DERJ DERJ Dent Res J Dent Res J Dental Research Journal 1735-3327 2008-0255 Wolters Kluwer - Medknow India DERJ-21-63 00002 10.4103/drj.drj_437_22 2 Review Article Efficacy of autologous platelet concentrates for root coverage of Miller’s Class I and II gingival recession defects: A systematic review and meta-analysis Yaghini Jaber 1 Mogharehabed Ahmad 1 Feizi Awat 2 Yazdanfar Fatemeh 3 fatmayz1374@gmail.com Department of Periodontology, Dental Implant Research Center, Dental Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran Department of Epidemiology and Biostatistics, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran Department of Periodontology, Dental Student’s Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran Address for correspondence: Dr. Fatemeh Yazdanfar, Department of Periodontology, Dental Student’s Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran. E-mail: fatmayz1374@gmail.com 11 2024 26 11 2024 21 1 63 29 06 2022 05 04 2024 22 08 2024 Copyright: © 2024 Dental Research Journal 2024 This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License (http://creativecommons.org/licenses/by-nc-sa/4.0/), which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ABSTRACT Background:

This systematic review and meta-analysis aimed to assess the efficacy of autologous platelet concentrate (APCs) in comparison with coronally-advanced flap alone or in combination with connective tissue graft or other biomaterials or bioactive agents for root coverage (RC) of Miller’s Class I and II gingival recession defects by measuring the keratinized mucosa width (KMW).

 Materials and Methods:

This systematic review and meta-analysis was conducted in accordance with the preferred reporting items for systematic reviews and meta-analysis guidelines. An electronic search of the literature was conducted in PubMed, EMBASE, Scopus, Cochrane, Web of Science, Magiran, Scientific Information Database, and Irandoc for randomized clinical trials (RCTs) that used APCs for RC in their intervention group. Eligible articles were retrieved by assessment of titles and abstracts and then the full texts. The risk of bias was assessed by the Cochrane Library Risk of Bias Assessment Tool. Meta-analysis was carried out by RevMan 5.3 software. In the case of homogeneity, variables were reported as weighted mean difference (WMD) with 95% confidence interval (CI) for each group.

 Results:

The search yielded 689 articles; out of which, 32 were eligible for study inclusion. Meta-analysis did not show any additional effect for RC and KMW with APCs. Clinical parameters were as follows: RC: WMD = −1.57 mm (95% CI: −2.49, −0.659; P = 0.001) and KMW: −0.106 mm (95% CI: −0.3222, 0.110; P = 0.337).

 Conclusion:

The application of APCs for RC of Miller’s Class I and II gingival recession defects does not seem to improve the clinical parameters.

 Key Words: Gingival recession mucogingival surgery periodontal plastic surgery platelet-rich fibrin root resorption OPEN-ACCESS TRUE INTRODUCTION

Gingival recession refers to apical displacement of the gingival margin and exposure of the cementoenamel junction and root surface to the oral cavity.[1] Several factors are responsible for gingival recession and denuding of root surfaces, such as periodontal disease, mechanical forces applied by incorrect toothbrushing, iatrogenic factors, faulty restorations and crowns in contact with the gingival margin, and anatomical factors such as tooth malposition and abnormal frenal attachments.[2-4]

Following the gingival recession, denuded root surfaces are exposed to the oral environment, which makes them highly susceptible to erosion and caries, hypersensitivity, and esthetic problems.[5]

A systematic review indicated that gingival recession defects that were left untreated progressed in the long term in patients with good oral hygiene.[6] Complete root coverage (RC) for the treatment of gingival recession provides a homogenous appearance and decreases the probing depth.[7] However, several factors need to be considered for the selection of surgical techniques. Among different surgical techniques, coronally advanced flap (CAF) is a commonly adopted method for RC in case of the presence of adequate keratinized mucosa width (KMW). CAF in combination with connective tissue graft (CTG) is the gold standard for RC and brings about the most favorable results in patients without proximal attachment loss.[8-11]

The alternative treatment options for CTG include different biomaterials and bioactive agents that were introduced over the past years aiming to minimize patient morbidity. For instance, several types of collagen-based membranes and dermal tissue derivatives with allograft or xenograft origin were introduced for RC. Despite the fact that such alternative materials provide an excellent 3D network for the migration and proliferation of fibroblasts, they have drawbacks such as limited regenerative potential and lack of long-term tissue keratinization.[12] Recently, different types of membranes derived from placental tissue were suggested for enhanced bioactivity; however, information regarding their long-term application is scarce.[13,14] Another strategy is to use regenerative growth factors alone or in combination with CTG or collagen membranes to induce the regenerative potential of fibroblasts at the defect site. Enamel matrix derivative (EMD) is among such materials. Animal and human studies have reported positive clinical and histological results for EMD in combination with CAF.[15,16]

