Repeated local delivery of hyaluronic acid gel as adjunctive treatment of residual pockets in periodontitis patients undergoing supportive periodontal care. A randomized controlled clinical trial

Initial non-surgical subgingival instrumentation (i.e., second step of therapy), either by hand or (ultra)sonic instruments (or a combination thereof), is a very successful treatment approach in periodontitis patients; on average, a shallow probing pocket depth (PPD) can be achieved in 3 out of 4 pockets [1, 2]. Recently, the World Workshop on the Classification of Periodontal and Peri‐Implant Diseases and Conditions [3] and the EFP S3 level Clinical Practice Guideline [1] have defined the goal of periodontal treatment. On the site level, pocket closure is defined as PPD ≤ 4 mm and no bleeding on probing (BoP), while on the patient level, a successfully treated stable periodontitis patient is characterized by having 1) PPD of ≤ 4 mm, 2) no PPD = 4 mm with BoP, and 3) full-mouth BoP < 10%. Although this goal is difficult to achieve in every patient, it has been shown that patients reaching these clinical endpoints present a reduced rate of disease progression/recurrence and tooth loss due to periodontitis during long-term supportive periodontal care (SPC) [4, 5]. Hence, the use of adjunct products (locally or systemically delivered) during the second step of therapy is frequently discussed, with the aim to 1) further improve the rate of pocket closure, 2) reduce the need for additional surgical therapy, and/or 3) improve the rate of achieving a successfully treated stable periodontitis patient. This in turn, should not only improve long-term stability of treatment and reduce tooth loss, but also minimize patient morbidity and eventually treatment costs. The various options and the efficacy of locally delivered adjuncts (i.e., host modulators or antimicrobials) during the second step of therapy have been evaluated extensively within the frames of the EFP S3 level Clinical Practice Guideline [6, 7]. It was finally suggested that only locally applied sustained-released chlorhexidine and antibiotics may be considered as valid options [1, 6, 7].

In this context, there is limited information about the “best” timepoint of delivery of locally applied adjuncts, in terms of (cost-)efficiency, i.e., whether they should be applied during the second step of therapy or during the third or fourth step of therapy at re-instrumentation of residual/relapsing pockets, respectively. Considering patient, societal, and/or possible biological impacts of unnecessary use of any adjunct measure, the latter approach would allow to limit their use to those patients/sites, which do not heal after the initial subgingival instrumentation. Two recent systematic reviews covered the efficacy of adjuncts for periodontitis patients with residual/relapsing pockets during SPC [8, 9]. Specifically, among locally delivered antimicrobials, sustained-release chlorhexidine and tetracycline fibres, ranked highest with a statistically and clinically significant additional PPD reduction of approximately 0.6 to 0.7 mm [9], while insufficient evidence is available for any other adjunctive treatment option (i.e., other than antimicrobials) [8].

Another locally delivered adjunct, however, which has neither been included in any of the above-mentioned systematic reviews nor in the EFP S3 level Clinical Practice Guideline, is hyaluronic acid (HyA). Various gels containing HyA in different concentrations have been, since several years, tested as adjuncts to non-surgical mechanical subgingival instrumentation and their efficacy has even been summarized in few systematic reviews [10‐12]. These reviews had well-comparable conclusions, i.e., most of the included clinical trials reported a positive, albeit moderate, effect in favour of HyA in terms of PPD and BoP reduction. However, there was a large variation in application modes and -frequency in the original studies, and all reviews stressed the need for further well-designed randomized controlled clinical trials (RCTs), including sufficient reporting of product details. In this context, it is currently not clear whether repeated application of a locally delivered adjunct is, in general, advantageous compared to single application, i.e., only just after instrumentation [13]. Nevertheless, 2 recent RCTs have assessed in-office HyA application specifically in re-instrumentation of residual/relapsing pockets. Each study tested a different HyA product and application frequency; in one of the studies HyA was applied subgingivally, once [14], while in the other study HyA was applied subgingivally at 2 consecutive appointments [15], but both showed a tendency in favour of HyA application.

