{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T04:26:38Z","timestamp":1786854398824,"version":"build-2736575974"},"reference-count":184,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wenzhou-Kean University"},{"id":[{"id":"https:\/\/ror.org\/05609xa16","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Materials"],"abstract":"<jats:p>Bacterial colonization and biofilm formation on orthopedic and dental implants remain major clinical complications, while conventional systemic antibiotics are often limited by poor penetration into biofilms and infected bone. These limitations have motivated the development of biomaterials with intrinsic antibacterial activity. Hydroxyapatite (HA), a major inorganic component of bone and teeth, possesses excellent biocompatibility, osteoconductivity, and bone-bonding ability but exhibits limited inherent antibacterial activity. Incorporation of therapeutic metal ions, including Ag+, Cu2+, Zn2+, Ti4+, Co2+, Ga3+, Sr2+, and Ce3+, has therefore emerged as a promising strategy for developing multifunctional HA-based biomaterials. This review critically examines the crystal-chemical basis of metal-ion incorporation into HA and discusses how ionic radius, oxidation state, charge-compensation mechanisms, dopant concentration, and synthesis conditions influence lattice occupancy, physicochemical properties, and biological performance. The antibacterial activity of metal-substituted and metal-modified HA systems generally involves interconnected mechanisms, including bacterial membrane damage, intracellular metabolic disruption, interference with enzymes and nucleic acids, reactive oxygen species (ROS)-mediated oxidative stress, and inhibition of bacterial adhesion and biofilm formation. Ag-, Cu-, Zn-, and Ga-containing HA systems show the most consistently reported antibacterial effects, although their efficacy and cytocompatibility depend strongly on dopant concentration and ion-release kinetics. Co-substituted HA may combine antibacterial activity with angiogenic and osteogenic stimulation, whereas Sr-substituted HA is primarily osteogenic and anti-resorptive, with variable antibacterial performance. Ti-modified HA and TiO2\/HA composites exhibit predominantly photoactive antibacterial behavior, while Ce-substituted HA shows concentration-, oxidation-state-, and synthesis-dependent biological effects. The review also evaluates protein adsorption, osteogenic and angiogenic signaling, macrophage-mediated immunomodulation, biological safety, and representative commercial and translational applications. Overall, metal-substituted HA represents a versatile platform for infection-resistant and regenerative hard-tissue biomaterials, provided that composition, phase structure, ion release, antibacterial efficacy, and cytocompatibility are systematically co-optimized before clinical translation.<\/jats:p>","DOI":"10.3390\/ma19163461","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:48:36Z","timestamp":1786722516000},"page":"3461","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metal-Substituted Hydroxyapatite Nanoparticles as Antimicrobial and Osteogenic Biomaterials for Hard-Tissue Applications"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5367-1869","authenticated-orcid":false,"given":"Ammar Z.","family":"Alshemary","sequence":"first","affiliation":[{"name":"Nanomaterials Research Center, Department of Chemistry, College of Science, Mathematics and Technology, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou 325060, China"},{"name":"Dorothy and George Hennings College of Science, Mathematics and Technology, Kean University, 1000 Morris Ave, Union, NJ 07083, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhishang","family":"Sun","sequence":"additional","affiliation":[{"name":"Nanomaterials Research Center, Department of Chemistry, College of Science, Mathematics and Technology, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou 325060, China"},{"name":"Dorothy and George Hennings College of Science, Mathematics and Technology, Kean University, 1000 Morris Ave, Union, NJ 07083, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kairui","family":"Shi","sequence":"additional","affiliation":[{"name":"Nanomaterials Research Center, Department of Chemistry, College of Science, Mathematics and Technology, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou 325060, China"},{"name":"Dorothy and George Hennings College of Science, Mathematics and Technology, Kean University, 1000 Morris Ave, Union, NJ 07083, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9355-8969","authenticated-orcid":false,"given":"Yimeng","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Science, Mathematics, and Technology, Wenzhou-Kean University, Wenzhou 325060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1033-7697","authenticated-orcid":false,"given":"\u0130smail Se\u00e7kin","family":"\u00c7ardakl\u0131","sequence":"additional","affiliation":[{"name":"Department of Metallurgical and Materials Engineering, Atat\u00fcrk University, Erzurum 25240, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Eliaz, N., and Metoki, N. (2017). Calcium phosphate bioceramics: A review of their history, structure, properties, coating technologies and biomedical applications. Materials, 10.","DOI":"10.3390\/ma10040334"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s40824-018-0149-3","article-title":"Bioactive calcium phosphate materials and applications in bone regeneration","volume":"23","author":"Jeong","year":"2019","journal-title":"Biomater. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1134\/S1990519X23700062","article-title":"Review of local cellular and molecular processes of bone tissue regeneration induced by calcium phosphate materials","volume":"18","author":"Miroshnichenko","year":"2024","journal-title":"Cell Tissue Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Liao, H., Hoekstra, J., Wolke, J., Leeuwenburgh, S.C.G., and Jansen, J. (2020). Injectable Calcium Phosphate Cements for the Reconstruction\/Repair of Oral and Cranio-Maxillofacial Bone Defects: Clinical Outcome and Perspectives. Organ Tissue Engineering, Springer.","DOI":"10.1007\/978-3-030-18512-1_17-1"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e00884","DOI":"10.1016\/j.heliyon.2018.e00884","article-title":"The Use of Hydroxyapatite Bone Substitute Grafting for Alveolar Ridge Preservation, Sinus Augmentation, and Periodontal Bone Defect: A Systematic Review","volume":"4","author":"Dewi","year":"2018","journal-title":"Heliyon"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1111\/j.1600-0757.2010.00366.x","article-title":"Current and Future Periodontal Tissue Engineering","volume":"56","author":"Izumi","year":"2011","journal-title":"Periodontology 2000"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s40824-017-0095-5","article-title":"Natural Graft Tissues and Synthetic Biomaterials for Periodontal and Alveolar Bone Reconstructive Applications: A Review","volume":"21","author":"Sheikh","year":"2017","journal-title":"Biomater. