{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:45:49Z","timestamp":1787654749312,"version":"build-2736575974"},"reference-count":109,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970948"],"award-info":[{"award-number":["81970948"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JFB"],"abstract":"<jats:p>Hyperlipidemia refers to the abnormal increase in plasma lipid level exceeding the normal range. At present, a large number of patients require dental implantation. However, hyperlipidemia affects bone metabolism, promotes bone loss, and inhibits the osseointegration of dental implants through the mutual regulation of adipocytes, osteoblasts, and osteoclasts. This review summarized the effects of hyperlipidemia on dental implants and addressed the potential strategies of dental implants to promote osseointegration in a hyperlipidemic environment and to improve the success rate of dental implants in patients with hyperlipidemia. We summarized topical drug delivery methods to solve the interference of hyperlipidemia in osseointegration, which were local drug injection, implant surface modification and bone-grafting material modification. Statins are the most effective drugs in the treatment of hyperlipidemia, and they also encourage bone formation. Statins have been used in these three methods and have been found to be positive in promoting osseointegration. Directly coating simvastatin on the rough surface of the implant can effectively promote osseointegration of the implant in a hyperlipidemic environment. However, the delivery method of this drug is not efficient. Recently, a variety of efficient methods of simvastatin delivery, such as hydrogels and nanoparticles, have been developed to boost bone formation, but few of them were applied to dental implants. Applicating these drug delivery systems using the three aforementioned ways, according to the mechanical and biological properties of materials, could be promising ways to promote osseointegration under hyperlipidemic conditions. However, more research is needed to confirm.<\/jats:p>","DOI":"10.3390\/jfb14040194","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T01:37:02Z","timestamp":1680226622000},"page":"194","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Effects of Hyperlipidemia on Osseointegration of Dental Implants and Its Strategies"],"prefix":"10.3390","volume":"14","author":[{"given":"Haiyang","family":"Sun","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhuai","family":"Meng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1717-5782","authenticated-orcid":false,"given":"Junyu","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianbing","family":"Wan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"Itc81","DOI":"10.7326\/AITC201712050","article-title":"Dyslipidemia","volume":"167","author":"Kopin","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1161\/CIR.0000000000000558","article-title":"Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association","volume":"137","author":"Benjamin","year":"2018","journal-title":"Circulation"},{"key":"ref_3","first-page":"1","article-title":"Osseointegrated implants in the treatment of the edentulous jaw. Experience from a 10-year period","volume":"16","author":"Hansson","year":"1977","journal-title":"Scand. J. Plast. Reconstr. Surg. Suppl."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3109\/17453678108991776","article-title":"Osseointegrated titanium implants. Requirements for ensuring a long-lasting, direct bone-to-implant anchorage in man","volume":"52","author":"Albrektsson","year":"1981","journal-title":"Acta Orthop. Scand."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1016\/j.cmet.2021.09.001","article-title":"Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases","volume":"33","author":"Song","year":"2021","journal-title":"Cell Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/prd.12179","article-title":"Osseointegration of titanium, titanium alloy and zirconia dental implants: Current knowledge and open questions","volume":"73","author":"Bosshardt","year":"2017","journal-title":"Periodontology 2000"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.actbio.2019.05.045","article-title":"Nano-scale modification of titanium implant surfaces to enhance osseointegration","volume":"94","author":"Souza","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s40729-019-0170-x","article-title":"The effect of hyperlipidemia on bone graft regeneration of peri-implantal created defects in rabbits","volume":"5","author":"Tekin","year":"2019","journal-title":"Int. J. Implant Dent."