© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

J Periodont Res 2015 All rights reserved

JOURNAL OF PERIODONTAL RESEARCH doi:10.1111/jre.12333

Review article

Xenogeneic collagen matrix for periodontal plastic surgery procedures: a systematic review and meta-analysis

M. A. Atieh1, N. Alsabeeha2, A. Tawse-Smith3, A. G. T. Payne4 1

Private Practice, Christchurch, New Zealand, Prosthetic Section, Ras Al-Khaimah Dental Centre, Ministry of Health, Ras Al-Khaimah, United Arab Emirates, 3Sir John Walsh Research Institute, Dean’s Office, Faculty of Dentistry, University of Otago, Dunedin, New Zealand and 4Private Practice, Whangarei, Northland, New Zealand 2

Atieh MA, Alsabeeha N, Tawse-Smith A, Payne AGT. Xenogeneic collagen matrix for periodontal plastic surgery procedures: a systematic review and metaanalysis. J Periodont Res 2015; doi: 10.1111/jre.12333. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Several clinical trials describe the effectiveness of xenogeneic collagen matrix (XCM) as an alternative option to surgical mucogingival procedures for the treatment of marginal tissue recession and augmentation of insufficient zones of keratinized tissue (KT). The aim of this systematic review and meta-analysis was to evaluate the clinical and patient-centred outcomes of XCM compared to other mucogingival procedures. Applying guidelines of the Preferred Reporting Items for Systematic Reviews and Meta analyses statement, randomized controlled trials were searched for in electronic databases and complemented by hand searching. The risk of bias was assessed using the Cochrane Collaboration’s Risk of Bias tool and data were analysed using statistical software. A total of 645 studies were identified, of which, six trials were included with 487 mucogingival defects in 170 participants. Overall meta-analysis showed that connective tissue graft (CTG) in conjunction with the coronally advanced flap (CAF) had a significantly higher percentage of complete/mean root coverage and mean recession reduction than XCM. Insufficient evidence was found to determine any significant differences in width of KT between XCM and CTG. The XCM had a significantly higher mean root coverage, recession reduction and gain in KT compared to CAF alone. No significant differences in patient’s aesthetic satisfaction were found between XCM and CTG, except for postoperative morbidity in favour of XCM. Operating time was significantly reduced with the use of XCM compared with CTG but not with CAF alone. There is no evidence to demonstrate the effectiveness of XCM in achieving greater root coverage, recession reduction and gain in KT compared to CTG plus CAF. Superior short-term results in treating root coverage compared with CAF alone are possible. There is limited evidence that XCM may improve aesthetic satisfaction, reduce postoperative morbidity and shorten the operating time. Further longterm randomized controlled trials are required to endorse the supposed advantages of XCM.

Momen A. Atieh, Independent Researcher, Periodontist, Milford Chambers, 249 Papanui Road, Merivale, Christchurch 8014, New Zealand Tel: +64 211 878 327 e-mail: [email protected] Key words: collagen; gingival recession; meta-

analysis; review Accepted for publication September 10, 2015

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Atieh et al.

Conventional periodontal plastic surgical procedures, such as coronally or laterally advanced flaps, autogenous soft tissue grafts, periosteal retention, denudation procedures, free gingival grafts (FGGs) and combination procedures have been historically used for treatment of marginal tissue recession (MTR) and insufficient keratinized tissue (KT) with predictable outcomes (1–7). Today, the connective tissue graft (CTG) in conjunction with a coronally advanced flap (CAF) remains the gold standard for the treatment of MTR in terms of percentage of root coverage (8,9), whereas FGG remains the treatment of choice for widening the zone of KT (10–12). Conventional mucogingival procedures by virtue of their necessity for a second surgical site result in high morbidity and are associated with postsurgical bleeding, patient discomfort and poor aesthetic outcomes. The multiple simultaneous treatment sites are clinically challenging because of the limited supply of donor tissues (13,14). To overcome such limitations, shifting treatment paradigms has been a preference for alternative surgical procedures using membranes and allografts. These recent techniques would allow treatment of multiple sites in one surgical intervention, preclude the need for a donor site, reduce the operating time and enhance the colour and texture match (15–19). Several short-term studies have shown that alternative grafting materials such as acellular dermal matrix (ADM) are comparable to autogenous soft tissue graft in terms of complete root coverage, reduction in soft tissue recession and KT gain (17,20– 24). A recent systematic review by Pini-Prato et al. (25) comparing ADM to CTG has shown similar outcomes between the two procedures in terms of complete root coverage but not in other clinical parameters of aesthetics, pain and overall prospective morbidity. The lack of comprehensive assessment of these parameters among current studies does not allow robust evaluation of the anticipated advantages of alternative procedures.

