{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T18:21:06Z","timestamp":1790965266705,"version":"4.1.0"},"reference-count":118,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/N027221\/1"],"award-info":[{"award-number":["EP\/N027221\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0201077","type":"journal-article","created":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T13:38:55Z","timestamp":1533130735000},"page":"e0201077","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Preclinical therapies to prevent or treat fracture non-union: A systematic review"],"prefix":"10.1371","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5313-9677","authenticated-orcid":true,"given":"Philippa M.","family":"Bennett","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah K.","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Dretzke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danai","family":"Bem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jowan G.","family":"Penn-Barwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2018,8,1]]},"reference":[{"key":"ref1","article-title":"Skeletal Trauma Basic Science, Management, and Reconstruction. One. Sixth ed","author":"M Brinker","year":"2003"},{"issue":"6","key":"ref2","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.injury.2011.03.046","article-title":"Treatment of long bone non-unions with polytherapy: indications and clinical results","volume":"42","author":"G Calori","year":"2011","journal-title":"Injury"},{"issue":"11","key":"ref3","doi-asserted-by":"crossref","first-page":"e162775","DOI":"10.1001\/jamasurg.2016.2775","article-title":"Epidemiology of fracture nonunion in 18 human bones","volume":"151","author":"R Zura","year":"2016","journal-title":"JAMA surgery"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/S0020-1383(07)80003-9","article-title":"Prevalence of long-bone non-unions","volume":"38","author":"C Tzioupis","year":"2007","journal-title":"Injury"},{"issue":"17","key":"ref5","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.2106\/JBJS.N.01090","article-title":"Time trade-off as a measure of health-related quality of life: long bone nonunions have a devastating impact","volume":"97","author":"PC Schottel","year":"2015","journal-title":"JBJS"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.injury.2014.04.002","article-title":"Delayed union and nonunions: epidemiology, clinical issues, and financial aspects","volume":"45","author":"DJ Hak","year":"2014","journal-title":"Injury"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"S11","DOI":"10.1016\/S0020-1383(07)80004-0","article-title":"Risk factors contributing to fracture non-unions","volume":"38","author":"G Calori","year":"2007","journal-title":"Injury"},{"key":"ref8","unstructured":"National Cancer Institute. NCI Dictionary of Cancer Terms <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.cancer.gov\/publications\/dictionaries\/cancer-terms?cdrid=44517\" xlink:type=\"simple\">https:\/\/www.cancer.gov\/publications\/dictionaries\/cancer-terms?cdrid=44517<\/ext-link> [cited 2017]. <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.cancer.gov\/publications\/dictionaries\/cancer-terms?cdrid=44517\" xlink:type=\"simple\">https:\/\/www.cancer.gov\/publications\/dictionaries\/cancer-terms?cdrid=44517<\/ext-link>."},{"issue":"5","key":"ref9","doi-asserted-by":"crossref","first-page":"376","DOI":"10.7326\/0003-4819-126-5-199703010-00006","article-title":"Systematic reviews: synthesis of best evidence for clinical decisions","volume":"126","author":"DJ Cook","year":"1997","journal-title":"Annals of internal medicine"},{"issue":"7438","key":"ref10","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1136\/bmj.328.7438.514","article-title":"Where is the evidence that animal research benefits humans?","volume":"328","author":"P Pound","year":"2004","journal-title":"BMJ: British Medical Journal"},{"issue":"9333","key":"ref11","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/S0140-6736(02)09812-4","article-title":"Systematic reviews of animal experiments","volume":"360","author":"P Sandercock","year":"2002","journal-title":"The Lancet"},{"issue":"1","key":"ref12","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s13643-015-0148-6","article-title":"Pre-clinical evaluation of therapies to prevent or treat bone non-union: a systematic review protocol","volume":"4","author":"SK Stewart","year":"2015","journal-title":"Systematic reviews"},{"key":"ref13","unstructured":"Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES). <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.dcn.ed.ac.uk\/camarades\/default.htm\" xlink:type=\"simple\">http:\/\/www.dcn.ed.ac.uk\/camarades\/default.htm<\/ext-link> <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.dcn.ed.ac.uk\/camarades\/default.htm\" xlink:type=\"simple\">http:\/\/www.dcn.ed.ac.uk\/camarades\/default.htm<\/ext-link> [13 August 2017]."