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/clr.95_13509","article-title":"Hyperlipidemia Impairs Implant Osseointegration","volume":"30","author":"Wang","year":"2019","journal-title":"Clin. Oral Implant. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.1563\/AAID-JOI-D-13-00105","article-title":"The effects of hyperlipidemia on implant osseointegration in the mouse femur","volume":"41","author":"Keuroghlian","year":"2015","journal-title":"J. Oral Implantol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e008","DOI":"10.1590\/1807-3107bor-2020.vol34.0008","article-title":"Effects of restraint stress and high-fat diet on osseointegration of titanium implants: An experimental study","volume":"34","author":"Dundar","year":"2020","journal-title":"Braz. Oral Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"187","DOI":"10.5125\/jkaoms.2016.42.4.187","article-title":"The effects of high-fat diet on implant osseointegration: An experimental study","volume":"42","author":"Yaman","year":"2016","journal-title":"J. Korean Assoc. Oral Maxillofac. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1002\/jat.3150","article-title":"Titanium dioxide nanoparticles increase plasma glucose via reactive oxygen species-induced insulin resistance in mice","volume":"35","author":"Hu","year":"2015","journal-title":"J. Appl. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15513","DOI":"10.1074\/jbc.R800006200","article-title":"Oxidized lipids formed non-enzymatically by reactive oxygen species","volume":"283","author":"Smith","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_15","first-page":"113","article-title":"Comparative effects of copper, iron, vanadium and titanium on low density lipoprotein oxidation in vitro","volume":"11","author":"Ani","year":"2007","journal-title":"Iran. Biomed. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1177\/0022034520983245","article-title":"Hyperlipidemia Impairs Osseointegration via the ROS\/Wnt\/\u03b2-Catenin Pathway","volume":"100","author":"Wang","year":"2021","journal-title":"J. Dent. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Yin, W., Li, Z., and Zhang, W. (2019). Modulation of Bone and Marrow Niche by Cholesterol. Nutrients, 11.","DOI":"10.3390\/nu11061394"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.ajpath.2012.05.034","article-title":"Hypercholesterolemia promotes an osteoporotic phenotype","volume":"181","author":"Pelton","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e93","DOI":"10.4317\/medoral.18298","article-title":"Osteoporosis, jawbones and periodontal disease","volume":"18","author":"Guiglia","year":"2013","journal-title":"Med. Oral Patol. Oral Y Cir. Bucal"},{"key":"ref_20","first-page":"3527872","article-title":"An 11-Year Retrospective Research Study of the Predictive Factors of Peri-Implantitis and Implant Failure: Analytic-Multicentric Study of 1279 Implants in Peru","volume":"2019","year":"2019","journal-title":"Int. J. Dent."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.plipres.2015.06.002","article-title":"Understanding the local actions of lipids in bone physiology","volume":"59","author":"During","year":"2015","journal-title":"Prog. Lipid Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1126\/science.289.5481.950","article-title":"Inhibition of adipogenesis by Wnt signaling","volume":"289","author":"Ross","year":"2000","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"242","DOI":"10.5312\/wjo.v5.i3.242","article-title":"Osteoporosis and obesity: Role of Wnt pathway in human and murine models","volume":"5","author":"Colaianni","year":"2014","journal-title":"World J. Orthop."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nm.3074","article-title":"WNT signaling in bone homeostasis and disease: From human mutations to treatments","volume":"19","author":"Baron","year":"2013","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.biocel.2016.10.018","article-title":"PPAR\u03b3 agonists induce adipocyte differentiation by modulating the expression of Lipin-1, which acts as a PPAR\u03b3 phosphatase","volume":"81","author":"Kim","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/nrrheum.2009.137","article-title":"Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis","volume":"5","author":"Takada","year":"2009","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"110422","DOI":"10.1016\/j.ygeno.2022.110422","article-title":"An integrative bioinformatics approach to decipher adipocyte-induced