Next Article in Journal
Neurosteroids: Structure-Uptake Relationships and Computational Modeling of Organic Anion Transporting Polypeptides (OATP)1A2
Previous Article in Journal
Adsorption of Mussel Protein on Polymer Antifouling Membranes: A Molecular Dynamics Study
Previous Article in Special Issue
Thiazole Analogues of the Marine Alkaloid Nortopsentin as Inhibitors of Bacterial Biofilm Formation
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 26
Issue 18
10.3390/molecules26185661
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Local Oral Delivery Agents with Anti-Biofilm Properties for the Treatment of Periodontitis and Peri-Implantitis. A Narrative Review

by
Shorouk Elnagdy
1,*,
Michail Raptopoulos
1,
Ioannis Kormas
1,2,
Alessandro Pedercini
1 and
Larry F. Wolff
1
1
Division of Periodontology, Department of Developmental and Surgical Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA
2
Department of Periodontics, College of Dentistry, Texas A&M University, Dallas, TX 75246, USA
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(18), 5661; https://doi.org/10.3390/molecules26185661
Submission received: 31 May 2021 / Revised: 26 August 2021 / Accepted: 10 September 2021 / Published: 17 September 2021
(This article belongs to the Special Issue Synthetic Small Molecules as Anti-biofilm Agents)
Browse Figures
Versions Notes

Abstract

:
Despite many discoveries over the past 20 years regarding the etiopathogenesis of periodontal and peri-implant diseases, as well as significant advances in our understanding of microbial biofilms, the incidence of these pathologies continues to rise. For this reason, it was clear that other strategies were needed to eliminate biofilms. In this review, the literature database was searched for studies on locally delivered synthetic agents that exhibit anti-biofilm properties and their potential use in the treatment of two important oral diseases: periodontitis and peri-implantitis.

1. Introduction

During the last two decades it has been shown that the biofilm comprises the predominant life-mode of most bacterial species [1]. Biofilms are complex structures where bacteria are usually densely packed in microcolonies and protected in a matrix of biopolymers [2]. In humans, bacteria are able to form biofilms at various body sites, and with the extensive use of medical devices in modern health care, this has provided even more new niches for bacterial biofilm formation and chronic infections.
Biofilms are complex communities of microorganisms adhering to a surface and grow in a four-dimensional process that resembles the development of organs. Initial colonization is followed by growth with the omission of bulk fluid and pellicle. Subsequently, differentiation occurs combined with aggregation of different species and forming mixed colonies. After continued differentiation and further growth, the microbial colonies become more structured and change in composition. Voids in the bulk form and the substratum loses some of its cells; further layers may be deposited. The final stage of biofilm development is the detachment of cells from the biofilm colony and their dispersal into the environment. This is an essential stage of the biofilm life cycle that contributes to biological dispersal, bacterial survival, and disease transmission. Like other stages of biofilm development, dispersal can be a complex process that involves numerous environmental signals, signal transduction pathways, and effectors [3].
It is estimated that about 80% of all microbial infections in humans are a direct result of biofilms. Key pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli have the ability to form biofilms in the human body and are associated with serious systemic diseases such as osteomyelitis, endocarditis, cystic fibrosis, pneumonia, chronic obstructive pulmonary disease, and many other systemic conditions [4,5,6,7,8,9,10,11,12]. In addition to systemic diseases, oral diseases, such as periodontitis and peri-implantitis, can also be a result of biofilm formation. For that reason, anti-biofilm agents have been introduced as treatment options. Specifically for periodontitis and peri-implantitis, commonly used anti-biofilm agents include a variety of antibiotics and the antiseptic chlorhexidine (CHX), which can be delivered systemically or locally [13,14,15,16,17]. Different systematic reviews have compared traditional non-surgical mechanical treatment for periodontitis and peri-implantitis with debridement combined with anti-biofilm agents or anti-biofilm agents alone [13,15,16,17,18]. For local delivery antibiotics, the results are still controversial [13,15,19]. Apart from antibiotics, local delivery of CHX combined with scaling and root planing (SRP) has been shown to improve the outcome of periodontal treatment [17]. Recently, antimicrobial agents isolated from animals, microbes, or plants have been introduced. An example of these agents is Chitosan, a nanotechnology product of animal origin, that has been described as biocompatible and nontoxic [20]. It has been proposed that Chitosan alone or in combination with antibiotics may be used to treat bacterial infections.
The ideal anti-biofilm approach should be able to disarm the pathogens, inhibiting an important virulence factor such as biofilm formation, without interfering with commensals viability which may cause microbial dysbiosis. Different from conventional antibiotics such as chlorhexidine, some of the novel treatment strategies for biofilm infections aim at specifically targeting unique biofilm characteristics to minimize or eliminate the drug resistance of oral biofilm. The purpose of this review is to reveal some of the novel anti-biofilm agents for the inhibition of oral biofilm, including nanoparticles, quaternary ammonium salts, and natural products.

2. Microbial Ecology of Dental Plaque

Saliva contains thousands of free-floating bacteria per milliliter that progressively deposit on dental/implant surfaces, first by non-specific mechanical and chemical means and then by specific interactions with surface-adsorbed saliva proteins. The initial colonizers of early dental plaque in the first few days are essentially composed of Gram-positive bacteria, mostly cocci [21]. The population then becomes increasingly complex, shifting progressively to a large Gram-negative community with the appearance of rods, filamentous organisms, vibrios, and spirochetes. Maturation of undisturbed dental plaque is very important because it is associated with the clinical development of gingival, periodontal and peri-implant mucosal inflammation [22,23]. This microbial succession is mediated by coaggregation between different bacterial species that corresponds to intergeneric specific cell-to-cell recognition via surface adhesins and receptors [24].
In more advanced disease states such as periodontitis, the diversity of the periodontal microbiota increases further. Supragingivally, it is composed of dense filament-containing plaque, while subgingivally due to a decrease in oxygen available in the surrounding environment, plaque is composed mainly of flagellated bacteria, spirochetes, and Gram-negative bacteria [25]. As previously mentioned, the early colonizers that initiate biofilm formation were mainly Gram-positive and belonged to the genera Streptococcus and Actinomyces that influence the local environment, which allows subgingival biofilm to become suitable for secondary colonizers such as Fusobacterium nucleatum [26,27]. This bacterium acts as a “bridging species”. Indeed, through coaggregation, it allows the adhesion of late colonizers and periopathogens like Porphyromonas gingivalis [24,28]. This succession during the colonization of the periodontal/peri-implant diseased crevice shows how the accumulation of commensal bacteria can induce a change in the local habitat such as the increase in pH, increase in gingival crevicular fluid (GCF), and decrease in oxygen, which allows periopathogens to colonize the periodontal/peri-implant crevice. This shift from a symbiotic microbial community to a more complex and aggressive microbiota is a risk predisposing the site to disease [29]. It is now well accepted that dental biofilms play a key role in the initiation and progression of periodontal and peri-implant diseases.

