascularizing semi-interpenetrating polymer network for delivering cells to the subcutaneous space.
abstract: Injectable hydrogels are suitable for local cell delivery to the subcutaneous space, but the lack of vasculature remains a limiting factor. Previously we demonstrated that biomaterials containing methacrylic acid promoted vascularization. Here we report the preparation of a semi-interpenetrating polymer network (SIPN), and its evaluation as an injectable carrier to deliver cells and generate blood vessels in a subcutaneous implantation site. The SIPN was prepared by reacting a blend of vinyl sulfone-terminated polyethylene glycol (PEG-VS) and sodium polymethacrylate (PMAA-Na) with dithiothreitol. The swelling of SIPN was sensitive to the PMAA-Na content but only small differences in gelation time, permeability and stiffness were noted. SIPN containing 20 mol% PMAA-Na generated a vascular network in the surrounding tissues, with 2-3 times as many vessels as was obtained with 10 mol% PMAA-Na or PEG alone. Perfusion studies showed that the generated vessels were perfused and connected to the host vasculature as early as seven days after transplantation. Islets embedded in SIPN were viable and responsive to glucose stimulation in vitro. In a proof of concept study in a streptozotocin-induced diabetic mouse model, a progressive return to normoglycemia was observed and the presence of insulin positive islets was confirmed when islets were embedded in SIPN prior to delivery. Our approach proposes a biomaterial-mediated strategy to deliver cells while enhancing vascularization.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, M5S 3G9, Canada.
authors.forename: Redouan
authors.initials: R
authors.lastname: Mahou
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, M5S 3G9, Canada.
authors.forename: David K Y
authors.initials: DKY
authors.lastname: Zhang
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, M5S 3G9, Canada.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Vlahos
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, M5S 3G9, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, M5S 3G9, Canada. Electronic address: michael.sefton@utoronto.ca.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sefton
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D002452:Cell Count; D002478:Cells, Cultured; D018914:Cells, Immobilized / Q000166:cytology*; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D004229:Dithiothreitol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D020100:Hydrogels / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D007267:Injections; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000379:methods; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D011109:Polymethacrylic Acids / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D001672:Biocompatible Materials; D020100:Hydrogels; D011109:Polymethacrylic Acids; C030613:polymethacrylic acid; D011092:Polyethylene Glycols; D004229:Dithiothreitol
keywords: Injectable hydrogels; Methacrylic acid; Semi-interpenetrating polymer network; Vascularization