transdifferentiation of osteoblast","volume":"114","author":"Salmi","year":"2022","journal-title":"Genomics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.jbspin.2014.02.013","article-title":"Bone marrow fat","volume":"81","author":"Hardouin","year":"2014","journal-title":"Joint Bone Spine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1002\/jbm.a.36060","article-title":"Basis of bone metabolism around dental implants during osseointegration and peri-implant bone loss","volume":"105","author":"Insua","year":"2017","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Muruganandan, S., Ionescu, A.M., and Sinal, C.J. (2020). At the Crossroads of the Adipocyte and Osteoclast Differentiation Programs: Future Therapeutic Perspectives. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072277"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00281-019-00754-3","article-title":"Molecular determinants for the polarization of macrophage and osteoclast","volume":"41","author":"Yang","year":"2019","journal-title":"Semin. Immunopathol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gai, Z., Wang, T., Visentin, M., Kullak-Ublick, G.A., Fu, X., and Wang, Z. (2019). Lipid Accumulation and Chronic Kidney Disease. Nutrients, 11.","DOI":"10.3390\/nu11040722"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1002\/jcsm.12901","article-title":"Pathogenesis of sarcopenia and the relationship with fat mass: Descriptive review","volume":"13","author":"Li","year":"2022","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_34","first-page":"71","article-title":"Functional-morphologic aspects of changes of mucosal gingiva microcirculatory bed vessels in experimental gingivitis against the background of hypercholesterolemia","volume":"121","author":"Maglakelidze","year":"2005","journal-title":"Georgian Med. News"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1902\/jop.1999.70.12.1429","article-title":"Association between periodontitis and hyperlipidemia: Cause or effect?","volume":"70","author":"Cutler","year":"1999","journal-title":"J. Periodontol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.atherosclerosis.2006.09.015","article-title":"Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: Molecular mechanisms and gene expression studies","volume":"193","author":"Norata","year":"2007","journal-title":"Atherosclerosis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1007\/s10753-013-9628-9","article-title":"Hyperlipidemia modifies innate immune responses to lipopolysaccharide via the TLR-NF-\u03baB signaling pathway","volume":"36","author":"Chen","year":"2013","journal-title":"Inflammation"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1194\/jlr.M063354","article-title":"ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction","volume":"56","author":"Wei","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1056\/NEJM197406062902306","article-title":"Treatment of hyperlipidemia","volume":"290","author":"Levy","year":"1974","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1146\/annurev.me.41.020190.002351","article-title":"Treatment of hyperlipidemia","volume":"41","author":"Kane","year":"1990","journal-title":"Annu. Rev. Med."},{"key":"ref_41","first-page":"S139","article-title":"Epidemiology and management of hyperlipidemia","volume":"23","author":"Karr","year":"2017","journal-title":"Am. J. Manag. Care"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1042\/BSR20110118","article-title":"Mechanisms of bone anabolism regulated by statins","volume":"32","author":"Ruan","year":"2012","journal-title":"Biosci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jconrel.2015.07.022","article-title":"Potential mechanisms and applications of statins on osteogenesis: Current modalities, conflicts and future directions","volume":"215","author":"Oryan","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e160","DOI":"10.1902\/jop.2013.130456","article-title":"Tooth loss, periodontitis, and statins in a population-based follow-up study","volume":"85","author":"Meisel","year":"2014","journal-title":"J. Periodontol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1007\/s40261-022-01208-9","article-title":"Effectiveness of Simvastatin Versus Gemfibrozil for Primary Prevention of Cardiovascular Events: A Retrospective Cohort Study of 223,699 Primary Care Patients","volume":"42","author":"Blais","year":"2022","journal-title":"Clin. Drug Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s00228-021-03239-1","article-title":"Comparison of statins for primary prevention of cardiovascular disease and persistent physical disability in older adults","volume":"78","author":"Zhou","year":"2022","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"189","DOI":"10.4143\/crt.2021.1527","article-title":"A Phase II Study of Preoperative Chemoradiotherapy with Capecitabine Plus Simvastatin in Patients with Locally Advanced Rectal Cancer","volume":"55","author":"Jo","year":"2023","journal-title":"Cancer Res. Treat."