Otten, Marieke Petronella Theodora

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Oral Biofilm as a Reservoir for Antimicrobials

Dissertations of the University of Groningen

   University of GroningenOral Biofilm as a Reservoir for AntimicrobialsOtten, Marieke Petronella TheodoraIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2011Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Otten, M. P. T. (2011). Oral Biofilm as a Reservoir for Antimicrobials. University of Groningen.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 04-06-2022Chapter 6  General discussion   Chapter 6   96  In this thesis, the hypothesis that the substantivity of antimicrobial oral health care products is enhanced by absorption and release of antimicrobial components in and from oral biofilm left behind after brushing was substantiated. In this chapter, we will consider the following biological aspects of the biofilm as a reservoir for antimicrobial agents: - development and prevention of oral diseases via changes in oral ecology - clinical relevance of the biofilm as a reservoir - perspectives for the future.   Development and prevention of oral diseases via changes in oral ecology In 1676 Antonie van Leeuwenhoek was the first to use a microscope to study dental plaque and he discovered the presence and existence of “animalcules”, later called bacteria. In the following years, the relationship between bacteria and diseases was observed and finally proven by Robert Koch, in his postulates, in 1890. Harald Löe and his coworkers were able to demonstrate that dental plaque is the primary etiologic factor in both gingivitis1 and caries2, in 1965 and 1970 respectively. These findings indicate that removal of the disease-causing bacteria will prevent the development of the disease. The most efficient way to remove disease-causing bacteria, incorporated in a biofilm, is complete removal of the total biofilm. This, however, is an impossibility, because 100% removal of the oral biofilm can never be achieved3. Apart from being impossible, it is probably undesirable since oral biofilm is a part of the resident microflora and normal ecology of the oral cavity4. Disturbance of this ecology can lead to the development of bacteria-related diseases, like caries and periodontal disease, but also to overgrowth of potentially pathogenic microorganisms like yeasts4. Modifying the composition of the oral biofilm might therefore have more clinical General discussion    97impact than aiming at complete removal. Therefore, it is important to obtain a better insight of the composition of the oral microflora to understand the exact role of bacteria in disease and how to act upon the bacteria. Currently, it is known that the oral biofilm has an open architecture, with a variety in spatial distribution of dead and live bacteria5. Furthermore, the oral biofilm composition is site and subject specific6. Nowadays, more insight is gained in the composition of oral biofilms by the use of diagnostic tools, like DGGE6, a technique described in chapter 5.  The inclusion of fluoride in toothpastes was a major factor in the decline of caries development7;8. This emphasizes the importance of adding chemo-therapeutical agents to oral hygiene products, like toothpastes and mouthrinses. Since bacteria are responsible for the development of oral diseases like caries and periodontal disease, controlling bacteria by adding agents, that reduce oral biofilm formation or its pathogenicity, to toothpastes and mouthrinses is a logical development. In chapter 2  it was studied whether known antimicrobial toothpastes and mouthrinses were capable of influencing oral biofilm development. To meet the in vivo situation, where saliva and water dilute the concentration of toothpaste and mouthrinse components, dilution series were made and studied. The outcomes of this study showed that dilution of the products did not result immediately in less growth inhibition, depending on the product and dilution studied. Nevertheless all products showed a significant decrease in growth inhibition at the highest dilution studied. In accordance with our findings, it was shown that rinsing with a beaker water after brushing and therewith diluting the toothpaste components, resulted in a higher level of caries9;10.    