Application of Chitosan Gels and the Impact on Dental and Periodontal Health of Patients: A Systematic ReviewABSTRACT
Objective: To identify and discuss the impact of the application of chitosan gels on the dental and periodontal health of patients.
Material and Methods: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and its protocol was registered in the International Prospective Register of Systematic Reviews. Searches were performed in the Embase, MEDLINE/PubMed, Elsevier/Scopus, and Web of Science databases using the descriptors "dentistry", "chitosan", "gels", "hydrogels", "oral health", "tooth", "gingiva", and "periodontics" combined with the Boolean operators "AND" and "OR". The risk of bias was assessed using the Cochrane Risk of Bias 2 tool for randomized controlled trials.
Results: A total of 30 studies were retrieved; after reviewing titles, abstracts, and full articles and applying the inclusion and exclusion criteria, only three were included. Subsequently, two studies were manually added through reference searches, bringing the total to 5. In the overall risk-of-bias analysis, only one study was classified as having a low risk of bias, three as having some concern, and one as having a high risk of bias.
Conclusion: Gels containing chitosan appear to have a promising positive impact on patients' dental and periodontal health. However, these results should be evaluated with caution due to the risk of bias identified in the studies.
Keywords:
Dentistry; Chitosan; Gels; Tooth; Periodontics.
Introduction
Caries and periodontal diseases are the most prevalent oral diseases, posing a significant public health concern [1]. Caries result from an imbalance in the enamel remineralization process, caused by acids produced by bacteria in the oral biofilm [2,3]. Periodontal diseases are also caused by the biofilm, leading to inflammatory and/or infectious processes that disturb the supporting tissues of the teeth [4]. Therefore, there is growing interest in alternative, less invasive therapies for biofilm reduction, and natural compounds such as chitosan have been described as potential treatments for these diseases, with some favorable results [5-13].
Chitosan is a biomaterial derived from chitin, which is mainly found in crustacean shells [14,15], in the exoskeleton of arthropods [16], and in the cell wall of fungi [17,18]. It can be used in different compositions, such as films and gels [9,19], and can be safely applied in the oral cavity [9,13,20].
In addition, chitosan has important properties, including low toxicity, biocompatibility, and antimicrobial activity [15]. Several bacteria, both Gram-positive (e.g., Streptococcus mutans and Streptococcus sanguinis [11,12]) and Gram-negative (e.g., Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis [8,12]), as well as fungi (e.g., Candida albicans [21,22]), are sensitive to chitosan. The antimicrobial action of chitosan results from its cationic nature, which interacts with anionic components present on the cell surface of microorganisms, such as lipopolysaccharides and proteins [23]. The antimicrobial action of chitosan can be enhanced when combined with other agents through synergism [9].
Studies have investigated the incorporation of chitosan into dental products, such as fluoridated toothpastes [24-26] and mouthwashes [10], as well as dental materials, such as intracanal medications [27] and varnishes to seal dental surfaces [28]. Furthermore, chitosan has been applied in gel form for the local treatment of periodontal diseases [8,9], for the healing of surgical wounds [29-32], for the control of microorganisms [13], and for the prevention of dental demineralization [20,33].
Thus, despite the promising effects of chitosan on dental and periodontal health, there is no evidence to support its clinical efficacy in dentistry, especially in gel form. Therefore, the objective of this study was to identify and discuss, through a systematic review, the impact of chitosan gel application on dental and periodontal health in patients, to contribute to the understanding of their clinical potential and to guide future research in this area.
Material and Methods
Protocol and Registration
This study followed the standards recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and its protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under number CRD42024586251, on 09/22/2024.
Information Sources and Search Strategies
The guiding question of this study, formulated according to the PICO scheme, was: "Does the application of chitosan gel, when related to a comparison and/or control group, have an impact on the dental and periodontal health of patients?" The study population consisted of dental patients; the intervention was the application of chitosan gel; the comparison was any gel that did not contain chitosan; and the outcome was the impact on dental and periodontal health.
Searches were conducted in the Embase, MEDLINE/PubMed, Elsevier/Scopus, and Web of Science databases, from July to September of 2024, without date restrictions. The descriptors "dentistry", "chitosan", "gels", "hydrogels", "oral health", "tooth", "gingiva", and "periodontics" were used in accordance with the Medical Subject Headings (MeSH) and the Health Sciences Descriptors (DeCS), combined with the Boolean operators “AND” and “OR”. The search strategies performed in the databases are represented in Table 1.