},{"issue":"7","key":"ref14","doi-asserted-by":"crossref","first-page":"e1000097","DOI":"10.1371\/journal.pmed.1000097","article-title":"Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement","volume":"6","author":"D Moher","year":"2009","journal-title":"PLoS medicine"},{"issue":"4","key":"ref15","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1046\/j.1472-8206.2003.00180.x","article-title":"Extracting numerical data from published reports of pharmacokinetics investigations: method description and validation","volume":"17","author":"IR Oliveira","year":"2003","journal-title":"Fundamental & clinical pharmacology"},{"issue":"7\u20138","key":"ref16","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/mrd.22489","article-title":"The ImageJ ecosystem: An open platform for biomedical image analysis","volume":"82","author":"J Schindelin","year":"2015","journal-title":"Molecular reproduction and development"},{"issue":"1","key":"ref17","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1471-2288-14-43","article-title":"SYRCLE\u2019s risk of bias tool for animal studies","volume":"14","author":"CR Hooijmans","year":"2014","journal-title":"BMC medical research methodology"},{"issue":"2","key":"ref18","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s10856-013-5091-2","article-title":"Use of chitosan and beta-tricalcium phosphate, alone and in combination, for bone healing in rabbits","volume":"25","author":"AS Azevedo","year":"2014","journal-title":"Journal of Materials Science-Materials in Medicine"},{"issue":"3","key":"ref19","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1097\/SAP.0b013e3181a73045","article-title":"Effect of use of slow release of bone morphogenetic protein-2 and transforming growth factor-Beta-2 in a chitosan gel matrix on cranial bone graft survival in experimental cranial critical size defect model","volume":"64","author":"HI Canter","year":"2010","journal-title":"Annals of Plastic Surgery"},{"issue":"5","key":"ref20","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1097\/SCS.0b013e3181af1529","article-title":"Osteogenesis mechanism of chitosan-coated calcium sulfate pellets on the restoration of segmental bone defects","volume":"20","author":"X Cui","year":"2009","journal-title":"Journal of Craniofacial Surgery"},{"issue":"6","key":"ref21","first-page":"694","article-title":"Histologic evaluation of chitosan as an accelerator of bone regeneration in microdrilled rat tibias","volume":"9","author":"F Ezoddini-Ardakani","year":"2012","journal-title":"Dental Research Journal"},{"issue":"3","key":"ref22","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1002\/jbm.a.31812","article-title":"Osteogenic activity of the mixture of chitosan and particulate dentin","volume":"87","author":"SS Park","year":"2008","journal-title":"Journal of Biomedical Materials Research Part A"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1155\/2015\/719574","article-title":"Histopathological, histomorphometrical, and radiographical evaluation of injectable glass-ceramic-chitosan nanocomposite in bone reconstruction of rat","volume":"2015","author":"M Seyedmajidi","year":"2015","journal-title":"International Journal of Biomaterials"},{"issue":"4","key":"ref24","doi-asserted-by":"crossref","first-page":"554","DOI":"10.3109\/14653241003709694","article-title":"Osteogenic comparison of expanded and uncultured adipose stromal cells","volume":"12","author":"WK Cheung","year":"2010","journal-title":"Cytotherapy"},{"issue":"2","key":"ref25","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1007\/s11033-013-2913-8","article-title":"Bioceramic-collagen scaffolds loaded with human adipose-tissue derived stem cells for bone tissue engineering","volume":"41","author":"N Daei-farshbaf","year":"2014","journal-title":"Molecular Biology Reports"},{"issue":"3","key":"ref26","article-title":"Periostin accelerates bone healing mediated by human mesenchymal stem cell-embedded hydroxyapatite\/tricalcium phosphate scaffold","volume":"10","author":"SC Heo","year":"2015","journal-title":"PLoS ONE"},{"issue":"4","key":"ref27","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1002\/jbm.a.31149","article-title":"Ectopic and in situ bone formation of adipose tissue-derived stromal cells in biphasic calcium phosphate nanocomposite","volume":"81","author":"Y Lin","year":"2007","journal-title":"Journal of Biomedical Materials Research Part A"},{"issue":"2","key":"ref28","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/jor.21219","article-title":"Low dose erythropoietin stimulates bone healing in mice","volume":"29","author":"P