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DOI: 10.1177/0022034513496428

2013 92: 773 originally published online 10 July 2013J DENT RESC. Stoecklin-Wasmer, A.W.S. Rutjes, B.R. da Costa, G.E. Salvi, P. Jüni and A. Sculean

Absorbable Collagen Membranes for Periodontal Regeneration: A Systematic Review

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773

C. Stoecklin-Wasmer1†, A.W.S. Rutjes2,3†, B.R. da Costa2,4, G.E. Salvi1, P. Jüni2,4, and A. Sculean1*

1Department of Periodontology, University of Bern, Freiburgstrasse 7, 3010 Bern, Switzerland; 2Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland; 3Centre for Aging Sciences (Ce.S.I.), G. d’Annunzio University Foundation, Palazzina SEBI 3° livello, Campus Universitario Chieti Scalo, 66100 Chieti Scalo, Italia; 4CTU Bern, Department of Clinical Research, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland; †authors contributed equally as co-first authors; *corresponding author, [email protected]

ABSTRACTGuided tissue regeneration (GTR) with bioabsorb-able collagen membranes (CM) is commonly used for the treatment of periodontal defects. The objective of this systematic review of randomized clinical trials was to assess the clinical efficacy of GTR procedures with CM, with or without bone substitutes, in peri-odontal infrabony defects compared with that of open flap debridement (OFD) alone. Primary outcomes were tooth loss and gain in clinical attachment level (CAL). Screening of records, data extraction, and risk-of-bias assessments were performed by two reviewers. Weighted mean differences were esti-mated by random effects meta-analysis. We included 21 reports on 17 trials. Risk of bias was generally high. No data were available for the primary outcome tooth loss. The summary treatment effect for change in CAL for GTR with CM compared with OFD was 1.58 mm (95% CI, 1.27 to 1.88). Despite large between-trial heterogeneity (I2 = 75%, p < .001), all trials favored GTR over OFD. No differences in treat-ment effects were detected between trials of GTR with CM alone and trials of GTR with CM in combi-nation with bone substitutes (p for interaction, .31). GTR with CM, with or without substitutes, may result in improved clinical outcomes compared with those achieved with OFD alone. Our findings support GTR with CM for the treatment of infrabony peri-odontal defects.

KEY WORDS: periodontal disease(s)/periodontitis, surgery, meta-analysis, biomaterial(s), guided tissue regeneration, clinical studies/trials.

DOI: 10.1177/0022034513496428

Received April 30, 2013; Last revision June 6, 2013; Accepted June 9, 2013

A supplemental appendix to this article is published elec-tronically only at http://jdr.sagepub.com/supplemental.


CLINICAL REVIEW

INTRODUCTION

Infrabony periodontal osseous defects represent a frequent sequela of peri-odontitis (Papapanou and Tonetti, 2000). Guided tissue regeneration (GTR)

regenerates connective tissue attachment (i.e., forming cementum by inserting collagen fibers and periodontal ligament) and alveolar bone in periodontal defects. A mechanical barrier prevents or retards the apical migration of the gingival epithelium and allows periodontal ligament and bone tissue to selec-tively repopulate the root surface during healing (Nyman et al., 1982; Gottlow et al., 1986; Stahl et al., 1990).

A systematic review that evaluated the effects of GTR with both non- bioabsorbable and bioabsorbable membranes showed that GTR improved attachment gain, reduced pocket depth, and resulted in less gingival recession and more hard-tissue fill than did open flap debridement (OFD) alone (Needleman et al., 2006). The different barrier types [expanded polytetrafluoroethylene (ePTFE) barrier, collagen-derived or polymeric bioabsorbable barrier type] exhibited no significant differences in results (Murphy and Gunsolley, 2003).

However, a second surgical procedure is necessary to remove non- bioabsorbable membranes, and this increases the risk that newly formed tis-sues will be compromised. Moreover, flap elevation for membrane removal may result in crestal bone resorption (Pihlstrom et al., 1983) and decrease coverage of the newly formed tissue, thus interrupting the healing process (Tonetti et al., 1993, 1996). The use of non-bioabsorbable membranes increases risk of membrane exposure and bacterial colonization and thus may inhibit healing (Nowzari et al., 1995). Bioabsorbable membranes, including collagen membranes (CM), have been developed for, and used in, GTR to prevent these problems.

Human histological studies have provided evidence that treatment of infrabony defects, with CM with or without the addition of bone substitutes, improves periodontal regeneration (Parodi et al., 1997; Camelo et al., 1998; Sculean et al., 2004). Combining CM with bone substitutes may prevent the barrier from collapsing, especially in non-contained infrabony defects, and may thus ensure space maintenance (Bunyaratavej and Wang, 2001).

The goal of this systematic review was to assess the clinical, radiographic, and safety outcomes of GTR with absorbable CM, alone or in association with bone substitutes, as compared with those achieved with OFD alone. We also aimed at assessing whether the variations between trials could be explained by characteristics of the procedure or by biases affecting individual trials.


JDR92910.1177/0022034513496428research-article2013

J Dent Res 92(9):773-781, 2013

774 Stoecklin-Wasmer et al. J Dent Res 92(9) 2013

METHODS

We followed a standard protocol for all review steps. We included randomized or quasi-randomized controlled trials (RCTs) with patients who displayed infrabony periodontal defects around sin-gle- or multi-rooted teeth. We excluded studies that addressed only furcation defects. We considered trials that compared GTR with bioabsorbable CM, with or without the application of bone substi-tutes and other bio-active materials, with OFD alone. Primary out-comes were tooth loss and change in clinical attachment level (CAL). Secondary outcomes were change in probing pocket depth (PPD), change in gingival recession (REC), radiographic hard-tis-sue fill, clinical hard-tissue fill (bone sounding, re-entry surgeries), and post-operative complications (membrane exposure, infection).

Literature Search

We searched electronic databases, without language restrictions: Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE through Ovid (from inception to January 8, 2013) (see Appendix Tables 1 and 2 for search algorithms). This was complemented by a hand search of the Journal of Periodontology, Journal of Clinical Periodontology, and Journal of Periodontal Research up to January 2013 and reviews of bibliographies of all relevant systematic review articles and included trial reports. In addition, we contacted GTR experts with the request to indi-cate any report we had not captured in our online and hand searches. We did not seek unpublished data.

Trial Selection, Data Collection, and Risk-of-Bias Assessment

Titles and abstracts of the search results were screened indepen-dently in duplicate (CS, GES). We considered only reports with available full text, and those were independently assessed by two review authors (CS, GES), who determined their eligibility. Disagreements were resolved by consensus or discussion with a third reviewer (AS). If several reports described the same trial, we chose the most recent report or most complete report as the main report. Remaining reports were checked for complemen-tary data on clinical outcomes, descriptions of study partici-pants, or design characteristics.

Data were extracted independently by two reviewers (CS, AR) and entered into a Web-based extraction form. We collected the following information: patient characteristics (sex, average age, periodontal diagnosis, smoking status); tooth-related characteris-tics (infrabony defect configuration); type of bioabsorbable CM used; type of bone substitute material applied, if applicable; surgi-cal flap design; post-operative care provided (including post-operative systemic antibiotics); enrollment in supportive periodontal treatment (SPT); clinical outcome variables at baseline and longest follow-up observation (tooth retention, CAL, PPD, REC, x-ray hard-tissue level, clinical hard-tissue level); post-operative complications (membrane exposure, infection); trial size, trial design, trial duration (defined as time from surgical intervention until end of follow-up); and number of study centers (single vs. multicenter). We considered concealment of allocation, blinding of patients, surgeons, and those performing outcome assessment, according to current guidelines of the Cochrane

Handbook (Higgins et al., 2011). We determined if analyses were conducted according to the intention-to-treat principle, and if we could detect selective outcome reporting or other biases.

We considered allocation concealment to be adequate if the investigators responsible for patient selection were unable to pre-dict which treatment was next before allocation. Central random-ization and sequentially numbered, sealed, opaque envelopes were considered adequate methods. Concealment was judged to be associated with high risk of bias (ROB) if evidence of inade-quate sequence generation was found. We decided that there was low risk of performance bias (Juni et al., 2001) if the treatment allocation was revealed to the surgeon only after mucoperiosteal flap elevation and defect debridement were completed. However, for split-mouth studies, both test and control sites would need to be prepared simultaneously to be considered at low risk of perfor-mance bias. If an attempt to blind patients was reported, we con-sidered blinding of patients to be associated with low risk of bias. Blinding of outcome assessment was judged to result in low risk of bias if the investigators who performed the outcome assess-ment were explicitly reported to be blind.

Statistical analyses were considered adequate if all random-ized patients were included in the analysis according to the intention-to-treat principle (Rutjes et al., 2012). Trials were con-sidered to have a high risk of selective reporting bias if we identi-fied 1 or more outcome measures in published reports for which results were not reported. We used a cut-off of 25 patients per group in case of parallel designs and 25 patients overall in case of split-mouth designs, to distinguish between small and moderate-to-large trials. This sample size yields a power of 80% to detect a biologically large difference between groups of 0.8 standard deviations, with a two-sided alpha of 0.05. We also examined how defects were ascertained as another source of bias. If multiple sites were measured, but only the deepest defect at baseline was considered in the analysis, we judged this to result in low risk of bias. If whole-tooth means were used, we judged this to be associ-ated with high risk of bias, since this resulted in a dilution of potential effects and a bias toward the null.

Data Synthesis and Analysis

We used results from intention-to-treat analyses at the longest follow-up, whenever reported. We calculated weighted mean differences (WMDs) in changes from baseline between experi-mental and control groups for clinical outcomes. Effect sizes were used if at least 1 trial expressed change values in percent-ages, when other trial(s) expressed results in millimeters. Here, the differences in mean change from baseline across treatment groups were divided by the pooled standard deviation. An effect size of -0.20 standard deviation units was considered a small difference between experimental and control groups, an effect size of -0.50 was a moderate difference, and an effect size of -0.80 a large difference (Cohen, 1988). If differences in mean changes were unavailable, we used the reported baseline and follow-up values to approximate them. If some of the required data were unavailable, we used the approximations previously described (Reichenbach et al., 2007). We expressed binary out-comes as risk ratios (RR) and excluded comparisons with zero events in both groups in the analyses (Sweeting et al., 2004). In studies that used a split-mouth design in which more than 1

J Dent Res 92(9) 2013 Absorbable Collagen Membranes for Periodontal Regeneration 775

tooth contributed to a single treatment arm, we adjusted the standard errors as follows:

If a report provided clinical outcome data for more than 1 site, we pooled the estimates of treatment effects within the trial to pre-vent it from being too heavily weighted in the overall analyses.