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/s41419-022-04784-y","article-title":"Simvastatin rescues memory and granule cell maturation through the Wnt\/\u03b2-catenin signaling pathway in a mouse model of Alzheimer\u2019s disease","volume":"13","author":"Tong","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"035013","DOI":"10.1088\/1748-6041\/10\/3\/035013","article-title":"Enhanced angiogenesis and osteogenesis in critical bone defects by the controlled release of BMP-2 and VEGF: Implantation of electron beam melting-fabricated porous Ti6Al4V scaffolds incorporating growth factor-doped fibrin glue","volume":"10","author":"Lv","year":"2015","journal-title":"Biomed. Mater."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1210\/en.2002-220682","article-title":"Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation","volume":"144","author":"Maeda","year":"2003","journal-title":"Endocrinology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s13577-011-0028-x","article-title":"Effect of simvastatin on the osteogenetic behavior of alveolar osteoblasts and periodontal ligament cells","volume":"25","author":"Liu","year":"2012","journal-title":"Hum. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1046\/j.1600-0501.2003.01015.x","article-title":"Simvastatin promotes osteogenesis around titanium implants","volume":"15","author":"Ayukawa","year":"2004","journal-title":"Clin. Oral Implants Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.1365-2842.2009.02011.x","article-title":"Simvastatin enhances bone formation around titanium implants in rat tibiae","volume":"37","author":"Ayukawa","year":"2010","journal-title":"J. Oral Rehabil."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1600-0501.2008.01630.x","article-title":"Effects of Simvastatin on bone healing around titanium implants in osteoporotic rats","volume":"20","author":"Du","year":"2009","journal-title":"Clin. Oral Implants Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1007\/s00774-021-01243-0","article-title":"Simvastatin reverses the harmful effects of high fat diet on titanium rod osseointegration in ovariectomized rats","volume":"39","author":"Sun","year":"2021","journal-title":"J. Bone Miner. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.12659\/MSM.892247","article-title":"Single-dose local simvastatin injection improves implant fixation via increased angiogenesis and bone formation in an ovariectomized rat model","volume":"21","author":"Tan","year":"2015","journal-title":"Med. Sci. Monit."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1111\/j.1600-0501.2007.01508.x","article-title":"Topical application of statin affects bone healing around implants","volume":"19","author":"Moriyama","year":"2008","journal-title":"Clin. Oral Implants Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1016\/j.actbio.2009.10.045","article-title":"Local application of fluvastatin improves peri-implant bone quantity and mechanical properties: A rodent study","volume":"6","author":"Moriyama","year":"2010","journal-title":"Acta Biomater."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1016\/j.biomaterials.2010.01.016","article-title":"The effect of a single remote injection of statin-impregnated poly (lactic-co-glycolic acid) microspheres on osteogenesis around titanium implants in rat tibia","volume":"31","author":"Masuzaki","year":"2010","journal-title":"Biomaterials"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1177\/0022034520916400","article-title":"Sdccag3 Promotes Implant Osseointegration during Experimental Hyperlipidemia","volume":"99","author":"Ren","year":"2020","journal-title":"J. Dent. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13578-018-0254-y","article-title":"MicroRNA-29a-3p enhances dental implant osseointegration of hyperlipidemic rats via suppressing dishevelled 2 and frizzled 4","volume":"8","author":"Liu","year":"2018","journal-title":"Cell. Biosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1111\/prd.12254","article-title":"Research on implants and osseointegration","volume":"79","author":"Guglielmotti","year":"2019","journal-title":"Periodontology 2000"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.dental.2006.06.025","article-title":"Surface treatments of titanium dental implants for rapid osseointegration","volume":"23","author":"Soueidan","year":"2007","journal-title":"Dent. Mater."