title: Combination of calcium sulfate and simvastatin-controlled release microspheres enhances bone repair in critical-sized rat calvarial bone defects.
abstract: Most allogenic bone graft substitutes have only osteoconductive properties. Developing new strategies to improve the osteoinductive activity of bone graft substitutes is both critical and practical for clinical application. Previously, we developed novel simvastatin-encapsulating poly(lactic-co-glycolic acid) microspheres (SIM/PLGA) that slowly release simvastatin and enhance fracture healing. In this study, we combined SIM/PLGA with a rapidly absorbable calcium sulfate (CS) bone substitute and studied the effect on bone healing in critical-sized calvarial bone defects in a rat model. The cytotoxicity and cytocompatibility of this combination was tested in vitro using lactate dehydrogenase leakage and a cell attachment assay, respectively. Combination treatment with SIM/PLGA and the CS bone substitute had no cytotoxic effect on bone marrow stem cells. Compared with the control, cell adhesion was substantially enhanced following combination treatment with SIM/PLGA and the CS bone substitute. In vivo, implantation of the combination bone substitute promoted healing of critical-sized calvarial bone defects in rats; furthermore, production of bone morphogenetic protein-2 and neovascularization were enhanced in the area of the defect. In summary, the combination of SIM/PLGA and a CS bone substitute has osteoconductive and osteoinductive properties, indicating that it could be used for regeneration of bone in the clinical setting.
authors.affiliation: Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan ; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Orthopaedics, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yin-Chih
authors.initials: YC
authors.lastname: Fu
authors.affiliation: Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan ; School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yan-Hsiung
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Orthopaedics, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chung-Hwan
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chih-Kuang
authors.initials: CK
authors.lastname: Wang
authors.affiliation: Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Orthopaedics, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Gwo-Jaw
authors.initials: GJ
authors.lastname: Wang
authors.affiliation: Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Orthopaedics, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Ho
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects; D018786:Bone Substitutes / Q000494:pharmacology; D002133:Calcium Sulfate / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000494:pharmacology; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D051379:Mice; D008863:Microspheres; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D012886:Skull / Q000187:drug effects / Q000473:pathology*; D013194:Staining and Labeling; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D018786:Bone Substitutes; D003692:Delayed-Action Preparations; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D019821:Simvastatin; D002133:Calcium Sulfate
keywords: calcium sulfate; calvarial bone defects; osteoconductive; osteoinductive; simvastatin