Clinical efficacy of titanium prepared platelet rich fibrin in periodontal regeneration: A systematic review and meta-analysis

Background Periodontal regeneration therapies frequently involve autologous platelet concentrates (APCs). They can be used in sinus lift surgeries and socket preservation, among other clinical settings. Platelet rich fibrin (PRF) membrane has been used to treat gingival recession in individuals or groups of individuals using a coronally progressed or lateral pedicle flap. In the treatment of mixed periodontic endodontic lesion/furcation defect, PRF functions as a healing and interpositional biomaterial, filling a cystic cavity. PRF is known to help the bone regeneration process. In the last few years, efforts have been made to enhance the PRFs characteristics and quality. One of them is titanium platelet rich fibrin (T-PRF). Third-generation platelet concentrate no longer contains silica, and its preparation in glass vacuum containers, that no longer creates any known concerns. The effectiveness PRF’s has been evaluated in connective tissue and bone repair. The aim of this study is to compare T-PRF to other platelet concentrates and different treatment modalities for periodontal regenerative procedures. Methods A protocol of this systematic review have been registered in prospero (CRD42022293545). The online database searched were PUBMED, COCHRANE for published articles up to November 2022 without language restrictions. Studies in trial registers, handsearching, bibliographic references of relevant articles were also checked. Data collection and analysis was done by individual authors. Independent eligibility assessments were conducted by four review authors. Then, using the standard Cochrane methodology, four review authors extracted the data and evaluated the risk of bias for individual studies. We developed “Summary of findings” tables and used GRADE to evaluate the evidence. Results Three studies were included for meta-analysis. Results of meta-analysis supported that T-PRF is effective for correction of both hard and soft tissue defects. Conclusions The overall qualitative and quantitative analysis suggest that T-PRF has superior structural properties and thicker fibrin network for ensuring predictable success periodontal regenerative procedures.

this study is to compare T-PRF to other platelet concentrates and different treatment modalities for periodontal regenerative procedures.

Methods
A protocol of this systematic review have been registered in prospero (CRD42022293545).The online database searched were PUBMED, COCHRANE for published articles up to November 2022 without language restrictions.Studies in trial registers, handsearching, bibliographic references of relevant articles were also checked.Data collection and analysis was done by individual authors.Independent eligibility assessments were conducted by four review authors.Then, using the standard Cochrane methodology, four review authors extracted the data and evaluated the risk of bias for individual studies.We developed "Summary of findings" tables and used GRADE to evaluate the evidence.

Results
Three studies were included for meta-analysis.Results of metaanalysis supported that T-PRF is effective for correction of both hard and soft tissue defects.

Conclusions
The overall qualitative and quantitative analysis suggest that T-PRF has superior structural properties and thicker fibrin network for ensuring predictable success periodontal regenerative procedures.
Introduction Description of the condition Plasma fractions with higher platelet concentrations, such as platelet-rich plasma (PRP) and platelet rich fibrin (PRF) are crucial to regeneration. 1 Their use has been successfully linked to connective tissue and bone repair. 2 PRP has been documented and used in a variety of applications with what appears to be clinical success.It is an autologous modification of fibrin glue that is created by techniques that concentrate autologous platelets. 1PRP supports bioactivity but exhibits no stimulant properties for activation of regenerative cells. 3Additionally, its preparation is technique sensitive. 4PRP preparation, on the other hand, takes time therefore various efforts have been made to modify and enhance the PRP's characteristics and quality which include Leukocyte platelet-rich fibrin (L-PRF).It was first described by Choukroun as cited by Dohan DM et al. (2006). 5It is regarded as a second-generation platelet concentrate and has been used to speed up wound healing during several surgical operations.Choukroun et al. first created PRF in France in 2001 as an autologous biomaterial that includes leucocytes. 68][9] Although PRF has been shown to produce positive therapeutic outcomes, some clinicians are concerned that the method's use of glass-evacuated collection tubes for blood with silica activators may pose a health risk. 10,11O'Connell provided a description of the inevitable silica interaction. 12lthough the silica in the tube is thick enough to settle with the red blood cells, some of the particles are still colloidally suspended in the buffy coat, fibrin, and platelet-poor layers of plasma.Therefore, when the product is used for therapy, the particles could come in contact with the patient. 13Silica, found in glass test tubes, is known for its ill effects.However, T-PRF, a third-generation platelet concentrate, is recognized for its ability to mitigate this problem.

