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1 The influence of tobacco smoking on the outcomes achieved by rootcoverage procedures A systematic review Leandro Chambrone, MSD, DDS; Daniela Chambrone, PhD, MSD, DDS; Francisco E. Pustiglioni, PhD, MSD, DDS; Luiz Armando Chambrone, PhD, MSD, DDS; Luiz A. Lima, PhD, MSD, DDS Frequently, the oral exposure of the root surface due to a displacement of the gingival margin apical to the cementoenamel junction (that is, gingival recession) leads to tactile and thermal dental hypersensitivity, root abrasion and deterioration in the smile s esthetics. 1 In such conditions, periodontal treatment itself is designed to stop the progression of recession and to reestablish a condition of health, function and esthetics through the use of clinically predictable procedures. With respect to the coverage of denuded root surfaces, researchers in several trials have described attempts to treat recession-type defects through the use of diverse surgical techniques such as laterally repositioned flaps, 2-4 coronally advanced flaps, 5,6 free gingival grafts, 7,8 subepithelial connectivetissue grafts, 1,9-13 acellular dermal matrix allografts 14,15 and guided tissue regeneration These periodontal plastic surgery procedures are indicated 1-19 for the treatment of Miller 20 Class I and Class II recessions. Additionally, investigators in systematic reviews evaluating different periodontal plastic surgery procedures have demonstrated that such techniques are effective in reducing the extent of exposed root surface, with a concomitant gain in clinical attachment level (CAL) and in the width of keratinized tissue (KT). 21,22 On the other hand, it ABSTRACT Background. The authors conducted a systematic review to evaluate the effect of smoking on the clinical outcomes achieved by periodontal plastic surgery procedures in the treatment of recessiontype defects. Types of Studies Reviewed. The authors performed an electronic search on MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) for randomized controlled clinical trials, controlled clinical trials and case series that involved at least six months follow-up. They looked for studies published through June 2008 that compared the outcome measures achieved by smokers and nonsmokers after they underwent periodontal plastic surgery procedures for treatment of gingival recession. Results. From a total of 632 references, the authors considered seven studies to be relevant. The meta-analysis indicated a statistically significant greater reduction in gingival recession (P <.001) and gain in clinical attachment level (P <.001) for nonsmokers when compared with smokers whose gingival recession was treated with subepithelial connective-tissue grafts. Additionally, nonsmokers exhibited significantly more sites with complete than did smokers (P =.001). For coronally advanced flaps, differences between the groups were not significant. Clinical Implications. The results of this review show that smoking may negatively influence gingival recession reduction and clinical attachment level gain. Additionally, smokers may exhibit fewer sites with complete. Key Words. Gingival recession; gingival recession/surgery; ; systematic review; smoking. JADA 2009;140(3): ARTICLE Dr. Leandro Chambrone is a didactic trainer, Division of Periodontics, Department of Stomatology, School of Dentistry, University of São Paulo, Av. Prof. Lineu Prestes, 2227 Cidade Universitária, , São Paulo SP, Brazil, chambrone@usp.br. Address reprint requests to Dr. Chambrone. Dr. Daniela Chambrone is an assistant professor, Discipline of Periodontics, Faculty of Dentistry, Methodist University of São Paulo, São Bernardo do Campo, Brazil. Dr. Pustiglioni is a professor and chair, Division of Periodontics, Department of Stomatology, School of Dentistry, University of Sao Paulo, São Paulo, Brazil. Dr. Luiz Armando Chambrone is a professor and chair, Discipline of Periodontics, Faculty of Dentistry, Methodist University of São Paulo, São Bernardo do Campo, Brazil. Dr. Lima is an associate professor, Division of Periodontics, Department of Stomatology, School of Dentistry, University of São Paulo, São Paulo, Brazil. C O N T J I N U A I N G D A 1 I O N E D U C A T 294 JADA, Vol March 2009

2 is difficult to predict accurately an individual tooth s clinical response to treatment over time, especially if the patient is exposed to one or more risk factors known to influence host response. 25,26 With respect to tobacco smoking, evidence is building that smoking may negatively affect the results achieved through periodontal plastic surgery procedures. Tobacco smoking is a recognized risk factor that affects the oral environment and ecology, vascularization of the gingival tissues, immune and inflammatory responses and the healing potential of the periodontal connective tissues. 27 Smokers are two to eight times more susceptible to periodontal disease than are nonsmokers. 