Collagen Matrix for Periodontal Plastic Surgery Procedures: a Meta-Analysis Update

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Collagen Matrix for Periodontal Plastic Surgery Procedures: A Meta-analysis Update

Chunmei Xu, DDS1* Treatment of gingival recession and QianTing Wang, DDS1* insufficient keratinized tissue (KT) is Jin Chen, PhD2 a common requirement to improve Yafei Wu, DDS, PhD1 periodontal health and solve es- 1 Lei Zhao, DDS, PhD thetic concerns.1 Today, coronally This review aims to evaluate the effectiveness of a collagen matrix (CM) utilized in advanced flap (CAF) with connec- periodontal plastic surgeries around natural teeth and implants. This review was tive tissue graft (CTG) is considered conducted based on the Preferred Reporting Items for Systematic Reviews and the gold standard to treat Miller Meta-Analyses guidelines. Review Manager 5.3 software was used for data analysis. Class I and II gingival recessions.2 Subgroup analyses were conducted by defect categories and follow-up periods. 3 The GRADE system was applied to classify the quality of evidences. Out of 3,652 For KT < 2 mm, free gingival grafts articles in the literature, 14 studies were included, totaling 1,260 defects in 565 (FGGs) may be the best option for participants. The meta-analysis showed that CM is superior to coronally advanced augmentation of KT.4–6 However, ﬂaps (CAF) regarding gains in mean root coverage (MRC) and width of keratinized the need for a second surgical site tissue (KTW). Insufficient evidence demonstrated that CM had higher complete increases postoperative discom- root coverage (CRC). Connective tissue graft (CTG) presented better results in fort, bleeding, and swelling from CRC, MRC, and KTW. Greater KTW was also found favoring CTG in implants. In 6,7 subgroup analysis, moderate evidence showed that, compared to CTGs, CMs the donor site. In addition, the present similar results in CRC, MRC, and KTW when treating single gingival patient’s esthetic evaluation of the recessions. CTGs showed greater efficiency in KTW of multiple gingival recessions surgical site is unpredictable.6 It is and long-term observations. CM presents suitable capabilities as an alternative to quite challenging to use the mul- soft tissue graft, while CTG still shows better results in most clinical parameters. tiple adjacent gingival recession Int J Periodontics Restorative Dent 2019;39:e129–e155. doi: 10.11607/prd.3814 (MAGR) method due to the limita- tions of the donor site or implant size.7,8 To overcome these disadvan- tages, alternative materials, such as acellular dermal matrix (ADM), have gradually become an alternative for periodontal plastic surger- 1 State Key Laboratory of Oral Diseases; National Clinical Research Center for Oral Diseases; ies.2,6,9–12 Some studies report that Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China. alternative materials can result in 2Department of Evidence Based Medicine and Clinical Epidemiology, West China Hospital, complete root coverage (CRC) Sichuan University, Chengdu, Sichuan, China. similar to that of CTG.13–18 However,

CTG with CAF is still associated *These authors contributed equally to this work. with increased esthetic satisfaction Correspondence to: Dr Lei Zhao, Department of Periodontics, West China Hospital of compared to other techniques.19 In Stomatology, Sichuan University, NO.14 Ren min South Road 3rd Section, addition, the application of ADM is Chengdu, Sichuan 610041, China. Fax: +86 28 85582167. Email: [email protected] still subject to ethical restrictions in Europe, China, and other countries Submitted March 9, 2018; accepted August 18, 2018. ©2019 by Quintessence Publishing Co Inc. and regions.

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Recently, some trials describe Materials and Methods Types of Intervention and the effectiveness of a novel bilay- Comparison ered porcine collagen matrix (CM) The systematic review was prepared in periodontal plastic surgeries. according to the guidelines of the The CM utilized in the surgery was This CM is composed of type I and Preferred Reporting Items for Sys- considered as experimental inter- type III collagens. The compact tematic Reviews and Meta-Analyses vention. Use of autografts like CTG layer with a low-porosity surface (PRISMA) statement.27 The criteria and FGG, which were thought to be is less cell-permeable. The porous used in this review for trial selection the gold standards for root coverage layer consists of diffusely packed were based on the PICO (patient, and KT augmentation, respectively, collagen fibers, which can support intervention, comparison, outcome) were comparator interventions. The blood clot stabilization and the in- method.28 most-used technique, CAF, was growth of soft tissue cells.20 Studies also set as comparator intervention. demonstrate20–23 that the spongy Studies included were grouped into layer facing the tooth facilitates Types of Studies four categories according to the good tissue integration with sur- techniques used in surgeries: CM vs rounding connective tissue, and Only randomized controlled trails CTG; CM vs CAF alone; CM vs FGG; the compact layer with less cell in- (RCTs) using the same porcine CM CM vs CTG in dental implants. filtration functions as a barrier for to treat gingival recessions or in- soft tissue regeneration. sufficient KT were considered for Some advantages that CM inclusion. Considering the hetero- Types of Outcome Measures presents include a lack of ethical geneity between results of different issues, no donor-site discomfort, studies at various time points, only Primary outcomes: percentage less postoperative morbidity, and RCTs followed up to 6 months, 12 of CRC and mean root coverage no limitation of the implant size.24,25 months, or both time points were (MRC); gain in width of KT (KTW). One meta-analysis demonstrated involved. Non-RCTs, animal studies, Secondary outcomes: recession that, compared with other tech- or trials lacking information like data reduction (RD); changes in recession niques, CM obtains enhanced of primary outcomes, allocation width (RW), gingival tissue thickness augmentation in KT.17 A previously methods, or other information for (GT), probing pocket depth (PPD), published systematic review report- assessing risk of bias were excluded. and clinical attachment level (CAL); ed numerous valuable conclusions participants’ esthetic satisfaction; about clinical and patient-centered postoperative discomfort and mor- outcomes, but no data about Types of Participants bidity; operating time. MAGRs and long-term results were reported due to the limited number Systemically and periodontally of included studies.26 healthy patients (≥ 18 years old) Search Strategy This systematic review and with demand for periodontal plas- meta-analysis aims to reevaluate tic surgeries to treat gingival reces- The following electronic databases the efficiency of CM in periodon- sion or insufficient KT were enrolled. were searched for ongoing and tal plastic surgeries involving teeth Patients with contraindications for unpublished trials up to November and implants and to provide more periodontal surgery or clinical signs 10, 2017: MEDLINE, EMBASE, The detailed information for CM’s clini- of active periodontal disease were Cochrane Central Register of Con- cal application. excluded. trolled Trials (CENTRAL), and the System for Information on Grey Lit- erature in Europe (http://www.open- grey.eu). The searching terms were

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© 2019 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER. e131 in English, but no language restric- reviewers separately. The final de- Final outcomes provided by tion was applied. The search was cision about the eligibility of all this review were evaluated by the performed independently and in studies was made by mutual agree- GRADE (Grading of Recommenda- duplicate by two reviewers (C.M.X. ments or in consultation with a third tions, Assessment, Development, and Q.T.W.). The following keywords author (Z.L.). The reasons for exclud- and Evaluation) system to classify were used as search terms in the ing studies were noted. the quality of the evidence. electronic databases: ([“Collagen matrix”(All fields)] OR [“collagen”(All fields)] OR [“matrix”(All fields)] Data Extraction Data Analysis OR [“xenogeneic collagen matrix”(All fields)] OR [“porcine The following information of in- Data were analyzed using a statisti- collagen matrix”(All fields)] OR cluded trials was extracted in- cal software program (Review Man- [“xenograft”(All fields)]) AND ([“gin- dependently by the same two ager, version 5.3). For dichotomous gival recession”(All fields) OR [“Mar- independent reviewers applying outcomes, the effect of the interven- ginal tissue recession”(All fields) a specifically designed data-col- tion was estimated by risk ratio (RR) OR [“Root coverage”(All fields) OR lection form in duplicate: authors’ and 95% confidence intervals (CIs). [“Keratinized gingiva”(All fields) OR names, study location, year of pub- For continuous outcomes, mean dif- [“Mucogingival therapy”(All fields) lication, numbers of participants ferences (MDs) and standard devia- OR [“Mucogingival surgery”(All and recession sites, source of study tions (SDs) were used to summarize fields) OR [“Periodontal surgery”(All funding, study design, method of the effect. The missing SD of an fields) OR [“Periodontal plastic randomization, duration of study, al- MD in an intervention group was surgery”(All fields)]). The bibliog- location concealment and blinding, computed from the CI, and the SD raphies of all eligible papers were length of observation period, type change of an MD change was calcu- scrutinized for additional studies. A of defects, patients’ characteristics, lated from a correlation coefficient hand-search of the last 10 years of comparison of interventions, and calculated from a study reported in relevant available dental journals outcomes. Any disagreements were considerable detail according to the (Journal of Clinical Periodontology, resolved by reaching a consensus or principles and techniques described Journal of Periodontology, Journal contacting corresponding authors in the Cochrane Handbook. of Periodontal Research, Clinical of the included studies. Inconsistencies in quantifying Oral Implants Research, and Inter- heterogeneity across studies were national Journal of Pharmaceutical expressed as an I2 statistic tested by Research and Development) was Quality Assessment Cochran’s Q test. An I2 value > 50% carried out to identify potential pa- indicated significant heterogene- pers to include. The two independent reviewers ap- ity, in which case a random-effects plied (in duplicate) the Cochrane model and sensitivity analysis were Collaboration’s Risk of Bias tool to applied. A fixed-effects model was Selection of Studies assess the risk of bias of included used when I2 < 50%. Statistical sig- RCTs. 29 After quality assessment nificance was set at P < .05. The The same two independent re- of six domains of the tool, relative generic inverse variance option in viewers who performed the search parts of studies were grouped into the statistical software program was also screened each article’s title, three categories15: low risk of bias if used to combine both split-mouth abstract, and keywords in dupli- all the criteria were met; moderate and parallel group trials. Subgroup cate. Then the full texts of studies risk of bias if three or more criteria analyses were conducted to explore that met the inclusion criteria were were partially met; high risk of bias related factors causing heteroge- obtained and assessed by the two if less than three criteria were met. neity. With fewer than 10 studies