Description of the intervention
Nonsurgical periodontal therapy, such as scaling and root planing (SRP) alone or SRP plus systemic or local antiinflammatory or antibacterial drugs, to surgical flap debridement, are the approaches for treatment of periodontitis cases. 14However, in cases of soft and hard tissue defects, surgical correction of the defects is of prime importance.For correction of bony defects, the use of autografts and allografts have been advocated. 15Autologous platelet concentrates when used in conjunction with bone grafts results in better improvement.A study by Olgun et al. (2018) reported clinical, radiographic and histological outcomes of bone that accelerated to four months compared to six months for allografts when combined with T-PRF. 16The desired outcome was seen in four months as compared to six months.Tunalı et al. in the year 2012 17 discovered a mature fibrin network when T-PRF clots were examined.In the T-PRF membrane, they discovered islets of bone tissue and newly developing connective tissue.These findings demonstrate that T-PRF could, within 30 days of treatment, cause the development of new bone and connective tissue in an experimental rabbit model of wound healing.

How the intervention might work
As mentioned above, the novel product termed T-PRF was prepared by Tunali et al. (2014) 13 utilising a modified L-PRF process.Authors took the advantage of Dohan Ehrenfest's taxonomy, which divides platelet-rich products into four main groups to prevent any misunderstanding about how to obtain these products.These four categories are determined according to the number of leukocytes and fibrin they contain, platelet-rich products: just platelet-rich plasma products, platelet-and leukocyte rich plasma products, platelet-rich fibrin, and platelet and leukocyte rich fibrin.The creation of T-PRF, a new platelet concentration, was motivated by the idea that titanium tubes would be more potent at activating platelets than the glass tubes used in Chouckron's approach.The distinguishing properties of T-PRF, particularly its improved biocompatibility, are produced by platelet activation with titanium as opposed to activation with silica particles. 18T-PRF fibrin network covers a larger area than L-PRF fibrin network, also fibrin seemed thicker in the T-PRF samples. 13

Preparation of Titanium Platelet Rich Fibrin (T-PRF)
Immediately before the procedure, intravenous blood is withdrawn into a 10 ml sterile titanium test tube without the use of an anticoagulant.The tubes are immediately spun in a centrifuge for 12 minutes at 2700 rpm.The creation of a structured fibrin clot in the middle of the tube, in between the red corpuscles at the bottom and the acellular plasma [Platelet Poor Plasma (PPP)] at the top, is made possible by centrifuging blood as soon as it is collected.The titanium is very active surface for coagulation.Hence, centrifugation is started in 30-60 seconds.After centrifugation the T-PRF is kept inside the tube for 10-15 minutes to keep activation process in continuation.

REVISED Amendments from Version 1
This revised systematic review incorporates the 2020 version of the PRISMA flow chart, whereas the earlier version utilized the 2010 version.Additionally, we have incorporated minor corrections based on feedback from reviewers.

Why it is important to do this review
Since the introduction of T-PRF by Tunali et al., 18 it has been assessed for various properties including its structural and biochemical characteristics.Tunalı et al. (2014) 19 described the structural properties of T-PRF, and compared it to L-PRF.T-PRF samples appeared to have a highly ordered network with continuous integrity.The fibrin network in T-PRF samples appeared to be thicker and to cover a wider area than the network in L-PRF samples, according to histomorphometric analyses.T-PRF is a naturally occurring leukocyte-and PRF product that has been defined for the first time in a human investigation.Titanium platelet activation appears to provide T-PRF with certain high features.[22] Systematic evaluation of the studies to assess the clinical efficacy have not been done to date.Therefore the objective of this systematic review is provide the best possible evidence for the use of T-PRF in periodontal regenerative procedures.

