Background

Periodontitis is an inflammatory disease of the periodontal tissues. It is caused by bacteria as an etiologic factor and modulated by the host [1, 2]. Subgingival populations of bacteria are organized in biofilms. Therefore, the primary goal of periodontal treatment is to eliminate or reduce the pathogenic species on dental surfaces. Scaling and root planing (SRP) still represents the highest standard of care and mechanically disrupts these biofilms. Nevertheless, a complete elimination of the pathogenic biofilm is not always achieved, due in great part to issues of site accessibility [3, 4].

In order to overcome the technical problems associated with subgingival biofilm management, previous research has examined numerous local adjunctive antibiotics and antiseptic agents as well as strategies that have been proposed and investigated in order to improve non-surgical therapy. Several local anti-infective and antibiotic agents are adjunctively placed directly into the periodontal pockets and have been shown to have an impact on bacterial biofilm pathogenicity and periodontal healing [5,6,7]. One such chemotherapeutic agent, chlorhexidine, was integrated into a biodegradable chip and placed in the periodontal pocket [8, 9]. Nevertheless, one of the few studies investigating a potential effect on periodontal pockets could not prove a benefit of chlorhexidine chips compared to systemic antibiotics [10]. Another approach in non-surgical periodontal treatment was the local application of antibiotic agents through numerous mechanisms [11]. Yet, showing a statistical advantage compares to SRP alone. The use of such agents has decreased in popularity due to manufacturing issues, difficult administration techniques, and financial reasons [7]. In addition, the use of locally applied antibiotics requires the use of higher concentrations (bacteriocidal vs. bacteriostatic) due to a rather fast wash-out time in the periodontal pocket. This, in turn, has given rise to growing criticism [12,13,14].

Hence, there has been increasing interest in natural alternatives. Green tea is one such substance and has gained attention based on promising scientific reports that show its health benefits, especially in beverages [15]. The active ingredients of green tea are polyphenols. Most of them are catechins (flavan-3-ols), which can be categorized in four main groups: Epigallocatechin-3-gallate (EGCG) being the most common type (59%), followed by epigallocatechin (EGC, 19%), epicatechin 3 gallate (ECG, 13.6%), and epicatechin (EC, 6.4%) [16]. In addition, whole green tea contains other antioxidants in the form of vitamins, such as carotinoids (A), ascorbate (C), and tocopherols (E) [15].

Polyphenols act as antioxidants through the induction of antioxidant enzymes such as glutathione S-transferase and superoxide dismutase. Other mechanisms by which catechins have an influence on the oxidation levels are through binding to iron and copper ions, thus reducing the impact of these ions on oxidation reactions. In addition, they prevent the activation of redox-sensitive transcription factors, which are mediators of inflammatory reactions. Catechins can also suppress other oxidation substances, such as nitric oxid synthase, cyclooxygenase 2 (COX-2), lipoxygenase 2 (LOX-2), and xanthine oxidase [15, 17].

Kushiyama and co-workers showed that green tea can have a preventive effect when taken regularly. It may even reduce the progression of an existing periodontitis [18]. Overall, green tea catechins have an anti-oxidant and anti-bacterial effect on pathogens such as Porphyromonas gingivalis and Prevotella intermedia. The mechanism of action is through the inhibiting effect of EGCG and EGC on cysteine proteases of P. gingivalis. [19, 20]. In vitro research also suggests an anti-inflammatory effect for other inflammatory processes, such as cardiovascular diseases [21].

Although multiple studies have been conducted to find evidence on the therapeutic effects and benefits of green tea, little is known about the use of this substance for periodontally diseased patients. Therefore, this systematic review was undertaken to evaluate the potentially beneficial effects of green tea extract as a topically applied adjunct to SRP during non-surgical periodontal therapy in patients with periodontal disease.

Materials and methods

Protocol

The current systematic review was conducted in accordance with the Preferred Reporting Items of Systematic Reviews (PRISMA) and Meta-analyses statement [22]. The focused question adopted the population, intervention, comparison, and outcome criteria [23].

The focused question for the present systematic review was: “What is the effect of green tea catechins as an adjunct to scaling and root planing (SRP+GT) compared to SRP and placebo on the PPD in patients with chronic periodontitis?

Literature search strategy and study selection

The following electronic search was conducted to identify research articles up to January 2017 dealing with green tea catechin as adjunct to SRP. The databases used for the search were CINAHL, Cochrane Library, MEDLINE, PubMed, and Scopus. The following combinations of search terms were used: “periodontal disease” OR “loss” OR “pocket” OR “abscess” OR “abscesses” OR “periodontitis” OR “attachment AND loss” AND “camellia AND chinensis” OR “green tea” OR “epigallocatechin” OR “gallate” OR “gallic acid” (Appendix 1).