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tails of study location. Nine trials Articles identified from search of were partially or totally supported electronic database (n = 3,652) by Geistlich Pharma, two were self- Studies excluded after scanning funded, one was supported by Re- titles and abstracts (n = 3,625) search Funding Agency from São Paulo State, one was supported Citations identified for by the Piracicaba Dental School, full-text assessment (n = 27) and one did not report the source Studies excluded with reasons for exclusion (n = 13) of monetary support. There were • Insufficient data for meta-analysis five RCTs in the CM vs CTG group, (n = 4) with three studies treating MAGRs; • Histologic study (n = 1) four studies in the CM vs CAF alone Studies included for meta-analysis • No detailed information of group, with only one study treat- (n = 14) resorbable membrane used (n = 1) • XCM differs from soft tissue ing MAGRs; one study in the CM vs substitute (n = 4) FGG group; three studies in the CM Trials applying Trials applying • XCM is not the variable used for vs CTG in dental implants group. XCM around XCM around comparison (n = 1) Details of included studies are natural teeth implants • Defects at surgical sites that may (n = 11) (n = 3) affect final outcomes (n = 2) shown in Tables 2 and 3.

Fig 1 Flow diagram for the search process and result. XCM = xenogeneic collagen matrix. Meta-analysis

CM vs CTG in Natural Teeth Five trials under moderate risk of in each group, publication bias was which a following long-term–results bias were included.30–34 The meta- not formally assessed due to the subgroup analysis was also con- analysis showed (Appendix 1) that limited power. ducted. The other 3 RCTs were all the CM group had significantly performed around dental implants. greater reductions in PPD (P = .0001, I2 = 9%, 95%CI: –0.16 to –0.05), Results surgery time (P < .00001, I2= 0%, Quality Assessment and Basic 95%CI: –17.87 to –14.40), and post- Results of the Search Characteristics of Included operative discomfort (P < .00001, Studies I2 = 34%, 95%CI: –6.77 to –3.38). The search strategy identified 3,652 Patient-centered esthetic satisfac- references (Fig 1), of which 27 ar- Results (Table 1) showed that all tion also favored the CM group ticles were considered eligible by RCTs were evaluated as having a (P = .14, I2 = 89%, 95%CI: –15.01 to scanning titles and keywords. Only moderate risk of bias. Among the 2.20), though no significant differ- 14 studies met the inclusion criteria RCTs, two trials were performed in ence was detected. after full-text evaluation and were the United States, three in Italy, two There was a significantly high- selected in the review.25,30–42 The in Spain, one in Hungary, one in er percentage of CRC (P = .0004, exclusion reasons for the 13 studies Poland, two in Brazil, and three were I2 = 58%, 95%CI: 1.17 to 1.72) and are noted in Fig 1. The hand-search multiple-center RCTs, of which one MRC (P = .03, I2 = 82%, 95%CI: 0.66 did not provide any further studies. was performed in Germany, Italy, to 16.31) in the CTG group, and Out of the 14 RCTs, 11 applied CM Sweden, and Spain; one in Germany greater changes were also found in in the treatment for natural teeth, of and Italy; and one provided no de- RD (P = .005, I2 = 58%, 95%CI: 0.08

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2 to 0.45), KTW (P < .00001, I = 47%, Table 1 Quality Assessment of Included RCTs 95%CI: 0.30 to 0.56), GT (P < .00001, 2 Study, Risk of I = 0%, 95%CI: 0.21 to 0.38), and publication year RSG ALC BOA ICD SLR OSB bias CAL (P < .0001, I2 = 48%, 95%CI: Sanz et al,25 2009 Y UN YYY UN Moderate 0.15 to 0.45). Obvious heterogeneity Tonetti et al,30 2018 YYYYY UN Moderate was detected in CRC, MRC, RD, and 2 Cies´lik-Wegemund et YYYYY UN Moderate RW (P = .23, I = 94%, 95%CI: –0.37 al,31 2016 to 1.57), with RW values not signifi- Aroca et al,32 2013 Y UN YYY UN Moderate cantly higher than the CM group. Cardaropoli et al,33 Y UN YYY UN Moderate 2012 CM vs CAF Alone in Natural Teeth McGuire and Y UN Y UN Y UN Moderate Five trials at moderate risk of bias Scheyer,34 2010 were included.35–39 The meta-anal- Jepsen et al,35 2013 YYYY UN UN Moderate ysis (Appendix 2) showed that the Cardaropoli et al,36 Y UN YYY UN Moderate CM group resulted in significant- 2014 ly better improvements in MRC Stefanini et al,37 2016 YYYY UN UN Moderate (P = .006, I2 = 65%, 95%CI: –13.86 Sangiorgio et al,38 YYYYY UN Moderate to –2.26), KTW (P = .006, I2 = 0%, 2017 95%CI: –0.50 to –0.09), CAL (P = .01, Moreira et al,39 2016 YYYYY UN Moderate I2 = 0%, 95%CI: –0.56 to –0.07), McGuire and Y UN YYY UN Moderate 40 and GT (P = .02, I2 = 93%, 95%CI: Scheyer, 2014 41 –0.74 to –0.06). Though CM shows Cairo et al, 2017 YYYNY UN Moderate a potential advantage in achieving Lorenzo et al,42 2012 YYYYY UN Moderate CRC (P = .05, I2 = 0%, 95%CI: 0.64 RCT = randomized controlled trial; RSG = random sequence generation; ALC = allocation concealment; BOA = blinding of outcome assessment; ICD = incomplete outcome data; to 1.00), this parameter presents no SLR = selective reporting; OSB = other source of bias; UN = unclear; Y = yes; N = no. significant difference between the two groups after sensitivity analysis or subgroups analysis. In addition, patients’ esthetic satisfaction, which CM vs FGG in Natural Teeth CM vs CTG in Dental Implants was not significantly different be- Only one trial at moderate risk of In this group, three trials at moder- tween two groups (P = .38, I2 = 0%, bias was included, which was not ate risk of bias were included.25,41,42 95%CI: –0.82 to 0.31), slightly fa- enough for a suitable meta-analy- Limited data demonstrated that the vored the CM group. No difference sis.40 However, this study also pro- final result favored CM in KTW (Ap- was found in terms of PPD (P = .73, vided a lot of useful information for pendix 3) (P = .92, I2 = 19%, 95%CI: I2 = 74%, 95%CI: –0.15 to 0.21) and this review. This trial found that FGG –0.29 to 0.27), though the difference RD (P = .61, I2 = 76%, 95%CI: –0.55 was associated with higher KT gain between the two groups was not to 0.32). Obvious heterogeneity was compared with CM, while patients statistically significant. All studies detected in MRC, GT, RD, and PPD, in the CM group reported greater in this analysis reported similar es- which indicated essential heteroge- esthetic satisfaction. No significant thetic satisfaction for both groups, neity analysis. Only one study35 pro- differences were detected in PPD, while the CM group presented bet- vided information for surgery time RD, and CAL. ter improvement in postoperative and postoperative discomfort, both discomfort and operating time. One of which favored CAF and were not trial41 showed that using CTG could suitable for meta-analysis. achieve greater GT gains.