We used a standard inverse-variance random-effects model to summarize the estimates of treatment effects across trials to account fully for between-study variance. We quantified between-study variance using the I2 statistic (Higgins et al., 2003), which describes the percentage of variation across trials attributable to heterogeneity rather than chance, and the corresponding Chi2 test. I2 values of 25%, 50%, and 75% were interpreted as low, moder-ate, and high between-trial heterogeneity, although the precision of trials included in the meta-analysis must be considered for interpretation of I2 values (Rücker et al., 2008).

For the primary outcome, the association between trial size and treatment effects was investigated in funnel plots. We plot-ted WMDs on the vertical axis against their standard errors on the horizontal axis. We assessed asymmetry by the asymmetry coefficient. We used the difference in size of WMDs per unit increase in standard error (Sterne and Egger, 2001), which is mainly a surrogate for sample size.

In all analyses, we differentiated between the 2 kinds of GTR: CM with and without bone substitutes. For the outcome CAL gain, we performed stratified analyses by risk-of-bias items: concealment of allocation; blinding of patients, surgeons, and outcome assessors; analysis in accordance with the intention-to-treat principle; selective outcome reporting; and other bias. We also evaluated the following trial characteristics: type of CM (cross-linked vs. native CM), protocol-mandated use of antibiot-ics, percentage of smokers at baseline, and percentage of defects with three-wall involvement. We used uni-variable random-effects meta-regression models to determine if these factors were associated with estimates of treatment effect (Thompson and Sharp, 1999). All statistical analyses were done in STATA version 12.1 (StataCorp, College Station, TX, USA). All p val-ues are two-sided.

RESULTS

Description of Studies

We identified 2,713 references, of which 46 were potentially eligible. Of the 46, 25 reports did not meet our inclusion criteria (see flow diagram in Appendix Fig. 1 and excluded reports in Appendix Table 3). The remaining 21 eligible reports described 17 trials with 35 arms and 507 patients (Blumenthal and Steinberg, 1990; Chung et al., 1990; Quteish and Dolby, 1992; al-Arrayed et al., 1995; Camargo et al., 2000, 2005; Lekovic et al., 2001; Sculean et al., 2003, 2005, 2007; Tonetti et al., 2004; Vouros et al., 2004; Heitz-Mayfield et al., 2006; Linares et al., 2006; Paolantonio et al., 2008, 2010; Boynuegri et al., 2009; Sowmya et al., 2010; Trombelli et al., 2010; Singh et al., 2012a,b). The mean ages of patients ranged from 41 to 51 yrs, and the average percentage of women, if reported, ranged from

29% to 70%. The number of patients randomized per trial ranged from 10 to 124. Smokers were explicitly included in 5 studies, were excluded in 7 studies and were not reported in 5 of the remaining studies. Six trials explicitly included patients with chronic periodontitis only. Ten trials reported morphology of

standard errornumber of teeth

number of patients.•

Figure 1. Methodological characteristics of included trials. (+) low risk of bias, (?) unclear, and (–) high risk of bias on a specific item.


infrabony defects: 1 trial considered three-wall defects only, and in 1 trial most infrabony lesions showed a three-wall configura-tion; in 8 trials, the majority of infrabony lesions represented two-wall defects. Two trials explicitly reported that some infrabony defects displayed the concomitant presence of furca-tion lesions. Initial furcation involvement (degree I) was present in 4 out of 38 defects in the trial by al-Arrayed et al. (1995) and in 4 out of 52 defects in Quteish and Dolby (1992), with equal distribution of furcation-involved defects in both trial arms. Nine trials used a parallel group design, and the remaining trials used a split-mouth design. Eight trials had follow-up durations of 6 mos, 1 trial had a follow-up period of 9 mos, 7 trials had a follow-up period of one yr, and 1 trial reported outcomes up to 60 mos. All studies were conducted in a single-center university setting except for 1 trial, which was multi-centric, conducted at a university and in private practices.

Six trials tested OFD against CM alone, 10 trials tested OFD against CM and bone substitutes, and 1 trial tested OFD against CM with and without bone substitutes. Porcine-derived CM were used in 7 trials, human CM were tested in 4 trials, and 4 trials evaluated non-porcine-derived xenogen CM. Two trials did not declare the origin of membranes used. Thirteen trials used sulcular incisions on the mucoperiosteal flap to access the infrabony defect, 3 applied papilla preservation techniques, and 1 trial did not report on flap design. Appendix Tables 4 and 5 list further clinical trial characteristics.

Fig. 1 and Appendix Table 6 present the methodological characteristics of trials. In none of the trials was the conceal-ment of allocation described in sufficient detail to allow for any

judgment on the potential risk of bias. Only 2 trials stated that randomization envelopes were used, but the trialists did not describe whether these were opaque and consecutively numbered (Tonetti et al., 2004; Vouros et al., 2004). One trial reported blinding of patients, 2 trials reported adequate blinding of surgeons (i.e., revealing treatment code only after the preparation of mucoperiosteal flaps and defect debridement), and 8 out of 17 trials reported blinding of outcome asses-sors. Thirteen trials had analyzed all patients according to the intention-to-treat principle, and 2 trials had sample sizes considered sufficiently large for clinically important treatment effects of 0.8 standard deviation units to be detected. Eight trials addressed all out-comes mentioned in the methods section in either the results or discussion section, but in the remaining 9 trials, selective outcome reporting was found for 1 or more outcomes.

Effects of Interventions

Tooth loss

None of the trials explicitly assessed tooth loss as an outcome. One trial incidentally reported 2 lost teeth, both in the OFD trial arm: 1 was extracted on request by the patient due to lack of improvement in tooth mobility, the other due to an accident (Tonetti et al., 2004).

Gain in clinical attachment level (CAL)

All included trials reported on change in attachment level. The overall analysis (Fig. 2) shows that GTR with bioabsorbable CM had a greater mean CAL gain compared with OFD, as indi-cated by a mean difference of 1.58 mm (95% CI, 1.27 to 1.88). An I2 of 71.9% indicated a high degree of between-trial hetero-geneity (p for heterogeneity < .001; Fig. 2), and an inspection of the funnel plot suggested a lack of non-significant results from small trials in the white area (Appendix Fig. 2). Subgroup analysis of trials reporting on CM alone showed a WMD in gain in CAL of 1.39 mm (95% CI, 0.99 to 1.78), whereas the combi-nation of CM and bone substitutes yielded a WMD of 1.71 mm (95% CI, 1.26 to 2.15) when compared with OFD only. Differences between the two subgroups were not statistically significant (p for interaction, .31).

Fig. 3 shows results from stratified analyses. Estimates varied to some extent, according to types of different charac-teristics, but CIs overlapped considerably between strata, and p values for interaction were all negative. Thirteen trials con-tributed to the analysis of a linear association between the percentage of smokers and gain in CAL, and 11 trials contrib-uted to the analysis on an association between the percentage of three-wall involvement and gain in CAL. We found little

NOTE: Weights are from random effects analysis

Overall (I2 = 71.9%, p < .001)

Author / Year

1.58 (1.27, 1.88)

Favors CM +/- boneFavors control0-3 -2.5 -2 -1.5 -1 -.5 0 .5 1 1.5 2 2.5 3

Mean differencein mm (95% CI)

Paolantonio 2008

Subtotal (I2 = 64.6%, p = .010)

Chung 1990

Paolantonio 2010

Blumenthal 1990al-Arrayed 1995

Quteish 1992

Boynuegri 2009

1.60 (1.19, 2.01)

1.39 (0.99, 1.78)

1.27 (0.61, 1.93)

1.60 (1.17, 2.03)

0.42 (-0.12, 0.96)1.22 (-0.79, 3.23)

1.70 (0.91, 2.49)

1.80 (1.19, 2.41)

GTR with collagen membrane

Lekovic 2001

Tonetti 2004

Sculean 2007

Subtotal (I2 = 75.0%, p < .001)

Trombelli 2010

Camargo 2000Camargo 2005

Sculean 2005

Singh 2012a

Blumenthal 1990

Sowmya 2010

Vouros 2004

2.33 (1.73, 2.92)

0.80 (0.24, 1.36)

2.30 (1.46, 3.14)

1.71 (1.26, 2.15)

0.30 (-1.35, 1.95)

1.51 (1.03, 1.98)2.96 (2.29, 3.63)

2.20 (1.50, 2.90)

1.00 (0.06, 1.94)

1.26 (0.72, 1.80)

1.50 (0.50, 2.50)

1.96 (0.64, 3.28)

GTR with collagen membrane and bone substitute

Weighted mean difference

Gain in clinical attachment level (mm)

Figure 2. Forest plot of weighted mean differences in gain in clinical attachment level expressed in mm in 18 comparisons from 17 trials.


evidence for a linear association between these characteristics and treatment effect (p from meta-regression, .43 and .81, respectively).

Probing pocket depth (PPD) reduction

Sixteen studies reported on changes in probing pocket depths. The analysis (Fig. 4) suggested that GTR with bioabsorbable CM had a greater mean reduction in PPD than did OFD, with a WMD of 1.52 mm (95% CI, 1.18 to 1.86). Subgroup analysis of studies showed that GTR with CM alone reduced PPD 1.66 mm more than did OFD (95% CI, 0.99 to 2.33) on average, while the combination of GTR with bone substitutes reduced PPD by 1.44 mm (95% CI, 1.04 to 1.85, p for interaction, .56).

Gingival recession (Rec)

Twelve studies assessed gingival recession as an outcome. The pooled estimate revealed no statistically significant difference between GTR (with or without the application of bone substi-tutes) and OFD (Fig. 5). The overall WMD was -0.06 (95% CI, -0.18 to 0.06). Treatment effects appeared more pronounced

with GTR and bone substitution than with GTR alone, with a borderline p for interaction of .056.

