Effectiveness of the use of platelet-rich fibrin associated with open flap debridement compared to open flap debridement alone for the treatment of periodontal intrabony defects: Overview of systematic reviews

Abstract

In the recent years, platelet-rich fibrin (PRF) has gained importance in regenerative medicine due to its attributed tissue-inducing properties. However, it is still unclear whether there are benefits from using PRF with open flap debridement (OFD) for the treatment of intrabony defects compared to OFD alone. For this reason, in this study, we performed an overview of systematic reviews with Friendly Summaries of the Body of Evidence using Epistemonikos methodology on the use of PRF with OFD compared to OFD alone for the treatment of intrabony defects. We performed a systematic search in the Epistemonikos database. We extracted data from the included systematic reviews and reanalyzed the data of primary studies and generated a summary of the findings table. We used Review Manager (RevMan) v5.3 software and GRADEpro software for data analysis and data presentation. Eighteen systematic reviews were included after full-text screening, which had 16 clinical trials. Results were reported by the mean difference (MD); the following outcomes were analyzed: change in intrabony defect depth (MD: 1.37 mm more), change in radiographic bone defect filling (MD: 37.26% more), change in probing depth (MD: 1.22 mm more), change in clinical attachment level (MD: 1.32 mm more), and change in gingival margin level (MD: 0.31 more). We concluded that applying PRF with OFD to treat an intrabony defect has some clinical advantages compared to OFD alone.

INTRODUCTION

Periodontitis is a chronic infectious disease that causes damage to periodontal tissues.[1] One of its consequences is alveolar bone resorption, which generates horizontal or vertical bone defects and supra- or intrabony defects, causing mobility and tooth loss.[2]

To treat intrabony defects, there are different periodontal surgical techniques[3] that involve various types of biomaterials such as bone grafts, membranes, platelet concentrates, growth factors, enamel matrix proteins, root surface demineralization, and guided tissue regeneration.[4] These procedures aim to induce an osteogenic effect to promote periodontal regeneration.[5]

Platelet-rich plasma and platelet-rich fibrin (PRF) have gained importance in regenerative medicine over the last two decades.[6] These platelet concentrates improve soft-tissue healing and produce periodontal regeneration through their tissue-inducing properties.[7] In addition, several studies highlight the role of PRF as an attachment promoter between bone and graft, and as a scaffold that facilitates regeneration,[8,9] wound closure, and mucosal healing.[10]

Open flap debridement (OFD) consists in the use of various periodontal flap techniques with intrasurcal incisions. The aim is to allow a better access to periodontal pockets and bone defects, adequate root debridement, and to promote periodontal regeneration.[11] OFD is used to treat intrabony defects and it is also included as a control procedure in clinical trials evaluating regenerative techniques.[12]

Several current clinical trials and systematic reviews that compare OFD plus PRF with OFD alone have indicated benefits for clinical attachment level (CAL) gain, decreased probing depth (PD), reduction, or filling of the bony defect.[1,2,8-10,13-18] However, this evidence is still unclear since the fast scientific progress in periodontics on regenerative treatments have led to different conclusions on the most effective treatment for patients with intrabony defects. Likewise, many periodontic specialists continue to use periodontal regenerative treatments with different biodegradable materials of synthetic and animal origin, not considering that these biomaterials have a higher risk of infection, hypersensitivity reactions, and poor biomechanical properties.[9] Thus, it is necessary to seek the certainty of the evidence on other treatments such as the use of PRF plus OFD and other biomaterials. With the aim, periodontic specialists make their treatment decisions considering the best available evidence, together with their clinical experience.

Studies such as those performed by Ajwani et al., in 2015, Najeeb et al., in 2017, and Miron et al., in 2021, conclude that when using PRF with OFD for the treatment of II or III wall intraosseous defects compared to OFD alone, there are additional benefits for both soft and hard tissues in terms of CAL gain, decreased PD, and bony defect filling.[2,6,9] However, Arbildo et al., in 2017, and Chen et al., in 2021, mention that it is difficult to reach conclusions for this intervention due to factors such as high heterogeneity of randomized clinical trials (RCTs) and low certainty of the evidence.[1,2]

Despite several studies have been published on the effectiveness of PRF with OFD to treat intrabony defects, we did not find any recent study or overview that synthesizes all available evidence. Therefore, the aim of the present study was to synthesize the available up-to-date evidence regarding the use of PRF in combination with OFD compared to OFD alone for the treatment of periodontal intrabony defects and to evaluate its therapeutic effectiveness through various outcomes. To assess the therapeutic effectiveness in hard tissues, radiographic changes (change in intrabony defect depth [IBD] and change in radiographic bone defect filling) will be evaluated. On the other hand, the effectiveness in soft tissues will be evaluated through the change in PD, change in CAL, and change in gingival margin level. All these parameters are considered clinically important, and they are commonly used for the evaluation of periodontal health in daily clinical practice.