Eligibility Criteria
The studies found were evaluated according to the inclusion and exclusion criteria. Randomized controlled clinical trials involving the application of chitosan gel in dental patients published in English, Spanish, or Portuguese were included in this study. Exclusion criteria were duplicated studies, in vitro studies, animal studies, and studies that did not use gels in the comparison or control groups. The selection of studies consisted of analysis and exclusion based on titles and abstracts, and the full reading of the articles. Furthermore, the references of the included studies were analyzed, and the existence of studies in the grey literature was investigated. Two authors (F.R.F. and M.O.S.) performed the entire search, and divergences were resolved through discussion. When necessary, a third author (M.S.O.) was responsible for resolving disagreements.
Data Collection and Extraction
Data from articles eligible for the systematic review were manually collected, extracted, and tabulated independently by two authors (F.R.F. and M.O.S.) using Microsoft Excel® (Microsoft Corporation, Redmond, Washington, USA). The data extracted were: names of the author(s) and year of publication; objective of the study; population assessed; composition of the Chitosan gel used; comparison group; control group; Chitosan properties; outcomes evaluated, and results.
Risk of Bias Assessment
The risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool, developed by Cochrane [34]. This tool is based on the evaluation of the study conduct process, based on five sections: 1) randomization bias - assesses whether the allocation of participants was random and the sequence was anonymous; 2) intervention bias - assesses whether participants and authors were blinded to the allocation and whether the treatment protocol was well controlled; 3) missing data bias - evaluates outcome data, such as loss to follow-up or exclusion of participants; 4) bias in outcome measurement - assesses whether outcome assessors were blinded to group allocation and whether measurement methods were appropriate and consistent; 5) bias in the selection of reported results - assesses whether all predefined outcomes were reported, ensuring that not only favorable results were reported.
Two authors (F.R.F. and A.M.O.) independently evaluated each section and assigned classifications according to standardized criteria. Divergences were discussed, and when no agreement was found, a third author (A.C.M.A.) was responsible for reaching a consensus. Section ratings were then combined to determine the overall risk of bias for each study: low risk of bias (all areas were assessed as low risk); some concern (at least one area presented “some concern”, but there was no high risk of bias in any other section); high risk of bias (three or more areas showed “some concern” or at least one section was considered high risk).
Results
In database searches, 30 studies were retrieved: eight from Embase, five from MEDLINE/PubMed, three from Elsevier/Scopus, and fourteen from Web of Science. The inclusion criteria were applied, and five studies were excluded due to duplication. After analyzing the titles and abstracts of the studies, 21 were excluded, 17 by the titles and four by the abstracts. Thus, four studies were considered eligible for full reading. Of these, one study was excluded because it used animals. After analyzing the references of the selected studies, four publications were added. These were read in full, and only two were added, since the others did not use gels in the comparison or control group. The entire study selection process is described in Figure 1, following PRISMA guidelines.
Finally, five studies were included in this systematic review, listed in Table 2. Of these, Akincibay et al. [9] was the oldest and Pelá et al. [20] the most recent. Population samples consisted of 15 to 47 individuals. The chitosan concentration in the gels ranged from 0.5% to 3%. The gels used as comparisonsand/or controls were chlorhexidine and water-based gels. The studies evaluated chitosan gels combined with other agents, and two studies compared these gels with a chitosan-only gel. Regarding the properties of chitosan, only two studies reported the degree of deacetylation, molecular weight, and solvent used. Four distinct purposes of the gel were described, with tissue healing and microbial control cited in two of the five included studies. Furthermore, regarding the location of the gel application, surgical wounds were most frequently described, followed by teeth and gingiva with chronic periodontitis. Among the assessments performed, postsurgical pain and degree of healing were the most frequently performed, followed by the plaque index (Table 2).
According to the risk of bias assessment (Table 3), considering the overall bias, one study was classified as high risk, three as some concern, and only one as low risk. For bias in randomization, most studies presented a low risk. For bias in intervention, most studies were classified as of some concern. For the bias due to the missing data section was addressed; all studies presented a low risk. For the bias in outcome measurement section, one study was classified as having some concern. In contrast, in the selection bias in reported results area, some studies presented a low risk of bias, while others raised some concerns.