Chapter 6   98  Clinical relevance of the biofilm as a reservoir Dental diseases like caries and periodontal disease are one of the most common bacterial infections in humans. The prevention of biofilm accumulation, and therewith gingival inflammation and caries, is an important part of preventive dentistry, and often done by recommending brushing twice per day with a toothpaste and possibly the supplementary use of a mouthrinse. The anti-plaque, anti-gingivitis and anti-caries effects of toothpastes and mouthrinses are therefore extensively promoted by their manufacturers. The anti-caries effect of toothpastes and mouthrinses is proven in multiple studies7;11 and a comprehensive review on the  anti-plaque and anti-gingivitis effects of several toothpaste and mouthrinse formulations was made by Gunsolley12. Despite the promising results of using toothpastes and mouthrinses in combination with mechanical cleaning, oral biofilm is always left behind3. Thus it can be concluded that chemical plaque-, gingivitis- and caries-control are challenging topics and subjects for discussion. From the literature it is already known that biofilms can be used as a reservoir for fluoride ions13. Therefore we hypothesized that biofilm left behind can also be used as a reservoir for antimicrobial toothpaste and mouthrinse components, and substantiated in chapters 2, 3, 4. In these chapters we demonstrated that biofilm can indeed act as a reservoir for oral antimicrobials, therewith contributing to prolonged action of the antimicrobial product.    Perspectives for the future  In this thesis, we described a new role for oral biofilm left behind after brushing as a reservoir for antimicrobial agents that may influence further biofilm development in vitro and in vivo upon their subsequent release from the biofilm.  For more clinically relevant parameters like caries decline, Cenci et al.14 showed that using a fluoride toothpaste resulted in decreased caries progression. In vitro General discussion    99research confirmed that fluoride, at low concentrations comparable to concentrations found in oral biofilm, can promote remineralization of enamel15. With respect to the current study, the effects of the antimicrobial agents absorbed in the biofilm on the surrounding oral surfaces in vivo in terms of clinical parameters needs further investigation. Another subject being worthwhile to study is to increase the penetration of antimicrobials in oral biofilm to enhance effects of absorption and subsequent release. For either fluoride16 and chlorhexidine17 it is known that both only have a superficial effect on an in vivo grown biofilm. The structure of the biofilm may restrict the penetration of an antimicrobial agent, i.e. by binding agents on the surface or outer layers18, or the molecules are simply to big to penetrate in the dense biofilm. The role of combining mechanical oral biofilm removal, that may fluff up biofilm-left-behind, with chemical treatment of the biofilm could improve penetration of antimicrobials in the biofilm and is an exciting option that has not yet been explored. Sonic toothbrushes induce fluid shear effects19;20 and yield the inclusion of air bubbles in the biofilm, exceeding the range of the bristles end. These processes result in non-contact removal of the biofilm, through fluid shear dynamics19 or acoustic pressure20. Possibly, these fluid dynamics and acoustic forces can also contribute to the deeper penetration of therapeutic agents in or even through the biofilm, to increase the delivery of therapeutic agents at hard to reach places, therewith enhancing the efficacy of those agents. In vitro studies have already shown that fluoride penetration through Streptococcus mutans biofilms is increased after using a powered toothbrush compared to diffusion alone21. Ongoing research on the contribution of hydrodynamic fluid forces towards the delivery of therapeutic agents in biofilms, to enhance the efficacy of  therapeutic agents in the prevention of dental diseases is needed to proof this concept.   Another approach to influence oral biofilms is to target the adsorbed salivary film on teeth to which the biofilm adheres. It was shown for instance, that amine Chapter 6   100  fluoride can adsorb to salivary conditioning films and influence initial bacterial adhesion and viability22. Recently, the structure and functional mechanism of the bacterial glucansucrase GH70 enzyme has been revealed23. The bacteria utilize the glucansucrase enzyme to produce polysaccharides that facilitate biofilm formation and enhances adhesion of bacteria to tooth surface from dietary sucrose. In the future, inhibitors of the glucansucrase enzyme might be developed, possibly resulting in anti-caries drugs or an improved penetration of antimicrobial or therapeutic agents in the biofilm.           