Thus, it seems reasonable to assess whether combined local application of HyA, i.e., subgingivally in-office, after mechanical instrumentation, and repeated supragingivally, by the patient, once per day for 3 months, has the potential to improve the rate of pocket closure compared to re-instrumentation alone in the treatment of residual pockets in periodontitis patients undergoing regular SPC.

Locally delivered chemotherapeutics are frequently used as adjunct to non-surgical treatment in periodontitis patients, either at the initial phase of treatment or at residual/relapsing pockets during a later stage of treatment. However, as initial non-surgical subgingival instrumentation is a rather successful treatment per se, a more site-specific approach for pockets that did not heal during the second step of therapy, and/or of relapsing pockets during SPC might be the more relevant approach. Herein, a HyA containing gel, repeatedly applied (daily) for a period of 3 months, as adjunct to re-instrumentation of residual/relapsing pockets in patients undergoing regular SPC, showed some tendency to improve the outcome, i.e., 10% higher rate of pocket closure was observed for the sites receiving HyA compared to those in the control group that received physiological saline solution (i.e., 57 versus 47% of the sites, respectively), after 12 months. Additionally, the percentage of experimental sites with PPD < 5 mm was about 1.4-times higher in the test/HyA group compared to the control/placebo group (i.e., 71 and 52% of the sites, respectively).

These results are in agreement with those reported in 2 recent RCTs [14, 15] assessing a HyA containing gel as adjunct to re-instrumentation of residual/relapsing pockets and showing that the use of a HyA containing gel resulted in a tendency for superior results compared to re-instrumentation only. Moreover, both studies reported in their test group a similar frequency of sites with PPD < 5 mm after 12 months as herein, i.e., 76 to 77% in the 2 previous studies and 71% herein [14, 15]. Further, in one of the RCT studies [15] reporting on pocket closure (i.e., PPD ≤ 4 mm without BoP), a comparable rate in the HyA group as herein was observed, i.e., in 59 and 57%, respectively. A significant difference, however, between those 2 RCTs and the current study regard the product characteristics of the applied HyA gel. Specifically, a non-crosslinked, middle molecular weight HyA with a relatively low concentration (0.3%) was used in this study, while the other studies either used a product with crosslinked, high-molecular HyA at a higher concentration [15] or a combination product with polynucleotides and high-molecular HyA at a higher concentration [14]. Laboratory studies on periodontal cells or periodontitis-associated pathogens have compared the effects of either non-crosslinked and crosslinked HyA [21‐23] or of HyA of different molecular weights [24]; none of the formulations tested showed any negative effect in terms of periodontal wound healing. In this context, due to the lack of comparative clinical trials up-to-now, it remains unclear whether different HyA characteristics indeed translate into clinically relevant differences. Another difference among those 2 RCTs and herein regard the application mode/frequency of HyA. In this study, the HyA containing gel was repeatedly (daily) applied supragingivally for 3 months by the patients in addition to the subgingival in-office applications. One of the previous studies [15] assessed the effect of a repeated in-office application after 3 months but failed to show any additional beneficial effect of HyA after the re-application; however, prior to re-application no additional subgingival instrumentation was performed in this specific study. Herein, only sites with remaining signs of pathology received a re-application in combination with subgingival re-instrumentation. In both groups (i.e., test and control) approximately 30% of the sites requiring re-instrumentation and re-application were judged as successfully treated at the end of the trial. Nevertheless, although re-treatment improved the situation in 1 out of 3 cases and no distinct beneficial effect of HyA could be noted, the number of sites requiring re-instrumentation (re-treatment) at 3 months, was significantly lower in the HyA group, comparing with the one receiving NaCl. Finally, also the current data do not allow any conclusion on any potential additional effect of repeated supragingival application by the patients for 3 months, as a third group with subgingival in-office delivery only was lacking herein.