28 Moreover, researchers have identified tobacco smoking as producing a negative effect on periodontal therapy, nonsurgical and surgical alike Moreover, smokers are more susceptible to needing periodontally related tooth extractions during maintenance care after undergoing periodontal treatment. 25,26 Even though previous systematic reviews provided some information of interest about smoking, the majority of trials included in these reviews did not include smokers, and the authors of these reviews did not delineate inclusion criteria in such a way as to warrant inclusion of all studies that have estimated the impact of smoking on clinical outcome measures To date, to our knowledge, no investigators have designed a systematic review that compares the effect of treatment of gingival recession in smokers and nonsmokers. Therefore, our objective in performing a systematic review was to evaluate the effect of tobacco smoking on clinical outcomes achieved by periodontal plastic surgery procedures in the treatment of recession-type defects. The research question on which we focused for this systematic review was Does tobacco smoking influence the outcome measures achieved by root-coverage procedures? MATERIALS AND METHODS Study selection, inclusion criteria and types of interventions. We undertook a systematic review of randomized controlled clinical trials, controlled clinical trials and case series with a follow-up period of at least six months. Owing to the limited number of randomized controlled clinical trials available in previous reviews that is, trials comparing data from smokers and nonsmokers as well as the impossibility of randomization in studies in which only one surgical procedure was tested, we included all levels of evidence in the review. We considered studies for inclusion if they involved the following: drecession areas selected for treatment classified as Miller 20 Class I or II that were treated surgically by means of periodontal plastic surgery procedures (such as acellular dermal matrix allografts, coronally advanced flaps, free gingival grafts, guided tissue regeneration and subepithelial connective-tissue grafts); doutcome measures from smokers and nonsmokers, recorded separately; dsubjects 18 years or older. In addition, we considered subjects to be smokers if they smoked 10 cigarettes or more per day at the time of the baseline examination. Outcome measures. Outcome measures were reported in terms of changes from baseline to each follow-up period. The following outcome measures were reported: dchange in gingival recession (GR); dchange in CAL; dchange in KT; dpercentage of sites exhibiting complete root coverage; dmean. Search strategy. To streamline the identification of studies included in or considered for this review, we developed detailed search strategies for each database we searched that were based on the strategy described below for searching the Cochrane Central Register of Controlled Trials (CENTRAL). We adopted a similar search strategy as reported by a recent Cochrane review regarding the effectiveness of different rootcoverage procedures in the treatment of recession-type defects. 22 We searched databases for articles published through June 2008, including papers and abstracts published in English-language journals. We searched MEDLINE, EMBASE, CENTRAL and the Cochrane Oral Health Group s Specialized Register databases. The search strategy we applied was as follows: (gingival recession OR ((recession NEAR gingiva*) ABBREVIATION KEY. CAF: Coronally advanced flap. CAL: Clinical attachment level. CENTRAL: Cochrane Central Register of Controlled Trials. GR: Gingival recession. KT: Keratinized tissue. MRC: Mean root coverage. NR: Not reported. PCRC: Percentage of complete. SCRC: Sites exhibiting complete. SCTG: Subepithelial connective-tissue graft. JADA, Vol March

3 OR (recession NEAR defect*) OR recession-type defect* ) OR ((exposure NEAR root*) OR (exposed NEAR root*)) OR (gingiva* NEAR defect*), OR denude* NEAR root surface* AND GUIDED TISSUE REGENERATION OR tissue NEAR regenerat* OR ((gingiva* NEAR esthetic*) OR (gingiva* NEAR aesthetic*)) OR periodont*) AND ( plastic surgery OR soft tissue graft* OR coronally advanced flap* OR laterally positioned flap* OR laterally-positioned flap* OR connective tissue graft* OR connective-tissue graft*, OR gingiva* NEAR transplant* OR dermal matrix NEAR graft* OR enamel matrix protein ). We conducted hand searching in several publications: Journal of Periodontology, Journal of Clinical Periodontology and International Journal of Periodontics and Restorative Dentistry. Validity assessment and data extraction. Two reviewers (L.C. and D.C.) independently screened titles, abstracts and full texts of the search results. They obtained full reports for all studies appearing to meet the inclusion criteria or in instances in which there was insufficient information from the title, key words and abstract to make a clear decision. The reviewers assessed agreement between them by means of calculating κ scores. They resolved disagreement regarding inclusion