Antimicrobial and Antibiofilm Properties of Hydroxyapatite/Nano-Hydroxyapatite in Preventing Dental Caries: A Systematic Review

Abstract

Controlling biofilm is a crucial strategy and an essential component of preventing dental caries. Considerable research has been conducted in recent years on the clinical application of hydroxyapatite (HAp) and hydroxyapatite nanoparticles (nHAp) in preventing dental caries. However, these studies have yet to investigate the effectiveness or mechanism of these substances as antibacterial and antibiofilm agents. This study aimed to provide a thorough analysis of the current evidence on the antibacterial and antibiofilm characteristics of HAp/nHAp in the prevention of dental caries. Searches were conducted across five databases: Cochrane Library, PubMed, Scopus, EBSCOhost, and ScienceDirect. Google Scholar was also searched. Titles, abstracts, and full text were evaluated following the guidelines set by the Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA). A methodological quality assessment of the studies was conducted using the QUIN tool. The initial retrieval totaled 15,047 studies, from which 3,487 were excluded. A total of 11,560 studies were screened based on the title and abstract, resulting in 24 full-text studies considered potentially eligible for inclusion (κ = 0.9599). Finally, 19 studies met all the defined inclusion criteria and were included in this comprehensive systematic review (κ = 0.8837). HAp/nHAp demonstrates antimicrobial activities against gram-negative and gram-positive bacteria and fungi. However, nHAp's antibiofilm efficacy remains limited. Further investigation is required to improve the efficacy of antibacterial and antibiofilm agents.

Keywords

biofilms - caries - hydroxyapatites - microbiota - systematic review

Publication History

Article published online:
01 May 2025

• References

• 1 Rather MA, Gupta K, Mandal M. Microbial biofilm: formation, architecture, antibiotic resistance, and control strategies. Braz J Microbiol 2021; 52 (04) 1701-1718
• 2 Zhao A, Sun J, Liu Y. Understanding bacterial biofilms: from definition to treatment strategies. Front Cell Infect Microbiol 2023; 13: 1137947
• 3 Meyer F, Schulze Zur Wiesche E, Amaechi BT, Limeback H, Enax J. Caries etiology and preventive measures. Eur J Dent 2024; 18 (03) 766-776
• 4 Meyer F, Enax J, Epple M, Amaechi BT, Simader B. Cariogenic biofilms: development, properties, and biomimetic preventive agents. Dent J 2021; 9 (08) 88
• 5 Kriswandini IL, Sidarningsih S, Hermanto AC, Tyas PR, Aljunaid MA. The influence of Streptococcus mutans biofilm formation in a polymicrobial environment (Streptococcus gordonii & Porphyromonas gingivalis). Eur J Dent 2024; 18 (04) 1085-1089
• 6 Zhang JS, Chu CH, Yu OY. Oral microbiome and dental caries development. Dent J 2022; 10 (10) 184
• 7 Spatafora G, Li Y, He X, Cowan A, Tanner ACR. The evolving microbiome of dental caries. Microorganisms 2024; 12 (01) 121
• 8 Yadav K, Prakash S. Dental caries: a microbiological approach. J Clin Infect Dis Pract 2017; 2 (01) 1-15
• 9 Begić G, Badovinac IJ, Karleuša L. et al. Streptococcus salivarius as an important factor in dental biofilm homeostasis: influence on Streptococcus mutans and Aggregatibacter actinomycetemcomitans in mixed biofilm. Int J Mol Sci 2023; 24 (08) 7249
• 10 Braga AS, Abdelbary MMH, Kim RR. et al. The effect of toothpastes containing natural extracts on bacterial species of a microcosm biofilm and on enamel caries development. Antibiotics (Basel) 2022; 11 (03) 414
• 11 Sahni K, Khashai F, Forghany A, Krasieva T, Wilder-Smith P. Exploring mechanisms of biofilm removal. Dentistry (Sunnyvale) 2016; 6 (04) 371
