The objective is to short review the current state of the art of dental antimicrobial agents in term of minimal invasive restorative dentistry. An outline of the most important aspects of dental antimicrobial agents was created, and a subsequent literature search for articles related was conducted. The current state of the art of antimicrobial agents includes a variety of species with broad ranges of properties. There is no agreement as to the choice of substances and concentration, however, there is a growing consensus regarding the need to use antimicrobial agents as additions into dental restorative materials’ compound in patients with high intensity of active caries disease.

Keywords: glass ionomer, antimicrobial

The objective is to short review the current state of the art of dental antimicrobial agents in term of minimal invasive restorative dentistry. An outline of the most important aspects of dental antimicrobial agents was created, and a subsequent literature search for articles related was conducted.

Background

Various studies have shown that glass ionomer cements (GICs)^1,2 have potential bioactivity, adhesion to hard tissues and also reduce the formation of plaque by Streptococcus mutans strains. ^3–12 The antibacterial activity of glass ionomer cements (GIC) is mostly attributed to their fluoride and other ions release for secondary caries inhibiting effect, which has been already confirmed in vitro with lower demineralization depths of the glass ionomer groups adjacent to the dental hard tissue.^13–19 Thus, these cements are expected to actively control microbial biofilm formation, while biofilms modulate the release of fluoride from GICs.^20,21 On the other hand, studies have shown that fluoride-releasing activity of GICs is insufficient for effective protection. Moreover, more viscous GICs release substantially less cumulative fluoride ions than less viscous ones resulting in no microbial balancing attribute in vivo.^22–28

The oldest documented medical use of an antimicrobial agent concerned copper mentioned in the Smith Papyrus; this Egyptian medical text, written between 2600 and 2200 B.C., describes the application of copper to sterilize chest wounds and drinking water. Ancient Egyptians and Greeks also used specific molds and plant extracts to treat infections. Earlier, since the time of the Persian kings, vessels made of Cu and Ag had been intentionally used for water disinfection and food preservation.^29–31

The first contemporary antimicrobial agent in the world was salvarsan, a remedy for syphilis that was synthesized by Ehrlich in 1910. In 1935, sulfonamides were developed by Domagk and other researchers. In 1928, Fleming discovered penicillin.³² The idea of using antiseptics to control dental decay was originally suggested by Miller in 1890. In 1893 Naegli observed lethal action of heavy metal ions upon microorganisms and called this phenomenon oligodynamic.³³

Contemporary concepts

Among contemporary antimicrobials modifying glass ionomers’ composition, non-organic, organic – synthetic, with antibiotics and natural, or hybrid agents can be distinguished.

Non-organic antimicrobials

Plenty of non-organic species have been tested, and among them zinc sulphate (ZnSO₄), strontium dioxide (SrO₂), barium sulphate (BaSO₄), ytterbium fluoride (YbF₃), copper, gold, palladium, platinum, strontium, zinc or silver nanoparticle (nCu, nAu, nPa, nPt, nSr, nZn, nAg), calcium-zinc-silicate, amorphous calcium phosphate nanoparticles (nACP), zinc oxide (ZnO), copper oxide (CuO), sodium hypochlorite (NaClO), copper iodide (CuI), fluoroapatite (FAp), borate glass, hydroxyapatite (HAp), porous nHAp, nanocrystalline calcium deficient hydroxyapatite (nCDHA), titanium dioxide nanoparticles (nTiO₂), zirconia dioxide (nZrO₂), monosodium gold(III)-titanate nanoparticles (nMST-Au(III)), magnesium carbonate apatite, forsterite nanoparticles (nMg₂SiO₄), amorphous peroxo-titanate (APT), tri-sodium citrate (TSC), sodium hypochlorite (SHC), boric acid (BA) niobium silicate, silver phosphoric zirconium (SPZ), tetrapod-like zinc oxide whisker (T-ZnOw), bioactive glass (BGN), fluorinated graphene (FG) have been intensively evaluated.^34–78

Synthetic

On the other hand, lately popular participation of synthetic organic substances like chlorhexidine digluconate, diacetate, dihydrochloride (CHG, CHA, CHHCl), alexidine (ALX), alexidine combined with N-acetylcysteine (NACALX), monomers 12-methacryloyloxydodecylpyridinium bromide (MDPB), quaternary ammonium dimethacrylate (QADM), furanone chloride and bromide (GLC), thymol, chloroxylenol polyquaternary ammonium salt (PQAS), cetrimide (CT), polyethyleneimine nanoparticles (nPEI), cetylpyridinium chloride (CPC), glutaraldehyde (GA), benzalkonium chloride (BACH), sodium fusidate (SF), triclosane (TRC) and triclosane with zinc citrate complex (TRC-ZnC), furanone (FN), Poly(Acrylic Acid-Co-DCAGAGM) GM-tethered 6-arm star-shaped poly(acrylic acid), 2,2’-bipyridine, 2-dimethylaminoethanol (DMAE-CB), anthocyanin, quaternary ammonium monomer dimethylaminododecyl methacrylate (DMADDM), 2-methacryloxylethyl dodecyl methyl ammonium bromide (MDMAB), dimethyl ammonium chloride (DMAC), octenidine dihydrochloride (OIDC) theobromine (THEO) is observed in many researches.^78–119

Antibiotics

Also antibiotics have been tested as potential additives to GICs compound, namely metronidazole, ciprofloxacin, cefaclor, minocycline or doxycycline.^120–124

Natural

Due to the widespread antibiotics resistance in the last decades, natural organic compounds, such as miswak extract (ME), grape seed extract (GSE), ethanolic extract of propolis (EEP), epigallocatechin-3-gallate (EGCG), morphogenetic proteins, cinnamon bark oil (CBO), chitosane (CHT), seashell powder, coumarin (CO) derivatives chitosane (CHT), seashell powder, coumarin (CO) derivatives, collagen, cellulose microfibers and nanocrystals, azadirachta indica (neem) or turmeric extracts have been previously tested as possible antimicrobial agents.^125–147