Recently, a new two-layer xenogeneic collagen matrix (XCM) (MucograftÒ; Geistlich Pharma, Wolhusen, Switzerland) for regenerative therapy around teeth and implants has been cleared by the European Union and United States Food and Drug Administration. This resorbable, threedimensional matrix is made up of pure types I and III collagen without cross-linking or chemical treatment. It has two components, i.e. (i) a compact structure of denser collagen and smooth texture to enhance wound healing and facilitate cell adhesion, and (ii) a porous surface facing the host tissue that supports clot formation, tissue integration and angiogenesis (26,27). The use of XCM in the treatment of MTR has shown promising results and thought to be a suitable substitute to the more common autogenous graft harvesting for mucogingival surgical procedures (27–29). Most of these studies are on small sample sizes that report controversial results. There is a need to review systematically the use of XCM and evaluate the clinical and patient-centred parameters to provide evidence-based decisions on its routine use. The aims of this systematic review and metaanalysis were to evaluate the use of XCM in comparison with CTG, CAF and FFG for the treatment of MTR and/or insufficient KT in terms of clinical parameters [root coverage, recession reduction, gain in KT, changes in probing pocket depth (PPD) and clinical attachment level and operating time] and patientrelated outcomes (aesthetic satisfaction, postoperative morbidity and discomfort).

Material and methods The systematic review was prepared according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (30) and the Cochrane Collaboration (31). The current review addresses a clearly focused question using the participant, intervention, comparison, outcome approach (32):

Participant: Patients with recession defects or lack of KT that needed a mucogingival procedure. Intervention: XCM. Comparison: Commonly used mucogingival procedures. Outcomes: Recession reduction, gain in KT, changes in PPD and clinical attachment level, and patient-related factors.

Types of studies Inclusion criteria— Inclusion criteria were randomized controlled trials (RCTs) that compared XCM with conventional mucogingival procedures in human study populations around teeth. They needed to report on root coverage, reduction of recession, gain of KT, changes in PPD and clinical attachment level as well as patientrelated outcomes including aesthetic satisfaction and morbidity. No language restrictions were applied. Exclusion criteria— Exclusion criteria were non-RCTs, retrospective, crosssectional, case series, case reports and those that did not provide enough information on the above parameters. Outcome measures Primary outcomes— Primary outcome measures are: percentage of complete root coverage (%); mean root coverage (%); recession reduction (mm); and gain in KT (mm). Secondary outcomes— Secondary outcome measures are: changes in gingival thickness (mm); changes in clinical attachment level (mm); changes in PPD (mm); participant’s aesthetic satisfaction; postoperative discomfort and morbidity; and operating time (min). Search strategy

The following electronic databases were searched for ongoing and unpublished trials up to January 12 2015: MEDLINE, EMBASE, The Cochrane Central Register of Controlled Trials

XCM for mucogingival surgery (CENTRAL), MetaRegister, Clinical Trials.gov, and the System for Information on Grey Literature in Europe (http://www.opengrey.eu) (Table 1). The search was performed independently and in duplicate by two authors (M.A. and N.A.). The bibliographies of all eligible papers were scrutinized for additional studies. A hand-search of the last 5 years of relevant dental journals (International Journal of Periodontics and Restorative Dentistry, Journal of Clinical Periodontology, Journal of Periodontal Research, Journal of Periodontology and Quintessence International) was carried out to identify potential papers. Selection of studies

Two reviewers (M.A. and N.A.) independently screened the retrieved citations in duplicate to identify relevant studies. The eligibility of initial citations was assessed on the basis of the title, abstract and keywords. The full texts of potentially relevant papers were then obtained and assessed for inclusion using an eligibility form. Any disagreements on the selection of studies were resolved by discussion and the reasons for excluding irrelevant papers were documented. Data collection

The following information was extracted independently by the two

authors (M.A. and N.A.) using a predesigned data extraction form: (i) study details: title, authors’ names, contact address, study location, language of publication, year of publication, published or unpublished data, source of study funding, study design (parallel group or split mouth), method of randomization, duration of study, allocation concealment and blinding (participants, investigators, outcome assessors); (ii) participants: demographic characteristics, inclusion/exclusion criteria, number of participants in test and control groups, number of withdrawals and reasons for dropouts; (iii) intervention: the use of XCM for treating MTR and/or insufficient KT; (iv) comparison: traditional techniques (i.e. CAF with or without CTG and FGG); (v) outcomes; and (vi) length of observation period. Any disagreements were resolved by reaching a consensus. Additional data were obtained by contacting corresponding authors of the included studies. Assessment of quality and risk of bias

The two reviewers (M.A. and N.A.) independently assessed the selected studies in duplicate to determine the risk of bias using the Cochrane Collaboration’s Risk of Bias tool (31). The tool comprises seven domains (sequence generation, allocation

