Efficacy of periodontal plastic surgery procedures in the treatment of localized facial gingival recessions. A systematic review

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1 J Clin Periodontol 2014; 41 (Suppl. 15): S44 S62 doi: /jcpe Efficacy of periodontal plastic surgery procedures in the treatment of localized facial gingival recessions. A systematic review Francesco Cairo 1, Michele Nieri 1 and Umberto Pagliaro 2 1 Department of Periodontology, University of Firenze, Firenze, Italy; 2 Private Practice, Campi Bisenzio-Firenze, Florence, Italy Cairo F, Nieri M, Pagliaro U. Efficacy of periodontal plastic surgery procedures in the treatment of localized gingival recessions. A systematic review. J Clin Periodontol 2014; 41 (Suppl. 15): S44 S62. doi: /jcpe Abstract Background: The aim of this Systematic Review (SR) was to assess the clinical efficacy of periodontal plastic surgery procedures in the treatment of localized gingival recessions (Rec) with or without inter-dental clinical attachment loss (ical). Material and Methods: Electronic and hand searches were performed to identify randomized clinical trials (RCTs) on treatment of single gingival recessions with at least 6 months of follow-up. Primary outcome variable was complete root coverage (CRC). Secondary outcome variables were recession reduction (RecRed) and keratinized tissue (KT) gain. To evaluate treatment effect, Odds Ratios were combined for dichotomous data and mean differences in continuous data using a random-effect model. Results: Fifty-one RCTs (53 articles) with a total of 1574 treated patients (1744 recessions) were included in this SR. Finally, 30 groups of comparisons were identified and a total of 80 meta-analyses were performed. Coronally Advanced Flap (CAF) was associated with higher probability of CRC and higher amount of RecRed than Semilunar Coronal Positioned Flap (SCPF). The combination CAF plus Connective Tissue Graft (CAF+CTG) or CAF plus Enamel Matrix Derivative (CAF+EMD) was more effective than CAF alone in terms of CRC and RecRed. The combination CAF plus Collagen Matrix (CAF+CM) achieved higher RecRed than CAF alone. In addition, CAF+CTG achieved CRC more frequently than CAF+EMD, SCPF, Free Gingival Graft (FGG) and Laterally Positioned Flap (LPS). CAF+CTG was also associated with higher RecRed than Barrier Membranes (CAF+GTR), CAF+EMD and CAF+CM. GTR was not able to improve the clinical efficacy of CAF. Studies adding Acellular Dermal Matrix (ADM) under CAF showed a large heterogeneity and not significant benefits compared with CAF alone. Multiple combinations, using more than a single graft/biomaterial under the flap, usually provide similar or less benefits than simpler, control procedures in term of root coverage outcomes. Conclusions: CAF procedures alone or with CTG, EMD are supported by large evidence in modern periodontal plastic surgery. CAF+CTG achieved the best clinical outcomes in single gingival recessions with or without ical. Key words: connective tissue graft; coronally advanced flap; gingival recession; periodontal plastic surgery; root coverage; systematic review Accepted for publication 13 October 2013 Conflict of interest and source of funding statement This study has been self-funded by the authors. Authors declare that they have no conflict of interest. S44

2 Systematic review on periodontal plastic surgery S45 The treatment of gingival recessions with periodontal plastic surgery procedures is possible request in modern dentistry (Nieri et al. 2013). The ultimate goal of these procedures is the complete root coverage (CRC) and pleasant aesthetic outcomes (Cairo et al. 2009, 2010). A previous systematic review (SR) committed by European Workshop in Periodontology for the treatment of single recession was focused on the clinical efficacy of Coronally Advanced Flap (CAF) and its related procedures. This SR showed that CAF alone was a safe and predictable procedure and the adjunctive use of Connective Tissue Graft (CTG) or Enamel Matrix Derivative (EMD) under CAF enhanced the probability of obtaining CRC (Cairo et al. 2008). The purpose of this SR was to answer at the following focused question: what is the clinical efficacy of periodontal plastic surgery procedures in the treatment of localized gingival recession with or without inter-dental clinical attachment loss? Material and Methods A detailed protocol was designed according to the PRIA (Preferred Reporting Items Systematic review and Meta-Analyses) statement (Liberati et al. 2009, Moher et al. 2009). The present manuscript was written according to PRIA checklist. Information sources and Search An expert operator (UP) conducted a search on electronic databases until April 2013 to identify studies included or investigated for this review. Three online evidence sources were used: The National Library of Medicine (MEDLINE by PubMed), on April , using the strategy: ( Gingival Recession/surgery [Mesh] OR Gingival Recession/therapy [Mesh]) AND ((Humans[Mesh]) AND (Randomized Controlled Trial[ptyp])); The Cochrane Database Trials Register, on April , using the following strategy: Gingival Recession [Search All Text] AND Root Coverage [Search All Text]. Embase, on April 30, 2013, using the following strategy: gingiva disease /exp/mj AND gingival recession /mj AND (randomized controlled trial)/lim AND (humans)/lim. There was no language restriction. Hand searching included a complete search of Journal of Clinical Periodontology, Journal of Periodontology, Journal of Periodontal Research, International Journal of Periodontics and Restorative Dentistry and PERIO up to April References from American Academy of Periodontology position paper (American Academy of Periodontology 1996), EFP review article (Wennstr om 1994) and previous systematic reviews dealing with root coverage procedures for single recession (Roccuzzo et al. 2002, Oates et al. 2003, Pagliaro et al. 2003, Clauser et al. 2003, Al-Hamdan et al. 2003, Gapski et al. 2005, Hwang & Wang 2006, Cheng et al. 2007, Chambrone et al. 2008, Cairo et al. 2008, Chambrone et al. 2009a,b, 2010, Ko & Lu 2010, Chambrone et al. 2012, Fu et al. 2012, Buti et al. 2013;) were checked for article identification. In addition, all authors of the identified studies, clinical experts or researchers in the field of periodontal plastic surgery were contacted in an attempt to identify unpublished data or studies not yet published. Selection Criteria used in this SR for studies selection were based on the PICOS method (Glossary of Evidence-Based Terms 2007) and were the following: Types of participants Patients with a clearly specified diagnosis of single gingival recession defect were included. Miller classification (Miller 1985) and Recession Type (RT) classification using the inter-dental clinical attachment level (Cairo et al. 2011) were considered. Single recessions with no loss (Miller I and II or RT1) or with minimal loss of inter-dental bone/clinical attachment (Miller III or RT2) were included. Types of interventions The following surgical procedures for the treatment of single recessions were considered: Coronally Advanced Flap (CAF); CAF plus Connective Tissue Graft (CAF+CTG); CAF plus Guided Tissue Regeneration (GTR) procedures for root coverage (CAF+GTR); CAF plus Enamel Matrix Derivative (CAF+EMD); CAF plus Acellular Dermal Matrix (CAF+ADM); CAF plus porcine Collagen Matrix (CAF+CM); CAF plus Platelet Concentrate Graft (CAF+PCG); CAF plus Human Fibroblast- Derived Dermal Substitute (CAF+HF-DDS); CAF plus Bone Graft Substitute (CAF+BGS); CAF plus Platelet-Rich Fibrin Membrane (CAF+P-RFM); CAF plus Semilunar Coronally Positioned Flap (CAF+SCPF); Double Papilla Flap (DPF) plus CTG (DPF+CTG); Semilunar Coronally Positioned Flap (SCPF); Laterally Positioned Flap (LPF); Free Gingival Graft (FGG). In addition, the following combinations of surgical techniques (applying more than a single graft/ biomaterial under the flap) for the treatment of single recessions were considered: CAF plus Bone Graft (BG) plus GTR (CAF+BG+GTR); CAF plus CTG plus EMD (CAF+CTG+EMD); CAF plus Beta-Tricalciun Phosphate (b-tcp) plus Recombinant Human Platelet-Derived Growth Factor-BB (rhpdgf- BB) (CAF+ b-tcp+ rhpdgf- BB); CAF plus GTR plus EMD (CAF+GTR+EMD); CAF plus CTG plus EMD (CAF+CTG+EMD); CAF plus ADM plus autologous gingival Fibroblasts (Fibr) (CAF+ADM+Fib); CAF plus GTR plus Hydroxyapatite (HP) (CAF+GTR+HP).