Garcia","year":"2011","journal-title":"Journal of Orthopaedic Research"},{"issue":"5","key":"ref29","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.bone.2011.08.004","article-title":"Erythropoietin stimulates bone formation, cell proliferation, and angiogenesis in a femoral segmental defect model in mice","volume":"49","author":"JH Holstein","year":"2011","journal-title":"Bone"},{"issue":"4","key":"ref30","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1080\/17453674.2016.1198200","article-title":"Increased bone formation in a rabbit long-bone defect model after single local and single systemic application of erythropoietin","volume":"87","author":"GW Omlor","year":"2016","journal-title":"Acta Orthopaedica"},{"issue":"7","key":"ref31","doi-asserted-by":"crossref","first-page":"e102010","DOI":"10.1371\/journal.pone.0102010","article-title":"EPO promotes bone repair through enhanced cartilaginous callus formation and angiogenesis","volume":"9","author":"L Wan","year":"2014","journal-title":"PLoS ONE"},{"issue":"11","key":"ref32","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1359\/JBMR.050701","article-title":"Vascular endothelial growth factor gene-activated matrix (VEGF 165-GAM) enhances osteogenesis and angiogenesis in large segmental bone defects","volume":"20","author":"F Geiger","year":"2005","journal-title":"Journal of Bone and Mineral Research"},{"key":"ref33","first-page":"90","article-title":"Vascular endothelial growth factor improves bone repair in a murine nonunion model","volume":"32","author":"CM Ogilvie","year":"2012","journal-title":"Iowa Orthopaedic Journal"},{"issue":"5","key":"ref34","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.bone.2008.06.019","article-title":"Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in a critical size defect model","volume":"43","author":"ZS Patel","year":"2008","journal-title":"Bone"},{"issue":"38","key":"ref35","first-page":"7118","article-title":"Vascular endothelial growth factor and nano-hydroxyapatite\/collagen composite in the repair of femoral defect in rats","volume":"15","author":"Xu Cz","year":"2011","journal-title":"Journal of Clinical Rehabilitative Tissue Engineering Research"},{"issue":"10","key":"ref36","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.3727\/096368916X690980","article-title":"Combined use of mesenchymal stromal cell sheet transplantation and local injection of SDF-1 for bone repair in a rat nonunion model","volume":"25","author":"G Chen","year":"2016","journal-title":"Cell Transplantation"},{"issue":"9","key":"ref37","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1002\/mabi.201500178","article-title":"Synergistic Effects of SDF-1alpha and BMP-2 Delivery from Proteolytically Degradable Hyaluronic Acid Hydrogels for Bone Repair","volume":"15","author":"JL Holloway","year":"2015","journal-title":"Macromolecular Bioscience"},{"issue":"13\u201314","key":"ref38","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1089\/ten.tea.2014.0571","article-title":"Sequential Treatment with SDF-1 and BMP-2 Potentiates Bone Formation in Calvarial Defects","volume":"21","author":"HD Hwang","year":"2015","journal-title":"Tissue engineering Part A"},{"issue":"4","key":"ref39","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/clr.12364","article-title":"New bone formation in bone defects after melatonin and porcine bone grafts: experimental study in rabbits","volume":"26","author":"JL Calvo-Guirado","year":"2015","journal-title":"Clinical Oral Implants Research"},{"issue":"1","key":"ref40","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/jor.21205","article-title":"Role of local insulin augmentation upon allograft incorporation in a rat femoral defect model","volume":"29","author":"J Dedania","year":"2011","journal-title":"Journal of Orthopaedic Research"},{"issue":"7","key":"ref41","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1113\/expphysiol.2007.041962","article-title":"Stimulation of intramembranous bone repair in rats by ghrelin","volume":"93","author":"F Deng","year":"2008","journal-title":"Experimental Physiology"},{"issue":"1","key":"ref42","doi-asserted-by":"crossref","first-page":"174","DOI":"10.5114\/aoms.2012.30950","article-title":"Adenovirus-mediated transfer of VEGF into marrow stromal cells combined with PLGA\/TCP scaffold increases vascularization and promotes bone repair in vivo","volume":"10","author":"C Duan","year":"2014","journal-title":"Archives of Medical Science"},{"issue":"3","key":"ref43","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s10529-014-1703-2","article-title":"Lentivirus-mediated Wnt10b overexpression enhances fracture healing in a rat atrophic non-union model","volume":"37","author":"F Gao","year":"2015","journal-title":"Biotechnology