Table 1. Databases and search terms Databases

Keywords

Published studies PubMed (1965 – January 12, 2015)

(gingival recession* OR marginal tissue recession* OR root coverage OR keratinized gingiva OR mucogingival surgery OR mucogingival therapy OR periodontal surgery) AND (collagen matrix OR xeno* collagen) (gingival recession/OR marginal tissue recession.mp. OR root coverage.mp. OR keratinized gingiva.mp. OR mucogingival.mp. OR periodontal surgery.mp.) AND (collagen OR (xeno collagen adj5 matrix)).mp. (exp gingival recession OR mucogingival.mp. OR periodontal surgery.mp.) AND (collagen OR collagen adj5 matrix OR xeno).mp

EMBASE via Ovid (1974 – January 12, 2015)

Cochrane Central Register of Controlled Trials (CENTRAL) via Ovid (January 12, 2015) Unpublished studies MetaRegister of controlled trials OpenGrey (www.opengrey.eu) ClinicalTrials.gov (August 20, 2014)

(gingival recession or mucogingival surgery or mucogingival therapy or periodontal surgery or collagen or collagen graft or xenogeneic collagen)

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concealment, blinding of participants and investigators, blinding of outcome assessment, incomplete data outcome, selective outcome reporting and potential sources of bias). The first part of the tool described each domain while the second part categorized the studies into those having: (i) low risk of bias if all the criteria were met; (ii) unclear risk of bias if one or more criteria were partially met; or (iii) high risk of bias if one or more criteria were not met. Data analysis

Data were analysed using a statistical software program (Review Manager (RevMan) software, version 5.0, The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). Dichotomous data such as the percentage of root coverage were expressed as risk ratio (RR) estimates and 95% confidence intervals (CIs). Continuous data such as recession reduction, gain in KT and clinical attachment level were expressed as mean difference (MD) and 95% CIs. When the standard deviation of the mean difference was not reported, the square root of the sum of the variances of the measures was used to compute the standard deviation, with a conservative assumption that the covariance between treatment groups was zero. A fixed-effects model was used to pool the results from more than one study except where notable heterogeneity was present in which case the random-effects model was used. The generic inverse variance option in the statistical software program was used to combine both split mouth and parallel group trials. With fewer than 10 studies, publication bias was not formally assessed because the power to detect publication bias is limited (31). The statistical heterogeneity between trials was tested by means of the Cochran’s test for heterogeneity and I2 statistic. An I2 value of > 50 indicated a significant heterogeneity. The unit of analysis was the recession site rather than the participant, as the outcomes may vary among the treated sites.

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Results Characteristics of the trial settings and investigators

Identification

A total of 645 references were identified from the databases (Fig. 1). Titles and abstracts were assessed independently and in duplicate by two review authors (M.A. and N.A.). Only 14 studies were eligible for full text evaluation, of which, eight studies were excluded (26,33–38). The remaining six trials, on adult participants only, were included for the present review (39–44) (Table 2). The hand search did not provide any further studies. Of the six included studies, two were conducted in the United States (43,44), two in Italy (40,41), one in Switzerland (39) and

one multicentre trial that was conducted in Germany, Italy, Sweden and Spain (42). Study designs were described as split-mouth in four trials (39,42–44) and parallel group in two trials (40,41). Five trials were supported by the XCM manufacturing industry, while one was self-funded (41). Four trials were conducted at private practice setting, one in a university setting (39), while the multicentre study (42) was conducted in both settings.

Characteristics of the interventions

1 XCM vs. CTG: three trials (39,40,43). 2 XCM vs. CAF: two trials (41,42). 3 XCM vs. FGG: one trial (44).

Total studies identified from electronic database after duplicates removed (n = 645)

Total studies identified from other sources (n = 0)

Screening

Studies excluded after title and abstract screening (n = 631)

Eligibility

Full-text articles retrieved for detailed evaluation (n = 14)

Full-text excluded (n = 8) for the following reasons: -

Inclusion

-

Final number of studies included in the review (n = 6) (Aroca et al. 2013; Cardaropoli et al. 2012; Cardaropoli et al. 2014; Jepsen et al. 2013; McGuire and Scheyer 2010; McGuire and Scheyer 2014)

Fig. 1. Flowchart of the search process.

-

-

Randomization was not clear (Castro and Grados 2014; Nevins et al. 2010; Nevins et al. 2011) Case series or reports (Molnar et al. 2013; Schlee et al. 2014; Rotunda and Pini-Prato 2012) Separate data for teeth sites could not be obtained (Sanz et al. 2009) Animal study (Sculean et al. 2014)

Characteristics at baseline Inclusion criteria—

1 Age ≥ 18 years of age (39,42–44). 2 Periodontally and systemically healthy participants (39). 3 Adequate plaque control with full mouth plaque score ≤ 25% (39) and ≤ 20% (42). 4 Type of defects: a Miller’s class I or II (39–42). b Dehiscence-type recession defects (≥ 3 mm deep by > 3 mm wide) (43). c Insufficient zones of KT < 2 mm (44).