Some attention was given to the hybrid version of antimicrobial agents, i.e. casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), chlorhexidine–hexametaphosphate nanoparticles (nCHX–HMP), chlorhexidine-bioactive glass, chitosan/ chlorhexidine-cetrimide, chitosane-titanium dioxide nanoparticles CHT-nTiO₂, chlorhexidine-encapsulated mesoporous silica nanoparticles, 12-methacryloyloxydodecylpyridinium bromide (MDPB)-nAg.^145–160

The Cariostatic effect of GIC is still questionable, and it is also claimed that the low pH of GICs during setting reaction may contribute more than the fluoride leached to their antibacterial properties and that no antibacterial activity is exhibited after setting,^164–167 thus, the ability of GICs to ions exchange might lead to the hypothesis that GICs could potentially be used as carrier systems/delivery matrix for other active components, e.g. antimicrobial agents^{168, 169} in term of caries balancing, microbiome colonization inhibition.

F₃ The prevalence of caries and the increase in drug resistance in the pathogenic microbiome at an alarming rate is a matter of serious concern. Therefore, there is a pressing demand to discover novel holistic strategies and identify new solutions, taking into account dental restorative materials. Changes in oral ecosystem may induce shifts of biofilm microflora towards pathologies of teeth hard tissues, gingiva and bone. The caries disease still remains a major systemic health problem in humans.

The caries cavity is an adverse effect of homeostasis confusion towards demineralization and proteolysis; remineralization through restoration may level this pathology with GICs – biomimetic materials of the first choice in an active form. Possibly the modification of GIC – a ‘Grandbiomaterial Inactivating Caries’ with microbial inhibiting agents^167–169 would help to solve the holistic problem in high intensity active caries disease patients and be a step ahead in minimal invasive dentistry, taking into consideration equivalent dietary, behavioral, hygiene and prophylaxis aspects.

There is no agreement as to the choice of substances and concentration, however, there is a growing consensus regarding the need to use antimicrobial agents as additions into dental restorative materials’ compound in patients with high intensity of active caries disease.

None.

The author declares there are no conflicts of interest.

