{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:05:50Z","timestamp":1790143550498,"version":"4.0.1"},"reference-count":30,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"natural science basic research program of Shaanxi Province","award":["2022JM-603"],"award-info":[{"award-number":["2022JM-603"]}]},{"name":"natural science basic research program of Shaanxi Province","award":["2018PT31"],"award-info":[{"award-number":["2018PT31"]}]},{"name":"natural science basic research program of Shaanxi Province","award":["2021TD04"],"award-info":[{"award-number":["2021TD04"]}]},{"name":"Xi\u2019an Medical University","award":["2022JM-603"],"award-info":[{"award-number":["2022JM-603"]}]},{"name":"Xi\u2019an Medical University","award":["2018PT31"],"award-info":[{"award-number":["2018PT31"]}]},{"name":"Xi\u2019an Medical University","award":["2021TD04"],"award-info":[{"award-number":["2021TD04"]}]},{"name":"fourth batch of university level funds for key disciplines of Xi\u2019an Medical University: Clinical Science of Stomatology","award":["2022JM-603"],"award-info":[{"award-number":["2022JM-603"]}]},{"name":"fourth batch of university level funds for key disciplines of Xi\u2019an Medical University: Clinical Science of Stomatology","award":["2018PT31"],"award-info":[{"award-number":["2018PT31"]}]},{"name":"fourth batch of university level funds for key disciplines of Xi\u2019an Medical University: Clinical Science of Stomatology","award":["2021TD04"],"award-info":[{"award-number":["2021TD04"]}]},{"name":"Sci-Tech Innovation Team of Xi\u2019an Medical University","award":["2022JM-603"],"award-info":[{"award-number":["2022JM-603"]}]},{"name":"Sci-Tech Innovation Team of Xi\u2019an Medical University","award":["2018PT31"],"award-info":[{"award-number":["2018PT31"]}]},{"name":"Sci-Tech Innovation Team of Xi\u2019an Medical University","award":["2021TD04"],"award-info":[{"award-number":["2021TD04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Polymers"],"abstract":"<jats:p>Bone fractures and defects are a major health issue and have reportedly affected over 455 million individuals globally to date. Bone tissue engineering has gained great success in bone defect repair and bone reconstruction based on the use of nano-hydroxyapatite (nHA) or collagen (COL). Both nHA and COL exhibit osteogenic induction capacity to support bone tissue regeneration; however, the former suffers from poor flexibility and the latter lacks mechanical strength. Biological scaffolds created by combining nHA and COL (nHA\/COL) can overcome the drawbacks imposed by individual materials and, therefore, have become widely applied in tissue engineering. The composite scaffolds can further promote tissue reconstruction by allowing the loading of various growth factors. Naringin (NG) is a natural flavonoid. Its molecular weight is 580.53 Da, lower than that of many growth factors, and it causes minimal immune responses when being introduced in vivo. In addition, naringin is safe, non-toxic, inexpensive to produce, and has superior bio-properties. In this study, we introduced NG into a nHA\/COL scaffold (NG\/nHA\/COL) and exploited the potentials of the NG\/nHA\/COL scaffold in enhancing bone tissue regeneration. NG\/nHA\/COL scaffolds were fabricated by firstly combining nHA and collagen at different compositional ratios, followed by NG encapsulation. NG release tests showed that the scaffold with a nHA\/COL mass ratio of 7:3 exhibited the optimal property. The in vitro cell study showed the desirable biocompatibility of the NG\/nHA\/COL scaffold, and its effective promotion for the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), as proved by an increased alkaline phosphatase (ALP) activity, the formation of more calcium nodules, and a higher expression of osteogenic-related genes involving Osteocalcin (OCN), BMP-2, and Osteopontin (OPN), compared with the control and nHA\/COL groups. When administered into rats with skull defects, the NG\/nHA\/COL scaffold significantly promoted the reconstruction of bone tissues and the early repair of skull defects, indicating the great potential of NG\/nHA\/COL scaffolds in bone tissue engineering.