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cheah, C.W., Al-Namnam, N.M., Lau, M.N., Lim, G.S., Raman, R.P.C., Fairbairn, P., and Ngeow, W.C. (2021). Synthetic Material for Bone, Periodontal, and Dental Tissue Regeneration: Where Are We Now, and Where Are We Heading Next?. Materials, 14.","DOI":"10.3390\/ma14206123"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Alsahafi, R., Mitwalli, H., Balhaddad, A.A., Weir, M.D., Xu, H.H.K., and Melo, M.A.S. (2021). Regenerating Craniofacial Dental Defects With Calcium Phosphate Cement Scaffolds: Current Status and Innovative Scope Review. Front. Dent. Med., 2.","DOI":"10.3389\/fdmed.2021.743065"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1097\/00000658-192001000-00006","article-title":"Studies in bone growth: Triple calcium phosphate as a stimulus to osteogenesis","volume":"71","author":"Albee","year":"1920","journal-title":"Ann. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Gaihre, B., Uswatta, S., and Jayasuriya, A.C. (2017). Reconstruction of Craniomaxillofacial Bone Defects Using Tissue-Engineering Strategies With Injectable and Non-Injectable Scaffolds. J. Funct. Biomater., 8.","DOI":"10.3390\/jfb8040049"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e1504","DOI":"10.1002\/wnan.1504","article-title":"Recent Progress on Fabrication and Drug Delivery Applications of Nanostructured Hydroxyapatite","volume":"10","author":"Mondal","year":"2017","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kumar, P., Saini, M., Dehiya, B.S., Sindhu, A., Kumar, V., Kumar, R., Lamberti, L., Pruncu, C.I., and Thakur, R. (2020). Comprehensive Survey on Nanobiomaterials for Bone Tissue Engineering Applications. Nanomaterials, 10.","DOI":"10.3390\/nano10102019"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"rbae129","DOI":"10.1093\/rb\/rbae129","article-title":"Advancements in nanohydroxyapatite: Synthesis, biomedical applications and composite developments","volume":"12","author":"Zhao","year":"2025","journal-title":"Regen. Biomater."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1111\/ijac.13229","article-title":"Multisubstituted Hydroxyapatite Powders and Coatings: The Influence of the Codoping on the Hydroxyapatite Performances","volume":"16","author":"Cacciotti","year":"2019","journal-title":"Int. J. Appl. Ceram. Technol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Radulescu, D.-E., Vasile, O.R., Andronescu, E., and Ficai, A. (2023). Latest Research of Doped Hydroxyapatite for Bone Tissue Engineering. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713157"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"20150190","DOI":"10.1098\/rsif.2015.0190","article-title":"Synthesis, characterization and modelling of zinc and silicate co-substituted hydroxyapatite","volume":"12","author":"Friederichs","year":"2015","journal-title":"J. R. Soc. Interface"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3435","DOI":"10.1039\/c2cp23163h","article-title":"Unravelling the specific site preference in doping of calcium hydroxyapatite with strontium from ab initio investigations and Rietveld analyses","volume":"14","author":"Zeglinski","year":"2012","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"609024","DOI":"10.1155\/2014\/609024","article-title":"Atomistic simulation of intrinsic defects and trivalent and tetravalent ion doping in hydroxyapatite","volume":"2014","author":"Santos","year":"2014","journal-title":"Adv. Condens. Matter Phys."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"14448","DOI":"10.1016\/j.ceramint.2020.02.242","article-title":"Synthesis, characterization and in vitro evaluation of zinc and strontium binary doped hydroxyapatite for biomedical application","volume":"46","author":"Ullah","year":"2020","journal-title":"Ceram. Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1111\/jace.18853","article-title":"Ca-vacancy effect on the stability of substitutional divalent cations in calcium-deficient hydroxyapatite","volume":"106","author":"Saito","year":"2023","journal-title":"J. Am. Ceram. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"415676","DOI":"10.1016\/j.physb.2024.415676","article-title":"Novel synthesis and crystallographic results of zinc substituted hydroxyapatite with high thermal stability","volume":"676","author":"Bianchi","year":"2024","journal-title":"Phys. B Condens. Matter"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12070","DOI":"10.1016\/j.ceramint.2017.06.062","article-title":"Strontium and zinc co-substituted nanophase hydroxyapatite","volume":"43","author":"Lowry","year":"2017","journal-title":"Ceram. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1021\/acs.cgd.3c01502","article-title":"Ti-Modified Hydroxyapatites: Synthesis, Crystal Chemistry, and Photocatalytic Activity","volume":"24","author":"Korneev","year":"2024","journal-title":"Cryst. Growth Des."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"031009","DOI":"10.1115\/1.4071647","article-title":"Correlating Phase Evolution and Morphology of Hydroxyapatite\u2013Titanium Composites With Titanium Content and Thermal Processing","volume":"148","author":"Dhamale","year":"2026","journal-title":"J. Eng. Mater. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"rbae041","DOI":"10.1093\/rb\/rbae041","article-title":"Effect of a synthetic hydroxyapatite-based bone grafting material compared to established bone substitute materials on regeneration of critical-size bone defects in the ovine scapula","volume":"11","author":"Neckel","year":"2024","journal-title":"Regen. Biomater."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Liu, W., Cheong, N., He, Z., and Zhang, T. (2025). Application of hydroxyapatite composites in bone tissue engineering: A review. J. Funct. Biomater., 16.","DOI":"10.3390\/jfb16040127"},{"key":"ref_28","first-page":"100231","article-title":"A review on antimicrobial strategies in mitigating biofilm-associated infections on medical implants","volume":"6","author":"Kadirvelu","year":"2024","journal-title":"Curr. Res. Microb. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s00402-026-06225-3","article-title":"Comparative effectiveness of antimicrobial implant surface coatings in preventing orthopaedic implant-associated infections: A network meta-analysis","volume":"146","author":"Elsheikh","year":"2026","journal-title":"Arch. Orthop. Trauma Surg."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Liu, X., Ma, P., Liu, X., Liu, S., Liu, X., Wang, R., and Gao, H. (2026). Resistance mechanisms of bacterial biofilms on orthopedic implants and research progress on novel anti-biofilm coatings. Front. Bioeng. Biotechnol., 14.","DOI":"10.3389\/fbioe.2026.1707232"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Imran, E., Mei, M.L., Li, K.C., Ratnayake, J., Ekambaram, M., and Cooper, P.R. (2024). Dental applications of ion-substituted hydroxyapatite: A review of the literature. Dent. J., 12.","DOI":"10.3390\/dj12100304"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wang, X., Huang, S., and Peng, Q. (2023). Metal ion-doped hydroxyapatite-based materials for bone defect restoration. Bioengineering, 10.","DOI":"10.3390\/bioengineering10121367"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"29339","DOI":"10.1038\/s41598-024-80303-7","article-title":"Effect of silver ion and silicate group on the antibacterial and antifungal properties of nanosized hydroxyapatite","volume":"14","author":"Pinchuk","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_34","first-page":"264","article-title":"Investigation of the antibacterial activity of synthesized hydroxyapatite Sr-doped nanocomposite","volume":"14","author":"Jamarun","year":"2024","journal-title":"J. Appl. Pharm. Sci."