Methods
Protocol Development Update: This review protocol has been officially registered in Prospero under the registration number CRD42022293545.To assess the methodological quality of this systematic review, we have adopted the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.This tool, available at www.prisma-statement.org/,serves as a guide for evaluating systematic reviews.It builds upon the original QUOROM guideline and facilitates the assessment of systematic reviews encompassing both randomized and non-randomized controlled trials.
Focused Question: The primary inquiry of this systematic review is as follows: What is the efficacy of Titanium Platelet Rich Fibrin in periodontal regenerative procedures for patients diagnosed with chronic periodontitis, as observed in adults aged 18 years and older, based on the collective evidence derived from existing literature encompassing both randomized and non-randomized clinical trials?We searched PubMed, Cochrane, Embase database without language restrictions.We used Medical subject headings (MeSH) or equivalent and textword terms.We searched the metaRegister of controlled trials (mRCT), National clinical trials government website.Additionally, we checked the reference lists of reviews, retrieved articles for additional studies, and performed citation searches on key articles manually by going through each reference of the included articles.We intended to use randomised controlled trials (RCTs) that assessed outcomes in an open or blinded manner.Short abstracts (typically meeting reports), non-randomised research, experimental pain studies, animal model studies, case reports, and clinical observational studies were all omitted.

Selection of studies
An open source online screening tool Rayyan 23 (RRID:SCR_017584) was used by review writers.They independently screened the search results (RO, PD, PB, KB).By reading through the abstracts of each study that the search produced, the eligibility of each research was established.The review writers excluded studies that did not distinctly meet the inclusion criteria.For all included studies' complete texts were acquired.Primary reviewers independently screened the complete texts of these studies to pick the most pertinent studies (RO, PD, PB, KB).The respective authors were reached by phone or email to get the required clarification for any missing data or information in the studies that had an impact on the study selection criteria.In cases of disagreement or dispute, a fifth author was asked for a judgement (KD).Prior to evaluation, the trials were not anonymized.Any language restrictions in the study selection process were not taken into consideration as a constraint for carrying out this evaluation.The complete review includes a PRISMA flow chart 32 that shows the precise status of all identified studies in accordance with the recommendation found in "Part 2, Section 11.2.1 of the Cochrane Guidelines for Systematic Reviews of Interventions". 24Irrespective of the reporting of outcome data, studies were included in this review as shown in Figure 1.

Data extraction and management
The data extraction from "included studies" was performed by four reviewers (RO, CS, KB, and KD) and given in the "characteristics of studies table" using a pre-defined data extraction form (Table 1).Data were extracted based on the nature of research, participant information, intervention information, and reported results.The disagreement between the main reviewers was resolved by the third reviewer (PB).The fourth reviewer successfully addressed the "risk of bias evaluation" discrepancy (KB).We have included a total of nine studies for qualitative analysis and have been included in the characteristics of studies table (Table 1).All the studies were matched for type of intervention, type of defect and participant details.Three studies were included and matched for meta-analysis followed by quantitative analysis. 20,22,25sessment of risk of bias in included studies Four reviewers (RO, PD, CS, and SH) from each included study independently evaluated the risk of bias (RoB) using the Cochrane domain-based, two-part tool as outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions. 24The fourth reviewer was able to resolve the disagreement between the main reviewers (KB).Sequence generation, allocation concealment, participant and staff blinding, blinding of outcome evaluation, incomplete outcome data, biased outcome reporting, and other bias, such as baseline imbalance, were all areas in which we evaluated the RoB.

Measures of treatment effect
In parallel-group RCTs, the unit of analysis was the individual subject.The Elbourne-recommended method is used to integrate the cross-over designed trials into the meta-analysis. 26Measurements from experimental intervention periods and control intervention periods, respectively, were taken for these trials, and they were analysed under the assumption that it was a parallel group study of intervention versus control.

Assessment of heterogeneity
The Chi 2 test (P value set at 0.10 for statistical significance) was used to examine clinical heterogeneity, and the I 2 statistic was utilised to quantify heterogeneity in the outcomes of the included studies using RevMan manager version 5.0. 27Significant heterogeneity is defined as I 2 over 75%; substantial heterogeneity is defined as I 2 between 50% and 90%; moderate heterogeneity is defined as I 2 between 30% and 60%; and mild heterogeneity is defined as I 2 less than 40%.If      statistical heterogeneity with I 2 more than or equal to 50% is found, relevant causes were investigated using predefined subgroup analysis, and a random-effects model was used and reported.

Data synthesis
Only when it was determined that the participants, interventions, comparisons, and results of the included studies were adequately comparable to yield a conclusion with clinical relevance and significance was a meta-analysis performed.
We intended to carry out the meta-analysis using the Cochrane Collaboration's open source RevMan 2014 statistical software (RRID: SCR_003581).If statistical heterogeneity with I 2 higher than or equal to 50% is found, the sources of the heterogeneity were found, and a random-effects model meta-analysis was then carried out.In a meta-analysis, four papers were used.Table 2 presents data from all three investigations (Data Entry).