letters"},{"issue":"4","key":"ref44","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.bone.2007.06.018","article-title":"VEGF producing bone marrow stromal cells (BMSC) enhance vascularization and resorption of a natural coral bone substitute","volume":"41","author":"F Geiger","year":"2007","journal-title":"Bone"},{"issue":"1","key":"ref45","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1002\/jbm.b.33359","article-title":"Serum albumin coating of demineralized bone matrix results in stronger new bone formation","volume":"104","author":"DB Horvathy","year":"2016","journal-title":"Journal of Biomedical Materials Research Part B, Applied Biomaterials"},{"issue":"1","key":"ref46","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/jor.20658","article-title":"Effect of cell-based VEGF gene therapy on healing of a segmental bone defect","volume":"27","author":"R Li","year":"2009","journal-title":"Journal of Orthopaedic Research"},{"issue":"1","key":"ref47","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1177\/0954411915616987","article-title":"Individual and combined effects of noise-like whole-body vibration and parathyroid hormone treatment on bone defect repair in ovariectomized mice","volume":"230","author":"T Matsumoto","year":"2016","journal-title":"Proceedings of the Institution of Mechanical Engineers Part H, Journal of engineering in medicine"},{"issue":"4","key":"ref48","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1902\/jop.2015.150302","article-title":"Serotonin Inhibits Osteoblast Differentiation and Bone Regeneration in Rats","volume":"87","author":"SS Nam","year":"2016","journal-title":"Journal of Periodontology"},{"issue":"10","key":"ref49","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.1002\/jbm.a.35472","article-title":"Bacterial cellulose-hydroxyapatite composites with osteogenic growth peptide (OGP) or pentapeptide OGP on bone regeneration in critical-size calvarial defect model","volume":"103","author":"SC Pigossi","year":"2015","journal-title":"Journal of Biomedical Materials Research Part A"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.actbio.2015.09.008","article-title":"Repair of segmental ulna defects using a beta-TCP implant in combination with a heparan sulfate glycosaminoglycan variant","volume":"28","author":"B Rai","year":"2015","journal-title":"Acta Biomaterialia"},{"issue":"Suppl 4","key":"ref51","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1590\/S0102-86502006001000010","article-title":"Bone repair in rats treated with sodic diclofenac and calcitonin","volume":"21","author":"MC Sassioto","year":"2006","journal-title":"Acta Cirurgica Brasileira"},{"issue":"2","key":"ref52","first-page":"193","article-title":"Histologic, morphometric, and densitometric study of peri-implant bone in rabbits with local administration of growth hormone","volume":"20","author":"IF Tresguerres","year":"2005","journal-title":"International Journal of Oral & Maxillofacial Implants"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.2147\/DDDT.S80778","article-title":"The effects of amlodipine and platelet rich plasma on bone healing in rats","volume":"9","author":"Y Atalay","year":"2015","journal-title":"Drug Des Devel Ther"},{"issue":"1","key":"ref54","article-title":"Aspirin promotes bone marrow mesenchymal stem cell-based calvarial bone regeneration in mini swine","volume":"6","author":"Y Cao","year":"2015","journal-title":"Stem Cell Research and Therapy"},{"issue":"2","key":"ref55","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jcms.2015.11.009","article-title":"Evaluation of the effects of platelet-rich fibrin on bone regeneration in diabetic rabbits","volume":"44","author":"MC Durmuslar","year":"2016","journal-title":"Journal of Cranio-Maxillo-Facial Surgery"},{"issue":"4","key":"ref56","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1097\/SCS.0000000000001741","article-title":"Evaluation of Amniotic Multipotential Tissue Matrix to Augment Healing of Demineralized Bone Matrix in an Animal Calvarial Model","volume":"26","author":"P Konofaos","year":"2015","journal-title":"Journal of Craniofacial Surgery"},{"issue":"12","key":"ref57","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.1016\/j.injury.2016.09.039","article-title":"Synergistic effects of HBO and PRP improve bone regeneration with autologous bone grafting","volume":"47","author":"J Schneppendahl","year":"2016","journal-title":"Injury"},{"issue":"2","key":"ref58","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s10195-014-0321-z","article-title":"Evaluations of guided bone regeneration in canine radius segmental defects using autologous periosteum combined with fascia lata under stable external fixation","volume":"16","author":"Z Yu","year":"2015","journal-title":"Journal