Exclusion criteria—

1 Uncontrolled medical conditions or systemic contraindications to surgery (39–44). 2 Diseases affecting connective tissue metabolism (42). 3 Infectious diseases (39,44). 4 Presence of acute infectious lesions in the area intended for surgery (44). 5 Use of systemic antibiotics for endocarditis prophylaxis or in the past 3 mo (39). 6 Medications or having treatments with an effect on mucosal healing in general (e.g. steroids, large doses of anti-inflammatory drugs) (42). 7 Taking intramuscular or intravenous bisphosphonates (44). 8 Pregnant or lactating females (39– 44). 9 Smoking (39–44). 10 History of a gingival grafting procedure on the test or control teeth or the teeth adjacent to the study site (44). 11 Drug and alcohol abuse (39). 12 Allergic to collagen and/or allergy to iodine or shellfish (42,44). 13 Molars, mobile teeth and crowns and bridges (40,43). 14 Participants in other clinical trials involving therapeutic interventions (either medical or dental) within the past 6 mo (42,44).

XCM: 72 CTG: 81 XCM: 94.32  11.68 CTG: 96.97  6.74 XCM: 2.86  0.39 CTG: 2.95  0.69 XCM: 1.23  0.61 CTG: 1.27  0.65 XCM: 1.00  0.32 CTG: 1.23  0.47 XCM: 0.27  0.41 CTG: 0.23  0.26 XCM: 2.41  0.83 CTG: 2.95  0.82 NR

XCM: 42 CTG: 85

XCM: 71  21 CTG: 90  18 XCM: 1.30  0.78c CTG: 1.60  0.58c XCM: 0.3  1.14c CTG: 0.7  1.06c XCM: 0.20  0.36c CTG: 0.50  0.25c XCM: 0.00  0.36c CTG: 0.00  0.36c XCM: 1.3  0.85 CTG: 1.7  0.64 Patient satisfaction (VAS) XCM: 92.9  8.4 CTG: 90.6  7.9

Gingival thickness (mm) Probing pocket depth (mm) Clinical attachment level (mm) Aesthetic satisfactione

2

2

Time of suture removal (weeks) Complete root coverage (%) Mean root coverage (%) Recession reduction (mm) Width of KT (mm)

Miller’s class I and II MTR with recession depth ranging 2.5–4.5 mm and KT ranging 1–3.5 mm

Miller’s class I and II MTR with recession depth > 2 mm

Periodontal probea no. 15 reamer

b

PROED Institute for Professional Education in Dentistry, Turin, Italy 18/22

RCT (parallel group)

Cardaropoli et al. (40) (XCM vs. CTG)

Type of defects

Periodontal probea VAS

22/156

Number recruited (participants/ recession sites) Method of assessment

Location

RCT (split-mouth design) University of Bern, Bern, Switzerland

Study design

Aroca et al. (39) (XCM vs. CTG)

Table 2. Characteristics of the included studies

XCM: 0.50  0.79d CTG: 0.24  0.72d XCM: 2.26  1.16d CTG: 2.85  0.60d No statistically significant treatment difference in texture match (data not available for analysis)

XCM: 88.5  21.2d CTG: 99.3  3.5d XCM: 2.78  0.64d CTG 3.17  0.36d XCM: 1.11  0.79d CTG: 1.09  1.53d NR

NR

Dehiscence-type recessions measuring ≥ 3 mm deep by > 3 mm wide and KT widths ranging from 0.5 to 5 mm NR

Periodontal probea VAS

25/50

RCT (split-mouth design) Private practice, Houston, TX, USA

McGuire and Scheyer (43) (XCM vs. CTG)

XCM: 93.25  10.01 CAF: 81.49  23.45 XCM: 2.28  1.00c CAF: 1.85  1.38c XCM: 1.07  1.25c CAF: 0.7  1.48c XCM: 0.97  0.61c CAF: 0.13  0.51c XCM: 0.06  0.62c CAF: 0.03  0.63c XCM: 2.23  1.13c CAF: 1.88  1.35c NR

XCM: 72 CAF: 58

2

Miller’s class I and II MTR with recession depth ranging 1 to 5 mm

Periodontal probea no. 15 reamer

PROED Professional Education in Dentistry, Turin, Italy 32/113

RCT (parallel group)

Cardaropoli et al. (40) (XCM vs. CAF)