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Table 2 Characteristics of Included Studies (in Natural Teeth) Cies´lik- McGuire and Cardaropoli McGuire and Wegemund Scheyer,34,a CM vs et al,33 Aroca et al,32 Scheyer,34,a et al,31 Tonetti et al,30 CTG CM vs CTG CM vs CTG CM vs CTG CM vs CTG CM vs CTG Year of 2010 2012 2013 2010 2016 2018 publication Study location United States Italy Hungary United States Poland 14 centers (not specified) Study design Split-mouth Parallel group Parallel group Split-mouth Parallel group Parallel group Participants/ 25/50 18/22 22/156 25/50 28/106 187/485 recession sites Methods of Periodontal Periodontal Periodontal Periodontal Periodontal Periodontal assessment probe, VASb probec probe,c VASb probe,c VASb probe,d VASb probe,c VASb Type of Dehiscence-type Miller Class I or II Miller Class I and II Dehiscence-type Miller Class I and II At least two adja- defects recession defects recession multiple adjacent recession defects multiple adjacent cent recessions of ≥ 3 mm deep × gingival recession ≥ 3 mm deep × gingival recession the gingival margin ≥ 3 mm wide ≥ 3 mm wide (one of which is at least ≥ 3 mm) Complete NR CM: 72 CM: 42 CM: 70.6 CM: 70 CM: 48 root coverage CTG: 81 CTG: 85 CTG: 94.1 CTG: 83 CTG: 70 (%) Mean root CM: 88.5 ± 21.2 CM: 94.32 ± 11.68 CM: 71 ± 21 CM: 89.5 ± 19.2 CM: 91 ± 13 NR coverage (%) CTG: 99.3 ± 3.5 CTG: 96.97 ± 6.74 CTG: 90 ± 18 CTG: 97.5 ± 10.4 CTG: 95 ± 11 Recession CM: –2.78 ± 0.678 CM: –2.86 ± 0.39 CM: –1.3 ± 0.624e CM: –2.61 ± 0.727 CM: –2.6 ± 0.744e CM: –1.7 ± 1.1 depth (mm) CTG: –3.17 ± 0.388 CTG: –2.95 ± 0.69 CTG: –1.6 ± 0.479e CTG: –3.10 ± 0.460 CTG: –2.5 ± 0.84e CTG: –2.1 ± 1.0 Recession CM: –3.22 ± 1.647 NR CM: –2.4 ± 1.021e CM: –2.72 ± 1.769 CM: –2.9 ± 0.822e NR width (mm) CTG: –4.22 ± 0.969 CTG: –3.3 ± 0.915e CTG: –4.04 ± 1.114 CTG: –2.6 ± 0.822e Width of KT CM: 1.11 ± 0.824 CM: 1.23 ± 0.61 CM: 0.3 ± 0.674e CM: 1.34 ± 1.018 CM: 0.8 ± 1.366e CM: –0.1 ± 1.1 (mm) CTG: 1.09 ± 1.599 CTG: 1.27 ± 0.65 CTG: 0.7 ± 0.615e CTG: 1.26 ± 1.526 CTG: 1.0 ± 1.311e CTG: 0.5 ± 1.2 Gingival thick- NR CM: 1.00 ± 0.32 CM: 0.2 ± 0.247e NR NR NR ness (mm) CTG: 1.23 ± 0.47 CTG: 0.5 ± 0.334e Probing CM: 0.50 ± 0.824 CM: 0.27 ± 0.41 CM: –0.1 ± 0.2e CM: 0.34 ± 0.800 NR CM: 0.1 ± 0.7 pocket depth CTG: 0.24 ± 0.751 CTG: 0.23 ± 0.26 CTG: 0 ± 0.2e CTG: 0.32 ± 0.630 CTG: 0.3 ± 0.8 (mm) Clinical CM: –2.26 ± 1.211 CM: –2.41 ± 0.83 CM: –1.3 ± 0.691e CM: –2.28 ± 1.042 CM: –2.6 ± 0.754e NR attachment CTG: –2.85 ± 0.630 CTG: –2.95 ± 0.82 CTG: –1.7 ± 0.525e CTG: –2.70 ± 0.678 CTG: –2.6 ± 0.765e level (mm) Esthetic Not statistically NR CM: 92.9 ± 8.4 NR CM: 98.8 ± 1.9 NR satisfaction significant (data not CTG: 90.6 ± 7.9 CTG: 87.7 ± 18.0 available) Postoperative Not statistically NR CM: 7.3 ± 3.4 NR Test group reported CM: 9.2 ± 14.1 discomfort significant (data not CTG: 12.8 ± 7.5 significantly greater CTG: 11.6 ± 17.6 and morbidity available) pain than control group Operating NR NR CM: 42.5 ± 4.8 NR NR CM: 53.2 ± 17.7 time (min) CTG: 58.6 ± 6.6 CTG: 69.7 ± 24.3 Follow-up 12 12 12 6 6 6 period (mo) Source of Supported in part Geistlich Pharma Funded through a Supported in part NR Supported in part study funding by an educational supplied the col- grant from Geistlich by an educational by an unrestricted grant from lagen membranes grant from grant from Geistlich Pharma used in this research. Geistlich Pharma Geistlich Pharma Method of Computer- Computer- Computer- Computer- Computer- Computer- randomization generated generated generated generated generated generated randomization randomization randomization randomization randomization randomization Blinding Masked examiner Masked examiner Masked examiner Masked examiner Masked examiner Masked examiner and questionnaire aThe long-term observation studies with long-term outcomes of part of patients. bVisual analogue scale was used to evaluate patient-centered outcomes. c#15 UNC Novatech Color-Coded Probe, Hu-Friedy. dCP15 periodontal probe, Carl Martin. eThe missing standard deviation of a mean difference was calculated from a correlation coefﬁcient calculated from a study reported in considerable detail according to the principles and techniques described in the Cochrane Handbook. CM = collagen matrix; CTG = connective tissue graft; VAS = visual analog scale; NR = not reported; KT = keratinized tissue.

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Table 2 Characteristics of Included Studies (in Natural Teeth), continued

McGuire and Jepsen et al,35 Cardaropoli et al,36 Stefanini et al,a Moreira et al,39 Sangiorgio et al,38 Scheyer,40 CM vs CAF alone CM vs CAF alone CM vs CAF alone CM vs CAF alone CM vs CAF alone CM vs FGG Year of 2013 2014 2016 2016 2017 2014 publication Study location Germany, Italy, Italy Germany, Italy Brazil Brazil United States Sweden, and Spain Study design Split-mouth Split-mouth Split-mouth Parallel group Parallel group Split-mouth Participants/ 45/90 32/113 45/90 40/40 34/34 30/60 recession sites Methods of Periodontal Periodontal Periodontal Periodontal Periodontal Periodontal assessment probe,c VASb probec probe,c VASb probe,c VASb probe,c VASb probec Type of Miller Class I and II Miller Class I and II Miller Class I and II Miller Class I or II Miller Class I and II Keratinized tissue defects recession multiple adjacent recession recession recession < 2 mm recession Complete CM: 36 CM: 72 CM: 42 CM: 40 CM: 53 NR root coverage CAF: 31 CAF: 58 CAF: 38 CAF: 35 CAF: 24 (%) Mean root CM: 75.29 ± 26.68 CM: 93.25 ± 10.01 CM: 76.28 ± 28.07 CM: 77 ± 0.21 CM: 87.20 ± 15.01 NR coverage (%) CAF: 72.66 ± 26.19 CAF: 81.49 ± 23.45 CAF: 75.05 ± 26.24 CAF: 72 ± 0.14 CAF: 68.04 ± 24.11 Recession CM: –2.59 ± 1.11 CM: –2.28 ± 0.874e CM: –2.48 ± 1.47 CM: –2.41 ± 0.73 CM: –2.71 ± 0.51 CM: –0.13 ± 0.52 depth (mm) CAF: –2.32 ± 0.99 CAF: –1.85 ± 1.104e CAF: –2.26 ± 1.17 CAF: –2.25 ± 0.50 CAF: –2.16 ± 0.75 FGG: –0.22 ± 0.49 Recession CM: –1.91 ± 1.73 NR CM: –2.07 ± 1.85 NR NR NR width (mm) CAF: –1.84 ± 1.48 CAF: –2.09 ± 1.55 Width of KT CM: 0.93 ± 1.15 CM: 1.07 ± 0.74e CM: 1.06 ± 1.07 CM: 0.20 ± 0.695e CM: 0.35 ± 1.04 CM: 2.04 ± 0.653e (mm) CAF: 0.57 ± 0.98 CAF: 0.7 ± 0.85e CAF: 0.64 ± 1.05 CAF: 0.15 ± 0.775e CAF: 0.30 ± 1.4 FGG: 3.65 ± 0.537e Gingival thick- CM: 0.59 ± 0.44 CM: 0.97 ± 0.403e CM: 0.52 ± 0.46 CM: 0.40 ± 0.19 CM: 0.36 ± 0.47 NR ness (mm) CAF: 0.34 ± 0.55 CAF: 0.13 ± 0.332e CAF: 0.27 ± 0.43 CAF: 0.14 ± 0.29 CAF: 0.13 ± 0.32 Probing CM: –0.11 ± 0.446e CM: 0.06 ± 0.314e CM: –0.07 ± 0.431 CM: –0.05 ± 0.247e CM: –0.18 ± 0.50 CM: 0.08 ± 0.49 pocket depth CAF: –0.29 ± 0.441e CAF: –0.03 ± 0.316e CAF: –0.3 ± 0.411 CAF: 0.10 ± 0.272e CAF: –0.03 ± 0.74 FGG: 0.05 ± 0.55 (mm) Clinical CM: –2.7 ± 1.354e CM: –2.23 ± 0.944e CM: –2.7 ± 1.341 CM: –2.46 ± 0.858 CM: –2.87 ± 0.75 CM: 0.05 ± 0.70 attachment CAF: –2.61 ± CAF: –1.88 ± 1.107e CAF: –2.71 ± 1.217 CAF: –2.15 ± CAF: –2.18 ± 1.11 FGG: –0.12 ± 0.61 level (mm) 1.243e 0.773e e Esthetic NR NR CM: 8.58 ± 1.86 CM: 94.0 ± 10.46 CM: 8.65 ± 1.58 (preference) satisfaction CAF: 8.38 ± 2.46 CAF: 93.5 ± 7.45 CAF: 8.29 ± 1.36 CM: 70 (n = 21) FGG: 30 (n = 9) Postoperative CM: 0.68 ± 1.21 NR NR NR NR NR discomfort CAF: 0.59 ± 0.91 and morbidity Operating CM: 39 ± 14 NR NR NR NR CM: 11.13 ± 3.66 time (min) CAF: 31 ± 14 FGG: 10.73 ± 3.85 Follow-up 6 12 12 6 6 6 period (mo) Source of Supported by a Self-funded Self-funded Supported by the Supported by Supported partly study funding research grant from Piracicaba Dental Research Fund- by an educational Geistlich Pharma School, State Uni- ing Agency from grant provided by versity of Campinas São Paulo State Geistlich Pharma (FAPESP) Method of Computer- Computer- Computer- Computer- Computer- Computer- randomization generated generated generated generated generated generated randomization randomization randomization randomization randomization randomization Blinding Masked examiner Masked examiner Masked examiner Masked examiner Masked examiner Masked examiner and patient aThe long-term observation studies with long-term outcomes of part of patients. bVisual analogue scale was used to evaluate patient-centered outcomes. c#15 UNC Novatech Color-Coded Probe, Hu-Friedy. dCP15 periodontal probe, Carl Martin. eThe missing standard deviation of a mean difference was calculated from a correlation coefﬁcient calculated from a study reported in considerable detail according to the principles and techniques described in the Cochrane Handbook. CM = collagen matrix; CTG = connective tissue graft; VAS = visual analog scale; NR = not reported; KT = keratinized tissue.