of Orthopaedics and Traumatology"},{"issue":"8","key":"ref59","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1902\/jop.2016.160009","article-title":"Ozone Therapy Enhances Osseous Healing in Rats With Diabetes With Calvarial Defects: A Morphometric and Immunohistochemical Study","volume":"87","author":"AL Alpan","year":"2016","journal-title":"Journal of Periodontology"},{"issue":"8","key":"ref60","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/clr.12413","article-title":"Biphasic beta-TCP mixed with silicon increases bone formation in critical site defects in rabbit calvaria","volume":"26","author":"JL Calvo-Guirado","year":"2015","journal-title":"Clinical Oral Implants Research"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.msec.2015.12.003","article-title":"Osteogenic effect of tricalcium phosphate substituted by magnesium associated with Genderm membrane in rat calvarial defect model","volume":"61","author":"NM Costa","year":"2016","journal-title":"Materials Science & Engineering C, Materials for Biological Applications"},{"issue":"8","key":"ref62","doi-asserted-by":"crossref","first-page":"958","DOI":"10.5966\/sctm.2013-0209","article-title":"In vivo hypobaric hypoxia performed during the remodeling process accelerates bone healing in mice","volume":"3","author":"M Durand","year":"2014","journal-title":"Stem Cells Translational Medicine"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.actbio.2015.10.005","article-title":"Guided bone regeneration using resorbable membrane and different bone substitutes: Early histological and molecular events","volume":"29","author":"I Elgali","year":"2016","journal-title":"Acta Biomaterialia"},{"issue":"4","key":"ref64","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/jor.22805","article-title":"Hyperbaric oxygen therapy improves angiogenesis and bone formation in critical sized diaphyseal defects","volume":"33","author":"JP Grassmann","year":"2015","journal-title":"Journal of Orthopaedic Research"},{"issue":"1","key":"ref65","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/odi.12381","article-title":"New bone formation induced by surface strontium-modified ceramic bone graft substitute","volume":"22","author":"JW Park","year":"2016","journal-title":"Oral Diseases"},{"issue":"3","key":"ref66","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0172614","article-title":"Vibration acceleration promotes bone formation in rodent models","volume":"12","author":"R Uchida","year":"2017","journal-title":"PLoS ONE"},{"issue":"3","key":"ref67","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1007\/s12011-012-9584-5","article-title":"Systemic treatment with vanadium absorbed by Coprinus comatus promotes femoral fracture healing in streptozotocin-diabetic rats","volume":"151","author":"G Wang","year":"2013","journal-title":"Biological Trace Element Research"},{"issue":"7","key":"ref68","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.jcms.2012.11.030","article-title":"Isotretinoin effect on the repair of bone defects\u2014a study in rat calvaria","volume":"41","author":"HT de Oliveira","year":"2013","journal-title":"Journal of Cranio-Maxillo-Facial Surgery"},{"issue":"1","key":"ref69","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/jbm.a.31261","article-title":"A novel bone substitute composite composed of tricalcium phosphate, gelatin and drynaria fortunei herbal extract","volume":"84","author":"GC Dong","year":"2008","journal-title":"Journal of Biomedical Materials Research Part A"},{"key":"ref70","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.aanat.2016.07.009","article-title":"A silver carp skin derived collagen in bone defect treatment-A histological study in a rat model","volume":"208","author":"J Hadzik","year":"2016","journal-title":"Annals of Anatomy"},{"issue":"1","key":"ref71","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s10735-016-9705-0","article-title":"Histochemical examination of systemic administration of eldecalcitol combined with guided bone regeneration for bone defect restoration in rats","volume":"48","author":"X Han","year":"2017","journal-title":"Journal of Molecular Histology"},{"issue":"10","key":"ref72","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.1002\/jbm.a.35793","article-title":"Deferoxamine released from poly(lactic-co-glycolic acid) promotes healing of osteoporotic bone defect via enhanced angiogenesis and osteogenesis","volume":"104","author":"P Jia","year":"2016","journal-title":"Journal of Biomedical Materials Research Part A"},{"key":"ref73","article-title":"Bone-healing capacity of PCL\/PLGA\/duck beak scaffold in critical bone defects in a rabbit model","author":"JY Lee","year":"2016","journal-title":"BioMed Research