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/cid.12045","article-title":"Accelerated and enhanced bone formation on novel simvastatin-loaded porous titanium oxide surfaces","volume":"16","author":"Nyan","year":"2014","journal-title":"Clin. Implant Dent. Relat. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1177\/0885328213486364","article-title":"Simvastatin-activated implant surface promotes osteoblast differentiation in vitro","volume":"28","author":"Walter","year":"2014","journal-title":"J. Biomater. Appl."},{"key":"ref_66","first-page":"369","article-title":"Bone responses to simvastatin-loaded porous implant surfaces in an ovariectomized model","volume":"27","author":"Yang","year":"2012","journal-title":"Int. J. Oral Maxillofac. Implants"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"025017","DOI":"10.1088\/1748-605X\/aa95f1","article-title":"Osteogenic effects of simvastatin-loaded mesoporous titania thin films","volume":"13","author":"Angelome","year":"2018","journal-title":"Biomed. Mater."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"211","DOI":"10.11607\/jomi.3147","article-title":"In vitro and in vivo evaluation of the osteogenic ability of implant surfaces with a local delivery of simvastatin","volume":"29","author":"Zhao","year":"2014","journal-title":"Int. J. Oral Maxillofac. Implants"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2041731413515670","DOI":"10.1177\/2041731413515670","article-title":"Enhanced in vitro osteoblast differentiation on TiO2 scaffold coated with alginate hydrogel containing simvastatin","volume":"4","author":"Pullisaar","year":"2013","journal-title":"J. Tissue Eng."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"831504","DOI":"10.1155\/2015\/831504","article-title":"Influence of simvastatin-loaded implants on osseointegration in an ovariectomized animal model","volume":"2015","author":"Fang","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1111\/clr.12707","article-title":"Topical applications of vitamin D on implant surface for bone-to-implant contact enhance: A pilot study in dogs part II","volume":"27","year":"2016","journal-title":"Clin. Oral Implants Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/j.1532-849X.2009.00446.x","article-title":"Vitamin D and bone physiology: Demonstration of vitamin D deficiency in an implant osseointegration rat model","volume":"18","author":"Kelly","year":"2009","journal-title":"J. Prosthodont."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"140201","DOI":"10.1098\/rsob.140201","article-title":"Promoting effect of 1,25(OH)2 vitamin D3 in osteogenic differentiation from induced pluripotent stem cells to osteocyte-like cells","volume":"5","author":"Kato","year":"2015","journal-title":"Open Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s00774-009-0084-4","article-title":"1-Alpha, 25-dihydroxy vitamin D3 inhibits osteoclastogenesis through IFN-beta-dependent NFATc1 suppression","volume":"27","author":"Sakai","year":"2009","journal-title":"J. Bone Miner. Metab."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1359\/jbmr.2000.15.4.770","article-title":"Alfacalcidol inhibits bone resorption and stimulates formation in an ovariectomized rat model of osteoporosis: Distinct actions from estrogen","volume":"15","author":"Shiraishi","year":"2000","journal-title":"J. Bone Miner. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1007\/BF00296065","article-title":"A novel synthetic vitamin D analogue, 2 beta-(3-hydroxypropoxy)1 alpha, 25-dihydroxyvitamin D3 (ED-71), increases bone mass by stimulating the bone formation in normal and ovariectomized rats","volume":"54","author":"Tsurukami","year":"1994","journal-title":"Calcif. Tissue Int."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.plipres.2016.09.003","article-title":"DHCR7: A vital enzyme switch between cholesterol and vitamin D production","volume":"64","author":"Prabhu","year":"2016","journal-title":"Prog. Lipid Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jacc.2017.05.031","article-title":"Vitamin D and Cardiovascular Disease: Controversy Unresolved","volume":"70","author":"Quyyumi","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1097\/ID.0000000000000051","article-title":"Evaluation of simvastatin grafting around immediate dental implants in dogs","volume":"23","author":"Mansour","year":"2014","journal-title":"Implant Dent."