by discussing the issue with another reviewer (L.A.C.). They contacted authors when necessary for clarification of data or to obtain missing data. They excluded data in cases in which they did not reach agreement. The reviewers extracted data regarding the following issues: dcitation, publication status and year of publication; dlocation of trial; dstudy design (randomized controlled clinical trial, controlled clinical trial and case series); dcharacteristics of participants; dcharacteristics of interventions; dmethodological quality of trials. Quality assessment. The two reviewers (L.C. and D.C.) assessed the methodological quality of the included studies by focusing on the following issues: method of randomization and allocation concealment (exclusively for randomized trials), blindness of examiners and completeness of the follow-up period. Data synthesis. We collated data into evidence tables and grouped them according to type of intervention and type of study. We performed a descriptive summary to determine the quantity of data, checking further for variations in terms of study characteristics and results. In cases in which a trial s original design did not explore differences between smokers and nonsmokers, yet the study s results included individual patient data (baseline and final measurements), we used the nonparametric Mann-Whitney U test to evaluate the study s outcomes according to smoking status. We used random-effects meta-analyses throughout. For continuous data, we expressed pooled outcomes as weighted mean differences with their associated 95 percent confidence interval (CIs). For dichotomous data, these were predominantly pooled risk ratios and associated 95 percent CIs. We calculated risk difference and number needed to treat for sites exhibiting complete for which the study s results reached a level of P <.05. We assessed statistical heterogeneity by calculating χ 2. We performed analyses using Review Manager (RevMan) statistical analysis software (Version 5.0, The Nordic Cochrane Centre, The Cochrane Collboration, Copenhagen, Denmark). We conducted variance imputation methods to estimate appropriate variance estimates in cases in which a trial did not include the appropriate standard deviation of the differences. 32,33 During the conduction of metaanalysis, we pooled data from trials reporting results from different periods of follow-up according to the longest follow-up period. Additionally, we assessed the significance of discrepancies in the estimates of the treatment effects from the different trials by means of the Cochran Q test for heterogeneity and the I 2 statistic. RESULTS Results of the search. Our initial search resulted in the identification of 632 articles. Subsequently, we excluded 535 of them on the basis of title and abstract and screened the full text of 97 studies that we considered to be potentially relevant for this review. Of these, we excluded 87 articles during full-text screening because they did not provide individual patient data (which would allow for the extraction of data from both groups separately) or comparisons between smokers and nonsmokers 5,13-16,18, ; in addition, we excluded two articles because they involved a follow-up period of less than six months 115,116 and one article because we considered it a duplicate report. 117 The κ scores between examiners were > 0.75, indicating a good level of agreement. By the end of the search phase, we considered 296 JADA, Vol March 2009

4 TABLE 1 Characteristics of included studies. STUDY METHODS SUBJECTS INTERVENTIONS AND NO. OF PATIENTS TREATED PER GROUP OUTCOMES SITE AND FUNDING Andia and Colleagues 118 (2008) Controlled clinical trial, parallel design, one treatment group, 24 months duration 22 subjects, aged years, with at least one Miller Class I or II buccal gingival recession of at least 3 millimeters; no subject was excluded from the study Subepithelial connective-tissue graft (SCTG) 11 nonsmokers 11 smokers ( 20 cigarettes per day for a minimum of five years) Change in gingival recession (GR) Change in clinical attachment level (CAL) Percentage of complete Mean (as determined via automated controlled force probe) University-based and supported by the National Council for Scientific and Technological Development, Brazil Erley and Colleagues 119 (2006) Controlled clinical trial, parallel design, one treatment group, six months duration 17 subjects, one female, aged years, with at least one Miller Class I or II buccal gingival recession of at least 2 mm (22 recession defects); no subject was excluded from the study SCTG Nine nonsmokers, 10 sites Eight smokers, 12 sites 10 cigarettes per day (as verified by a salivary cotinine test) Change in GR Change in CAL Change in keratinized tissue (KT) Percentage of complete Mean (as determined via manual probe) Hospital-based and funded by Clinical Investigation Department, Fort Gordon, Army Dental Corps, and the Fort Gordon Dental Activity, Fort Gordon, Ga. Pini Prato and Colleagues 6 (2005) Case series, one