International"},{"issue":"5","key":"ref74","doi-asserted-by":"crossref","first-page":"309","DOI":"10.3109\/21691401.2013.821411","article-title":"The modification experimental study in vivo of nano-bone gelatin","volume":"42","author":"W Li","year":"2014","journal-title":"Artificial Cells, Nanomedicine, & Biotechnology"},{"issue":"1","key":"ref75","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.jep.2012.02.041","article-title":"Evaluation of Cameroonian plants towards experimental bone regeneration","volume":"141","author":"FT Ngueguim","year":"2012","journal-title":"Journal of Ethnopharmacology"},{"issue":"1","key":"ref76","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jep.2013.03.063","article-title":"Ethanol extract of Peperomia pellucida (Piperaceae) promotes fracture healing by an anabolic effect on osteoblasts","volume":"148","author":"FT Ngueguim","year":"2013","journal-title":"Journal of Ethnopharmacology"},{"issue":"3","key":"ref77","doi-asserted-by":"crossref","first-page":"e33228","DOI":"10.1371\/journal.pone.0033228","article-title":"Locally administrated perindopril improves healing in an ovariectomized rat tibial osteotomy model","volume":"7","author":"X Zhao","year":"2012","journal-title":"PLoS ONE"},{"key":"ref78","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.bone.2015.12.052","article-title":"Combination therapy with BMP-2 and a systemic RANKL inhibitor enhances bone healing in a mouse critical-sized femoral defect","volume":"84","author":"S Bougioukli","year":"2016","journal-title":"Bone"},{"issue":"8","key":"ref79","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0070234","article-title":"Testosterone Delivered with a Scaffold Is as Effective as Bone Morphologic Protein-2 in Promoting the Repair of Critical-Size Segmental Defect of Femoral Bone in Mice","volume":"8","author":"BH Cheng","year":"2013","journal-title":"PLoS ONE"},{"issue":"1","key":"ref80","doi-asserted-by":"crossref","first-page":"16","DOI":"10.5606\/ehc.2016.04","article-title":"The effect of teicoplanin on fracture healing: an experimental study","volume":"27","author":"H Gocer","year":"2016","journal-title":"Eklem hastaliklari ve cerrahisi = Joint Diseases & Related Surgery"},{"issue":"12","key":"ref81","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1016\/j.biomaterials.2007.12.031","article-title":"The effect of mesenchymal populations and vascular endothelial growth factor delivered from biodegradable polymer scaffolds on bone formation","volume":"29","author":"JM Kanczler","year":"2008","journal-title":"Biomaterials"},{"issue":"4","key":"ref82","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1177\/0883911511407402","article-title":"Nano-hydroxyapatite\/chitosan sponge-like biocomposite for repairing of rat calvarial critical-sized bone defect","volume":"26","author":"X Ma","year":"2011","journal-title":"Journal of Bioactive and Compatible Polymers"},{"issue":"4","key":"ref83","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3109\/08977194.2012.683188","article-title":"Systemically delivered insulin-like growth factor-I enhances mesenchymal stem cell-dependent fracture healing","volume":"30","author":"TJ Myers","year":"2012","journal-title":"Growth Factors"},{"issue":"9","key":"ref84","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.jcyt.2013.05.004","article-title":"Mobilization of endogenous stem cell populations enhances fracture healing in a murine femoral fracture model","volume":"15","author":"CA Toupadakis","year":"2013","journal-title":"Cytotherapy"},{"issue":"1","key":"ref85","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1007\/s12011-013-9763-z","article-title":"Enhanced healing of rat calvarial critical size defect with selenium-doped lamellar biocomposites","volume":"155","author":"Y Wang","year":"2013","journal-title":"Biological Trace Element Research"},{"issue":"8","key":"ref86","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1002\/jor.22849","article-title":"Local application of a proteasome inhibitor enhances fracture healing in rats","volume":"33","author":"T Yoshii","year":"2015","journal-title":"Journal of Orthopaedic Research"},{"issue":"12","key":"ref87","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1016\/j.archoralbio.2015.09.002","article-title":"The effects of dental pulp stem cells on bone regeneration in rat calvarial defect model: micro-computed tomography and histomorphometric analysis","volume":"60","author":"F Asutay","year":"2015","journal-title":"Arch Oral Biol"},{"issue":"12","key":"ref88","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0144541","article-title":"Medicarpin, a Natural Pterocarpan, Heals Cortical Bone Defect by Activation of Notch and Wnt Canonical Signaling Pathways","volume":"10","author":"M Dixit","year":"2015","journal-title":"PLoS