{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:03:31Z","timestamp":1787166211700,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T00:00:00Z","timestamp":1665187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National key research and development program","award":["2020YFC2009004"],"award-info":[{"award-number":["2020YFC2009004"]}]},{"name":"National key research and development program","award":["2019-08"],"award-info":[{"award-number":["2019-08"]}]},{"name":"New clinical practical technology in the Medical Affairs Department of Qilu Hospital of Shandong University","award":["2020YFC2009004"],"award-info":[{"award-number":["2020YFC2009004"]}]},{"name":"New clinical practical technology in the Medical Affairs Department of Qilu Hospital of Shandong University","award":["2019-08"],"award-info":[{"award-number":["2019-08"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Materials"],"abstract":"<jats:p>Research on regulation of the immune microenvironment based on bioactive materials is important to osteogenic regeneration. Hydroxyapatite (HAP) is believed to be a promising scaffold material for dental and orthopedic implantation due to its ideal biocompatibility and high osteoconductivity. However, any severe inflammation response can lead to loosening and fall of implantation, which cause implant failures in the clinic. Morphology modification has been widely studied to regulate the host immune environment and to further promote bone regeneration. Here, we report the preparation of nHAPs, which have uniform rod-like shape and different size (200 nm and 400 nm in length). The morphology, biocompatibility, and anti-inflammatory properties were evaluated. The results showed that the 400 nm nHAPs exhibited excellent biocompatibility and osteoimmunomodulation, which can not only induce M2-phenotype macrophages (M2) polarization to decrease the production of inflammatory cytokines, but also promote the production of osteogenic factor. The reported 400 nm nHAPs are promising for osteoimmunomodulation in bone regeneration, which is beneficial for clinical application of bone defects.<\/jats:p>","DOI":"10.3390\/ma15196986","type":"journal-article","created":{"date-parts":[[2022,10,9]],"date-time":"2022-10-09T04:00:02Z","timestamp":1665288002000},"page":"6986","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Biocompatible Nano-Hydroxyapatites Regulate Macrophage Polarization"],"prefix":"10.3390","volume":"15","author":[{"given":"Da-Wang","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China"},{"name":"Institute of Stomatology, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Cheng","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China"},{"name":"Department of Orthopaedics, Taian City Central Hospital, Tai\u2019an 271000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Xiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China"},{"name":"Institute of Stomatology, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China"},{"name":"Institute of Stomatology, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Qiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren-Hua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Outpatient Department, Qilu Hospital of Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0856-5359","authenticated-orcid":false,"given":"Lei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.actbio.2018.06.023","article-title":"Differential effect of hydroxyapatite nano-particle versus nano-rod decorated titanium micro-surface on osseointegration","volume":"76","author":"Bai","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.biomaterials.2018.02.010","article-title":"A multifaceted coating on titanium dictates osteoimmunomodulation and osteo\/angio-genesis towards ameliorative osseointegratioxn","volume":"162","author":"Bai","year":"2018","journal-title":"Biomaterials"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jbiomech.2009.09.009","article-title":"Intrinsic extracellular matrix properties regulate stem cell differentiation","volume":"43","author":"Reilly","year":"2010","journal-title":"J. Biomech."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.bbrc.2015.09.081","article-title":"Intrinsic and extrinsic mechanical properties related to the differentiation of mesenchymal stem cells","volume":"473","author":"Lee","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"127362","DOI":"10.1016\/j.cej.2020.127362","article-title":"Strontium-zinc phosphate chemical conversion coating improves the osseointegration of titanium implants by regulating macrophage polarization","volume":"408","author":"Zhao","year":"2021","journal-title":"Chem. Eng. J."