<\/jats:p>","DOI":"10.3390\/polym14163260","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T09:46:24Z","timestamp":1660124784000},"page":"3260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Naringin Release from a Nano-Hydroxyapatite\/Collagen Scaffold Promotes Osteogenesis and Bone Tissue Reconstruction"],"prefix":"10.3390","volume":"14","author":[{"given":"Yanping","family":"Zuo","sequence":"first","affiliation":[{"name":"Department of Prosthodontics, School of Stomatology, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiwen","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuchan","family":"Xiong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, University Medical Center Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengfang","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, School of Stomatology, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaochao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, School of Stomatology, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, School of Stomatology, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S16","DOI":"10.1016\/j.injury.2011.06.199","article-title":"Allograft bone matrix versus synthetic bone graft substitutes","volume":"42","author":"Zimmermann","year":"2011","journal-title":"Injury"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e22","DOI":"10.2106\/JBJS.ST.18.00099","article-title":"Induced-Membrane Technique in the Management of Posttraumatic Bone Defects","volume":"9","author":"Azi","year":"2019","journal-title":"JBJS Essent. Surg. Tech."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Liu, Y.S., Yushan, M., and Liu, Z.H. (2021). Treatment of diaphyseal forearm defects caused by infection using Ilizarov segmental bone transport technique. BMC Musculoskelet. Disord., 22.","DOI":"10.1186\/s12891-020-03896-w"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1080\/03602532.2020.1758713","article-title":"Nano-hydroxyapatite use in dentistry: A systematic review","volume":"52","author":"Bordea","year":"2020","journal-title":"Drug Metab. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1016\/j.actbio.2011.03.019","article-title":"Nanoscale hydroxyapatite particles for bone tissue engineering","volume":"7","author":"Zhou","year":"2011","journal-title":"Acta Biomater."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.2147\/IJN.S360670","article-title":"Synthesis, Characterization, Functionalization and Bio-Applications of Hydroxyapatite Nanomaterials: An Overview","volume":"17","author":"Munir","year":"2022","journal-title":"Int. J. Nanomed."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.actbio.2018.11.039","article-title":"Three-dimensional (3D) Printed Scaffold and Material Selection for Bone Repair","volume":"84","author":"Zhang","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3813","DOI":"10.1016\/j.actbio.2011.07.002","article-title":"Various preparation methods of highly porous hydroxyapatite\/polymer nanoscale biocomposites for bone regeneration","volume":"7","author":"Sun","year":"2011","journal-title":"Acta Biomater."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1016\/j.addr.2003.08.010","article-title":"Collagen sponges for bone regeneration with rhBMP-2","volume":"55","author":"Geiger","year":"2003","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/jbm.a.35593","article-title":"In vitro mineralization of MC3T3-E1 osteoblast-like cells on collagen\/nano-hydroxyapatite scaffolds coated carbon\/carbon composites","volume":"104","author":"Cao","year":"2016","journal-title":"J.Biomed. Mater. Res. A"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.actbio.2013.11.029","article-title":"Design of a composite biomaterial system for tissue engineering applications","volume":"10","author":"Jiang","year":"2014","journal-title":"Acta Biomater."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1016\/j.msec.2012.06.011","article-title":"Interaction of cell culture with composition effects on the mechanical properties of polycaprolactone-hydroxyapatite scaffolds fabricated via selective laser sintering (SLS)","volume":"32","author":"Eosoly","year":"2012","journal-title":"Mater. Sci. Eng."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e231","DOI":"10.1016\/j.dental.2020.12.006","article-title":"Influence of bone formation by composite scaffolds with different proportions of hydroxyapatite and collagen","volume":"37","author":"Ou","year":"2021","journal-title":"Dent. Mater."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.drudis.2018.05.012","article-title":"Bioinspired bone therapies using naringin: Applications and advances","volume":"23","author":"Lavrador","year":"2018","journal-title":"Drug Discov. Today"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2009.01.035","article-title":"Effects of naringin on the proliferation and osteogenic differentiation of human bone mesenchymal stem cell","volume":"607","author":"Zhang","year":"2009","journal-title":"Eur. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1007\/s00776-013-0362-9","article-title":"Naringin promotes osteoblast differentiation and effectively reverses ovariectomy-associated osteoporosis","volume":"18","author":"Li","year":"2013","journal-title":"J. Orthop. Sci."},{"key":"ref_17","first-page":"283941","article-title":"A novel porous gelatin composite containing naringin for bone repair","volume":"2013","author":"Chen","year":"2013","journal-title":"Evid.-Based Complementary Altern. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"89","DOI":"10.4062\/biomolther.2012.20.1.089","article-title":"Effects of Ethyl Acetate Extract of Poncirus trifoliata Fruit for Glucocorticoid-Induced Osteoporosis","volume":"20","author":"Yoon","year":"2012","journal-title":"Biomol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4759","DOI":"10.3892\/mmr.2015.3996","article-title":"Naringin promotes differentiation of bone marrow stem cells into osteoblasts by upregulating the expression levels of microRNA-20a and downregulating the expression levels of PPAR\u03b3","volume":"12","author":"Fan","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_20","first-page":"408","article-title":"Naringin enhances osteogenic differentiation through the activation of ERK signaling in human bone marrow mesenchymal stem cells","volume":"20","author":"Wang","year":"2017","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_21","first-page":"5098","article-title":"Naringin promotes osteogenic differentiation of bone marrow stromal cells by up-regulating Foxc2 expression via the IHH signaling pathway","volume":"8","author":"Lin","year":"2016","journal-title":"Am. J. Transl. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7130653","DOI":"10.1155\/2016\/7130653","article-title":"Naringin Stimulates Osteogenic Differentiation of Rat Bone Marrow Stromal Cells via Activation of the Notch Signaling Pathway","volume":"2016","author":"Yu","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1016\/j.biomaterials.2005.11.009","article-title":"Effect of naringin collagen graft on bone formation","volume":"27","author":"Wong","year":"2006","journal-title":"Biomaterials"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"317","DOI":"10.4012\/dmj.2016-220","article-title":"In vitro evaluation of electrospun PLGA\/PLLA\/PDLLA blend fibers loaded with naringin for guided bone regeneration","volume":"37","author":"Guo","year":"2018","journal-title":"Dent. Mater. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1080\/10717544.2019.1568620","article-title":"Electrosprayed naringin-loaded microsphere\/SAIB hybrid depots enhance bone formation in a mouse calvarial defect model","volume":"26","author":"Yang","year":"2019","journal-title":"Drug Deliv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e13043","DOI":"10.1111\/cpr.13043","article-title":"Naringin-inlaid silk fibroin\/hydroxyapatite scaffold enhances human umbilical cord-derived mesenchymal stem cell-based bone regeneration","volume":"54","author":"Zhao","year":"2021","journal-title":"Cell Prolif."},{"key":"ref_27","first-page":"57","article-title":"Bone injury and fracture healing biology","volume":"28","author":"Oryan","year":"2015","journal-title":"Biomed. Environ. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"dmm033084","DOI":"10.1242\/dmm.033084","article-title":"Animal models for bone tissue engineering and modelling disease","volume":"11","author":"McGovern","year":"2018","journal-title":"Dis. Models Mech."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/term.1968","article-title":"A review of hydrogel use in fracture healing and bone regeneration","volume":"10","year":"2016","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e1901239","DOI":"10.1002\/adhm.201901239","article-title":"Gelatin Templated Polypeptide Co-Cross-Linked Hydrogel for Bone Regeneration","volume":"9","author":"Qiao","year":"2020","journal-title":"Adv. Healthc. Mater."}],"container-title":["Polymers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4360\/14\/16\/3260\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:06:46Z","timestamp":1760141206000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4360\/14\/16\/3260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,10]]},"references-count":30,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["polym14163260"],"URL":"https:\/\/doi.org\/10.3390\/polym14163260","relation":{},"ISSN":["2073-4360"],"issn-type":[{"value":"2073-4360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,10]]}}}