1. Wilson AD, Kent BE. A new translucent cement for dentistry. Brit Dent J. 1972;15:133–135.
2. McLean JW, Wilson AD. Fissure sealing and filling with an adhesive glass-ionomer cement. Brit Dent J. 1974;136(7):269–276.
3. Tobias RS. Antibacterial properties of dental restorative materials: a review. Int Endodont J. 1988;21(2):155–160.
4. Benderli Y, Ulukapi H, Balkanli O, et al. In vitro plaque formation on some dental filling materials. J Oral Rehabil. 1997;24(1):80–83.
5. Nicholson JW. Adhesive dental materials–A review. Int J Adhes Dent. 1998;18:229–236.
6. Herrera M, Castillo A, Bravo M, et al. Antibacterial activity of resin adhesives, glass ionomer and resin-modified glass ionomer cements and a compomer in contact with dentin caries samples. Oper Dent. 2000;25(4):265-269.
7. Wilson NHF. Direct adhesive materials: current perceptions and evidence–future solutions. J Dent. 2001;29:307–316.
8. Woodfine B, Clarke J, Billington RW. Glass- ionomers and standards. J Dent. 2006;34: 614-622.
9. Tegginmani VS, Goel B, Uppin V, et al. Comparison of antibacterial activity of glass-ionomer cement and amalgam in class two restorations by streptococcus mutans count analysis at fixed intervals: an in vivo study. J Contemp Dent Pract. 2013;14(3):381–386.
10. Łuczaj-Cepowicz E, Marczuk-Kolada G, Zalewska A, et al. Antibacterial activity of selected glass ionomer cements. Postepy Hig Med Dosw. 2014;68:23–28.
11. Hugar SM, Assudani HG, Patil V, et al. Comparative evaluation of the antibacterial efficacy of type II glass ionomer cement, type IX glass ionomer cement, and Amalgomer™ ceramic reinforcement by modified “Direct Contact Test”: an in vitro study. Int J Clin Pediatr Dent. 2016;9(2):114–117.
12. Nicholson JW. Emerging ethical issues in restorative dentistry. New Bioethics. 2017;23(3):236–248.
13. Seppa L, Forss H, Ogaard B. The effect of fluoride application on fluoride release and the antibacterial action of glass ionomers. J Dent Res. 1993;72(9):1310–1314.
14. Hayacibara MF, Rosa OPS, Koo H, et al. Effects of fluoride and aluminum from ionomeric materials on S. mutans Biofilm. J Dent Res. 2003;82(4):267–271.
15. Duque C, Negrini Tde C, Hebling J, et al. Inhibitory activity of glass-ionomer cements on cariogenic bacteria. Oper Dent. 2005;30(5):636–640.
16. Burke FM, Ray NJ, McConnell RJ. Fluoride-containing restorative materials. Int Dent J. 2006;56(1):33–43.  
17. Amend S, Frankenbergerber R, Lückerb S, et al. Secondary caries formation with a two-species biofilm artificial mouth. Dent Mater. 2018;34(5):786–796.
18. Hegde NN, Attavar SH, Hegde MN, et al. Antibacterial activity of dental restorative material: An in vitro study. J Conserv Dent. 2018;21(1):42–46.
19. Krämer K, Schmidt M, Lücker S, et al. Glass ionomer cement inhibits secondary caries in an in vitro biofilm model. Clin Oral Invest. 2018;22(2):1019–1031.
20. Hahnel S, Ionescu AC, Cazzaniga G, et al. Biofilm formation and release of fluoride from dental restorative materials in relation to their surface properties. J Dent. 2017;60:14–24.
21. Bueno LS, Silva RM, Magalhães APR, et al. Positive correlation between fluoride release and acid erosion of restorative glass-ionomer cements. Dent Mater. 2019;35(1):135–143.
22. Quan DTH, Nga TT, Mc Intyre J. Fluoride release from Fuji IX and other fast-setting GICs. J Dent Res. 1995;74:440.
23. Papagiannoulis L, Kakaboura A, Eliades G. In vivo vs in vitro anticariogenic behavior of glass-ionomer and resin composite restorative materials. Dent Mater. 2002;18(8):561–569.
24. Smales RJ, Yip HK. The atraumatic restorative treatment (ART) approach for the management of dental caries. Quintessence Int. 2002;33(6):427–432.
25. Botelho MG. Inhibitory effects on selected oral bacteria of antibacterial agents incorporated in a glass ionomer cement. Caries Res. 2003;37(2):108–114.
26. Frencken JE, Imazato S, Toi C, et al. Antibacterial effect of chlorhexidine-containing glass ionomer cement in vivo: a pilot study. Caries Res. 2007;41(2):102–107.
27. Imazato S. Bio-active restorative materials with antibacterial effects: new dimension of innovation in restorative dentistry. Dent Mater. 2009;28(1):11–19.
28. Hafshejani TM, Zamaniana A, Venugopalb JR, et al. Antibacterial glass-ionomer cement restorative materials: A critical review on the current status of extended release formulations. J Control Release. 2017;262:317–328.
29. Wainwright M. Moulds in ancient and more recent medicine. Mycologist. 1989;3(1):21–23.
30. Grass G, Rensing Ch, Solioz M. Metallic copper as an antimicrobial surface. Appl Environ Microbiol. 2011;77(5):1541–1547.
31. Lemire JA, Harrison JJ, Turner RJ. Antimicrobial activity of metals: Mechanisms, molecular targets and applications. Nat Rev Microbiol. 2013;11(6):371–384.
32. Saga T, Yamaguchi K. History of Antimicrobial Agents and Resistant Bacteria. JMAJ. 2009;52(2):103–108.
33. McCue MW, McDougal FG, Shay DE. The antibacterial properties of some dental restorative materials. Oral Surg Med Oral Pathol. 1951;4(9):1180–1184.
34. Darling M, Hill RG. Novel polyalkenoate (glass ionomer) dental cements based on zinc silicate glasses. Biomaterials. 1994;15(4):299–306.
35. Deb S, Nicholson JW. The effect on strontium oxide on glass ionomer cements. J Mater Sci Mater Med. 1999;10(8):471–474.
36. Guida A, Towler M, Wall J, et al. Preliminary work on the antibacterial effect of strontium in glass ionomer cements. J Mater Sci Lett. 2003;22(20):1401–1403.