treatment group, six months duration 60 subjects, with one Miller Class I buccal gingival recession of at least 2 mm (individual patient data available for analysis); no subject was excluded from the study Coronally advanced flap (CAF) 49 nonsmokers 11 smokers ( 10 cigarettes per day) Change in GR Change in CAL Change in KT Percentage of complete Mean (as determined via manual probe) Practice-based Silva and Colleagues 121 (2007) Controlled clinical trial, parallel design, one treatment group, 24 months duration (examinations at six, 12 and 24 months after procedure) 20 subjects, nine female, aged years, with one having Miller Class I buccal gingival recession (2 to 3 mm in depth); no subject was excluded from the study CAF 10 nonsmokers 10 smokers ( 10 cigarettes per day for a minimum of five years) Change in GR Change in CAL Change in KT Percentage of complete Mean (as determined via automated controlled force probe) University-based Souza and Colleagues 122 (2008) Controlled clinical trial, parallel design, one treatment group, six months duration 30 subjects, 10 female, aged years, with one Miller Class I or II buccal gingival recession of at least 3 mm; no subject was excluded from the study SCTG 15 nonsmokers 15 smokers ( 10 cigarettes per day for a minimum of five years) Change in GR Change in CAL Change in KT Percentage of complete Mean (as determined via automated controlled force probe and manual probe) University-based and supported by the National Council for Scientific and Technological Development, Brazil Trombelli and Scabbia 19 (1997) Case series, parallel design, one treatment group, six months duration 22 subjects, 12 female, aged years, with one Miller Class I or II buccal gingival recession of at least 4 mm; no subject was excluded from the study Guided tissue regeneration nonresorbable membrane 13 nonsmokers Nine smokers ( 10 cigarettes per day) Change in GR Change in CAL Change in KT Mean (as determined via manual probe) Practice-based JADA, Vol March

5 Potentially relevant articles identified and screened for retrieval from CENTRAL, MEDLINE and EMBASE (n = 631) and hand searching (n = 1) Full-text articles screened to identify potentially relevant studies for review (n = 97) Articles initially included in the review (n = 7) BUT one controlled clinical trial was reported in two articles SO in total, 6 articles included in review Articles included in meta-analyses (n = 5) seven articles eligible; their data are the basis of this review (Table 1). 6,19, However, data from one study were reported in two articles according to the follow-up period (short term and long term). 120,121 Therefore, we cited the article with the shorter follow-up period 120 and the article describing the longer follow-up period under the one study name. 121 Figure 1 is a flow chart of studies assessed and excluded at various stages of the review. Characteristics of the included studies. Of the six included studies, we categorized four as controlled clinical trials 118,119,121,122 and two as case series. 6,19 Four trials had been conducted at university dental clinics. 118,119,121,122 Three studies had been performed in Brazil, 118,121,122 two in Italy 6,19 and one in the United States. 119 In total, 64 smokers and 107 nonsmokers received treatment and three types of periodontal plastic surgery procedures were evaluated (coronally advanced flaps, guided tissue regeneration and subepithelial connective-tissue grafts). Quality assessment of included studies. Examiner blinding was evident in three trials, 119,121,122 while in the remaining articles it was unclear or not stated. Also, we noted a clear accounting of participants in all studies (Table 1). Outcomes measures. Researchers observed changes in GR depth, CAL and KT during the course of each study. Most of the investigators reported a statistically significant reduction in initial recession means, with a concomitant gain in CAL 19,118,119,121,122 and KT 19,119,122 for smokers and nonsmokers. With respect to intergroup comparisons (smokers versus nonsmokers), researchers in five trials reported statistically significant superior recession reduction 19,118,119,121,122 and CAL gain for nonsmokers 118,121,122 when compared with smokers (Table 2). In one study designed to evaluate the postsurgical position of the gingival margin, examining the individual patient data from 11 smokers and 49 nonsmokers allowed us to perform intergroup comparisons. 6 Within groups, we found statistically significant changes from baseline to the sixmonth evaluation for GR, CAL and KT. Betweengroups analyses by Mann-Whitney U test showed no statistically significant differences in the mean postoperative recession depth (P =.75), CAL (P =.90) and width of KT (P =.10). 6 In addition, we performed two sets of interstudy comparisons a total of eight meta-analyses, four Articles excluded on basis of title and abstract (n = 535) Excluded articles that did not fulfill inclusion criteria (n = 90) Articles not included in meta-analyses (n = 1) Figure 1. Flow chart of manuscripts screened through the review process. CENTRAL: Cochrane Central Register of Controlled Trials. 298 JADA, Vol March 2009