Two of the authors (Y.v.W. and S.L.S.) independently screened the titles and abstracts for inclusion. The collection of search terms from the electronic database resulted in 234 titles in January 2017. A third reviewer (P.R.S.) re-examined the search. In case of disagreement, the study in doubt was also evaluated by a fourth reviewer (S.J.G.) and solved through discussion. Finally, eight studies were selected for full text assessment (Fig. 1).

Fig. 1
figure 1

Literature screening procedure (flow-chart)

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Inclusion and exclusion criteria

The eligibility criteria for the search included original publications investigating green tea extract as an adjunct to SRP compared to SRP alone. Based on the following criteria, abstracts were included: publications in English, German, or Spanish language; randomized clinical trials; extract of green tea explicitly used as an adjunct to non-surgical therapy in patients with chronic periodontitis (SRP); the extract was explicitly used as a local delivery device, either in a strip or gel.

Reasons for excluding publications were as follows: in vitro study, case report, the study population was treated for gingivitis, only green tea and not a green tea extract was used, or green tea was not used in a local delivery device; the study population suffered from a systemic disease (for example diabetes) (Appendix Table 5).

Data extraction

From each study, the following data were collected in a data extraction file: number of subjects, chemical composition of the green tea extract, chemical composition of the placebo device, study period, point in time of application of the test and control device, PPD at baseline and study end, PI at baseline and study end and GI at baseline and study end.

Data analysis and synthesis

At baseline and study end, mean and standard deviations were extracted from the studies. A major statistical challenge was the lack of reported standard deviations on the changes in parameters from baseline to endpoint. Additionally, outcomes between different treatments are correlated in a split-mouth design. Therefore, an analysis was conducted between individual values at baseline and endpoint of the two different treatments in the same individual. Probing pocket depths (PPD) were defined as the primary outcome measure, Plaque (PI) and Gingiva Index (GI) as secondary outcome measures. The open source software R with the package “metafor” was used for a random effects analysis according to the method of DerSimonian and Laird [24]. Several combinations for the correlation of the baseline and endpoint values, as well as the correlation between the two measured differences of test and control groups reflecting the split-mouth design, were used (Tables 1, 2, 3 and 4). The combination with the smallest lower confidence interval found is reported in Fig. 2 (conservative estimate).

Table 1 Study characteristics of included studies to the review. Last study was excluded from the meta-analysis
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Table 2 Results of probing pocket depth
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Table 3 Results of gingiva index
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Table 4 Results of plaque index
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Fig. 2
figure 2

Meta-analysis, changes in respect to PPD

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Report of risk of bias for individual studies

The methodological and reporting quality of the studies included was rated through a modified version of the Cochrane Collaboration‘s Tool [25] (Appendix Table 6). The studies of interest, given their adequate reporting of items, were evaluated for quality and risk of bias.

Results

Study selection

The electronic data search initially identified 234 studies. After reviewing the titles and abstracts, 226 of these studies were excluded. After analyzing the full text of eight studies, four studies had to be excluded; one due to the inclusion criteria of patients being diagnosed with diabetes [26], another due to missing information on study design and sample size [27], and the third because no information on study design and sample size was presented. The fourth study got excluded due to the nature of the study with only six participants included into the study [28]. Four studies were designed in a randomized, double-blinded split-mouth model and could be included in the meta-analysis [29,30,31,32]. Further, one randomized, double-blinded, placebo controlled parallel-group study did not fit the meta-analysis requirements and will be described separately [33]. Figure 1 demonstrates the selection process in a flow-chart.

Description of characteristics and results

The characteristics of the study are described in Table 1. Study characteristics, relevant for the specific research question are described as follows.

Population

Two studies included subjects between 30 and 55 years of age [29, 31]. Two studies included patients older than 35 years [32, 33]. One study did not provide age [30]. The ethnicity of the subjects was not disclosed. In fact, three studies were performed in India, one in Japan and one in Thailand, which suggests populations of Asian descent. Only one study from Mendoza, Argentina, evaluated a Caucasian population. All studies described chronic periodontitis and a cut-off measurement of > 5 mm PPD. In some studies, patients had to display > 5 mm PPD on at least two sites bilaterally in order to meet the inclusion criteria. The study conducted by Chava and co-workers included patients with 4 to 6 mm PPD on > 30% of sites [31]. All split-mouth designed studies defined the allocation of the PPD measurements in the specific quadrants. The following exclusion criteria were defined by four studies: Periodontal treatment with and without antibiotic treatment in the past 6 months, smokers, lactating and pregnant women, and systemic diseases. Another study excluded patients who had undergone topical or systemic antibiotic treatment either during the past 60 days or during the study period [30]. The studies included to the meta-analysis examined a total of 34 patients treated with catechin strips and 80 patients treated with catechin gel. However, the number of treated teeth was not declared.