Researchers have recently focused on the development of regenerative treatments with an autologous origin that decrease the risk of cross-contamination and are cost-effective. These investigations led to the development of autologous platelet concentrates (APCs) by Choukroun et al.[17] Attempts are ongoing to find alternatives to CTG. The use of biomaterials such as acellular dermal matrix, collagen membranes, or EMD has some limitations due to the high cost and clinical conditions of patients.[18] APC is a new biomaterial, the efficacy of which needs to be investigated in prospective trials with long follow-up periods. The predictability of RC with APC, its effects on healing, and the molecular mechanisms of its function have yet to be fully elucidated.[19] Furthermore, the effects of APC are often compared with CTG, and other alternatives have not been assessed. Considering the diversity of APC products and the controversial results regarding their efficacy, this systematic review and meta-analysis were conducted to assess the efficacy of APCs for RC in Miller’s Class I and II gingival recession defects by measuring the clinical parameters such as RC and KMW, in comparison with other therapeutic modalities. Using these materials, there will be no need for autogenous intraoral soft-tissue grafts, thereby reducing patient discomfort and morbidity, leading to increasing quality of their lives. On the other side, concentrated growth factors in APCs are promising in long-term outcome stability and comparable results with conventional methods.

 MATERIALS AND METHODS Population, intervention, comparisons, and outcome protocol

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) checklist.[20] The study was approved by the ethics committee of Isfahan University of Medical Sciences (IR.MUI.RESEARCH.REC.1400.398).

The study question was designed according to the population, intervention, comparisons, and outcomes as follows:

Population (P): Patients with Miller’s Class I and II gingival recession defects. Intervention (I): Use of APCs. Comparison (C): CAF alone or in combination with CTG, or other biomaterials and bioactive agents. Outcomes (O): RC and KMW. Study design (S): Randomized clinical trials (RCTs).

 Focused question

The focused question of the study was that “whether APCs, in comparison with CAF alone or in combination with CTG, or other biomaterials and bioactive agents can improve RC and KMW in patients with Miller’s Class I and II gingival recession defects.”

 Search strategy

An electronic search was conducted in PubMed, EMBASE, Scopus, Cochrane, Web of Science, Magiran, Scientific Information Database (SID), and Irandoc. Furthermore, the bibliography of previous systematic reviews was searched [Supplementary File 1 and Supplementary Table 1].

 Eligibility criteria Inclusion criteria

Teeth with Miller’s Class I and II gingival recession defects confirmed by radiography and clinical examination. Studies in which the test group received APC (all types of APCs) + CAF and the control group received CAF alone or in combination with CTG or biomaterial and Articles in English or Farsi.

 Exclusion criteria

Animal or in vitro studies, case reports, and case series, follow-up <6 months, and patients under orthodontic treatment.

 Data extraction

The eligibility of the articles retrieved from the electronic search was evaluated by two independent examiners (J.Y. and A.M.). The titles and abstracts were evaluated to eliminate irrelevant articles. Next, the full texts were independently assessed by the two examiners. Disagreements were resolved by discussion. Concordance between the two examiners was evaluated by the Cohen’s kappa coefficient. Data were extracted according to predesigned forms. In case of missing data, correspondence was performed with the corresponding author. Table 1 presents the extracted data items. The outcomes included RC and KMW after treatment compared with baseline.

General characteristics of included studies in the meta-analysis

 Risk of bias assessment

Assessment of the risk of bias was conducted according to the Revised Cochrane Risk of Bias Tool for Randomized Trials. Based on the risk of bias in all six items, each article was categorized as having a low risk of bias if it had a low risk of bias in all six items, high risk of bias if it had a high risk of bias in at least one item, or unclear risk of bias if at least one item had unclear risk of bias.

To assess the publication bias, the funnel plots were drawn to assess the symmetry of each variable according to the Cochrane Handbook for Systematic Reviews of Interventions.[21]

 Assessment of treatment effect

The weighted mean difference (WMD; change score) and 95% confidence interval (95% CI) were calculated for each variable in each treatment group. Data were reported in millimeters for all four variables.