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Table 3 Characteristics of Included Studies (in Dental Implants) analysis was applied to these clinical parameters, after which a great Cairo et al,41 Sanz et al,25 Lorenzo et al,42 CM vs CTG CM vs CTG CM vs CTG reduction of these parameters was Year of 2017 2009 2012 detected. Significantly greater out- publication comes in terms of CRC (P < .00001, Study location Italy Spain Spain 2 Study design Parallel group Parallel group Parallel group I = 0%, 95%CI: 1.22 to 1.62), MRC 2 Participants/ 60/60 20/20 24/24 (P = .02, I = 0%, 95%CI: 0.83 to recession sites 8.03), RD (P < .00001, I2 = 0%, Methods of Periodontal North Carolina North Carolina assessment probe,a VASb University probe, VASb University probe, VASb 95%CI: 0.23 to 0.46), and RW (P < 2 Type of defects Single sites Minimal keratinized Minimal keratinized .00001, I = 0%, 95%CI: 0.67 to 1.24) tissue ≤ 1 mm tissue ≤ 1 mm were found in the CTG group com- Recession depth NR NR CTG: 0.5 ± 1.0 pared with the CM group. (mm) CM: 0.4 ± 1.51 As for the CM vs CAF compari- Width of KT (mm) CTG: 0.9 ± 0.8 CTG: 2.4 ± 0.655c CTG: 2.33 ± 1.162c CM: 1.1 ± 0.8 CM: 2.1 ± 0.395c CM: 2.3 ± 0.290c son group (Appendix 5), sensitiv- Gingival thickness CTG: 1.2 ± 0.3 NR NR ity analysis was performed among (mm) CM: 0.9 ± 0.2 MRC, RD, GT, and PPD. Eventually, Probing pocket NR NR CTG: 0.0 ± 1.13 MRC (P < .0001, I2 = 0%, 95%CI: depth (mm) CM: –0.4 ± 1.07 –19.24 to –7.22), RD (P = .02, I2 = 0%, Width of keratinized NR NR NR mucosa (%) 95%CI: –0.56 to –0.05), and GT Esthetic CTG: 91 ± 9 Not significant Not significant (P < .00001, I2 = 0%, 95%CI: –0.36 satisfaction CM: 95 ± 5 to –0.14) turned out to be in favor of Postoperative Less pain favoring CTG: 4.01 ± 8.5 NR discomfort and CM (P < .0001) CM: 2.30 ± 2.39 the CM group at low heterogene- morbidity ity. The CAF group showed greater Operating time Less chair time favor- CTG: 47.20 ± 10 CTG: 46.25 2 (min) ing CM (P < .0001) CM: 30.80 ± 7 CM: 32.50 change in PPD (P = .01, I = 40%, Length of observa- 6 6 6 95%CI: 0.03 to 0.21) than the CM tion period (mo) group after sensitivity analysis. Source of study Partially supported by Partially supported by Supported by a funding a research grant from a research grant from research grant from Geistlich Pharma. Geistlich Pharma. Geistlich Pharma. Method of Computer-generated Code derived from a Computer-generated Subgroup Analysis randomization randomization randomized list randomization Blinding Masked examiner Masked examiner Masked examiner Subgroup analyses were performed a#15 UNC Novatech Color-Coded Probe, Hu-Friedy. bVisual analogue scale was used to evaluate patient-centered outcomes. by two related factors: follow-up cThe missing standard deviation of a mean difference was calculated from a correlation coefﬁcient calculated from a study reported in considerable detail according to the periods and defect categories. Con- principles and techniques described in the Cochrane Handbook. sidering the characteristics of the CM = collagen matrix; CTG = connective tissue graft; VAS = visual analog scale; NR = not reported; KT = keratinized tissue. included studies and the target of the review, for each clinical parameter, only the subgroup with at least Sensitivity Analysis of defects and follow-up periods. two available studies included was Random-effect model was applied eligible for meta-analysis. Eventu- When I2 values were over 50%, sen- among clinical outcomes with high ally, four subgroups were presented sitivity analyses were performed by heterogeneity. in the comparison group CM vs excluding particular studies one by In the CM vs CTG comparison CTG in natural teeth, which were: one, and the results showed that the group (Appendix 4), obvious het- MAGRs, single gingival recession heterogeneity of some clinical out- erogeneity was found regarding (SGR), and the 6- and 12-month comes were both related to types CRC, MRC, RD, and RW. Sensitivity stages. In comparison, in the group

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© 2019 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER. e137 of CM vs CAF alone in natural teeth, CM may not have a better outcome four levels for rating the quality of there was only one eligible study when treating SGR. Regarding CAL, evidence: high, moderate, low, and in the MAGRs group, and thus the the CTG group showed obvious ad- very low, which is identified based on MAGRs subgroup was not avail- vantages over the CM group when the study design (RCT) and specific able for this comparison. Due to treating SGR and achieved better criteria to lower or raise the quality of the limited number of studies and 12-month results, which were not studies included in that group.43 insufficient data, and in an effort to found in the MAGR and 6-month As the results showed in Tables maintain the quality of the analy- subgroups. 4 and 5, all outcomes were identi- sis, no subgroup analysis was per- The results of subgroup analy- fied at a moderate level of quality formed with information provided sis for comparison CM vs CAF alone in the CM vs CTG and CM vs CAF by only one study in other groups or were presented in Appendices 10 alone comparisons. Additionally, clinical parameters. through 12. No difference was de- the only outcomes of the group CM As the results show in Appendi- tected between CM and CAF alone vs CTG for dental implants were ces 6 to 9, the CTG group showed in all subgroups at low heterogene- also identified at moderate level of greater efficiency in achieving CRC in ity in terms of CRC and MRC. Sig- quality (Table 6). the MAGRs and 6-month–observa- nificantly better improvements were tion subgroups, while no difference found in both RD and GT of the SGR was found between the CM and CTG and 6-month subgroups. Although Discussion groups in the SGR and 12-month– the results of RD and GT in the observation subgroups. As for MRC, 12-month–observation subgroup CM was first applied in periodon- only the 6-month subgroup results showed no statistical significance, tal plastic surgeries for augmenta- showed significance with low het- the high heterogeneity may indicate tion of KTW in 2009,25 and a series erogeneity, while no difference was potential demand for more studies of studies and systemic reviews found between the CTG group and to detect the difference. Meanwhile, were subsequently conducted to CM group in the MAGR, SGR, and PPD and KTW in the 12-month sub- evaluate the effectiveness of CM in 12-month subgroups. In terms of group presented better outcomes in treating gingival recession and in- RD, the CTG group presents greater CM group, showing greater efficacy sufficient KT. advantages in the subgroups SGR in achieving stable long-term results. According to a network meta- and 12 months, but limited evidence No significant difference was found analysis published in 2013 that in- was observed to determine the in CAL of the 12-month subgroup. cluded two studies of SGR,17 CM significant difference in the MAGR plus CAF was less effective than and 6-month subgroups. Two sub- ADM with CAF in terms of RD and groups (MAGR and 6 months) of RW Quality Classification of CAL but more effective than enamel showed no statistically significant Evidence of the Review matrix derivative (EMD) with CAF. different outcomes compared to This network meta-analysis sug- the results of the overall analysis of The GRADE system was applied gests that CM is possibly the best the group. CM could present similar to evaluate the quality of evidence option for KT gain. In contrast, CM outcomes in KTW gain in the SGR in the three comparison groups ranks as the last to obtain an advis- subgroup at low heterogeneity, but (CM vs CTG; CM vs CAF alone in able rate of CRC compared with CTG had a significantly higher gain natural teeth; CM vs CTG for den- ADM or EMD. Although this net- in KTW in the MAGR and 12-month– tal implants). Outcomes at low het- work meta-analysis provides wider observation subgroups. The PPD in erogeneity of overall meta-analysis information about the clinical effi- the SGR subgroup showed different or after sensitivity analysis were as- cacy of CM compared with several outcomes compared with the overall sessed by GRADE using a different other periodontal plastic proce- group analysis, which indicated that process. The GRADE system has dures, it involves only two studies