• 12 Allaker RP, Memarzadeh K. Nanoparticles and the control of oral infections. Int J Antimicrob Agents 2014; 43 (02) 95-104
• 13 Carrouel F, Viennot S, Ottolenghi L, Gaillard C, Bourgeois D. Nanoparticles as anti-microbial, anti-inflammatory, and remineralizing agents in oral care cosmetics: a review of the current situation. Nanomaterials (Basel) 2020; 10 (01) 140
• 14 Wang L, Hu C, Shao L. The antimicrobial activity of nanoparticles: present situation and prospects for the future. Int J Nanomedicine 2017; 12: 1227-1249
• 15 O'Hagan-Wong K, Enax J, Meyer F, Ganss B. The use of hydroxyapatite toothpaste to prevent dental caries. Odontology 2022; 110 (02) 223-230
• 16 Du M, Chen J, Liu K, Xing H, Song C. Recent advances in biomedical engineering of nano-hydroxyapatite including dentistry, cancer treatment and bone repair. Compos B Eng 2021; 215: 108790
• 17 Moraes G, Zambom C, Siqueira WL. Nanoparticles in dentistry: a comprehensive review. Pharmaceuticals (Basel) 2021; 14 (08) 752
• 18 Vandiver J, Dean D, Patel N, Bonfield W, Ortiz C. Nanoscale variation in surface charge of synthetic hydroxyapatite detected by chemically and spatially specific high-resolution force spectroscopy. Biomaterials 2005; 26 (03) 271-283
• 19 Nozari A, Ajami S, Rafiei A, Niazi E. Impact of nano hydroxyapatite, nano silver fluoride and sodium fluoride varnish on primary teeth enamel remineralization: an in vitro study. J Clin Diagn Res 2017; 11 (09) ZC97-ZC100
• 20 Imran E, Cooper PR, Ratnayake J, Ekambaram M, Mei ML. Potential beneficial effects of hydroxyapatite nanoparticles on caries lesions in vitro: a review of the literature. Dent J 2023; 11 (02) 40
• 21 Rethlefsen ML, Kirtley S, Waffenschmidt S. et al; PRISMA-S Group. PRISMA-S: an extension to the PRISMA statement for reporting literature searches in systematic reviews. Syst Rev 2021; 10 (01) 39
• 22 Methley AM, Campbell S, Chew-Graham C, McNally R, Cheraghi-Sohi S. PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv Res 2014; 14 (01) 579
• 23 Sheth VH, Shah NP, Jain R, Bhanushali N, Bhatnagar V. Development and validation of a risk-of-bias tool for assessing in vitro studies conducted in dentistry: The QUIN. J Prosthet Dent 2024; 131 (06) 1038-1042
• 24 Jakab A, Palkovics D. T Szabó V, et al. Mechanical performance of extensive restorations made with short fiber-reinforced composites without coverage: a systematic review of in vitro studies. Polymers (Basel) 2024; 16 (05) 590
• 25 Sodagar A, Akhavan A, Hashemi E. et al. Evaluation of the antibacterial activity of a conventional orthodontic composite containing silver/hydroxyapatite nanoparticles. Prog Orthod 2016; 17 (01) 40
• 26 da Silva Ribeiro CF, Dionizio A, Teodoro Araújo T. et al. Effect of experimental toothpaste containing hydroxyapatite nanoparticles and propolis, with and without fluoride, on the microcosm biofilm and enamel demineralization. Biofouling 2023; 39 (03) 339-348
• 27 Jayasree R, Kumar TSS, Mahalaxmi S, Abburi S, Rubaiya Y, Doble M. Dentin remineralizing ability and enhanced antibacterial activity of strontium and hydroxyl ion co-releasing radiopaque hydroxyapatite cement. J Mater Sci Mater Med 2017; 28 (06) 95
• 28 Pinheiro SRL, da Silva CC, da Silva LA, Cicotti MP. Antimicrobial capacity of a hydroxyapatite-lysozyme-lactoferrin-lactoperoxidase combination against Streptococcus mutans for the treatment of dentinal caries. Indian J Dent Res 2020; 31 (06) 916-920
• 29 Jantová S, Theiszová M, Letasiová S, Birosová L, Palou TM. In vitro effects of fluor-hydroxyapatite, fluorapatite and hydroxyapatite on colony formation, DNA damage and mutagenicity. Mutat Res 2008; 652 (02) 139-144