Clinical and radiographic hard-tissue fill (HTF)

Fig. 6A shows results from meta-analyses of all the 8 studies that contributed outcomes for clinical hard-tissue fill. The results dem-onstrated that GTR improved clinical HTF over OFD, with a WMD of 2.22 mm (95% CI, 1.54 to 2.90). The combination of GTR and bone substitutes was associated with larger treatment effects than with GTR alone (p for interaction, .004). Radiographic hard-tissue fill was assessed in 4 trials, with an overall effect size of 2.35 standard deviation units (95% CI, 1.68 to 3.03). No differ-ences were detected between GTR with CM alone and GTR with CM in combination with bone substitutes, when compared with OFD (p for interaction, .70) (Fig. 6B).

Post-operative complications: wound infection and membrane exposure

Thirteen trials reported that no wound infections had occurred, neither in experimental groups (216 teeth in 192 patients) nor in

62/62

I2

All trials

Type of GTRCollagen membraneCollagen membrane and bone

Flap designPapilla preservationSulcular incisions

Type of membraneCross-linkedNatural form

Protocol-mandatedantibiotics useYesNo

Ascertainment of defectAt deepest defectUsing whole-tooth mean

Type of designParallelSplit-mouth

SettingSingle-center or unclearMulti-center

Blinding of patientsLow ROBHigh or unclear ROB

Blinding of surgeonsLow ROBHigh or unclear ROB

Blinding of outcome assessorsLow ROBHigh or unclear ROB

Intention-to-treatLow ROBHigh or unclear ROB

Selective outcome reportingLow ROBHigh or unclear ROB

Trial sizeModerate to largeSmall

18

711

315

411

135

108

99

171

117

315

810

144

810

216

322/319

106/106216/213

88/88234/231

67/67220/217

239/23683/83

217/214105/105

159/156163/163

260/257

12/12310/307

88/86234/233

144/142178/177

274/27248/47

170/170152/149

90/90232/229

1.58 (1.27, 1.88)

1.39 (0.99, 1.78)1.71 (1.26, 2.15)

1.09 (0.38, 1.81)1.67 (1.34, 2.01)

1.34 (0.87, 1.81)1.79 (1.42, 2.15)

1.60 (1.23, 1.96)1.56 (1.02, 2.10)

1.78 (1.30, 2.26)1.34 (1.01, 1.68)

1.57 (1.23, 1.92)1.59 (1.07, 2.11)

1.63 (1.33, 1.94)0.80 (0.24, 1.36)

0.30 (-1.35, 1.95)1.61 (1.30, 1.91)

1.00 (0.22, 1.77)1.66 (1.34, 1.97)

1.84 (1.41, 2.26)1.40 (1.00, 1.79)

1.60 (1.25, 1.94)1.50 (0.87, 2.12)

1.54 (1.18, 1.90)1.64 (1.12, 2.15)

1.87 (-0.24, 3.98)1.54 (1.27, 1.81)

72%

65%75%

68%72%

0%71%

78%37%

76%58%

55%81%

70%n/a

36%72%

n/a73%

67%69%

77%41%

66%78%

96%59%

.31

.16

.22

.82

.15

.94

.18

.20

.17

.15

.81

.73

.55

-

-

Favors control Favors cm +/- bone

0-3 -2.5 -2 -1.5 -1 -.5 0 .5 1 1.5 2 2.5 3

Characteristic Trials, nSites in the experimental group / control group, n/N

p for interaction



Figure 3. Results of stratified analyses of the gain in clinical attachment level. Note: n/a = not applicable.


control groups (216 teeth in 193 patients). Membrane exposure was reported in 3 trials of CM alone and occurred in a median of 24% of patients (range, 0% to 29%), and in 9 trials of CM with bone substitute, with a median percentage of patients with

membrane exposure of 11% (range, 0% to 43%) (Appendix Fig. 3).

DISCUSSION

The present meta-analysis showed that, in infrabony defects, GTR with bioab-sorbable CM barriers, either alone or in association with bone substitutes, yielded more beneficial effects than OFD for our primary outcome CAL gain. The overall weighted mean differ-ence was 1.58 mm. However, there were no data available for the other primary outcome, “tooth loss”. Analysis of sec-ondary outcomes demonstrated that reduction of PPD was greater in GTR with CM compared with OFD (WMD of 1.52 mm), as was the increase in clinical and radiographic defect fill, which showed WMDs of 2.22 mm and 2.35 mm, respectively. We did not detect differ-ences between experimental and control interventions for gingival recession change. In addition, we stratified the analysis by the use of bone substitutes in the experimental group (trials of GTR with CM alone vs. trials of GTR with CM and bone substitutes). Even though the effects of CM were larger in trials with, as compared with trials without bone substitutes, the non-significant p value for interaction indicated that this difference could be a chance finding. This information may bear clinical rele-vance, since it indicates that GTR with the combination of CM and bone substi-tutes may not additionally improve the outcomes compared with the use of CM alone and is in agreement with findings from previous systematic reviews (Murphy and Gunsolley, 2003). Nonetheless, caution is indicated, since the majority of the defects in our meta-analysis were self-contained (e.g., they displayed a two- to three-wall configura-tion), thus possibly preventing mem-brane collapse and diminishing the need for space-maintaining bone substitutes. Although our meta-regression analysis did not show any association between morphology and treatment outcomes, such an association cannot be ruled out. Previous studies have suggested that non-contained (e.g., displaying one-wall

configuration) infrabony defects may yield better clinical out-comes with the combination of CM and bone substitutes (Paolantonio, 2002; Cortellini and Tonetti, 2005). Regarding adverse healing outcomes, no study observed wound infections

NOTE: Weights are from random effects analysisOverall (I2 = 73.6%, p < .001)


Subtotal (I2 = 68.8%, p < .001)Vouros 2004

Sculean 2007

Paolantonio 2010

Blumenthal 1990Camargo 2000

Boynuegri 2009

Lekovic 2001

al-Arrayed 1995

Singh 2012a

Subtotal (I2 = 82.4%, p < .001)

Tonetti 2004

Paolantonio 2008

Trombelli 2010

Quteish 1992

Camargo 2005

Sowmya 2010

Blumenthal 1990

Sculean 2005


Author / Year

1.52 (1.18, 1.86)

1.44 (1.04, 1.85)2.58 (1.51, 3.65)

1.50 (0.14, 2.86)

2.30 (1.66, 2.94)

1.22 (0.68, 1.76)1.37 (0.38, 2.36)

1.40 (0.52, 2.28)

1.95 (1.43, 2.48)

1.43 (0.77, 2.09)

1.11 (0.22, 2.00)

1.66 (0.99, 2.33)

0.50 (-0.08, 1.08)

2.40 (1.75, 3.05)

0.00 (-1.60, 1.60)

2.00 (1.12, 2.88)

2.16 (1.66, 2.67)

1.10 (0.46, 1.74)

0.48 (-0.06, 1.02)

1.80 (1.03, 2.57)

--

-

Favors control Favors CM +/- bone0-2 -1.5 -1 -.5 0 .5 1 1.5 2


Probing pocket depth reduction in mm

2.5 3 3.5 4


Figure 4. Forest plot of weighted mean differences in probing pocket depth reduction expressed in mm in 17 comparisons from 16 trials.


Overall (I2 = 67.1%, p < .001)

Blumenthal 1990

Sculean 2005

Trombelli 2010

Paolantonio 2010

Subtotal (I2 = 65.0%, p = .002)

Tonetti 2004

Camargo 2005

Subtotal (I2 = 73.1%, p = .024)

Author / Year

Camargo 2000

Sowmya 2010

Blumenthal 1990

Paolantonio 2008

Lekovic 2001

Sculean 2007Singh 2012a

-0.06 (-0.18, 0.06)

-0.28 ( 0.82, 0.26)

-0.30 (-0.96, 0.36)

-0.40 (-1.31, 0.51)

0.60 (-0.03, 1.23)

-0.10 (-0.21, 0.02)

-0.40 (-0.77, 0.03)

0.04 (0.01, 0.08)

0.33 (-0.30, 0.96)

-0.25 (-0.54, 0.05)

0.10 (-0.77, 0.97)

-0.33 (-0.87, 0.21)

0.70 (0.16, 1.24)

-0.07 (-0.13, -0.01)

-0.90 (-1.83, 0.03)0.11 (-0.43, 0.65)

-

- -

-

- -- -

- - -

- -

Favors CM +/- bone Favors control0-1.5 -1 -.5 0 .5 1 1.5





Gingival recession in mm

Figure 5. Forest plot of weighted mean differences in gingival recession expressed in mm in 13 comparisons from 12 trials.


in the post-surgical phase in either treat-ment groups. In contrast, of the 11 trials that reported on membrane exposure, 7 observed this kind of untoward event. Taken together, these findings indicate that, despite the fact that treatment of infrabony periodontal defects by means of GTR with CM (with or without bone substitutes) resulted in superior clinical outcomes compared with those achieved with OFD alone, we still cannot ascertain whether this regenerative approach may indeed prevent tooth loss.

Factors that have been repeatedly suggested to have a potential influence on wound-healing are membrane expo-sure and subsequent bacterial coloniza-tion (Selvig et al., 1992; Nowzari et al., 1995; Ling et al., 2003). However, in the present study, it was not feasible to ana-lyze the effect of membrane exposure on clinical outcomes, because subgroup outcome data were not available in the trials. However, the present findings are in agreement with those from a previous systematic review (Needleman et al., 2006), which failed to demonstrate an effect of barrier exposure on healing, despite frequently reported exposure.

There are several other limitations. The included trials were generally of poor methodological quality and report-ing. None of the included trials reported on the number of patients screened for inclusion. Most studies failed to report on the time point of communicating treatment allocation to surgeons. Only 3 studies of parallel design reported this. Therefore, we are uncertain about per-formance bias causing an overestimation of treatment effects if surgeons con-sciously or unconsciously performed better at flap preparation and defect debridement in experimental groups than in control groups. We generally found a high degree of heterogeneity, which we were unable to explain. This means that the true magnitude of treatment effects remains unclear. Inspection of the funnel plot suggested a selective lack of non-significant results for small trials with large standard errors. This is likely to have introduced bias due to small study effects, even though the fun-nel plot did not satisfy the conventional criteria for asymmetry.