General conclusion  There is in vitro and in vivo evidence that the oral biofilm can act as a reservoir for antimicrobial therapeutic agents, as described in this thesis for antimicrobial agents. Therewith, the biofilm as a reservoir contributes to the long-lasting activity of oral antimicrobials, derived from toothpastes and mouthrinses. This is important since the biofilm is mostly left behind on places that are both hard to reach, like interdental regions, pits and fissures, and most at risk for the development of diseases, like caries and gingival diseases.     General discussion    101Reference List   1. Loe H, Theilade E, Jensen SB. Experimental gingivitis in man. J. Periodontol. 1965;36:177-187.  2. Von der Fehr FR, Loe H, Theilade E. Experimental caries in man. Caries Res. 1970;4:131-148.  3. Van der Weijden GA, Echeverria JJ, Sanz M et al. Mechanical Supragingival Plaque Control. In: Lindhe J, Lang NP, Karring T, eds. Clinical Periodontology and Implant Dentistry. Copenhagen: Blackwell Munskgaard; 2008:705-733.  4. Marsh PD, Nyvad B. The oral microflora and biofilms on teeth. In: Fejerskov O, Kidd E, eds. Dental Caries, the disease and its clinical management. Oxford: Blackwell Munksgaard; 2008:163-187.  5. Auschill TM, Arweiler NB, Netuschil L et al. Spatial distribution of vital and dead microorganisms in dental biofilms. Arch. Oral Biol. 2001;46:471-476.  6. Aas JA, Paster BJ, Stokes LN et al. Defining the normal bacterial flora of the oral cavity. J. Clin. Microbiol. 2005;43:5721-5732.  7. Bratthall D, Hansel-Petersson G, Sundberg H. Reasons for the caries decline: what do the experts believe? Eur. J. Oral Sci. 1996;104:416-422.  8. Marinho VC, Higgins JP, Sheiham A et al. Fluoride toothpastes for preventing dental caries in children and adolescents. Cochrane Database Syst. Rev. 2003;CD002278.  9. Ashley PF, Attrill DC, Ellwood RP et al. Toothbrushing habits and caries experience. Caries Res. 1999;33:401-402.  10. O'Mullane DM, Kavanagh D, Ellwood RP et al. A three-year clinical trial of a combination of trimetaphosphate and sodium fluoride in silica toothpastes. J. Dent. Res. 1997;76:1776-1781. Chapter 6   102   11. Marinho VC, Higgins JP, Logan S et al. Topical fluoride (toothpastes, mouthrinses, gels or varnishes) for preventing dental caries in children and adolescents. Cochrane Database Syst. Rev. 2003;CD002782.  12. Gunsolley JC. A meta-analysis of six-month studies of antiplaque and antigingivitis agents. J. Am. Dent. Assoc. 2006;137:1649-1657.  13. Duckworth RM, Gao XJ. Plaque as a Reservoir for Active Ingredients. In: Duckworth RM, ed. The Teeth and Their Environment. Basel: Karger; 2006:132-149.  14. Cenci MS, Tenuta LM, Pereira-Cenci T et al. Effect of microleakage and fluoride on enamel-dentine demineralization around restorations. Caries Res. 2008;42:369-379.  15. Lynch RJ, Mony U, Ten Cate JM. The effect of fluoride at plaque fluid concentrations on enamel de- and remineralisation at low pH. Caries Res. 2006;40:522-529.  16. Watson PS, Pontefract HA, Devine DA et al. Penetration of fluoride into natural plaque biofilms. J. Dent. Res. 2005;84:451-455.  17. Zaura-Arite E, van Marle J, Ten Cate JM. Confocal microscopy study of undisturbed and chlorhexidine-treated dental biofilm. J. Dent. Res. 2001;80:1436-1440.  18. Marsh PD. Plaque as a biofilm: pharmacological principles of drug delivery and action in the sub- and supragingival environment. Oral Dis. 2003;9 Suppl 1:16-22.  19. Hope CK, Wilson M. Effects of dynamic fluid activity from an electric toothbrush on in vitro oral biofilms. J. Clin. Periodontol. 2003;30:624-629.  20. Busscher HJ, Jager D, Finger G et al. Energy transfer, volumetric expansion, and removal of oral biofilms by non-contact brushing. Eur. J. Oral Sci. 2010;118:177-182. General discussion    103 21. Stoodley P, Nguyen D, Longwell M et al. Effect of the Sonicare FlexCare power toothbrush on fluoride delivery through Streptococcus mutans biofilms. Compend. Contin. Educ. Dent. 2007;28 (9 suppl 1):15-22.  22. Van der Mei HC, Engels E, De Vries J et al. Effects of amine fluoride on biofilm growth and salivary pellicles. Caries Res. 2008;42:19-27.  23. Vujicic-Zagar A, Pijning T, Kralj S et al. Crystal structure of a 117 kDa glucansucrase fragment provides insight into evolution and product specificity of GH70 enzymes. Proc. Natl. Acad. Sci. U.S.A 2010;107:21406-21411 Chapter 6   104         

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Oral Biofilm as a Reservoir for Antimicrobials

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