3. Management of Biofilm-Induced Oral Chronic Infections

The biofilm-forming capacity of bacteria is currently recognized as an important virulence determinant in the development of the various systemic infections. Bacteria have the ability to survive under various conditions of stress, including antibiotics, nutrient limitations, and immune responses [30,31]. Despite all the discoveries of the past 20 years regarding the etiopathogenesis of periodontal and peri-implant diseases, as well as the significant advances in our understanding of microbial biofilms, the incidence of these biofilm pathologies continues to rise [32,33]. Periodontitis is a biofilm-associated inflammatory disease related to a switch from a symbiotic to a dysbiotic microbiota [34]. Peri-implant diseases are associated with microbiomes that differ from those of periodontitis [35,36,37,38,39]. Control of the subgingival dysbiotic dental biofilm to restore homeostasis between the microbial community and its host remains the main purpose of currently available clinical treatments for these peri-implant and periodontal diseases. This primarily involves giving instructions for proper oral hygiene, as well as non-surgical mechanical debridement of the periodontal and peri-implant pockets [40,41]. Unfortunately, for advanced periodontal lesions with probing pocket depths of ≥7 mm, these treatments are less efficient, with about 15% showing no improvement [42].
The relative failure of mechanical treatment in peri-implantitis and periodontitis can be related to local factors, such as deep pockets, unfavorable root anatomy, or rough implant surface threads, making complete and efficient mechanical debridement difficult [43]. As illustrated in Figure 1, the comparison between periodontal health and disease around natural teeth as well as a comparison between peri-implant health and disease are primarily associated with biofilm accumulation around tooth and implant surfaces. To improve clinical results, some authors proposed the use of conventional antibiotics or local antiseptics as adjunctive treatment to the mechanical debridement of diseased pockets; their use is now recommended for the treatment of aggressive periodontitis [44].
In vitro studies have evaluated how common anti-biofilm agents affect oral biofilm. Minocycline released in agar disk cultivation has shown a reduction of Aggregatibacter actinomycetemcomitans [45]. Similarly, minocycline was able to inhibit the biofilm formation of Streptococcus gordonii and P. gingivalis [46]. Moreover, in an in vitro study comparing doxycycline against an amoxicillin and metronidazole regimen it was shown that doxycycline was more effective against A. actinomycetemcomitans [47]. Four different antibiotics (tetracycline, minocycline, doxycycline, and ofloxacin) were compared against Prevotella intermedia in vitro, a key bacterial component of subgingival plaque. Of these four antibiotics, ofloxacin managed to eradicate P. intermedia from the plaque [48]. CHX has often been used against the periodontal biofilm. CHX, at a high concentration, has been proven to be bactericidal against most oral bacteria [49]. It affects bacterial metabolism and inhibits biofilm formation [50]. However, other studies suggest that CHX alone cannot completely disrupt the periodontal biofilm and mechanical debridement is still the key component of the periodontal treatment regimen [51].

4. Non-Surgical Management of Periodontitis

The traditional non-surgical treatment for periodontitis consists of SRP. Moreover, delivery of local antimicrobial agents has been proposed as an adjunct to mechanical debridement. CHX Gluconate Chip is a product that has been used in combination with SRP leading to better results compared to SRP alone [15]. Local delivery treatment with a chip containing CHX is shown in Figure 2. It has been shown that the number of pockets ≥7 mm-deep that reduced ≥2 mm was almost doubled in patients treated with SRP plus CHX Gluconate Chip compared to SRP alone [52]. Improvement of pocket depth (PD), Clinical Attachment Level (CAL) with the CHX Gluconate Chip as an adjunct to SRP has also been shown for pockets ≥ 5 mm [17]. Moreover, studies have shown mean improvement in PD between 2.3 and 3.4 mm and CAL gain 1.0–2.3 mm [53]. However, CHX Gluconate Chip does not seem to offer any additional benefit to SRP alone during the maintenance phase of periodontal treatment [54].
In addition to CHX Gluconate Chip local administration, local antibiotic delivery has been used as an adjunct to SRP. Different tetracyclines and metronidazole are the locally administered antibiotics that have been commonly used, resulting in significant improvement in PD and CAL [19,55]. Local antibiotic delivery reduces PD by 1.5 mm on average, while other studies have shown that tetracycline, doxycycline, minocycline, and CHX offer a reduction of 0.7 mm, 0.5 mm, 0.4 mm, and <0.4 mm, respectively [16,19]. Minocycline is delivered in the form of spheres or gel, is bioresorbable, and its additional benefit in PD reduction is 0.9 mm in pockets ≥ 7 mm [13,56]. Tetracycline is administered as fibers and they have to be removed after 7–10 days. The additional benefit of administered tetracycline in combination with SRP compared to SRP alone is still controversial, but it has been reported that administration in pockets with PD ≥ 5 mm improves significantly PD and CAL measurements along with other clinical parameters [13,56,57]. Doxycycline applied locally as a gel has been shown to improve PD and CAL, as well as control clinical inflammation in treated patients [58]. Metronidazole local delivery when used as an adjunct to SRP did not show any additional improvements to SRP [13,56]. Generally, local delivery antibiotics are recommended in pockets ≥ 5 mm especially in patients that do not respond as expected to traditional SRP [14,59]. The molecules used in local delivery as adjuncts in treatment of periodontitis are listed in Table 1.

5. Clinical Signs and Management of Peri-Implantitis

Peri-implantitis is an inflammatory disease characterized by biofilm deposition on the implant surfaces. Bleeding on probing (BoP) with or without suppuration, visual signs of inflammation, increased PD, and increased radiographic bone loss from the initial bone remodeling are the characteristic features of peri-implantitis [60,61]. Smoking and history of periodontitis are considered important risk indicators for peri-implantitis [62].
Regarding peri-implantitis, surgical and non-surgical treatment options have been proposed. As an adjunct to those treatments, local antimicrobial agents are frequently used. Biofilm removal with plastic instruments followed by tetracycline HCl fiber application for 10 days showed significant PD reduction from 6 to 4.1 mm without significantly affecting the intrabony component of the peri-implant lesion after one year [63]. Moreover, P. intermedia/nigrescens, Fusobacterium sp., Bacteroides forsythus, and Campylobacter rectus were significantly reduced. Similarly, a randomized control study has shown that local application of Minocycline with peri-implantitis surgery accompanied by application at 1, 3, and 6 months after surgery resulted in 66.7% PD reduction to <5 mm compared to 36.3% reduction in the control group [64]. Local administration of minocycline spheres may also significantly reduce the levels of A. actinomycetemcomitans in peri-implantitis cases and maintain these low levels of A. actinomycetemcomitans for up to one year. On the other hand, reductions of Tannerella forsythia, P. gingivalis, and Treponema denticola treated with minocycline spheres could only be maintained for 180 days.
Multiple reports from reviews also support the use of local antimicrobial agents. The use of CHX or minocycline spheres can improve both PD and BoP as well as reduce microbial pathogens [40,43,65]. However, when CHX gel was compared with minocycline spheres, it was shown that minocycline spheres therapy managed to improve both PDs and BoP scores when compared to CHX gel. CHX gel only managed to reduce BoP [43,65,66,67]. The combination of CHX rinse with local application of a slow-release doxycycline gel was found to improve the clinical parameters around implants with peri-implantitis [62,67]. On the other hand, a randomized control clinical trial suggested that local administration of CHX for implant surface disinfection during peri-implantitis surgery had no significant additional clinical benefit on PDs and BoP [68].
Subgingival irrigation as a nonsurgical treatment of periodontal and peri-implant diseases remains controversial [69]. There is a lack of randomized controlled clinical trials, and the data do not allow for distinguishing between the relative efficacy of various available treatment methods [70]. Therefore, the development of new strategies to better treat severe periodontitis and peri-implantitis are still needed. To this end, one approach would be to investigate new clinical strategies to control more efficiently the periodontal and peri-implant biofilms and pathogens associated with periodontitis and peri-implantitis. Molecules used in local delivery as adjunctive treatment of peri-implantitis are listed in Table 2.

