The main goal of the treatment of periodontitis is to remove the plaque formed by the subgingival flora on the root surface. Scaling and root planing is still the most effective methods for mechanically removing plaque. However, due to the complex anatomical shape of the teeth, the instrument cannot effectively reach the infected area, so it is difficult to completely remove the plaque [21,22,23,24]. In order to achieve better plaque clearance, many studies have combined topical antibiotics or antibacterials in periodontal non-surgical treatment [25,26,27,28]. It was reported that SRP combined with topical use of minocycline could reduce the probing depth by an additional 0.49 mm, and topical use of tetracycline can reduce the probing depth by an additional 0.47 mm. Using metronidazole and chlorhexidine could also get similar results. However, because the elution rate of the drug in the periodontal pocket was very fast and the maintenance time was short, a higher concentration was needed to increase the bacteriostatic effect and maintain a longer time, which may cause some controversy [29,30,31], such as antibiotics may cause bacterial resistance . As an alternative to antibiotics, chlorhexidine had a low possibility for inducing bacterial resistance. However, due to the damaging effect of chlorhexidine on the protein, when chlorine was transported into the periodontal pocket during periodontal treatment, it may be detrimental to periodontal tissue healing .
As a natural product, EGCG has been widely recognized for its ability to resist inflammation and anti-oxidation and inhibit P. gingivalis and Plasmodium [13, 34]. In addition to resisting inflammation and inhibiting microorganisms, EGCG can also inhibit MMP-9 expression in osteoblasts, reduce osteoclast formation, and induce osteoclast apoptosis to reduce alveolar bone absorption through caspase-mediated apoptosis [13, 34]. It was also demonstrated in animal experiments that it inhibited the absorption of alveolar bone. EGCG can inhibit inflammatory alveolar bone resorption induced by lipopolysaccharide by inhibiting membrane-bound prostaglandin synthetase 1 and 2 (mPGES-1, mPGES-2) expression, thereby reducing prostaglandin E2 induced by lipopolysaccharide. At the same time, EGCG can also inhibit RANKL and prevent osteoblasts from differentiating into osteoclasts . In addition, in recent years, studies have been conducted on oral EGCG in mice with periodontitis, attachment loss, alveolar bone resorption, and expression of inflammatory factors were inhibited [36, 37]. Moreover, there are no reports of side effects in current clinical studies, so there is great potential for application in the treatment of periodontitis.
In this study, we used an ultrasonic scaler as a means of delivering drugs that differed from previous studies. The premise of using this method is that the EGCG solution did not significantly decrease after being atomized through the ultrasonic scaler, and our previous study has shown that the 2 mg/mL EGCG solution was stable, and 5 mg/mL was used in this clinical study, which was more stable .In terms of concentration selection, studies by Asah et al.  and Hiraasaw et al.  showed that 0.50 mg/mL and 1.00 mg/mL were the lowest EGCG inhibitory concentrations, respectively, whereas gel or chips were used in the past, and the concentration previous studies used was mostly above 10 mg/mL [17, 18], so the concentration used in this study was safe and effective, and no patients indicated that there was any discomfort throughout the study. The experimental design method of split-mouth was because the inflammation of both sides of the chronic periodontitis patients was relatively similar without obvious local promotion factors. In this way, the effects of individual factors on the test side and the control side could be minimized.
In previous studies, Hiraasaw et al.  reported that at week 8, the mean probing depth in the test group which used catechin HPC chips was significantly lower than that of the control group which use placebo, but only 8 subjects were included. Kudva et al.  and Hattarki et al.  also used catechin HPC chips, studies showed probing depth, gingival index, and plaque index significantly improved at 21 days and 5 weeks. Chava et al.  delivered catechin in a thermoreversible slow-release gel into the periodontal pocket of patients with chronic periodontitis. After 4 weeks, probing depth, clinical attachment level, and the gingival index had significant improvement compared to the placebo-treated group. However, the longest-running study of Rattanasuwan et al. , which injected a gel of catechin into periodontal pockets, showed that from 1 to 6 months, probing depth, clinical attachment level, plaque index, or gingival index were not significantly different from those of the placebo-treated group. Only bleeding on probing had a statistical difference between the two groups at 3 months. Probing depth and clinical attachment level in our study also had no significant difference between the test side and control side, which was inconsistent with the previous research results. However, the improvement of the test side was larger than the control side, which seemed to show the potential effect. On the other hand, the bleeding index had significant improvement at 12 weeks. The reasons for the differences in the results may be that the frequency, concentration, and method of using EGCG differed from previous literature. In previous studies, whether using chips or a gelatinous agent, most of the repeated administrations were performed several times after subgingival scaling and root planing. But our study was only administered at baseline and was not repeated until the review, so the frequency of EGCG was lower than in the previous literature. In terms of concentration selection, as discussed above, the concentration of EGCG used in this study was lower than in previous studies and may have an impact on the results of the study.
As for the method of using EGCG, Gregory et al.  evaluated the penetration depth of the water coolant for medicament lavage of an ultrasonic scaler into periodontal pockets, using a stain instead of distilled water to eject from the tip of the ultrasonic scaler. The results showed that the probing depth from 3.0 to 9.0 mm, the stain could reach the position where the ultrasonic tip could reach, which had a linear relationship with the probing depth. But the disadvantage was that the area where the rinsing liquid reached was relatively limited, basically along the working path of the ultrasonic working tip, the dispersion of the dye-colored stain was localized to the area of the ultrasonic probe with very little lateral dispersion. The study implied that the ultrasonic instrument may be effective to mechanically remove plaque and calculus at the same time as delivering a chemotherapeutic agent to the base of the periodontal pocket. On the other hand, the teeth in the study of Gregory et al.  were clinically needed to be extracted, the inflammation of the gingiva was heavy, and the periodontal pockets were slack, probably were the reasons why the stain could reach 9.0 mm. We thought that the level of gingival inflammation, the tightness of the periodontal pockets would influence the penetration depth of periodontal pockets that the drug could reach in this method of administration. Moreover, Chapple et al.  and Taggart et al.  also used an ultrasonic scaler to deliver 0.02% chlorhexidine as an adjunct to scaling and root planing. And there was no statistically significant difference between the two groups. In conclusion, previous studies using tablets or gels for local administration may maintain a longer elution time in the periodontal pockets, whereas the present study used an ultrasound tip to deliver EGCG which had a short elution time. Comparing with the research of Wang et al. , a new-type scaler tip with the terminal outlet was applied, which could deliver EGCG solution to the bottom of periodontal pockets, the results showed a significant PPD reduction after 6 months. In this study, the solution originated from the base of the tip rather than the top of the tip, so the EGCG aqueous solution may only reach a limited area in periodontal pockets. Perhaps this was one of the reasons why EGCG in the present study did not play a significant role. On the other hand, the effect of EGCG may be covered up by scaling and root planing. For the periodontal pocket where the probing depth was not so deep, it would be improved by complete scaling and root planing, thus whether the use of EGCG could not be well-reflected.
In addition, the experimental design of the split-mouth could eliminate the individual differences between the test group and the control group as much as possible, but the accompanying problem was that the EGCG solution may flow to the control side during the treatment on the test side, which was an interference with the results of the control group. In order to avoid interference caused by these factors as much as possible, only maxillary teeth were chosen, and a strong suction was used in the course of treatment to further prevent the rinsing liquid from flowing to the opposite side.
In view of the above-mentioned problems, the subsequent research should include more deep periodontal pockets, on the one hand, and improve the drug-delivery method of EGCG, on the other hand, explore the appropriate concentration of EGCG solution, appropriately enlarge the sample size, and extend the observation time.
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