It is unfortunate that none of the included trials reported on our primary outcome, “tooth loss”. Only 1 of the included trials would have a sufficiently long follow-up of 5 yrs to allow for the clinically meaningful interpretation of effects of different treatments on tooth loss. All other trials were limited to a

follow-up of 6 to 12 mos. When follow-up time is limited in clinical trials, surrogate endpoints, such as clinical attachment loss, are substitutes for true, patient-relevant clinical endpoints, such as tooth loss (Hujoel, 2004). However, unless additional long-term trials ascertain this outcome, it remains difficult in our view to understand whether CM indeed enhance tooth reten-tion. Conversely, the inclusion of 5-year results from the trial by Sculean et al. (2007) could have biased results for the other primary outcome, CAL gain, toward the null, since changes in


Overall (I2 = 95.3%, p < .001)

Blumenthal 1990

Subtotal (I2 = 0.0%, p = .471)

Paolantonio 2010

Camargo 2005

Subtotal (I2 = 83.5%, p < .001)

Blumenthal 1990

Camargo 2000

Author / Year

Chung 1990

Sowmya 2010

Lekovic 2001

Paolantonio 2008

2.22 (1.54, 2.90)

1.49 (0.95, 2.03)

1.47 (1.16, 1.79)

0.90 (-0.20, 2.00)

3.42 (3.38, 3.46)

2.99 (2.50, 3.48)

3.37 (3.03, 3.71)

2.60 (1.37, 3.83)

1.16 (0.40, 1.92)

2.10 (1.55, 2.65)

3.06 (1.76, 4.35)

1.70 (1.21, 2.19)

Favors control Favors CM +/- bone0-2 -1.5 -1 -.5 0 1.5 1.5 2




Hard-tissue fill, clinical (in mm)


3 3.52.5

A


Overall (I2 = 48.8%, p = .119)

Boynuegri 2009

Subtotal (I2 = 17.3%, p = .298)

Author / Year

Singh 2012a

Subtotal

Sowmya 2010

Vouros 2004

2.35 (1.68, 3.03)

3.35 (2.11, 4.59)

2.10 (1.54, 2.66)

ES (95% CI)

2.34 (1.29, 3.38)

3.35 (2.11, 4.59)

2.50 (1.62, 3.37)

1.62 (0.84, 2.40)

ES (95% CI)

Favors control Favors CM +/- bone0-2 -1.5 -1 -.5 0 .5 1 1.5 2 2.5 3 3.5 4 4.5

Effect size



Hard-tissue fill, radiographic in standard deviation units

B

Figure 6. Forest plot of weighted mean differences in hard-tissue fill. Panel A: clinical, expressed in mm in 9 comparisons from 8 trials. Panel B: radiographic, expressed in standard deviation units in 4 trials.


CAL beyond 1 yr could be mainly a function of SPT rather than of the allocated interventions. A post hoc sensitivity analysis based on 1-year data from this trial showed much the same results, however (data available on request).

We were unable to satisfactorily address 2 clinically relevant questions: whether defect configuration (Tonetti et al., 1993) and whether smoking (Cortellini and Tonetti, 2004) affect regenera-tive treatment effects. Our preliminary results of aggregate level data do not point toward an association of treatment effects with these characteristics. However, we could have missed associa-tions because of the ecological fallacy (Piantadosi et al., 1988). To address these issues properly, a meta-analysis of individual patient data, infeasible given the resource constraints, would be required to perform proper subgroup analyses in smokers and non-smokers and across different defect configurations.

This is the first systematic review to analyze the outcomes of GTR with CM as compared with OFD, without considering any other types of barrier membranes. Combining trials of different barrier membranes, Needleman et al. (2006) reported a weighted mean difference of 1.22 mm for our primary outcome of CAL gain (95% CI 0.80 to 1.64), favoring GTR procedures with membranes over OFD. Murphy and Gunsolley (2003) reported mean differences in CAL gain in a subgroup of trials with CM compared with OFD to be around 0.95 mm. Our estimate tends to be slightly more beneficial, but confidence intervals from our and previous meta-analyses overlap, which indicates that our results are compatible with those reported in previous publications.

In conclusion, GTR with CM, with or without bone substitutes, may lead to improved clinical outcomes compared with those achieved with OFD alone. Our meta-analysis lends support to this concept in the treatment of infrabony periodontal defects.

ACKNOWLEDGMENTS

This work was funded by the authors’ own institution. The authors declare no conflict of interest with respect to the author-ship and/or publication of this article.

REFERENCESal-Arrayed F, Adam S, Moran J, Dowell P (1995). Clinical trial of cross-

linked human type I collagen as a barrier material in surgical periodon-tal treatment. J Clin Periodontol 22:371-379.

Blumenthal N, Steinberg J (1990). The use of collagen membrane barriers in conjunction with combined demineralized bone-collagen gel implants in human infrabony defects. J Periodontol 61:319-327.

Boynuegri D, Ozcan G, Senel S, Uc D, Uraz A, Ogus E, et al. (2009). Clinical and radiographic evaluations of chitosan gel in periodontal intraosseous defects: a pilot study. J Biomed Mater Res B Appl Biomater 90:461-466.

Bunyaratavej P, Wang HL (2001). Collagen membranes: a review. J Periodontol 72:215-229.

Camargo PM, Lekovic V, Weinlaender M, Nedic M, Vasilic N, Wolinsky LE, et al. (2000). A controlled re-entry study on the effectiveness of bovine porous bone mineral used in combination with a collagen mem-brane of porcine origin in the treatment of intrabony defects in humans. J Clin Periodontol 27:889-896.

Camargo PM, Lekovic V, Weinlaender M, Vasilic N, Madzarevic M, Kenney EB (2005). A reentry study on the use of bovine porous bone mineral, GTR, and platelet-rich plasma in the regenerative treatment of intrabony defects in humans. Int J Periodontics Restorative Dent 25:49-59.

Camelo M, Nevins ML, Schenk RK, Simion M, Rasperini G, Lynch SE, et al. (1998). Clinical, radiographic, and histologic evaluation of human periodontal defects treated with Bio-Oss and Bio-Gide. Int J Periodontics Restorative Dent 18:321-331.

Chung KM, Salkin LM, Stein MD, Freedman AL (1990). Clinical evaluation of a biodegradable collagen membrane in guided tissue regeneration. J Periodontol 61:732-736.

Cohen J (1988). Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum.

Cortellini P, Tonetti MS (2004). Long-term tooth survival following regen-erative treatment of intrabony defects. J Periodontol 75:672-678.

Cortellini P, Tonetti MS (2005). Clinical performance of a regenerative strategy for intrabony defects: scientific evidence and clinical experi-ence. J Periodontol 76:341-350.

Gottlow J, Nyman S, Lindhe J, Karring T, Wennstrom J (1986). New attach-ment formation in the human periodontium by guided tissue regenera-tion. Case reports. J Clin Periodontol 13:604-616.

Heitz-Mayfield L, Tonetti MS, Cortellini P, Lang NP (2006). Microbial colonization patterns predict the outcomes of surgical treatment of intrabony defects. J Clin Periodontol 33:62-68.

Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003). Measuring incon-sistency in meta-analyses. BMJ 327:557-560.

Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. (2011). The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928.

Hujoel PP (2004). Endpoints in periodontal trials: the need for an evidence-based research approach. Periodontology 2000 36:196-204.

Juni P, Altman DG, Egger M (2001). Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 323:42-46.

Lekovic V, Camargo PM, Weinlaender M, Kenney EB, Vasilic N (2001). Combination use of bovine porous bone mineral, enamel matrix pro-teins, and a bioabsorbable membrane in intrabony periodontal defects in humans. J Periodontol 72:583-589.

Linares A, Cortellini P, Lang NP, Suvan J, Tonetti MS (2006). Guided tissue regeneration/deproteinized bovine bone mineral or papilla preservation flaps alone for treatment of intrabony defects. II: Radiographic predic-tors and outcomes. J Clin Periodontol 33:351-358.

Ling LJ, Hung SL, Lee CF, Chen YT, Wu KM (2003). The influence of membrane exposure on the outcomes of guided tissue regeneration: clinical and microbiological aspects. J Periodontal Res 38:57-63.

Murphy KG, Gunsolley JC (2003). Guided tissue regeneration for the treat-ment of periodontal intrabony and furcation defects. A systematic review. Ann Periodontol 8:266-302.

Needleman IG, Worthington HV, Giedrys-Leeper E, Tucker RJ (2006). Guided tissue regeneration for periodontal infra-bony defects. Cochrane Database Syst Rev 2:CD001724.

Nowzari H, Matian F, Slots J (1995). Periodontal pathogens on polytetra-fluoroethylene membrane for guided tissue regeneration inhibit heal-ing. J Clin Periodontol 22:469-474.

Nyman S, Lindhe J, Karring T, Rylander H (1982). New attachment follow-ing surgical treatment of human periodontal disease. J Clin Periodontol 9:290-296.

Paolantonio M (2002). Combined periodontal regenerative technique in human intrabony defects by collagen membranes and anorganic bovine bone. A controlled clinical study. J Periodontol 73:158-166.

Paolantonio M, Perinetti G, Dolci M, Perfetti G, Tete S, Sammartino G, et al. (2008). Surgical treatment of periodontal intrabony defects with calcium sulfate implant and barrier versus collagen barrier or open flap debridement alone: a 12-month randomized controlled clinical trial. J Periodontol 79:1886-1893.

Paolantonio M, Femminella B, Coppolino E, Sammartino G, D’Arcangelo C, Perfetti G, et al. (2010). Autogenous periosteal barrier membranes and bone grafts in the treatment of periodontal intrabony defects of single-rooted teeth: a 12-month reentry randomized controlled clinical trial. J Periodontol 81:1587-1595.

Papapanou PN, Tonetti MS (2000). Diagnosis and epidemiology of peri-odontal osseous lesions. Periodontol 2000 22:8-21.

Parodi R, Carusi G, Santarelli G, Nanni F, Pingitore R, Brunel G (1997). Guided tissue regeneration employing a collagen membrane in a human periodontal bone defect: a histologic evaluation. Int J Periodontics Restorative Dent 17:282-291.


Piantadosi S, Byar DP, Green SB (1988). The ecological fallacy. Am J Epidemiol 127:893-904.

Pihlstrom BL, McHugh RB, Oliphant TH, Ortiz-Campos C (1983). Comparison of surgical and nonsurgical treatment of periodontal dis-ease. A review of current studies and additional results after 61/2 years. J Clin Periodontol 10:524-541.

Quteish D, Dolby AE (1992). The use of irradiated-crosslinked human col-lagen membrane in guided tissue regeneration. J Clin Periodontol 19:476-484.