METHODS

Search strategy and study selection

An overview was conducted using the Friendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE) methodology[19] to synthesize the best available evidence on the use of PRF when performing periodontal regeneration for the treatment of intrabony defects, which was our research question based on the Population, Intervention, Comparison, and Outcome strategy – population (P): chronic periodontitis patients with one or more intrabony defects; intervention (I): PRF; comparison (C): conventional OFD; and outcomes (O): bone defect reduction distance (IBD), PD, CAL, and gingival margin level.

Furthermore, to answer the question, a systematic search was conducted in the Epistemonikos’s database of systematic reviews, which brings data from multiple sources, including MEDLINE, EMBASE, Cochrane Library, and LILACS.[20] In addition, we searched in LILACS, PubMed/MEDLINE, and Cochrane Library for studies that were not initially included through Epistemonikos. In all searches, there were no language restrictions. Articles were included until June 13, 2022.

The main terms used for the search were “intrabony defects,” “intrabony,” “intrabone,” “intrabon*,” “PRF membrane,” “PRF,” “fibrin membrane,” “PRF,” and “fibrin” [Appendix 1]. Duplicate articles were manually removed through Mendeley v1.19.8 software (Elsevier, Amsterdam, Netherlands).

Eligibility criteria

Only systematic reviews that met the following criteria were included: studies of adult patients with chronic periodontitis with one or more bone defects who had received OFD together with PRF as therapy or OFD alone. Exclusion criteria included systematic reviews involving clinical trials to evaluate patients with systemic disease or with pregnancy or lactation in the case of women; or smokers or users of drugs known to affect periodontal therapy outcomes.

Data extraction and management

Two authors (OJPM, JMPV) independently screened systematic reviews for eligibility by title and abstract, followed by a full text screening. Primary studies from the systematic reviews that met the inclusion criteria were selected for data extraction. Any disagreement between the two authors was resolved by discussion and consensus with arbitration of a third author (CMMG) when necessary. A matrix in the XLSX format was used as an instrument for data collection using the Microsoft Excel program, which included the search strategy, characteristics of systematic reviews and primary studies, assessment of the risk of bias for primary studies, and relevant dichotomous or continuous outcomes. Review Manager (RevMan) v5.3 (The Cochrane Collaboration, London, United Kingdom) software was used for data analysis, and GRADEpro software (McMaster University and Evidence Prime Inc, Ontario, Canada) software was used to evaluate the certainty of the evidence. In addition, a Summary of Findings table (SoF table) was generated, following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The research protocol is available on request from the corresponding author.

Statistical analysis

RevMan v5.3 software was used to add the extracted data. Regarding the measures of treatment effect, only outcomes with continuous data were included. A meta-analysis for each outcome was generated using a random-effects model and inverse-variance weighting. Results were reported by the mean difference (MD), and they were calculated with 95% confidence intervals (CIs). The unit of analysis for all predefined outcomes was the periodontal sites of therapeutic intervention. We assessed a statistical heterogeneity in each meta-analysis using the Tau², I², and Chi-square statistic tests. Heterogeneity was considered substantial if the I² was >75% and if either Tau² was greater than zero or if there was a low P value (<0.50) in the Chi-square test for heterogeneity [Appendix 2].

For findings’ interpretation and to rate the certainty of evidence, we used the GRADE approach and GRADEpro software. The overall certainty of evidence was assessed for each outcome by downgrading the evidence from “high certainty” to “moderate,” “low,” or “very low” according to each domain of GRADE approach, including risk of bias, indirectness of evidence, inconsistency, and imprecision of effect estimates.