6. Emerging Anti-Biofilm Strategies

Periodontal disease is primarily of bacterial etiology, from multispecies biofilms of Gram-negative anaerobic microorganisms. The deleterious effects are caused by the resultant inflammatory response to the microbial insult. Therefore, the development of a treatment that combines anti-biofilm activity with anti-inflammatory activity would be of great utility. Naturally occurring antimicrobial peptides (AMPs) such as defensins have been suggested as a novel alternative to standard antibiotics because they exhibit broad-spectrum activity as well as a variety of immunomodulatory activities with little development of antibiotic resistance. However, AMP development as exogenous antibiotics is difficult for large-scale production due to limited availability. Moreover, AMPs have poor tissue distribution and potential systemic toxicity. However, the development of synthetic AMP molecule mimetics has provided an unlimited supply of such agents. An example of small molecule AMP mimetics is mPE, which mimics natural AMPs and has shown promising results with potent activity against key periodontal pathogens such as P. gingivalis and A. actinomycetemcomitans. Importantly, this compound can also inhibit the lipopolysaccharide (LPS)-mediated induction of TNF-α from macrophages and, thus, mitigate the inflammatory response of bacterial biofilm [71].
The emergence of more natural anti-plaque agents that are safer for humans and more specific against oral pathogens would be more desirable. It has been shown that a compound named Macelignan, one of the bioactive compounds found in nutmeg, has a potent anti-biofilm activity against oral primary colonizers such as Streptococcus mutans, Streptococcus sanguis, and Actinomyces viscosus. While this study was in vitro, the promising role of this compound as an anti-biofilm agent for treating periodontitis and peri-implantitis should be substantiated further through clinical studies [72,73]. The ideal anti-biofilm approach is to promote the dispersion of formed biofilms, eliminate pathogens, and impede the formation of new biofilms while avoiding the elimination of commensals, which may cause microecology dysbiosis [74,75,76]. Some of the novel treatment strategies for biofilm infections target unique biofilm characteristics to minimize or eliminate the drug resistance of oral biofilm [77].

7. Synthetic Agents

Another anti-biofilm approach would be the use of nanoparticles. Nanoparticles such as silver, copper oxide, zinc oxide, titanium oxide, and graphene, could be used to control biofilm formation [78,79,80]. Additionally, quaternary ammonium polyethyleneimine, chitosan, and silica nanoparticles have also been suggested effective in controlling biofilms [78,81,82]. Silver nanocoating applied directly on dentin, tooth, or implant surfaces can prevent biofilm formation on dentin and inhibit bacterial growth. This suggests that Silver Nanoparticles (AgNPs) could protect the tooth from pathogenic dental plaque and secondary caries when applied as a dentin coating [83]. Importantly, AgNPs exhibit the anti-biofilm potential against Enterococcus faecalis, which is known as one of the main causes of secondary and persistent endodontic infections. An illustration for the treatment of periodontitis with nanoparticles containing anti-biofilm molecules is shown in Figure 3.
Chitosan is a nontoxic natural cationic polysaccharide with characteristics of adhesiveness, antimicrobial activity, biocompatibility, and biodegradability [84,85]. The bactericidal property of chitosan nanoparticles (CNPs) is attributed to their high surface charge density, which permits them to interact with the negative charge surface of bacterial cells, causing bacterial cell death [86]. Ag-conjugated CNPs can inhibit the growth and adherence of P. gingivalis and reduce the biofilm formation on dental implants, thus, representing a potential anti-biofilm coating material for titanium dental implants [87].
Other promising nanoparticles are the Mesoporous Silica Nanoparticles [MSNs). When encapsulated with the antimicrobial agent CHX they can attach on microbes and release CHX for up to 48 h [88]. Additionally, MSNs have demonstrated potent antibacterial activity against S. mutans, Streptococcus sobrinus, F. nucleatum, A. actinomycetemcomitans either in a planktonic state or in monospecies biofilms. MSNs have been shown to suppress multispecies biofilms of S. mutans, F. nucleatum, A. actinomycetemcomitans, and P. gingivalis for up to 72 h [89].

8. Natural Products

Natural products have been shown to exhibit biological activities that make them promising candidates as alternative or adjunctive therapies in reducing dysbiotic oral biofilm [90]. Tea has been proven to have many health benefits including antioxidant, antidiabetic, hypocholesterolemic, antibacterial, anti-inflammatory, and cancer-preventive properties [91,92,93]. Its activity against oral biofilm formation is mainly attributed to polyphenols [91,94,95,96,97]. An epidemiologic study demonstrated that frequent consumption of green tea was positively correlated with good periodontal health [98]. Consistently, in vitro studies demonstrated polyphenol compounds present in green tea could significantly inhibit the growth, adherence, and biofilm formation of P. gingivalis, as well as suppress the activity of collagenase and matrix metalloproteinases [99,100,101,102]. In addition, phenol compounds enhance gingival keratinocyte integrity to protect from invasion or adherence of P. gingivalis [102]. Cranberry, a highly nutritious fruit, is known for its high concentration of total polyphenols, making it an excellent antioxidant and has been reported to be beneficial for fighting bacterial infection [103]. Cranberries have demonstrated potential inhibitory effect against bacteria related to dental caries and periodontal diseases [104]. Proanthocyanins (PACs) and flavonols are the most active components of the cranberry that can disrupt biofilm formation of S. mutans [105,106,107]. PACs are also effective in the prevention and management of periodontitis. They reduce biofilm formation, bacterial adherence, and invasiveness to the human epithelial cells and proteinase activity of P. gingivalis [108,109].

9. Conclusions

The present review has confirmed the extensive previous and current research efforts related to the use of local antimicrobial agents in periodontal and peri-implant therapy. However, many challenges and opportunities lie ahead. These include the use of nanomaterials, such as silver nanoparticles, instead of conventional antimicrobial/anti-biofilm materials, and the combination of one or more ions to take advantage of the synergistic effects of multiple ions. In addition to synthetic agents, natural products such as polyphenol compounds present in green tea and cranberry fruit have promising anti-biofilm properties. Nevertheless, further research is needed to identify and elucidate in depth the biocidal mechanisms by which different ions act against the specific pathogens, and to provide evidence and quantitative experimental data to identify these ions or nanoparticles. The anti-biofilm molecules, ions, or nanoparticles could then potentially serve more effectively as anti-biofilm agents in the control of periodontal and peri-implant diseases, either in suspensions or after incorporation into biomedical devices (biomaterials).

Author Contributions

Conceptualization, S.E., M.R., I.K., A.P. and L.F.W.; methodology, S.E., M.R., I.K, A.P. and L.F.W.; investigation, S.E., M.R., I.K., A.P. and L.F.W.; resources, S.E., M.R., I.K., A.P. and L.F.W.; writing—original draft preparation, S.E., M.R. and L.F.W., writing—review and editing, S.E., M.R., I.K., A.P. and L.F.W., visualization, S.E., I.K. and L.F.W., supervision, S.E. and L.F.W., projection administration S.E., I.K. and L.F.W., funding acquisition, L.F.W. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by a Division of Periodontal Research Grant (Wolff, LF).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to thank J. Michael Stolley (StolleyScientificIllustration) for the designing and preparation of the included illustrations.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not available.

