Comment on “Ozonized Hydrogel and Chlorhexidine Gel for Peri‐Implant Mucositis: A 24‐Month Randomized Controlled Trial”

The article by Scribante et al., offers a meticulously designed and extensively reported comparative clinical evaluation of two non-surgical interventions for peri-implant mucositis (Scribante et al. 2025). It critically addresses the efficacy of an ozonated sunflower oil-based hydrogel versus a standard 1% chlorhexidine gel over a substantial follow-up period of 24 months. Ozonated oil formations, such as Oral Ozone and Rinozone (Multiossigen S.p.A., Bergamo) demonstrate antimicrobial and anti-inflammatory properties, effectively supporting oral hygiene and promoting gingival health in various dental conditions. The longitudinal scope, methodological rigor, and split-mouth randomized controlled design all contribute to the study strengths, yet several aspects deserve further scrutiny in terms of scientific reasoning, generalizability, and clinical translation. One of the most commendable elements is the study commitment to rigorous methodology. The adoption of a split-mouth design minimizes inter-individual variability, allowing each participant to serve as their own control. This approach enhances internal validity, especially when assessing localized conditions such as peri-implant mucositis. Moreover, the investigators ensured thorough calibration of examiners and utilized standardized, reproducible assessment protocols for both clinical and radiographic data. These measures strengthen the credibility of the findings by minimizing observer bias and enhancing the reproducibility of the results (Scribante et al. 2025). The statistical treatment of the data appears robust and appropriate to the design and distribution characteristics of the measurements. The use of non-parametric tests such as the Friedman test and Dunn's post hoc analysis is fitting given the non-normal distribution of clinical indices. The decision to present both implant-level and patient-level analyses provides a holistic view of the therapeutic outcomes and acknowledges variability in individual site responses within the same patient, which is often overlooked in similar studies (Butera et al. 2023; Nardi et al. 2022). The clarity in data presentation, particularly the time-based comparisons, is another positive aspect, aiding interpretation and facilitating clinical applicability. From a clinical standpoint, the study's primary finding, that the ozonated hydrogel outperforms chlorhexidine in reducing bleeding on probing, plaque index, and other inflammatory markers without inducing adverse events, holds potential implications for peri-implant care. Chlorhexidine, while widely accepted for its antimicrobial efficacy, is often associated with side effects like taste alteration, mucosal irritation, and staining (Silvestri and McEnery-Stonelake 2013). The ozonated gel's favorable safety profile, combined with superior clinical efficacy, suggests it may represent a valuable adjunct in peri-implant maintenance, particularly in patients where long-term chlorhexidine use is contraindicated or undesirable. However, despite the compelling results, there are areas of concern that merit deeper critique. First and foremost is the question of generalizability. The sample size, while statistically justified for detecting differences in bleeding scores, remains modest with just 30 patients. Although 360 peri-implant sites were treated, these were distributed across a relatively small number of individuals, most of whom appear to have good compliance and systemic health. The exclusion of smokers, diabetics, and those with previous peri-implantitis, while methodologically sound for reducing confounders, also limits the applicability of findings to real-world populations, where such comorbidities are common and influence disease progression and treatment outcomes (Scribante et al. 2025). Moreover, the study's open-label nature introduces the possibility of performance and detection bias. While blinding the clinical examiner and data analyst partially mitigates this risk, the inability to blind patients and care providers could influence behaviors or assessments. Given the subjective nature of some indices (e.g., marginal mucosal condition), this could subtly skew outcomes despite efforts at standardization. Additionally, the use of visually distinct gels, while aiding patient compliance, inadvertently reveals group allocation and further complicates full blinding. Another limitation concerns the interpretation of recurrence. While the study defines recurrence rigorously, as the reappearance of one or more clinical signs after resolution, it remains unclear whether recurrence was analyzed in relation to patient-level behavioral factors, such as oral hygiene adherence or prosthetic complications. These variables are known to influence peri-implant health but were not explicitly modeled in the statistical analysis. Future studies could strengthen their conclusions by incorporating multivariate analyses that control for such potentially confounding variables. The trial also invites scrutiny with regard to its clinical relevance (Scribante et al. 2025). While statistically significant differences were found in several parameters, it is essential to consider whether these differences are clinically meaningful. For example, while the ozonated gel reduced bleeding scores more rapidly and consistently, the control group also achieved substantial improvements over time. This raises the question of whether ozonated gel represents a significant advancement in therapeutic efficacy, or merely a marginal improvement over an already effective intervention. Cost-effectiveness, patient preference, and ease of use, all critical in clinical decision-making, were not addressed, yet they are crucial for guiding implementation in everyday practice. A further area deserving of attention is the biochemical mechanism of action for ozonated sunflower oil. The study alludes to its antimicrobial and anti-inflammatory properties, referencing prior research, but does not directly investigate or corroborate these mechanisms within the trial itself. Given the increasing interest in biologically active gels, future studies might include microbiological or biomarker analyses to substantiate the purported modes of action. Such mechanistic insights would provide a more compelling scientific rationale for adoption and help differentiate ozonated products from other antiseptics or bioactive formulations currently under investigation. Furthermore, it would be of paramount importance to forecast the effect of ozone on the oral microbiome composition, as a dysbiotic scenario is etiologically associated with tumors (Nocini et al. 2022; Meng et al. 2025). In our experience, ozone should co-operate with the oral mucosal immunity in assessing a healthy oral microbiome, but it would be interesting to hear from the authors about this issue. Lastly, the paper could have benefited from a more comprehensive discussion regarding limitations and avenues for future research. While the authors do acknowledge some constraints, their commentary remains relatively muted (Scribante et al. 2025). For instance, the lack of peri-implantitis progression in both groups is framed as a positive outcome but might also reflect the low baseline risk among the highly selective study cohort. Additionally, the reliance on periapical radiographs to assess marginal bone level, though standard in clinical settings, lacks the precision of CBCT imaging, which could detect subtle changes in bone density or morphology that are not apparent radiographically (Scribante et al. 2025). In conclusion, this study offers valuable insights into the long-term management of peri-implant mucositis and highlights the potential role of ozonated sunflower oil-based hydrogels as a superior alternative to chlorhexidine. The methodological rigor, clear outcome reporting, and statistically significant findings represent key strengths. Nonetheless, issues related to generalizability, blinding, clinical significance, and mechanistic validation warrant further investigation. As such, while the findings are promising and justify consideration of ozonated gels as a therapeutic adjunct, definitive endorsement will depend on replication in larger, more diverse cohorts, and a broader evaluation of patient-centered outcomes, including acceptability, cost-effectiveness, and real-world performance. Marianno Franzini: investigation, validation, formal analysis, supervision. Luigi Valdenassi: software, conceptualization, data curation, project administration, supervision. Maurizio Ciatti: investigation, validation, data curation, software, methodology, supervision. Salvatore Chirumbolo: conceptualization, investigation, writing – original draft, writing – review and editing, validation, supervision. The authors declare no conflicts of interest. The authors have nothing to rpeort.