• 30 Huang Y, Han Q, Peng X. et al. Disaggregated nano-hydroxyapatite (DnHAP) with inhibitory effects on biofilms and demineralization. J Dent Res 2023; 102 (07) 777-784
• 31 Luo W, Huang Y, Zhou X. et al. The effect of disaggregated nano-hydroxyapatite on oral biofilm in vitro . Dent Mater 2020; 36 (07) e207-e216
• 32 El-Gar YHA, Etman WM, Genaid TM, Al-Madboly LA. Potent antibacterial and antibiofilm activities of a synthetic remineralizing preparation of nano-hydroxyapatite against cariogenic Streptococcus mutans using an ex-vivo animal model. Front Dent Med 2022; 3: 738326
• 33 Park M, Sutherland JB, Rafii F. Effects of nano-hydroxyapatite on the formation of biofilms by Streptococcus mutans in two different media. Arch Oral Biol 2019; 107: 104484
• 34 Nambiar S, Kumari M, Mathew S, Hegde S, Ramesh P, Shetty N. Effect of nano-hydroxyapatite with biomimetic analogues on the characteristics of partially demineralised dentin: an in-vitro study. Indian J Dent Res 2021; 32 (03) 385-389
• 35 Ragab HS, Ibrahim FA, Abdallah FA, Al-Ghamdi A, El-Tantawy F, Yakuphanoglu F. Synthesis and in vitro antibacterial properties of hydroxyapatite nanoparticles. IOSR J Pharm Biol Sci 2014; 9 (01) 77-85
• 36 Lamkhao S, Phaya M, Jansakun C. et al. Synthesis of hydroxyapatite with antibacterial properties using a microwave-assisted combustion method. Sci Rep 2019; 9 (01) 4015
• 37 Ahmed HY, Safwat N, Shehata R. et al. Synthesis of natural nano-hydroxyapatite from snail shells and its biological activity: antimicrobial, antibiofilm, and biocompatibility. Membranes (Basel) 2022; 12 (04) 408
• 38 Mousavi SM, Hashemi SA, Yousefi K. et al. Antibacterial and cytotoxic efficacy of nano-hydroxyapatite synthesized from eggshell and sheep bones bio waste. Research Square:10.21203/RS.3.RS-2195140/V1.
• 39 El-Said GF, El Zokm GM, El-Sikaily A, Ismail MM. Comparison of crude nano-hydroxyapatite extracted from calcified seaweed in terms of composition, antibacterial activity, and cytotoxicity. Environ Nanotechnol Monit Manag 2024; 21: 100908
• 40 Hariani PL, Muryati M, Said M, Salni S. Synthesis of nano-hydroxyapatite from snakehead (Channa striata) fish bone and its antibacterial properties. Key Eng Mater 2020; 840: 293-299
• 41 Parajuli K, Prasad Malla K, Panchen N, Adhikari R. Isolation of antibacterial nano-hydroxyapatite biomaterial from waste buffalo bone and its characterization. Chem Chem Technol 2022; 16 (01) 133-141
• 42 Babayevska N, Woźniak-Budych M, Litowczenko J. et al. Novel nanosystems to enhance biological activity of hydroxyapatite against dental caries. Mater Sci Eng C 2021; 124: 112062
• 43 Resmim CM, Dalpasquale M, Vielmo NIC. et al. Study of physico-chemical properties and in vitro antimicrobial activity of hydroxyapatites obtained from bone calcination. Prog Biomater 2019; 8 (01) 1-9
• 44 Algamal Y, Khalil NM, Saddiq A, Baghdadi AM. Antimicrobial activity of hydroxyapatite nanoparticles prepared from marble wastes. Main Group Chem 2022; 21 (03) 865-873
• 45 Ibrahim AZ, Hussein AS, Said Gulam Khan HB, Ghazali N. Antibacterial activity of microwave synthesized hydroxyapatite against cariogenic bacteria: a preliminary study. Saudi Dent J 2024; 36 (08) 1117-1122
• 46 Rifada A, Af'idah BM, Aufia W. et al. Effect of nano hydroxyapatite in toothpaste on controlling oral microbial viability. IOP Conf Ser Mater Sci Eng 2020; 924: 012010
• 47 Xu X, Wang N, Wu M. et al. Programmed antibacterial and mineralization therapy for dental caries based on zinc-substituted hydroxyapatite/alendronate-grafted polyacrylic acid hybrid material. Colloids Surf B Biointerfaces 2020; 194: 111206