Forest plots
The analysis of the PI, PPD, CAL, DF was done separately for the interventional (OFD+T-PRF) and control groups (OFD alone).The details of the studies included for meta-analysis are given in Figures 2-5.All the included studies reported the use T-PRF combined with OFD.Three articles reported the use of T-PRF in infrabony defects, 20,22,25 one study reported use of T-PRF combined with allograft for patients with chronic periodontitis. 28Another study reported its use in sinus lift procedures. 16Two studies reported its use in gingival recession 21,29 and other in healing of extraction socket. 29Based on the overall similarities in participants, outcome and data three studies were found to be eligible for meta-analysis. 20,22,25he conclusion regarding the overall effect size estimates were made based on the meta-analysis.

Plaque index
All the included studies reported PI at baseline and after nine months. 20,22,25However, two studies reported data in the form of meanAEstandard deviation.All the studies showed statistically significant reduction in plaque index at nine months follow up period.The overall meta-analysis showed marginally significant reduction in plaque scores after nine months.(Mean Difference -0.52; 95% CI -1.30 to 0.27; p=0.03;I 2 78%; two studies; 33 participants).However, in view of significant heterogeneity (I 2 =78%), the results need to be interpreted with caution because of increased heterogeneity as shown in Table 3 and Figure 2.

Probing pocket depth
All the three included studies reported data on PPD at baseline and after nine months.All the studies reported significant reduction in PPD.The overall meta-analysis showed marginally significant reduction in PPD scores after nine months.

Clinical attachment loss
All the included studies reported clinical attachment loss (CAL) gain at baseline and after nine months.All the studies reported significant improvement in CAL gain.The overall meta-analysis showed marginally significant increase in CAL gain after nine months.(MD -0.12; 95% CI -0.59 to -0.35; p<0.0001; three studies; 62 participants).However the percentage of variation (I 2 -55%) was found to be minimum in all the three included studies, therefore making the interpretation of result favourable as shown in Table 5, Figure 4.

Defect fill
All the included studies reported defect fill at nine months.However quantitative assessment was only possible for two studies because of difference in reporting of outcomes. 20,22Significant defect fill was observed in both the studies.The overall meta-analysis showed a marginally significant increase in defect fill after nine months (MD -0.07; 95% CI -0.17 to -0.03; p=0.09; two studies; 47 participants).Overall defect fill was not statistically significant.However in spite of improvement in defect fill, in view of significant heterogeneity found the results needs to be interpreted with caution as shown in Table 6, Figure 5.

Risk of bias (ROB) in the studies
Allocation: One study reported use of the coin toss method for allocation hence was graded as low risk, 22 the other two did not report the method and hence were graded as unclear. 20,25Blinding: all the studies were double blinded and were kept in low-risk bias. 20,22,25Missing result information: discretionary reporting In terms of reporting, we classified all three studies as low risk.The bias in the behaviour or observations: since all procedures and observations were carried out by a single trained professional in each research, we classified the study as low risk in terms of performance or observational bias.Figures 6 and 7 show, respectively, a summary of the risk of bias in the included studies and its graphical depiction.