Discussion
Chitosan has been widely reported in the literature for its favorable biological properties, such as low toxicity, biocompatibility, and antimicrobial activity [15], making it a promising biomaterial for dentistry [35]. Chitosan gel increases cell permeability, leading to instability, cytoplasmic leakage, and bacterial death [36]. This mechanism disorganizes and reduces the biofilm on the tooth surface [37,38]. Furthermore, this disorganization facilitates the mechanical removal of the biofilm and the penetration of other antimicrobial agents [39].
In general, the sample sizes of the studies included in this systematic review varied, with larger samples in those evaluating chitosan in postsurgical wound healing. This is justified by the procedures used, namely the extraction of third molars, which is a standard procedure in dental practice. Larger samples better reflect the population reality and make the results more consistent and reliable.
In this systematic review, studies that used chitosan-containing gels in dental patients were identified and included. Among the five incorporated studies, all gels evaluated contained agents other than chitosan, such as chlorhexidine, metronidazole, sodium fluoride, dexpanthenol, allantoin, sodium saccharin, and CaneCPI-5 [9,13,20,31,32]. In two studies, chitosan was the main component in the gel [9,20].
Regarding studies that used gels with formulations containing different agents [9, 13, 20, 31, 32], these gels exhibit an enhancement effect, as a synergy between chitosan and other active ingredients has been demonstrated [9, 39-41]. In this regard, the application of a chitosan-metronidazole gel, as described by Akincibay et al. [9], reduced the depth of periodontal pockets and gingival inflammation. This association between a classic antimicrobial and a natural compound may have expanded the gel's spectrum of action, enabling it to target a broader range of microorganisms [42]. Furthermore, the study by Pelá et al. [20], through a combination of chitosan and sodium fluoride or CaneCPI-5, demonstrated a protective effect on enamel against dental erosion and abrasion, which corroborates the study by Pini et al. [33], who showed that a whitening gel containing chitosan caused less roughness on the enamel surface when compared to a whitening gel without chitosan. This can be explained by chitosan's ability to bind calcium and phosphorus ions on the enamel surface, forming a protective barrier that prevents demineralization.
Furthermore, two studies used commercial gels containing agents other than chitosan, such as chlorhexidine, dexpanthenol, and allantoin. They reported better healing and reduced inflammation compared with the control group (water-based gel) [31,32]. The studies by Sáez-Alcaide et al. [31] and Zorrilla et al. [32], which evaluated only gels with varied formulations, prevented analysis of the effect of chitosan alone.
Regarding the types of gels used as comparisons and controls in the studies, chlorhexidine was the most frequently used, as it is considered the gold standard for intraoral antimicrobial treatments [43]. Therefore, comparing chlorhexidine with chitosan is important to assess their antimicrobial effects. Zorrilla et al. [32] compared a chitosan gel with a water-based control. Although the results were favorable, the comparison with a gel without antimicrobial action may have overestimated the effect of chitosan. On the other hand, the studies by Akincibay et al. [9] and Pelá et al. [20] compared chitosan gels with a group using another gel and an untreated control. This was interesting because it demonstrated the isolated effect of chitosan compared to the natural healing process.
The concentration of chitosan used in the gels was described in four studies, varying between 0.5% [31,32], 1% [9], and 3% [20]. A high concentration, such as 3%, could increase antimicrobial activity, as there is greater availability of the agent and more interaction with bacterial extracellular membranes, promoting stronger biofilm disorganization and reduced bacterial effects on the enamel [11]. Furthermore, the higher the concentration, the greater the gel's viscosity, providing a more efficient surface barrier against acids produced by bacteria [44]. On the other hand, lower concentrations may lead to a less pronounced chitosan effect, which may have been the objective of studies that associated chitosan with other agents [31, 32]. Lower chitosan concentrations, such as 0.5% and 1%, have lower viscosity and, therefore, greater flow, which may be beneficial in some intraoral regions, such as the periodontal tissue [11,45].