37. Lucas ME, Arita K, Nishino M. Toughness, bonding and fluoride-release properties of hydroxyapatite-added glass ionomer cement. Biomaterials. 2003;24(21):3787–3794.
38. Osinaga PWR, Grande RHM, Ballester RY, et al. Zinc sulphate addition to glass-ionomer cements: influence on physical and antibacterial properties, zinc and fluoride release. Dent Mater. 2003;19(3):212–217.
39. Gu YW, Yap AUJ, Cheang P, et al. Effects of incorporation of HA/ZrO2 into glass ionomer cement (GIC). Biomaterials. 2005;26(7):713–720.
40. Gu YW, Yap AUJ, Cheang P, et al. Zirconia-glass ionomer cement-a potential substitute for miracle mix. Scripta Materialia. 2005;52(2):113–116.
41. Boyd D, Towler MR, Law RV, et al. An investigation into structure and reactivity of calcium-zinc-silicate ionomer glasses using MAS-NMR spectroscopy. J Mater Sci: Mater Med. 2006;17(5):397–402.
42. Prentice LH, Tyas MJ, Burrow MF. The effect of ytterbium fluoride and barium sulphate nanoparticles on the reactivity and strength of a glass-ionomer cement. Dent Mater. 2006;22:746–751.
43. Karaś J, Kupka T, Paluch D, et al. Is the Novel Acid-base Cement for Direct Dental Restorations Capable to Be an Oral Cavity Eco-friendly Biomaterial? P J Environment Stud. 2007;16(2C):163­–168.
44. Bertolini MJ, Zaghete MA, Gimenes R, et al. Determination of the properties of an experimental glass polyalkenoate cement prepared from niobium silicate powder containing fluoride. Dent Mater. 2008;24(1):124–28.
45. Moshaverinia A, Ansar S, Moshaverinia M, et al. Effects of incorporation of hydroxyapatite and fluorapatite nanobioceramics into conventional glass ionomer cement (GIC). Acta Biomater. 2008;4(2):432–40.
46. Koenraads H, van der Kroon G, Frencken JE. Compressive strength of two newly developed glass-ionomer materials for use with the Atraumatic Restorative Treatment (ART) approach in class II cavities. Dent Mater. 2009;25:551–56.
47. Wren AD, Boyd D, Thornton R, et al. Antibacterial Properties of a Tri-Sodium Citrate Modified Glass Polyalkenoate Cement. Inc. J Biomed Mater Res. Part B: Appl Biomater. 2009;90B:700–709.
48. Elsaka SE, Hamouda IM, Swain MV. Titanium dioxide nanoparticles addition to a conventional glass-ionomer restorative: Influence on physical and antibacterial properties. J Dent. 2011;39:589–598.
49. Goenka S, Balu R, Kumar TSS. Effects of nanocrystalline calcium deficient hydroxyapatite incorporation in glass ionomer cements. J Mech Behavior Biomed Mat. 2012;7:69–76.
50. Hassan U, Farroq I, Mahdi S, Ullah R, Rana H. Newer glass ionomer cements having strontium ion and the effect of their release on acidic medium. Int J Prosthodont Rest Dent. 2012; 2(2), 57-60
51. Laiteerapong A, LochaiwatanaY, Hirata I, et al. A novel glass ionomer cement containing MgCO3 apatite induced the increased proliferation and differentiation of human pulp cells in vitro. Dent Mater J. 2012;31(5):772–778.
52. Tiwari S, Nandlal B. Comparative evaluation of fluoride release from hydroxyapatite incorporated and conventional glass ionomer cement: An in vitro study. J Indian Soc Pedodot Prev Dent. 2012;4(30):284–287.
53. Khaghani M, Doostmohammadi A, Golniya Z, et al. Preparation, Physicochemical Characterization, and Bioactivity Evaluation of Strontium-Containing Glass Ionomer Cement. Ceramics. 2013;1–7.
54. Kupka T, Orlicki R, Zaikov GE. Experimental adhesive biomaterial in the development of restorative concept towards the biomimetic dentistry. In: Pharmaceutical and Medical Biotechnology: New Perspectives. In: R Orlicki, C Cieńciala, LP Krylova, et al. Nova Publisher, Inc. 2013, New York, USA. p. 259–272.
55. Mirghaderi F, Monshi A, Kasiri M. Preparation of an experimental glass-ionomer cements and evaluation of their properties. Res Chem Intermed. 2013;39:3901–3910.
56. Wren AW, Coughlan A, Hall MM, et al. Comparison of a SiO2-CaO-ZnO-SrO glass polyalkenoate cement to commercial dental materials: ion release, biocompatibility and antibacterial properties. J Mater Sci Mater Med. 2013;24:2255–2264.
57. Sayyedan FS, Fathi M, Edris H, et al. Dent Res J. (Isfahan). 2013;10(4):452–459.
58. Zoergiebel J, Ile N. Evaluation of a conventional glass ionomer cement with new zinc formulation: effect of coating, aging and storage agents. Clin Oral Invest. 2013;17:619–626.  
59. Nishimura T, Shinonaga Y, Abe Y, et al. Porous hydroxyapatite can improve strength and bioactive functions of glass ionomer cement. Nano Biomed.2014;6(2):53–62.
60. Shen L, Coughlan A, Towler M, et al. Degradable borate glass polyalkenoate cements. J Mater Sci: Mater Med. 2014;25:965–973.
61. Vanajassun P, Nivedhitha MS, Nishad NT, et al. Effects of zinc oxide nanoparticles in combination with conventional glass ionomer cement: in vitro study. Adv Hum Biol. 2014;4(3):31–36.
62. Eiampongpaiboon T, Whasun O Chung, James D Bryers, et al. Antibacterial activity of gold-titanates on Grampositive cariogenic bacteria. Acta Biomat Odontol Scand. 2015;1(2–4):51–58.
63. Farrugia Ch, Camilleri J. Antimicrobial properties of conventional restorative filling materials and advances in antimicrobial properties of composite resins and glass ionomer cements — a literature review. Dent Mater. 2015;31:89–99.
64. Gacia-Contereras R, Scougall-Vilchis, Contreras-Bulnes R, et al. Mechanical, antibacterial and bond strength properties of nano-titanium-enriched glass ionomer cement. J Appl Oral Sci. 2015;23(3):321–328.