References

  1. Flemming, H.-C.; Wuertz, S. Bacteria and archaea on Earth and their abundance in biofilms. Nat. Rev. Microbiol. 2019, 17, 247–260. [Google Scholar] [CrossRef]
  2. Tolker-Nielsen, T. Biofilm Development. Microbiol. Spectr. 2015, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Palmer, R.J.; White, D.C. Developmental biology of biofilms: Implications for treatment and control. Trends Microbiol. 1997, 5, 435–440. [Google Scholar] [CrossRef]
  4. Chung, P.Y.; Toh, Y.S. Anti-biofilm agents: Recent breakthrough against multi-drug resistantStaphylococcus aureus. Pathog. Dis. 2014, 70, 231–239. [Google Scholar] [CrossRef] [Green Version]
  5. Tolker-Nielsen, T. Pseudomonas aeruginosabiofilm infections: From molecular biofilm biology to new treatment possibilities. APMIS 2014, 122, 1–51. [Google Scholar] [CrossRef]
  6. Omar, A.; Wright, J.; Schultz, G.; Burrell, R.; Nadworny, P. Microbial Biofilms and Chronic Wounds. Microorganisms 2017, 5, 9. [Google Scholar] [CrossRef] [Green Version]
  7. James, G.A.; Swogger, E.; Wolcott, R.; Pulcini, E.D.; Secor, P.; Sestrich, J.; Costerton, J.W.; Stewart, P.S. Biofilms in chronic wounds. Wound Repair Regen. 2008, 16, 37–44. [Google Scholar] [CrossRef]
  8. Anderson, G.G. Intracellular Bacterial Biofilm-Like Pods in Urinary Tract Infections. Science 2003, 301, 105–107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Justice, S.S.; Hung, C.; Theriot, J.A.; Fletcher, D.A.; Anderson, G.G.; Footer, M.J.; Hultgren, S.J. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc. Natl. Acad. Sci. USA 2004, 101, 1333–1338. [Google Scholar] [CrossRef] [Green Version]
  10. Rosen, D.A.; Hooton, T.M.; Stamm, W.E.; Humphrey, P.A.; Hultgren, S.J. Detection of Intracellular Bacterial Communities in Human Urinary Tract Infection. PLoS Med. 2007, 4, e329. [Google Scholar] [CrossRef]
  11. Rosen, D.A.; Pinkner, J.S.; Walker, J.N.; Elam, J.S.; Jones, J.M.; Hultgren, S.J. Molecular Variations in Klebsiella pneumoniae and Escherichia coli FimH Affect Function and Pathogenesis in the Urinary Tract. Infect. Immun. 2008, 76, 3346–3356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Cascioferro, S.; Carbone, D.; Parrino, B.; Pecoraro, C.; Giovannetti, E.; Cirrincione, G.; Diana, P. Therapeutic Strategies to Counteract Antibiotic Resistance in MRSA Biofilm-associated Infections. ChemMedChem 2021, 16, 65–80. [Google Scholar] [CrossRef]
  13. Killoy, W.J. Chemical treatment of periodontitis: Local delivery of antimicrobials. Int. Dent. J. 1998, 48, 305–315. [Google Scholar] [CrossRef] [PubMed]
  14. Hussein, I.; Ranka, M.; Gilbert, A.; Davey, K. Locally Delivered Antimicrobials in the Management of Periodontitis: A Critical Review of the Evidence for their Use in Practice. Dent. Update 2007, 34, 494–506. [Google Scholar] [CrossRef]
  15. Paquette, D.W.; Ryan, M.E.; Wilder, R.S. Locally delivered antimicrobials: Clinical evidence and relevance. J. Dent. Hyg. 2008, 82, 10–15. [Google Scholar]
  16. Jepsen, K.; Jepsen, S. Antibiotics/antimicrobials: Systemic and local administration in the therapy of mild to moderately advanced periodontitis. Periodontology 2000 2016, 71, 82–112. [Google Scholar] [CrossRef] [PubMed]
  17. Rosa, C.D.D.R.D.; de Luna Gomes, J.M.; de Moraes, S.L.D.; Lemos, C.A.A.; da Fonte, T.P.; de Oliveira Limirio, J.P.J.; Pellizzer, E.P. Use of chlorhexidine chip after scaling and root planning on periodontal disease: A systematic review and meta-analysis. Saudi Dent. J. 2021, 33, 1–10. [Google Scholar] [CrossRef]
  18. Herrera, D.; Alonso, B.; León, R.; Roldán, S.; Sanz, M. Antimicrobial therapy in periodontitis: The use of systemic antimicrobials against the subgingival biofilm. J. Clin. Periodontol. 2008, 35, 45–66. [Google Scholar] [CrossRef]
  19. Bonito, A.J.; Lux, L.; Lohr, K.N. Impact of Local Adjuncts to Scaling and Root Planing in Periodontal Disease Therapy: A Systematic Review. J. Periodontol. 2005, 76, 1227–1236. [Google Scholar] [CrossRef] [PubMed]
  20. Khan, F.; Pham, D.T.N.; Oloketuyi, S.F.; Manivasagan, P.; Oh, J.; Kim, Y.-M. Chitosan and their derivatives: Antibiofilm drugs against pathogenic bacteria. Colloids Surf. B Biointerfaces 2020, 185, 110627. [Google Scholar] [CrossRef]
  21. Theilade, E.; Wright, W.H.; Jensen, S.B.; Loe, H. Experimental gingivitis in man. II. A longitudinal clinical and bacteriological investigation. J. Periodontal Res. 1966, 1, 1–13. [Google Scholar] [CrossRef]
  22. Löe, H.; Theilade, E.; Jensen, S.B. Experimental Gingivitis in Man. J. Periodontol. 1965, 36, 177–187. [Google Scholar] [CrossRef] [PubMed]
  23. Zitzmann, N.U.; Berglundh, T.; Marinello, C.P.; Lindhe, J. Experimental peri-implant mucositis in man. J. Clin. Periodontol. 2001, 28, 517–523. [Google Scholar] [CrossRef] [PubMed]
  24. Kolenbrander, P.E.; Palmer, R.J.; Rickard, A.H.; Jakubovics, N.S.; Chalmers, N.I.; Diaz, P.I. Bacterial interactions and successions during plaque development. Periodontology 2000 2006, 42, 47–79. [Google Scholar] [CrossRef] [PubMed]
  25. Listgarten, M.A.; Hellden, L. Relative distribution of bacteria at clinically healthy and periodontally diseased sites in humans*. J. Clin. Periodontol. 1978, 5, 115–132. [Google Scholar] [CrossRef] [PubMed]
  26. Diaz, P.I.; Chalmers, N.I.; Rickard, A.H.; Kong, C.; Milburn, C.L.; Palmer, R.J.; Kolenbrander, P.E. Molecular Characterization of Subject-Specific Oral Microflora during Initial Colonization of Enamel. Appl. Environ. Microbiol. 2006, 72, 2837–2848. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Li, J.; Helmerhorst, E.J.; Leone, C.W.; Troxler, R.F.; Yaskell, T.; Haffajee, A.D.; Socransky, S.S.; Oppenheim, F.G. Identification of early microbial colonizers in human dental biofilm. J. Appl. Microbiol. 2004, 97, 1311–1318. [Google Scholar] [CrossRef]
  28. Socransky, S.S.; Haffajee, A.D. Periodontal microbial ecology. Periodontology 2000 2005, 38, 135–187. [Google Scholar] [CrossRef]
  29. Marsh, P.D. Microbial ecology of dental plaque and its significance in health and disease. Adv. Dent. Res. 1994, 8, 263–271. [Google Scholar] [CrossRef]
  30. Rybtke, M.; Hultqvist, L.D.; Givskov, M.; Tolker-Nielsen, T. Pseudomonas aeruginosa Biofilm Infections: Community Structure, Antimicrobial Tolerance and Immune Response. J. Mol. Biol. 2015, 427, 3628–3645. [Google Scholar] [CrossRef] [PubMed]
  31. Ciofu, O.; Tolker-Nielsen, T. Tolerance and Resistance of Pseudomonas aeruginosa Biofilms to Antimicrobial Agents—How P. aeruginosa Can Escape Antibiotics. Front. Microbiol. 2019, 10, 913. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Kassebaum, N.J.; Bernabé, E.; Dahiya, M.; Bhandari, B.; Murray, C.J.L.; Marcenes, W. Global burden of severe periodontitis in 1990-2010: A systematic review and meta-regression. J. Dent. Res. 2014, 93, 1045–1053. [Google Scholar] [CrossRef] [PubMed]
