Published in:

12-08-2024 | Doxycycline | Review Article

Exploring the effectiveness of doxycycline in restorative dentistry: a systematic review of in vitro studies

Authors: Bruna Tavares Carneiro, Marina Minici Dumont Prado, Iara de Oliveira Nogueira, Allyson Nogueira Moreira, Carolina Bosso André

Published in: Odontology | Issue 1/2025

Abstract

This systematic review evaluated the efficacy of doxycycline in MMP inhibition, its antibacterial action, and other properties relevant to dental materials testing. The study protocol was registered at the Open Science Framework (https://doi.org/10.17605/OSF.IO/ZVK2T). Reporting was based on PRISMA statement. The search was carried out in the databases: PubMed, Scopus, Web of Science, Embase, Lilacs, and Google Scholar. Articles were restricted to Portuguese, English, and Spanish, with no date limit. In vitro studies were selected based on the following outcomes: DOX antibacterial and anti-metalloproteinase activity and its influence in physico-chemical properties. Two researchers independently selected the articles and collected the data. Of 1507 documents, 82 were fully evaluated and 21 were included. Different forms of doxycycline incorporation were found, both as free form and incorporated into carrier agents. The drug was tested as primers, incorporated in adhesive or glass ionomer cement. No studies were found that evaluated its incorporation in resin composite or resin cement. The results confirmed the therapeutic properties of the medication, with more significant results when incorporated in an adhesive. However, although promising, the use of this substance requires standardization in application methods and adopted concentrations, allowing for more direct comparisons between studies. Furthermore, long-term studies are interesting to conduct, ensuring biocompatibility and complete understanding of long-term effects on dental materials.

Ferreira Zandoná A, Santiago E, Eckert GJ, Katz BP. Pereira De Oliveira S, Capin OR, Mau M, Zero DT The natural history of dental caries lesions: a 4-year observational study. J Dent Res. 2012;91(9):841–6. https://doi.org/10.1177/0022034512455030.CrossRefPubMedPubMedCentral

Ferracane JL. Resin composite–state of the art. Dent Mater. 2011;27:29–38. https://doi.org/10.1016/j.dental.2010.10.020.CrossRefPubMed

Sabbagh J, McConnell RJ, McConnell MC. Posterior composites: Update on cavities and filling techniques. J Dent. 2017;57:86–90. https://doi.org/10.1016/j.jdent.2016.11.010.CrossRefPubMed

Carrilho MRO, Carvalho RM, Tay FR, Yiu C, Pashley DH. Durability of resin-dentin bonds related to water and oil storage. Am J Dent. 2005;18(6):315–9.PubMed

Liu Y, Tjäderhane L, Breschi L, Mazzoni A, Li N, Mao J, Pashley DH, Tay FR. Limitations in bonding to dentin and experimental strategies to prevent bond degradation. J Dent Res. 2011;90:953–68. https://doi.org/10.1177/0022034510391799.CrossRefPubMedPubMedCentral

Pashley DH, Tay FR, Breschi L, Tjäderhane L, Carvalho RM, Carrilho M, Tezvergil-Mutluay A. State of the art etch-and-rinse adhesives. Dent Mater. 2011;27(1):1–16. https://doi.org/10.1016/j.dental.2010.10.016.CrossRefPubMed

Tjäderhane L, Nascimento FD, Breschi L, Mazzoni A, Tersariol ILS, Geraldeli S, Tezvergil-Mutluay A, Carrilho M, Carvalho RM, Tay FR, Pashley DH. Strategies to prevent hydrolytic degradation of the hybrid layer-A review. Dent Mater. 2013;29(10):999–1011. https://doi.org/10.1016/j.dental.2013.07.016.CrossRefPubMedPubMedCentral

Breschi L, Mazzoni A, Ruggeri A, Cadenaro M, Di Lenarda R, De Stefano DE. Dental adhesion review: aging and stability of the bonded interface. Dent Mater. 2008;24(1):90–101. https://doi.org/10.1016/j.dental.2007.02.009.CrossRefPubMed

Nakabayashi N, Nakamura M, Yasuda N. Hybrid layer as a dentin-bonding mechanism. J Esthet Dent. 1991;3(4):133–8. https://doi.org/10.1111/j.1708-8240.1991.tb00985.x.CrossRefPubMed

10.

