Evaluation of Adjuvant Systems in Non-Surgical Peri-Implant Treatment: A Literature Review

Can the use of lasers, ozone, probiotics, glycine and/or erythritol, and chlorhexidine in combination with non-surgical peri-implant treatment have additional beneficial effects on the clinical parameters? Objectives: The non-surgical treatment of peri-implant pathologies is based on mechanical debridement to eliminate bacterial biofilm and reduce tissue inflammation; some additional therapies have been studied to achieve more detailed clinical results. Materials and methods: A literature search for publications until January 2022 was conducted. The research question is formulated following the Problem, Intervention, Comparison/Control, and Outcome. Studies investigating adjunctive therapies were included. Results: In total, 29 articles were included. Most of the studies did not show any additional benefit of these therapies in the evaluation of bleeding on probing, probing pocket depth, or plaque index; among the proposed treatments, the use of laser was the one most studied in the literature, with the achievement of a reduction of bleeding and pocket depth. More studies would be needed to assess the benefit of other therapies. Conclusions: This review showed no significant improvements in the state of health in support of mechanical debridement therapy. However, the few benefits found would deserve to be considered in new clinical studies.

According to these data reported in the literature, peri-implant mucositis affects 43% of patients, variable in a range from 19 to 65%. In comparison, peri-implantitis affects 20% of patients, with a range from 1 to 47%: it should be noted that the data cannot be entirely reliable, as the studies analyzed have used different criteria for the definition of peri-implant pathologies [2,3].
In the new classification of periodontal and peri-implant diseases, conditions are classified for the first time. The definition of implant health emerges, i.e., the absence of clinical signs of inflammation, including bleeding (BoP) and suppuration, the stability

Focused Question
Can the use of lasers, ozone, probiotics, glycine, erythritol, or chlorhexidine, combined with non-surgical peri-implant treatment, have additional beneficial effects on the clinical parameters?

Eligibility Criteria
Type of studies. Randomized controlled clinical trials, prospective clinical trials, and in vivo retrospective clinical trials were included.
Types of participants. Participants with the peri-implant disease were considered. Type of interventions. The experimental group was assisted by one or more laser treatments such as diode lasers, Er: YAG laser, Nd: YAG laser, Er, Cr: YSGG laser, LLLT (Low-Level Laser Therapy), PDT (Photodynamic therapy); ozone treatments such as ozone gas, ozone water, ozone gel; treatments with probiotics such as Lactobacillus or Bifidobacterium; treatments with glycine and erythritol air-polishing or perio-polishing; chlorhexidine treatments such as chlorhexidine mouthwash or gel. One or more control groups were administered a placebo or control treatment other than the experimental one.

Search Strategy
The review is based on the research of studies about the PICO model (Population/Problem, Intervention, Comparison/Control, Outcome), detected through bibliographic analysis in electronic databases on Pubmed (MEDLINE) and Google Scholar. Initially, all abstracts of clinical studies were taken into account, which assessed the possible benefit of the addition of laser therapy, ozone therapy, probiotics, glycine and erythritol, and chlorhexidine to non-surgical peri-implant treatment in the treatment of peri-implant diseases.

Search Outcome and Evaluation
The first research outcomes were PI, BoP, and PPD [18][19][20]. Information was extracted from each study on (I) participants' characteristics (age and peri-implant disease); (II) intervention placebo or no treatment or comparison treatment (different from the one tested); (III) outcome (possible benefits of adjunctive treatments); (IV) clinical data examined (PPD, BoP, and PI); (V) follow-up.
Initially, all abstracts about the topic under review were collected, and then, following a complete reading of the articles, all those not in agreement with the eligibility criteria were discarded. We included only studies in agreement with the criteria of inclusion: (I) studies where the authors did not evaluated at least one of the outcomes taken into account by us, (II) studies where one of the adjunctive treatments taken into account by us were not evaluated as a test group, and (III) in vitro or animal studies were excluded. As a result, articles that did not consider at least one of the selected additional systems and that did not analyze at least one of the clinical incidences (PI, BoP, and PPD) were eliminated.

Results
A total of 29 studies were therefore identified: 13 articles where the experimental group was treated with laser, 2 articles where the experimental group was treated with ozone, 4 articles where the experimental group was treated with glycine and/or erythritol, 6 articles where the experimental group was treated with probiotics, and 4 articles where the experimental group was treated with chlorhexidine ( Figure 1).
The results are shown in Table 1. The use of diode laser as adjunctive therapy to the conventional treatment of peri-implant mucositis showed promising results, being more effective in reducing the inflammation of the peri-implant tissue