In general, reducing the number of residual pockets after active periodontal treatment (i.e., step 1 to 3) has been shown beneficial in terms of disease recurrence/progression and tooth loss in various studies focusing on long-term SPC after active periodontal treatment [4, 25‐29]. Thus, it is reasonable to assume that any treatment measure, such as the use of locally applied adjuncts, that improve the rate of pocket closure – irrespective the stage of treatment – may contribute positively also to the long-term outcome. In this context, HyA containing gels as adjunct to subgingival instrumentation in the second step of therapy have shown some potential in terms of PPD and BoP reduction [10‐12], which has been re-confirmed by more recent RCTs [30‐33].

Compared to other studies with a similar study design but assessing different products as adjuncts to re-instrumentation of residual pockets in SPC patients, the frequency of pocket closure appeared a bit lower herein. For example, 2 recent RCTs assessing the adjunctive effect of flapless application of enamel matrix derivatives [34], sodium hypochlorite gel [35], and chlorhexidine gel [35] reported pocket closure (i.e., PPD ≤ 4 mm without BoP) in 80, 78, and 63% of the sites compared to 57% herein. Hence, and considering the lack of RCTs directly comparing these products, HyA appeared similarly effective to CHX gel, but slightly inferior to enamel matrix derivatives and sodium hypochlorite gel. The latter might be of specific interest, as the combination of sodium hypochlorite gel with crosslinked HyA gel has recently received attention as combined adjunctive treatment in periodontitis patients. However, a recent retrospective case series including 29 SPC patients with residual/relapsing pockets reported for this combined approach a somewhat lower pocket closure rate of 25% [36].

Among the confounders used for adjusting of the present analysis, two had a significant effect on the outcome at final evaluation, i.e., plaque control and compliance/time, which are both well in agreement with the literature. Specifically, herein the presence of plaque, which was assessed at each experimental site at each SPC session, significantly lowered the odds of achieving pocket closure. To successfully motivate patients for continuous high levels of plaque control during SPC is a well-known clinical challenge and recent long-term SPC studies re-confirmed the clinical relevance of it [4, 37]. Both studies, including 100 [4] and > 200 individuals [37], respectively, undergoing approximately 10 years of SPC after active periodontal treatment, showed an increased risk for disease recurrence and tooth loss due to periodontitis with poor plaque control. Further, the patients of the present RCT showed in general and independent of group allocation a significant improvement over time, which became significant after 12 months. Specifically, also in the control/placebo group almost 50% of the experimental sites achieved pocket closure at the end of the trial. This effect size of achieving pocket closure by mechanical re-instrumentation only is well comparable with previous studies reporting rates of 42 to 60% [34, 35, 38]. In addition, study participation per se probably has a beneficial effect on the compliance from a patient perspective but also from the perspective of the treating dentist/dental hygienist, who might be more insisting on keeping the 3-month interval. In this context, it has been shown, that a shorter time between consecutive SPC sessions can result over time in reduced PPD and periodontal stability, while a longer time may lead to periodontal instability and subsequently tooth loss [39].

The present study – performed under “real-life” conditions – comes with some limitations, such as a relatively high drop-out rate of 30%, which did not permit us reaching the intended sample size in the control/placebo group, i.e., 26 instead of 30 participants were analyzed. The high drop-out rate is at least partly owed to participants missing their scheduled appointments during the Covid-19 pandemic, i.e., although a range of 2.5 to 5 months between 2 SPC sessions was accepted, almost 10% of the participants (i.e., 2 and 5 of the test/HyA and control/placebo group, respectively) were excluded from the analysis due to too long intervals. Nevertheless, as the time between 2 SPC sessions appears as a relevant factor [39], this parameter was included in the regression analyses herein, to correct in the model the slight variation in SPC intervals. However, as the present trial was performed in parallel-group design, the patients did not receive both products, which in turn should limit any bias due to insufficient patient blinding. In this context it was interesting, that the groups presented no significant difference regarding patient opinion about the consistency and taste of the product; both products were well accepted by the patients, which in turn may indicate good compliance.