Reichenbach S, Sterchi R, Scherer M, Trelle S, Burgi E, Burgi U, et al. (2007). Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 146:580-590.

Rücker G, Schwarzer G, Carpenter JR, Schumacher M (2008). Undue reli-ance on I(2) in assessing heterogeneity may mislead. BMC Med Res Methodol 8:79.

Rutjes AW, Juni P, da Costa BR, Trelle S, Nuesch E, Reichenbach S (2012). Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med 157:180-191.

Sculean A, Berakdar M, Chiantella GC, Donos N, Arweiler NB, Brecx M (2003). Healing of intrabony defects following treatment with a bovine-derived xenograft and collagen membrane. A controlled clinical study. J Clin Periodontol 30:73-80.

Sculean A, Stavropoulos A, Windisch P, Keglevich T, Karring T, Gera I (2004). Healing of human intrabony defects following regenerative periodontal therapy with a bovine-derived xenograft and guided tissue regeneration. Clin Oral Investig 8:70-74.

Sculean A, Chiantella GC, Windisch P, Arweiler NB, Brecx M, Gera I (2005). Healing of intra-bony defects following treatment with a com-posite bovine-derived xenograft (Bio-Oss Collagen) in combination with a collagen membrane (Bio-Gide PERIO). J Clin Periodontol 32:720-724.

Sculean A, Schwarz F, Chiantella GC, Donos N, Arweiler NB, Brecx M, et al. (2007). Five-year results of a prospective, randomized, controlled study evaluating treatment of intra-bony defects with a natural bone mineral and GTR. J Clin Periodontol 34:72-77.

Selvig KA, Kersten BG, Chamberlain AD, Wikesjö UM, Nilvéus RE (1992). Regenerative surgery of intrabony periodontal defects using ePTFE barrier membranes: scanning electron microscopic evaluation of retrieved membranes versus clinical healing. J Periodontol 63:974-978.

Singh VP, Nayak DG, Uppoor AS, Shah D (2012a). Nano-crystalline hydroxyapatite bone graft combined with bioresorbable collagen

membrane in the treatment of periodontal intrabony defects: a random-ized controlled clinical trial. J Indian Soc Periodontol 16:562-568.

Singh VP, Nayak DG, Uppoor AS, Shah D (2012b). Clinical and radiographic evaluation of nano-crystalline hydroxyapatite bone graft (Sybograf) in combination with bioresorbable collagen membrane (Periocol) in peri-odontal intrabony defects. Dent Res J (Isfahan) 9:60-67.

Sowmya NK, Tarun Kumar AB, Mehta DS (2010). Clinical evaluation of regenerative potential of type I collagen membrane along with xeno-genic bone graft in the treatment of periodontal intrabony defects assessed with surgical re-entry and radiographic linear and densitomet-ric analysis. J Indian Soc Periodontol 14:23-29.

Stahl SS, Froum S, Tarnow D (1990). Human histologic responses to guided tissue regenerative techniques in intrabony lesions. Case reports on 9 sites. J Clin Periodontol 17:191-198.

Sterne JA, Egger M (2001). Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol 54:1046-1055.

Sweeting MJ, Sutton AJ, Lambert PC (2004). What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 23:1351-1375.

Thompson SG, Sharp SJ (1999). Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med 18:2693-2708.

Tonetti MS, Pini-Prato G, Cortellini P (1993). Periodontal regeneration of human intrabony defects. IV. Determinants of healing response. J Periodontol 64:934-940.

Tonetti MS, Prato GP, Cortellini P (1996). Factors affecting the healing response of intrabony defects following guided tissue regeneration and access flap surgery. J Clin Periodontol 23:548-556.

Tonetti MS, Cortellini P, Lang NP, Suvan JE, Adriaens P, Dubravec D, et al. (2004). Clinical outcomes following treatment of human intrabony defects with GTR/bone replacement material or access flap alone. A multicenter randomized controlled clinical trial. J Clin Periodontol 31:770-776.

Trombelli L, Simonelli A, Pramstraller M, Wikesjö UM, Farina R (2010). Single flap approach with and without guided tissue regeneration and a hydroxyapatite biomaterial in the management of intraosseous peri-odontal defects. J Periodontol 81:1256-1263.

Vouros I, Aristodimou E, Konstantinidis A (2004). Guided tissue regenera-tion in intrabony periodontal defects following treatment with two bioabsorbable membranes in combination with bovine bone mineral graft. A clinical and radiographic study. J Clin Periodontol 31:908-917.

DS1

C. Stoecklin-Wasmer1†, A.W.S. Rutjes2,3†, B.R. da Costa2,4, G.E. Salvi1, P. Jüni2,4, and A. Sculean1*

1Department of Periodontology, University of Bern, Freiburgstrasse 7, 3010 Bern, Switzerland; 2Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland; 3Centre for Aging Sciences (Ce.S.I.), G. d’Annunzio University Foundation, Palazzina SEBI 3° livello, Campus Universitario Chieti Scalo, 66100 Chieti Scalo, Italia; 4CTU Bern, Department of Clinical Research, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland; †authors contributed equally as co-first authors; *corresponding author, [email protected]

J Dent Res DOI: 10.1177/0022034513496428


APPENDIX

CLINICAL REVIEW

RCT = randomized,controlled trial; CAL = clinical attachment level tr to legend and add .

2710 records identified through database searching

3 additional records identified through other sources

1588 records after duplicates (1125) removed

1588 records screened

1542 records excluded

46 full-text articles assessed for eligibility

21 records on 17 RCTsincluded in systematic

review

25 full-text articles excluded

Not relevant to the intervention n = 18Not an RCT n = 1Potentially relevant, available in abstract form only n = 6

17 RCTs included in meta-analysis on CAL outcome

Identification

Screening

Eligibility

Included

Appendix Figure 1. Flow diagram. RCT = randomized, controlled trial; CAL = clinical attachment level.

DS2 Stoecklin-Wasmer et al. J Dent Res


Overall (I2 = 0.0%, p = .749)

Sculean 2007

Lekovic 2001*

Singh 2012a

Paolantonio 2008

Trombelli 2010*

Blumenthal 1990*

Blumenthal 1990*

Subtotal (I2 = 0.0%, p = .501)

Trial / Year

Subtotal (I2 = 0.0%, p = .751)


Sowmya 2010*


Sculean 2005

Camargo 2000

Paolantonio 2010

Vouros 2004

3 / 14

0 / 18

1 / 9

4 / 17

No. of teeth / total

0 / 12

0 / 15

0 / 15

0 / 10

4 / 16

6 / 22

4 / 14

6 / 14

0.25 (0.17, 0.33)

0.21 (-0.00, 0.43)

0.11 (-0.12, 0.34)

0.24 (0.03, 0.44)

0.25 (0.15, 0.35)

Incidence (95% CI)

0.26 (0.10, 0.41)

0.25 (0.04, 0.46)

0.27 (0.09, 0.46)

0.29 (0.05, 0.52)

0.43 (0.17, 0.69)

0.25 (0.17, 0.33)

0.21 (-0.00, 0.43)

0.11 (-0.12, 0.34)

0.24 (0.03, 0.44)

0.25 (0.15, 0.35)

0.26 (0.10, 0.41)

0.25 (0.04, 0.46)

0.27 (0.09, 0.46)

0.29 (0.05, 0.52)

0.43 (0.17, 0.69)

Incidence of membrane exposure (%) 0 0 .1 .2 .3 .4 .5 .6 .7 .8 .9 1

Appendix Figure 3. Incidence of membrane exposure. Note: *Comparisons with 0 events in both trial arms did not contribute to the analysis.

0

.2

.4

.6

.8

-3 -2 -1 0 1 2 3Weighted mean difference

Sta

ndar

d er

ror o

f wei

ghte

d m

ean

diffe

renc

e


Appendix Figure 2. Contour-enhanced funnel plot for effects on the gain of clinical attachment level. Contour areas display areas of sig-nificance at p ≤ .05 (gray) and non-significance (white).

J Dent Res Absorbable Collagen Membranes for Periodontal Regeneration DS3

Appendix Table 1. Search Terms for MEDLINE and EMBASE

MEDLINE* EMBASE*

Search terms related to periodontitis 1. in*ra*bon* defect*.mp.2. in*ra-bon* defect*.mp.3. intra-osseous.mp.4. intraosseous.mp.5. (angular adj1 defect*).mp.6. (vertical adj1 defect*).mp.7. exp periodontitis/8. exp periodontal disease/Search terms related to guided tissue regeneration 9. exp tissue regeneration/10. guided tissue regeneration.mp.11. gtr.mp.12. barrier* membrane*.mp.13. (resorbable adj10 membrane*).mp.14. (bioabsorb$ adj10 membrane*).mp.15. (periodontal adj5 regeneration).mp.16. exp xenograft/17. (collagen adj1 membrane*).mp.18. collagen barrier*.mp.19. xenograft$.mp.20. graft*.ti,ab.21. bon* substitut*.mp.22. exp Bone Substitutes/23. exp Biocompatible Materials/24. biomaterial*.mp.

Search terms related to design 25. randomized controlled trial.pt.26. controlled clinical trial.pt.27. randomized.ab.28. placebo.ab.29. drug therapy.fs.30. randomly.ab.31. trial.ab.32. groups.ab.

Search terms related to periodontitis1. exp periodontitis/ or exp periodontal disease/2. in*ra*bon* defect*.mp.3. in*ra-bon* defect*.mp.4. intra-osseous.mp.5. intraosseous.mp.6. (angular adj1 defect*).mp.7. (vertical adj1 defect*).mp.Search terms related to guided tissue regeneration 8. exp tissue regeneration/ 9. guided tissue regeneration.mp.10. gtr.mp.11. resorbable membrane*.mp.12. (resorbable adj10 membrane*).mp.13. (periodontal adj5 regeneration).mp.14. exp xenograft/15. (collagen adj1 membrane*).mp.16. collagen barrier*.mp.17. xenograft$.mp.18. (bioabsorb$ adj10 membrane*).mp.19. (bioabsorb$ adj10 barrier*).mp.20. barrier membrane*.mp.21. exp bone graft/22. graft$.ti,ab.23. bon* substitut*.mp.24. exp biomaterial/25. biomaterial*.mp.Search terms related to design26. random$.tw.27. factorial$.tw.28. (crossover$ or cross-over$).tw.29. placebo$.tw.30. (doubl$ adj blind$).tw.31. (singl$ adj blind$).tw.32. assign$.tw.33. allocat$.tw.34. volunteer$.tw.35. Crossover Procedure.sh.36. Double-blind Procedure.sh.37. Randomized Controlled Trial.sh.38. Single-blind Procedure.sh.