Only two studies [9,20] described other properties of chitosan besides its concentration. It is known that the degree of deacetylation and molecular weight affect chitosan's solubility and its ability to interact with the bacterial surface [45]. Only Pelá et al. [20] reported the formulation's pH. A pH of 5.5 is considered critical, as values below this level result in an imbalance in the demineralization process of tooth enamel, which can predispose to caries [1,46]. On the other hand, acidic pH favors the adhesion and antimicrobial action of chitosan, as it has amino groups (-NH₂) in its structure and, when in an acidic medium, these groups are protonated, making it positively charged (NH₃⁺) [44,45]. However, if the pH is higher than 6.5, the amino groups lose their positive charge, making chitosan insoluble and with less adhesion capacity [45].
In the studies included in this review, Akincibay et al. [9] and Poornima et al. [13] used periodontal indices to evaluate the effectiveness of chitosan gels. When assessing biofilm using the plaque index, Akincibay et al. [9] demonstrated a significant reduction with 1% chitosan gel combined with metronidazole compared with the gel containing only chitosan. In this investigation, the gel with different agents demonstrated better performance in microbial control in patients with chronic periodontitis, possibly by targeting a broader range of microorganisms [42]. The gingival and bleeding index showed a significant reduction with 1% chitosan gel compared to the control group [9]. Furthermore, the 1% chitosan group had the lowest gingival index at the 24th week of evaluation. This better performance over time can be explained by its better flow in periodontal tissues [11,45] and consequent reduction in local inflammation. The study by Poornima et al. [13] did not report the chitosan concentration used in their gel, and therefore, it was not possible to compare its effect on the periodontal index.
Regarding postsurgical healing using chitosan gel combined with other agents [31,32], two studies demonstrated a significant effect of chitosan compared with control gels. This can be explained by its antimicrobial effect and low toxicity [15].
In the risk of bias analysis of this systematic review, it was observed that the study by Akincibay et al. [9] presented some concerns regarding randomization, intervention, and outcome measurement, since the authors did not describe the method used for randomization and whether the study evaluators were blinded to the intervention and outcome measurement. In the evaluation of the intervention, the study by Poornima et al. [13] was classified as having low risk of bias, as it was the only one carrying out the intention-to-treat analysis recommended by Cochrane, which avoids selection bias and ensures that participants remain in the original group to which they were randomized, even if they did not complete the treatment or follow the protocol. The studies by Akincibay et al. [9] and Pelá et al. [20] were classified as having some concerns regarding the selection of reported results, as they did not register their studies on a clinical trials platform. Overall, the study by Akincibay et al. [9] was classified as high risk, Poornima et al. [13] as low risk, and the other three studies as of some concern. This indicates that although these studies may have potential biases, they were not serious and did not completely compromise the results; however, they do require caution in interpreting their conclusions. It is noteworthy that only two studies included in this review reported following the Consolidated Standards of Reporting Trials (CONSORT) guidelines in developing their work [13,31].
Due to differences in the distribution of the populations analyzed. In the interventions and results of the studies included in this review, it was not possible to quantitatively estimate heterogeneity or to perform a meta-analysis using forest plot graphs. For this reason, the analysis of the studies was performed only qualitatively.
This systematic review has limitations that should be considered, such as the small number of included studies, which limited the generalizability of the results, and the fact that only two studies evaluated the effect of chitosan gel alone, which limited our discussion.
According to this systematic review, the clinical application of chitosan in gel form for dental patients warrants further investigation. There is still no strong scientific evidence on the use of chitosan and its impact on dental and periodontal health, as only five studies were selected, and four showed potential bias. However, the gels appear to hold promise in reducing microbial load and reducing the risk of caries and periodontal disease. Therefore, it is suggested that randomized controlled clinical trials be conducted with larger sample sizes and more extended follow-up periods to better evaluate the efficacy of chitosan as an antimicrobial agent for other intraoral applications.
Conclusion
Gels containing chitosan appear to have a promising positive impact on dental and periodontal health, including improvements in plaque, gingival, and gingival bleeding indices, probing depth, tissue healing, and protection of enamel against erosion and dental abrasion. However, these results should be evaluated with caution due to the risk of bias identified in some studies included in this systematic review.
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Financial Support
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001 and the Minas Gerais State Agency for Research and Development (FAPEMIG).
Data Availability
The data used to support the findings of this study can be made available upon request to the corresponding author.
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Academic Editor:
Ana Maria Gondim Valença