3 S46 Cairo et al. Comparison between interventions All possible comparisons between the considered surgical procedures were investigated. Type of outcome measures The following outcome measures were considered: Primary outcome. Recession defects that obtained complete root coverage (CRC). Secondary outcomes. Change in gingival recession expressed as recession reduction in millimetres at follow-up visit (RecRed), Change in width of keratinized tissue (KT) expressed as KT gain in millimetres at follow-up visit (KT gain), Biological complications during the post-operative healing period (Complications), Patient discomfort during the post-operative healing period (Post-operative pain), Patient preference in term of aesthetic result at follow-up visit (Aesthetic satisfaction), Patient perception of root sensitivity at follow-up visit (Root sensitivity). Types of studies In this systematic review, only randomized controlled clinical trials (RCTs), including split-mouth model, for the treatment of single gingival recession of at least 6 months duration were considered. In this SR, the following items were considered as exclusion criteria: RCTs comparing variations of a same technique (i.e. CAF with releasing incisions versus CAF without releasing incisions), RCTs with unclear/not specified type of treated recessions, RTCs treating multiple gingival recessions or treating both single and multiple recessions, RTCs with multiple treated sites into a single patient without appropriate statistical analysis and unavailable individual patient data (IPD), Validity assessment The quality assessment of the included trials was independently performed in a duplicate form by two review authors (F.C. and U.P.). According to Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011] (Higgins & Green 2011), three main quality criteria were examined: allocation concealment, blinding treatment outcomes to outcome assessors and completeness of follow-up (for detailed explanation see Cairo et al and additional material section, Data S2: Validity assessment). After quality assessment, studies were grouped into two categories: Low risk of bias, if all three quality criteria were met. High risk of bias, if one or more of the three quality criteria was not met. Data abstraction The titles and abstracts (when available) of all reports identified through the electronic and manual searches were independently screened by two review authors (F.C. and U.P.). When studies met the inclusion criteria or when insufficient data from abstracts for evaluating inclusion criteria were gained, the full article was obtained. The full text of all studies of possible relevance was independently assessed by two review authors (F.C. and U.P.). All studies meeting the inclusion criteria then underwent to quality assessment and data recording. When disagreement between the two reviewers was revealed, consensus was achieved by discussion with the third reviewer/ statistical advisor (M.N.). Then, data were independently extracted and inserted into a computer by two review authors (F.C. and U.P.) using specifically designed data-collection forms. Patient characteristics, treatments, clinical outcomes, complications and study quality were systematically registered. When clinical data on CRC were lacking, authors of the trials were contacted. Study characteristics Only randomized clinical trials (RCTs), with or without a splitmouth design, were included in the systematic review. Eligible RCTs, with a follow-up duration 6 months, had to compare the results of at least 2 of the investigated surgical techniques in patients with Miller Class I, II or III (Miller 1985) or Recession Types 1 or 2 (Cairo et al. 2011) defects. CRC had to be expressed as the number or the percentage of treated teeth of each considered study arm that achieved total root coverage at the follow-up visit. RecRed had to be expressed as mean recession reduction in millimetres of the treated teeth of each study arm at follow-up visit. KT Gain had to be expressed as mean keratinized tissue width increase in millimetres of the treated teeth of each study arm at follow-up visit. Complications, Postoperative pain, Aesthetic satisfaction and Root sensitivity had to be described at least in a narrative form. Quantitative data synthesis For dichotomous outcomes (CRC), the estimates of effect of an intervention were expressed as odds ratio (OR) together with 95% confidence intervals (CI). For continuous outcomes, mean differences and standard deviations were used to summarize the data from each group. In each patient, only one site for each technique was considered. In fact, multiple sites in same patient are not independent as are exposed to similar patient-related risk factors. When studies with multiple sites were identified, the presence of Individual Patient Data (IPD) was checked and multiple sites were eliminated. This allowed the selection of a single recession for technique in the single patient. OR were combined for dichotomous data and mean differences in continuous data using a randomeffect model. Data from split-mouth studies were combined with data from parallel group trials with the method outlined by Elbourne et al. (2002), using the generic inverse variance method in the RevMan. The techniques described by Follmann et al. (1992) were used to calculate the standard error of the difference in split-mouth studies, where the