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Alipour, M., Firouzi, N., Aghazadeh, Z., Samiei, M., Montazersaheb, S., Khoshfetrat, A.B., and Aghazadeh, M. (2021). The osteogenic differentiation of human dental pulp stem cells in alginate-gelatin\/Nano-hydroxyapatite microcapsules. BMC Biotechnol, 21.","DOI":"10.1186\/s12896-020-00666-3"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1089\/ten.tea.2016.0162","article-title":"Biomaterials Influence Macrophage-Mesenchymal Stem Cell Interaction In Vitro","volume":"22","author":"Grotenhuis","year":"2016","journal-title":"Tissue Eng. Part A"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.actbio.2017.01.056","article-title":"Promoting tissue regeneration by modulating the immune system","volume":"53","author":"Julier","year":"2017","journal-title":"Acta Biomater."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.actbio.2015.12.003","article-title":"Titanium surface characteristics, including topography and wettability, alter macrophage activation","volume":"31","author":"Hotchkiss","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1073\/pnas.1018501108","article-title":"TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells","volume":"108","author":"Glass","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6692","DOI":"10.1016\/j.biomaterials.2011.05.078","article-title":"Immune responses to implants\u2014A review of the implications for the design of immunomodulatory biomaterials","volume":"32","author":"Franz","year":"2011","journal-title":"Biomaterials"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"119833","DOI":"10.1016\/j.biomaterials.2020.119833","article-title":"Nano-particle mediated M2 macrophage polarization enhances bone formation and MSC osteogenesis in an IL-10 dependent manner","volume":"239","author":"Mahon","year":"2020","journal-title":"Biomaterials"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6581","DOI":"10.1021\/acsnano.9b00489","article-title":"A Biomimetic Hierarchical Nanointerface Orchestrates Macrophage Polarization and Mesenchymal Stem Cell Recruitment To Promote Endogenous Bone Regeneration","volume":"13","author":"Jin","year":"2019","journal-title":"ACS Nano"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2006697","DOI":"10.1002\/adfm.202006697","article-title":"3D Printing Hydrogel Scaffolds with Nanohydroxyapatite Gradient to Effectively Repair Osteochondral Defects in Rats","volume":"31","author":"Zhang","year":"2020","journal-title":"Adv. Funct. Mater."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1908381","DOI":"10.1002\/adfm.201908381","article-title":"Bioinspired Mineral\u2013Organic Bone Adhesives for Stable Fracture Fixation and Accelerated Bone Regeneratio","volume":"30","author":"Bai","year":"2019","journal-title":"Adv. Funct. Mater."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"33717","DOI":"10.1021\/acsami.7b13313","article-title":"One-Dimensional Hydroxyapatite Nanostructures with Tunable Length for Efficient Stem Cell Differentiation Regulation","volume":"9","author":"Ma","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1177\/039139880502800111","article-title":"The influence of X-ray radiation on the mineral\/organic matrix interaction of bone tissue: An FT-IR microscopic investigation","volume":"28","author":"Hubner","year":"2005","journal-title":"Int. J. Artif. Organs"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5921","DOI":"10.1016\/j.biomaterials.2014.03.073","article-title":"Tissue-engineered cartilage with inducible and tunable immunomodulatory properties","volume":"35","author":"Glass","year":"2014","journal-title":"Biomaterials"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111512","DOI":"10.1016\/j.msec.2020.111512","article-title":"Interleukin-4 assisted calcium-strontium-zinc-phosphate coating induces controllable macrophage polarization and promotes osseointegration on titanium implant","volume":"118","author":"Zhao","year":"2021","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1007\/s10266-020-00569-x","article-title":"Morpho-functional effects of different universal dental adhesives on human gingival fibroblasts: An in vitro study","volume":"109","author":"Pagano","year":"2021","journal-title":"Odontology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S1471-4906(02)02302-5","article-title":"Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes","volume":"23","author":"Mantovani","year":"2002","journal-title":"Trends Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.pt.2004.01.004","article-title":"Alternatively activated macrophages during parasite infections","volume":"20","author":"Noel","year":"2004","journal-title":"Trends Parasitol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nri1412","article-title":"Fibrotic disease and the T(H)1\/T(H)2 paradigm","volume":"4","author":"Wynn","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1038\/ni.1937","article-title":"Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm","volume":"11","author":"Biswas","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4353","DOI":"10.1038\/s41467-019-12384-2","article-title":"Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24","volume":"10","author":"Yu","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3858","DOI":"10.4049\/jimmunol.1302821","article-title":"CCL2 