Discussion
Autologous platelet concentrates (APCs) are known to improve or accelerate the bone regeneration process. 20Efficacy of plasma fractions with higher platelet concentrations, such as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) have been successfully linked to connective tissue and bone repair.Evidence from in-vitro studies stated that plasma fractions enhance the quality and quantity of bone defects induced experimentally. 21,22Since past few years, efforts have been made to enhance the PRFs characteristics and quality.Titanium Platelet Rich Fibrin (T-PRF) is one of them. 23ecause silica is no longer contained in the third-generation platelet concentrate, there are no longer any recognised risks associated with using glass vacuum containers to prepare PRF.APCs when used in conjunction with bone substitutes to produce new bone is not backed up by any compelling evidence.However, When T-PRF was used in conjunction with DFDBA during sinus-lifting surgeries, Olgun et al. ( 2018) observed rapid bone development in 4 months as opposed to 6 months in their clinical, radiological, and histological data. 24ere are seventeen pieces of literature published on T-PRF.Two in-vitro studies have been performed by Tunali et al. 18,19 They discovered a mature fibrin network.In the T-PRF membrane, they discovered islets of bone tissue and newly developing connective tissue.These findings demonstrate that T-PRF could, within 30 days of treatment, cause the development of new bone and connective tissue in a rabbit model of wound healing.They have also described the structural properties of T-PRF, and it was compared to L-PRF.Another in-vitro study evaluated the regulation of gingival keratinocyte adherence, dissemination, and cytokine expressions on titanium and PRF surfaces. 30Ustao glu et al.
(2016) 29 in their clinical study assessed the T-PRF's clinical effects on human palatal mucosal wound healing (PMWH), and its impact on "time-dependent variations in palatal soft-tissue thickness (PSTT), a novel idea, was discovered.Out of the above-mentioned studies, three studies were included for meta-analysis. 20,22,25Results of meta-analysis supported that T-PRF is effective for correction of both hard and soft tissue defects.We included three studies that have reported data from 100 participants, aged 18+ years, that have used T-PRF in infrabony defects treated with open flap debridement.Studies have reported data on periodontal parameters like pocket depth, gingival bleeding, clinical attachment loss.Indices including plaque index and gingival index.Meta analysis was done for PPD, CAL, PI and defect fill parameters.The overall results of meta-analysis suggest that T-PRF is a better alternative to other platelet concentrates for both hard and soft tissue parameters.

Conclusion
This review focused on answering if T-PRF is a better alternative when compared with other platelet concentrates for periodontal regenerative procedures.The overall qualitative and quantitative analysis suggest that T-PRF have superior structural properties and thicker fibrin network.It provides superior results when used alone or combined with autograft or allograft.However, due to limited number of studies done so far, we recommend that more high quality RCTs to be conducted on this topic.

Recommendation
This systematic review examines the sufficient clinical and radiographic evidence regarding the regenerative capabilities of T-PRF, either alone or in combination with bone grafts, for both hard and soft tissue procedures.However, there is a need for well-designed and adequately powered randomized controlled trials (RCTs) that demonstrate the clinical and histologic outcomes of T-PRF, in order to fully understand and confirm its potential role in regenerative dentistry.
Future studies should aim to address the current heterogeneity in the literature, particularly in the selection of optimal biological agents that facilitate accelerated bone growth, variations in formulations, investigative methods, and durations of follow-up.Additionally, there should be a focus on emphasizing the application of T-PRF membranes.
From a scientific and clinical perspective, the challenge posed by the barrier concept in guided bone regeneration (GBR) mechanisms is likely to inspire new research inquiries and broaden future clinical opportunities for bone regeneration, particularly in relation to alveolar ridge preservation (ARP).

Yes
Is

Sara Bernardi
Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy Davide Gerardi Universita degli Studi dell'Aquila, L'Aquila, Abruzzo, Italy Dear authors, congratulations for the study and your contribution to the research.This systematic review and meta-analysis discusses about the efficacy of T-PRF in periodontal regenerative procedures, an interesting topic regarding a specific type of autologous platelet concentrates, thus T-PRF, applied to the widely-studied field of periodontal regeneration.The search strategy is well defined and clear.However, I suggest some revisions in order to improve the quality of the manuscript.
Introduction: I suggest to deepen the description of APCs, giving a more complete description of the protocol to obtain T-PRF, but also describing the histological characteristics of platelets concentrates, from the cited fibrin network to the other components of PRF.
Besides, it would be useful to describe the differences between the first and the second generations of autologous platelet concentrates and their application in the different fields of oral surgery and periodontology, focusing on the involvement of T-PRF and periodontal regeneration procedures.
Discussion: the discussion should me more consistent; the aim of the study is to compare T-PRF to other APCs in periodontal regeneration, so, before comparing the results, I suggest to add more information, according to the results of the study, about the APCs that in the included studies have been compared to the main subject of discussion, thus the T-PRF.
Moreover, the different periodontal regenerative techniques compared should be shortly described.These two topics can help to evaluate the advantages and disadvantages of T-PRF, in relation to the other interventions.
Finally, I suggest to highlight the limits of the study, from which the future perspectives and recommendations, explained in the conclusion, derive.
Are the rationale for, and objectives of, the Systematic Review clearly stated?Yes

Are sufficient details of the methods and analysis provided to allow replication by others? Yes
Is the statistical analysis and its interpretation appropriate?I cannot comment.A qualified statistician is required.