Intervention/comparison

All included studies performed SRP and an adjunct application of either a green tea catechin strip or gel on the test sites. Funosas and co-workers performed either SRP alone or placed a placebo gel as a control. This study evaluated both control group possibilities in different quadrants [30]. Within the identified studies, three publications examined green tea gel and three studies used a hydroxypropyl cellulose strip as carrier for the green tea extract. The local delivery device (LDD) was placed once after SRP, except in one study. Rattanasuwan et al. repeated the application 1 and 2 weeks after SRP with no further intervention [33]. Study periods ranged from 3 weeks to 8 months.

Outcomes

All studies registered PPD at baseline and study end for the test and control groups. All studies observed sites with at least 5 mm PPD. In addition to PPD, GI was evaluated by Chave et al., and GI and PL in four other the studies [31].

  1. a)

    Probing pocket depth (PPD)

Within the test group, PPD at baseline ranged from 4.93 to 6.43 mm and at study end from 2.87 to 5.14 mm (Table 2). Within the control group, PPD at baseline ranged from 4.77 to 5.71 mm and at study end from 2.83 to 5.14 mm. The reduction of PPD (Δ PPD) within the test group ranged from 1.28 to 2.71 mm with a mean of 1.89 mm and within the control group from 0.57 to 2.67 mm with a mean of 1.34 mm. Chava et al. reported a minor standard deviation for ΔPPD for the test and control groups, 0.07 mm and 0.02 mm, respectively [31].

  1. b)

    Gingival index (GI)

Table 3 displays the baseline GI for the test group, which ranged from 1.67 to 2, and at study end from 0.01 to 0.96. Equal to the test group, GI at baseline in the control group ranged from 1.67 to 2 and at study end from 0.16 to 1.1. The reduction of GI within the test group ranged from 0.71 to 1.91 with a mean reduction of 1.21 and within the control group from 0.64 to 1.97 with a mean reduction of 1.1.

  1. c)

    Plaque index (PI)

Only two studies documented PI Scores, whereby Hattarki et al. provided identical data for the test and control groups [29, 32]. Mean PL reduction in the test group was 1.12 and in the control group 0.99 (Table 4).

  1. d)

    Meta-analysis PPD

SRP treatment with adjunctive green tea catechin application resulted in a 0.74 mm PPD reduction [0.35, 1.13; 95% CI] in favor of green tea compared to SRP alone (Fig. 2). One study presented a very small standard error [31]. To fit statistical measurements, the study was removed and the results remained statistically significant with a 0.57 mm [0.35, 0.78; 95% CI] PPD reduction after SRP treatment with green tea application.

  1. e)

    Rattanasuwan (parallel-group study)

This study was excluded from the meta-analysis because of their parallel-group design and reported no difference between test and control groups (0.04 mm in favor of SRP+GT) [33]. Nevertheless, the study observed 48 patients over a period of 6 months, where patient populations in the meta-analysis studies ranged from 14 to 50 patients [29, 30, 32].

  1. f)

    Adverse effects

Only Chava et al. provided the information that no adverse events occurred during their study [31]. The other studies did not mention the occurrence of adverse reactions, one way or the other.

  1. g)

    Bleeding on probing (BOP)

Only Rattanasuwan et al. evaluated BOP as a secondary outcome, and showed a significantly higher reduction in the test group after 3 months [33].

Discussion

This study evaluated the clinical efficacy of topically applied green tea catechin substances as a natural adjunct to SRP, as compared to SRP alone or using a placebo. PPD reduction was the primary outcome parameter for determining efficacy. Five randomized controlled clinical trials with a split-mouth design, and using green tea catechins as an adjunct to SRP, could be included in this systematic review. Overall, the adjunctive application of the test agent resulted in an observed weighed mean difference in PPD reduction of 0.74 mm [0.35–1.13; 95% CI] favoring the test group.

Systemic antibiotics as an adjunct to SRP have shown great success in the treatment of periodontal disease, but are associated with the development of bacterial resistance and systemic adverse events [34, 35]. Therefore, the local application of natural alternative substances with a local anti-inflammatory effect, such as green tea catechin, is of great clinical interest.

