title: Therapeutic effect of local administration of low-dose simvastatin-conjugated gelatin hydrogel for fracture healing.
abstract: Several reports have shown the therapeutic effect of statins on bone formation and neovascularization. However, the effect of the systemic administration of statins is limited due to its metabolism in the liver and clearance in the digestive system. In addition, high-dose administration may cause adverse side effects. To avoid low-efficacy/frequent side effects of high-dose statin treatment, we utilized biodegradable gelatin hydrogel as a drug delivery system of statin for fracture healing. A femoral fracture was created in rats with periosteum cauterization leading to nonunion at 8 weeks postfracture. Rats received local administration of either simvastatin-conjugated gelatin hydrogel (ST-Gel group) or gelatin hydrogel alone (Gel group). Approximately 70% of animals in the ST-Gel group achieved fracture union radiographically and histologically, while only 7% of animals achieved fracture healing in the Gel group. Functional bone healing was also significantly greater with increased angiogenesis- and osteogenesis-related growth factor expressions in periosteal granulation tissue in the ST-Gel group than in the Gel group. Simvastatin locally applied with gelatin hydrogel to fracture sites at a dose similar to that used in clinical settings successfully induced fracture union in a rat unhealing bone fracture model via its effect on both angiogenesis and osteogenesis.
authors.affiliation: Group of Vascular Regeneration, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Fukui
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Taro
authors.initials: T
authors.lastname: Shoji
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Mifune
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akimaru
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kawamoto
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kuroda
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kuroda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D005260:Female; D005269:Femur / Q000098:blood supply / Q000000981:diagnostic imaging / Q000187:drug effects; D017102:Fracture Healing / Q000187:drug effects*; D005780:Gelatin / Q000494:pharmacology*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D011859:Radiography; D051381:Rats; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D000277:Adjuvants, Pharmaceutic; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D005780:Gelatin; D019821:Simvastatin