4 Systematic review on periodontal plastic surgery S47 appropriate data were not presented. The significance of any discrepancies in the estimates of the treatment effects from different trials was assessed by means of Cochran s test for heterogeneity and the I 2 statistic, which describes the percentage total variation across studies that is due to heterogeneity rather than change. It was planned to undertake sensitivity analyses to examine the effect of the study quality for CRC. Evaluation of the strength of evidence Evidence regarding CRC and RecRed provided by RTCs was rated using different levels of methodological strength modified from GRADE (grading of recommendations assessments development and evaluation) (Guyatt et al. 2008). Three different strength of evidence were considered: High: at least 3 RCTs of low risk of bias and low heterogeneity Moderate: > 1 RCT and at least 1 RCTs of low risk of bias, low I 2 Low: lack of RCT or RCT at high risk of bias or high heterogeneity Results Study selection The search results are presented in Fig. 1. The electronic search in Fig. 1. Literature search process and results. MEDLINE (by PubMed), in the Cochrane Collaboration databases, and in EMBASE provided, respectively, 294, 141 and 159 articles published until April Subsequently, after reading all the abstracts and discarding duplicates, 161 articles were selected. Twentytwo of these 161 articles were not published in the journals selected for the hand searching of the present systematic review. The hand searching found 103 articles and 14 of these were not found by the electronic search. The search of the grey literature (unpublished data) by contact with all the authors of the identified studies and clinical experts or researchers in the field of mucogingival surgery provided the complete data of one trial (Barros et al. 2013). Finally, by crossing the literature searches (electronic, manual and unpublished data searches) to eliminate duplicates, 176 articles (161 by electronic, 14 by hand-search and 1 still unpublished study by grey literature search) were selected. The full text reading of the 176 articles allowed the selection of 51 studies (53 reports) (Table 1) that met the inclusion criteria of this systematic review and the exclusion of 123 articles from the analysis. Rejected studies at this stage are listed in Table 2 (characteristics of excluded studies) and the reason for exclusion was recorded. Forty-three of the 52 selected studies allowed 20 comparisons between single surgical techniques (Fig. 2), whereas nine studies led to nine adjunctive comparisons between single techniques and combinations of surgical procedures (Fig. 3). Furthermore, only one contacted research group (Joly et al. 2007) was able to provide additional unpublished data on CRC. For six selected RCTs, two articles with different follow-up durations were published. In this case, studies with follow-up 5 years were considered as long-term observation of short-term studies. When multiple studies were restricted to follow-ups < 5 years, the manuscript with longest follow-up was considered, although both papers were checked to retrieve all data when necessary. When multiple studies showed also follow-up 5 years, the shorter observation was considered, to limit the possible influence of self-performed and professional maintenance on the clinical efficacy of tested technique. In details, the six multiple publications were managed for meta-analysis as follow: Amarante et al. (2000) showed a 6-month follow-up whereas Leknes et al. (2005) corresponded to the (1- and 6-year follow-ups). One-year data from Leknes et al. (2005) were considered. H agewald et al. (2002) showed a 1-year follow-up whereas Spahr et al. (2005) presented the 2-year follow-up in the same sample of patients. Data from Spahr et al. (2005) were considered for metaanalysis. C^ortes et al. (2004) reported 6- months follow-up whereas C^ortes et al. (2006) described 2-years follow-up. Both publications were utilized to retrieve data. McGuire & Nunn (2003) showed 6-month follow-up whereas McGuire et al. (2012) presented the 10-year follow-up. Data from McGuire & Nunn (2003) were considered for meta-analysis. Haghighati et al. (2009) reported 1-year follow-up whereas Moslemi et al. (2012) described a 5-year follow-up. Data from Haghighati et al. (2009) were considered.

5 S48 Cairo et al. Table 1. Fifty-one included studies (53 articles) Comparations between single and/or combinations of techniques Study Comparison (Test versus Control) Study Design MRC Test (%) MRC Control (%) CRC Test (%) CRC Control (%) da Silva et al. (2004) Cortellini et al. (2009) 1. CAF+CTG versus CAF P Amarante et al. (2000) Lins et al. (2003) Leknes et al. (2005) 2. CAF+GTR versus CAF Modica et al. (2000) Del Pizzo et al. (2005) Spahr et al. (2005) Castellanos et al. (2006) Pilloni et al. (2006) 3. CAF+EMD versus CAF P P Woodyard et al. (2004) C^ortes et al. (2004, 2006) Mahajan et al. (2007) 4. CAF+ADM versus CAF P P Huang et al. (2005) 5. CAF+PCG versus CAF P Nazareth & Cury (2010) 6. CAF+BGS versus CAF Jepsen et al. (2013) 7. CAF+CM versus CAF Santana et al. (2010a) 8. SCPF versus CAF Santana et al. (2010b) 9. LPF versus CAF P Jepsen et al. (1998) Trombelli et al. (1998) Zucchelli et al. (1998) Borghetti et al. (1999) Tatakis & Trombelli (2000) Romagna-Genon (2001) Wang et al. (2001) 10. CAF+GTR versus CAF+CTG P 11. CAF+EMD versus CAF+CTG B U B 38.9 U Abolfazli et al. (2009) McGuire et al. (2003) Aichelmann-Reidy et al. (2001) 12. CAF+ADM versus CAF+CTG Paolantonio et al. (2002b) P Tal et al. (2002) Joly et al. (2007) Haghighati et al. (2009) Barros et al. (2013) McGuire & Scheyer (2010) 13. CAF+CM versus CAF+CTG Wilson et al. (2005), 14. CAF+HF-DDS versus CAF+CTG Bittencourt et al. (2009) 15. SCPF versus CAF+CTG Jankovic et al. (2012) 16. CAF+P-RFM versus CAF+CTG Jahnke et al. (1993) 17. FGG versus CAF+CTG Paolantonio et al. (1997) P Ricci et al. (1996) 18. DPF+CTG versus CAF+GTR P Paolantonio (2002a) P Jankovic et al. (2010) 19. CAF+P-RFM versus CAF+EMD Zucchelli et al. (2012) 20. LPF versus CAF+CTG P Comparations between single or combinations of techniques and multiple combinations of techniques Rasperini et al. (2011) 21. CAF+CTG+EMD versus P CAF+CTG McGuire et al. (2009) 22. CAF+b-TCP+rhPDGF-BB versus CAF+CTG Jhaveri et al. (2010) 23. CAF+ADM+Fib versus CAF+CTG Paolantonio (2002a) 24. CAF+GTR+HP versus DPF+CTG P Paolantonio (2002a) 25. CAF+GTR+HP versus CAF+GTR P Dodge et al. (2000) Kimble et al. (2002) 26. CAF+BG+GTR versus CAF+GTR P Trabulsi et al. (2004) 27. CAF+GTR+EMD versus CAF+GTR P