65. Gjorgievska E, van Tendeloo G, Nicholson JW, et al. The Incorporation of Nanoparticles into Conventional Glass-Ionomer Dental Restorative Cements. Microsc Microanal. 2015;21:392–406.
66. Jaegermann Z, Ciołek L, Zaczyńska E, et al. In vitro biological evaluation of new dental biomaterials. Engineering of Biomaterials. 2015;131:32–39.
67. Bariker RH, Mandroli PS. An invitro evaluation of antibacterial effect of Amalgomer CR and Fuji VII against bacteria causing severe early childhood caries. J Indian Soc Pedod Prev Dent. 2016;34:23–29.
68. Chu HH, Shinonaga Y, Nishimura T, et al. Behavior of trace elements in novel apatite-ionomer cement. Nano Biomed. 2016;8(2):101–111.
69. Tiwari S, Kenchappa M, Bhayya D, et al. Antibacterial Activity and Fluoride Release of Glass-Ionomer Cement, Compomer and Zirconia Reinforced Glass-Ionomer Cement. J Clin Diagn Res. 2016;10(4):90–93.
70. Kim D-A, Lee J-H, Jun S-K, et al. Sol–gel-derived bioactive glass nanoparticle-incorporated glass ionomer cement with or without chitosan for enhanced mechanical and biomineralization properties. Dent Mater. 2017;33:805–817.
71. Renné WG, Lindner A, Mennito AS, et al. Antibacterial properties of copper iodide-doped glass ionomer-based materials and effect of copper iodide nanoparticles on collagen degradation. Clin Oral Invest. 2017;21:369–379.
72. El-Wassefy NA, El-Mahdy RH, El-Kholany NR. The impact of silver nanoparticles integration on biofilm formation and mechanical properties of glass ionomer cement. J Esthet Restor Dent. 2017;30(2):1–7.
73. Kupka T, Karolus M, Fryc M. The newest clinical version of glass-polyalkenoate restorative biomaterial infused with 3YTZP nanocrystals. J Appl Biotechnol Bioeng. 2018;5(6):338–340.
74. Malik S, Ahmed MA, Choudhry Z, et al. Fluoride release from glass ionomer cement containing fluoroapatite and hydroxyapatite. J Ayub Med Coll Abbottabad. 2018;30(2):198–202.
75. Paiva L, Fidalgo TKS, da Costa LP, et al. Antibacterial properties and compressive strength of new one-step preparation silver nanoparticles in glass ionomer cements (NanoAg-GIC). J Dent. 2018;69:102–109.
76. Sun L, Yana Z, Duan Y, et al. Improvement of the mechanical, tribological andantibacterial properties of glass ionomer cements by fluorinated graphene. Dent Mater.2018;34:115–e127.
77. Laiteerapong A, Reichl F-X, Hickel R, et al. Effect of eluates from zirconia-modified glassionomer cements on DNA double-stranded breaks in human gingival fibroblast cells. Dent Mater. 20119; 35(3):444–449.
78. Prasad MP, Maradia MA. Antibacterial activity of conventional and modified glass ionomer cement against Streptococcus mutans. J Appl Biol Biotechnol. 2014;2(3):17–20.
79. Jedrychowski JR, Caputo AA, Kerper S. Antibacterial and mechanical properties of restorative materials combined with chlorhexidine. J Oral Rehab. 1983;10(5):373–381.
80. Ribeiro J, Ericson D. In vitro antibacterial effect of chlorhexidine added to glass-ionomer cements. ScandJ Dent Res. 1991;99:533–540.
81. Botelho MG. Compressive strength of glass ionomer cements with dental antibacterial agents. SADJ. 2004;59(2):51–53.
82. Palmer G, Jones FH, Billington RW, et al. Chlorhexidine release from an experimental glass ionomer cement. Biomater. 2004;25(23):5423–5431.
83. Takahashi Y, Imazato S, Kaneshiro AV, et al. Antibacterial effects and physical properties of glass-ionomer cements containing chlorhexidine for the ART approach. Dent Mater. 2006;22:647–652.
84. Hoszek A, Ericson D. In Vitro Fluoride Release and the Antibacterial Effect of Glass Ionomers Containing Chlorhexidine Gluconate. Oper Dent. 2008;33(6):696–701.
85. Türkün LS, Murat Türkün, Entuğrul F, et al. Long-Term Antibacterial Effects and Physical Properties of Chlorhexidine-Containing Glass Ionomer Cement. J Esthet Restor Dent. 2008;20:29–45.
86. Deepalakshmi M, Poorni S, Miglani R, et al. Evaluation of the antibacterial and physical properties of glass ionomer cements containing chlorhexidine and cetrimide: an in-vitro study. Indian J Dent Res. 2010;21(4): 552–556.
87. Mulla Z, Edwards M, Nicholson JW. Release of sodium fusidate from glass-ionomer dental cement. J Mater Sci: Mater Med. 2010;21:1997–2000.
88. Sainulabdeen S, Neelakantan P, Ramesh S, et al. Antibacterial activity of triclosan incorporated glass ionomer cements--an in vitro pilot study. J Clin Pediatr Dent.. 2010;35:157–161.
89. Pawluk KM. Release of antimicrobial compounds from glass-ionomer dental cements. PhD thesis. London: University of Greenwich. 2011.
90. Tüzüner T, Goz A, Er K, et al. Antibacterial Activity and Physical Properties of Conventional Glass-ionomer Cements Containing Chlorhexidine Diacetate/Cetrimide Mixtures. J Esthet Restor Dent .2011;23(1):46–55.
91. Ahluwalia P, Chopra S, Thomas AM. Strength characteristics and marginal sealing ability of chlorhexidine-modified glass ionomer cement: An in vitro study. J Indian Soc Pedodontics Preventive Dent. 2012; 30(1):41–46.
92. Borges FMC, Sampaio de Melo MA, et al. Antimicrobial effect of chlorhexidine digluconate in dentin: In vitro and in situ study. J Conserv Dent. 2012;15 (1):22–26.
93. Dimkov A, Nicholson WJ, Gjorgievska E, et al. Compresive Strength and Setting Time Determination Of Glass-ionomer Cements Incorporated With Cetylpyridinium Chloride and Benzalkonium Chloride. Sec Biol Med Sci. 2012;33(1):243–263.