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Table 4 Quality of Evidence from the Comparison of CM and CTG in Natural Teeth Quality assessment No. of patients Effect No. of Risk of Other Relative studies Design bias1 Inconsistency Indirectness Imprecision considerations CM CTG (95% CI) Absolute Quality Importance Complete root coverage (follow-up mean 6 months) 3 Randomized trials Serious No serious inconsistency2 No serious indirectness No serious imprecision None 195/279 137/278 RR 1.40 20 more per 100 Moderate Critical (69.9%) (49.3%) (1.22–1.62) (from 11 more to 31 more) 37.4% 15 more per 100 (from 8 more to 23 more) Recession reduction (follow-up mean 9 months; better indicated by lower values) 4 Randomized trials Serious No serious inconsistency2 No serious indirectness No serious imprecision None 356 357 – MD 0.35 higher Moderate Important (0.23 to 0.46 higher) Changes of recession width (follow-up mean 9 months; better indicated by lower values) 2 Randomized trials Serious No serious inconsistency2 No serious indirectness No serious imprecision None 103 103 – MD 0.95 higher Moderate Important (0.67 lower to 1.24 higher) Width of keratinized tissue (follow-up median 12 months; better indicated by higher values) 5 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 404 415 – MD 0.43 higher Moderate Critical (0.30 to 0.56 higher) Changes of probing pocket depth (follow-up mean 9 months; better indicated by lower values) 4 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 356 357 – MD 0.11 lower Moderate Critical (0.16 to 0.05 lower) Changes in clinical attachment level (follow-up median 12 months; better indicated by lower values) 4 Randomized trials Serious No serious inconsistency2 No serious indirectness No serious imprecision None 173 161 – MD 0.30 higher Moderate Important (0.15 to 0.45 higher) Changes in gingival tissue thickness (follow-up mean 12 months; better indicated by higher values) 2 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 89 89 – MD 0.3 higher Moderate Important (0.21 to 0.38 higher) Esthetic satisfaction (follow-up mean 9 months; better indicated by higher values) 2 Randomized trials Serious No serious inconsistency2 No serious indirectness No serious imprecision None 125 137 – MD 6.4 lower Moderate Important (15.01 lower to 2.2 higher) Postoperative discomfort and morbidity (follow-up mean 9 months; better indicated by lower values) 2 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 169 172 – MD 5.08 lower Moderate Important (6.77 to 3.38 lower) Operating time (follow-up mean 9 months; better indicated by lower values) 2 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 169 172 – MD 16.13 lower Moderate Important (17.87 to 14.40 lower) CM = collagen matrix; CTG = connective tissue graft; CI = confidence interval; RR = risk ratio; MD = mean difference. 1All studies showed unclear risk of bias in the evaluation of quality. 2High heterogeneity. of CM. Another review published in and KTW. No significant difference demonstrates comprehensive eval- 2014 mentions the comparison of was observed between CM and uation of the application of CM in CM vs CAF alone for SGR,44 but only CAF in the parameters CRC and RD, both clinical and patient-centered one study is included in this net- while CM had a statistically greater parameters.26 The results of that re- work meta-analysis. A newly pub- gain of KTW than CAF. Meta-anal- view indicate that CTG presents sig- lished systemic review included two ysis has not been performed in this nificantly higher efficacy compared studies in the comparison of CM vs review, thus no detailed information with CM in improving CRC, RD, CTG for SGR in natural teeth at 6- of comparisons among different GT, and CAL. CM exhibits greater or 12-month follow-ups.45 This latest techniques is provided. changes compared with CAF alone review45 reports similar outcomes in A recent review of six papers in terms of MRC, RD, KTW, and GT. the CM group compared with the firstly reports a systemic evaluation In terms of other clinical parameters, CTG group in terms of CRC, RD, and meta-analysis of CM, which like PPD, RW, or patient-centered

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CAF group). A significantly higher Table 4 Quality of Evidence from the Comparison of CM and CTG in Natural Teeth reduction of PPD was observed in Quality assessment No. of patients Effect CAF group in this review. In terms of No. of Risk of Other Relative patients’ esthetic satisfaction, which 1 studies Design bias Inconsistency Indirectness Imprecision considerations CM CTG (95% CI) Absolute Quality Importance is not mentioned in the published Complete root coverage (follow-up mean 6 months) review, no significant difference was 3 Randomized trials Serious No serious inconsistency2 No serious indirectness No serious imprecision None 195/279 137/278 RR 1.40 20 more per 100 Moderate Critical (69.9%) (49.3%) (1.22–1.62) (from 11 more to 31 more) detected between the two groups. 37.4% 15 more per 100 When compared with CTG, (from 8 more to 23 more) two more papers were included in Recession reduction (follow-up mean 9 months; better indicated by lower values) 4 Randomized trials Serious No serious inconsistency2 No serious indirectness No serious imprecision None 356 357 – MD 0.35 higher Moderate Important the comparison, with CM exhibit- (0.23 to 0.46 higher) ing significantly greater efficiency in Changes of recession width (follow-up mean 9 months; better indicated by lower values) improving PPD as well as reducing 2 Randomized trials Serious No serious inconsistency2 No serious indirectness No serious imprecision None 103 103 – MD 0.95 higher Moderate Important (0.67 lower to 1.24 higher) postoperative discomfort and sur- Width of keratinized tissue (follow-up median 12 months; better indicated by higher values) gery time, which were not mentioned 5 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 404 415 – MD 0.43 higher Moderate Critical in the published review. The non– (0.30 to 0.56 higher) statistically significant differences Changes of probing pocket depth (follow-up mean 9 months; better indicated by lower values) 4 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 356 357 – MD 0.11 lower Moderate Critical noted in MRC and KTW in the pub- (0.16 to 0.05 lower) lished review26 are found significantly Changes in clinical attachment level (follow-up median 12 months; better indicated by lower values) favoring CTG in the present review. 4 Randomized trials Serious No serious inconsistency2 No serious indirectness No serious imprecision None 173 161 – MD 0.30 higher Moderate Important (0.15 to 0.45 higher) An additional measure parameter is Changes in gingival tissue thickness (follow-up mean 12 months; better indicated by higher values) patients’ esthetic satisfaction, which 2 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 89 89 – MD 0.3 higher Moderate Important presented no significant difference (0.21 to 0.38 higher) between the groups. Yet, CTG main- Esthetic satisfaction (follow-up mean 9 months; better indicated by higher values) 2 Randomized trials Serious No serious inconsistency2 No serious indirectness No serious imprecision None 125 137 – MD 6.4 lower Moderate Important tains its advantage in achieving bet- (15.01 lower to 2.2 higher) ter CRC, RD, RW, GT, and CAL in this Postoperative discomfort and morbidity (follow-up mean 9 months; better indicated by lower values) review, as reported above. 2 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 169 172 – MD 5.08 lower Moderate Important (6.77 to 3.38 lower) Moreover, an analysis of the Operating time (follow-up mean 9 months; better indicated by lower values) effectiveness of CM used around 2 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 169 172 – MD 16.13 lower Moderate Important dental implants to improve KT has (17.87 to 14.40 lower) not been previously mentioned, and CM = collagen matrix; CTG = connective tissue graft; CI = confidence interval; RR = risk ratio; MD = mean difference. 1All studies showed unclear risk of bias in the evaluation of quality. this review demonstrates that CM 2 High heterogeneity. can result in advisable outcomes in KT similar to those of CTG. The outcomes like postoperative dis- sis and sensitivity analysis and with analysis potentially indicates with comfort and esthetic satisfaction, two more studies included in the moderate-level evidence that CM the published review provides fi- comparison of CM vs CAF alone in can also reach suitable results in the nite evidence as a result of a limited natural teeth, CM exhibits signifi- treatment of peri-implant–induced number of included studies. cantly greater gains in MRC and KT. insufficient KT. Compared with the previously Though CM also shows greater im- The present review includes mentioned study, the present sys- provement in CRC, this parameter more studies with different follow- temic analysis involves more stud- presents no significant difference up periods and types of defects ies and provides more detailed between two groups after sensitiv- than previously published meta- information for the comparison of ity and subgroup analysis. Signifi- analyses on the same subject. To CM with other techniques. In this re- cant differences were also detected evaluate overall the clinical efficien- view, according to the overall analy- in CAL and GT (favoring the CM and cy of CM, a detailed subgroup and