Ozone
The two studies [13,33] selected for the review are published in English and conducted in Italy and in the USA; a total of 46 patients with mucositis were analyzed.
Patients were followed for 21 days in one of the two studies considered and for 2 months in the other, analyzing ozone gas [13] and ozone water [33], respectively, as regards their possible efficacy in some clinical indices: the first study analyzed PI, noting statistically significant differences between the treatment groups, while the second recounted improvements in terms of PPD, BoP, and PI always in the test group.
The results are shown in Table 2.
Patients were followed in a range of 3-12 months of glycine/erythritol treatment: almost all studies analyzed the beneficial effects of glycine [34][35][36], while only one study evaluated the efficacy of erythritol [14]. PPD was taken into account in all studies, BoP in 75% of studies, and PI in 25% of studies. Comparing treatment groups, both experimental and control groups showed positive changes during follow-up, showing no statistically significant differences. However, in one study, a greater improvement was found in bleeding on probing [35].
The results are shown in Table 3.
Patients were followed in a range from 6 weeks to 3 months of treatment with probiotics: almost all studies analyzed the beneficial effects of Lactobacillus reuteri [14,37,38,40,41], whereas only one study evaluated the efficacy of Lactobacillus brevis in combination with Lactobacillus plantarum [39]; as regards clinical indices, PPD was taken into account in 66.7% of the studies, BoP in 100% of the studies and PI in 66.7% of the studies. Comparing treatment groups, both experimental and control groups showed positive changes during follow-up, showing no statistically significant differences: however, in one study, an improvement of probing depth was greater [38], while another study showed an improvement in the plaque index only in the experimental group treated with Lactobacillus reuteri [37].
The results are shown in Table 4. Following the administration of probiotics or placebo, the clinical variables, except for probing pocket depth, slightly and progressively increased up to 3 months of follow-up, but without reaching baseline levels

Chlorhexidine
The four studies [15,[42][43][44] selected for the review are published in English and conducted in Switzerland [15], Brazil [42], Sweden [43], and Spain [44]; a total of 158 patients were analyzed (an average of 39-40 patients) where all studies involved patients with mucositis. Patients were followed in a range of 3-12 months of treatment: the studies examined analyzed the beneficial effects of chlorhexidine in gel or mouthwash at different percentages; with regard to clinical indices, PPD and BoP were taken into account in all studies, and PI in half of the studies involved. By comparing treatment groups, both experimental and control groups showed positive changes during follow-up, showing no statistically significant differences. However, some studies have seen more improvement in PPD [43] and BoP [43,44].
The results are shown in Table 5. The PPD was significantly reduced (p < 0.05) after 12 weeks compared to baseline in the test group but not in the control group

Risk of Bias
Randomization, allocation concealment, blinding, outcome data, and outcome recording were evaluated.
For randomization, participants should be allocated to groups using a true randomization sequence; if studies used the date of birth, admission date, or admission number, it was not evaluated as true randomization.
For allocation concealment, participants and investigators should not be able to predict allocation before the participant is entered into the study, such as centralized allocation (telephone use or web-generated numbering) or sequential numbers contained in anonymous envelopes.
Participants and investigators should be unaware of allocation for blinding to ensure that everyone receives the same amount of care, secondary treatment, or diagnostic testing.
All randomized participants, including those who withdrew from the study or did not receive their intended intervention (intention-to-treat), should be included in the outcome analysis.
For outcome recording, outcomes should be reported for each outcome identified at the outset, primary and secondary; study reports should not focus only on those outcomes that are favorable or those that demonstrate a statistically significant difference between groups.
The risk of bias has been assessed according to the type of randomization and the allocation concealment, the blinding, the outcome data, and the registration of the outcomes, based on the information described in the articles.
For the assessment of risk bias, a color was assigned for each variable analyzed; each color corresponded to a risk value, such as low, moderate, or high. In cases where the information was complete and inherent to the variable considered, a low risk of bias was attributed (green symbol). In cases where the information was scarce or not complete/ missing, a moderate risk was attributed (yellow symbol). Finally, in the cases in which the information was not adequate concerning the variables, for example, randomization based on the date of birth, a high risk of bias was attributed (red symbol).
Tables 6-10 show the risk of bias in the main articles examined; this review presents a relatively low risk of bias. Green symbol: low risk of bias; yellow symbol: moderate risk of bias (also used for lack of information); red symbol: high risk of bias.