  33. Tarnow, D.P. Increasing Prevalence of Peri-implantitis: How Will We Manage? J. Dent. Res. 2016, 95, 7–8. [Google Scholar] [CrossRef] [PubMed]
  34. Hajishengallis, G.; Lamont, R.J. Beyond the red complex and into more complexity: The polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology. Mol. Oral Microbiol. 2012, 27, 409–419. [Google Scholar] [CrossRef] [Green Version]
  35. Lang, N.P.; Berglundh, T. Periimplant diseases: Where are we now?—Consensus of the Seventh European Workshop on Periodontology. J. Clin. Periodontol. 2011, 38, 178–181. [Google Scholar] [CrossRef] [Green Version]
  36. Becker, S.T.; Beck-Broichsitter, B.E.; Graetz, C.; Dörfer, C.E.; Wiltfang, J.; Häsler, R. Peri-Implantitis versus Periodontitis: Functional Differences Indicated by Transcriptome Profiling. Clin. Implant Dent. Relat. Res. 2012, 16, 401–411. [Google Scholar] [CrossRef] [PubMed]
  37. Carcuac, O.; Berglundh, T. Composition of Human Peri-implantitis and Periodontitis Lesions. J. Dent. Res. 2014, 93, 1083–1088. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Kumar, P.S.; Mason, M.R.; Brooker, M.R.; O’Brien, K. Pyrosequencing reveals unique microbial signatures associated with healthy and failing dental implants. J. Clin. Periodontol. 2012, 39, 425–433. [Google Scholar] [CrossRef] [Green Version]
  39. Lafaurie, G.I.; Sabogal, M.A.; Castillo, D.M.; Rincón, M.V.; Gómez, L.A.; Lesmes, Y.A.; Chambrone, L. Microbiome and Microbial Biofilm Profiles of Peri-Implantitis: A Systematic Review. J. Periodontol. 2017, 88, 1066–1089. [Google Scholar] [CrossRef] [PubMed]
  40. Figuero, E.; Graziani, F.; Sanz, I.; Herrera, D.; Sanz, M. Management of peri-implant mucositis and peri-implantitis. Periodontology 2000 2014, 66, 255–273. [Google Scholar] [CrossRef]
  41. Badersten, A.; Nilvéus, R.; Egelberg, J. Effect of nonsurgical periodontal therapy. I. Moderately advanced periodontitis. J. Clin. Periodontol. 1981, 8, 57–72. [Google Scholar] [CrossRef]
  42. Badersten, A.; Nilveus, R.; Egelberg, J. Effect of nonsurgical periodontal therapy. II. Severely advanced periodontitis. J. Clin. Periodontol. 1984, 11, 63–76. [Google Scholar] [CrossRef]
  43. Renvert, S.; Roos-Jansåker, A.-M.; Claffey, N. Non-surgical treatment of peri-implant mucositis and peri-implantitis: A literature review. J. Clin. Periodontol. 2008, 35, 305–315. [Google Scholar] [CrossRef] [PubMed]
  44. Keestra, J.A.J.; Grosjean, I.; Coucke, W.; Quirynen, M.; Teughels, W. Non-surgical periodontal therapy with systemic antibiotics in patients with untreated aggressive periodontitis: A systematic review and meta-analysis. J. Periodontal Res. 2014, 50, 689–706. [Google Scholar] [CrossRef]
  45. Wu, L.; Chen, W.; Li, F.; Morrow, B.R.; Garcia-Godoy, F.; Hong, L. Sustained Release of Minocycline From Minocycline-Calcium-Dextran Sulfate Complex Microparticles for Periodontitis Treatment. J. Pharm. Sci. 2018, 107, 3134–3142. [Google Scholar] [CrossRef] [PubMed]
  46. Schmid, J.-L.; Kirchberg, M.; Sarembe, S.; Kiesow, A.; Sculean, A.; Mäder, K.; Buchholz, M.; Eick, S. In Vitro Evaluation of Antimicrobial Activity of Minocycline Formulations for Topical Application in Periodontal Therapy. Pharmaceutics 2020, 12, 352. [Google Scholar] [CrossRef] [PubMed]
  47. Oettinger-Barak, O.; Dashper, S.G.; Catmull, D.V.; Adams, G.G.; Sela, M.N.; Machtei, E.E.; Reynolds, E.C. Antibiotic susceptibility of Aggregatibacter actinomycetemcomitans JP2 in a biofilm. J. Oral Microbiol. 2013, 5, 20320. [Google Scholar] [CrossRef] [PubMed]
  48. Takahashi, N.; Ishihara, K.; Kimizuka, R.; Okuda, K.; Kato, T. The effects of tetracycline, minocycline, doxycycline and ofloxacin on Prevotella intermedia biofilm. Oral Microbiol. Immunol. 2006, 21, 366–371. [Google Scholar] [CrossRef]
  49. Karpiński, T.M.; Szkaradkiewicz, A.K. Chlorhexidine-pharmaco-biological activity and application. Eur Rev. Med. Pharmacol Sci. 2015, 19, 1321–1326. [Google Scholar]
  50. Baehni, P.; Takeuchi, Y. Anti-plaque agents in the prevention of biofilm-associated oral diseases. Oral Dis. 2003, 9, 23–29. [Google Scholar] [CrossRef]
  51. Zanatta, F.B.; Antoniazzi, R.P.; Rösing, C.K. Staining and calculus formation after 0.12% chlorhexidine rinses in plaque-free and plaque covered surfaces: A randomized trial. J. Appl. Oral Sci. 2010, 18, 515–521. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Killoy, W.J. The use of locally-delivered chlorhexidine in the treatment of periodontitis. Clinical results. J. Clin. Periodontol. 1998, 25, 953–958. [Google Scholar] [CrossRef] [PubMed]
  53. Szulc, M.; Zakrzewska, A.; Zborowski, J. Local drug delivery in periodontitis treatment: A review of contemporary literature. Dent. Med. Probl. 2018, 55, 333–342. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Rodrigues, I.F.G.; Machion, L.; Casati, M.Z.; Nociti, F.H.; de Toledo, S.; Sallum, A.W.; Sallum, E.A. Clinical Evaluation of the Use of Locally Delivered Chlorhexidine in Periodontal Maintenance Therapy. J. Periodontol. 2007, 78, 624–628. [Google Scholar] [CrossRef]
  55. Herrera, D.; Matesanz, P.; Martín, C.; Oud, V.; Feres, M.; Teughels, W. Adjunctive effect of locally delivered antimicrobials in periodontitis therapy. A systematic review and meta-analysis. J. Clin. Periodontol. 2020, 47 (Suppl. 22), 239–256. [Google Scholar] [CrossRef]
  56. Etienne, D. Locally delivered antimicrobials for the treatment of chronic periodontitis. Oral Dis. 2003, 9, 45–50. [Google Scholar] [CrossRef] [PubMed]
  57. Pavia, M.; Nobile, C.G.A.; Angelillo, I.F. Meta-Analysis of Local Tetracycline in Treating Chronic Periodontitis. J. Periodontol. 2003, 74, 916–932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Herrera, D.; Matesanz, P.; Bascones-Martínez, A.; Sanz, M. Local and Systemic Antimicrobial Therapy in Periodontics. J. Evid. Based Dent. Pract. 2012, 12, 50–60. [Google Scholar] [CrossRef]
  59. Trombelli, L.; Tatakis, D. Periodontal diseases: Current and future indications for local antimicrobial therapy. Oral Dis. 2003, 9, 11–15. [Google Scholar] [CrossRef] [PubMed]
  60. Berglundh, T.; Armitage, G.; Araujo, M.; Avila-Ortiz, G.; Blanco, J.; Camargo, P.; Chen, S.; Cochran, D.; Derks, J.; Figuero, E.; et al. Peri-implant diseases and conditions: Consensus report of workgroup 4 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. BDJ 2018, 89, S313–S318. [Google Scholar]