NR

NR

Periodontal probea Injection needleb and a silicon marker VAS Miller’s class I and II MTR with no more than 2 mm difference in recession depth of two defects within one patient 1 (lateral sutures) 2 (sling sutures) XCM: 36 CAF: 31 XCM: 75.29  26.68 CAF: 72.66  26.19 XCM: 2.59  1.11 CAF: 2.32  0.99 XCM: 0.93  1.15 CAF: 0.57  0.98 XCM: 0.59  0.44 CAF: 0.34  0.55 NR

RCT (split-mouth design) Multicenter (Germany, Italy, Sweden and Spain) 45/90

Jepsen et al. (42) (XCM vs. CAF)

XCM: 0.08  0.49 FGG: 0.05  0.55 XCM: 0.05  0.70 FGG: 0.12  0.61 70% preferred XCM 30% preferred FGG

XCM: 0.13  0.52 FGG: 0.22  0.49 XCM: 2.04  1.07c FGG: 3.65  0.93c NR

NR

NR

NR

Insufficient zones of KT (< 2 mm)

Periodontal probea Schiller iodine

30/60

RCT (split-mouth design) Private practice, Houston, TX, USA

McGuire and Scheyer (44) (XCM vs. FGG)

XCM for mucogingival surgery

5

12 12 12

NR NR

XCM: 42.5  4.8 CTG: 58.6  6.6 12 Operating time (min) Follow-up period (mo)

CAF, coronally advanced flap; CTG, connective tissue graft; FGG, free gingival graft; KT, keratinized tissue; MTR, marginal tissue recession; NR, not reported; RCT, randomized controlled trial; XCM, xenogeneic collagen matrix. a PCP UNC-15 (Hu-Friedy, Chicago, IL, USA). b Sopira Carpule 0.3 9 16 mm (Heraeus Kulzer, Hanau, Germany). c Standard deviation obtained from the sum of variances of the measures (assuming the covariance between treatment groups was zero). d Standard deviation was obtained from confidence intervals for treatment group means. e Visual analogue scale was used to evaluate participant-related outcomes.

XCM: 11.13  3.66 FGG: 10.73  3.85 6

NR

Pain evaluation by VAS: 7d XCM: 2.32  2.08 CAF: 2.04  1.82 14 d XCM: 0.68  1.21 CAF: 0.59  0.91 XCM: 39  14 CAF: 31  14 6 NR

No statistically significant treatment difference between sites in VAS pain scores at 1 wk, 4 wks, or 6 mo (Data not available for analysis) NR NR Patient complaints (VAS) XCM: 7.3  3.4 CTG: 12.8  7.5 Postoperative discomfort and morbiditye

Aroca et al. (39) (XCM vs. CTG)

Cardaropoli et al. (40) (XCM vs. CTG)

McGuire and Scheyer (43) (XCM vs. CTG)

Cardaropoli et al. (40) (XCM vs. CAF)

Jepsen et al. (42) (XCM vs. CAF)

McGuire and Scheyer (44) (XCM vs. FGG)

Atieh et al.

Table 2. (continued)

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Characteristics of the interventions

All the trials used local anaesthetic only. The six included trials covered a wide variety of interventions and comparisons, which were grouped under three categories. 1 XCM vs. CTG: three trials (39,40,43) compared the use of XCM with CTG in conjunction with CAF for treatment of Miller’s class I and II MTR and dehiscencetype recessions measuring ≥ 3 mm deep by > 3 mm wide. Two trials (40,43) used CAF to achieve soft tissue coverage whereas one trial (39) used a modified coronally advanced tunnel technique to prepare the receiving bed. In one trial (43), the exposed root surface was treated with 24% EDTA for 2 min to remove the smear layer while root planing was performed in all trials. Based on anatomical and morphological factors, CTG was harvested from the posterior palate using several techniques (45–47). 2 XCM vs. CAF: two trials (41,42) compared the use of XCM (in combination with CAF) with CAF alone for the treatment of Miller’s class I and II MTR. One trial (41) used a modified CAF procedure for multiple recession sites. The technique involved an oblique submarginal incision in the interdental areas with intrasulcular incision at the recession defects. The other trial (42) used a CAF procedure, as described by de Sanctis and Zucchelli (48). 3 XCM vs. FGG: one trial (44) compared the use of XCM with FGG for the treatment of insufficient zones of KT (< 2 mm). A technique, as described by Bjorn (1), was used in this trial (44). The recipient bed was prepared slightly larger than the XCM and FGG grafts using a split-thickness approach and a full-thickness one to separate the periosteum and remove the muscle fibres. XCM was prepared as widely as possible to compensate for shrinkage. All the trials followed a standard postoperative care regimen that

XCM for mucogingival surgery

and FFG were used for the treatment of the remaining 60 sites in 30 participants who had insufficient KT width KT (< 2 mm).

involved the use of chlorhexidine mouth rinse for the first 2 wk, prevention of excessive muscle traction or trauma, and brushing using a soft toothbrush with minimal pressure to the soft tissues following suture removal. Professional oral hygiene recalls were scheduled 3 and 6 mo postoperatively. Oral antibiotics and analgesics were prescribed in five of the six trials (39–43).