},{"key":"ref_35","first-page":"e52177","article-title":"The synthesis, characterization, and assessment of antibacterial properties of an orthodontic adhesive containing cerium-substituted hydroxyapatite nanoparticles: An in vitro study","volume":"16","author":"Singh","year":"2024","journal-title":"Cureus"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/jbm.b.35151","article-title":"Investigating the structure, solubility, and antibacterial properties of silver-and copper-doped hydroxyapatite","volume":"111","author":"Weiss","year":"2023","journal-title":"J. Biomed. Mater. Res. B Appl. Biomater."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13453","DOI":"10.1039\/D5RA00792E","article-title":"Photocatalytic TiO 2\/HAP nanocomposite for antimicrobial treatment, promineralization, and tooth whitening","volume":"15","author":"Wang","year":"2025","journal-title":"RSC Adv."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lebedev, V.N., Kharovskaya, M.I., Lazoryak, B.I., Solovieva, A.O., Fadeeva, I.V., Amirov, A.A., Koliushenkov, M.A., Orudzhev, F.F., Baryshnikova, O.V., and Yankova, V.G. (2024). Strontium and copper Co-doped multifunctional calcium phosphates: Biomimetic and antibacterial materials for bone implants. Biomimetics, 9.","DOI":"10.3390\/biomimetics9040252"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jac\/dkae380","article-title":"Bactericidal versus bacteriostatic antibacterials: Clinical significance, differences and synergistic potential in clinical practice","volume":"80","author":"Ishak","year":"2025","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1128\/AAC.46.6.1940-1945.2002","article-title":"Broad-spectrum bactericidal activity of Ag2O-doped bioactive glass","volume":"46","author":"Bellantone","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1039\/C9TB02710F","article-title":"Substituted hydroxyapatite coatings of bone implants","volume":"8","author":"Arcos","year":"2020","journal-title":"J. Mater. Chem. B"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1098\/rsfs.2012.0012","article-title":"A review of protein adsorption on bioceramics","volume":"2","author":"Wang","year":"2012","journal-title":"Interface Focus"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"23393","DOI":"10.1021\/acsnano.5c06573","article-title":"Exploring the Impact of Biotic and Abiotic Surfaces on Protein Binding Modulation and Bacteria Attachment: Integrating Biological and Mathematical Approaches","volume":"19","author":"Souza","year":"2025","journal-title":"ACS Nano"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/s41522-025-00907-3","article-title":"Emerging non-antibiotic strategies for implant-associated biofilm infections by reprogramming the dysregulated immune microenvironment","volume":"12","author":"Zhang","year":"2026","journal-title":"npj Biofilms Microbiomes"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s40824-022-00269-3","article-title":"Surface coating of orthopedic implant to enhance the osseointegration and reduction of bacterial colonization: A review","volume":"26","author":"Bohara","year":"2022","journal-title":"Biomater. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Xiang, B., Jiang, J., Wang, H., and Song, L. (2025). Research progress of implantable materials in antibacterial treatment of bone infection. Front. Bioeng. Biotechnol., 13.","DOI":"10.3389\/fbioe.2025.1586898"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e25","DOI":"10.2106\/JBJS.OA.25.00157","article-title":"Local Antibiotic Delivery Systems and Their Applications in Orthopaedic Surgery","volume":"10","author":"Hoveidaei","year":"2025","journal-title":"JBJS Open Access"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Luboja\u0144ski, A., Zakrzewski, W., Sam\u00f3l, K., Bieszczad-Czaja, M., \u015awita\u0142a, M., Wiglusz, R., Watras, A., Mielan, B., and Dobrzy\u0144ski, M. (2024). Application of nanohydroxyapatite in medicine\u2014A narrative review. Molecules, 29.","DOI":"10.3390\/molecules29235628"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Popowski, W., Koseski, D., Domanowska, D., Zalewska, M., and Popowska, M. (2025). Bacterial colonization of bone substitute materials used in oral surgery: Mechanisms, clinical implications, and preventive strategies\u2014A narrative review. Front. Microbiol., 16.","DOI":"10.3389\/fmicb.2025.1715632"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.microc.2018.10.007","article-title":"Co-doped hydroxyapatites as potential materials for biomedical applications","volume":"144","author":"Yilmaz","year":"2019","journal-title":"Microchem. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"201785","DOI":"10.1098\/rsos.201785","article-title":"Ion release from hydroxyapatite and substituted hydroxyapatites in different immersion liquids: In vitro experiments and theoretical modelling study","volume":"8","author":"Mocanu","year":"2021","journal-title":"R. Soc. Open Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"103013","DOI":"10.1016\/j.cis.2023.103013","article-title":"Hydroxyapatite: A journey from biomaterials to advanced functional materials","volume":"321","author":"Mondal","year":"2023","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"100227","DOI":"10.1016\/j.mtbio.2022.100227","article-title":"Bone mineral: A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin","volume":"14","author":"Liu","year":"2022","journal-title":"Mater. Today Bio"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Lara-Ochoa, S., Ortega-Lara, W., and Guerrero-Beltr\u00e1n, C.E. (2021). Hydroxyapatite nanoparticles in drug delivery: Physicochemistry and applications. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13101642"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"105092","DOI":"10.1016\/j.jddst.2023.105092","article-title":"Enhancing drug loading and release with hydroxyapatite nanoparticles for efficient drug delivery: A review synthesis methods, surface ion effects, and clinical prospects","volume":"90","author":"Safitri","year":"2023","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"100609","DOI":"10.1016\/j.hybadv.2026.100609","article-title":"Functionalized hydroxyapatite nanocomposites for localized drug delivery in bone cancer","volume":"12","author":"Singh","year":"2026","journal-title":"Hybrid Adv."},{"key":"ref_57","first-page":"173","article-title":"Nanocrystalline hydroxyapatite and zinc-doped hydroxyapatite as carrier material for controlled delivery of ciprofloxacin","volume":"1","author":"Ramasamy","year":"2011","journal-title":"3 Biotech"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Iconaru, S.L., Predoi, D., Ciobanu, C.S., Negrila, C.C., Trusca, R., Raaen, S., Rokosz, K., Ghegoiu, L., Badea, M.L., and Cimpeanu, C. (2024). Novel Antimicrobial Agents Based on Zinc-Doped Hydroxyapatite Loaded with Tetracycline. Antibiotics, 13.","DOI":"10.3390\/antibiotics13090803"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"123969","DOI":"10.1016\/j.ijpharm.2024.123969","article-title":"Doxorubicin loaded cerium substituted hydroxyapatite nanoparticles: A promising new therapeutic approach for bone regeneration, doxorubicin delivery, and cancer treatment","volume":"654","author":"Moaness","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Maggi, L., Friuli, V., Cerea, B., Bruni, G., Berbenni, V., and Bini, M. (2024). Physicochemical characterization of hydroxyapatite hybrids with meloxicam for dissolution rate improvement. Molecules, 29.","DOI":"10.3390\/molecules29112419"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5947","DOI":"10.1021\/acsbiomaterials.9b00893","article-title":"Surface Phenomena Enhancing the Antibacterial and Osteogenic Ability of Nanocrystalline Hydroxyapatite, Activated by Multiple-Ion Doping","volume":"5","author":"Sprio","year":"2019","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5554","DOI":"10.1016\/j.jeurceramsoc.2018.07.056","article-title":"Nanostructural insights into the dissolution behavior of Sr-doped hydroxyapatite","volume":"38","author":"Zhu","year":"2018","journal-title":"J. Eur. Ceram. Soc."