De Munck J, Van Den Steen PE, Mine A, Van Landuyt KL, Poitevin A, Opdenakker G, Van Meerbeeck B. Inhibition of enzymatic degradation of adhesive-dentin interfaces. J Dent Res. 2009;88(12):1101–6. https://doi.org/10.1177/0022034509346952.CrossRefPubMed

11.

Van Meerbeek B, Yoshihara K, Van Landuyt K, Yoshida Y, Peumans M. From buonocore’s pioneering acid-etch technique to self-adhering restoratives a status perspective of rapidly advancing dental adhesive technology. J Adhes Dent. 2020;22(1):7–34. https://doi.org/10.3290/j.jad.a43994.CrossRefPubMed

12.

Demarco FF, Corrêa MB, Cenci MS, Moraes RR, Opdam NJM. Longevity of posterior composite restorations: not only a matter of materials. Dent Mater. 2012;28(1):87–101. https://doi.org/10.1016/j.dental.2011.09.003.CrossRefPubMed

13.

Mazzoni A, Tjäderhane L, Checchi V, Di Lenarda R, Salo T, Tay FR, Pashley DH, Breschi L. Role of dentin MMPs in caries progression and bond stability. J Dent Res. 2015;94(2):241–51. https://doi.org/10.1177/0022034514562833.CrossRefPubMedPubMedCentral

14.

Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827–39. https://doi.org/10.1161/01.RES.0000070112.80711.3D.CrossRefPubMed

15.

Mazzoni A, Pashley DH, Nishitani Y, Breschi L, Mannello F, Tjäderhane L, Toledano M, Pashley EL, Tay FR. Reactivation of inactivated endogenous proteolytic activities in phosphoric acid-etched dentine by etch-and-rinse adhesives. Biomaterials. 2006;27(25):4470–6. https://doi.org/10.1016/j.biomaterials.2006.01.040.CrossRefPubMed

16.

Mazzoni A, Mannello F, Tay FR, Tonti GAM, Papa S, Mazzotti G, Di Lenarda R, Pashley DH, Breschi L. Zymographic analysis and characterization of MMP-2 and -9 forms in human sound dentin. J Dent Res. 2007;86(5):436–40. https://doi.org/10.1177/154405910708600509.CrossRefPubMed

17.

de Moraes IQS. do Nascimento TG, da Silva AT, de Lira LMSS, Parolia A Porto ICC de M Inhibition of matrix metalloproteinases: a troubleshooting for dentin adhesion. Restor Dent Endod. 2020;45(3):e31. https://doi.org/10.5395/rde.2020.45.e31.CrossRefPubMedPubMedCentral

18.

Boelen GJ, Boute L, d’Hoop J, EzEldeen M, Lambrichts I, Opdenakker G. Matrix metalloproteinases and inhibitors in dentistry. Clin Oral Investig. 2019;23(7):2823–35. https://doi.org/10.1007/s00784-019-02915-y.CrossRefPubMed

19.

Yaghmoor RB, Jamal H, Abed H, Allan E, Ashley P, Young A. Incorporation of MMP inhibitors into dental adhesive systems and bond strength of coronal composite restorations: a systematic review and meta-analysis of in vitro studies. Jpn Dent Sci Rev. 2022;58:298–315. https://doi.org/10.1016/j.jdsr.2022.09.004.CrossRefPubMedPubMedCentral

20.

Freitas PH, André CB, Fronza BM, Giannini M, Rosalen PL, Consani S, et al. Physicochemical properties metalloproteinases inhibition and antibiofilm activity of doxycycline-doped dental adhesive. J Dent. 2021. https://doi.org/10.1016/j.jdent.2020.103550.CrossRefPubMed

21.