Xenogeneic collagen matrix vs. connective tissue graft

Characteristics of the outcome measures Primary outcome measures—

1 Percentage of complete root coverage (39–42). 2 Mean root coverage (39–43). 3 Recession reduction (39–44). 4 Gain in KT (39–44).

Secondary outcome measures—

1 Changes in gingival thickness (39,40, 42–44). 2 Changes in PPD (39–41,43,44). 3 Changes in clinical attachment level (39–41,43,44). 4 Participant’s aesthetic satisfaction (39,43,44). 5 Postoperative discomfort and morbidity (39,42,43). 6 Operating time (39,42,44).

Risk of bias in included studies

The assessment of risk of bias is summarized in Fig. 2. Allocation (selection bias)— The random sequence generation was clearly described in all the trials and was assessed at low risk of bias for this domain. One trial (42) described adequate concealment of allocation and was assessed at low risk of bias for this domain. The remaining five studies (39–41,43,44) did not provide sufficient information to enable a clear judgement and hence considered under unclear risk of bias. Blinding— Blinding of participants to the selected intervention was not

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Fig. 2. Risk of bias summary.

possible due to the nature of intervention, which required either a second surgical site to obtain autogenous soft tissue grafts or the use of xenogeneic grafts only. On the other hand, blinding of outcome assessment was both possible and essential to reduce the risk of detection bias. All the trials (39–44) clearly reported blinded outcome assessment and therefore were assessed as low risk of bias for this domain. Incomplete outcome data and selective reporting— In all trials, the outcome

data were reported in full without any withdrawals and the risks of attrition and reporting bias were assessed as low. Other potential sources of bias— Only one of the six trials (41) was selffunded. The remaining trials declared support from the manufacturer of the XCM being tested either in the form of material supply or research grant and therefore were assessed at unclear risk for this domain. Effects of interventions

In total, 487 mucogingival defects in 170 participants were included in this review; of which 427 recession defects were treated in 140 participants using XCM, CAF and CTG in conjunction with CAF. In one trial (44), XCM

Three trials (39,40,43) at unclear risk of bias were included in the meta-analyses. In primary outcomes, the complete root coverage ranged 42–72% for the test group and 81–85% for the control group, while the mean root coverage ranged 71  21 to 94.32  11.68% and 90  18 to 99.3  3.5% for the test and control groups, respectively. The mean recession reduction ranged 1.30  0.78 mm to 2.86  0.39 mm for the test group and 1.60  0.58 to 3.17  0.36 mm. The overall meta-analysis showed that CTG had significantly higher percentage of complete root coverage (RR 1.85; 95% CI 1.10–3.11; p = 0.02) (Fig. 3A), mean root coverage (MD 12.43; 95% CI 8.17–16.68; p < 0.0001) (Fig. 3B), and mean recession reduction (MD 0.30; 95% CI 0.14–0.47; p < 0.0001) (Fig. 3C). However, the meta-analysis found insufficient evidence to determine whether there is a difference between XCM and CTG in terms of changes in the width of KT (MD 0.24; 95% CI 0.03 to 0.51; p = 0.08) (Fig. 3D). Substantial heterogeneity was only detected for mean root coverage [v2 = 10.31, df = 2 (p = 0.006); I2 = 81%]. In secondary outcomes, the overall meta-analysis showed that CTG had significantly greater gingival thickness (MD 0.29; 95% CI 0.20–0.39; p < 0.0001) (Fig. 3E) and clinical attachment level (MD 0.44; 95% CI 0.23–0.65; p < 0.0001) (Fig. 3F), but showed no significant differences between XCM and CTG with regard to PPD (MD 0.02, 95% CI 0.13 to 0.08; p = 0.69) (Fig. 3G). No substantial heterogeneity was detected. For patient-related outcomes, one trial (39) found no difference between XCM and CTG in participant’s aesthetic satisfaction (Fig. 3H), but a significant difference in postoperative morbidity was detected in favour of

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Fig. 3. Comparison of XCM vs. CTG. Outcomes: (A) complete root coverage; (B) mean root coverage (mm); (C) recession reduction (mm); (D) width of keratinized tissue (mm); (E) changes in gingival tissue thickness (mm); (F) changes in clinical attachment level (mm); (G) changes of probing pocket depth (mm); (H) participant’s aesthetic satisfaction; (I) postoperative discomfort and morbidity; (J) operating time (mm). CTG, connective tissue graft; XCM, xenogeneic collagen matrix.