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.2147\/IJN.S246764","article-title":"The antibacterial mechanism of silver nanoparticles and its application in dentistry","volume":"15","author":"Yin","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Ma, X., Zhou, S., Xu, X., and Du, Q. (2022). Copper-containing nanoparticles: Mechanism of antimicrobial effect and application in dentistry-a narrative review. Front. Surg., 9.","DOI":"10.3389\/fsurg.2022.905892"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"More, P.R., Pandit, S., Filippis, A.D., Franci, G., Mijakovic, I., and Galdiero, M. (2023). Silver nanoparticles: Bactericidal and mechanistic approach against drug resistant pathogens. Microorganisms, 11.","DOI":"10.3390\/microorganisms11020369"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Mosina, M., Siverino, C., Stipniece, L., Sceglovs, A., Vasiljevs, R., Moriarty, T.F., and Locs, J. (2023). Gallium-doped hydroxyapatite shows antibacterial activity against pseudomonas aeruginosa without affecting cell metabolic activity. J. Funct. Biomater., 14.","DOI":"10.3390\/jfb14020051"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Li, F., Liu, F., Huang, K., and Yang, S. (2022). Advancement of gallium and gallium-based compounds as antimicrobial agents. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.827960"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"26426","DOI":"10.1038\/s41598-024-76088-4","article-title":"Enhanced antimicrobial efficacy of hydroxyapatite-based composites for healthcare applications","volume":"14","author":"Hassanain","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1007\/s00723-025-01777-w","article-title":"Ce (III) Ions in Hydroxyapatite: Nanoscale Environment Investigation","volume":"56","author":"Sadovnikova","year":"2025","journal-title":"Appl. Magn. Reson."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Rodrigues, A.S., Batista, J.G., Rodrigues, M.\u00c1., Thipe, V.C., Minarini, L.A., Lopes, P.S., and Lug\u00e3o, A.B. (2024). Advances in silver nanoparticles: A comprehensive review on their potential as antimicrobial agents and their mechanisms of action elucidated by proteomics. Front. Microbiol., 15.","DOI":"10.3389\/fmicb.2024.1440065"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"9954","DOI":"10.1039\/D5TB01113B","article-title":"Balancing antibacterial activity and toxicity in silver-loaded hydroxyapatite: The impact of the silver nanoparticle incorporation method","volume":"13","author":"Kucukosman","year":"2025","journal-title":"J. Mater. Chem. B"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1186\/1556-276X-7-324","article-title":"Antibacterial activity of silver-doped hydroxyapatite nanoparticles against gram-positive and gram-negative bacteria","volume":"7","author":"Ciobanu","year":"2012","journal-title":"Nanoscale Res. Lett."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1101\/cshperspect.a000414","article-title":"The bacterial cell envelope","volume":"2","author":"Silhavy","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_74","first-page":"53","article-title":"The effect of charge at the surface of silver nanoparticles on antimicrobial activity against gram-positive and gram-negative bacteria: A preliminary study","volume":"16","author":"Abbaszadegan","year":"2015","journal-title":"J. Nanomater."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"8140","DOI":"10.1021\/la3003838","article-title":"Antibacterial activity of glutathione-coated silver nanoparticles against Gram positive and Gram negative bacteria","volume":"28","author":"Taglietti","year":"2012","journal-title":"Langmuir ACS J. Surf. Colloids"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.nantod.2015.04.002","article-title":"Antibacterial activity of silver nanoparticles: A surface science insight","volume":"10","author":"Ouay","year":"2015","journal-title":"Nano Today"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"34185","DOI":"10.1021\/acsomega.1c05921","article-title":"Investigation of antibacterial activity and cell viability of Ag\/Mg and Ag\/Zn co-doped hydroxyapatite derived from natural limestone","volume":"6","author":"Sinulingga","year":"2021","journal-title":"ACS Omega"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3892\/etm.2025.12801","article-title":"Ionic silver coating of orthopedic implants may impair osteogenic differentiation and mineralization","volume":"29","author":"Kontakis","year":"2025","journal-title":"Exp. Ther. Med."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Gokcekaya, O., Ergun, C., Webster, T., Bahadir, A., Ueda, K., Narushima, T., and Nakano, T. (2021). Effect of Precursor Deficiency Induced Ca\/P Ratio on Antibacterial and Osteoblast Adhesion Properties of Ag-Incorporated Hydroxyapatite: Reducing Ag Toxicity. Materials, 14.","DOI":"10.3390\/ma14123158"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1002\/jbm.b.31985","article-title":"Antibacterial effect and cytotoxicity of Ag-doped functionally graded hydroxyapatite coatings","volume":"100","author":"Bai","year":"2012","journal-title":"J. Biomed. Mater. Res. B Appl. Biomater."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"fuaf060","DOI":"10.1093\/femsre\/fuaf060","article-title":"Emerging strategies of bacterial adaptation mechanisms to silver and metal oxide nanomaterials","volume":"50","year":"2026","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.actbio.2020.09.044","article-title":"Biological properties of copper-doped biomaterials for orthopedic applications: A review of antibacterial, angiogenic and osteogenic aspects","volume":"117","author":"Jacobs","year":"2020","journal-title":"Acta Biomater."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3421","DOI":"10.1038\/s41598-024-53704-x","article-title":"Exploring the various effects of Cu doping in hydroxyapatite nanoparticle","volume":"14","author":"Noori","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1007\/s10534-024-00620-2","article-title":"Copper doped hydroxyapatite nanocomposite thin films: Synthesis, physico\u2013chemical and biological evaluation","volume":"37","author":"Ciobanu","year":"2024","journal-title":"Biometals"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1039\/D2NJ04130H","article-title":"Crystallographic characterization and application of copper doped hydroxyapatite as a biomaterial","volume":"47","author":"Tuntun","year":"2023","journal-title":"New J. Chem."},{"key":"ref_86","unstructured":"National Institutes of Health, Office of Dietary Supplements (2026, July 25). Copper: Fact Sheet for Health Professionals, Available online: https:\/\/ods.od.nih.gov\/factsheets\/Copper-HealthProfessional\/."