Aasi O, Alahmad YA, Beesh M, Swed A. Microbiological and analytical evaluation of semi-solid formulations of doxycycline hyclate under accelerated stability conditionsand analytical evaluation of semi-solid formulations of doxycycline hyclate under accelerated stability conditions. Baghdad Sci J. 2024. https://doi.org/10.21123/bsj.2024.8841.CrossRef

22.

Tan KR, Magill AJ, Parise ME, Arguin PM. Doxycycline for malaria chemoprophylaxis and treatment: report from the CDC expert meeting on malaria chemoprophylaxis. Am J Trop Med Hyg. 2011;84(4):517–31. https://doi.org/10.4269/ajtmh.2011.10-0285.CrossRefPubMedPubMedCentral

23.

Kogawa A. Salgado HR Doxycycline hyclate: a review of properties, applications and analytical methods. Int J Life sci Pharm Res. 2012;2(4):11–25.

24.

Metzger Z, Belkin D, Kariv N, Dotan M, Kfir A. Low-dose doxycycline inhibits bone resorption associated with apical periodontitis. Int Endod J. 2008;41(4):303–9. https://doi.org/10.1111/j.1365-2591.2007.01363.x.CrossRefPubMed

25.

Hass V, Luque-Martinez IV, Gutierrez MF, Moreira CG, Gotti VB, Feitosa VP, Koller G, Otuki MF, Loguercio AD, Reis A. Collagen cross-linkers on dentin bonding: stability of the adhesive interfaces, degree of conversion of the adhesive, cytotoxicity and in situ MMP inhibition. Dent Mater. 2016;32(6):732–41. https://doi.org/10.1016/j.dental.2016.03.008.CrossRefPubMed

26.

Silva Sousa AB, Vidal CMP, Leme-Kraus AA, Pires-de-Souza FCP, Bedran-Russo AK. Experimental primers containing synthetic and natural compounds reduce enzymatic activity at the dentin-adhesive interface under cyclic loading. Dent Mater. 2016;32(10):1248–55.CrossRefPubMed

27.

De Castilho ARF, Duque C, Negrini TDC, Sacono NT, De Paula AB, Sacramento PA, de Souza Costa CA, Spolidorio CM, Puppin-Rontani RM. Mechanical and biological characterization of resin-modified glass-ionomer cement containing doxycycline hyclate. Arch Oral Biol. 2012;57(2):131–8. https://doi.org/10.1016/j.archoralbio.2011.08.009.CrossRefPubMed

28.

Toledano M, Yamauti M, Osorio E, Osorio R. Zinc-inhibited MMP-mediated collagen degradation after different dentine demineralization procedures. Caries Res. 2012;46(3):201–7. https://doi.org/10.1159/000337315.CrossRefPubMed

29.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021. https://doi.org/10.1136/bmj.n71.CrossRefPubMedPubMedCentral

30.

Delgado AH, Sauro S, Lima AF, Loguercio AD, Della Bona A, Mazzoni A, Collares FM, Staxrud F, Ferracane J, Tsoi J, Amato J, Neuhaus KW, Ceballos L, Breschi L, Hannig M, Melo MA, Ozcan M, Scotti N, Opdam N, Yamaguchi S, Paris S, Turkun LS, Doméjean S, Rosa V, Palin W, Schewendick F. RoBDEMAT: A risk of bias tool and guideline to support reporting of pre-clinical dental materials research and assessment of systematic reviews. J Dent. 2022. https://doi.org/10.1016/j.jdent.2022.104350.CrossRefPubMed

31.

Ricci HA, Sanabe ME, Costa SCA, de, Hebling J. Effect of chlorhexidine on bond strength of two-step etch-and-rinse adhesive systems to dentin of primary and permanent teeth. Am J Dent. 2010;23(3):128–32.PubMed

32.

De Lacerda OH, Tedesco TK, Rodrigues-Filho LE, Soares FZM, De Oliveira RR. Doxycycline as a matrix metalloproteinase inhibitor to prevent bond degradation: the effect of acid and neutral solutions on dentin bond strength. Gen Dent. 2016;64(2):14–7.

33.