XCM (Fig. 3I). For the operating time, the meta-analysis showed that the use of XCM significantly reduced the surgical time compared to CTG (MD 16.10; 95% CI 17.92 to 14.28; p < 0.0001) (Fig. 3J).

Xenogeneic collagen matrix vs. coronally advanced flap

Two trials (41,42) at unclear risk of bias were included in the metaanalyses. In primary outcomes, the

complete root coverage ranged 36– 72% for the test group and 31–58% for the control group, while the mean root coverage ranged 75.29  26.68 to 93.25  10.01% and 72.66  26.19 to 81.49  23.45% for the test and

XCM for mucogingival surgery

9

Fig. 3. Continued.

control groups, respectively. The mean recession reduction ranged 2.28  1.00 to 2.59  1.11 mm and 1.85  1.38 to 2.32  0.99 mm for the test and control groups respectively. The overall meta-analysis showed no significant differences between XCM and CAF in the percentage of complete root coverage (RR 0.86; 95% CI 0.66–1.11; p = 0.24) (Fig. 4A), but XCM had a significantly higher mean root coverage (MD 9.26; 95% CI 14.97 to 3.55; p = 0.001) (Fig. 4B), recession reduction (MD 0.35; 95% CI 0.66 to 0.03; p = 0.03) (Fig. 4C) and gain in KT

(MD 0.36; 95% CI 0.69 to 0.04; p = 0.03) (Fig. 4D). No substantial heterogeneity was detected. In secondary outcomes, the overall meta-analysis showed that XCM had a significantly greater gingival thickness (MD 0.55; 95% CI 0.70 to 0.39; p < 0.0001) (Fig. 4E), but no significant differences between the two groups was found in terms of clinical attachment level and PPD (Fig. 4F and G). Only one trial (42) reported on the postoperative morbidity and operating time and found no significant difference between XCM and CAF (MD 0.09; 95% CI 0.36 to 0.54; p = 0.70) (Fig. 4H) in postoper-

ative morbidity but a significantly shorter surgical time was noted with the use of CAF (MD 8.00; 95% CI 2.22–13.78; p = 0.007) (Fig. 4I). Xenogeneic collagen matrix vs. free gingival grafts

One trial (44) with unclear risk of bias was included in the meta-analysis. This trial showed no significant differences between XCM and FGG with regards to recession reduction, clinical attachment level, PPD and operating time (Fig. 5A, C and D), but a significantly higher gain in KT was found with FGG (MD 1.61; 95% CI 1.10–

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Fig. 4. Comparison of XCM vs. CAF. Outcomes: (A) complete root coverage; (B) mean root coverage (mm); (C) recession reduction (mm); (D) width of keratinized tissue (mm); (E) changes in gingival tissue thickness (mm); (F) changes in clinical attachment level (mm); (G) changes of probing pocket depth (mm); (H) postoperative discomfort and morbidity; (I) operating time (mm). CAF, coronally advanced flap; XCM, xenogeneic collagen matrix.

2.12; p < 0.0001) (Fig. 5B) while XCM showed a significantly improved aesthetic satisfaction (RR 0.43; 95% CI 0.23–0.78; p = 0.006) (Fig. 5E). Sample size

Six trials (39–44) reported a priori calculation for the sample size.

Discussion Summary of main results

The review revealed only six RCTs evaluating different comparisons of the XCM with CTG, CAF alone and FGG. However, due to their limited number and moderate quality of the

trials evaluated, the review provides only moderate to low quality evidence. Further research may change the estimates and the CIs presented. The six RCTs included in this review were divided into three categories: XCM vs. CTG: from the three trials (39,40,43), there was some evidence of more root coverage and recession

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Fig. 4. Continued

reduction favouring CTG with moderate heterogeneity. There was no evidence of difference in the width of KT, but a significant gain in the gingival thickness for CTG. However, some evidence showed that XCM reduced the postoperative discomfort and significantly reduced the surgical time. XCM vs. CAF: from the two trials (41,42), there was some evidence that XCM had significantly more root coverage and recession reduction with concomitant gain in KT, but insufficient evidence to determine that XCM or CAF had significantly greater reduction in postoperative discomfort and morbidity. Nevertheless, CAF was associated with a significantly shorter surgical time. XCM vs. FGG: there was no evidence of difference either in recession reduction, clinical attachment level, PPD or operating time. Low-quality evidence indicated that sites treated with FGG showed a significant gain in KT compared with XCM. Despite

the lack of significant gain of KT, XCM improved the participant’s aesthetic satisfaction. Histologically, XCM was associated with similar histological appearance to FGG. However, its inherent ability to differentiate oral epithelium in a way similar to autogenous graft remains a speculated mechanism that warrants further investigation. Overall completeness and applicability of evidence