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Wang, C.Z., Wang, Y.H., Lin, C.W., Lee, T.C., Fu, Y.C., Ho, M.L., and Wang, C.K. (2018). Combination of a Bioceramic Scaffold and Simvastatin Nanoparticles as a Synthetic Alternative to Autologous Bone Grafting. Int. J. Mol. Sci, 19.","DOI":"10.3390\/ijms19124099"},{"key":"ref_81","first-page":"3953","article-title":"Effects of simvastatin gel on bone regeneration in alveolar defects in miniature pigs","volume":"124","author":"Chen","year":"2011","journal-title":"Chin. Med. J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1021\/acsbiomaterials.1c00462","article-title":"Simvastatin-Incorporated Drug Delivery Systems for Bone Regeneration","volume":"7","author":"Jin","year":"2021","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1007\/s13233-012-0097-z","article-title":"In vitro evaluation of simvastatin acid (SVA) coated beta-tricalcium phosphate (\u03b2-TCP) particle on bone tissue regeneration","volume":"20","author":"Yang","year":"2012","journal-title":"Macromol. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3580","DOI":"10.1002\/jbm.a.35499","article-title":"Controlled release of simvastatin-loaded thermo-sensitive PLGA-PEG-PLGA hydrogel for bone tissue regeneration: In vitro and in vivo characteristics","volume":"103","author":"Yan","year":"2015","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"119038","DOI":"10.1016\/j.ijpharm.2020.119038","article-title":"Formulation of simvastatin chitosan nanoparticles for controlled delivery in bone regeneration: Optimization using Box-Behnken design, stability and in vivo study","volume":"577","author":"Delan","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_86","first-page":"79","article-title":"3D printed poly(\u03b5-caprolactone) scaffolds function with simvastatin-loaded poly(lactic-co-glycolic acid) microspheres to repair load-bearing segmental bone defects","volume":"17","author":"Zhang","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1002\/mabi.201500450","article-title":"Poly(l-Lactic Acid)\/Gelatin Fibrous Scaffold Loaded with Simvastatin\/Beta-Cyclodextrin-Modified Hydroxyapatite Inclusion Complex for Bone Tissue Regeneration","volume":"16","author":"Lee","year":"2016","journal-title":"Macromol. Biosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1208\/s12248-012-9442-6","article-title":"Controlled Release of Simvastatin from In situ Forming Hydrogel Triggers Bone Formation in MC3T3-E1 Cells","volume":"15","author":"Park","year":"2013","journal-title":"AAPS J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.jconrel.2009.12.027","article-title":"Sustained release of water-insoluble simvastatin from biodegradable hydrogel augments bone regeneration","volume":"143","author":"Tanigo","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.eurpolymj.2015.10.022","article-title":"Osteogenic potential of simvastatin loaded gelatin-nanofibrillar cellulose-\u03b2 tricalcium phosphate hydrogel scaffold in critical-sized rat calvarial defect","volume":"73","author":"Sukul","year":"2015","journal-title":"Eur. Polym. J."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"8161","DOI":"10.1016\/j.biomaterials.2011.07.045","article-title":"Photo-cured hyaluronic acid-based hydrogels containing simvastatin as a bone tissue regeneration scaffold","volume":"32","author":"Bae","year":"2011","journal-title":"Biomaterials"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"7741","DOI":"10.1039\/D1TB01256H","article-title":"Co-delivery of simvastatin and demineralized bone matrix hierarchically from nanosheet-based supramolecular hydrogels for osteogenesis","volume":"9","author":"Zhang","year":"2021","journal-title":"J. Mater. Chem. B"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1039\/D1TB00063B","article-title":"Hierarchically porous calcium-silicon nanosphere-enabled co-delivery of microRNA-210 and simvastatin for bone regeneration","volume":"9","author":"Liu","year":"2021","journal-title":"J. Mater. Chem. B"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.actbio.2020.06.022","article-title":"\u03b2-tricalcium phosphate for bone substitution: Synthesis and properties","volume":"113","author":"Bohner","year":"2020","journal-title":"Acta Biomater."