RESULTS

The systematic search brought a total of 1589 articles, of which 257 were duplicates. 1332 articles were then screened by title and abstract and 18 studies were included for full-text screening. Eleven systematic reviews were finally included to develop this FRISBEE overview,[1,2,8-10,13-18] which subsequently included 16 RCTs [Figure 1].[21-36]

Figure 1.

PRISMA flowchart of systematic reviews’ selection process and included studies. n – number of registers

All studies included systemically healthy adult patients with chronic periodontitis and at least one bone defect larger than 3 mm. Of the 16 trials, 11 analyzed bone defects in vital teeth,[21-25,27-30,34,35] one in nonvital teeth,[32] and four did not specify whether they analyzed vital or nonvital teeth.[26,31,33,36]

All trials compared the use of OFD associated with PRF versus OFD alone when performing periodontal regeneration for the treatment of intrabony defects. Follow-up ranged from nine[21-26,28-31,33,35,36] to 12 months.[27,32,34]

The trials measured multiple outcomes, which were grouped by systematic review as follows:

1. Change in IBD in millimeters (baseline – 9–12-month follow-up)

2. Change in radiographic bone defect filling (baseline – 9–12-month follow-up)

3. Change in PD (baseline – 9–12-month follow-up)

4. Change in CAL (baseline – 9–12-month follow-up)

5. Change in gingival margin level (baseline – 9–12-month follow-up).

Information regarding the effects of PRF for the treatment of intrabony defects was based on 16 RCTs involving 742 periodontal sites of therapeutic intervention in 634 patients [Table 1], which included young people and adults aged between 17 and 55 years.

Table 1.

Summary of Findings table using the Grading of Recommendations, Assessment, Development, and Evaluation approach

Use of PRF compared to OFD alone for the treatment of intrabony defects
Patient or population: Patients with chronic periodontitis with at least one intrabony defect Intervention: PRF Comparison: OFD alone
Outcomes	Absolute effects*		Relative effect (95% CI)	Certainty of the evidence (GRADE)
	With OFD	With PRF
Change in IBD (9-12-month follow-up)	0.80 mm	2.17 mm	-	⨁⨁ Lowa,b
	MD 1.37 mm more (0.74-2.0 more)
Change in RBF (9-12-month follow-up)	10.48%	47.74%	-	⨁⨁ Lowa,c
	MD 37.26% more (33.81-40.72 more)
Change in PD (9-12-month follow-up)	2.7 mm	4.19 mm	-	⨁ Very lowa,d,e
	MD 1.22 more (0.98-1.47 more)
Change in CAL (9-12-month follow-up)	2.49 mm	3.81 mm	-	⨁ Very lowa,e,f
	MD 1.32 more (1.0-1.64 more)
Change in gingival margin level (gingival recession)	−0.17 mm	0.14 mm	-	⨁ Very lowa,e,g,h
	MD 0.31 more (0.18-0.44 more)

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ^aThe certainty of the evidence was downgraded in one level for risk of bias since in most of the included trials were not blinded to either participants or personnel. Furthermore, in some trials, the generation of randomization sequence and its concealment are not clear and have selective reporting; ^bThe certainty of evidence was downgraded in one level due to inconsistency since the meta-analysis presents heterogeneity (I2: 99%); ^cThe certainty of evidence was downgraded in one level due to inconsistency since the meta-analysis presents heterogeneity (I2: 96%); ^dThe certainty of evidence was downgraded in one level due to inconsistency since the meta-analysis presents heterogeneity (I2: 86%); ^eThe certainty of evidence was downgraded in one level due to imprecision since each end of the confidence interval leads to a different decision; ^fThe certainty of evidence was downgraded in one level due to inconsistency since the meta-analysis presents heterogeneity (I2: 90%); ^gThe certainty of evidence was downgraded in one level due to inconsistency since the meta-analysis presents heterogeneity (I2: 96%); ^hThe certainty of evidence was downgraded in one level due to the indirectness of evidence, as it corresponds to a surrogate outcome. GRADE working group grades of evidence - High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low certainty: we have a very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. Follow the link to access the interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_bb2aa43f-cec4-4ed5-a4c8-3e71d89c8fc6-1650671278373. PRF – Platelet-rich fibrin; OFD – Open flap debridement alone; SD – Standard deviation; CI – Confidence interval; MD – Mean difference; PD – Probing depth; IBD – Intrabony defect depth; RBF – Radiographic bone defect filling; CAL – Clinical attachment level; GRADE – Grading of Recommendations, Assessment, Development, and Evaluation; iSOF – Interactive Summary of Findings

All trials measured the change in PD and the change in CAL. Thirteen trials in the study evaluated the change in IBD in millimeters (626 sites, 518 patients),[21-23,25,26,28-33,35,36] 10 trials assessed the outcome mean change in radiographic bone defect filling (526 sites, 418 patients),[22,24-28,30,31,33,34] and 11 trials measured the change in gingival margin level (512 sites, 441 teeth).[21,23,24,26,28,30-35] There was no clinical trial that reported infection and treatment failure events as outcomes.