The comparison, which included six RCTs, was divided into three categories to evaluate XCM against a variety of other common mucogingival surgeries. The inclusion of a small number of trials has limited the number of sites/participants for each analysis, which in turn increased the risk of overestimation of the intervention effects (49). It is expected, however, that such risk will decrease with time as the included trials were published

in the last 4 years and the number of the included trials will increase in the future, as XCM is relatively new material. The inclusion of a small number of trials is mostly related to the predetermined inclusion and exclusion criteria we used that resulted in excluding a number of studies that were not randomized or lacked the data required for analysis. In addition, the analysis has limited the comparisons to one traditional surgical technique at one time, which may have limited the heterogeneity among the included trials. Because all researchers applied almost similar inclusion criteria in the selection of trial participants, the influence of defect severity in terms of extent of recession depth and width, width of KT and attachment level at baseline and other patient-related factors on the clinical outcomes was not evaluated. Even though substantial heterogeneity was not noted due to such stringent inclusion criteria, the

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Fig. 5. Comparison of XCM vs. FGG. Outcomes: (A) recession reduction (mm); (B) width of keratinized tissue (mm); (C) changes in clinical attachment level (mm); (D) changes of probing pocket depth (mm); (E) participant’s aesthetic satisfaction; (F) operating time (mm). FGG, free gingival graft; XCM, xenogeneic collagen matrix.

findings of the included trials and hence the meta-analyses have limited applicability to clinical practice. Moreover, the included trials had a short observation period (≤ 12 mo) and therefore the long-term stability of XCM-based root coverage is not known. It has previously been shown that CTG achieves better long-term

root coverage compared with guided tissue regeneration (50) and ADM (21). In both studies, negative longterm changes were observed with both guided tissue regeneration and ADM and further long-term studies of XCM are still needed to guide clinicians in selecting the appropriate mucogingival surgical technique.

Quality of the evidence

All the included trials identified the method of randomization. However, the majority of them did not report the method of allocation concealment. None of the trials described any masking of the participants or the clinician providing the treatment.

XCM for mucogingival surgery Although such blinding may not be possible due to the nature of the intervention, it may still be viewed as an additional shortcoming with the analysis of the current literature. Nevertheless, the included trials were consistent in confirming the blinding of outcome assessors. Potential biases in the review process

The rigid and uniform inclusion criteria applied in recruiting participants may well explain the low to moderate heterogeneity observed between the studies. In clinical reality, however, where clinicians tend to treat patients with varied site defects not falling within the selected criteria, the extrapolation of the current finding may not be possible and hence interpretation of review results must be done with caution. Patient-reported measures involving assessment of aesthetics pain and overall discomfort are increasingly reported in the literature (13,14). In this review, the reported data for patient-related outcomes were limited to allow robust comparison with commonly used procedures. The fact that all but one trial (41) had commercial affiliation may favour the publication of trials with positive outcomes. However, the impact of publication bias is not clear, as formal testing for such bias was not possible due to the limited number of included trials. Agreements and disagreements with other studies or reviews

To the knowledge of the authors, the present review is the first to target a specific question related to the use of XCM and included up to date RCTs comparing XCM to other common mucogingival surgical procedures. Several reviews were published evaluating different surgical techniques for the treatment of MTR and insufficient KT (8,9,25,51–55). The majority of these reviews confirmed the role of CTG in conjunction with CAF as the gold standard for the treatment of MTR but also showed promising

results using ADM. Further RCTs using longer-term data was a common recommendation. The review showed some improvements in conducting and reporting RCTs in terms of describing the method of randomization, calculating the sample size and carrying out a blinded assessment of the outcome. Nevertheless, researchers should consider reporting longer-term data (> 12 mo) based on well-designed RCTs that follow the Consolidated Standards of Reporting Trials (CONSORT) guidelines (www.consort-statement.org), take a more pragmatic approach in selecting participants and report both clinical and patientcentred outcomes. Moreover, the analysis of cost-effectiveness and cost– benefit of using alternative techniques is invaluable in guiding clinicians to select the appropriate mucogingival procedure for their patients.

Conclusions There is no evidence to demonstrate the effectiveness of XCM in achieving greater root coverage, recession reduction and gain in KT compared to CTG plus CAF. Superior short-term results in treating root coverage compared with CAF alone are possible. There is limited evidence that XCM may improve aesthetic satisfaction, reduce postoperative morbidity and shorten the operating time. Further long-term RCTs are required to endorse the supposed advantages of XCM.

Conflict of interest The authors report no conflicts of interest related to this review.

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