Discussion
Dental implants represent a dental therapy aimed at replacing missing elements in different clinical situations: however, one of the most frequent complications that can lead to the loss of the implant in the presence of peri-implant inflammation, which involves the surrounding hard and soft tissues. This can also be determined by other factors such as the overload of the implant, defects in the materials and techniques used, poor bone quality in the implant area, and systemic pathologies or drug therapies that inhibit bone remodeling [45,46].
The prevention of peri-implant diseases is therefore based on the elaboration of a structured plan that includes individual assessments, minimization of the risk factors, stabilization of the optimal conditions of the surrounding hard and soft tissues, and finally, choice of the correct type of implant, followed by an approach as atraumatic as possible [47]. On the other hand, the treatment includes a non-surgical conservative approach and a surgical approach aimed at decontaminating the implant surfaces. This includes mechanical implant debridement with plastic, titanium, or carbon curettes, ultrasonic instrumentation, or air-and perio-polishing technique [48]. In addition, therapies such as photodynamic or local antiseptic dressings with chlorhexidine, hydrogen peroxide, or sodium percarbonate may support antimicrobial therapy [45][46][47]; this would facilitate the reduction of the pocket depth from 0.5 to 1.0 mm and the bleeding on probing from 15 to 40% [45].
The stabilization of oral hygiene is, therefore, a key element in the prevention of mucositis and peri-implantitis: the goal of therapy should be to resolve the inflammation of the soft tissues and maintain the stability of the supporting bone, trying to instruct the patient in the correct methods of oral hygiene; mechanical debridement and oral hygiene instructions, with or without the addition of supportive therapies, would appear to be as effective as reported into the totality of the studies examined in this review.
The use of laser for the treatment of peri-implant pathologies has been extensively studied, as well as for non-surgical periodontal treatment, leading to a reduction of bleeding on probing from 100 to 43% (following repeated sessions with diode lasers in a 2-year follow-up) [49], but also a reduction in pocket depth (also with photo-modulating therapy) [13]. These results agree with some studies shown in the table (Table 1), which showed improvements in terms of PPD and BoP. Clinical studies conducted by Schwarz, et al., in fact, have reported significant decreases in probing pocket depth (also in pockets of 6 mm, reporting a reduction from 4.6 ± 0.9 mm to 4.1 ± 0.4 mm and from 5.9 ± 0.9 mm to 5.5 ± 0.6 mm) and bleeding on probing, finding improvements even six months after the start of treatment [10,22,24] These results are also found in other studies, such as in a clinical study [25] where the reduction in the probing pocket depth varies from 4.04 ± 0.54 mm at 2.98 ± 0.70 mm and an improvement in the BoP from 44 positive sites to 6 positive sites at the end of the follow-up.
Less significant results compared to the use of the laser as a support to the mechanical debridement in the non-surgical therapy of mucositis and peri-implantitis are reported by studies related to the use of probiotics or gel and mouthwashes based on chlorhexidine. Concerning probiotics, little has been studied in this type of therapy, unlike non-surgical periodontal treatment [50], where improvements in clinical parameters are reported [50][51][52]. Some studies report a significant reduction in probing pocket depth a month after mechanical debridement, with a reduction ranging from 0.5 mm (Table 4) to 1.09 mm [35]; these results are in agreement with another study in the literature, where a postbiotic-based gel appears to be able to reduce inflammatory indices, but they are improvements that would deserve to be evaluated and supported by further research [53]. Less significant in terms of probing pocket depth but also studied as a powerful antibacterial and antimicrobial agent is chlorhexidine, which is often associated with irrigating the peri-implant pockets and would favor the reduction of bleeding probing [44,45]. Despite the improvements observed, both through the use of probiotics (in the analyzed studies Lactobacilli reuteri was used) and through the use of chlorhexidine, it would seem that these additional therapies do not lead to more valid results than just mechanical debridement; although several studies in the literature support the benefits of chlorhexidine as an antiseptic agent, it should also be remembered that there are several related adverse events, such as pigmentation of oral soft tissues and teeth, hypersensitivity reactions, taste alteration, burning sensation, ulceration, or erosion of the oral mucosa [54]. The same applies to air-and perio-polishing methods and to the use of ozone, which would not lead to different results compared to the control therapies administered to patients; moreover, as regards the use of ozone, literature is scarce, and consequently, it cannot be said with certainty that it is good therapy in the resolution of implant pathologies or not, although one study has shown improvements in all the clinical parameters analyzed [30].
From the analyzed studies, following the objective of this review, namely, to determine the effectiveness of therapies in terms of bleeding on probing, probing pocket depth, and plaque index, this last parameter does not seem to have been analyzed about particular clinical improvements: only a study with the use of probiotics has favored a modification of the plaque index [36].
Unfortunately, there is a large discrepancy between all the studies that have been analyzed in this review that presents limitations: first of all, it is always difficult to define the probing pocket depth, as there is no standard method used in all studies, and it is a variable also influenced by the thickness of the tissues and the positioning of the implant; from this, it follows that the presence of a pocket is not always synonymous with a disease state of the patient. Another negative point that emerges from the reported articles is that there is no great support literature that can define the effectiveness of these therapies in supporting mechanical debridement. Therefore, it is impossible to perform a valid comparison: also, about the causal therapeutic choice, not all studies were performed in the same way.
What emerges from the clinical results reported by the studies is that these are still valid therapies that have been proven to be good in the treatment of gingivitis and periodontitis. This suggests that further studies should be carried out to validate the findings.

Conclusions
Based on the results discussed, it can be hypothesized that these additional therapies may provide other clinical benefits in the non-surgical treatment of peri-implant diseases.
Analyzing the effects in terms of improving bleeding on probing, the probing pocket depth, and the plaque index of some therapies supporting the mechanical debridement for the treatment of peri-implant pathologies, although some improvements have emerged, therapies that can provide additional benefits cannot be defined. Considering the reduction in clinical parameters found, these systems should be further studied and analyzed, especially for ozone, glycine/erythritol, probiotics, and chlorhexidine treatment.