94. Du X, Huang X, Huang C, et al. Inhibition of early biofilm formation by glass-ionomer incorporated with chlorhexidine in vivo: a pilot study. Aust Dent J. 2012;57:58–64.
95. Tüzüner T, Ulusu T. Effect of antibacterial agents on the surface hardness of a conventional glassionomer cement. J Appl Oral Sci. 2012;20:45–49.
96. Abd El-Baky RM, Hussien SM. Comparative Antimicrobial Activity and Durability of Different Glass Ionomer Restorative Materials with and without Chlorohexidine. J Adv Biotechnol Bioeng. 2013;1:14–21.
97. Garza ADG, Haraszthy Brewer JD, Monaco E, et al. An in vitro study of antimicrobial agents incorporated into interim restorative materials.Open J Stomatol. 2013;3:94–98.
98. Howard L, Weng Y, Huang R, Zhou Y, Xie D. Preparation and evaluation of a novel antibacterial glass-ionomer cement. J Biomed Sci Engineering. 2013;6:1117–1128.
99. IZ SG, Ertugrul F, Eden E, et al. Biocompatibility of glass ionomer cements with and without chlorhexidine. Eur J Dent. 2013;7:89–93.
100. Kim H-S, Chang SW, Baek S-H, et al. The antibacterial properties of some dental restorative materials. Antimicrobial effect of alexidine and chlorhexidine against Enterococcus faecalis infection. Int J Oral Sci. 2013;5:26–31.
101. Mathew SM, Thomas AM, Koshy G, et al. Evaluation of the Microleakage of Chlorhexidine-Modified Glass Ionomer Cement: An in vivo Study. Int J ClinPediatr Dent. 2013;6(1):7–11.  
102. Prabhakar AR, Pattanshetti K, Sugandhan S. A Comparative Study of Color Stability and Fluoride Release from Glass Ionomer Cements Combined with Chlorhexidine. Int J Clin Pediatr Dent. 2013;6(1):26–29.
103. Silveira LFM, Baca P, Arias-Moliz MT, et al. Antimicrobial activity of alexidine alone and associated with N-acetylcysteine against Enterococcus faecalis biofilm. Int J Oral Sci. 2013;5:146–149.
104. Becci de Oliveira AC, Marti LM, Zuanon ACC, et al. Influence of the addition of chlorhexidine diacetate on bond strength of a high-viscosity glass ionomer cement to sound and artificial caries-affected dentin. Rev Odontol. 2014;43(1):1–7.
105. Marti LM, Mata M, Ferraz-Santos B , Azevedo ER , Giro EMA , Zuanon ACC. Addition of Chlorhexidine Gluconate to a Glass Ionomer Cement: A Study on Mechanical, Physical and Antibacterial Properties. Braz Dent J. 2014;25(1):33–37.
106. Somani R, Jaidka S, Jawa D, et al. Comparative evaluation of microleakage in conventional glass ionomer cements and triclosan incorporated glass ionomer cements. Contemp Clin Dent. 2014;5(1):85–88.
107. Satpute T, Mulay S. Effect of Addition of Novel Chlorhexidine Nanoparticles to a Type II GIC on Its Microshear Bond Strength to Dentin. Int J Dent Sci Res. 2015;3(4):102–106.
108. Jaidka S, Somani R, Singh DJ, et al. Comparative evaluation of compressive strength, diametral tensile strength and shear bond strength of GIC type IX, chlorhexidine-incorporated GIC and triclosan-incorporated GIC: An in vitro study. J Int Soc Prev Community Dent. 2016;Suppl 1):64–69.
109. Lacerda-Santos R, Sampaio GA, Moura MFL, et al. Effect of Different Concentrations of Chlorhexidine in Glass-ionomer Cements on In Vivo Biocompatibility. J Adhes Dent. 2016;18:325–330.
110. Somani R, Jaidka S, Singh DJ, et l. Comparative Evaluation of Shear Bond Strength of Conventional Type II Glass Ionomer Cement and Triclosan Incorporated Type II Glass Ionomer Cement: An in Vitro Study. Adv Hum Biol. 2015;5(2):88–92.
111. Wang S-P, Ge Y, Zhou X-D, et al. Effect of anti-biofilm glass–ionomer cement on Streptococcus mutans biofilms. Int J Oral Sci. 2016;8:76–83.
112. Yadiki JV, Jampanapalli SR, Konda S,et al. Comparative evaluation of the antimicrobial properties of glass ionomer cements with and without chlorhexidine gluconate. Int J Pediatr Dent. 2016;9:99–103.
113. Becci de Oliveira AC, Marti LM, Zuanon ACC, et al. Long-term influence of associating an antibacterial agent with GIC on bond strength to caries-affected dentin. BJOS. 2017;16(e17035):1–10.
114. Duque C, Aida KL, Pereira JA, et al. In vitro and in vivo evaluations of glass-ionomer cement containing chlorhexidine for Atraumatic Restorative Treatment. J Appl Oral Sci. 2017;25(5):541–550.
115. Joshi JS, Roshan NM, Sakeenabi B, et al. inhibition of residual cariogenic bacteria in atraumatic restorative treatment by chlorhexidine: disinfection or incorporation. Pediatric Dent. 2017;39(4):308–312.
116. Machado JC, Oliveira JP, Duque C, et al. Effect of storage time and Effect of chlorhexidine addition on the mechanical properties of glass ionomer cements. BJOS. 2017;16:1–9.
117. Tüzüner T. In-vitro evaluation of the microhardness amd fluoride releasing properties of chlorhexidine+benzalkonium chloride mixtures incorporated into glass ionomer cement. Cumhuriyet Dent J. 2018;21(2):103–108.
118. Vamsi K, Siddiqui F. Antimicrobial Effect of an Experimental Glass Ionomer Cement against Pathogens associated with Deep Carious Lesions. J Contemp Dent Pract. 2018;19(7):824–829.
119. Yesilyurt C, Er K, Tasdemir K, et al. Antibacterial Activity and Physical Properties of Glass-ionomer Cements Containing Antibiotics. Operative Dent. 2009;34(1):18–23.
120. Cevallos González FM, dos Santos Araújo EM, Lorenzetti Simionato RM, Siriani LF, Vega ACA, Medeiros IS, Matos AB. Effects of theobromine addition on chemical and mechanical properties of a conventional glass ionomer cement. Prog Biomater. 2019:1–7.