Regarding the main results:

1. The use of PRF associated with OFD compared to OFD alone could increase the change in IBD during follow-up and baseline (MD: 1.37 mm; 0.74–2.0 more), which means that the use of PRF associated with OFD could help in bone regeneration and decrease IBD more effectively than the use of OFD alone (low certainty of evidence)

2. The use of PRF associated with OFD compared to OFD alone could increase the change in radiographic bone defect filling (MD: 37.26%; 33.81–40.72 more), which means that there is some evidence regarding the advantage in the use of PRF associated with OFD compared to OFD alone (low certainty of evidence)

3. It is unclear whether the use of PRF associated with OFD compared to OFD alone decreases PD because the certainty of the evidence has been assessed as very low

4. It was not possible to establish whether the use of PRF associated with OFD compared to OFD alone increases the change in CAL because the certainty of the evidence has been assessed as very low

5. It is unclear whether the use of PRF associated with OFD compared to OFD alone modifies the level of the gingival margin because the certainty of the evidence has been assessed as very low.

DISCUSSION

The results of this study are applicable to all patients with chronic periodontitis and bone defects >3 mm around permanent teeth. Our study evaluated five outcomes; four of which were considered critical when evaluating periodontal bone regeneration, such as changes in IBD, in radiographic bone defect filling, in PD, and in CAL. In addition, the change in gingival margin level was evaluated as a surrogate outcome because the identified systematic reviews also reported this outcome even when the objective of the intervention was the regeneration of the intrabony defect.

According to our research, the clinical benefits of using OFD plus PRF for the treatment of intrabony defects confirm previous clinical observations related to increased intraosseous fill depth and increased radiographic bone fill. Several authors including Miron et al., 2021, Castro et al., 2017, Cid, 2017, and Verma et al., 2017, stated that PRF provides leukocytes, platelets, and growth factors (recombinant human platelet-derived growth factor).[16,18,37,38] In addition to decreasing the production of proinflammatory cytokines,[16] which favor angiogenesis, the elimination of bacteria and improved clinical results for bone formation and filling,[18] which overall confirm our results.

For the outcomes of decreased PD, change in CAL, and gingival margin gain, the benefits of using OFD plus PRF are not clear enough, because the certainty of the evidence was low to very low (GRADE approach) for the reviews studied. Regarding the clinically observed results, Li et al., in 2019, and Cid, 2017, indicated gains in PD and CALs.[10,37] Furthermore, Li et al., in 2019, Arbildo et al., in 2017, and Almutairi in 2017 showed that by adding PRF to coating treatments for gingival recessions and intrabony defects,[1,39,40] there was clinical improvement in both root coverage with gain of the gingival margin and decrease in the depth of probing, hence the level of clinical attachment. Therefore, when comparing the results according to the evidence versus what was clinically observed, it is inferred that the use of PRF as an adjuvant in the treatment of infrabony defects reduces inflammation and pain as well as improves the regeneration of soft and hard tissues.

When applying the GRADE methodology criteria, there were problems with the risk of bias, inconsistency, and imprecision domains. Several trials had a high risk of bias due to inadequate blinding of participants and evaluators,[23,25-27,29,30,32-35] and the allocation concealment in randomization was not clear.[25,26,28-30,33-35] Furthermore, a high heterogeneity in the magnitude of the effect was reported in six outcomes with an I2 ranging from 86% to 99%. In terms of imprecision, three clinical trials suggested different conclusions regarding the therapeutic efficacy of the use of PRF in association with OFD due to the extreme values of the CIs.[21,33,31] However, the strength of this study was the large sample size, since between 512 and 742 periodontal sites of therapeutic intervention were included for the analysis of each outcome.