Combining terms33. or/1-834. or/9-2435. or/27-3436. and/25-26,3737. exp animals/ not humans.sh.38. 36 not 3739. limit 38 to yr=“1982 -Current”

Combining terms39. or/1-740. or/8-2541. or/26-3842. and/26-27,4543. animal/44. animal/ and human/45. 43 not 4446. 42 not 4447. limit 46 to yr=“1982 -Current”

* MEDLINE and EMBASE searched through the OVID platform on January 8, 2013.

DS4 Stoecklin-Wasmer et al. J Dent Res

Appendix Table 2. Search Terms for the Cochrane Databases

Cochranea

Search terms related to periodontitis#1 MeSH descriptor: [Periodontitis] explode all trees#2 MeSH descriptor: [Periodontal Diseases] explode all trees#3 vertical near/1 defect*:ti,ab,kw (Word variations have been searched)#4 angular near/1 defect*:ti,ab,kw (Word variations have been searched)#5 intraosseous:ti,ab,kw (Word variations have been searched)#6 “intra osseous”:ti,ab,kw (Word variations have been searched)#7 in*ra bon* defect*:ti,ab,kw (Word variations have been searched)#8 in*ra*bon* defect*:ti,ab,kw (Word variations have been searched)#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8Search terms related to guided tissue regeneration#10 MeSH descriptor: [Guided Tissue Regeneration] explode all trees#11 guided tissue regeneration:ti,ab,kw (Word variations have been searched)#12 gtr:ti,ab,kw (Word variations have been searched)#13 barrier* membrane*:ti,ab,kw (Word variations have been searched)#14 resorbable near/5 membrane*:ti,ab,kw (Word variations have been searched)#15 periodontal near/5 regeneration:ti,ab,kw (Word variations have been searched)#16 bioabsorb* near/5 membrane*:ti,ab,kw (Word variations have been searched)#17 collagen near/1 membrane*:ti,ab,kw (Word variations have been searched)#18 collagen barrier*:ti,ab,kw (Word variations have been searched)#19 “graft”:ti,ab,kw (Word variations have been searched)#20 bon* substitut*:ti,ab,kw (Word variations have been searched)#21 biomaterial*:ti,ab,kw (Word variations have been searched)#22 MeSH descriptor: [Bone Substitutes] explode all trees#23 MeSH descriptor: [Biocompatible Materials] explode all trees#24 MeSH descriptor: [Transplantation, Heterologous] explode all treesCombining terms#25 #10 or #11 or #12 or #13 or #14#26 #15 or #16 or #17 or #18 or #19 or #20 or #21#27 #22 or #23 or #24#28 #25 or #26 or #27#29 #9 and #28

aSearches in all databases embedded in Cochrane, including the Central Register of Controlled Trials, DARE, and Cochrane reviews search, performed on January 9, 2013.

J Dent Res Absorbable Collagen Membranes for Periodontal Regeneration DS5

Appendix Table 3. List of Excluded Reports

Report Reason for Exclusion

Aimetti et al. (2005) Intervention does not fitBatista et al. (1999) Intervention does not fitBratthall et al. (1996) No full text availableCamargo et al. (2001) No full text availableCamargo et al. (2009) Intervention does not fitChristgau et al. (1996) No full text availableChristgau et al. (1997) No full text availableChristgau et al. (2003) Intervention does not fitCortellini et al. (1996a) Study design does not fitCortellini et al. (1996b) Intervention does not fitCortellini et al. (1998) Intervention does not fitJoly et al. (2000) No full text availableJoly et al. (2002) Intervention does not fitKeles et al. (2006) Intervention does not fitKim et al. (1996) Intervention does not fitKuru et al. (2004) Intervention does not fitLekovic et al. (2000) No full text availableLoos et al. (2002) Intervention does not fitProestakis et al. (1992) Intervention does not fitSculean et al. (2001) Intervention does not fitSculean et al. (2004) Intervention does not fitSculean et al. (2008) Intervention does not fitStavropoulos et al. (2003) Intervention does not fitTonetti et al. (1996) Intervention does not fitTonetti et al. (1998) Intervention does not fit

Appendix Table 3. References to Reports Excluded in This Review

Aimetti M, Romano F, Pigella E, Pranzini F, Debernardi C (2005). Treatment of wide, shallow, and predominantly 1-wall intrabony defects with a bioabsorbable membrane: a randomized controlled clinical trial. J Periodontol 76:1354-1361.

Batista EL Jr, Novaes AB Jr, Simonpietri JJ, Batista FC (1999). Use of bovine-derived anorganic bone associated with guided tissue regenera-tion in intrabony defects. Six-month evaluation at re-entry. J Periodontol 70:1000-1007.

Camargo PM, Lekovic V, Weinlaender M, Divnic-Resnik T, Pavlovic M, Kenney EB (2009). A surgical reentry study on the influence of platelet-rich plasma in enhancing the regenerative effects of bovine porous bone mineral and guided tissue regeneration in the treatment of intrabony defects in humans. J Periodontol 80:915-923.

Christgau M, Aslanidis C, Felden A, Hiller KA, Schmitz G, Schmalz G (2003). Influence of interleukin-1 gene polymorphism on periodontal regeneration in intrabony defects. J Periodontal Res 38:20-27.

Cortellini P, Paolo G, Prato P, Tonetti MS (1996a). Long-term stability of clinical attachment following guided tissue regeneration and conven-tional therapy. J Clin Periodontol 23:106-111.

Cortellini P, Pini Prato G, Tonetti MS (1996b). Periodontal regeneration of human intrabony defects with bioresorbable membranes. A controlled clinical trial. J Periodontol 67:217-223.

Cortellini P, Carnevale G, Sanz M, Tonetti MS (1998). Treatment of deep and shallow intrabony defects. A multicenter randomized controlled clinical trial. J Clin Periodontol 25:981-987.

Joly JC, Palioto DB, de Lima AF, Mota LF, Caffesse R (2002). Clinical and radiographic evaluation of periodontal intrabony defects treated with guided tissue regeneration. A pilot study. J Periodontol 73:353-359.

Keles GC, Cetinkaya BO, Isildak I, Koprulu H, Acikgoz G (2006). Levels of platelet activating factor in gingival crevice fluid following peri-odontal surgical therapy. J Periodontal Res 41:513-518.

Kim CK, Choi EJ, Cho KS, Chai JK, Wikesjo UM (1996). Periodontal repair in intrabony defects treated with a calcium carbonate implant and guided tissue regeneration. J Periodontol 67:1301-1306.

Kuru L, Griffiths GS, Petrie A, Olsen I (2004). Changes in transforming growth factor-beta1 in gingival crevicular fluid following periodontal surgery. J Clin Periodontol 31:527-533.

Loos BG, Louwerse PH, Van Winkelhoff AJ, Burger W, Gilijamse M, Hart AA, et al. (2002). Use of barrier membranes and systemic antibiotics in the treatment of intraosseous defects. J Clin Periodontol 29:910-921.

Proestakis G, Bratthall G, Söderholm G, Kullendorff B, Grondahl K, Rohlin M, et al. (1992). Guided tissue regeneration in the treatment of infrabony defects on maxillary premolars. A pilot study. J Clin Periodontol 19:766-773.

Sculean A, Windisch P, Chiantella GC, Donos N, Brecx M, Reich E (2001). Treatment of intrabony defects with enamel matrix proteins and guided tissue regeneration. A prospective controlled clinical study. J Clin Periodontol 28:397-403.

Sculean A, Donos N, Schwarz F, Becker J, Brecx M, Arweiler NB (2004). Five-year results following treatment of intrabony defects with enamel matrix proteins and guided tissue regeneration. J Clin Periodontol 31:545-549.

Sculean A, Kiss A, Miliauskaite A, Schwarz F, Arweiler NB, Hannig M (2008). Ten-year results following treatment of intra-bony defects with enamel matrix proteins and guided tissue regeneration. J Clin Periodontol 35:817-824.

Stavropoulos A, Karring ES, Kostopoulos L, Karring T (2003). Deproteinized bovine bone and gentamicin as an adjunct to GTR in the treatment of intrabony defects: a randomized controlled clinical study. J Clin Periodontol 30:486-495.

Tonetti MS, Prato GP, Cortellini P (1996). Factors affecting the healing response of intrabony defects following guided tissue regeneration and access flap surgery. J Clin Periodontol 23:548-556.

Tonetti MS, Cortellini P, Suvan JE, Adriaens P, Baldi C, Dubravec D, et al. (1998). Generalizability of the added benefits of guided tissue regen-eration in the treatment of deep intrabony defects. Evaluation in a multi-center randomized controlled clinical trial. J Periodontol 69:1183-1192.