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"678","DOI":"10.3390\/powders2040042","article-title":"Cu-substituted hydroxyapatite powder: Mechanochemical synthesis using different copper sources and thermal stability","volume":"2","author":"Eremina","year":"2023","journal-title":"Powders"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Ramos-Z\u00fa\u00f1iga, J., Bruna, N., and P\u00e9rez-Donoso, J. (2023). Toxicity Mechanisms of Copper Nanoparticles and Copper Surfaces on Bacterial Cells and Viruses. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310503"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Saraeva, I., Tolordava, E., Yushina, Y., Sozaev, I., Sokolova, V., Khmelnitskiy, R., Sheligyna, S., Pallaeva, T., Pokryshkin, N., and Khmelenin, D. (2022). Direct Bactericidal Comparison of Metal Nanoparticles and Their Salts against S. aureus Culture by TEM and FT-IR Spectroscopy. Nanomaterials, 12.","DOI":"10.3390\/nano12213857"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"49402","DOI":"10.1021\/acsami.1c11236","article-title":"High-Resolution Microscopical Studies of Contact Killing Mechanisms on Copper-Based Surfaces","volume":"13","author":"Chang","year":"2021","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"15845","DOI":"10.1021\/acsnano.4c02825","article-title":"CuCo2O4 Nanoflowers with Multiple Enzyme Activities for Treating Bacterium-Infected Wounds via Cuproptosis-like Death","volume":"18","author":"Wang","year":"2024","journal-title":"ACS Nano"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/adhm.201500712","article-title":"Towards a Molecular Understanding of the Antibacterial Mechanism of Copper-bearing Titanium Alloys against Staphylococcus aureus","volume":"5","author":"Li","year":"2015","journal-title":"Adv. Healthc. Mater."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"11631","DOI":"10.1021\/acsami.0c22746","article-title":"Effective Antibacterial Activity of Degradable Copper-Doped Phosphate-Based Glass Nanozymes","volume":"13","author":"Liu","year":"2021","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.colsurfb.2012.03.021","article-title":"A novel study of antibacterial activity of copper iodide nanoparticle mediated by DNA and membrane damage","volume":"96","author":"Pramanik","year":"2012","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_95","first-page":"50","article-title":"Unexpected Enhancement of the Antibacterial Activity of Copper Ions in the Presence of Nanobubbles","volume":"96","author":"Zheng","year":"2025","journal-title":"Langmuir ACS J. Surf. Colloids"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"6083","DOI":"10.1016\/j.apsusc.2010.03.124","article-title":"Synthesis, characterization and antimicrobial activity of copper and zinc-doped hydroxyapatite nanopowders","volume":"256","year":"2010","journal-title":"Appl. Surf. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Benali, Y., Predoi, D., Rokosz, K., Ciobanu, C.S., Iconaru, S.L., Raaen, S., Negrila, C.C., Cimpeanu, C., Trusca, R., and Ghegoiu, L. (2024). Physico-chemical properties of copper-doped hydroxyapatite coatings obtained by vacuum deposition technique. Materials, 17.","DOI":"10.3390\/ma17153681"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Prosolov, K., Lastovka, V., Khimich, M., Glukhov, I., Kashin, A., Luginin, N., and Sharkeev, Y. (2023). Influence of Cu Substitution on the Properties of Hydroxyapatite Targets and Deposited Coatings. Coatings, 13.","DOI":"10.3390\/coatings13081410"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1177\/08853282231198726","article-title":"Selenium-and\/or copper-substituted hydroxyapatite: A bioceramic substrate for biomedical applications","volume":"38","author":"Korowash","year":"2023","journal-title":"J. Biomater. Appl."},{"key":"ref_100","unstructured":"National Institutes of Health, Office of Dietary Supplements (2026, July 25). Zinc: Fact Sheet for Health Professionals, Available online: https:\/\/ods.od.nih.gov\/factsheets\/Zinc-HealthProfessional\/."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"11405","DOI":"10.1039\/D3TB01874A","article-title":"Zinc-based biomaterials for bone repair and regeneration: Mechanism and applications","volume":"11","author":"Wen","year":"2023","journal-title":"J. Mater. Chem. B"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"5640","DOI":"10.1007\/s12011-023-03631-1","article-title":"The role of zinc in bone tissue health and regeneration\u2014A review","volume":"201","author":"Molenda","year":"2023","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Dornelas, J., Dornelas, G., Rossi, A., Piattelli, A., Di Pietro, N., Romasco, T., Mour\u00e3o, C.F., and Alves, G.G. (2024). The incorporation of zinc into hydroxyapatite and its influence on the cellular response to biomaterials: A systematic review. J. Funct. Biomater., 15.","DOI":"10.3390\/jfb15070178"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Fosca, M., Streza, A., Antoniac, I.V., Vadal\u00e0, G., and Rau, J.V. (2023). Ion-doped calcium phosphate-based coatings with antibacterial properties. J. Funct. Biomater., 14.","DOI":"10.3390\/jfb14050250"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Guerra-L\u00f3pez, J.R., Bianchi, A.E., Ramos, M.A., Ubertino, M., Ferraresi-Curotto, V., G\u00fcida, J.A., Barbaro, K., Zhukova, A.A., Grigorieva, V.Y., and Rau, J.V. (2025). Preparation of Zinc-doped hydroxyapatite ceramics and evaluation of biocompatibility and antibacterial activity. J. Funct. Biomater., 16.","DOI":"10.3390\/jfb16030088"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Predoi, D., Iconaru, S.L., Predoi, M.V., Motelica-Heino, M., Guegan, R., and Buton, N. (2019). Evaluation of antibacterial activity of zinc-doped hydroxyapatite colloids and dispersion stability using ultrasounds. Nanomaterials, 9.","DOI":"10.3390\/nano9040515"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s40820-015-0040-x","article-title":"Review on zinc oxide nanoparticles: Antibacterial activity and toxicity mechanism","volume":"7","author":"Sirelkhatim","year":"2015","journal-title":"Nano-Micro Lett."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"21964","DOI":"10.1021\/acsanm.4c03941","article-title":"Antibacterial activity of zinc-doped hydroxyapatite and vancomycin-loaded gelatin nanoparticles against intracellular staphylococcus aureus in human thp-1 derived macrophages","volume":"7","author":"Cuypers","year":"2024","journal-title":"ACS Appl. Nano Mater."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e14434","DOI":"10.1016\/j.heliyon.2023.e14434","article-title":"Hydrothermally synthesized titanium\/hydroxyapatite as photoactive and antibacterial biomaterial","volume":"9","author":"Fatimah","year":"2023","journal-title":"Heliyon"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/j.msec.2010.06.011","article-title":"Antibacterial efficacy and cytotoxicity studies of copper (II) and titanium (IV) substituted hydroxyapatite nanoparticles","volume":"30","author":"Li","year":"2010","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"811","DOI":"10.4028\/www.scientific.net\/MSF.993.811","article-title":"Cobalt element doping for biomedical use: A review","volume":"993","author":"Liu","year":"2020","journal-title":"Mater. Sci. Forum"},{"key":"ref_112","unstructured":"Office of Dietary Supplements (2026, July 25). National Institutes of Health Vitamin B12 Fact Sheet for Health Professionals, Available online: https:\/\/ods.od.nih.gov\/factsheets\/VitaminB12-HealthProfessional\/."