  61. Renvert, S.; Persson, G.R.; Pirih, F.Q.; Camargo, P.M. Peri-implant health, peri-implant mucositis, and peri-implantitis: Case definitions and diagnostic considerations. J. Periodontol. 2018, 89, S304–S312. [Google Scholar] [CrossRef]
  62. Renvert, S.; Polyzois, I. Treatment of pathologic peri-implant pockets. Periodontology 2000 2017, 76, 180–190. [Google Scholar] [CrossRef]
  63. Mombelli, A.; Feloutzis, A.; Brägger, U.; Lang, N.P. Treatment of peri-implantitis by local delivery of tetracycline. Clin. Oral Implant Res. 2001, 12, 287–294. [Google Scholar] [CrossRef]
  64. Cha, J.K.; Lee, J.S.; Kim, C.S. Surgical Therapy of Peri-Implantitis with Local Minocycline: A 6-Month Randomized Controlled Clinical Trial. J. Dent. Res. 2019, 98, 288–295. [Google Scholar] [CrossRef]
  65. Renvert, S.; Lessem, J.; Dahlen, G.; Lindahl, C.; Svensson, M. Topical minocycline microspheres versus topical chlorhexidine gel as an adjunct to mechanical debridement of incipient peri-implant infections: A randomized clinical trial. J. Clin. Periodontol. 2006, 33, 362–369. [Google Scholar] [CrossRef]
  66. Renvert, S.; Lessem, J.; Dahlén, G.; Renvert, H.; Lindahl, C. Mechanical and Repeated Antimicrobial Therapy Using a Local Drug Delivery System in the Treatment of Peri-Implantitis: A Randomized Clinical Trial. J. Periodontol. 2008, 79, 836–844. [Google Scholar] [CrossRef]
  67. Renvert, S.; Polyzois, I.N. Clinical approaches to treat peri-implant mucositis and peri-implantitis. Periodontology 2000 2015, 68, 369–404. [Google Scholar] [CrossRef] [PubMed]
  68. Carcuac, O.; Derks, J.; Charalampakis, G.; Abrahamsson, I.; Wennström, J.; Berglundh, T. Adjunctive Systemic and Local Antimicrobial Therapy in the Surgical Treatment of Peri-implantitis. J. Dent. Res. 2015, 95, 50–57. [Google Scholar] [CrossRef]
  69. Greenstein, G.; Research, S. Position Paper: The Role of Supra- and Subgingival Irrigation in the Treatment of Periodontal Diseases. J. Periodontol. 2005, 76, 2015–2027. [Google Scholar] [PubMed]
  70. Esposito, M.; Grusovin, M.G.; Worthington, H.V. Interventions for replacing missing teeth: Treatment of peri-implantitis. Cochrane Database Syst. Rev. 2012, 1, 6–14. [Google Scholar] [CrossRef]
  71. Hua, J.; Scott, R.W.; Diamond, G. Activity of antimicrobial peptide mimetics in the oral cavity: II. Activity against periopathogenic biofilms and anti-inflammatory activity. Mol. Oral Microbiol. 2010, 25, 426–432. [Google Scholar] [CrossRef] [PubMed]
  72. Chen, C.-P.; Lin, C.-C.; Tsuneo, N. Screening of Taiwanese crude drugs for antibacterial activity against Streptococcus mutans. J. Ethnopharmacol. 1989, 27, 285–295. [Google Scholar] [CrossRef]
  73. Yanti; Rukayadi, Y.; Kim, K.-H.; Hwang, J.-K. In vitro anti-biofilm activity of macelignan isolated fromMyristica fragrans Houtt. against oral primary colonizer bacteria. Phytother. Res. 2008, 22, 308–312. [Google Scholar] [CrossRef] [PubMed]
  74. Rabin, N.; Zheng, Y.; Opoku-Temeng, C.; Du, Y.; Bonsu, E.; Sintim, H.O. Agents that inhibit bacterial biofilm formation. Future Med. Chem. 2015, 7, 647–671. [Google Scholar] [CrossRef] [PubMed]
  75. Wu, H.; Moser, C.; Wang, H.-Z.; Høiby, N.; Song, Z.-J. Strategies for combating bacterial biofilm infections. Int. J. Oral Sci. 2014, 7, 1–7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Chen, L.; Wen, Y. The role of bacterial biofilm in persistent infections and control strategies. Int. J. Oral Sci. 2011, 3, 66–73. [Google Scholar] [CrossRef] [Green Version]
  77. Davies, D. Understanding biofilm resistance to antibacterial agents. Nat. Rev. Drug Discov. 2003, 2, 114–122. [Google Scholar] [CrossRef]
  78. Allaker, R.P.; Memarzadeh, K. Nanoparticles and the control of oral infections. Int. J. Antimicrob. Agents 2014, 43, 95–104. [Google Scholar] [CrossRef]
  79. Hemeg, H. Nanomaterials for alternative antibacterial therapy. Int. J. Nanomed. 2017, 12, 8211–8225. [Google Scholar] [CrossRef] [Green Version]
  80. Rai, M.K.; Deshmukh, S.D.; Ingle, A.P.; Gade, A.K. Silver nanoparticles: The powerful nanoweapon against multidrug-resistant bacteria. J. Appl. Microbiol. 2012, 112, 841–852. [Google Scholar] [CrossRef]
  81. Besinis, A.; De Peralta, T.; Tredwin, C.J.; Handy, R.D. Review of Nanomaterials in Dentistry: Interactions with the Oral Microenvironment, Clinical Applications, Hazards, and Benefits. ACS Nano 2015, 9, 2255–2289. [Google Scholar] [CrossRef] [Green Version]
  82. Shrestha, A.; Zhilong, S.; Gee, N.K.; Kishen, A. Nanoparticulates for Antibiofilm Treatment and Effect of Aging on Its Antibacterial Activity. J. Endod. 2010, 36, 1030–1035. [Google Scholar] [CrossRef]
  83. Besinis, A.; De Peralta, T.; Handy, R.D. Inhibition of biofilm formation and antibacterial properties of a silver nano-coating on human dentine. Nanotoxicology 2014, 8, 745–754. [Google Scholar] [CrossRef]
  84. Ong, T.H.; Chitra, E.; Ramamurthy, S.; Siddalingam, R.P.; Yuen, K.H.; Ambu, S.P.; Davamani, F. Correction: Chitosan-propolis nanoparticle formulation demonstrates anti-bacterial activity against Enterococcus faecalis biofilms. PLoS ONE 2017, 12, e0176629. [Google Scholar] [CrossRef] [Green Version]
  85. Kong, M.; Chen, X.G.; Xing, K.; Park, H.J. Antimicrobial properties of chitosan and mode of action: A state of the art review. Int. J. Food Microbiol. 2010, 144, 51–63. [Google Scholar] [CrossRef]
  86. Shi, Z.; Neoh, K.G.; Kang, E.T.; Wang, W. Antibacterial and mechanical properties of bone cement impregnated with chitosan nanoparticles. Biomaterials 2006, 27, 2440–2449. [Google Scholar] [CrossRef]
  87. Divakar, D.D.; Jastaniyah, N.T.; Altamimi, H.G.; Alnakhli, Y.O.; Muzaheed; Alkheraif, A.A.; Haleem, S. Enhanced antimicrobial activity of naturally derived bioactive molecule chitosan conjugated silver nanoparticle against dental implant pathogens. Int. J. Biol. Macromol. 2018, 108, 790–797. [Google Scholar] [CrossRef]
  88. Li, X.; Wong, C.-H.; Ng, T.-W.; Zhang, C.-F.; Leung, K.C.-F.; Jin, L. The spherical nanoparticle-encapsulated chlorhexidine enhances anti-biofilm efficiency through an effective releasing mode and close microbial interactions. Int. J. Nanomed. 2016, 11, 2471–2480. [Google Scholar]
  89. Seneviratne, C.J.; Leung, K.C.-F.; Wong, C.-H.; Lee, S.-F.; Li, X.; Leung, P.C.; Lau, C.B.S.; Wat, E.; Jin, L. Nanoparticle-Encapsulated Chlorhexidine against Oral Bacterial Biofilms. PLoS ONE 2014, 9, e103234. [Google Scholar] [CrossRef] [Green Version]
  90. Jeon, J.G.; Rosalen, P.L.; Falsetta, M.L.; Koo, H. Natural Products in Caries Research: Current (Limited) Knowledge, Challenges and Future Perspective. Caries Res. 2011, 45, 243–263. [Google Scholar] [CrossRef]