DS6

App

endi

x Ta

ble

4. T

rial D

escr

iptio

ns

Tria

lD

esig

n

No.

of

Tria

l A

rms

No.

of

Stud

y C

ente

rsN

o. o

f Pat

ient

s Ra

ndom

ized

No.

of

Teet

h In

volv

edFo

llow

-up

Dur

atio

nFr

actio

n of

Fe

mal

es (%

)M

ean

Age

(y

rs)

Frac

tion

of

Smok

ers

(%)

Type

of

Perio

dont

itis

32

1C

ombi

natio

nO

utco

mes

Incl

uded

al-A

rray

ed e

t al

., 19

95sp

lit-m

outh

21

14nr

67/

14 (5

0%)

44nr

Oth

er18

/38

16/3

84/

38n/

aC

AL;

PPD

Blum

enth

al a

nd

Stei

nber

g,

1990

split

-mou

th5

110

7112

4/10

(40%

)nr

nrO

ther

19/7

125

/71

3/71

24/7

1C

AL;

PPD

; REC

; HTF

clin

; M

embr

ane

exp;

In

fect

ion

Boyn

uegr

i et a

l.,

2009

para

llel

41

20nr

69/

20 (4

5%)

nr0/

20 (0

%)

Chr

onic

nrnr

nrnr

CA

L; P

PD; H

TF R

x

Cam

argo

et a

l.,

2000

split

-mou

th2

nr22

446

nr43

14/2

2 (6

4%)

nr11

/44

33/4

40/

44n/

aC

AL;

PPD

; REC

; HTF

clin

; M

embr

ane

exp;

In

fect

ion

Cam

argo

et a

l.,

2005

split

-mou

th2

128

566

12/2

8 (4

3%)

4112

/28

(43%

)O

ther

21/5

635

/56

0/56

n/a

CA

L; P

PD; R

EC; H

TF c

lin

; Inf

ectio

nC

hung

et a

l.,

1990

split

-mou

th2

115

3012

8/15

(53%

)nr

nrnr

nrnr

nrnr

CA

L; P

PD; H

TF c

lin

Leko

vic

et a

l.,

2001

split

-mou

th2

118

366

8/18

(44%

)42

12/1

8 (6

7%)

Oth

er11

/36

25/3

60/

36n/

aC

AL;

PPD

; REC

; HTF

clin

; M

embr

ane

exp;

In

fect

ion

Paol

anto

nio

et

al.,

20

08pa

ralle

l3

151

5112

29/5

1 (5

7%)

460/

51 (0

%)

Chr

onic

nrnr

nrnr

CA

L; P

PD; R

EC; H

TF c

lin;

Mem

bran

e ex

p;

Infe

ctio

nPa

olan

toni

o

et a

l.,

2010

para

llel

31

4242

1222

/42

(52%

)48

0/42

(0%

)C

hron

icnr

nrnr

nrC

AL;

PPD

; REC

; HTF

clin

; M

embr

ane

exp;

In

fect

ion

Qut

eish

and

D

olby

, 199

2sp

lit-m

outh

21

1952

6nr

nrnr

Oth

ernr

nrnr

nrC

AL;

PPD

; Inf

ectio

n

Scul

ean

et a

l.,

2005

para

llel

21

3232

1217

/32

(53%

)nr

0/32

(0%

)nr

5/32

18/3

29/

32n/

aC

AL;

PPD

; REC

; HTF

clin

; M

embr

ane

exp;

In

fect

ion

Scul

ean

et a

l.,

2007

para

llel

21

2828

6015

/28

(54%

)nr

5/28

(18%

)C

hron

ic4/

2815

/28

9/28

n/a

CA

L; P

PD; R

EC; H

TF c

lin;

Mem

bran

e ex

p;

Infe

ctio

nSi

ngh

et a

l.,

2012

apa

ralle

l2

116

206

7/16

(44%

)nr

0/16

(0%

)nr

0/18

12/1

80/

186/

18C

AL;

PPD

; REC

; HTF

Rx;

M

embr

ane

exp;

In

fect

ion

Sow

mya

et a

l.,

2010

split

-mou

th2

110

209

7/10

(70%

)46

0/10

(0%

)nr

20/2

00/

200/

200/

20C

AL;

PPD

; REC

; HTF

clin

; H

TF R

x; M

embr

ane

exp;

Infe

ctio

nTo

netti

et a

l.,

2004

para

llel

210

124

124

12nr

/124

(62%

)50

nrC

hron

icnr

nrnr

n/a

CA

L; P

PD; R

EC; H

TF c

lin

Trom

belli

et a

l.,

2010

para

llel

21

2424

67/

24 (2

9%)

512/

24 (8

%)

nr6/

2411

/24

7/24

n/a

CA

L; P

PD; R

EC;

Mem

bran

e ex

p;

Infe

ctio

nVo

uros

et a

l.,

2004

para

llel

31

3440

1223

/34

(68)

nr0/

34 (0

%)

Chr

onic

nrnr

nrn/

aC

AL;

PPD

; HTF

clin

; HTF

Rx

; Mem

bran

e ex

p

nr =

not

rep

orte

d; n

/a =

not

app

licab

le;

CA

L =

clin

ical

atta

chm

ent l

evel

; PP

D =

pro

bing

poc

ket d

epth

; RE

C =

gin

giva

l rec

essi

on;

HTF

clin

= h

ard-

tissu

e fil

l, cl

inic

al;

HTF

Rx

= ha

rd-ti

ssue

fill,

ra

diog

raph

ic; M

embr

ane

exp

= m

embr

ane

expo

sure

Mor

phol

ogy

(wal

ls)

DS7

App

endi

x Ta

ble

5. D

escr

iptio

n of

Tria

l Arm

s an

d In

terv

entio

ns

Tria

lIn

clud

ed T

rial A

rms

Flap

Des

ign

Col

lage

n M

embr

ane

(CM

)Bo

ne G

raft

Cro

ss-li

nked

M

embr

ane

Prot

ocol

-m

anda

ted

Ant

ibio

tic U

se

Post-

surg

ical

C

are

Prov

ided

Supp

ortiv

e Pe

riodo

ntal

Th

erap

y Pr

ovid

edA

scer

tain

men

t of D

efec

t

al-A

rray

ed e

t al.,

19

95O

FD v

s. G

TR C

MSu

lcul

ar

inci

sion

sFr

eeze

-drie

d cr

oss-l

inke

d hu

man

type

I C

Mn/

aye

sno

yes

yes

Unc

lear

if m

easu

rem

ents

of th

e 6

site

s w

ere

aver

aged

, or

if th

e de

epes

t def

ect w

as u

sed

Blum

enth

al a

nd

Stei

nber

g,

1990

OFD

vs.

GTR

CM

vs

. GTR

CM

+

bone

Sulc

ular

in

cisi

ons

CM

(sou

rce

/ br

and

not

repo

rted)

auto

lyze

d an

tigen

-ext

ract

ed

allo

gene

ic fr

eeze

-drie

d bo

ne

- col

lage

n ge

l im

plan

t

nrye

sye

sye

s≥

1 to

oth

per

quad

rant

per

pat

ient

was

in

clud

ed in

the

anal

yses

for

each

trea

tmen

t m

odal

ity; r

esul

ts w

ere

aver

aged

Boyn

uegr

i et a

l.,

2009

OFD

vs.

GTR

CM

Sulc

ular

in

cisi

ons

CM

(sou

rce

/ br

and

not

repo

rted)

soa

ked

in

chito

san

gel 1

%

n/a

nrye

snr

nrN

o re

port

on n

umbe

r of

teet

h in

clud

ed p

er

patie

nt, o

r if

mea

sure

men

ts w

ere

aver

aged

, or

if o

nly

the

deep

est d

efec

ts at

bas

elin

e w

ere

cons

ider

edC

amar

go e

t al.,

20

00O

FD v

s. G

TR

CM

+ b

one

Sulc

ular

in

cisi

ons

Porc

ine

CM

(Bio

-Gid

e)C

ance

llous

bov

ine

poro

us

bone

min

eral

(BPB

M)

gran

ules

(0.2

5-1.

0 m

m) (

Bio-

Oss

)

noye

sye

sye

sA

dequ

ate

Cam

argo

et a

l.,

2005

OFD

vs.

GTR

C

M +

bon

eSu

lcul

ar

inci

sion

sPo

rcin

e C

M (B

io-G

ide)

Can

cello

us B

PBM

gra

nule

s (0

.25-

1.00

mm

) (Bi

o-O

ss)

and

coag

ulat

ed p

late

let-r

ich

plas

ma

noye

sye

sye

sA

dequ

ate

Chu

ng e

t al.,

1990

OFD

vs.

GTR

CM

Sulc

ular

in

cisi

ons

Bovi

ne c

ross

-link

ed C

M (P

erio

-Ba

rrie

r)n/

aye

sno

yes

yes

Out

com

es w

ere

mea

sure

d at

6 p

robi

ng s

ites

per

toot

h; w

hole

-toot

h m

eans

wer

e us

ed fo

r an

alys

isLe

kovi

c et

al.,

20

01O

FD v

s. G

TR

CM

+ b

one

Sulc

ular

in

cisi

ons

Bovi

ne c

olla

gen/

PLA

m

embr

ane

(Bio

-Gid

e C

ompo

site

)

BPBM

gra

nule

s (B

io-O

ss) a

nd

enam

el m

atrix

pro

tein

s (E

mdo

gain

)

noye

sye

sye

sA

dequ

ate

Paol

anto

nio

et

al.,

20

08O

FD v

s. G

TR C

MSu

lcul

ar

inci

sion

sLy

ophi

lized

hum

an

peric

ardi

um C

M (T

utop

last

Peric

ardi

um)

n/a

noye

sye

sye

sU

ncle

ar if

mea

sure

men

ts of

the

6 si

tes

wer

e av

erag

ed, o

r if

the

deep

est d

efec

t was

use

d

Paol

anto

nio

et

al.,

20

10O

FD v

s. G

TR C

MPa

pilla

pr

eser

vatio

nLy

ophi

lized

hum

an

peric

ardi

um C

M (T

utop

last

Peric

ardi

um)

n/a

noye

sye

sye

sU

ncle

ar if

mea

sure

men

ts of

the

6 si

tes

wer

e av

erag

ed, o

r if

the

deep

est d

efec

t was

use

d

Qut

eish

and

D

olby

, 199

2O

FD v

s. G

TR C

MSu

lcul

ar

inci

sion

sIrr

adia

ted,

glu

tara

ldeh

yde-

cros

slink

ed h

uman

pla

cent

a C

M (t

ype

I)

n/a

yes

nonr

nrA

dequ

ate

Scul

ean

et a

l.,

2005

OFD

vs.

GTR

C

M +

bon

eSu

lcul

ar

inci

sion

sPo

rcin

e C

M (B

io-G

ide

Perio

)Bo

vine

-der

ived

xen

ogra

ft (B

io-

Oss

Col

lage

n)no

noye

sye

sA

dequ

ate

Scul

ean

et a

l.,

2007

OFD

vs.

GTR

C

M +

bon

eSu

lcul

ar

inci

sion

sPo

rcin

e C

M (B

ioG

ide

Perio

)BP

BM g

ranu

les

(0.2

5-1.

0 m

m)

(Bio

-Oss

)no

yes

yes

yes

Ade

quat

e

Sing

h et

al.,

2012

aO

FD v

s. G

TR

CM

+ b

one

nrFi

sh C

M (P

erio

Col

)N

ano-

crys

talli

ne

Hyd

roxy

apat

ite (H

A) b

one

repl

acem

ent g

raft

(Syb

ogra

f)

noye

sye

sye

sA

dequ

ate

Sow

mya

et a

l.,

2010

OFD

vs.