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1007\/s11051-013-1644-z","article-title":"Cobalt-doped nanohydroxyapatite: Synthesis, characterization, antimicrobial and hemolytic studies","volume":"15","author":"Tank","year":"2013","journal-title":"J. Nanopart. Res."},{"key":"ref_114","first-page":"39","article-title":"Hydrothermal Synthesis of Cobalt-Doped Hydroxyapatite Nanoparticles: Structure, Magnetic Behaviour, Bioactivity and Antibacterial Activity","volume":"16","author":"Yazdani","year":"2019","journal-title":"Iran. J. Mater. Sci. Eng."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.msec.2015.08.052","article-title":"Cobalt doped proangiogenic hydroxyapatite for bone tissue engineering application","volume":"58","author":"Kulanthaivel","year":"2016","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"108554","DOI":"10.1016\/j.mtcomm.2024.108554","article-title":"Cobalt-doped hydroxyapatite for bone tissue engineering: Synthesis, characterization and in vitro biocompatibility of real-time extract","volume":"38","author":"Yan","year":"2024","journal-title":"Mater. Today Commun."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/s41598-024-84055-2","article-title":"Effect of cobalt ions doping on morphology and electrochemical properties of hydroxyapatite coatings for biomedical applications","volume":"15","author":"Parhizkar","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2409200","DOI":"10.1002\/advs.202409200","article-title":"A Multifunctional Cobalt-Containing Implant for Treating Biofilm Infections and Promoting Osteointegration in Infected Bone Defects Through Macrophage-Mediated Immunomodulation","volume":"12","author":"Yan","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"9149","DOI":"10.3390\/cimb46080541","article-title":"Antimicrobial activity of gallium (III) compounds: Pathogen-dependent targeting of multiple iron\/heme-dependent biological processes","volume":"46","author":"Choi","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"31122","DOI":"10.1039\/D5RA04216J","article-title":"Antibacterial activity and mechanistic insights of gallium-based nanoparticles: An emerging frontier in metal-based antimicrobials","volume":"15","author":"Ikhazuagbe","year":"2025","journal-title":"RSC Adv."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Pajor, K., Michalicha, A., Belcarz, A., Pajchel, L., Zgadzaj, A., Wojas, F., and Kolmas, J. (2022). Antibacterial and cytotoxicity evaluation of new hydroxyapatite-based granules containing silver or gallium ions with potential use as bone substitutes. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23137102"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"112839","DOI":"10.1039\/C6RA23424K","article-title":"Designing Ga (iii)-containing hydroxyapatite with antibacterial activity","volume":"6","author":"Kurtjak","year":"2016","journal-title":"RSC Adv."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Almuradova, E., and Cicin, I. (2023). Cancer-related hypercalcemia and potential treatments. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1039490"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"You, J., Zhang, Y., and Zhou, Y. (2022). Strontium functionalized in biomaterials for bone tissue engineering: A prominent role in osteoimmunomodulation. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.928799"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"10902","DOI":"10.1039\/D5RA00308C","article-title":"Exploring the role of strontium-based nanoparticles in modulating bone regeneration and antimicrobial resistance: A public health perspective","volume":"15","author":"Akobundu","year":"2025","journal-title":"RSC Adv."},{"key":"ref_126","first-page":"152512","article-title":"Synthesis, surface chemical characterization, and enhanced osteoblast response of strontium-substituted hydroxyapatite nanoparticles for alveolar bone regeneration","volume":"15","author":"Qiao","year":"2025","journal-title":"J. Nanostruct. Chem."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Mirkovi\u0107, M., Sknepnek, A., Kalijadis, A., Krsti\u0107, A., \u0160uljagi\u0107, M., Peri\u0107, M., and Andjelkovi\u0107, L. (2025). Nanostructured Sr-Doped Hydroxyapatite: A Material with Antimicrobial Potential. Nanomaterials, 15.","DOI":"10.3390\/nano15211651"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1007\/s12011-021-02697-z","article-title":"Synthesis of Silver-and Strontium-Substituted Hydroxyapatite with Combined Osteogenic and Antibacterial Activities","volume":"200","author":"Li","year":"2022","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1016\/j.actbio.2008.05.005","article-title":"Strontium-substituted hydroxyapatite coatings synthesized by pulsed-laser deposition: In vitro osteoblast and osteoclast response","volume":"4","author":"Capuccini","year":"2008","journal-title":"Acta Biomater."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1016\/j.msec.2019.02.053","article-title":"Osteogenic, anti-osteoclastogenic and immunomodulatory properties of a strontium-releasing hybrid scaffold for bone repair","volume":"99","author":"Torres","year":"2019","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"101931","DOI":"10.1016\/j.mtchem.2024.101931","article-title":"A novel calcium phosphate-based ceramic scaffolds with unexpected high osteogenic activity by strontium doping","volume":"36","author":"Lu","year":"2024","journal-title":"Mater. Today Chem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"3368","DOI":"10.1016\/j.ceramint.2020.09.182","article-title":"Strontium substituted hydroxyapatite promotes direct primary human osteoblast maturation","volume":"47","author":"Stipniece","year":"2020","journal-title":"Ceram. Int."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1007\/s13346-021-00946-1","article-title":"Osteointegration, antimicrobial and antibiofilm activity of orthopaedic titanium surfaces coated with silver and strontium-doped hydroxyapatite using a novel blasting process","volume":"11","author":"Sullivan","year":"2021","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Maqbool, M., Nawaz, Q., Rehman, M.A.U., Cresswell, M., Jackson, P., Hurle, K., Detsch, R., Goldmann, W., Shah, A., and Boccaccini, A. (2021). Synthesis, Characterization, Antibacterial Properties, and In Vitro Studies of Selenium and Strontium Co-Substituted Hydroxyapatite. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084246"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1016\/j.ceramint.2025.12.012","article-title":"Preparation and characterization of superhydrophilic Sr-doped hydroxyapatite coatings for medical implant surfaces","volume":"52","author":"Lu","year":"2025","journal-title":"Ceram. Int."