  91. Hamilton-Miller, J.M. Antimicrobial properties of tea (Camellia sinensis L.). Antimicrob. Agents Chemother. 1995, 39, 2375–2377. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Mitscher, L.A.; Jung, M.; Shankel, D.; Dou, J.-H.; Steele, L.; Pillai, S.P. Chemoprotection: A review of the potential therapeutic antioxidant properties of green tea (Camellia sinensis) and certain of its constituents. Med. Res. Rev. 1997, 17, 327–365. [Google Scholar] [CrossRef]
  93. Wu, C.D.; Wei, G.X. Tea as a functional food for oral health. Nutrition 2002, 18, 443–444. [Google Scholar] [CrossRef]
  94. Kawamura, J.; Takeo, T. Antibacterial activity of tea catechin to Streptococcus mutans. Nippon. Shokuhin Kogyo Gakkaishi 1989, 36, 463–467. [Google Scholar] [CrossRef]
  95. Sakanaka, S.; Kim, M.; Taniguchi, M.; Yamamoto, T. Antibacterial Substances in Japanese Green Tea Extract against Streptococcus mutans, a Cariogenic Bacterium. Agric. Biol. Chem. 1989, 53, 2307–2311. [Google Scholar] [CrossRef]
  96. Nakahara, K.; Kawabata, S.; Ono, H.; Ogura, K.; Tanaka, T.; Ooshima, T.; Hamada, S. Inhibitory effect of oolong tea polyphenols on glycosyltransferases of mutans Streptococci. Appl. Environ. Microbiol. 1993, 59, 968–973. [Google Scholar] [CrossRef] [Green Version]
  97. Ooshima, T.; Minami, T.; Aono, W.; Izumitani, A.; Sobue, S.; Fujiwara, T.; Kawabata, S.; Hamada, S. Oolong Tea Polyphenols Inhibit Experimental Dental Caries in SPF Rats Infected with Mutatis Streptococci. Caries Res. 1993, 27, 124–129. [Google Scholar] [CrossRef]
  98. Kushiyama, M.; Shimazaki, Y.; Murakami, M.; Yamashita, Y. Relationship Between Intake of Green Tea and Periodontal Disease. J. Periodontol. 2009, 80, 372–377. [Google Scholar] [CrossRef]
  99. Asahi, Y.; Noiri, Y.; Miura, J.; Maezono, H.; Yamaguchi, M.; Yamamoto, R.; Azakami, H.; Hayashi, M.; Ebisu, S. Effects of the tea catechin epigallocatechin gallate on Porphyromonas gingivalis biofilms. J. Appl. Microbiol. 2014, 116, 1164–1171. [Google Scholar] [CrossRef]
  100. Sakanaka, S.; Aizawa, M.; Kim, M.; Yamamoto, T. Inhibitory Effects of Green Tea Polyphenols on Growth and Cellular Adherence of an Oral Bacterium, Porphyromonas gingivalis. Biosci. Biotechnol. Biochem. 1996, 60, 745–749. [Google Scholar] [CrossRef] [Green Version]
  101. Makimura, M.; Hirasawa, M.; Kobayashi, K.; Indo, J.; Sakanaka, S.; Taguchi, T.; Otake, S. Inhibitory Effect of Tea Catechins on Collagenase Activity. J. Periodontol. 1993, 64, 630–636. [Google Scholar] [CrossRef] [PubMed]
  102. Lagha, A.B.; Groeger, S.; Meyle, J.; Grenier, D. Green tea polyphenols enhance gingival keratinocyte integrity and protect against invasion by Porphyromonas gingivalis. Pathog. Dis. 2018, 108, 790–797. [Google Scholar] [CrossRef]
  103. Vinson, J.A.; Bose, P.; Proch, J.; Al Kharrat, H.; Samman, N. Cranberries and Cranberry Products: Powerful in Vitro, ex Vivo, and in Vivo Sources of Antioxidants. J. Agric. Food Chem. 2008, 56, 5884–5891. [Google Scholar] [CrossRef]
  104. Bodet, C.; Grenier, D.; Chandad, F.; Ofek, I.; Steinberg, D.; Weiss, E.I. Potential Oral Health Benefits of Cranberry. Crit. Rev. Food Sci. Nutr. 2008, 48, 672–680. [Google Scholar] [CrossRef] [PubMed]
  105. Duarte, S.; Gregoire, S.; Singh, A.P.; Vorsa, N.; Schaich, K.; Bowen, W.H.; Koo, H. Inhibitory effects of cranberry polyphenols on formation and acidogenicity of Streptococcus mutans biofilms. FEMS Microbiol. Lett. 2006, 257, 50–56. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Gregoire, S.; Singh, A.P.; Vorsa, N.; Koo, H. Influence of cranberry phenolics on glucan synthesis by glucosyltransferases and Streptococcus mutans acidogenicity. J. Appl. Microbiol. 2007, 103, 1960–1968. [Google Scholar] [CrossRef]
  107. Steinberg, D. Effect of a high-molecular-weight component of cranberry on constituents of dental biofilm. J. Antimicrob. Chemother. 2004, 54, 86–89. [Google Scholar] [CrossRef]
  108. La, V.D.; Howell, A.B.; Grenier, D. Anti-Porphyromonas gingivalis and Anti-Inflammatory Activities of A-Type Cranberry Proanthocyanidins. Antimicrob. Agents Chemother. 2010, 54, 1778–1784. [Google Scholar] [CrossRef] [Green Version]
  109. Labrecque, J. Effects of a high-molecular-weight cranberry fraction on growth, biofilm formation and adherence of Porphyromonas gingivalis. J. Antimicrob. Chemother. 2006, 58, 439–443. [Google Scholar] [CrossRef] [Green Version]
Molecules 26 05661 g001 550
Figure 1. Periodontal health versus periodontitis around natural tooth structure (left); peri-implant health versus peri-implantitis around an implant surface (right).
Figure 1. Periodontal health versus periodontitis around natural tooth structure (left); peri-implant health versus peri-implantitis around an implant surface (right).
Molecules 26 05661 g001
Molecules 26 05661 g002 550
Figure 2. Local delivery treatment with chip containing Chlorhexidine (A) after non-surgical periodontal debridement to reduce biofilm; (B) small chip (4.5 × 3.5 mm2) composed of biodegradable hydrolyzed gelatin matrix, crosslinked with glutaraldehyde, also contains glycerine and water, into which 2.5 mg Chlorhexidine Gluconate is incorporated; (C) Perio Chip inserted into periodontal pocket; (D) improvement in PD and CAL with Perio Chip as an adjunct to SRP.
Figure 2. Local delivery treatment with chip containing Chlorhexidine (A) after non-surgical periodontal debridement to reduce biofilm; (B) small chip (4.5 × 3.5 mm2) composed of biodegradable hydrolyzed gelatin matrix, crosslinked with glutaraldehyde, also contains glycerine and water, into which 2.5 mg Chlorhexidine Gluconate is incorporated; (C) Perio Chip inserted into periodontal pocket; (D) improvement in PD and CAL with Perio Chip as an adjunct to SRP.
Molecules 26 05661 g002
Molecules 26 05661 g003 550
Figure 3. Illustration for the treatment of periodontitis with nanoparticles containing anti-biofilm molecules (A) Delivery of anti-biofilm nanoparticles into diseased sites; (B) ability of nanoparticles to attach to and incorporate into biofilm and release active agents such as CHX for up to 48 h; (C) gradual reduction of multispecies biofilm; (D) elimination of biofilm and established state of health. A similar therapeutic approach could be used for the treatment of peri-implantitis.