The clinical benefit measured appears to be in line with previous reviews on the effect of other antimicrobial substances frequently used as adjuncts in non-surgical periodontal therapy [33, 36, 37]. Only one systematic review evaluated alternative locally applied agents and compared the PPD reduction to SRP alone [36]. The most frequently used and studied antimicrobial agents, chlorhexidine, minocycline, and doxycycline, were also investigated in this review. Minocycline, locally applied as a gel or microencapsulated agent, showed a significant PPD reduction, whereas the use of chlorhexidine or doxycycline only displayed a significant effect on CAL gain.

The systematic review by Bonito and co-workers [11] showed an estimated reduction in PPD of 0.49 mm in favor of locally applied minocycline as an adjunct to SRP compared to SRP alone. Locally applied tetracycline presented a PPD reduction of 0.47 mm. The application of metronidazole and chlorhexidine were below these benchmark results. The review by Matesanz-Pérez [37] showed a PPD reduction value of 0.73 mm when tetracycline fibers were applied as an adjunct to SRP. Doxycyclin and minocyclin showed less prominent effects in terms of PPD reduction, with mean values of 0.57 mm and 0.47 mm. The parallel-group study, which was not included in the meta-analysis treated 48 patients in a 6-month investigation, being the longest study launched. Nevertheless, no benefit in PPD reduction could be observed [33]. The findings of the present systematic review are therefore within the range of earlier findings for well-investigated locally applied antimicrobial or antibiotic agents.

Green tea is a non-fermented product of the Camellia sinensis leaf and has been used historically as a natural medicine for oral diseases [38]. Not surprisingly, all studies included in the current work, except one, were performed in Asia. Because of the applied language restriction, potentially relevant articles, which were not published in English, German, or Spanish, were not included in this work. This may expose an overall publication bias. The different concentrations and release patterns of the green tea catechins within the broad range of materials used and the repeated application protocol of the LDD used in at least one of the studies could also lead to biased results and must be taken into consideration when interpreting these positive results.

The studies included and analyzed showed a high degree of heterogeneity in terms of population characteristics, different green tea catechins used, carriers, application protocols and study periods. In addition, the sample sizes of the studies included were generally rather small. Hirasawa and co-workers only included six patients and therefore got excluded from the systematic review [28]. Three studies included patients ranged from 30 to 55 years of age [29, 31]. One study did not mention the age of the patients included [30]. Furthermore, two studies did not exclude smokers from the study [28, 30]. The inconsistencies of these studies (age, diagnosis, and smoking) are potential confounders and could lead to a misinterpretation of the real effect of green tea catechin.

Two studies included teeth with a PPD of 4 mm to 8 mm [29, 31], whereas two studies included teeth with a PPD greater than 5 mm only [30, 32]. No study classified the general condition of the teeth studied in terms of, i.e., number of roots, furcation involvement, or restorations. These anatomical and restorative factors potentially affect the healing response and effects after SRP and may interfere in the effectiveness of the green tea catechins. The study periods varied from 3 weeks to 8 months, which may have an impact on the healing effect as endpoint. In addition, applied maintenance protocols were also inconsistently reported. Unfortunately, due to the small number of included studies, no stratification of the studies was possible.

In the current review, two different carriers were used for the sustained release of the green tea catechins. Two studies used a hydroxypropyl cellulose strip [29, 32], while the remaining studies used a carboxymethyl-cellulose-gel, a gel manufactured with carbomer and poloxamer or a thermosensitive hydro-alcoholic-gel. Furthermore, every study used custom-made green tea catechin products, which were manufactured by the research group itself or were purchased from different manufacturers (Sunphenon® or Geltec, both Mumbai, India).

Most of the studies investigated the adjunct of green tea catechin to SRP and compared the results to a control group which received a local placebo device as an adjunct to SRP. In two studies, the control group received only SRP without any local placebo material [29, 32]. Furthermore, all studies applied the local delivery devices once immediately after SRP.

Although green tea and its base catechins represent a natural product, adverse effects should also be considered. Unfortunately, only one study by Chava and co-workers explicitly reported no adverse effects and assessed this aspect [31].

Conclusion

The current meta-analysis found that the adjunctive application of green tea catechins result in a beneficial reduction of the probing pocket depth as compared to scaling and root planing with or without placebo. However, due to the high heterogeneity of the data and several risks of bias, this evidence needs to be interpreted with caution. To evaluate the true benefit of green tea catechin in the treatment of chronic periodontitis, further long-term investigations need to be conducted.