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Table 5 Quality of Evidence from Comparison of CM and CAF Alone in Natural Teeth Quality assessment No. of patients Effect No. of Risk of Other Relative studies Design bias Inconsistency Indirectness Imprecision considerations CM CAF (95% CI) Absolute Quality Importance Complete root coverage (follow-up mean 9 months) 4 Randomized trials Serious1 No serious inconsistency No serious indirectness No serious imprecision None 60/137 78/140 RR 0.80 11 fewer per 100 Moderate Critical (43.8%) (55.7%) (0.64 to 1.0) (from 20 fewer to 0 more) 40% 8 fewer per 100 (from 14 fewer to 0 more) Recession reduction (follow-up mean 8 months; better indicated by lower values) 3 Randomized trials Serious1 No serious inconsistency2 No serious indirectness No serious imprecision None 182 182 – MD 0.31 lower Moderate Important (0.56 to 0.05 lower) Width of keratinized tissue (follow-up median 6 months; better indicated by higher values) 4 Randomized trials Serious1 No serious inconsistency No serious indirectness No serious imprecision None 137 140 – MD 0.29 lower Moderate Critical (0.50 to 0.09 lower) Changes in gingival tissue thickness (follow-up mean 8 months; better indicated by higher values) 3 Randomized trials Serious1 No serious inconsistency2 No serious indirectness No serious imprecision None 82 82 – MD 0.25 lower Moderate Important (0.36 to 0.14 lower) Changes in probing pocket depth (follow-up mean 10 months; better indicated by lower values) 3 Randomized trials Serious1 No serious inconsistency2 No serious indirectness No serious imprecision None 120 117 – MD 0.12 higher Moderate Important (0.03 to 0.21 higher) Changes in clinical attachment level (follow-up mean 9 months; better indicated by lower values) 4 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 140 137 – MD 0.31 lower Moderate Important (0.56 to 0.07 lower) Esthetic satisfaction (follow-up mean 9 months; better indicated by higher values) 2 Randomized trials Serious1 No serious inconsistency No serious indirectness No serious imprecision None 62 62 – MD 0.25 lower Moderate Important (0.82 lower to 0.31 higher) CM = collagen matrix; CAF = coronally advanced flap; CI = confidence interval; RR = risk ratio; MD = mean difference. 1All studies showed unclear risk of bias in the evaluation of quality. 2High heterogeneity.

Table 6 Quality of Evidence from the Comparison of CM and CTG in Dental Implants Quality assessment No. of patients Effect No. of Risk of Other Relative studies Design bias Inconsistency Indirectness Imprecision considerations CM CTG (95% CI) Absolute Quality Importance Width of keratinized tissue (follow-up mean 6 months; better indicated by higher values) 3 Randomized trials Serious1 No serious inconsistency No serious indirectness No serious imprecision None 50 52 – MD 0.01 lower Moderate Critical (0.29 lower to 0.27 higher) CM = collagen matrix; CTG = connective tissue graft; CI = confidence interval; MD = mean difference. 1All studies showed unclear risk of bias in the evaluation of quality.

sensitivity analysis was performed nificant differences in subgroups this comparison also show no sig- to obtain more information. By SGR and CRC at 6 and 12 months. nificant difference between CM and grouping studies into subgroups of The insignificant results with no ob- CAF. Additionally, the heterogene- various defects and follow-up peri- served heterogeneity may be due ity in the three subgroups is so high ods, the heterogeneity among stud- to the limited number of papers that the truly estimated effects can’t ies was reduced for most clinical included, which were not enough be revealed completely. Lastly, CM parameters. to draw a meaningful conclusion. shows greater effects in improving In the comparison of CM vs Secondly, the MRC for SGR and the KTW at the 12-month stage with no CAF, outcomes initially had insig- 6-month and 12-month stages in heterogeneity observed, which may

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in the SGR and 6-month subgroups, Table 5 Quality of Evidence from Comparison of CM and CAF Alone in Natural Teeth while the CTG group had a great- Quality assessment No. of patients Effect er gain in KTW in the MGR and No. of Risk of Other Relative 12-month subgroups. studies Design bias Inconsistency Indirectness Imprecision considerations CM CAF (95% CI) Absolute Quality Importance In the subgroup analysis, though Complete root coverage (follow-up mean 9 months) different outcomes were provided 4 Randomized trials Serious1 No serious inconsistency No serious indirectness No serious imprecision None 60/137 78/140 RR 0.80 11 fewer per 100 Moderate Critical (43.8%) (55.7%) (0.64 to 1.0) (from 20 fewer to 0 more) than the overall estimated effects 40% 8 fewer per 100 presented before, the unevenly (from 14 fewer to 0 more) presented heterogeneity limited Recession reduction (follow-up mean 8 months; better indicated by lower values) 3 Randomized trials Serious1 No serious inconsistency2 No serious indirectness No serious imprecision None 182 182 – MD 0.31 lower Moderate Important the quality of evidence. Since the (0.56 to 0.05 lower) subgroups were classified by single Width of keratinized tissue (follow-up median 6 months; better indicated by higher values) factors (types of defects or various 4 Randomized trials Serious1 No serious inconsistency No serious indirectness No serious imprecision None 137 140 – MD 0.29 lower Moderate Critical (0.50 to 0.09 lower) follow-up periods), studies of differ- Changes in gingival tissue thickness (follow-up mean 8 months; better indicated by higher values) ent defects could be included in the 3 Randomized trials Serious1 No serious inconsistency2 No serious indirectness No serious imprecision None 82 82 – MD 0.25 lower Moderate Important same follow-up–period subgroup, (0.36 to 0.14 lower) which may explain the high hetero- Changes in probing pocket depth (follow-up mean 10 months; better indicated by lower values) 3 Randomized trials Serious1 No serious inconsistency2 No serious indirectness No serious imprecision None 120 117 – MD 0.12 higher Moderate Important geneity detected. All these results (0.03 to 0.21 higher) suggest that the subgroups for two Changes in clinical attachment level (follow-up mean 9 months; better indicated by lower values) comparisons cannot avoid all poten- 4 Randomized trials Serious No serious inconsistency No serious indirectness No serious imprecision None 140 137 – MD 0.31 lower Moderate Important (0.56 to 0.07 lower) tial factors that may affect the analy- Esthetic satisfaction (follow-up mean 9 months; better indicated by higher values) sis outcomes. Therefore, to increase 2 Randomized trials Serious1 No serious inconsistency No serious indirectness No serious imprecision None 62 62 – MD 0.25 lower Moderate Important the reliability of the results, it is nec- (0.82 lower to 0.31 higher) essary to conduct more clinical trials CM = collagen matrix; CAF = coronally advanced flap; CI = confidence interval; RR = risk ratio; MD = mean difference. 1All studies showed unclear risk of bias in the evaluation of quality. with larger numbers of patients and 2 High heterogeneity. longer observation periods for different defects. Table 6 Quality of Evidence from the Comparison of CM and CTG in Dental Implants Remarkably, the patient- Quality assessment No. of patients Effect centered esthetic-satisfaction analysis in the comparison of CM vs CTG No. of Risk of Other Relative studies Design bias Inconsistency Indirectness Imprecision considerations CM CTG (95% CI) Absolute Quality Importance in natural teeth was performed Width of keratinized tissue (follow-up mean 6 months; better indicated by higher values) based on information provided by 3 Randomized trials Serious1 No serious inconsistency No serious indirectness No serious imprecision None 50 52 – MD 0.01 lower Moderate Critical two MAGR studies. One study34 (0.29 lower to 0.27 higher) reported familiar patient-centered CM = collagen matrix; CTG = connective tissue graft; CI = confidence interval; MD = mean difference. 1All studies showed unclear risk of bias in the evaluation of quality. esthetic satisfaction in SGR with no significant difference, and in the present study, the esthetic satisfac- suggest that CM has better long- 6-month subgroups still slightly fa- tion in the comparison of CM vs term stability in KTW compared vor CTG. In terms of MRC, only the CAF in natural teeth also presented with CAF alone. The difference in 6-month follow-up subgroup was no significant difference in SGR be- KTW at the 6-month stage shows found to be significantly greater in tween the two groups (though the no significant difference. the CTG group, and the other three CM group was favored slightly). As for the comparison of CM subgroups showed insignificant Therefore, CM can possibly provide vs CTG, CM had an effect similar to differences between CM and CTG advisable esthetic satisfaction com- CTG in the SGR and 12-month subgroups in MRC. For KTW, the CM pared with CTG and CAF alone, es- groups in CRC, while the MGR and group showed comparable results pecially for MAGRs in root-coverage