6 Systematic review on periodontal plastic surgery S49 Table 1. (continued) Comparations between single and/or combinations of techniques Study Comparison (Test versus Control) Study Design MRC Test (%) MRC Control (%) CRC Test (%) CRC Control (%) Alkan & Parlar (2011) 28. CAF+CTG+EMD versus CAF+EMD Alves et al. (2012) 29. CAF+ADM+EMD versus CAF+ADM Cairo et al. (2012) 30. CAF+CTG versus CAF P , Split-Mouth design; P, Parallel design; MRC, Mean% of Root Coverage; CRC, Complete Root Coverage;, Not Reported; CAF, Coronally Advanced Flap; CTG, subepithelial Connective Tissue Graft; GTR, Guided Tissue Regeneration procedures for root coverage; B, Bioabsorbable barrier membrane; U, Unsorbable barrier membrane; EMD, Enamel Matrix Derivative; ADM, Acellular Dermal Matrix; CM, porcine Collagen Matrix; PCG, Platelet Concentrate Graft; HF-DDS, Human Fibroblast-Derived Dermal Substitute; BGS, Bone Graft Substitute; P-RFM, Platelet-Rich Fibrin Membrane; SCPF, Semilunar Coronally Positioned Flap; DPF, Double Papilla Flap; LPF, Laterally Positioned Flap; FGG, Free Gingival Graft. BG, Bone Graft; b-tcp, Beta-Tricalciun Phosphate; rhpdgf-bb, Recombinant Human Platelet-Derived Growth Factor-BB; Fib, autologous gingival Fibroblasts; HP, Hydroxyapatite. Table 2. Characteristics of the 123 excluded articles Reason for exclusion Study Unspecified classification of recession Not surgical therapy Aimetti et al. (2005). Comparison between variations of a same surgical technique Study not dealing root coverage Guinard & Caffesse (1978), Caffesse & Guinard (1978, 1980),Espinel & Caffesse (1981). Ibbott et al. (1985), Oles et al. (1985), Caffesse et al. (1987, 2000), Bouchard et al. (1994, 1997), Trombelli et al. (1995b (313), 1996), Roccuzzo et al. (1996), Matarasso et al. (1998), Pini Prato et al. (1999, 2000, Pini Prato et al. 2011), Henderson et al. (2001), Del Pizzo et al. (2002), Zucchelli et al. (2003, 2009a (577), 2009b (1083), 2010), Al-Zahrani et al. (2004), Barros et al. (2004, 2005, 2007), Burkhardt & Lang (2005), Francetti et al. (2005), Tozum et al. (2005), Rahmani & Lades (2006), Kassab et al. (2006), Bittencourt et al. (2007, 2012), Lucchesi et al. (2007), Felipe et al. (2007), Andrade et al. (2008, 2010), Santamaria et al. (2008, 2009a (434), 2009b (791)), Byun et al. (2009), Barker et al. (2010), Mazzocco et al. (2011), Ozturan et al. (2011), Ayub et al. (2012), Kuru & Selin (2012), Mahajan et al. (2012) Wei et al. (2000), Harris et al. (2001), McGuire & Nunn (2005), Bertoldi et al. (2007), Sanz et al. (2009), Dilsiz et al. (2010a (337), 2010b (511)), Nevins et al. (2010, 2011), McGuire et al. (2011) Also Miller Class III gingival recession defects treated Cueva et al. (2004) Same pool of patients with a shorter follow-up of an Hagewald et al. (2002), McGuire & Nunn (2003), Bittencourt et al. (2006), included study in this systematic review Haghighati et al. (2009) Not RCT Pini Prato et al. (1992, 1996, 2010), Trombelli et al. (1995a (14)), Wennstr om & Zucchelli (1996), Harris (1997, 1998, 2000), Ozcan et al. (1997), Muller et al. (1999), Duval et al. (2000), Cordioli et al. (2001), Nemcovsky et al. (2004), Harris et al. (2005), Hirsch et al. (2005), Berlucchi et al. (2005), McGuire & Scheyer (2006), Silva et al. (2006), Moses et al. (2006), Erley et al. (2006), Keceli et al. (2008), Santamaria et al. (2010), Schlee & Esposito (2011) Shorter follow-up duration Laney et al. (1992), Maurer et al. (2000), Lafzi et al. (2007, 2011), Papageorgakopoulos et al. (2008), Han et al. (2008), Barbosa et al. (2009), Shepherd et al. (2009), de Toledo et al. (2009), Baghele & Pol (2012) Comparison with untreated recessions Borghetti & Louise (1994) Data not useful for meta-analysis Rosetti et al. (2000) Only abstract available Barros et al. (2003) Histological study McGuire et al. (2009) Multiple or not only single gingival recessions treated Un-appropriate statistical analysis RCT, Randomized Clinical Trial. Ito et al. (2000), Dembowska & Drozdzik (2007), Shin et al. (2007), De Souza et al. (2008), Aroca et al. (2009, 2010), Pourabbas et al. (2009), Henriques et al. (2010), Nickles et al. (2010), Aleksic et al. (2010), Ozcelik et al. (2011), Carney et al. (2012), Cordaro et al. (2012), Roman et al. (2013). Novaes et al. (2001), Berlucchi et al. (2002), Cetiner et al. (2003), Cheung & Griffin (2004), Bahashemrad et al. (2009), Cardaropoli & Cardaropoli (2009), Cardaropoli et al. (2012), Kuis et al. (2013)

7 S50 Cairo et al. Fig. 2. Schematic drawing of comparisons of surgical techniques for single gingival recessions covering 43 studies (45 articles) enclosed in the systematic review. Bittencourt et al. (2006) showed 6-month follow-up whereas Bittencourt et al. (2009) reported 30-month follow-up. The longest follow-up was considered for meta-analysis. Fig. 3. Schematic drawing of comparisons for multiple combinations techniques (applying more than a single graft/biomaterial under the flap) covering nine studies (nine articles) enclosed in the systematic review. The quality assessment of enclosed studies showed that only 13 of 51 RTCs (25%) were rated at low risk of bias (Aichelmann-Reidy et al. 2001, Wang et al. 2001, Kimble et al. 2002, Huang et al. 2005, Del Pizzo et al. 2005, Spahr et al. 2005, Wilson et al. 2005, Cortellini et al. 2009, McGuire & Scheyer 2010, McGuire et al. 2012, Zucchelli et al. 2012, Cairo et al. 2012, Jepsen et al. 2013) Among a total of 51 RTCs only a very limited number (8%) showed long-term outcomes of treatment with a follow-up of at least 5 years (Paolantonio et al. 1997, Leknes et al. 2005, Moslemi et al. 2011, McGuire et al. 2012).

