1 INTRODUCTION

Gingival recession (GR) is characterized by displacement of the gingival margin below the level of cemento-enamel junction (Cortellini & Bissada, 2018). Several etiological factors like age, anatomical, physiological, pathological, trauma, hygiene, abnormal frenal attachment, and so on, were identified for this condition (Fu et al., 2012) which may account for its relatively high incidence in the population (Rios et al., 2014; Susin et al., 2004). It affects more than 50% of population including healthy individuals. Recession of 1 mm or more is prevalent in aged 30 years and older. The risk increases with age. Root exposure leads to hypersensitivity, cervical caries, aesthetics complications, and non-carious cervical lesions (Jepsen et al., 2017).

Root coverage procedures (RCP) have shown to be effective in treating single and multiple GRs (Cairo et al., 2014; Tavelli, Barootchi, et al., 2018; Tavelli, Barootchi, et al., 2019; Tavelli, Ravidà, et al., 2019), and in literature, several techniques were proposed. Nevertheless, the superiority of coronally advanced flap (CAF) combined with connective tissue graft (CTG) is clear. Indeed, CAF + CTG is a gold standard in RCP for the best outcomes achieved in terms of mean root coverage, keratinized tissue width, gingival thickness and aesthetics results (Zucchelli et al., 2020).

However, the presence of a second surgical site, patient morbidity, and limited availability are the main drawbacks that have been largely described for CTG (Tavelli, Asa'ad, et al., 2018; Tavelli, Barootchi, et al., 2019; Tavelli, Ravidà, et al., 2019). For this reason, several CTG substitutes were introduced including Platelet rich plasma (PRP) or Platelet rich fibrin (PRF), acellular dermal matrix (ADM), enamel matrix derivate (EMD), and xenogeneic collagen matrix (CMX). These biomaterials suffer from limitations in term of shape, consistency and size. PRF is a living cellular graft enriched with growth factors and it is a good alternative to CTG for the availability and the easy handling (Dohan et al., 2006; Miron et al., 2020). The ADM is soft CTG generated by a de-cellularization process preserving the extracellular skin matrix with high costs and it is not in use for ethical problems in diverse countries (McGuire et al., 2020; Tavelli et al., 2020). EMD is a porcine fetal tooth material extracted and manipulated as a gel used as an enhancer in oral regenerative procedures (McGuire & Nunn, 2003). CMX is another biomaterial, which has different layers of collagen fibers and porous layer facilitating blood clot formation and in-growth of tissue from adjacent sites (McGuire & Scheyer, 2016; Vignoletti et al., 2011).

Several studies revealed the comparison among CAF + CTG and each alternative therapy during a follow-up period of 6–12 months showing divergent results (Keceli et al., 2015; McGuire & Scheyer, 2010; Tonetti et al., 2018). According to the authors in the literature, a direct, indirect and mixed evidence for all these biomaterials contributing to the success of root coverage is not present and data extracted from non-systematic comparisons might be confusing and not well interpreted. In addition, the data from all studies are heterogeneous (differences in estimates of effect across studies that assessed the same comparison), which makes difficult to compare all materials. A conventional pairwise meta-analysis results in only one pooled effect estimate. Therefore, a novel method of weighing the effect estimate through network meta-analysis (NMA) has been proposed.

Previous network systematic reviews tried to collect data evaluating the clinical advantages for each CTG substitute with several limitations such as the follow-up period of 6-months which might be a limit, the inclusion of randomized clinical trials (RCTs) with a high risk of bias influencing results and the inclusion of RCTs with smoker patients or RCTs where the absence or presence of smoker patients was not reported (Buti et al., 2013; Moraschini et al., 2020). Thus, the purpose of this systematic review and NMA was to compare the clinical effects among patients who have one or more gingival recession sites and corrected with intervention of CTG substitutes and compared with controls or CAF alone or in combination for regeneration of keratinised gingival width (KGW), clinical attachment level (CAL), recession width (RW), recession height (RH), pocket depth outcomes during a long follow-up period.

2 MATERIAL AND METHODS

This review was performed in accordance with of PRISMA guidelines. The protocol for this review and NMA was registered in PROSPERO with registration ID: CRD42020208010.

The eligibility of study was decided based on PICO format.

Type of Patients: Patients who had one or more than one site of gingival recession was considered for assessment and further review analysis.

Type of Intervention: CAF or/and CTG Substitutes.

Type of Comparator: Compared with Placebo, Control or CAF or/and combination of CAF + biomaterials or CTG substitutes.

Type of outcomes: KGW, CAL, Recession Height, Recession Width, Pocket Depth were the outcomes.

Type of Duration: More than 6 months' follow-up periods.

2.1 Research question

What is the treatment effect of different biomaterials like CTG, EMD, ADM, PRP/PRF, CMX, and combination of these when used in adjunct to CAF for root coverage?