},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Liu, L., Hou, S., Xu, G., Gao, J., Mu, J., Gao, M., He, J., Su, X., Yang, Z., and Liu, Y. (2024). Evaluation of osteogenic properties of a novel injectable bone-repair material containing strontium in vitro and in vivo. Front. Bioeng. Biotechnol., 12.","DOI":"10.3389\/fbioe.2024.1390337"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"128788","DOI":"10.1016\/j.surfcoat.2022.128788","article-title":"Physicochemical, osteogenic and antimicrobial properties of graphene oxide reinforced silver\/strontium-doped hydroxyapatite on titanium for potential orthopedic applications","volume":"446","author":"Huang","year":"2022","journal-title":"Surf. Coat. Technol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1016\/j.actbio.2012.04.004","article-title":"Antibacterial and biological characteristics of plasma sprayed silver and strontium doped hydroxyapatite coatings","volume":"8","author":"Fielding","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Chen, S., Wang, Y., Bao, S., Yao, L., Fu, X., Yu, Y., Lyu, H., Pang, H., Guo, S., and Zhang, H. (2024). Cerium oxide nanoparticles in wound care: A review of mechanisms and therapeutic applications. Front. Bioeng. Biotechnol., 12.","DOI":"10.3389\/fbioe.2024.1404651"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"8601","DOI":"10.1021\/acsomega.3c03661","article-title":"Advanced biological applications of cerium oxide nanozymes in disease related to oxidative damage","volume":"9","author":"Bai","year":"2024","journal-title":"ACS Omega"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"433","DOI":"10.2298\/JSC150824007C","article-title":"Cerium doped hydroxyapatite nanoparticles synthesized by coprecipitation method","volume":"81","author":"Ciobanu","year":"2016","journal-title":"J. Serbian Chem. Soc."},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Predoi, D., Iconaru, S.L., Predoi, M.V., Groza, A., Gaiaschi, S., Rokosz, K., Raaen, S., Negrila, C.C., Prodan, A.-M., and Costescu, A. (2020). Development of cerium-doped hydroxyapatite coatings with antimicrobial properties for biomedical applications. Coatings, 10.","DOI":"10.3390\/coatings10060516"},{"key":"ref_143","first-page":"100731","article-title":"Cerium, copper, gallium, manganese and silver substituted hydroxyapatite: Cytotoxicity and antibacterial activity toward multidrug-resistant clinical isolates","volume":"18","author":"Ivankovic","year":"2025","journal-title":"J. Hazard. Mater. Adv."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Kubiak-Mihkelsoo, Z., Kostrz\u0119bska, A., B\u0142aszczyszyn, A., Pitu\u0142aj, A., Dominiak, M., Gedrange, T., Nawrot-Hadzik, I., Matys, J., and Hadzik, J. (2025). Ionic doping of hydroxyapatite for bone regeneration: Advances in structure and properties over two decades\u2014A narrative review. Appl. Sci., 15.","DOI":"10.3390\/app15031108"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"178123","DOI":"10.1155\/2014\/178123","article-title":"Substituted hydroxyapatites with antibacterial properties","volume":"2014","author":"Kolmas","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Jadbabaee, S., Mohebi Far, F., Esmaeili, J., and Kolahdoozan, M. (2025). The role of ion-doped hydroxyapatite in drug delivery, tissue engineering, wound healing, implants, and imaging. Chemistry, 7.","DOI":"10.3390\/chemistry7050137"},{"key":"ref_147","first-page":"35","article-title":"Silver ion doped hydroxyapatite-coated titanium pins prevent bacterial colonization","volume":"32","author":"Sevencan","year":"2020","journal-title":"Jt. Dis. Relat. Surg."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1016\/j.msec.2012.12.018","article-title":"Antibacterial, cytotoxicity and physical properties of laser--silver doped hydroxyapatite layers","volume":"33","author":"Kocourek","year":"2013","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"104730","DOI":"10.1016\/j.ultsonch.2019.104730","article-title":"Enhanced antibacterial and corrosion resistance properties of Ag substituted hydroxyapatite\/functionalized multiwall carbon nanotube nanocomposite coating on 316L stainless steel for biomedical application","volume":"59","author":"Sivaraj","year":"2019","journal-title":"Ultrason. Sonochem."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.msec.2016.10.079","article-title":"Incorporation of silver and strontium in hydroxyapatite coating on titanium surface for enhanced antibacterial and biological properties","volume":"71","author":"Geng","year":"2017","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"28231","DOI":"10.1016\/j.ceramint.2022.06.128","article-title":"Bactericidal and in vitro osteogenic activity of nano sized cobalt-doped silicate hydroxyapatite","volume":"48","author":"Alshemary","year":"2022","journal-title":"Ceram. Int."},{"key":"ref_152","first-page":"513","article-title":"Antibacterial and magnetic response of site-specific cobalt incorporated hydroxyapatite","volume":"46","author":"Gupta","year":"2019","journal-title":"Ceram. Int."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1002\/jbm.a.36249","article-title":"New hydroxyapatite nanophases with enhanced osteogenic and anti-bacterial activity","volume":"106","author":"Ballardini","year":"2018","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_154","first-page":"195","article-title":"Zn\/Sr dual ions-collagen co-assembly hydroxyapatite enhances bone regeneration through procedural osteo-immunomodulation and osteogenesis","volume":"10","author":"Zhong","year":"2021","journal-title":"Bioact. Mater."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"25292","DOI":"10.1039\/D6RA01689H","article-title":"Harnessing copper\u2013strontium synergy in an injectable composite for multi-pathway bone regeneration","volume":"16","author":"Zhu","year":"2026","journal-title":"RSC Adv."},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Zhang, H., Wu, Z., Wang, Z., Yan, X., Duan, X., and Sun, H. (2025). Advanced surface modification techniques for titanium implants: A review of osteogenic and antibacterial strategies. Front. Bioeng. Biotechnol., 13.","DOI":"10.3389\/fbioe.2025.1549439"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.ijbiomac.2022.03.166","article-title":"Assessment of protein adhesion behaviour and biocompatibility of magnesium\/Co-substituted HA-based composites for orthopaedic application","volume":"208","author":"Dubey","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"9572","DOI":"10.1039\/D2DT00969B","article-title":"Surface modification of hydroxyapatite nanoparticles for bone regeneration by controlling their surface hydration and protein adsorption states","volume":"51","author":"Liu","year":"2022","journal-title":"Dalton Trans."},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Dorm, B., Iemma, M., Neto, B.D., Francisco, R.C.L., Dini\u0107, I., Ignjatovi\u0107, N., Markovi\u0107, S., Vukovic, M., \u0160kapin, S., and Trovatti, E. (2022). Synthesis and Biological Properties of Alanine-Grafted Hydroxyapatite Nanoparticles. Life, 13.","DOI":"10.3390\/life13010116"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.actbio.2024.11.026","article-title":"Deoxygenated hydroxyapatite inhibits macrophage inflammation through fibronectin restricted adsorption","volume":"191","author":"Zhou","year":"2024","journal-title":"Acta Biomater."},{"key":"ref_161","first-page":"56","article-title":"Constructions of ROS-responsive titanium-hydroxyapatite implant for mesenchymal stem cell recruitment in peri-implant space and bone formation in osteoporosis microenvironment","volume":"18","author":"Chen","year":"2022","journal-title":"Bioact. Mater."