8 Systematic review on periodontal plastic surgery S51 Study characteristics Included studies The list of included studies is presented in Table 1. The 51 selected studies (53 articles) allowed the comparisons showed in Fig. 2. For all the other possible comparisons investigated in the systematic review, no eligible study was found. In the case of Modica et al. (2000), two of the 12 participants were excluded from meta-analyses because they participated in a splitmouth study with more than one pair of bilateral gingival recessions. Hence, IPD of the remaining 10 pair of recession defects were re-analysed. Among included studies, 2 RTCs were multicentre (Cortellini et al. 2009, Jepsen et al. 2013) while all others were single centre study. Among the enclosed RCTs Ten studies (Jahnke et al. 1993, Paolantonio (2002a), Paolantonio et al. 2002b, Kimble et al. 2004, Huang et al. 2005, Bittencourt et al. 2009, Jhaveri et al. 2010, Alkan & Parlar 2011, Moslemi et al. 2011, Nazareth & Cury 2010) were completely supported by public institutes for research, One study (Cortellini et al. 2009) was supported by private institutes for research, Thirteen studies (Trombelli et al. 1998, Tatakis & Trombelli 2000, Aichelmann-Reidy et al. 2001, Wang et al. 2001, Tal et al. 2002, McGuire et al. 2012, Trabulsi et al. 2004, Leknes et al. 2005, Spahr et al. 2005, Wilson et al. 2005, McGuire et al. 2009, McGuire & Scheyer 2010, Jepsen et al. 2013) were supported, in part, by companies whose products were being used as interventions in the trials, Three studies (Mahajan et al. 2007, Santana et al. 2010a,b) specified that the authors not received founding, Three studies (Alves et al. 2012, Cairo et al. 2012, Zucchelli et al. 2012) specified that the authors self-supported the research, Twenty-one studies (Ricci et al. 1996, Paolantonio et al. 1997, Jepsen et al. 1998, Zucchelli et al. 1998, Borghetti et al. 1999, Dodge et al. 2000, Modica et al. 2000, Romagna-Genon 2001, Lins et al. 2003, C^ortes et al. 2006, da Silva et al. 2004, Woodyard et al. 2004, Del Pizzo et al. 2005, Castellanos et al. 2006, Pilloni et al. 2006, Joly et al. 2007, Abolfazli et al. 2009, Jankovic et al. 2010, Rasperini et al. 2011, Jankovic et al. 2012, Barros et al. 2013) did not report how the study was supported. Excluded studies There were 123 excluded studies. The reasons for exclusion are reported in Table 2 (Characteristics of the 123 excluded studies). Results of the analyses Clinical outcomes from 51 RCTs (corresponding to 53 articles) with 1574 patients and 1744 treated recessions were included in this SR. A total of 80 meta-analyses were performed. Table 3 reported the results of meta-analyses for CRC (primary outcome), RecRed (secondary outcome) and KT Gain (secondary outcome) for each possible comparison between surgical procedures. Among different RTCs, only a single study evaluating root coverage at Rec with ical (Cairo et al. 2012) was enclosed in the SR. Main results can be summarized in: CAF+CTG was more effective than CAF in term of CRC (p = 0.03), RecRed (p = 0.005) and KT gain (p = ) for Rec with no ical. CAF+CTG was more effective than CAF in term of RecRed (p = 0.03) and KT gain (p < ) for Rec with ical. The adjunctive use of GTR was not able to improve CAF with no significant difference with the control procedure (CRC p = 0.41; RecRed p = 0.11) The adjunctive use of EMD yielded to significant improvement of CAF alone in term of CRC (p = 0.003), RecRed (p = 0.002) and KT gain (p = ). Multiple combinations, using more than a single graft/biomaterial under the flap, usually provide similar or less benefits than simpler, control procedures. Figures 4 9 showed some metaanalyses for CRC, corresponding to comparisons CAF+CTG versus CAF, CAF+GTR versus CAF, CAF+ GTR versus CAF+CTG, CAF+EMD versus CAF+CTG, CAF+CM versus CAF and CAF+CM versus CAF+ CTG. All performed meta-analyses were presented in the online material as supplementary information (Data S1). Evaluation of the strength of evidence The evaluation of the strength of evidence using the modified GRADE system showed for CRC that three groups of comparisons were at moderate strength of evidence (CTG+CAF > CAF; CAF+EMD > CAF; CAF+CTG > CAF+ GTR), while other comparisons were considered at low strength of evidence. No comparison for CRC was rated at high strength of evidence. For RecRed, two groups of comparisons were at moderate strength of evidence (CTG + CAF > CAF; CAF+CTG>CAF+GTR), while other comparisons were considered at low strength of evidence. No comparison for RecRed was rated at high strength of evidence. Aesthetic satisfaction Few studies evaluated aesthetic satisfaction following therapy, mainly collecting patient opinion with no standardized approaches. No metaanalysis throughout conventional system was possible. Possible aesthetic evaluation of the clinical outcomes included a double assessment by patient and periodontist (Wang et al. 2001, Aichelmann-Reidy et al. 2001). Lately, the Root coverage Esthetic Score (RES), a standardized system to aesthetic evaluation after root coverage, was introduced (Cairo et al. 2009, 2010) and applied in recent RCTs (Jhaveri et al. 2010, Cairo et al. 2012, Roman et al. 2013). Root sensitivity Very few studies evaluated Root sensitivity following root coverage procedures. No meta-analysis was performed for this variable due to the fact that data were few and heterogeneous. Cortellini et al. (2009) compared CAF+CTG versus CAF,

9 S52 Cairo et al. Table 3. Results of the meta-analyses: 51 RCTs (53 articles) with a total of 1574 treated patients (1744 recessions) were considered Comparations between single and/or combinations of techniques Comparison CRC RecRed KT Gain 1. CAF+CTG versus CAF (2 studies, 1 at low risk of bias, moderate strength 2. CAF+GTR versus CAF (2 studies at high risk of bias, low strength 3. CAF+EMD versus CAF (5 studies, 2 at low risk of bias, moderate strength of evidence for CRC and low for RecRed) 4. CAF+ADM versus CAF (3 studies at high risk of bias, low strength 5. CAF+PCG versus CAF (1 study at low risk of bias, low strength 6. CAF+BGS versus CAF 7. CAF+CM versus CAF (1 study at low risk of bias, low strength 8. SCPF versus CAF 9. LPF versus CAF 10. CAF+GTR versus CAF+CTG (6 studies, 1 at low risk of bias, moderate strength 11. CAF+EMD versus CAF+CTG (2 studies, 1 at low risk of bias, low strength 12. CAF+ADM versus CAF+CTG (6 studies, 1 at low risk of bias, low strength 13. CAF+CM versus CAF+CTG (1 study at low risk of bias, low strength 14. CAF+HF-DDS versus CAF+CTG (1 study at low risk of bias, low strength p = 0.03 OR = % CI: p = 0.41 OR = 0.58 (favouring CAF) 95% CI: Better CAF+EMD p = OR = % CI: I 2 = 15% p = 0.31 OR = 4.83 (favouring CAF+ADM) 95% CI: I 2 = 67% p = 0.79 (favouring CAF+PCG) OR = % CI: p = 0.65 OR = 0.73 (favouring CAF) 95% CI: p = 0.61 (favouring CAF+CM) OR = % CI: Better CAF p = OR = % CI: p = 0.63 OR = 0.63 (favouring CAF) 95% CI: p = 0.06 OR = 0.45 (favouring CAF+CTG) 95% CI: I 2 = 32% p = 0.71 OR = 0.61 (favouring CAF+CTG) 95% CI: p = 0.68 OR = 0.79 (favouring CAF+CTG) 95% CI: I 2 = 63% p = 1.00 OR = % CI: p = MD = 0.49 mm 95% CI: p = 0.11 MD = % CI: Better CAF+EMD p = MD = % CI: I 2 = 51% p = 0.10 MD = 0.70 mm 95% CI: I 2 = 80% p = 0.57 MD = % CI: p = 0.34 MD = % CI: Better CAF+CM p = 0.05 MD = % CI: Better CAF p < MD = % CI: 1.69 to 1.11 p = 0.26 MD = % CI: p = MD = % CI: 0.65 to 0.10 I 2 = 46% p = 0.03 MD = % CI: p = 0.36 MD = % CI: I 2 = 70% p = 0.03 MD = % CI: 0.64 to 0.14 p = MD = % CI: p = 0.30 MD = % CI: Better CAF+EMD p = MD = % CI: I 2 = 53% Better CAF+ADM p = 0.02 MD = % CI: p = 0.38 MD = % CI: p = 1.00 MD = % CI: Better CAF+CM p = 0.04 MD = % CI: Better SCPF p < MD = % CI: Better LPF p < MD = % CI: p = MD = % CI: 1.98 to 0.39 I 2 = 92% p < MD = % CI: 1.78 to 0.72 p = 0.07 MD = % CI: I 2 = 73% p = 0.95 MD = % CI:

10 Systematic review on periodontal plastic surgery S53 Table 3. (continued) Comparations between single and/or combinations of techniques Comparison CRC RecRed KT Gain 15. SCPF versus CAF+CTG 16. CAF+P-RFM versus CAF+CTG 17. FGG versus CAF+CTG (2 studies at high risk of bias, low strength 18. DPF+CTG versus CAF+GTR (2 studies at high risk of bias, low strength 19. CAF+P-RFM versus CAF+EMD 20. LPF versus CAF+CTG p = 0.04 OR = % CI: p = 0.62 OR = 0.69 (favouring CAF+CTG) 95% CI: p < OR = % CI: p = 0.28 OR = 0.44 (favouring DPF+CTG) 95% CI: p = 0.71 OR = 1.24(favouring CAF+ P- RFM) 95% CI: p = 0.05 OR = % CI: p = 0.25 MD = % CI: p = 0.90 MD = % CI: I 2 = 74% p = 0.10 MD = % CI: p = 0.07 MD = % CI: p = MD = % CI: 0.95 to 0.17 p = 0.38 MD = % CI: I 2 = 97% Better CAF+EMD p = MD = % CI: 0.63 to 0.23 Better LPF p = MD = % CI: 1.57 to 0.67 Comparations between single or combinations of techniques and multiple combinations of techniques Comparison CRC RecRed KT Gain 21. CAF+CTG+EMD versus CAF+CTG 22. CAF+b-TCP+rhPDGF-BB versus CAF+CTG 23. CAF+ADM+Fib versus CAF+CTG 24. CAF+GTR+HP versus DPF+CTG 25. CAF+GTR+HP versus CAF+GTR 26. CAF+BG+GTR versus CAF+GTR 27. CAF+GTR+EMD versus CAF+GTR p = 0.27 OR = 1.83 (favouring CAF+CTG+EMD) 95% CI: p = 0.59 OR = 1.56 (favouring CAF+ADM+Fib) 95% CI: p = 0.71 OR = 0.76 (favouring DPF+CTG) 95% CI: p = 0.43 OR = 1.71 (favouring CAF+GTR+HP) 95% CI: p = 0.35 OR = 2.00 (favouring CAF+BG+GTR) 95% CI: p = 0.09 OR = 0.13(favouring CAF+ GTR) 95% CI: p = 0.27 MD = 0.30 CI95% CI: p = MD = % CI: 0.64 to 0.16 p = 0.84 MD = % CI: p = 0.25 MD = % CI: Better CAF+BG+GTR p = 0.04 MD = % CI: p = 0.62 MD = % CI: p = 1.00 MD = % CI: p = 0.01 MD = % CI: 0.54 to 0.06 Better DPF+CTG p = MD = % CI: 2.64 to 1.62 p = 0.62 MD = % CI: p = 0.09 MD = % CI: p = 0.55 MD = % CI:

11 S54 Cairo et al. Table 3. (continued) Comparations between single and/or combinations of techniques Comparison CRC RecRed KT Gain 28. CAF+CTG+EMD versus CAF+EMD 29. CAF+ADM+EMD versus CAF+ADM p = 0.33 OR = 0.47 (favouring CAF+ EMD) 95% CI: p = 0.23 OR = 3.56 (favouring CAF+ ADM+EMD) 95% CI: p = 1.00 MD = % CI: p = 0.11 MD = % CI: p = 0.61 MD = % CI: p = 0.85 MD = % CI: Comparations of techniques for gingival recession with loss of interdental clinical attachment (Miller CLASS III OR CLASS RT2) Comparison CRC RecRed KT Gain 30. CAF+CTG versus CAF 1 study at low risk of bias, low strength p = 0.13 OR = 3.33 (favouring CAF+CTG) 95% CI: p = 0.03 MD = % CI: p < MD = % CI: CRC: Complete Root Coverage; RecRed: Recession Reduction; KT Gain: Keratinized Tissue Gain; : No Statistical Significant Difference; OR: Odds Ratio; 95% CI: 95% Confidence Intervals (in millimeters); I 2 : Percentage total variation across studies (Heterogeneity); MD: Mean Difference in millimeters; CAF: Coronally Advanced Flap; CTG: subepithelial Connective Tissue Graft; GTR: Guided Tissue Regeneration procedures for root coverage; EMD: Enamel Matrix Derivative; ADM: Acellular Dermal Matrix; CM: porcine Collagen Matrix; PCG: Platelet Concentrate Graft; HF-DDS: Human Fibroblast-Derived Dermal Substitute; BGS: Bone Graft Substitute; P-RFM: Platelet-Rich Fibrin Membrane; SCPF: Semilunar Coronally Positioned Flap; DPF: Double Papilla Flap; LPF: Laterally Positioned Flap; FGG: Free Gingival Graft. BG: Bone Graft; b-tcp: Beta-Tricalciun Phosphate; rhpdgf-bb: Recombinant Human Platelet-Derived Growth Factor-BB; Fib: autologous gingival Fibroblasts; HP: Hydroxyapatite. Fig. 4. Comparison between CAF+CTG versus CAF for CRC. CAF: Coronally Advanced Flap; CTG: Connective Tissue Graft; CRC: Complete Root Coverage. reporting no statistically significant differences in root sensitivity (12% in the test group and 12% in the control group) 6 months following therapy. Similarly, Cairo et al. (2012) reported 15% of sites with residual sensitivity for CAF-treated sites and no residual sensitivity for CAF+CTG-treated sites 6 months after therapy. McGuire et al. (2012) in a 10-year follow-up study comparing CAF+EMD (test) versus CAF+CTG (control) reported one of nine control sites with root hypersensitivity versus three of nine test sites with root hypersensitivity. Post-operative pain and complications The reporting of information on pain ad complications in RCTs on root coverage procedures is infrequent and data were heterogeneous not allowing a possible meta-analysis. Complications were frequently not investigated or reported in anecdotal forms. In studies on GTR, the membrane exposure was reported as a frequent complication. Amarante et al. (2000) reported exposure of several membranes in CAF+GTR sites, whereas Lins et al. (2003) reported the exposure of all membranes in all treated sites (10/10). In comparisons between CAF+BM+ versus CAF+CTG, membrane exposure was reported as a possible complication (7/15 in Jepsen et al. 1998, 2/12 in Trombelli et al. 1998, 5, /12