121. Castilho AR, Duque C, Negrini TC, et al. Mechanical and biological characterization of resin-modified glass-ionomer cement containing doxycycline hyclate. Arch Oral Biol. 2012;57(2):131–8.
122. Ferreira JMS, Pinheiro SL, Sampaio FC, et al. Use of Glass Ionomer Cement Containing Antibiotics to Seal off Infected Dentin: a Randomized Clinical Trial. Braz Dent J. 2013;24(1):68–73.
123. Mittal S, Soni H, Sharma DK, et al. Comparative evaluation of the antibacterial and physical properties of conventional glass ionomer cement containing chlorhexidine and antibiotics. J Int Soc Prevent Communit Dent. 2015;5:268–275.
124. Castilho ARF, Duque C, Kreling PF, et al. Doxycycline-containing glass ionomer cement for arresting residual caries: an in vitro study and a pilot trial. J Appl Oral Sci. 2018;26(e20170116):1–8.
125. Limapornvanich A, Jitpukdeebodintra S, Hengtrakool Ch, et al. Bovine serum albumin release from novel chitosan-fluoro-aluminosilicate glass ionomer cement: Stability and cytotoxicity studies. J Dent. 2009;37:686–690.
126. Giacomelli E, Mota EG, Oshima HMS, et al. Development of glass ionomer cement modified with seashell powder as a scaffold material for bone formation. Rev Odonto Sci. 2011;26(1):40–44.
127. El Tatari A, de Soet JJ, de Gee AJ, et al. Influence of salvadora persica (miswak) extract on physical and antimicrobial properties of glass ionomer cement. Europ Arch Paediatric Dent. 2011;12(1):22–25.
128. Prabhakar AR, Sharma D, Sugandhan S. Comparative evaluation of the remineralizing effect and surface microhardness of glass ionomer cement containing grape seed extract and casein phosphopeptide amorphous calcium phosphate: An in vitro study. Eur Arch Paediatric Dent. 2012;13(3):138–143.
129. Topcuoglu N, Ozan F, Ozyurt M, et al. In vitro antibacterial effects of glassionomer cement containing ethanolic extract of propolis on Streptococcus mutans. Europ J Dent. 2012;6:428–433.
130. Hu J, Du X, Huang C, et al. Antibacterial and physical properties of EGCG-containing glass ionomer cements. J Dent. 2013;41:927–934.
131. Abraham D, Thomas AM, Chopra S, et al. A Comparative Evaluation of Microleakage of Glass Ionomer Cement and Chitosan-modified Glass Ionomer Cement: An in vitro Study. Int J Clin Pediatr Dent. 2014;7(1):6–10.
132. Hatunoglu E, Ozturk F, Bilenrer T, et al. Antibacterial and mechanical properties of propolis added to glass ionomer cement. Angle Orthodont. 2014;84(2):368–373.
133. Alhalawani AMF, Rodriguez O, Curran DJ, et al. A glass polyalkenoate cement carrier for bone morphogenetic proteins. J Mater Sci: Mater Med. 2015;26:151.
134. Altunsoy M, Tanriver M, Turkan U, et al. In vitro evaluation of microleakage and microhardness of ethanolic extracts of Propolis in different proportions added to glass ionomer cement. J Clin Pediatr Dent. 2016;40:136–140.
135. Prabhakar AR, Balehosur DV, Basappa N. Comparative Evaluation of Shear Bond Strength and Fluoride Release of Conventional Glass Ionomer with 1% Ethanolic Extract of Propolis Incorporated Glass Ionomer Cement –Invitro Study. Journal of Clinical and Diagnostic Research. 201;10(5):88–91.
136. Salem AM, Jones SJ, Ellis IR, et al. Investigating the addition of collagen and its integrin binding sequence (RGD) to glass polyalkenoate: In terms of material and cellular properties to explore a more biocompatible method of root caries restoration. J Dent. 2016;54:68–76.
137. Bhanushali S, Srilatha KT, Girish MS. Antimicrobial Efficacy of Cinnamon Bark Oil on Lactobacillus acidophilus and its Effect on Compressive Strength of Glass Ionomer Cement. World J Dent. 2017;8(3):164–170.
138. Kabil NS, Badran AS, Wassel MO. Effect of the addition of chlorhexidine and miswak extract on the clinical performance and antibacterial properties of conventional glass ionomer: an in vivo study. Int J Paediatric Dent. 2017; 27:380–387.
139. Kumar RS, Ravikumar N, Kavitha S, et al. Nanochitosan modified glass ionomer cement with enhanced mechanical properties and fluoride release. Int J Biol Macromol. 2017;104:1860–1865.
140. Menezes-Silva R, Pereira FV, Santos MH, et al. Biocompatibility of a New Dental Glass Ionomer Cement with Cellulose Microfibers and Cellulose Nanocrystals. Brazilian Dent J. 2017;28(2):172–178.
141. Nakamura K, Nakanishi K, Bando Y, et al. Charge and controlled release of epigallocatechin gallate by glass ionomer cement containing nanoporous silica particles. Nano Biomed. 2017;9(1):29–34.
142. Rahman FSA, Osman H, Mohamad D. Release profile of synthesized coumarin derivatives as a novel antibacterial agent from glass ionomer cement (GIC). Advanced Mat Sustainability Growth. 2017;100008:1–6.
143. Subramaniam P, Girish Babu KL, Neeraja G, et al. Does Addition of Propolis to Glass Ionomer Cement Alter its Physicomechanical Properties? An In Vitro Study. J Clin Pediatric Dent. 2017;41(1);62–66.
144. Kumari DP, Khijmatgar S, Chowdhury A, et al. An evaluation of the physical properties of a new atraumatic restorative treatment material containing azadirachta indica (neem). J Evolution Med Dent Sci. 2018;7(38):4201–4207.
145. Elgamily H, Ghallab O, El-Sayed H, et al. Antibacterial potency and fluoride release of a glass ionomer restorative material containing different concentrations of natural and chemical products: An in-vitro comparative study. J Clin Exp Dent. 2018;10(4):e312–320.