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.actbio.2019.06.023","article-title":"Surface treatments on titanium implants via nanostructured ceria for antibacterial and anti-inflammatory capabilities","volume":"94","author":"Li","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"128913","DOI":"10.1016\/j.cej.2021.128913","article-title":"Titania nanotube array supported nanoceria with redox cycling stability ameliorates oxidative stress-inhibited osteogenesis","volume":"415","author":"Shao","year":"2021","journal-title":"Chem. Eng. J."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s12011-012-9423-8","article-title":"The effects of Ce on the proliferation, osteogenic differentiation and mineralization function of MC3T3-E1 cells in vitro","volume":"149","author":"Liu","year":"2012","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1002\/jcb.24451","article-title":"TGF-\u03b2\/BMP signaling pathway is involved in cerium-promoted osteogenic differentiation of mesenchymal stem cells","volume":"114","author":"Liu","year":"2013","journal-title":"J. Cell. Biochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1700678","DOI":"10.1002\/advs.201700678","article-title":"Valence State Manipulation of Cerium Oxide Nanoparticles on a Titanium Surface for Modulating Cell Fate and Bone Formation","volume":"5","author":"Li","year":"2018","journal-title":"Adv. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"8452","DOI":"10.1039\/D1NR00790D","article-title":"Mesoporous silica coated CeO(2) nanozymes with combined lipid-lowering and antioxidant activity induce long-term improvement of the metabolic profile in obese Zucker rats","volume":"13","author":"Zeng","year":"2021","journal-title":"Nanoscale"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1056\/NEJMoa1614362","article-title":"Health Effects of Overweight and Obesity in 195 Countries over 25 Years","volume":"377","author":"Afshin","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.fertnstert.2021.06.002","article-title":"Obesity and infertility: Are hyperlipidemia and hyperinsulinemia the bad guys?","volume":"116","author":"Zippl","year":"2021","journal-title":"Fertil. Steril."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"17093","DOI":"10.1038\/nrdp.2017.93","article-title":"Familial hypercholesterolaemia","volume":"3","author":"Defesche","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0149-7634(05)80233-7","article-title":"Obesity, hyperlipidemia and non-insulin-dependent diabetes: A unified theory","volume":"17","author":"Poothullil","year":"1993","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e535","DOI":"10.1161\/CIR.0000000000000450","article-title":"Contributory Risk and Management of Comorbidities of Hypertension, Obesity, Diabetes Mellitus, Hyperlipidemia, and Metabolic Syndrome in Chronic Heart Failure: A Scientific Statement from the American Heart Association","volume":"134","author":"Bozkurt","year":"2016","journal-title":"Circulation"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/j.ijom.2019.01.015","article-title":"Is there an association between overweight\/obesity and dental implant complications? A systematic review and meta-analysis","volume":"48","author":"Monteiro","year":"2019","journal-title":"Int. J. Oral Maxillofac. Surg."},{"key":"ref_107","first-page":"77","article-title":"Is a high level of total cholesterol a risk factor for dental implants or bone grafting failure? A retrospective cohort study on 227 patients","volume":"9","author":"Tirone","year":"2016","journal-title":"Eur. J. Oral Implantol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3827933","DOI":"10.1155\/2022\/3827933","article-title":"Simvastatin in the Treatment of Colorectal Cancer: A Review","volume":"2022","author":"Zang","year":"2022","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1111\/clr.12641","article-title":"Systemic vitamin D supplementation and local bone formation after maxillary sinus augmentation\u2014A randomized, double-blind, placebo-controlled clinical investigation","volume":"27","author":"Dietrich","year":"2016","journal-title":"Clin. Oral Implants Res."}],"container-title":["Journal of Functional Biomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4983\/14\/4\/194\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:07:06Z","timestamp":1760123226000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4983\/14\/4\/194"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,30]]},"references-count":109,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["jfb14040194"],"URL":"https:\/\/doi.org\/10.3390\/jfb14040194","relation":{},"ISSN":["2079-4983"],"issn-type":[{"value":"2079-4983","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,30]]}}}