6 TABLE 2 Outcome measures from included studies. STUDY AND SUBJECTS, ACCORDING TO SMOKING STATUS INTERVENTION TYPE AND FOLLOW-UP PERIOD Change in Recession Depth (mean ± SD) (mm*) Change in Clinical Attachment Level (mean ± SD) (mm) OUTCOME MEASURE Change in Keratinized Tissue (mean ± SD) (mm) SCRC (n/n) PCRC (%) MRC (%) Andia and Colleagues 118 (2008) Subepithelial connective-tissue graft (SCTG) Nonsmokers 24 months # # NR ** 3/ Smokers 24 months NR 0/ Erley and SCTG Colleagues 119 (2006) Nonsmokers 6 months # / Smokers 6 months / Pini Prato and Colleagues 6 (2005) Coronally advanced flap (CAF) Nonsmokers 6 months / Smokers 6 months / Silva and CAF Colleagues 121 (2007) Nonsmokers 6 months # / months # / months # / Smokers 6 months / months # / months # / Souza and SCTG Colleagues 122 (2008) Nonsmokers 6 months # # / Smokers 6 months / Trombelli and Scabbia (1997) 19 Guided tissue regeneration Nonsmokers 6 months # / Smokers 6 months / * mm: Millimeters. SCRC: Sites exhibiting complete. PCRC: Percentage of complete. MRC: Mean. Significant difference within group. # Significant difference between groups. ** NR: Not reported. comparing outcomes for subepithelial connectivetissue graft procedures and four comparing outcomes for coronally advanced flaps for changes in GR, CAL and KT and for the number of sites exhibiting complete (Table 3). For subepithelial connective-tissue grafts, the results indicated a statistically significant greater reduction in GR, with the weighted mean difference 0.78 mm (95 percent CI, 1.06 to 0.51) (Figure 2) and significant CAL gain, with the weighted mean difference 0.75 mm (95 percent CI, 1.13 to 0.38) (Figure 3, page 301) for nonsmokers, when compared with smokers, whereas the width of KT differences between smokers and nonsmokers was not significant (P =.97). For coronally advanced flaps, we found that the differences in GR reduction and gains in CAL and KT between smokers and nonsmokers were not significant. Complete and mean root coverage. The percentages of complete and mean showed marked variation. Subepithelial connective-tissue grafts resulted in 27.0 to 80.0 percent complete for nonsmokers and 0 to 25.0 percent for smokers. Similarly, coronally advanced flaps resulted in 20.0 to 55.1 percent complete root cov- JADA, Vol March

7 TABLE 3 Summary of meta-analyses. TREATMENT COMPARED STUDY OUTCOME STATISTICAL METHOD EFFECT SIZE IN mm* (95% CI ) P VALUE HETEROGENEITY χ 2 P Value I 2 (%) Coronally Advanced Flap Pini Prato and colleagues 6 (2005), Silva and colleagues 121 (2007) Change in gingival recession Change in clinical attachment level Change in keratinized tissue WMD 95% CI 0.09 ( 0.81 to 0.63) WMD 95% CI 0.01 ( 0.54 to 0.56) WMD 95% CI 0.22 ( 1.40 to 0.97) RR 95 % CI 0.30 (0.02 to 5.78) Subepithelial Connective- Tissue Graft Andia and colleagues 118 (2008), Erley and colleagues 119 (2006), Souza and colleagues 122 (2008) Change in gingival recession Change in clinical attachment level Change in keratinized tissue WMD 95% CI 0.78 ( 1.06 to 0.51) < WMD 95% CI 0.75 ( 1.13 to 0.38) < WMD 95% CI 0.02 ( 1.05 to 1.02) RR 95% CI 0.24 (0.10 to 0.58) * mm: Millimeters. CI: Confidence interval. WMD: Weighted mean difference. RR: Risk ratio. Comparison made with two studies (data from Andia and colleagues study were not available). Figure 2. Forest plot of random effects meta-analysis evaluating the difference in gingival recession change between smokers and nonsmokers after treatment with subepithelial connective-tissue graft. IV: Inverse variance. CI: Confidence interval. τ: Kendall tau. z: z test. erage for nonsmokers and 0 to 54.5 percent for smokers (Table 2). For guided tissue regeneration, complete was 38.5 percent for nonsmokers and 11.1 percent for smokers. Between smokers and nonsmokers who received subepithelial connective-tissue grafts, nonsmokers achieved more complete. They showed a significant difference in the number of sites with complete when compared with smokers (risk ratio, 0.24; 95 percent CI, 0.10 to 0.58) in the two arms of the trials (Figure 4). Moreover, we observed little evidence of heterogeneity (χ 2 for heterogeneity = 0.92, df = 2, P =.63, I 2 = 0 percent). In addition, we calculated the risk difference (that is, the difference between the proportions of subjects exhibiting complete in the two groups) and number needed to treat for this comparison; the results were 0.41 (95 percent CI, 0.59 to 0.24; P <.001) and 3.00, respectively. DISCUSSION In this review, we explored the literature regarding the potential effect of smoking on the results achieved by periodontal plastic surgery procedures, with the aim of evaluating differences 300 JADA, Vol March 2009