12 Systematic review on periodontal plastic surgery S55 Fig. 5. Comparison between CAF+GTR versus CAF for CRC. CAF: Coronally Advanced Flap; GTR: Guided Tissue Regeneration; CRC: Complete Root Coverage. Fig. 6. Comparison between CAF+EMD versus CAF for CRC. CAF: Coronally Advanced Flap; EMD: Enamel Matrix Derivative; CRC: Complete Root Coverage. Fig. 7. Comparison between CAF+GTR versus CAF+CTG for CRC. CAF: Coronally Advanced Flap; GTR: Guided Tissue Regeneration; CTG: Connective Tissue Graft; CRC: Complete Root Coverage.

13 S56 Cairo et al. Fig. 8. Comparison between CAF+EMD versus CAF+CTG for CRC. CAF: Coronally Advanced Flap; EMD: Enamel Matrix Derivative; CTG: Connective Tissue Graft; CRC: Complete Root Coverage. Fig. 9. (a)comparison between CAF+CM versus CAF for CRC. CAF: Coronally Advanced Flap; CM: Collagen Matrix; CRC: Complete Root Coverage. (b) Comparison between CAF+CM versus CAF+CTG for CRC. CAF: Coronally Advanced Flap; CM: Collagen Matrix; CTG: Connective Tissue Graft; CRC: Complete Root Coverage. in Tatakis & Trombelli 2000). Jepsen et al. (1998) reported a similar incidence of post-operative pain for both treatments (5/15 patients). On the other hand, Romagna-Genon (2001) described postoperative discomfort for the palatal donor site for the CTG. Sites treated with BM were more frequently symptom-free compared with CTG sites. None of the patients reported exposure of the membrane. No complication was reported in comparisons between CAF+EMD versus CAF (Modica et al. 2000), CAF+ADM versus CAF (Woodyard et al. 2000, C^ortes et al. 2004) and CAF+ADM versus CAF+CTG (Joly et al. 2007). In a comparison between CAF+EMD versus CAF+CTG, McGuire & Nunn (2003) reported higher discomfort for CTG procedure (p = 0.011) 1 month following therapy, whereas no difference between the two approaches was reported at the 1-year follow-up.

14 Systematic review on periodontal plastic surgery S57 More recently, the use of CON- SORT guidelines in reporting RTCs improved also information on patient-related outcomes by using Visual Analogue Scale (VAS). That is, Cortellini et al. (2009) reported higher number of cases of swelling in CAF+CTG group compared with CAF group, and these differences were statistically significant (for CAF+CTG, VAS = whereas for CAF, VAS = ). Furthermore, CAF+CTG was associated with longer surgical time (p < ), higher number of days with post-operative morbidity (p = ) and greater number of post-operative analgesics (p = ) than CAF alone in a RCT on single recession with ical (Cairo et al. 2012). Finally, add of CM underneath CAF was not associated with increased post-operative morbidity than CAF (Jepsen et al. 2013). Long-term stability of the outcome variables A very limited number (8%) of RTCs showed long-term outcomes of treatment with a follow-up of at least 5 years (Paolantonio et al. 1997, Leknes et al. 2005, Moslemi et al. 2011, McGuire et al. 2012); three of four studies were long-term update of previously published short-term outcomes (Leknes et al. 2005, Moslemi et al. 2011, McGuire et al. 2012). Leknes et al. (2005) reported a significant reduction in CRC and mean RecRed for both CAF+GTR and CAF-treated sites when comparing 6-year follow-up with the 1-year and 6- month follow-ups (Amarante et al. 2000). Moslemi et al. (2011) reported the 5-year follow-up of a shortterm study (Haghighati et al. 2009) comparing CAF+ADM versus CAF+CTG. At last follow-up, significant relapses were detected in CRC and reduction in RD and RW in both groups with no statistically significant difference. Patients reporting horizontal tooth-brushing habits were more prone to develop Rec relapse (p = 0.01). McGuire & Nunn (2012) reported the long-term follow-up (10 years) of short-term study comparing CAF+EMD versus CAF+CTG (McGuire & Nunn 2003) considering 9 of 17 original patients. The authors described stability of achieved outcomes in the long-term with no significant difference between the two procedures. Discussion The focused question of this systematic review was what is the clinical efficacy of periodontal plastic surgery procedures in the treatment of localized gingival recessions with or without inter-dental clinical attachment loss? The current article covered 35 years of clinical research in mucogingival surgery, starting from the late 1970s when Raul Caffesse s group published the early RTCs on the treatment of single gingival recession (Guinard & Caffesse 1978, Caffesse & Guinard 1978, 1980, Espinel & Caffesse 1981). From this historical perspective, it has been observed that several paradigms changed during the last decades. Between 1970s and 1980s gold standard procedures were considered the free gingival graft (FGG) and laterally positioned flap (LPF) even if the scientific background was mostly represented by case-series studies. In the late 1980s a complete description of the CAF procedure was presented (Allen & Miller 1989) opening a new era of treatment, not only focused on the reconstruction of an adequate amount of attached gingiva but also effective in enhancing soft tissue aesthetics. The definition of Periodontal Plastic Surgery was then introduced (Miller 1993, American Academy of Periodontology 1996), thus capturing the target of contemporary treatment. In modern evidence-based era, the interest was mostly focused on the predictability of soft tissue reconstruction over the exposed root thus obtaining CRC along with pleasant aesthetics (Cairo et al. 2009, Kerner et al. 2009, Cairo et al. 2010). The flap design for root coverage procedure: coronally advanced flap versus different flap designs Among the different types of flap designs used in periodontal plastic surgery, the most frequent approach was the Coronally Advanced Flap (Allen & Miller 1989). This technique became very popular in the 1990s and several combinations by adding grafts, barriers or biomaterials over the root were suggested (Cairo et al. 2008). On the other hand, flap designs different from CAF as LPS or SCPF showed a very limited number of RCTs and should be considered with caution in modern treatment. When considering the pure flap design, RTCs comparing the CAF technique to LPF (Santana et al. 2010a) or SCPF (Santana et al. 2010b) are available. The results of the present meta-analysis showed that CAF is superior to different flap designs in term of probability to obtain CRC. Interestingly, the use of LPF is associated with higher amount of KT gain than CAF after healing (Santana et al. 2010b); however, it should be taken into account that the presence of a well-represented amount of KT from the adjacent site is pre-requisite to perform LPF. The efficacy of CAF alone as reliable method to obtain root coverage is associated with the flap design that is able to maintain an adequate blood supply for the gingival margin, as demonstrated by the classical paper from M ormann & Ciancio (1977). In this angiographic study, some aspects of flap design were stressed, including a broad enough flap base to incorporate major gingival vessels, a proper flap s length to width ratio, a minimal residual tension and the careful preparation of the partial thickness flap (M ormann & Ciancio 1977). These findings represent a milestone in the development of modern in periodontal plastic surgery and provide a nice interpretation of soft tissue healing process over the exposed root surface after mucogingival surgery. The clinical efficacy of Coronally Advanced Flap plus Connective Tissue Graft Data from this SR showed that CAF+CTG could be considered the gold standard for treatment of the single gingival recession. In fact, two RCTs for Rec with no ical (da Silva et al. 2004, Cortellini et al. 2009) and one for Rec with ical (Cairo et al. 2012) showed that this