GTR

C

M +

bon

eSu

lcul

ar

inci

sion

sXe

noge

n C

M (H

ealig

uide

)Xe

noge

n D

MBM

type

I co

llage

n (O

sseo

graf

t)no

yes

nono

Unc

lear

if m

easu

rem

ents

of th

e 6

site

s w

ere

aver

aged

, or

if th

e de

epes

t def

ect w

as u

sed

Tone

tti e

t al.,

2004

OFD

vs.

GTR

C

M +

bon

ePa

pilla

pr

eser

vatio

nPo

rcin

e C

M (B

io-G

ide)

.BP

BM g

ranu

les

(Bio

-Oss

)no

yes

yes

yes

Ade

quat

e

Trom

belli

et a

l.,

2010

OFD

vs.

GTR

C

M +

bon

ePa

pilla

pr

eser

vatio

nEq

uine

cro

ss-li

nked

CM

(P

arog

uide

)H

A-b

ased

bio

mat

eria

l (Bi

ostit

e)ye

sno

yes

yes

Ade

quat

e

Vour

os e

t al.,

2004

OFD

vs.

GTR

C

M +

bon

eSu

lcul

ar

inci

sion

sPo

rcin

e C

M (B

ioG

ide)

BPBM

gra

nule

s (B

io-O

ss

spon

gios

a)no

yes

yes

yes

Ade

quat

e

OFD

= o

pen

flap

debr

idem

ent;

GTR

= g

uide

d tis

sue

rege

nera

tion;

CM

= c

olla

gen

mem

bran

e; b

one

= bo

ne s

ubsti

tute

; nr

= no

t rep

orte

d; n

/a =

not

app

licab

le.

DS8

App

endi

x Ta

ble

6. M

etho

dolo

gica

l Cha

ract

eris

tics

of T

rials

Aut

hor/

Ye

ar

Gen

erat

ion

of

Allo

catio

n Se

quen

ceD

escr

iptio

n of

Allo

catio

n G

ener

atio

n

Con

ceal

men

t of

Allo

catio

n M

etho

dD

escr

iptio

n of

Con

ceal

men

tBl

indi

ng o

f the

Sur

geon

Blin

ding

of O

utco

me

Ass

esso

rs

Con

trol G

roup

ITT:

nu

mbe

rs a

naly

zed

/ nu

mbe

rs

rand

omiz

ed

Expe

rimen

tal

Gro

up IT

T:

num

bers

ana

lyze

d /

num

bers

ra

ndom

ized

al-A

rray

ed

et a

l.,

1995

uncl

ear

Allo

catio

n of

mat

ched

bila

tera

l les

ions

w

as “

deci

ded

by r

ando

m d

esig

n an

d w

hen

appr

opria

te”.

Ran

dom

izat

ion

met

hod

not r

epor

ted.

uncl

ear

nrTh

e su

rgeo

n w

as b

linde

d un

til a

fter

debr

idem

ent a

t th

e fir

st de

fect

. At t

he

seco

nd d

efec

t, th

e su

rgeo

n w

as n

ot b

linde

d (s

plit-

mou

th d

esig

n).

Ass

esso

r w

as n

ot th

e su

rgeo

n an

d w

as b

lind

to th

e si

tes.

19 /

nr

anal

yzed

19 /

nr

anal

yzed

Blum

enth

al

and

Stei

nber

g,

1990

uncl

ear

Rand

omiz

atio

n se

emed

per

qu

adra

nt,

allo

catin

g ea

ch o

f the

4 q

uadr

ants

to

1 of

the

4 ex

perim

enta

l gro

ups.

A

lloca

tion

of th

e co

ntro

l tee

th

rem

aine

d un

clea

r.

uncl

ear

nrnr

nr15

/15

ana

lyze

dC

M: 1

5 /

15

anal

yzed

; CM

+

bone

: 15

/ 15

ana

lyze

d

Boyn

uegr

i et

al.,

200

9un

clea

rN

ot m

entio

ned

if a

rand

omiz

atio

n m

etho

d w

as u

sed.

uncl

ear

nrnr

nr5

/ 5

anal

yzed

5 /

5 an

alyz

ed

Cam

argo

et

al.,

200

0co

in-to

ssin

gTw

o in

terp

roxi

mal

site

s w

ere

rand

omly

as

sign

ed to

the

expe

rimen

tal o

r co

ntro

l gro

ups.

uncl

ear

nrnr

Ass

esso

rs w

ere

not t

he s

urge

ons

and

wer

e bl

ind

to th

e si

tes.

22 /

22

anal

yzed

22 /

22

anal

yzed

Cam

argo

et

al.,

20

05

coin

-toss

ing

Two

inte

rpro

xim

al s

ites

wer

e ra

ndom

ly

assi

gned

to th

e ex

perim

enta

l or

cont

rol g

roup

s.

uncl

ear

nrnr

Ass

esso

r w

as n

ot th

e su

rgeo

n an

d w

as b

lind

to th

e si

tes.

28 /

28

anal

yzed

28 /

28

anal

yzed

Chu

ng e

t al.,

19

90un

clea

rEx

perim

enta

l site

s w

ere

rand

omly

se

lect

ed fo

r te

st tre

atm

ent;

mat

chin

g co

ntra

late

ral s

ite s

erve

d as

a c

ontro

l w

ithin

the

sam

e pa

tient

.

uncl

ear

nrnr

nr10

/ 1

5 an

alyz

ed10

/ 1

5 an

alyz

ed

Leko

vic

et a

l.,

2001

coin

-toss

ing

Two

inte

rpro

xim

al s

ites

wer

e ra

ndom

ly

assi

gned

to th

e ex

perim

enta

l or

cont

rol g

roup

s.

uncl

ear

nrnr

Ass

esso

r w

as n

ot th

e su

rgeo

n an

d w

as b

lind

to th

e si

tes.

18 /

18

anal

yzed

18 /

18

anal

yzed

Paol

anto

nio

et

al.,

20

08

com

pute

r-ge

nera

ted

“com

pute

r-gen

erat

ed ta

ble”

uncl

ear

nrnr

Ass

esso

r w

as b

lind

to th

e si

tes.

17 /

17

anal

yzed

17 /

17

anal

yzed

Paol

anto

nio

et

al.,

20

10

com

pute

r-ge

nera

ted

“com

pute

r-gen

erat

ed ta

ble”

uncl

ear

nrnr

Ass

esso

r w

as b

lind

to th

e si

tes.

14 /

14

anal

yzed

14 /

14

anal

yzed

Qut

eish

and

D

olby

, 19

92

uncl

ear

Rand

omiz

atio

n m

etho

d no

t rep

orte

d.un

clea

rnr

nrnr

26 /

26

anal

yzed

26 /

26

anal

yzed

Scul

ean

et a

l.,

2005

uncl

ear

Def

ects

wer

e ra

ndom

ly a

ssig

ned

befo

re

surg

ery

to th

e tw

o tre

atm

ent g

roup

s w

ith th

e ra

ndom

ized

blo

ck a

ppro

ach.

uncl

ear

nrnr

Ass

esso

r w

as n

ot a

war

e of

su

rgic

al p

roce

dure

to b

e pe

rform

ed (b

linde

d at

ba

selin

e). U

ncle

ar b

lindi

ng a

t fo

llow

-up

asse

ssm

ent.

16 /

16

anal

yzed

16 /

16

anal

yzed

Scul

ean

et a

l.,

2007

uncl

ear

Def

ects

wer

e ra

ndom

ly a

ssig

ned

befo

re

surg

ery

to th

e tw

o tre

atm

ent g

roup

s w

ith th

e ra

ndom

ized

blo

ck a

ppro

ach.

uncl

ear

nrnr

Ass

esso

r w

as n

ot th

e su

rgeo

n.

Blin

ding

unc

lear

.9

/ 14

ana

lyze

d10

/ 1

4 an

alyz

ed

Sing

h et

al.,

20

12a

coin

-toss

ing

“coi

n fli

p” m

etho

dun

clea

rnr

nr

nr9

/ 10

ana

lyze

d9

/ 10

ana

lyze

d

Sow

mya

et

al.,

201

0un

clea

rRa

ndom

izat

ion

met

hod

not r

epor

ted.

“T

he s

ites

wer

e di

vide

d ra

ndom

ly.”

uncl

ear

nrnr

nr10

/ 1

0 an

alyz

ed10

/ 1

0 an

alyz

ed

Tone

tti e

t al.,

20

04co

mpu

ter-

gene

rate

dA

ssig

nmen

t was

per

form

ed b

y a

cent

ral

study

reg

istra

r us

ing

a cu

stom

-mad

e pr

ogra

m b

ased

on

bala

nced

ran

dom

pe

rmut

ed b

lock

s

enve

lope

sU

se o

f a c

entra

l reg

istra

r an

d se

aled

env

elop

es, n

ot

repo

rted

if la

tter

wer

e op

aque

or

cons

ecut

ivel

y nu

mbe

red.

The

surg

eon

was

blin

ded

until

afte

r de

brid

emen

tA

sses

sor

and

surg

eon

wer

e id

entic

al. N

o bl

indi

ng.

59 /

62

anal

yzed

61 /

62

anal

yzed

Trom

belli

et

al.,

201

0co

mpu

ter-

gene

rate

d“c

ompu

ter-g

ener

ated

ran

dom

izat

ion

list”

uncl

ear

nrTh

e su

rgeo

n w

as b

linde

d un

til a

fter

debr

idem

ent.

Ass

esso

r w

as b

lind

to th

e si

tes.

12 /

12

anal

yzed

12 /

12

anal

yzed

Vour

os e

t al.,

20

04co

mpu

ter-

gene

rate

dC

ompu

ter

rand

omiz

atio

n pr

ogra

m.

Rand

omiz

atio

n se

ems

to b

e at

the

toot

h le

vel.

enve

lope

sSe

aled

env

elop

es, n

ot

repo

rted

if th

ese

wer

e op

aque

or

cons

ecut

ivel

y nu

mbe

red.

The

surg

eon

was

blin

ded

until

afte

r de

brid

emen

tA

sses

sor

was

not

the

surg

eon

and

was

blin

d to

the

site

s.12

/ 1

2 an

alyz

ed14

/ 1

4 an

alyz

ed

ITT

= in

tent

ion-

to-tr

eat;

nr =

not

rep

orte

d.

journal of dental research … · j dent res 2013 92: 773 originally published online 10 july 2013...

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