8 Figure 3. Forest plot of random effects meta-analysis evaluating the difference in clinical attachment level change between smokers and nonsmokers after treatment with subepithelial connective-tissue graft. IV: Inverse variance. CI: Confidence interval. τ: Kendall tau. z: z test. Figure 4. Forest plot of random effects meta-analysis evaluating the difference in the number of sites exhibiting complete between smokers and nonsmokers after treatment with subepithelial connective-tissue graft. IV: Inverse variance. CI: Confidence interval. τ: Kendall tau. z: z test. in clinical outcomes. Six trials fulfilled the proposed inclusion criteria, providing data from patients treated with coronally advanced flaps, guided tissue regeneration and subepithelial connective-tissue grafts. When we accumulated evidence from individual studies, the pooled data suggested that tobacco smoking affects root coverage. 19,118,119,121,122 Likewise, the results of our meta-analyses showed that the use of subepithelial connective-tissue grafts was less effective in smokers than in nonsmokers in reducing the extent of exposed root surface and in improving the CAL. These findings may support the hypothesis that smoking decreases the expected success of periodontal plastic surgery procedures. On the other hand, we should discuss some inherent limitations of our review. We found no statistically significant differences between smokers and nonsmokers when investigators used coronally advanced flap procedures. Despite this fact, we should note that there remains cause for concern that smoking can affect root-coverage outcomes, because only two studies in which investigators used this procedure were available for analysis, and one of these trials (a two-year controlled clinical trial) showed that smokers long-term healing response was indeed affected by their tobacco use. 121 Within-study comparisons revealed that recession reduction, clinical attachment gain, mean and the number of sites exhibiting complete were less evident in smokers. 121 Furthermore, we should note that we also found differences in the applied methodology in each trial (that is, inclusion criteria, variability between surgical procedures, examiner blinding and follow-up period). With respect to the study protocol, an important issue we evaluated in trials reporting results from smokers was how the individual studies defined a subject as a smoker, and how the investigators ascertained the accuracy of this classification. Erley and colleagues 119 reported that they classified subjects as smokers if they reported using 10 or more cigarettes per day, which the researchers later verified by means of a salivary cotinine sample (negative, 0 to 10 nanograms per JADA, Vol March

9 milliliter; low, 10 to 20 ng/ml; medium, 20 to 40 ng/ml; high, more than 40 ng/ml). The researchers used these cotinine levels to confirm the subject s self-reported smoking history. This study s results showed that the percentage of mean at six months varied according to the level of cotinine (84.2 percent for 10- to 40-ng/mL levels and 76.6 percent for levels > 40 ng/ml), and that higher levels of cotinine were negatively associated with the mean (r = 0.97). 119 In the remaining trials, 6,19,118, 121,122 the investigators considered subjects to be smokers if they reported the use of at least 10 cigarettes per day at the time of the initial examination, but these authors conducted no cotinine tests. Additionally, we excluded the results from one further study comparing the outcomes for smokers and nonsmokers treated with acellular dermal matrix grafts because the investigators did not report how they had defined patients as smokers. 63 Palmer and colleagues 27 and Johnson and Guthmiller 28 observed that tobacco smoking demonstrated a long-term effect that harms the vascularization of a person s periodontal tissues rather than a simple vasoconstrictive effect that follows a smoking event. Alterations consist of chronic reductions in gingival blood flow, vascularity, gingival crevicular fluid levels and oxygen saturation of hemoglobin; suppression of neutrophil functions; negative effects on cytokines and growth factor production; inhibition of fibroblast growth; inhibition of collagen production by gingival fibroblasts; and less attachment of periodontal ligament fibroblasts to root surfaces. 27,28 The combination of such effects may have affected the healing response of smokers, especially those treated with subepithelial connective-tissue grafts. As previously noted, having observed an adequate blood supply is critical for revascularization of connective-tissue grafts. 