title: Evaluation of bone repair of critical size defects treated with simvastatin-loaded poly(lactic-co-glycolic acid) microspheres in rat calvaria.
abstract: OBJECTIVE
  Statins are hypolipemiant drugs with osteoinductive effect. We evaluated the potential of simvastatin loaded into poly(lactic-co-glycolic acid) (PLGA) microspheres to heal critical size defects in rat calvaria.
  
  
  METHODS
  PLGA scaffolds (50:50 ratio) were synthesized as pure membranes or as microspheres loaded with 2.5% simvastatin. Critical size defects (5-mm diameter) were created in the parietal bone of 3-month-old male Wistar rats; they were either left filled with blood clot (C group), covered with a PLGA membrane (M group) or with PLGA microspheres loaded with simvastatin (MSI group) or not (MM group), and then covered with the PLGA membrane. The defects were evaluated after 30 or 60 days by light and electron microscopy, immunohistochemistry for osteopontin (OPN), bone sialoprotein (BSP) and osteoadherin (OSAD), and immunocytochemistry for OPN.
  
  
  RESULTS
  Scanning electron microscopy showed that the calvarial defects treated with MSI were almost completely healed after 60 days, while groups M and C presented less bone formation, whereas the bone matrix formed into the defects of MSI group was more organized and mature. The immunolabeling for OPN and BSP on the matrix in groups C and M showed typical areas of primary bone unlike the MSI that presented weak labeling at the formed area. In the MSI group, there was an intense immunostaining for OSAD in osteoid, as well as in osteocyte cytoplasm. The immunocytochemistry showed intense labeling for OPN with homogeneous distribution in the interfibrillar spaces in all groups after 30 days and after 60 days; however, while C and M groups exhibited similar aspect, the MSI specimens showed weak labeling. The ultrastructural evaluation showed the interaction between the biomaterial and the surrounding tissue where some cells established intimate contact with microspheres.
  
  
  CONCLUSIONS
  The repair of critical size bone defects was accelerated and enhanced by the implantation of simvastatin-loaded PLGA microspheres.
authors.affiliation: Department of Biomaterials and Oral Biology, School of Dentistry, University of São Paulo, São Paulo, Brazil.
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ferreira
authors.affiliation: Department of Biomaterials and Oral Biology, School of Dentistry, University of São Paulo, São Paulo, Brazil.
authors.forename: Vivian
authors.initials: V
authors.lastname: Bradaschia-Correa
authors.affiliation: Department of Biomaterials and Oral Biology, School of Dentistry, University of São Paulo, São Paulo, Brazil.
authors.forename: Mariana M
authors.initials: MM
authors.lastname: Moreira
authors.affiliation: Department of Biomaterials and Oral Biology, School of Dentistry, University of São Paulo, São Paulo, Brazil.
authors.forename: Natasha D M
authors.initials: ND
authors.lastname: Marques
authors.affiliation: Department of Biomaterials and Oral Biology, School of Dentistry, University of São Paulo, São Paulo, Brazil vearana@usp.br.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Arana-Chavez
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D001861:Bone Regeneration / Q000187:drug effects / Q000502:physiology; D018786:Bone Substitutes; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D058574:Integrin-Binding Sialoprotein / Q000378:metabolism; D019344:Lactic Acid; D008297:Male; D008422:Materials Testing; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D053495:Osteopontin / Q000378:metabolism; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000008:administration & dosage*; D012886:Skull / Q000187:drug effects / Q000293:injuries* / Q000502:physiology; D054457:Tissue Scaffolds
chemical_list: D000924:Anticholesteremic Agents; D018786:Bone Substitutes; D016326:Extracellular Matrix Proteins; D058574:Integrin-Binding Sialoprotein; D011509:Proteoglycans; C506897:Spp1 protein, rat; C113360:osteoadherin; D053495:Osteopontin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D019821:Simvastatin
keywords: Bone regeneration; PLGA; osteoconduction; osteoinduction; simvastatin