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© 2019 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER. e142 surgeries. An obviously significant (at 6 months) to 95.5% (at 5 years). Acknowledgments difference in postoperative discom- No significant difference in patient fort was also noted in MAGRs in the satisfaction was observed after 5 This paper was self-supported, and the au- comparison of CM vs CTG in natural years. The two studies showed sta- thors have stated explicitly that this research teeth. One study34 in this group re- ble long-term results of CM in both did not receive any specific grant from funding agencies in the public, commercial, or ported insignificant results in SGR, root coverage and patient satisfac- not-for-profit sectors. The authors declare 31 but another study was associated tion, though the changes were in- no conflicts of interest. with more-severe postoperative dis- consistent, and demonstrated that comfort in the CM group of MAGRs. the long-term stability of CM is infe- Most studies suggest that CM could rior to CTG but superior to CAF. References effectively decrease postoperative In summary, not only can the pain and edema, but due to lim- addition of CM effectively improve 1. Nieri M, Pini Prato GP, Giani M, Magnani ited information, there is limited evi- the clinical efficacy of CAF alone, it N, Pagliaro U, Rotundo R. Patient per- ceptions of buccal gingival recessions dence to support these conclusions. is also related with potentially high- and requests for treatment. J Clin Peri- Besides, shorter surgery time in the er patient-centered esthetic sat- odontol 2013;40:707–712. 2. Chambrone L, Chambrone D, Pustiglioni CM group as compared with CTG isfaction and lower postoperative FE, Chambrone LA, Lima LA. Can subgroup was also estimated from two discomfort compared with CTG. epithelial connective tissue grafts be studies30,32 treating MAGRs, and no From this review, it can be inferred considered the gold standard proce- dure in the treatment of Miller Class I and available information was reported that CM is a promising alternative II recession-type defects? J Dent 2008; by studies treating SGRs. for autogenous soft tissue grafts 36:659–671. 3. Lang NP, Löe H. The relationship be- A multicenter clinical trial after in periodontal plastic surgeries. In tween the width of keratinized gingiva 3 years of observation concluded a the future, more high-quality RCTs and gingival health. J Periodontol 1972; long-term stability of CM with two conducted with different defects, 43:623–627. 4. Agudio G, Nieri M, Rotundo R, Cortellini of six centers (18/45 participants) various techniques, and long-term P, Pini Prato G. Free gingival grafts to remained.46 The MRC grew from follow-up periods are suggested to increase keratinized tissue: A retro- spective long-term evaluation (10 to 25 89.9% (at 6 months) up to 91.7% clarify the differences between CM years) of outcomes. J Periodontol 2008; (at 3 years) after surgery in the CM and autogenous soft tissue grafts. 79:587–594. group, while MRC in the CAF group 5. Metin M, Dolanmaz D, Alkan A. Evalu- ation of autogenous grafts used in dropped from 83.7% (at 6 months) vestibuloplasty. J Int Med Res 2003;31: to 82.8% (at 3 years). CRC of the two Conclusions 335–339. 6. Camargo PM, Melnick PR, Kenney EB. groups was the same after 3 years. The use of free gingival grafts for aes- Using a visual analog scale to as- CM is a promising substitute relat- thetic purposes. Periodontol 2000 sess overall satisfaction with the ed with advisable patient-centered 2001;27:72–96. 7. Griffin TJ, Cheung WS, Zavras AI, treatment showed better results in outcomes. CM in combination with Damoulis PD. Postoperative compli- the CM group (9.75) than the CAF CAF is not superior to CTG plus cations following gingival augmentation procedures. J Periodontol 2006; group (9.57). On the contrary, an- CAF in CRC, MRC, and KTW pa- 77:2070–2079. other clinical trial47 comparing the rameters, but CM can effectively im- 8. Wessel JR, Tatakis DN. Patient out- efficacy of CM and CTG treatments prove the clinical efficiency of CAF comes following subepithelial connective tissue graft and free gingival graft at the 5-year follow-up in 17 patients alone in CRC, MRC, and KTW. procedures. J Periodontol 2008;79: reported that the MRC of the CM 425–430. 9. Cairo F, Pagliaro U, Nieri M. Treatment group changed from 89.5% (at 6 of gingival recession with coronally ad- months) to 77.6% (at 5 years), and in vanced flap procedures: A systematic the CTG group changed from 97.5% review. J Clin Periodontol 2008;35(suppl 8):s136–s162.

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10. Chambrone L, Sukekava F, Araújo MG, 20. Ghanaati S, Schlee M, Webber MJ, et 30. Tonetti MS, Cortellini P, Pellegrini G, Pustiglioni FE, Chambrone LA, Lima al. Evaluation of the tissue reaction to et al. Xenogenic collagen matrix or LA. Root-coverage procedures for the a new bilayered collagen matrix in vivo autologous connective tissue graft as treatment of localized recession-type and its translation to the clinic. Biomed adjunct to coronally advanced flaps for defects: A Cochrane systematic review. Mater 2011;6:015010. coverage of multiple adjacent gingival J Periodontol 2010;81:452–478. 21. Camelo M, Nevins M, Nevins ML, Sch- recession: Randomized trial assessing 11. Hofmänner P, Alessandri R, Laugisch upbach P, Kim DM. Treatment of gin- non-inferioirity in root coverage and su- O, et al. Predictability of surgical gival recession defects with xenogenic periority in oral health-related quality of techniques used for coverage of mul- collagen matrix: A histologic report. life. J Clin Periodontol 2018;45:78–88. tiple adjacent gingival recessions—A Int J Periodontics Restorative Dent 31. Cies´lik-Wegemund M, Wierucka- systematic review. Quintessence Int 2012;32:167–173. Młynarczyk B, Tanasiewicz M, Gilowski 2012;43:545–554. 22. Schmitt CM, Tudor C, Kiener K, et al. Ł. Tunnel technique with collagen matrix 12. Sanz M, Simion M, Working Group 3 Vestibuloplasty: Porcine collagen ma- compared with connective tissue graft of the European Workshop on Peri- trix versus free gingival graft: A clini- for treatment of periodontal recession: odontology. Surgical techniques on cal and histologic study. J Periodontol A randomized clinical trial. J Periodontol periodontal plastic surgery and soft 2013;84:914–923. 2016;87:1436–1443. tissue regeneration: Consensus report 23. Vignoletti F, Nuñez J, de Sanctis F, Lo- 32. Aroca S, Molnár B, Windisch P, et al. of Group 3 of the 10th European Work- pez M, Caffesse R, Sanz M. Healing of Treatment of multiple adjacent Miller shop on Periodontology. J Clin Peri- a xenogeneic collagen matrix for kera- Class I and II gingival recessions with odontol 2014;41(suppl 15):s92–s97. tinized tissue augmentation. Clin Oral a modified coronally advanced tunnel 13. Madeley E, Duane B. Coronally ad- Implants Res 2015;26:545–552. (MCAT) technique and a collagen matrix vanced flap combined with connective 24. Herford AS, Akin L, Cicciu M, Maio- or palatal connective tissue graft: A ran- tissue graft; treatment of choice for rana C, Boyne PJ. Use of a porcine domized, controlled clinical trial. J Clin root coverage following recession? Evid collagen matrix as an alternative to au- Periodontol 2013;40:713–720. Based Dent 2017;18:6–7. togenous tissue for grafting oral soft 33. Cardaropoli D, Tamagnone L, Roffredo 14. Guan W. Liao H, Guo L, Wang C, Cao tissue defects. J Oral Maxillofac Surg A, Gaveglio L. Treatment of gingival Z. Root coverage using a coronally ad- 2010;68:1463–1470. recession defects using coronally advanced flap with or without acellular 25. Sanz M, Lorenzo R, Aranda JJ, Martin vanced flap with a porcine collagen dermal matrix: A meta-analysis. J Peri- C, Orsini M. Clinical evaluation of a new matrix compared to coronally advanced odontal Implant Sci 2016;46:22–34. collagen matrix (Mucograft prototype) flap with connective tissue graft: A ran- 15. Cheng GL, Fu E, Tu YK, et al. Root cov- to enhance the width of keratinized domized controlled clinical trial. J Peri- erage by coronally advanced flap with tissue in patients with fixed prosthetic odontol 2012;83:321–328. connective tissue graft and/or enamel restorations: A randomized prospec- 34. McGuire MK, Scheyer ET. Xenogeneic matrix derivative: A meta-analysis. J tive clinical trial. J Clin Periodontol collagen matrix with coronally advanced Periodontal Res 2015;50:220–230. 2009;36:868–876. flap compared to connective tissue with 16. Cairo F, Nieri M, Pagliaro U. Efficacy of 26. Atieh MA, Alsabeeha N, Tawse-Smith coronally advanced flap for the treat- periodontal plastic surgery procedures A, Payne AG. Xenogeneic collagen ment of dehiscence-type recession de- in the treatment of localized facial gin- matrix for periodontal plastic sur- fects. J Periodontol 2010;81:1108–1117. gival recessions. A systematic review. J gery procedures: A systematic review 35. Jepsen K, Jepsen S, Zucchelli G, et al. Clin Periodontol 2014;41(suppl 15):s44– and meta-analysis. J Periodontal Res Treatment of gingival recession defects s62. 2016;51:438–452. with a coronally advanced flap and a 17. Buti J, Baccini M, Nieri M, La Marca M, 27. Moher D, Liberati A, Tetzlaff J, Altman xenogeneic collagen matrix: A multi- Pini-Prato GP. Bayesian network meta- DG, PRISMA Group. Preferred reporting center randomized clinical trial. J Clin analysis of root coverage procedures: items for systematic reviews and meta- Periodontol 2013;40:82–89. Ranking efficacy and identification analyses: The PRISMA statement. BMJ 36. Cardaropoli D, Tamagnone L, Roffredo of best treatment. J Clin Periodontol 2009;339:b2535. A, Gaveglio L. Coronally advanced flap 2013;40:372–386. 28. Miller SA, Forrest JL. Enhancing your with and without a xenogenic collagen 18. Hofmänner P, Alessandri R, Laugisch practice through evidence-based deci- matrix in the treatment of multiple re- O, et al. Predictability of surgical sion making: PICO, learning how to ask cessions: A randomized controlled clini- techniques used for coverage of mul- good questions. J Evid Base Dent Pract cal study. Int J Periodontics Restorative tiple adjacent gingival recessions—A 2001;1:136–141. Dent 2014;34(suppl 3):s97–s102. systematic review. Quintessence Int 29. Higgins JP, Altman DG, Gøtzsche PC, 37. Stefanini M, Jepsen K, de Sanctis M, 2012;43:545–554. et al. The Cochrane Collaboration’s tool et al. Patient-reported outcomes and 19. Cairo F, Pagliaro U, Buti J, et al. 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38. Sangiorgio JPM, Neves FLDS, Rocha 42. Lorenzo R, García V, Orsini M, Martin 46. Jepsen K, Stefanini M, Sanz M, Zuc- Dos Santos M, et al. Xenogenous colla- C, Sanz M. Clinical efficacy of a xeno- chelli G, Jepsen S. Long-term stability gen matrix and/or enamel matrix deriva- geneic collagen matrix in augmenting of root coverage by coronally advanced tive for treatment of localized gingival keratinized mucosa around implants: A flap procedures. J Periodontol 2017;88: recessions: A randomized clinical trial. randomized controlled prospective clin- 626–633. Part I: Clinical outcomes. J Periodontol ical trial. Clin Oral Implants Res 2012;23: 47. McGuire MK, Scheyer ET. Long-term 2017;88:1309–1318. 316–324. results comparing xenogeneic collagen 39. Moreira ARO, Santamaria MP, Silvério 43. Aguayo-Albasini JL, Flores-Pastor B, matrix and autogenous connective tis- KG, et al. Coronally advanced flap with Soria-Aledo V. GRADE system: Clas- sue grafts with coronally advanced flaps or without porcine collagen matrix for sification of quality of evidence and for treatment of dehiscence-type reces- root coverage: A randomized clinical tri- strength of recommendation [in Span- sion defects. J Periodontol 2016;87:221– al. Clin Oral Investig 2016;20:2539–2549. ish]. Cir Esp 2014;92:82–88. 227. 40. McGuire MK, Scheyer ET. Randomized, 44. Cairo F, Nieri M, Pagliaro U. Efficacy of controlled clinical trial to evaluate a xe- periodontal plastic surgery procedures nogeneic collagen matrix as an alter- in the treatment of localized facial gin- native to free gingival grafting for oral gival recessions. A systematic review. soft tissue augmentation. J Periodontol J Clin Periodontol 2014;41(suppl 15): 2014;85:1333–1341. s44–s62. 41. Cairo F, Barbato L, Tonelli P, Batalocco 45. Amine K, El Amrani Y, Chemlali S, Kissa G, Pagavino G, Nieri M. Xenogeneic col- J. Alternatives to connective tissue graft lagen matrix versus connective tissue in the treatment of localized gingival re- graft for buccal soft tissue augmentation cessions: A systematic review. J Stoma- at implant site. A randomized, controlled tol Oral Maxillofac Surg 2018;119:25–32. clinical trial. J Clin Periodontol 2017; 44:769–776.