Feitosa SA, Palasuk J, Kamocki K, Geraldeli S, Gregory RL, Platt JA, Windsor LJ, Bottino MC. Doxycycline-encapsulated nanotube-modified dentin adhesives. J Dent Res. 2014;93(12):1270–6. https://doi.org/10.1177/0022034514549997.CrossRefPubMedPubMedCentral

34.

Palasuk J, Windsor LJ, Platt JA, Lvov Y, Geraldeli S, Bottino MC. Doxycycline-loaded nanotube-modified adhesives inhibit MMP in a dose-dependent fashion. Clin Oral Investig. 2018;22(3):1243–52. https://doi.org/10.1007/s00784-017-2215-y.CrossRefPubMed

35.

Zheng P, Chen H. Evaluate the effect of different mmps inhibitors on adhesive physical properties of dental adhesives, bond strength and mmp substarte activity. Sci Rep. 2017;7(1):4975. https://doi.org/10.1038/s41598-017-04340-1.CrossRefPubMedPubMedCentral

36.

Iskander M, Elkassas D, Mohsen MA. Effect of two matrix metalloproteinase inhibitors on the color stability of a nanofilled resin composite. Oper Dent. 2015;40(1):E11-20. https://doi.org/10.2341/12-428-L.CrossRefPubMed

37.

Elkassas Dr DW, Fawzi EM, El Zohairy A. The effect of cavity disinfectants on the micro-shear bond strength of dentin adhesives. Eur J Dent. 2014;8(2):184–90. https://doi.org/10.4103/1305-7456.130596.CrossRef

38.

Soares EF, Naves LZ, Correr AB, Costa AR, Consani S, Soares CJ, Garcia-Godoy F, Correr-Sobrinho L. Effect of radiotherapy, adhesive systems and doxycycline on the bond strength of the dentin-composite interface. Am J Dent. 2016;29(6):352–6.PubMed

39.

Oh S, Jung HS, Kim HJ, Jang JH, Kim DS, Choi KK, Kim SY. Effect of zinc on the collagen degradation in acid-etched dentin. J Dent Sci. 2018;13(2):97–102. https://doi.org/10.1016/j.jds.2017.10.008.CrossRefPubMedPubMedCentral

40.

de Carvalho RV, Vieira EO, Gaviolli E, Graunke A, Chisini LA, Bacchi A, Ghiggi PC, Van de Sande FH. Doxycycline as a dentin pretreatment agent for MMP-2 inhibition and maintaining hybrid layer stability over time. Int J Adhes Adhes. 2020. https://doi.org/10.1016/j.ijadhadh.2019.102510.CrossRef

41.

Toledano-Osorio M, Osorio R, Aguilera FS, Medina-Castillo AL, Toledano M, Osorio E, Acosta S, Chen R, Aparicio C. Polymeric nanoparticles protect the resin-dentin bonded interface from cariogenic biofilm degradation. Acta Biomater. 2020;111:316–26. https://doi.org/10.1016/j.actbio.2020.05.002.CrossRefPubMed

42.

Parsaie Z, Firouzmandi M, Mohammadi N. Evaluating the Effect of Pretreatment with matrix metalloproteinase inhibitors on the shear bond strength of composite resin to primary teeth dentin: a 6-month in vitro study. Contemp Clin Dent. 2021;12(4):408–13. https://doi.org/10.4103/ccd.ccd_662_20.CrossRefPubMedPubMedCentral

43.

Mohammadi N, Parsaie Z, Jafarpour D, Bizolm F. Effect of different matrix metalloproteinase inhibitors on shear bond strength of composite attached to primary teeth dentin. European J Gen Dent. 2020;9(3):147–51. https://doi.org/10.4103/ejgd.ejgd_167_20.CrossRef

44.

Palasuk J. 2015 Synthesis characterization and matrix metalloproteinase inhibition of doxycycline modified dental adhesives https://doi.org/10.7912/C2/1610

45.