Are the conclusions drawn adequately supported by the results presented in the review? Yes
If this is a Living Systematic Review, is the 'living' method appropriate and is the search schedule clearly defined and justified?('Living Systematic Review' or a variation of this term should be included in the title.)Yes Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Dentistry
We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.

Introduction:
"One of them is titanium....".There seems to be a disconnect between the statement and its previous sentence.

○
The objective statement for the SR is not clearly mentioned in the main text.Authors should write the objective statement

Results:
Authors should write a short description of the included studies (table 2) By Using RevMan, Table 3

Conclusions:
The overall effect for plaque Index, Clinical Attachment Loss was found to be not significant and only Probing Depth was found to be significant, with marginal significance in defect fill with only two studies.Therefore, the conclusion statement should be made with caution.

4.
Results Section: Due to the generation of forest plots and tables using Review Manager, we were unable to combine them into a single figure.However, we have ensured that both formats are presented clearly for better visualization and interpretation.

Description of Included Articles:
A concise description of the included articles has been added to provide readers with a brief overview of each study's characteristics.

6.
We believe that these revisions have strengthened the manuscript and improved its overall quality.
Competing Interests: No competing interests were disclosed.
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Figure 2 .
Figure 2. Forest plot of Plaque index.

Figure 3 .
Figure 3. Forest plot of probing pocket depth.

Figure 4 .
Figure 4. Forest plot of clinical attachment loss.
Uzun et al. (2017) 21 compared the results of connective tissue graft with autologous T-PRF (CTG).T-PRF (63 teeth) or CTG were utilized to treat 114 Miller Class I/II gingival recessions with abrasion defects utilizing a modified tunnel technique (51 teeth).Olgun et al. (2018) 16 investigated the differences between using an allograft or totally autologous T-PRF in sinus-lifting surgeries on the clinical, radiological, and histological levels.Arabaci et al. (2018) 20 T-PRF and open flap debridement (OFD) were examined for their effects on biological markers in gingival crevicular fluid (GCF) and periodontal results.TPRF+OFD or OFD alone were used to treat 29 subjects with chronic periodontitis.Ustao glu et al. (2019) 31 analysis of extraction sockets preserved by L-PRF and T-Fractal PRF's dimension (FD) and early soft tissue

○Fig 1 :
Fig 1: Authors are suggested to use the 2020 PRISMA Checklist and The Flow Diagram

○ 3 .
Are the rationale for, and objectives of, the Systematic Review clearly stated?PartlyAre sufficient details of the methods and analysis provided to allow replication by others?PartlyIs the statistical analysis and its interpretation appropriate?YesAre the conclusions drawn adequately supported by the results presented in the review?PartlyIf this is a Living Systematic Review, is the 'living' method appropriate and is the search schedule clearly defined and justified?('Living Systematic Review' or a variation of this term should be included in the title.)Partly Competing Interests: No competing interests were disclosed.Reviewer Expertise: Periodontology, Dental Implantology, Biofilm Formation, Clinical Dentistry, Periodontal Regeneration, Biomaterials, Quality of Life Research I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.Research Question and PICOT: We have rephrased the research question and PICOT (Population, Intervention, Comparison, Outcome, Time) elements in a more concise and understandable manner.Additionally, we have included the PROSPERO registration number in this section for transparency.PRISMA Checklist and Flow Diagram:We have updated the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Checklist to the 2020 version and included the updated Flow Diagram to accurately reflect our review process.

Table 1 .
Characteristics of studies.

Table 3 .
Data of plaque index for forest plot.

Table 4 .
Data of probing pocket depth for forest plot.

Table 5 .
Data of clinical attachment loss for forest plot.

Table 6 .
Data of defect fill for forest plot.

the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the 'living' method appropriate and is the search schedule clearly defined and justified? ('Living Systematic Review' or a variation of this term should be included in the title.) Yes Competing Interests:
No competing interests were disclosed.

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Version 1
https://doi.org/10.5256/f1000research.144303.r219505© 2023 Bernardi S et al.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
and Fig 2, Table 4 and Fig 3, Table 5 and Fig 4, Table 6 and Fig 5 can be combined into one.That is a standard and more appealing way to represent the Forest plots along with associated data.Authors are suggested to change. ○