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Appendix 1 Comparison of CM vs CTG in Natural Teeth. (1) CRC = complete root coverage; (2) MRC = mean root coverage; (3) RD = recession reduction; (4) RW = changes of recession width; (5) KTW = width of keratinized tissue; (6) PPD = changes of probing pocket depth; (7) CAL = changes in clinical attachment level; (8) GT = changes in gingival tissue thickness; (9) Aesthetic satisfaction; (10) Postoperative discomfort; (11) Surgery time. CM = collagen matrix; CTG = connective tissue graft.

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Appendix 2 Comparison of CM vs CAF in Natural Teeth. (1) CRC = complete root coverage; (2) MRC = mean root coverage; (3) RD = recession reduction; (4) KTW = width of keratinized tissue; (5) GT = changes in gingival tissue thickness; (6) PPD = changes of probing pocket depth; (7) CAL = changes in clinical attachment level; (8) Aesthetic satisfaction. CM = collagen matrix; CAF = coronally advanced flap.

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Appendix 3 KTW (Comparison of CM vs CTG in Dental Implants). KTW = width of keratinized tissue; CM = collagen matrix; CTG = connective tissue graft.

Appendix 4 Heterogeneity Analysis for Comparison of CM vs CTG in Natural Teeth. (1) CRC = complete root coverage; (2) MRC = mean root coverage; (3) RD = recession reduction; (4) RW = changes of recession width. CM = collagen matrix; CTG = connective tissue graft.

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Appendix 5 Heterogeneity Analysis for Comparison of CM vs CAF in Natural Teeth. (1) MRC = mean root coverage; (2) RD = recession reduction; (3) GT = changes in gingival tissue thickness; (4) PPD = changes of probing pocket depth. CM= collagen matrix; CAF = coronally advanced flap.

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Appendix 6 Subgroup Analysis in CM vs CTG for MAGRs in Natural Teeth. (1) CRC = complete root coverage; (2) MRC = mean root coverage; (3) RD = recession reduction; (4) RW = changes of recession width; (5) KTW = width of keratinized tissue; (6) CAL = changes in clinical attachment level; (7) PPD = changes of probing pocket depth. CM = collagen matrix; CTG = connective tissue graft; MAGR = multiple adjacent gingival recession.

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Appendix 7 Subgroup Analysis in CM vs CTG for SGR in Natural Teeth. (1) CRC = complete root coverage; (2) MRC = mean root coverage; (3) RD = recession reduction; (4) KTW = width of keratinized tissue; (5) PPD = changes of probing pocket depth; (6) CAL = changes in clinical attachment level. CM = collagen matrix; CTG = connective tissue graft; SGR = single gingival recession.

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Appendix 8 Subgroup Analysis in CM vs CTG for the 6-Month Stage in Natural Teeth. (1) CRC = complete root coverage; (2) MRC = mean root coverage; (3) RD = recession reduction; (4) RW = changes of recession width; (5) CAL = changes in clinical attachment level; (6) KTW = width of keratinized tissue. CM = collagen matrix; CTG = connective tissue graft.

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Appendix 9 Subgroup Analysis in CM vs CTG for the 12-Month Stage in Natural Teeth. (1) CRC = complete root coverage; (2) MRC = mean root coverage; (3) RD = recession reduction; (4) CAL = changes in clinical attachment level; (5) KTW = width of keratinized tissue. CM = collagen matrix; CTG = connective tissue graft.

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Appendix 10 Subgroup Analysis in CM vs CAF Alone for SGR in Natural Teeth. (1) CRC = complete root coverage; (2) MRC = mean root coverage; (3) RD = recession reduction; (4) GT = changes in gingival tissue thickness; (5) PPD = changes of probing pocket depth. CM = collagen matrix; CAF = coronally advanced flap; SGR = single gingival recession.

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Appendix 11 Subgroup Analysis in CM vs CAF Alone for the 6-Month Stage in Natural Teeth. (1) CRC = complete root coverage; (2) MRC = mean root coverage; (3) GT = changes in gingival tissue thickness; (4) RD = recession reduction; (5) PPD = changes of probing pocket depth; (6) KTW = width of keratinized tissue; (7) CAL = changes in clinical attachment level. CM = collagen matrix; CAF = coronally advanced flap; SGR = single gingival recession.

The International Journal of Periodontics & Restorative Dentistry

Appendix 12 Subgroup Analysis in CM vs CAF Alone for the 12-Month Stage in Natural Teeth. (1) CRC = complete root coverage; (2) MRC = mean root coverage; (3) RD = recession reduction; (4) GT = changes in gingival tissue thickness; (5) KTW = width of keratinized tissue; (6) PPD = changes of probing pocket depth; (7) CAL = changes in clinical attachment level. CM = collagen matrix; CAF = coronally advanced flap.

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