1,10-13,119 Moreover, the success of a periodontal plastic surgery procedure usually is associated with the re-establishment of the gingival wall over previously exposed root surfaces, with a concomitant improvement in CAL and esthetics and a decrease in dental hypersensitivity. In the studies we included in this review, both smokers and nonsmokers demonstrated improvement in GR depth, CAL and KT; however, nonsmokers exhibited greater improvement than smokers in all of these measures. Authors of all studies we included reported statistically significant changes in the recorded outcome measures from baseline to the most recent follow-up evaluations (Table 2). Besides, not all periodontal plastic surgery procedures may result in an identical range of root coverage. Previous reviews have indicated that subepithelial connective-tissue grafts produce results that are better in terms of mean and complete than those of other techniques In spite of the limited number of studies included in this systematic review, we found a similar tendency for both outcomes among smokers. With respect to mean and complete, we found a marked variation in results (Table 2), as well as a statistically significant greater chance of achieving complete root coverage with subepithelial connective-tissue grafts, in nonsmokers when compared with smokers. Differences between techniques, the operator s level of experience, recession localization and gingival anatomy 8,123 may be linked to the great variability of results we observed between the included studies. Some of these conditions may cause the patient s wound to reopen during healing. 123 Additionally, we calculated the number needed to treat to determine how many smokers would need to be treated with subepithelial connective-tissue graft procedures to result in one more patient s achieving complete than would have done so in the nonsmokers group. The number needed to treat for smokers to obtain one more site exhibiting complete root coverage than nonsmokers was three (that is, three patients who smoke need to be treated so that one can achieve this benefit over nonsmoking patients). As previously mentioned, investigators in one study reported their data in two articles according to the follow-up period (short term and long term). 120,121 They found that mean and complete decreased across time, both in smokers and in nonsmokers. 120,121 Nonetheless, this recurrence of GR seemed to be more evident among smokers. Thus, this evidence regarding both the mean and the number of sites exhibiting complete provides compelling support for the concept that behavioral, environmental and individual factors may be associated with the recurrence of GR. Consequently, researchers should evaluate the possible causes of the recession, as well as whether these undesirable changes in root-coverage outcomes will lead to deterioration in the patient s oral esthetic status 302 JADA, Vol March 2009

10 and functional conditions over time. Mechanisms of host response in the periodontal tissues are complex and involve numerous systems of interactions. 124 Although lifestyle change (in this case, smoking cessation) cannot reverse the effects of smoking immediately, it may improve wound healing conditions in the future. In light of this discussion, it seems reasonable that patients should be encouraged to quit smoking. It has been advocated that smoking cessation in the time surrounding the immediate surgical procedure may be beneficial. 28,40,41,119 While there are several examples of the use of periodontal plastic surgery procedures to cover exposed root surfaces, studies regarding the effects of smoking on the outcomes of such procedures are particularly important. Other researchers have recognized that smokers especially so-called heavy smokers (patients who smoke 20 or more cigarettes per day) have more GR than do nonsmokers. 28,125 Heavy smokers expose themselves to tobacco products (nicotine and tar) many times per day. 27 As tobacco smokers experience widespread negative systemic effects of their tobacco use, this long-term exposure will affect the oral cavity as well. Clearly, identification of the specific factors associated with the healing process in smokers is an area in which much more research is needed. CONCLUSIONS In our systematic review of the limited information available, we found that the treatment of recession-type defects by means of periodontal plastic surgery procedures led to statistically significant improvements in GR and CAL for both smokers and nonsmokers. Our meta-analysis showed that subepithelial connective-tissue grafts provide significantly more and clinical attachment gain for nonsmokers than for smokers. However, coronally advanced flaps produced similar outcomes for smokers and nonsmokers in terms of changes in GR, CAL and width of KTs. There was a noticeable variation in the percentages of mean and complete between studies and procedures. Smokers who received subepithelial connective-tissue grafts for treatment of GR had fewer sites exhibiting complete than did nonsmokers. Overall, nonsmokers had the best outcomes. Implications for research. Further comparisons between smokers and nonsmokers (in the form of controlled clinical trials) are necessary to corroborate our findings of the effects of tobacco smoking on periodontal plastic surgery procedures. Randomized controlled clinical trials performed with smokers are needed to evaluate periodontal plastic surgery procedures and to determine which techniques provide the best results. Researchers should evaluate differences between light and heavy smokers in these trials. In future trials, researchers should include baseline and final measurements of individual defects (GR, CAL, KT and GR width) and patient-based outcomes (esthetics and dental hypersensitivity). Implications for practice. Patients who smoke should be encouraged to quit before undergoing any periodontal plastic surgery procedure, with the goal of improving the expected outcomes as well as their overall health. However, if patients cannot achieve this, clinicians should encourage them to consider, at the least, reducing the number of cigarettes smoked per day or avoiding smoking completely during the early phase of healing. Disclosure. None of the authors reported any disclosures. 