 Statistical analysis

The random effect model was used for pooling data using RevMan 5.3 software. Data from split-mouth and parallel design RCTs were analyzed separately and also in combination.

 RESULTS Selection of studies

A total of 788 articles were retrieved from the eight databases as follows: PubMed (167 articles), ISI (Web of Science) (152 articles), Scopus (157 articles), EMBASE (141 articles), Cochrane (130 articles), SID (15 articles), Magiran (22 articles), and Irandoc (2 articles). A manual search also yielded one thesis. Of all, 540 were duplicates and excluded. Assessment of title and abstract of articles yielded 42 relevant articles. After reading the full text of the articles, 7 were excluded since they were case reports or case series, 2 were excluded due to language other than English and Farsi, and one was excluded due to the absence of a control group. Finally, 32 articles underwent qualitative and quantitative analysis [Figure 1]. Studies with more than 1 control group were included as separate records in the meta-analysis.

Selection of studies.

 Descriptive findings

This meta-analysis on the efficacy of APCs for RC evaluated 32 studies on RC and 31 studies on KMW. Table 1 presents the characteristics of the included studies.

 Analytical findings Root coverage

A total of 32 articles regarding RC underwent meta-analysis. Considering the I2 statistics and Cochrane test which were significant for heterogeneity (P < 0.001), the random-effect model was applied to pool the results of studies. Studies with a control group (CTG + CAF, CAF, modified coronally-advanced flap [MCAF], and amniotic membrane + CAF) and an intervention group (platelet-rich fibrin [PRF] + MCAF, PRF + CAF, PRF + ammonitic membrane) were compared regarding RC. The results showed no significant difference between the intervention and control groups in RC [Figure 2; WMD = 0.023 mm, 95% CI: −0.118, −0.15; I2 = 99.3%, Z = 0.32, P = 0.751].

Comparison of the intervention and control groups regarding root coverage.

Publication bias of articles regarding RC was evaluated by the funnel plot and Begg and Egger’s test. Although the results showed no significant difference (P > 0.05) and confirmed the absence of publication bias, the funnel plot was not symmetrical. Thus, to control for the negative effect of publication bias on the results, the Trim and Fill technique was applied, which changed the results, and revealed a significant difference between the intervention and control groups regarding RC in favor of the control group (WMD = −1.57 mm, 95% CI: −2.49, −0.659; Z = −3.371, P = 0.001; P for Egger’s test = 0.376 and P for Begg’s test = 0.858).

To control for the negative effect of duration of follow-up, age, number of surgical sites, and blood volume obtained for centrifugation as confounders on the difference in RC between the intervention and control groups, meta-regression analysis was performed, which showed no significant difference between the two groups after this adjustment (F [3,13] = 0.90, P = 0.4899). Accordingly, none of the abovementioned variables had a confounding effect on the difference between the two groups regarding RC.

A detailed subgroup analysis was conducted to assess the impact of various qualitative variables on the differences in RC between the intervention and control groups. The results of this analysis, including additional statistical details and findings, are provided in the Supplementary File 1. Sensitivity analysis revealed that none of the studies had a significant effect on the pooled standardized mean difference (SMD).

 Keratinized mucosa width

Thirty-one studies regarding KMW underwent meta-analysis. The I2 statistic and Cochrane test results were significant for heterogeneity (P < 0.001). Thus, the random-effect model was applied to pool the results of studies. Studies with the control groups of CAF, CTG + CAF, amniotic membrane + CAF, and MCAF and the intervention groups of PRF + MCAF, amniotic membrane + PRF, and PRF + CAF underwent meta-analysis. The results revealed no significant difference in KMW between the intervention and control groups [Figure 3, WMD = −0.106 mm, 95% CI: −0.322, 0.110; I2 = 99.7%, Z = 0.96, P = 0.337].

Comparison of the intervention and control groups regarding keratinized mucosa width.

Publication bias regarding KMW was evaluated by the funnel plot and Begg and Egger’s test. Although the results showed no significant difference (P > 0.05) and confirmed the absence of publication bias, the funnel plot was not symmetrical. Thus, to control for the negative effect of publication bias on the results, the Trim and Fill technique was applied, which changed the results, and showed a significant difference between the control and intervention groups regarding KMW in favor of the control group (WMD = −0.418 mm, 95% CI: −0.704, 0.132; I2 = 99.7%, Z = −2.867, P = 0.004; P for Egger’s test = 0.145 and P for Begg’s test = 0.760).