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.1007\/s12011-022-03382-5","article-title":"Magnesium (Mg2\u2009+), Strontium (Sr2\u2009+), and Zinc (Zn2\u2009+) Co-substituted Bone Cements Based on Nano-hydroxyapatite\/Monetite for Bone Regeneration","volume":"201","author":"Dias","year":"2022","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1038\/s41598-022-05207-w","article-title":"PLA\/Hydroxyapatite scaffolds exhibit in vitro immunological inertness and promote robust osteogenic differentiation of human mesenchymal stem cells without osteogenic stimuli","volume":"12","author":"Bernardo","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"133382","DOI":"10.1016\/j.cej.2021.133382","article-title":"Remotely-activatable extracellular matrix-mimetic hydrogel promotes physiological bone mineralization for enhanced cranial defect healing","volume":"431","author":"Tan","year":"2021","journal-title":"Chem. Eng. J."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12938-023-01067-1","article-title":"Calcium-to-phosphorus releasing ratio affects osteoinductivity and osteoconductivity of calcium phosphate bioceramics in bone tissue engineering","volume":"22","author":"Jin","year":"2023","journal-title":"Biomed. Eng. OnLine"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/mabi.201800096","article-title":"Strontium-Substituted Hydroxyapatite-Gelatin Biomimetic Scaffolds Modulate Bone Cell Response","volume":"18","author":"Panzavolta","year":"2018","journal-title":"Macromol. Biosci."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"111580","DOI":"10.1016\/j.colsurfb.2021.111580","article-title":"Strontium substituted hydroxyapatite with \u03b2-lactam integrin agonists to enhance mesenchymal cells adhesion and to promote bone regeneration","volume":"200","author":"Cirillo","year":"2021","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"rbaf066","DOI":"10.1093\/rb\/rbaf066","article-title":"Strontium-incorporated hydroxyapatite nanocomposites promoting bone formation and angiogenesis by modulating M2 macrophage polarization in the bone microenvironment","volume":"12","author":"Li","year":"2025","journal-title":"Regen. Biomater."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"7193","DOI":"10.1039\/D5NR05524E","article-title":"Engineering osteoinductive hydroxyapatite via zinc and strontium co-substitution","volume":"18","author":"Durairaj","year":"2026","journal-title":"Nanoscale"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"213968","DOI":"10.1016\/j.bioadv.2024.213968","article-title":"Regulation of osteogenesis and angiogenesis by cobalt, manganese and strontium doped apatitic materials for functional bone tissue regeneration","volume":"163","author":"Silingardi","year":"2024","journal-title":"Biomater. Adv."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.actbio.2024.01.003","article-title":"Osteogenic-angiogenic coupled response of cobalt-containing mesoporous bioactive glasses in vivo","volume":"176","author":"Biomaterialia","year":"2024","journal-title":"Acta Biomater."},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Bosch-Ru\u00e9, \u00c8., D\u00edez-Tercero, L., Rodr\u00edguez-Gonz\u00e1lez, R., Bosch-Canals, B.M., and P\u00e9rez, R. (2021). Assessing the potential role of copper and cobalt in stimulating angiogenesis for tissue regeneration. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0259125"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.actbio.2018.03.048","article-title":"Fine-tuning pro-angiogenic effects of cobalt for simultaneous enhancement of vascular endothelial growth factor secretion and implant neovascularization","volume":"72","author":"Chai","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"111032","DOI":"10.1016\/j.msec.2020.111032","article-title":"Improved osteogenesis and angiogenesis of a novel copper ions doped calcium phosphate cement","volume":"114","author":"Lin","year":"2020","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"59051","DOI":"10.1021\/acsami.1c16300","article-title":"Tunable and Controlled Release of Cobalt Ions from Metal-Organic Framework Hydrogel Nanocomposites Enhances Bone Regeneration","volume":"13","author":"Sun","year":"2021","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_176","doi-asserted-by":"crossref","unstructured":"Huang, S.-M., Chen, W.-C., Liu, S.-M., Ko, C.-L., Chen, J.-C., and Shih, C. (2024). Insights into the Various Cellular Antimicrobial Responses, Biocompatibility, Osteogenesis, Wound Healing, and Angiogenesis of Copper-Doped Nano-Hydroxyapatite Composite Calcium Phosphate Bone Cement In Vitro. J. Compos. Sci., 8.","DOI":"10.3390\/jcs8100424"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/j.matdes.2015.08.069","article-title":"Effects of silicate and carbonate substitution on the properties of hydroxyapatite prepared by aqueous co-precipitation method","volume":"87","author":"Bang","year":"2015","journal-title":"Mater. Des."},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Bigi, A., Boanini, E., and Gazzano, M. (2016). Ion substitution in biological and synthetic apatites. Biomineralization and Biomaterials, Fundamentals and Applications, Woodhead Publishing (Elsevier).","DOI":"10.1016\/B978-1-78242-338-6.00008-9"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"15384","DOI":"10.1038\/s41598-023-42271-2","article-title":"Calcination and ion substitution improve physicochemical and biological properties of nanohydroxyapatite for bone tissue engineering applications","volume":"13","author":"Kurzyk","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_180","doi-asserted-by":"crossref","unstructured":"Tite, T., Popa, A., Balescu, L., Bogdan, I., Pasuk, I., Ferreira, J., and Stan, G. (2018). Cationic Substitutions in Hydroxyapatite: Current Status of the Derived Biofunctional Effects and Their In Vitro Interrogation Methods. Materials, 11.","DOI":"10.3390\/ma11112081"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"7","DOI":"10.4236\/jbnb.2010.11002","article-title":"Changes of Surface Composition and Morphology after Incorporation of Ions into Biomimetic Apatite Coating","volume":"1","author":"Xia","year":"2010","journal-title":"J. Biomater. Nanobiotechnol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"102609","DOI":"10.1016\/j.mtbio.2025.102609","article-title":"Silver integrated hybrids and nanocomposites for next-generation biomedicine: Beyond antimicrobial coatings toward smart sense\u2013response\u2013heal platforms","volume":"35","author":"Tabrizi","year":"2025","journal-title":"Mater. Today Bio"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"101067","DOI":"10.1016\/j.artd.2022.10.017","article-title":"Case Series of Silver Oxide\u2013Containing Hydroxyapatite Coating in Antibacterial Cementless Total Hip Arthroplasty: Clinical Results of 50 Cases at 5-Year Follow-Up","volume":"19","author":"Kawano","year":"2022","journal-title":"Arthroplast. Today"},{"key":"ref_184","doi-asserted-by":"crossref","unstructured":"Morimoto, T., Hirata, H., Eto, S., Hashimoto, A., Kii, S., Kobayashi, T., Tsukamoto, M., Yoshihara, T., Toda, Y., and Mawatari, M. (2022). Development of Silver-Containing Hydroxyapatite-Coated Antimicrobial Implants for Orthopaedic and Spinal Surgery. Medicina, 58.","DOI":"10.3390\/medicina58040519"}],"container-title":["Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1996-1944\/19\/16\/3461\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T04:15:13Z","timestamp":1786853713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1996-1944\/19\/16\/3461"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":184,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ma19163461"],"URL":"https:\/\/doi.org\/10.3390\/ma19163461","relation":{},"ISSN":["1996-1944"],"issn-type":[{"value":"1996-1944","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]}}}