2.2 Search strategy

An electronic database search was carried out in PUBMED, CENTRAL, SCOPUS, and EMBASE to identify the potentially eligible articles using the following strategy:

“((((Coronally advanced flap) OR (CAF)) OR (modified coronally advanced flap)) OR (coronally displaced flap)) AND ((((((((((((Enamel matrix derivative) OR (Connective tissue graft)) OR (Guided tissue regeneration)) OR (Collagen matrix)) OR (Acellular dermal matrix)) OR (platelet rich fibrin)) OR (platelet rich plasma)) OR (PRF)) OR (PRP)) OR (barrier membrane)) OR (amniotic membrane)) OR (hyaluronic acid)) OR (Emdogain)) OR (CTG)).”

A manual search in periodontal journals like Journal of Clinical Periodontology, Journal of Periodontal Research, Journal of Periodontal and Implant Science, International Journal of Periodontics and Restorative Dentistry, and Journal of Periodontology. There were no limits or filters applied during the search. Both studies relevant to the topic in areas of systematic reviews and clinical trials were searched.

2.3 Inclusion criteria Randomized Clinical Trials (Both parallel and split mouth design) Study follow up duration at least 12 months Minimum sample size of 10 per group CAF procedure should be employed both in test and control group. The test group should have any of the biomaterials in adjunct to CAF compared to control group with a different biomaterial or none in adjunct to CAF. Treatment of Class 1 and 2 gingival recessions only. Both isolated and multiple recession 2.4 Exclusion criteria Studies not in English Study participants under any medication which could influence the outcome of treatment. Teeth with non-carious cervical lesions (NCCL) Animal studies 2.5 Study selection

The studies from the databases searches were compiled into citation manager to remove duplicates and screened for all titles and abstract by two independent reviewers (M.K and A.C.D). The eligible studies were then subjected to full text assessment and included for qualitative assessment. In case of disagreement or uncertainty while selecting the eligible articles, an expert third reviewer (M.D.F) was consulted until a consensus was reached. Detailed reasons were mentioned for all excluded studies.

2.6 Data extraction

The qualitative data was extracted using excel spreadsheet. The data extraction was carried out by using two independent reviewers (M.Dd, H.A.V.). In cases like missing or unclear data or need for additional data or raw data, the authors were approached through emails or telephone for enquiring the details of missing or unclear information.

2.7 Outcomes

The primary outcomes that were assessed in this review were keratinized gingival width (KGW) and the percentage of root coverage (%RC). The secondary outcomes assessed included CAL, RW, and RD.

2.8 Data synthesis

The data extracted were both qualitative and quantitative. The former were related to demographics of the study and type of publication. The quantitative data for the different outcomes allowed to undertake NMA. The NMA enables to develop a network geometry plot, where the number of studies and subjects between the comparators are projected. The risk of bias in each network was also estimated. The predictive interval plots (Prl) were calculated to predict the effects of future clinical studies incorporating heterogeneity. The surface under the cumulative ranking curve (SUCRA) was calculated for each treatment. Treatments were ranked based on their respective performances. Treatments with SUCRA values with higher percentage of being first were ranked higher and values with lower percentage were ranked lower (0–100%). The multidimensional scale ranking was employed to rank the biomaterials based on their dissimilarity. The network estimates for all comparisons are treated as proximity data aimed to reveal their latent structure. By this, the dissimilarity between any two treatments was distinguished. NMA was carried out using Stata version 16 (StataCorp, College Station, TX) by a single reviewer (S.K).

3 RESULTS

This qualitative and NMA analysis was carried out by assessing 39 RCTs analyzing the stability of CAF when used alone or in combination with different biomaterials in treatment of class I and II gingival recession defects, over at least 12 months follow-up. The electronic database search and manual search of related journals and bibliographies yielded a total of 1223 articles. The searches from different databases were imported to a citation manager (ENDNOTE) to identify 938 articles after removing duplicates. All the articles were subjected to title and abstract screening, and were narrowed down to identify 56 potentially eligible studies. These studies were subjected to detailed full text assessment by two independent reviewers. Out of 56 eligible studies, 39 RCTs were included in this systematic review and 19 were considered for NMA. The detailed process of study selection is provided in the PRISMA flow chart (Figure 1). The rest of 17 articles were excluded with detailed reason for exclusion (refer Table 1).

PRISMA flow chart diagram

TABLE 1. List of excluded studies Sl no. Study Reason of exclusion 1. Tavelli, Barootchi, et al. (2019); Tavelli, Ravidà, et al. (2019) Coronally advanced flap compared to tunnel technique 2. Stefanini et al. (2018) Not a randomized clinical trial but a case series 3. Bellver-Fernández et al. (2016) Test group has less than 10 sites 4. Wang et al. (2015) Same biomaterial used in both groups 5. Wang et al. (2014) Same biomaterial used in both groups 6. Zucchelli et al. (2014) Same biomaterial used in both groups 7. Aroca et al. (2013) Tunnel technique has been used in both the groups 8. McGuire et al. (2012) Less than 10 patients as sample size 9. Aleksic et al. (2010) Study in Russian language 10. Aroca et al. (2009) Follow up till 6 months 11. Pourabbas et al. (2009) Follow up till 6 months 12. Moses et al. (2006) Two separate procedures have been compared 13. Dominiak et al. (2006) Three separate procedures have been compared 14. Nemcovsky et al. (2004) Inclusion of cervically abraded teeth 15. Wennström et al. (1996) Non-randomized, prospective clinical study 16. Pini-Prato et al.( 2010) Non randomized study 17. Henriques et al. (2010) Class III gingival recessions 3.1 Characteristics of included studies

The demographic and interventional characteristics of all included studies are presented in Tables 2 and 3, respectively.