Our conclusions are consistent with nine of the identified systematic reviews, which showed the clinical advantages of PRF in association with OFD in terms of changes of PD, insertion level gain, and radiographic bone defect filling.[1,2,8-10,13,15-17] Our study does not agree with the conclusion of the review by Baghele et al., in which all periodontal clinical parameters have a negligible gain except for radiographic bone defect filling.[13] In the same way, our study does not agree with the results of change in the gingival margin from three of the included reviews,[1,2,10] as we found no evidence that the use of PRF has clinical relevance on gingival margin gain. Nevertheless, the review performed by Shah et al.[15] reached the same conclusion, despite the certainty of the evidence of these therapeutic effects is low for the change in IBD and radiographic bone defect filling, and very low for the change in PD and CAL. For this reason, it is necessary to perform new clinical trials with better randomization and blinding protocols to obtain a more reliable conclusion.

In addition, using the keywords described in the methods section, we identified 12 ongoing RCTs on this topic on the World Health Organization’s International Clinical Trials Registry Platform and on clinical trials.gov.[41-52] Furthermore, we identified 19 ongoing systematic reviews in the National Institute for Health Research’s International Prospective Register of Systematic Reviews (PROSPERO)[53-71] about the use of autologous platelet concentrates in the periodontal therapy of intrabony defects that, in the future, could provide relevant evidence about the clinical question raised in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Appendix

Appendix 1.

Search strategy performed in the different databases

Databases	Search details
Epistemonikos	title:((title:(intrabony%20defects)%20OR%20abstract:(intrabony%20defects))%20OR%20(title:(intrabony)%20OR%20abstract:(intrabony))%20OR%20(title:(intrabone)%20OR%20abstract:(intrabone))%20OR%20(title:(intrabon*)%20OR%20abstract:(intrabon*))%20AND%20(title:(PRF%20membrane)%20OR%20abstract:(PRF%20membrane))%20OR%20(title:(PRF)%20OR%20abstract:(PRF))%20OR%20(title:(fibrin%20menbrane)%20OR%20abstract:(fibrin%20menbrane))%20OR%20(title:(Platelet-rich%20fibrin)%20OR%20abstract:(Platelet-rich%20fibrin))%20OR%20(title:(fibrin)%20OR%20abstract:(fibrin)))%20OR%20abstract:((title:(intrabony%20defects)%20OR%20abstract:(intrabony%20defects))%20OR%20(title:(intrabony)%20OR%20abstract:(intrabony))%20OR%20(title:(intrabone)%20OR%20abstract:(intrabone))%20OR%20(title:(intrabon*)%20OR%20abstract:(intrabon*))%20AND%20(title:(PRF%20membrane)%20OR%20abstract:(PRF%20membrane))%20OR%20(title:(PRF)%20OR%20abstract:(PRF))%20OR%20(title:(fibrin%20menbrane)%20OR%20abstract:(fibrin%20menbrane))%20OR%20(title:(Platelet-rich%20fibrin)%20OR%20abstract:(Platelet-rich%20fibrin))%20OR%20(title:(fibrin)%20OR%20abstract:(fibrin))))&protocol=no#
PubMed/Medline	(((((((((((((Intrabony defects) OR (Intrabony)) OR (intrabone)) AND (bone graft)) OR (bone grafting)) OR (Bone grafts)) OR (bone regenaration)) OR (Grafts)) OR (bone replacement grafts)) AND (Platelet-rich fibrin)) OR (fibrin menbrane)) OR (fibrin)) OR (Prf)) OR (Prf membrane)
LILACS	(intrabony defects) AND (bone grafts) AND (prf membrane)
	ID	Search
Cochrane Library	#1	Intrabony defects
	#2	Intrabony
	#3	Intrabone
	#4	Intrabon*
	#5	(#1) or (#2) or (#3) or (#4)
	#6	Grafts bone
	#7	Grafts
	#8	Bone grafting
	#9	Bone replacement grafts
	#10	(#6) or (#7) or (#8) or (#9)
	#11	(#5) and (#10)
	#12	PRF membrane
	#13	Fibrin
	#14	PRF
	#15	Fibrin membrane
	#16	Platelet-rich fibrin
	#17	(#12) or (#13) or (#14) or (#15) or (#16)
	#18	(#11) and (#17)

APPENDIX 2.

META-ANALYSIS GRAPH FOR EACH OUTCOME