To control for the negative effect of duration of follow-up, age, number of surgical sites, and blood volume obtained for centrifugation as confounders on the difference in KMW between the intervention and control groups, meta-regression analysis was performed, which showed no significant effect of these variables on the results (F [4,13] = 1.01, P = 0.4399). Accordingly, none of the abovementioned confounding variables had a significant effect on the observed difference in KMW between the two groups.

Details on the subgroup analysis of KMW differences between intervention and control groups are available in the Supplementary File 2. Sensitivity analysis showed that none of the studies had a significant effect on pooled SMD.

 Qualitative assessment

Table 2 presents the risk of bias in the reviewed studies.

Risk of bias in the reviewed studies

 DISCUSSION

It has been reported that CAF in combination with APC may show a higher success rate compared with other techniques that include the application of APC.[22-25] The focused question of this systematic review and meta-analysis was that whether APCs, in comparison with CAF alone or in combination with CTG, or other biomaterials and bioactive agents can improve RCand KMW in patients with Miller’s Class I and II gingival recession defects. The search yielded 689 articles; out of which, 32 were eligible for study inclusion. Meta-analysis did not show any additional effect for RC and KMW with APCs. Clinical parameters were as follows: RC: WMD = −1.57 mm (95% CI: −2.49, −0.659; P = 0.001) and KMW: −0.106 mm (95% CI: −0.3222, 0.110; P = 0.337).

The current meta-analysis included all types of APCs used as biomaterial in the intervention group and all different types of treatments performed for the control groups without the use of APC, making it a comprehensive systematic review. Subgroup analyses were also carried out for a more in-depth assessment. However, only one RCT had a low risk of bias, and the rest of them had an unclear risk of bias. Thus, the results should be interpreted with caution. This is a common challenge because blinding of personnel in the process of preparation of APC is not possible. However, the CONSORT guideline should be precisely followed in RCTs to increase the quality and transparency of the studies.

RCTs included in this systematic review used different APC products including PRF membrane, platelet-rich plasma (PRP) along with collagen sponge as a drug carrier, and PRP gel for the intervention group. None of the studies assessed the quality or quantity of platelet products regarding the level of growth factors, cytokines, or other biomolecular components. Due to different preparation methods, the APC products may not have the same level of quality and characteristics; this issue can limit accurate interpretation of results especially since subgroup analysis based on the type of product was not performed.

The present study evaluated the effects of APC products with four techniques of MCAF, CAF, amniotic membrane + CAF, and CTG + CAF on RC and KMW. Except for two studies that used PRP, the remaining studies used PRF, which has optimal properties such as low cost, relatively simple preparation process, no need for a donor site, high concentration of cytokines, immune cells, and growth factors, and stability of sutures. The potential of these products in the reduction of postoperative symptoms and enhancement of tissue healing through induction of angiogenesis and matrix biosynthesis has been previously discussed.[26] However, relatively fast degradation and subsequently decreased release of biomolecules can interfere with the primary stability of periodontal tissue unlike CTG.[27] CAF + CTG is the gold standard for RC.[28,29]

With respect to the effect of APC on RC, the results showed statistically superior outcomes in the control groups that did not use APC; although the clinical significance of this finding is questionable. This result was in contrast to the findings of previous systematic reviews. Li et al.[30] compared three types of APCs with CAF; out of which, PRF and concentrated growth factors showed higher efficacy, and PRP was not superior to CAF in any parameter. This result may be due to the long and sensitive preparation process and the need for the addition of artificial thrombin for the preparation of PRP since the fibrin network obtained as such is not perfectly suitable for attachment of cytokines or cell proliferation, compared with PRF. In PRP, growth factors are mainly released in the first few days and this process continues for only 7 days. Furthermore, the 3D fibrin network of PRF improves cell proliferation and migration and protects the growth factors against proteolysis for a longer period of time. Release of growth factors continues for 21 days. Moreover, it contains a higher number of white blood cells. Such structural superiorities of PRF over PRP are probably responsible for superior results regarding RC.[31-33] However, high heterogeneity, type of teeth, APC preparation protocol, duration of follow-up, and a limited number of reviewed studies are the drawbacks of the study by Li et al.[30] Miron et al.,[34] only compared PRF + CAF with CAF alone, Li et al.[30] compared CAF alone and in combination with APC, and Panda et al.[35] compared L-PRF and CAF; however, no comparison was made between CTG as the gold standard with PRF, and single and multiple recession defects were analyzed all in one group. Mancini et al.[19] compared L-PRF and CAF alone and reported improvement of RC by APC. However, Del Fabbro et al.[36] reported no improvement in any parameter with APC. Platelet-derived growth factors have a short half-life. Thus, it appears that APCs only affect the very early stages of bone and soft-tissue healing and can enhance tissue regeneration and healing only in the very 1st weeks after surgery. Thus, studies with a shorter follow-up probably report better results for APC compared with those with longer follow-ups. However, in the present study, the follow-up time had no significant effect on any parameter. Tooth position, baseline KMW and gingival thickness (GT), and papillary dimensions can also affect the results.[37,38] Moreover, the success of CAF depends on the postoperative position of the displaced flap margin. More coronal suturing of the gingival margin increases the possibility of achieving a complete RC.[39] Most studies did not report the magnitude of coronal displacement of gingival margin postoperatively. Panda et al.[35] found no significant difference between CAF and L-PRF + CAF in complete RC but mentioned high heterogeneity of the results. It appears that the magnitude of coronal displacement of the gingival margin should be taken into account in future studies.