TABLE 2. Demographic characteristics of included studies Sl no. Author and year Study design Age in years (range, mean SD) Type of recession No. of patients No. of sites Test procedure Control procedure Follow-up 1. Barakat and Dayoub (2020) RCT split-mouth 20–45 Single 20 40 CAF + PCM CAF + CTG 12 months 2. Rotundo et al. (2021) RCT parallel > 18 Multiple 24 61 CAF + CMX

CAF

12 months 3. Aydinyurt et al. (2019) RCT split-mouth 18–55 Single 19 38 CAF + CTG + EMD

CAF + CTG

12 months 4. Pilloni et al. (2019) RCT parallel 21–47 Single 30 30

CAF + HA

CAF

18 months 5. Rotundo et al. (2019) RCT parallel > 18 Multiple 24 61

CAF + CMX

CAF

12 months 6. França-Grohmann et al. (2019) RCT parallel 29.74 Single 30 30

CAF + EMD

CAF

12 months 7. Gürlek et al. (2020) RCT split-mouth > 18 Multiple 15 82

CAF + ADM

CAF + CTG 18 months 8. Matoh et al. (2019) RCT split-mouth 21–52 Single 10 20

CAF + CM

CAF + CTG

12 months 9. Francetti et al. 2018) RCT parallel > 18 Single 20 NR

CAF + CTG

CAF 60 months 10. Kuka et al. (2018) RCT parallel 21–41 Multiple 24 52

CAF + PRF

CAF 12 months 11. Rasperini et al. (2018) RCT parallel 37–63 Single 25 25

CAF + CTG

CAF 108 months 12. Çetiner et al. (2018) RCT split-mouth 20–67 Multiple 12 84

CAF + ADM + PRP

CAF + ADM

12 months 13. Abou-Arraj et al. (2017) RCT parallel 24–74 Single 17 17 CAF + ADM-A CAF + ADM-B 12 months 14. Jepsen et al.et al. (2017) RCT split-mouth 20–73 Single 18 36 CAF + CMX CAF 36 months 15. Cairo et al. (2016) RCT parallel 20–53 Multiple 32 74 CAF + CTG CAF 12 months 16. McGuire & Scheyer, (2016 RCT split-mouth 51.3 ± 13.9 Single 17 34

CAF + CMX

CAF + CTG

60 months 17. Godavarthi et al. (2016) RCT split-mouth 41.4 ± 7.6 Single 14 28 CAF + PPG CAF + ADM 12 months 18. Stefanini et al. (2016) RCT split-mouth 39.5 ± 13.8 Multiple 45 41 CAF + CMX CAF 12 months 19. Lops et al. (2015) RCT parallel 46 Single 28 28 CAF + CTG CAF 12 months 20. Cairo et al. (2015) RCT parallel 45.9 ± 10.3 Single 24 24 CAF + CTG CAF 36 months 21. Milinkovic et al. (2015) RCT split-mouth 18–55 Both 18 36 CAF + AFCC CAF + CTG 12 months 22. McGuire et al. (2014) RCT split-mouth 29–68 Both 30 60 CAF+ rhPDGF-BB CAF + CTG 60 months 23. Ahmedbeyli et al. (2014) RCT parallel 22–40 Multiple 24 48 CAF + ADM CAF 12 months 24. Zucchelli et al. (2014) RCT parallel >18 Multiple 50 50 CAF + CTG CAF 60 months 25. Cardaropoli et al. (2014) RCT parallel 38.4 ± 11.1 Multiple 32 113 mCAF+CM mCAF 12 months 26. Alkan and Parlar (2013) RCT split-mouth 35–53 Multiple 12 56 CAF + EMD CAF + CTG 12 months 27. Kuis et al. (2013) RCT split-mouth 20–52 Multiple 37 114 CAF + CTG CAF 60 months 28. Köseoğlu et al. (2013) RCT split-mouth 19–41 Single 11 22 CAF + CMX + GF CAF + CMX 12 months 29. Roman et al. (2013) RCT split-mouth 21–28 Both 42 57 CAF + CTG + EMD CAF + CTG 12 months 30. Kumar and Murthy (2013) RCT split-mouth 18–60 Single 12 24 CAF + PCG CAF + CTG 12 months 31. Cordaro et al. (2012) RCT split-mouth 18–60 Multiple 10 58 CAF + EMD CAF 24 months 32. Cardaropoli et al. 2012) RCT split-mouth 21–59 Multiple 18 22 CAF + CMX CAF + CTG 12 months 33. Alkan and Parlar (2011) RCT split-mouth 23–42 Single 12 24 CAF + EMD