15 S58 Cairo et al. combination was associated with higher probability to obtain CRC than CAF alone. Interestingly, when considering Rec with ical, the use of CTG was associated with 57% of CRC (Cairo et al. 2012), thus confuting the paradigm suggesting a limit for root coverage due to the baseline inter-dental bone loss (Miller 1985). Furthermore, CTG procedure is more effective than the CAF procedure to augment keratinized tissue, leading to a final increase in approximately 1 mm of KT. When considering potential materials underneath CAF compared with CTG, add of ADM or GTR was less effective than CAF+CTG in term of root coverage outcomes. Furthermore, CAF+CTG was similarly effective than CAF+ EMD for CRC and more effective than CAF+CM for RecRed. In addition, the use of CTG with different overlaying flap design as Double Papilla Coronally Advanced Flap was also associated with better root coverage outcomes than FGG (Jahnke et al. 1993, Paolantonio et al. 1997). A possible hypothesis to explain the clinical efficacy of CTG may be related with the specific healing model of the procedure. In fact, the high stability of the wound over CTG is associated with graft vascularization originated from both the periodontal plexus and the overlying flap leading to a complete blood supply for the graft after 2 weeks (Guiha et al. 2001). Furthermore, CTG could be considered biological filler able to adapt the inner of the flap to the root surface thus limiting the post-operative shrinkage of CAF in apical direction (Cairo et al. 2008, Cortellini et al. 2009). This hypothesis is supported by data from a recent RCT for the treatment of RT2 single Rec (Cairo et al. 2012): the CAF-treated sites showed an increasing apical shift of the gingival margin between 3 and 6 months, whereas the CAF+CTGtreated sites showed a consistent stability in the same time frame. This resulted into a significant reduction in sites completely covered in CAF-treated sites, while in the CAF+CTG group the number of sites with CRC was the same at 3- and 6-month follow-ups. Alternatives to connective tissue graft underneath the flap: enamel matrix derivative, acellular dermal matrix, barriers membranes and collagen matrix The use of CTG implies an obvious increase in patient discomfort compared with procedures requiring a single surgical site in the mouth (Cairo et al. 2012). To reduce patient morbidity, several biomaterials/barriers/replacement grafts were tested. Considering data from these meta-analyses, biomaterials able or not able to improve CAF can be distinguished. In the last 15 years, barrier membranes for regeneration and ADM were extensively used for root coverage. A large evidence showed limited clinical benefits in using these materials. GTR was extensively tested in comparison to CAF+CTG or CAF alone: the current meta-analysis showed that bilaminar procedure or CAF alone was associated with significant higher probability to obtain CRC and RedRed than CAF+GTR. In addition, a high incidence of complications as membrane exposure was frequently reported (Jepsen et al. 1998, Trombelli et al. 1998, Tatakis & Trombelli 2000). Based on these data, the use of GTR for root coverage seems to be poorly indicated in modern periodontal plastic surgery. ADM, an allograft of cadaveric origin, was compared in six RTCs with CAF+CTG (Aichelmann-Reidy et al. 2001, Paolantonio 2002a, Paolantonio et al. 2002b,, Tal et al. 2002, Joly et al. 2007, Haghighati et al. 2011, Barros et al. 2013) and in two RTCs with CAF alone (Woodyard et al. 2004, C^ortes et al. 2006), showing inferior outcomes than CTG and no additional benefit when added to CAF, although not significant and with high heterogenic I 2 index. These data seem to suggest caution in applying ADM for root coverage. On the other hand, EMD and CM show promising results to improve the clinical efficacy of CAF. EMD was extensively tested in comparison with CAF alone (Modica et al. 2000, Del Pizzo et al. 2005, Spahr et al. 2005, Castellanos et al Pilloni et al. 2006), showing higher significant probability to improve root coverage outcomes. Two RTCs (McGuire et al. 2003, Abolfazli et al. 2009) showed also that CAF+EMD was inferior to CAF+CTG in term of CRC, although this result was not significant. Initial data support also benefit in using CM, 3D-matrix made of porcine collagen able to promote soft tissue regeneration. One RCT (Jepsen et al. 2013) showed that CM was able to improve the probability of obtaining RecRed than CAF alone, whereas one RCT (McGuire & Scheyer 2010) showed less RecRed and similar KT gain compared with CAF+CTG. Therefore, data from the present SR suggest that EMD and CM are useful biomaterials in current periodontal plastic surgery, but further studies are necessary to definitively evaluate indications for treatment and associated clinical benefits. Multiple combinations for root coverage Among 51 enclosed RCTs, nine studies tested multiple combinations (application of more than a single graft/biomaterial under the flap) for treating the single gingival recession compared with a simpler technique. These approaches included the addition of EMD to CAF+CTG (Rasperini et al. 2011, Alkan & Parlar 2011), the use of ADM and cultured fibroblasts under CAF (Jhaveri et al. 2010), the use recombinant human platelet-derived growth factor under GTR and CAF (McGuire et al. 2009), the addition of bone graft under GTR (Paolantonio 2002a, Dodge et al. 2000, Kimble et al. 2004) and the use of EMD under GTR (Trabulsi et al. 2004) or in combination with ADM (Alves et al. 2012). Among these studies, only a single RCT (Dodge et al. 2000) showed that CAF+ GTR+ BG was associated with better significant RecRed than CAF+GTR. The results of the present metaanalyses showed that multiple combinations usually provide similar or less benefits than the simpler, control procedures in term of root coverage outcomes. Clinicians and researchers should consider this finding in planning further studies on the treatment of single gingival recessions. Furthermore, the reader should consider that cost-benefit ratio and practicality are key factors in selecting a