Subgroup analysis showed similar results between the control and intervention groups regarding study design (split-mouth versus parallel) and centrifugation protocol (speed and time). RC was greater in the control group in studies on single recession defects in the maxilla and maxillary anterior region. RC was greater in CAF alone compared with CAF + APC. However, RC was greater in CAF + APC compared with CAF + CTG. In the present study, subgroup analysis on different APC products was not performed, which may explain the difference between the present results and the findings of previous systematic reviews. Also, no significant difference was noted between the intervention and control groups in RC in studies with high and unclear risk of bias, and there was only one study with low risk of bias.

Regarding the effect of APCs on KMW, the findings showed inferior results in APC groups compared with the control groups. Furthermore, the control group showed superior results in multiple recession defects. This result was in contrast to the findings of Mancini et al.,[19] who reported higher KMW in multiple recession defects in the APC group compared with CAF alone. They discussed that superior results in the CAF + CTG group compared with the intervention group in KMW were due to the fact that CTG serves as a scaffold, and increases the blood clot stability and GT, resulting in stability of the outcome in the long term. Moreover, induction of keratinization of the superficial epithelium by CTG explains higher KMW.[38-40] However, the present study found no significant difference between CAF + CTG and CAF + PRF. Furthermore, superior results were obtained in the control group regarding KMW in the anterior and maxillary canine/premolar regions and 2700 rpm/12 min centrifugation protocol. However, a previous study showed that a lower speed of centrifugation was associated with higher content of cells and growth factors.[41] In contrast, superior results were noted in the intervention group in the maxilla and maxillary anterior region. In comparison of CAF and MCAF alone or along with PRF, greater KMW was noted in the PRF group, which was in line with the results of Li et al.,[30] Akhtar et al.,[42] and Moraschini et al.,[43] and different from the results of Miron et al.,[34] Panda et al.,[35] Del Fabbro et al.,[36] and Rodas et al.[44] On the other hand, the effect of PRF on the proliferation of keratinocytes has been confirmed in vitro,[45] but the present study found no significant difference in this parameter. No consensus exists regarding the KMW required for periodontal health. Furthermore, KMW affects the selection of surgical technique, which may also explain the variations in the results. It appears that the presence of the small amount of KMW in the use of biomaterials plus CAF brings about better results.[46]

A high number of studies with unclear and high risk of bias, and moderate and high heterogeneity of the studies were among the limitations of this study. Thus, the results should be interpreted with caution. The majority of studies had a 6-month follow-up and only one study had a 5-year follow-up. Some studies did not mention the smoking status of patients, and one study included smokers smoking less than 20 cigarettes a day. The centrifugation protocol and system had not been mentioned in some studies. Furthermore, all types of APC products were assessed in one group, and subgroup analysis was not performed for this parameter.

Future studies should include more studies with low risk of bias and longer follow-ups, if available, and perform subgroup analysis for different types of APC products.

 CONCLUSION

The results showed the superiority of the control group in RC and KMW. In total, it appears that the application of APCs for RC of Miller’s Class I and II gingival recession defects does not improve the clinical parameters. Although considering the amount of heterogeneity that exists, conclusions should be made with caution.

Financial support and sponsorship

Nil.

 Conflicts of interest

The authors of this manuscript declare that they have no conflicts of interest, real or perceived, financial or non-financial in this article.

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