ONE"},{"issue":"4","key":"ref89","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1002\/jor.20103","article-title":"The use of heparan sulfate to augment fracture repair in a rat fracture model","volume":"24","author":"RA Jackson","year":"2006","journal-title":"Journal of Orthopaedic Research"},{"issue":"12","key":"ref90","doi-asserted-by":"crossref","first-page":"2962","DOI":"10.1007\/s11999-008-0493-z","article-title":"Percutaneous nonviral delivery of hepatocyte growth factor in an osteotomy gap promotes bone repair in rabbits: A preliminary study","volume":"466","author":"H Matsubara","year":"2008","journal-title":"Clinical Orthopaedics and Related Research"},{"issue":"1","key":"ref91","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.bone.2013.01.019","article-title":"Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation","volume":"54","author":"G Sisask","year":"2013","journal-title":"Bone"},{"issue":"1","key":"ref92","first-page":"103","article-title":"Effects of cilostazol on fracture healing: an experimental study","volume":"50","author":"T Alic","year":"2016","journal-title":"Acta Orthop Traumatol Turc"},{"key":"ref93","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.bone.2017.02.012","article-title":"Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair","volume":"98","author":"GS Baht","year":"2017","journal-title":"Bone"},{"issue":"23","key":"ref94","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.2106\/JBJS.N.00057","article-title":"Parameters for lithium treatment are critical in its enhancement of fracture-healing in rodents","volume":"96","author":"J Bernick","year":"2014","journal-title":"Journal of Bone & Joint Surgery\u2014American Volume"},{"key":"ref95","first-page":"4125","article-title":"Degradability, bioactivity, and osteogenesis of biocomposite scaffolds of lithium-containing mesoporous bioglass and mPEG-PLGA-b-PLL copolymer","volume":"10","author":"Y Cai","year":"2015","journal-title":"International Journal of Nanomedicine"},{"issue":"6","key":"ref96","first-page":"676","article-title":"Effect of pentoxifylline on healing of segmental bone defects and angiogenesis","volume":"49","author":"G Cakmak","year":"2015","journal-title":"Acta orthopaedica et traumatologica turcica"},{"issue":"1","key":"ref97","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.ijpharm.2015.09.003","article-title":"Bone critical defect repair with poloxamine-cyclodextrin supramolecular gels","volume":"495","author":"C Del Rosario","year":"2015","journal-title":"International Journal of Pharmaceutics"},{"issue":"1","key":"ref98","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.bone.2012.10.014","article-title":"Localized deferoxamine injection augments vascularity and improves bony union in pathologic fracture healing after radiotherapy","volume":"52","author":"A Donneys","year":"2013","journal-title":"Bone"},{"issue":"5\u20136","key":"ref99","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1089\/ten.tea.2016.0308","article-title":"Enhanced Mandibular Bone Repair by Combined Treatment of Bone Morphogenetic Protein 2 and Small-Molecule Phenamil","volume":"23","author":"J Fan","year":"2017","journal-title":"Tissue Engineering\u2014Part A"},{"issue":"2","key":"ref100","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/jbm.b.33561","article-title":"Bone regeneration in critical bone defects using three-dimensionally printed beta-tricalcium phosphate\/hydroxyapatite scaffolds is enhanced by coating scaffolds with either dipyridamole or BMP-2","volume":"105","author":"S Ishack","year":"2017","journal-title":"Journal of Biomedical Materials Research\u2014Part B Applied Biomaterials"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.archoralbio.2015.11.001","article-title":"Efficacy of doxycycline release collagen membrane on surgically created and contaminated defects in rat tibiae: A histopathological and microbiological study","volume":"63","author":"E Kutan","year":"2016","journal-title":"Archives of Oral Biology"},{"issue":"4","key":"ref102","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1208\/s12249-015-0411-0","article-title":"The Effect of Local Delivery Doxycycline and Alendronate on Bone Repair","volume":"17","author":"PHJO Limirio","year":"2016","journal-title":"AAPS PharmSciTech"},{"issue":"1","key":"ref103","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jconrel.2013.06.024","article-title":"Locally delivered salicylic acid from a poly(anhydride-ester): impact on diabetic bone regeneration","volume":"171","author":"K Wada","year":"2013","journal-title":"Journal of Controlled Release"},{"issue":"3","key":"ref104","first-page":"196","article-title":"Comparative therapeutic use of Risedronate and Calcarea