Figure 3. Illustration for the treatment of periodontitis with nanoparticles containing anti-biofilm molecules (A) Delivery of anti-biofilm nanoparticles into diseased sites; (B) ability of nanoparticles to attach to and incorporate into biofilm and release active agents such as CHX for up to 48 h; (C) gradual reduction of multispecies biofilm; (D) elimination of biofilm and established state of health. A similar therapeutic approach could be used for the treatment of peri-implantitis.
Molecules 26 05661 g003
Table
Table 1. Molecules used in local delivery as adjunctive treatment of periodontitis.
Table 1. Molecules used in local delivery as adjunctive treatment of periodontitis.
Locally Administered AntimicrobialActive AgentResultsReferences
PeriochipChlorhexidine gluconate 2.5 mgIn combination with SRP reduced PDs > 2 mm compared to SRP alone after 9 months[52]
PeriochipChlorhexidine gluconate 2.5 mgIn combination with SRP improved the results of periodontal treatment compared to SRP alone[17]
PeriochipChlorhexidine gluconate 2.5 mgIn combination with SRP reduced PDs and resulted in CAL gain compared to SRP alone after 9 months[15]
PeriochipChlorhexidine gluconate 2.5 mgChip alone showed no statistically significant differences compared to SRP during maintenance period[54]
PeriochipChlorhexidine gluconate 2.5 mgIn combination with SRP studies showed statistically significant improvements to PD and CAL gain compared to SRP alone[19]
Periochip, PerioColChlorhexidine gluconate 2.5 mgIn combination with SRP most studies showed non statistically significant improvements compared to SRP alone[53]
PerioChipChlorhexidine gluconate 2.5mgIn combination with SRP studies showed statistically significant improvements to PD and CAL gain compared to SRP alone[14]
PeriochipChlorhexidine chipIn combination with SRP studies showed statistically significant improvements to PD and CAL gain compared to SRP alone[16]
ChlositeChlorhexidine gluconate gel 0.5% or 1%In combination with SRP studies showed no statistically significant improvements to PD and CAL gain compared to SRP alone[14]
ChlositeChlorhexidine gluconate 0.5% or 1%In combination with SRP most studies showed statistically significant improvements to PD and CAL gain compared to SRP alone[53]
AtridoxDoxycycline 10% or 50 mgAtridox alone showed equivalent results with SRP after 9 months[15]
AtridoxDoxycycline 10% or 50 mgIn combination with SRP results related to PDs and CAL compared to SRP alone were inconclusive[53]
AtridoxDoxycycline gel 8.8%In combination with SRP studies showed statistically significant improvements to PD and CAL gain compared to SRP alone[14]
-Tetracycline and citric acid gelIn combination with SRP statistically significant improvements of PD compared to SRP alone[19]
Periodontal Plus ABTetracycline fibers 8%In combination with SRP most studies showed statistically significant improvements to PD and CAL gain compared to SRP alone[53]
-tetracycline-loaded ethylene vinyl acetatefibers [TNC]In combination with SRP studies showed statistically significant improvements to PD compared to SRP alone[56]
-TetracyclineIn combination with SRP studies showed statistically significant improvements to PD and CAL gain compared to SRP alone[57]
ArestinMinocycline 1 mgIn combination with SRP reduced PDs compared to SRP alone after 9 months[15]
ArestinMinocycline 1 mgIn combination with SRP most studies showed statistically significant improvements to PD and CAL gain compared to SRP alone[53]
DentomycinMinocycline gel 2%In combination with SRP studies showed statistically significant improvements to PD and CAL gain compared to SRP alone[14]
ElyzolMetronidazole gel 25%In combination with SRP results related to PDs and CAL compared to SRP were inconclusive[53]
-Metronidazole gel 25%In combination with SRP studies showed no statistically significant improvements to PD compared to SRP alone[56]
ElyzolMetronidazole gel 25%In combination with SRP studies showed statistically significant improvements to PD compared to SRP alone[14]
Abbreviations: PD = Pocket depth; CAL = Clinical Attachment level; SRP = Scaling and Root Planing.
Table
Table 2. Molecules used in local delivery for the treatment of peri-implantitis.
Table 2. Molecules used in local delivery for the treatment of peri-implantitis.
Locally Administered AntimicrobialActive AgentResultsReferences
CorsodylChlorhexidine gel 1%SRP with minocycline reduced statistically significantly the PDs at 12 months Compared to SRP with CHX.[65]
-Chlorhexidine gelClinical parameters were statistically significantly improved.[43]
-Chlorhexidine gel 1%SRP with minocycline reduced statistically significantly the PDs at 90 days. Compared to SRP with CHX.[66]
-Chlorhexidine solution 0.2%The use of CHX to disinfect the implant surface during surgery had no additional benefit.[68]
ActisiteTetracycline HCl-containning fibersPDs were statistically significantly reduced at 12 months.[63]
-Tetracycline fibersClinical parameters were statistically significantly improved.[43]
Periocline2% minocycline HCl gelSurgery with minocycline statistically significantly reduced PDs and increased supporting bone levels compared to surgery alone.[64]
-1mg minocycline HClSRP with minocycline reduced statistically significantly the PDs at 90 days. Compared to SRP with CHX.[66]
ArestinMinocycline 1 mgSRP with minocycline reduced statistically significantly the PDs at 12 months Compared to SRP with CHX.[65]
Abbreviations: PD = Pocket Depth; CHX = Chlorhexidine. SRP = Scaling and Root Planing.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Elnagdy, S.; Raptopoulos, M.; Kormas, I.; Pedercini, A.; Wolff, L.F. Local Oral Delivery Agents with Anti-Biofilm Properties for the Treatment of Periodontitis and Peri-Implantitis. A Narrative Review. Molecules 2021, 26, 5661. https://doi.org/10.3390/molecules26185661

AMA Style

Elnagdy S, Raptopoulos M, Kormas I, Pedercini A, Wolff LF. Local Oral Delivery Agents with Anti-Biofilm Properties for the Treatment of Periodontitis and Peri-Implantitis. A Narrative Review. Molecules. 2021; 26(18):5661. https://doi.org/10.3390/molecules26185661

Chicago/Turabian Style

Elnagdy, Shorouk, Michail Raptopoulos, Ioannis Kormas, Alessandro Pedercini, and Larry F. Wolff. 2021. "Local Oral Delivery Agents with Anti-Biofilm Properties for the Treatment of Periodontitis and Peri-Implantitis. A Narrative Review" Molecules 26, no. 18: 5661. https://doi.org/10.3390/molecules26185661

APA Style

Elnagdy, S., Raptopoulos, M., Kormas, I., Pedercini, A., & Wolff, L. F. (2021). Local Oral Delivery Agents with Anti-Biofilm Properties for the Treatment of Periodontitis and Peri-Implantitis. A Narrative Review. Molecules, 26(18), 5661. https://doi.org/10.3390/molecules26185661

Article Metrics

Back to TopTop