• 48 Zhang M, He LB, Exterkate RAM. et al. Biofilm layers affect the treatment outcomes of NaF and Nano-hydroxyapatite. J Dent Res 2015; 94 (04) 602-607
• 49 Meyer F, Enax J. Hydroxyapatite in oral biofilm management. Eur J Dent 2019; 13 (02) 287-290
• 50 Guerfi Z, Kribaa OK, Djouama H. Chemical-physical behavior of Hydroxyapatite: a modeling approach. J Mech Behav Biomed Mater 2024; 150: 106229
• 51 ChemTube3D. Hydroxyapatite Ca₅(OH)(PO₄)₃ . Accessed January 28, 2024 at: https://www.chemtube3d.com/sshydroxyapatite/
• 52 Amaechi BT, AbdulAzees PA, Alshareif DO. et al. Comparative efficacy of a hydroxyapatite and a fluoride toothpaste for prevention and remineralization of dental caries in children. BDJ Open 2019; 5 (01) 18
• 53 Krzyściak W, Jurczak A, Kościelniak D, Bystrowska B, Skalniak A. The virulence of Streptococcus mutans and the ability to form biofilms. Eur J Clin Microbiol Infect Dis 2014; 33 (04) 499-515
• 54 Matsumoto-Nakano M. Role of Streptococcus mutans surface proteins for biofilm formation. Jpn Dent Sci Rev 2018; 54 (01) 22-29
• 55 Korona-Glowniak I, Skawinska-Bednarczyk A, Wrobel R. et al. Streptococcus sobrinus as a predominant oral bacteria related to the occurrence of dental caries in Polish children at 12 years old. Int J Environ Res Public Health 2022; 19 (22) 15005
• 56 Fragkou S, Balasouli C, Tsuzukibashi O. et al. Streptococcus mutans, Streptococcus sobrinus and Candida albicans in oral samples from caries-free and caries-active children. Eur Arch Paediatr Dent 2016; 17 (05) 367-375
• 57 Okada M, Soda Y, Hayashi F. et al. Longitudinal study of dental caries incidence associated with Streptococcus mutans and Streptococcus sobrinus in pre-school children. J Med Microbiol 2005; 54 (Pt 7): 661-665
• 58 Chenicheri S, R U, Ramachandran R, Thomas V, Wood A. Insight into oral biofilm: primary, secondary and residual caries and phyto-challenged solutions. Open Dent J 2017; 11 (01) 312-333
• 59 Lu Y, Lin Y, Li M, He J. Roles of Streptococcus mutans-Candida albicans interaction in early childhood caries: a literature review. Front Cell Infect Microbiol 2023; 13: 1151532
• 60 Kouidhi B, Zmantar T, Hentati H, Bakhrouf A. Cell surface hydrophobicity, biofilm formation, adhesives properties and molecular detection of adhesins genes in Staphylococcus aureus associated to dental caries. Microb Pathog 2010; 49 (1–2): 14-22
• 61 Lamooki SAP, Heris FS, Fathi A, Aminianpour N, Jandaghian Z, Ramandi MA. Prevalence and antimicrobial resistance of bacterial agents isolated from the cases of dental caries. Int Tinnitus J 2024; 27 (02) 211-216
• 62 Nasr-Eldin MA, El-Dougdoug NK, Elazab YH, Esmael A. Isolation and characterization of two virulent phages to combat Staphylococcus aureus and Enterococcus faecalis causing dental caries. J Pure Appl Microbiol 2021; 15 (01) 320-334
• 63 Zhou S, He TC, Zhang Y, Zhang H. Comparison of the main pathogenic microorganisms of various common oral diseases in children and adults. Pediatr Discov 2023; 1 (03) e35
• 64 Kim HJ, Yoo HJ. Inhibitory effects of Streptococcus salivarius K12 on formation of cariogenic biofilm. J Dent Sci 2023; 18 (01) 65-72
• 65 Rosier BT, Marsh PD, Mira A. Resilience of the oral microbiota in health: Mechanisms that prevent dysbiosis. J Dent Res 2018; 97 (04) 371-380
• 66 Marsh PD, Zaura E. Dental biofilm: ecological interactions in health and disease. J Clin Periodontol 2017; 44 (Suppl. 18) S12-S22
• 67 Idris A, Hasnain SZ, Huat LZ, Koh D. Human diseases, immunity and the oral microbiota: insights gained from metagenomic studies. Oral Sci Int 2017; 14 (02) 27-32
• 68 Lynge Pedersen AM, Belstrøm D. The role of natural salivary defences in maintaining a healthy oral microbiota. J Dent 2019; 80 (Suppl. 01) S3-S12