phosphorica\u2014allopathy versus homeopathy\u2014in bone repair in castrated rats","volume":"20","author":"C Werkman","year":"2006","journal-title":"Pesquisa Odontologica Brasileira = Brazilian Oral Research"},{"issue":"1","key":"ref105","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/jcp.21809","article-title":"Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: a novel role of the cysteinyl LT-1 receptor","volume":"221","author":"JJ Wixted","year":"2009","journal-title":"Journal of Cellular Physiology"},{"issue":"11","key":"ref106","doi-asserted-by":"crossref","first-page":"e7824","DOI":"10.1371\/journal.pone.0007824","article-title":"Survey of the quality of experimental design, statistical analysis and reporting of research using animals","volume":"4","author":"C Kilkenny","year":"2009","journal-title":"PloS one"},{"issue":"4","key":"ref107","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1093\/ilar.43.4.244","article-title":"Guidelines for the design and statistical analysis of experiments using laboratory animals","volume":"43","author":"MF Festing","year":"2002","journal-title":"ILAR journal"},{"key":"ref108","article-title":"The design of animal experiments: reducing the use of animals in research through better experimental design","author":"MF Festing","year":"2002"},{"issue":"7","key":"ref109","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1111\/j.1476-5381.2010.00873.x","article-title":"Guidelines for reporting experiments involving animals: the ARRIVE guidelines","volume":"160","author":"J McGrath","year":"2010","journal-title":"British journal of pharmacology"},{"issue":"12","key":"ref110","doi-asserted-by":"crossref","first-page":"6689","DOI":"10.1128\/IAI.71.12.6689-6692.2003","article-title":"Review of the use of statistics in infection and immunity","volume":"71","author":"CH Olsen","year":"2003","journal-title":"Infection and immunity"},{"issue":"7521","key":"ref111","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1136\/bmj.331.7521.903","article-title":"Standard deviations and standard errors","volume":"331","author":"DG Altman","year":"2005","journal-title":"Bmj"},{"key":"ref112","doi-asserted-by":"crossref","unstructured":"Marsh J, Slongo TF, Agel J, Broderick JS, Creevey W, DeCoster TA, et al. Fracture and dislocation classification compendium-2007: Orthopaedic Trauma Association classification, database and outcomes committee. LWW; 2007.","DOI":"10.1097\/00005131-200711101-00001"},{"issue":"12","key":"ref113","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1016\/j.biomaterials.2008.12.050","article-title":"The challenge of establishing preclinical models for segmental bone defect research","volume":"30","author":"JC Reichert","year":"2009","journal-title":"Biomaterials"},{"issue":"3","key":"ref114","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1093\/ilar\/ilu043","article-title":"The usefulness of systematic reviews of animal experiments for the design of preclinical and clinical studies","volume":"55","author":"R de Vries","year":"2014","journal-title":"ILAR journal"},{"issue":"3","key":"ref115","doi-asserted-by":"crossref","first-page":"e1000245","DOI":"10.1371\/journal.pmed.1000245","article-title":"Can animal models of disease reliably inform human studies?","volume":"7","author":"HB Van der Worp","year":"2010","journal-title":"PLoS medicine"},{"issue":"Supplement_1","key":"ref116","doi-asserted-by":"crossref","first-page":"79","DOI":"10.2106\/JBJS.G.01585","article-title":"Selection and development of preclinical models in fracture-healing research","volume":"90","author":"PF O\u2019Loughlin","year":"2008","journal-title":"JBJS"},{"issue":"14","key":"ref117","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1001\/jama.296.14.1731","article-title":"Translation of research evidence from animals to humans","volume":"296","author":"DG Hackam","year":"2006","journal-title":"Jama"},{"issue":"9","key":"ref118","doi-asserted-by":"crossref","first-page":"e43404","DOI":"10.1371\/journal.pone.0043404","article-title":"Publication bias in laboratory animal research: a survey on magnitude, drivers, consequences and potential solutions","volume":"7","author":"G ter Riet","year":"2012","journal-title":"PLoS One"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0201077","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T14:01:35Z","timestamp":1571666495000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0201077"}},"subtitle":[],"editor":[{"given":"Wisit","family":"Cheungpasitporn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2018,8,1]]},"references-count":118,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2018,8,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0201077","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,1]]}}}