146. Kumari DP, Shetty AV, Khijmatgar S, et al. Mutagenicity potential (affect) of new atraumatic restorative treatment (ART) material incorporated with Azadirachta indica (Neem) against Salmonella typhimurium. J Oral Biol craniofac Res. 2019;9:5–9.
147. Prabhakar AR, Yavagal ChM, Karuna YM, et al. Effect of Turmeric incorporation on fluoride release, Antibacterial activity and Physical properties of glass ionomer cement. An in-vitro comparative study. Int J Ayurvedic Med. 2014;5(1):91–101.
148. Mazzaoui SA, Burrow MF, Tyas MJ, et al. Incorporation of Casein Phosphopeptide-Amorphous Calcium Phosphate into a Glass-ionomer Cement. J Dent Res. 2003;82(11):914–918.
149. Zraikata H, Palamara JEA, Messer HH, et al. The incorporation of casein phosphopeptide–amorphous calcium phosphate into a glass ionomer cement. Dent Mater. 2011;27:235–243.
150. Xueqing H, Tiantian Y, Suling Z, et al. Anti-biofi lm Effect of Glass Ionomer Cements Incorporated with Chlorhexidine and Bioactive Glass. J Wuhan Univer Techn - Mater Sci Ed. 2012;27(2):270–275.
151. Zalizniak I, Palamara JEA, Wong RHK, et al. Ion release and physical properties of CPP–ACP modified GIC in acid solutions. J Dent. 2013;41:449–454.
152. Zhang Ke, Cheng L, Imazato S, et al. Effects of dual antibacterial agents MDPB and nano-silver in primer on microcosm biofilm, cytotoxicity and dentin bond properties. J Dent. 2013;41(5):464–474.
153. Hook ER, Owen OJ, Bellis CA, et al. Development of a novel antimicrobial releasing glass ionomer cement functionalized with chlorhexidine hexametaphosphate nanoparticles. J Nanobiotech. 2014;12(3):1–9.
154. Pinheiro SL, Azenha GR, De Milito F, et al. Antimicrobial capacity of casein phosphopeptide/amorphous calcium phosphate and enzymes in glass ionomer cement in dentin carious lesions. Acta Stomatol Croat. 2015;49:104–111.
155. Bellis CA, Nobbs AH, O’Sullivan DJ, et al. Glass ionomer cements functionalized with a concentrated paste of chlorhexidine hexametaphosphate provides dose-dependent chlorhexidine release over at least 14 months. J Dent. 2016;45:53–58.
156. Dashper SG, Catmull DV, Liu Sz-W, et al. Casein Phosphopeptide-Amorphous Calcium Phosphate Reduces Streptococcus mutans Biofilm Development on Glass Ionomer Cement and Disrupts Established Biofilms. PLOS ONE. 2016;2:1–14.
157. Gokhale N, Sood P, Hugar S, et al. Antibacterial efficacy after incorporation of CPP-ACP (GC Tooth Mousse TM) into glass Ionomer cement against Streptococcus Mutans: A preliminary in vitro study. J Pharm Negative Results. 2017;8:51–52.
158. Ibrahim MA, Priyadarshini BM, Neo J, et al. Characterization of Chitosan/TiO2 Nano-Powder Modif|ed Glass-Ionomer Cement for Restorative Dental Applications. J Esthet Rest Dent. 2017;29(2):146–156.
159. Mishra A, RK Pandey, Manickam N. Antibacterial effect and physical properties of chitosan chlorhexidine-cetrimide-modified glass ionomer cements. Indian Soc Pedod Prev Dent. 2017;35:28–33.
160. Yan h, Yang h, Li K, et al. Effects of Chlorhexidine-Encapsulated Mesoporous Silica Nanoparticles on the Anti-Biofilm and Mechanical Properties of Glass Ionomer Cement. Molecules. 2017;22(7):31225.
161. Zhao IS, Mei ML, Burrow MF, et al. Prevention of secondary caries using silver diamine fluoride treatment and casein phosphopeptide-amorphous calcium phosphate modified glass-ionomer cement. J Dent. 2017;57:38–44.
162. Bellis CA, Addison O, Nobb AH, et al. Glass ionomer cements with milled, dry chlorhexidine hexametaphosphate filler particles provide long-term antimicrobial properties with recharge capacity. Dent. 2018;3 4:1717–1726.
163. Pagano S, Chieruzzi M, Balloni S, et al. Biological, thermal and mechanical characterization of modified glass ionomer cements: The role of nanohydroxyapatite, ciprofloxacin and zinc L-carnosine. Materials Sci Engineering. 2019;C94:76–85.
164. DeSchepper EJ, White RR, von der Lehr W. Antibacterial effects of glass ionomers. Am J Dent. 1989;2:51–56.
165. Loyola-Rodriguez JP, Garcia-Godoy F, Lindquist R. Growth inhibition of glass ionomer cements on mutans streptococci. Pediatr Dent. 1994;16:346–349.  
166. van Amerongen WE. Dental caries under glass ionomer restorations. J Public Health Dent. 1996;56(3):150–154.
167. Ten Cate JM’B’. The need for antimicrobial approaches to improve caries control. Adv Dent Res. 2009;21:8–12.
168. Dimkov A, Nicholson JW, Gjorgievska E, et al. Studies on the Incorporation of Benzalkonium Chloride and Cetylpyridinium Chloride Antimicrobial Agents into Glass-Ionomer Dental Cements. Res J Pharm Biol Chem Sci. 2016;7(3):920–925.
169. Wang S-P, Ge Y, Zhou X-D, et al. Effect of anti-biofilm glass–ionomer cement on Streptococcus mutans biofilms. Int J Oral Sci. 2016;8:76–83.
170. Kupka T, Nowak J, Szczesio A, et al. Effect of addition of antimicrobial triclosan on selected properties of water-activated glass ionomer cement. J Stoma. 2016;69(5):492–500.
171. Kupka T, Nowak J, Szczesio A, et al. Impact of diacetate and digluconate chlorhexidine salts on strength properties of water-activated glass-polyalkenoate cement. Przem Chem. 2017;96(8):1756–1758.
172. Kupka T, Nowak J, Szczesio A, et al. Impact of modification with cetylpyridinium chloride – a potential cariogenic microbiota inhibitor, on selected physical-mechanical properties of the water-activated glass-ionomer. Acta Bioeng Biomech. 2018;20(3):19–24.