title: Local delivery of controlled-release simvastatin/PLGA/HAp microspheres enhances bone repair.
abstract: Statins are used clinically for reduction of cholesterol synthesis to prevent cardiovascular disease. Previous in vitro and in vivo studies have shown that statins stimulate bone formation. However, orally administered statins may be degraded during first-pass metabolism in the liver. This study aimed to prevent this degradation by developing a locally administered formulation of simvastatin that is encapsulated in poly(lactic-co-glycolic acid)/hydroxyapatite (SIM/PLGA/HAp) microspheres with controlled-release properties. The effect of this formulation of simvastatin on bone repair was tested using a mouse model of gap fracture bridging with a graft of necrotic bone. The simvastatin released over 12 days from 3 mg and 5 mg of SIM/PLGA/HAp was 0.03-1.6 μg/day and 0.05-2.6 μg/day, respectively. SIM/PLGA/HAp significantly stimulated callus formation around the repaired area and increased neovascularization and cell ingrowth in the grafted necrotic bone at week 2 after surgery. At week 4, both 3 mg and 5 mg of SIM/PLGA/HAp increased neovascularization, but only 5 mg SIM/PLGA/HAp enhanced cell ingrowth into the necrotic bone. The low dose of simvastatin released from SIM/PLGA/HAp enhanced initial callus formation, neovascularization, and cell ingrowth in the grafted bone, indicating that SIM/PLGA/HAp facilitates bone regeneration. We suggest that SIM/PLGA/HAp should be developed as an osteoinductive agent to treat osteonecrosis or in combination with an osteoconductive scaffold to treat severe bone defects.
authors.affiliation: Graduate Institute of Medicine, College of Life Science, Kaohsiung Medical University, Taiwan ; Department of Physiology, College of Life Science, Kaohsiung Medical University, Taiwan ; Orthopedic Research Center, College of Medicine, College of Life Science, Kaohsiung Medical University, Taiwan.
authors.forename: I-Chun
authors.initials: IC
authors.lastname: Tai
authors.forename: Yin-Chih
authors.initials: YC
authors.lastname: Fu
authors.forename: Chih-Kuang
authors.initials: CK
authors.lastname: Wang
authors.forename: Je-Ken
authors.initials: JK
authors.lastname: Chang
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Ho
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects*; D002214:Capsules / Q000008:administration & dosage / Q000138:chemical synthesis; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000138:chemical synthesis; D004058:Diffusion; D017886:Durapatite / Q000737:chemistry*; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D010020:Osteonecrosis / Q000188:drug therapy* / Q000473:pathology*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D019821:Simvastatin / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D017886:Durapatite; D019821:Simvastatin
keywords: bone fracture; controlled release; microspheres; poly(lactic-co-glycolic acid); statin