Münchow EA, Da Silva AF, Piva E, Cuevas-Suárez CE, De Albuquerque MTP, Pinal R, Gregory RL, Breschi L, Bottino MC. Development of an antibacterial and anti-metalloproteinase dental adhesive for long-lasting resin composite restorations. J Mater Chem B. 2020;8(47):10797. https://doi.org/10.1039/d0tb02058c.CrossRefPubMedPubMedCentral

46.

de Menezes LR, de Oliveira DCRS, Brito CA, da Silva EO. Use of the adhesive layer as a controlled release platform for doxycycline, as promising advancement for longer durability of dentin adhesion. Int J Adhes Adhes. 2021;108(2): 102889. https://doi.org/10.1016/j.ijadhadh.2021.102889.CrossRef

47.

Freitas PH, André CB, Fronza BM, Giannini M, Rosalen PL, Consani S, França R. Physicochemical properties, metalloproteinases inhibition, and antibiofilm activity of doxycycline-doped dental adhesive. J Dent. 2021;104: 103550. https://doi.org/10.1016/j.jdent.2020.103550.CrossRefPubMed

48.

Takahashi Y, Imazato S, Kaneshiro AV, Ebisu S, Frencken JE, Tay FR. Antibacterial effects and physical properties of glass-ionomer cements containing chlorhexidine for the ART approach. Dent Mater. 2006;22(7):647–52. https://doi.org/10.1016/j.dental.2005.08.003.CrossRefPubMed

49.

Pinheiro SL, Simionato MRL, Imparato JCP, Oda M. Antibacterial activity of glass-ionomer cement containing antibiotics on caries lesion microorganisms. Am J Dent. 2005;18(4):261–6.PubMed

50.

Prabhakar A, Prahlad D, Kumar S. Antibacterial activity, fluoride release, and physical properties of an antibiotic-modified glass ionomer cement. Pediatr Dent. 2013;35(5):411–5.PubMed

51.

de Castilho ARF, Duque C, Kreling PF, Pereira JA, de aula AB, Sinhoreti MAC, Puppin-Rontani RM. Doxycycline-containing glass ionomer cement for arresting residual caries: an in vitro study and a pilot trial. J Appl Oral Sci. 2018. https://doi.org/10.1590/1678-7757-2017-0116.CrossRefPubMedPubMedCentral

52.

Joshi R, Gokhale N, Hugar S, Soneta S, Badakar C, Patil V. Comparative evaluation of antibacterial efficacy of conventional glass-ionomer cement and bulk-fill alkasite material when combined with doxycycline and double antibiotic paste containing ciprofloxacin and metronidazole against Streptococcus mutans and Lactobacillus spp.: An in vitro study. J Indian Soc Pedod Prev Dent. 2020. https://doi.org/10.4103/JISPPD.JISPPD_143_20.CrossRefPubMed

53.

De Morais DC, Jackson JK, Kong JH, Ghaffari S, Palma-Dibb RG, Carvalho RM, Lange D, Manso AP. Characterization of polymethylmethacrylate microspheres loaded with silver and doxycycline for dental materials applications. Dent Mater. 2022;38(6):946–59. https://doi.org/10.1016/j.dental.2022.02.015.CrossRefPubMed

54.

Sudha K, Kotaiah TH, Reddy OS, Laxmi PS, Rao CL, Pavani TLN. A Comparative Evaluation of Shear Bond Strength of Resin-modified Glass Ionomer and Zirconomer Incorporated with 1.5% Doxycycline: An In Vitro Study. Ind J Dent Adv. 2017. https://doi.org/10.5866/2017.9.10159.CrossRef

55.

Birkedal-Hansen H, Moore WGI, Bodden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A, Engler JA. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993;4(2):197–250. https://doi.org/10.1177/10454411930040020401.CrossRefPubMed

56.

Golub LM, Sorsa T, Lee H-M, Ciancio S, Sorbi D, Ramamurthy NS, Gruber B, Salo T, Konttinen YT. Doxycycline inhibits neutrophil (PMN)-type matrix metalloproteinases in human adult periodontitis gingiva. J Clin Periodontol. 1995. https://doi.org/10.1111/j.1600-051x.1995.tb00120.x.CrossRefPubMed

57.

Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res. 1998;12(2):12–26. https://doi.org/10.1177/08959374980120010501.CrossRefPubMed

58.

Hashimoto M, Ohno H, Sano H, Kaga M, Oguchi H. In vitro degradation of resin-dentin bonds analyzed by microtensile bond test, scanning and transmission electron microscopy. Biomaterials. 2003;24(21):3795–803. https://doi.org/10.1016/s0142-9612(03)00262-x.CrossRefPubMed

59.

McCall KA, Huang CC, Fierke CA. Function and mechanism of zinc metalloenzymes. J Nutr. 2000;130(5S Suppl):1437S-S1446. https://doi.org/10.1093/jn/130.5.1437S.CrossRefPubMed

60.

Cunha BA, Sibley CM, Ristuccia AM. Doxycycline. Ther Drug Monit. 1982;4(2):115–35. https://doi.org/10.1097/00007691-198206000-00001.CrossRefPubMed

61.

Fereidooni R, Shahravan A, Manochehrifar H, Pardakhty A, Nosrati F, Mollaie HR. Niosomal doxycycline and triamcinolone: a novel approach to minimize cytotoxicity in endodontic medicaments. Iran Endod J. 2024;19(1):39–45. https://doi.org/10.22037/iej.v19i1.42608.CrossRefPubMedPubMedCentral

Title: Exploring the effectiveness of doxycycline in restorative dentistry: a systematic review of in vitro studies
Authors: Bruna Tavares Carneiro
Marina Minici Dumont Prado
Iara de Oliveira Nogueira
Allyson Nogueira Moreira
Carolina Bosso André
Publication date: 12-08-2024
Publisher: Springer Nature Singapore
Keyword: Doxycycline
Published in: Odontology / Issue 1/2025
Print ISSN: 1618-1247
Electronic ISSN: 1618-1255
DOI: https://doi.org/10.1007/s10266-024-00986-2

Regular dental check-up status and related factors among Thai residents in Japan

Gingival Diseases
Original Article

Dimensional changes over time in stereolithographic models fabricated with a 3D printer

Original Article

Correction: miR-708-3p targetedly regulates LSD1 to promote osteoblast differentiation of hPDLSCs in periodontitis

Open Access
Correction

Influence of melatonin supplementation on tissue response of endodontic sealers in Wistar rats

Original Article

Investigating the impact of post-curing cycles on surface hardness and color stability in 3D printed resin crowns

Original Article

METTL3 promotes immature dental pulp stem cells-induced angiogenesis by regulating ETS1 mRNA stability in an m6A-HuR-dependent manner

Original Article

Keynote series | Spotlight on managing health in obesity

Springer Medicine

Exploring the effectiveness of doxycycline in restorative dentistry: a systematic review of in vitro studies

Abstract

Other articles of this Issue 1/2025

Regular dental check-up status and related factors among Thai residents in Japan

Dimensional changes over time in stereolithographic models fabricated with a 3D printer

Correction: miR-708-3p targetedly regulates LSD1 to promote osteoblast differentiation of hPDLSCs in periodontitis

Influence of melatonin supplementation on tissue response of endodontic sealers in Wistar rats

Investigating the impact of post-curing cycles on surface hardness and color stability in 3D printed resin crowns

METTL3 promotes immature dental pulp stem cells-induced angiogenesis by regulating ETS1 mRNA stability in an m6A-HuR-dependent manner

Springer Medicine

Abstract

Please log in to get access to this content

Regular dental check-up status and related factors among Thai residents in Japan

Dimensional changes over time in stereolithographic models fabricated with a 3D printer

Correction: miR-708-3p targetedly regulates LSD1 to promote osteoblast differentiation of hPDLSCs in periodontitis

Influence of melatonin supplementation on tissue response of endodontic sealers in Wistar rats

Investigating the impact of post-curing cycles on surface hardness and color stability in 3D printed resin crowns

METTL3 promotes immature dental pulp stem cells-induced angiogenesis by regulating ETS1 mRNA stability in an m6A-HuR-dependent manner