Shapes Macrophage Polarization by GM-CSF and M-CSF: Identification of CCL2\/CCR2-Dependent Gene Expression Profile","volume":"192","author":"Nieto","year":"2014","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"240","DOI":"10.12659\/MSMBR.904014","article-title":"STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis","volume":"23","author":"Gong","year":"2017","journal-title":"Med. Sci. Monit. Basic Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.atherosclerosis.2019.07.022","article-title":"Allograft inflammatory factor-1 supports macrophage survival and efferocytosis and limits necrosis in atherosclerotic plaques","volume":"289","author":"Chinnasamy","year":"2019","journal-title":"Atherosclerosis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.joca.2008.11.011","article-title":"Proinflammatory cytokines inhibit osteogenic differentiation from stem cells: Implications for bone repair during inflammation","volume":"17","author":"Lacey","year":"2009","journal-title":"Osteoarthr. Cartil."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11051","DOI":"10.1038\/ncomms11051","article-title":"Inhibition of IL-1R1\/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration","volume":"7","author":"Martino","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/jcb.10435","article-title":"Fracture healing as a post-natal developmental process: Molecular, spatial, and temporal aspects of its regulation","volume":"88","author":"Gerstenfeld","year":"2003","journal-title":"J. Cell. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1359\/jbmr.2001.16.6.1004","article-title":"Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (Osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing","volume":"16","author":"Kon","year":"2001","journal-title":"J. Bone Miner. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1089\/ten.tea.2008.0253","article-title":"Chondrogenic Differentiation of Adipose-Derived Adult Stem Cells by a Porous Scaffold Derived from Native Articular Cartilage Extracellular Matrix","volume":"15","author":"Cheng","year":"2009","journal-title":"Tissue Eng. Part A"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s12016-015-8519-2","article-title":"Macrophage Polarization and Bone Formation: A review","volume":"51","author":"Horwood","year":"2016","journal-title":"Clin. Rev. Allerg. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s00441-017-2598-8","article-title":"Macrophage type modulates osteogenic differentiation of adipose tissue MSCs","volume":"369","author":"Zhang","year":"2017","journal-title":"Cell Tissue Res."},{"key":"ref_36","first-page":"65","article-title":"The Macrophage Polarization Regulates MSC Osteoblast Differentiation in vitro","volume":"46","author":"Gong","year":"2016","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3580","DOI":"10.1080\/15384101.2015.1100771","article-title":"Rap1 induces cytokine production in pro-inflammatory macrophages through NFkappaB signaling and is highly expressed in human atherosclerotic lesions","volume":"14","author":"Cai","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1189\/jlb.2VMR0214-120RR","article-title":"A river runs through it: How autophagy, senescence, and phagocytosis could be linked to phospholipase D by Wnt signaling","volume":"96","author":"Kantonen","year":"2014","journal-title":"J. Leukocyte Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"114773","DOI":"10.1016\/j.taap.2019.114773","article-title":"Suppression of macrophages\u2014Induced inflammation via targeting RAS and PAR-4 signaling in breast cancer cell lines","volume":"385","author":"Thabet","year":"2019","journal-title":"Toxicol. Appl. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.3389\/fimmu.2018.01273","article-title":"\u201cImmuno-Transient Receptor Potential Ion Channels\u201d: The Role in Monocyte- and Macrophage-Mediated Inflammatory Responses","volume":"9","author":"Santoni","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1186\/s13287-017-0730-z","article-title":"Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis","volume":"8","author":"Lin","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3892\/mmr.2020.11764","article-title":"BMP2 induces hMSC osteogenesis and matrix remodeling","volume":"23","author":"Cai","year":"2021","journal-title":"Mol. Med. Rep."}],"container-title":["Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1996-1944\/15\/19\/6986\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:48:15Z","timestamp":1760143695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1996-1944\/15\/19\/6986"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,8]]},"references-count":42,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ma15196986"],"URL":"https:\/\/doi.org\/10.3390\/ma15196986","relation":{},"ISSN":["1996-1944"],"issn-type":[{"value":"1996-1944","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,8]]}}}