• 69 Xiong F, Wen D, Li Q. Calcium-mediated regulation promotes the biofilm formation of two novel pyridine-degrading bacteria. Front Environ Sci 2022; 10: 815528
• 70 Menichetti A, Mavridi-Printezi A, Mordini D, Montalti M. Effect of size, shape and surface functionalization on the antibacterial activity of silver nanoparticles. J Funct Biomater 2023; 14 (05) 244
• 71 Safitri A, Srihardyastutie A, Roosdiana A, Sutrisno S. Antibacterial activity and phytochemical analysis of edible seaweed Eucheuma spinosum against Staphylococcus aureus . J Pure Appl Chem Res 2018; 7 (03) 308-315
• 72 Cieplik F, Rupp CM, Hirsch S. et al. Ca²⁺ release and buffering effects of synthetic hydroxyapatite following bacterial acid challenge. BMC Oral Health 2020; 20 (01) 85
• 73 Sudradjat H, Meyer F, Loza K, Epple M, Enax J. In vivo effects of a hydroxyapatite-based oral care gel on the calcium and phosphorus levels of dental plaque. Eur J Dent 2020; 14 (02) 206-211
• 74 Nobre CMG, Pütz N, Hannig M. Adhesion of hydroxyapatite nanoparticles to dental materials under oral conditions. Scanning 2020; 2020: 6065739
• 75 Kensche A, Holder C, Basche S, Tahan N, Hannig C, Hannig M. Efficacy of a mouthrinse based on hydroxyapatite to reduce initial bacterial colonisation in situ . Arch Oral Biol 2017; 80: 18-26
• 76 Nobre CMG, König B, Pütz N, Hannig M. Hydroxyapatite-based solution as adjunct treatment for biofilm management: an in situ study. Nanomaterials (Basel) 2021; 11 (09) 2452
• 77 Singh G, Singh RP, Jolly SS. Customized hydroxyapatites for bone-tissue engineering and drug delivery applications: a review. J Sol-Gel Sci Technol 2020; 94 (03) 505-530
• 78 Balu S, Sundaradoss MV, Andra S, Jeevanandam J. Facile biogenic fabrication of hydroxyapatite nanorods using cuttlefish bone and their bactericidal and biocompatibility study. Beilstein J Nanotechnol 2020; 11: 285-295
• 79 Pawinska M, Paszynska E, Amaechi BT, Meyer F, Enax J, Limeback H. Clinical evidence of caries prevention by hydroxyapatite: an updated systematic review and meta-analysis. J Dent 2024; 151: 105429
• 80 Ghosh R, Das S, Mallick SP, Beyene Z. A review on the antimicrobial and antibiofilm activity of doped hydroxyapatite and its composites for biomedical applications. Mater Today Commun 2022; 31: 103311
• 81 El Assal DW, Saafan AM, Moustafa DH, Al-Sayed MA. The effect of combining laser and nanohydroxy-apatite on the surface properties of enamel with initial defects. J Clin Exp Dent 2018; 10 (05) e425-e430
• 82 Sarembe S, Enax J, Morawietz M, Kiesow A, Meyer F. In vitro whitening effect of a hydroxyapatite-based oral care gel. Eur J Dent 2020; 14 (03) 335-341
• 83 Sims Jr KR, Maceren JP, Liu Y, Rocha GR, Koo H, Benoit DSW. Dual antibacterial drug-loaded nanoparticles synergistically improve treatment of Streptococcus mutans biofilms. Acta Biomater 2020; 115: 418-431
• 84 Chen R, Du M, Liu C. Strategies for dispersion of cariogenic biofilms: applications and mechanisms. Front Microbiol 2022; 13: 981203
• 85 Yu OY, Zhao IS, Mei ML, Lo ECM, Chu CH. Dental biofilm and laboratory microbial culture models for cariology research. Dent J 2017; 5 (02) 21
• 86 Limeback H, Enax J, Meyer F. Biomimetic hydroxyapatite and caries prevention: a systematic review and meta-analysis. Can J Dent Hyg 2021; 55 (03) 148-159
• 87 Ionescu AC, Cazzaniga G, Ottobelli M, Garcia-Godoy F, Brambilla E. Substituted nano-hydroxyapatite toothpastes reduce biofilm formation on enamel and resin-based composite surfaces. J Funct Biomater 2020; 11 (02) 36
• 88 Page MJ, McKenzie JE, Bossuyt PM. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71