1. Chambrone LA, Chambrone L. Subepithelial connective tissue grafts in the treatment of multiple recession-type defects. J Periodontol 2006;77(5): Grupe HE, Warren RF Jr. Repair of gingival defects by a sliding flap operation. J Periodontol 1956;27(2): Caffesse RG, Guinard EA. Treatment of localized gingival recessions, part IV: results after three years. J Periodontol 1980;51(3): Zucchelli G, Cesari C, Amore C, Montebugnoli L, De Sanctis M. Laterally moved, coronally advanced flap: a modified surgical approach for isolated recession-type defects (published correction appears in J Periodontol 2005;76[8]:1425). J Periodontol 2004;75(12): Bittencourt S, Del Peloso Ribeiro E, Sallum EA, Sallum AW, Nociti FH Jr, Casati MZ. Comparative 6-month clinical study of a semilunar coronary positioned flap and subepithelial connective tissue graft for the treatment of gingival recession. J Periodontol 2006;77(2): Pini Prato GP, Baldi C, Nieri M, et al. Coronally advanced flap: the post-surgical position of the gingival margin is an important factor for achieving complete. J Periodontol 2005;76(5): Miller PD Jr. Root coverage using the free soft tissue autograft following citric acid application, III: a successful and predictable procedure in areas of deep-wide recession. Int J Periodontics Resorative Dent 1985;5(2): Borghetti A, Gardella JP. Thick gingival autograft for the coverage of gingival recession: a clinical evaluation. Int J Periodontics Restorative Dent 1990;10(3): Raetzke P. Covering localized areas of root exposure employing the envelope technique. J Periodontol 1985;56(7): Langer B, Langer L. Subepithelial connective tissue graft technique for. J Periodontol 1985;56(12): Nelson SW. The subpedicle connective tissue graft: a bilaminar reconstructive procedure for the coverage of denuded root surfaces. J Periodontol 1987;58(2): Harris RJ. The connective tissue and partial thickness double pedicle graft: a predictable method of obtaining. J Periodontol 1992;63(5): Caffesse RG, De LaRosa M, Garza M, Munne-Travers A, Mondragon JC, Weltman R. Citric acid demineralization and subepithelial connective tissue grafts. J Periodontol 2000;71(4): Tal H, Moses O, Zohar R, Meir H, Nemcovsky C. Root coverage of JADA, Vol March

11 advanced gingival recession: a comparative study between acellular dermal matrix allograft and subepithelial connective tissue grafts. J Periodontol 2002;73(12): Barros RR, Novaes AB, Grisi MF, Souza SL, Taba MJ, Palioto DB. A 6-month comparative clinical study of a conventional and a new surgical approach for with acellular dermal matrix. J Periodontol 2004;75(10): Amarante ES, Leknes KN, Skavland J, Lie T. Coronally positioned flap procedures with or without a bioabsorbable membrane in the treatment of human gingival recession. J Periodontol 2000;71(6): Roccuzzo M, Bunino M, Needleman I, Sanz M. Periodontal plastic surgery for treatment of localized gingival recessions: a systematic review. J Clin Periodontol 2002;29(suppl 3): Tatakis DN, Trombelli L. Gingival recession treatment: guided tissue regeneration with bioabsorbable membrane versus connective tissue graft. J Periodontol 2000;71(2): Trombelli L, Scabbia A. Healing response of gingival recession defects following guided tissue regeneration procedures in smokers and non-smokers. J Clin Periodontol 1997;24(8): Miller PD Jr. A classification of marginal tissue recession. Int J Periodontics Restorative Dent 1985;5(2): Chambrone L, Chambrone D, Pustiglioni FE, Chambrone LA, Lima LA. Can subepithelial connective tissue grafts be considered the gold standard procedure in the treatment of Miller Class I and II recession-type defects? J Dent 2008;36(9): Chambrone L, Sukekava F, Araújo MG, Pustiglioni FE, Chambrone LA, Lima LA. Root coverage procedures for the treatment of localized recession-type defects. Cochrane Database Syst Rev (in press). 23. Oates TW, Robinson M, Gunsolley JC. Surgical therapies for the treatment of gingival recession: a systematic review. Ann Periodontol 2003;8(1): Roccuzzo M, Bunino M, Needleman I, Sanz M. Periodontal plastic surgery for treatment of localized gingival recessions: a systematic review. J Clin Periodontol 2002;29(suppl 3): Chambrone LA, Chambrone L. Tooth loss in well maintained patients with chronic periodontitis during long-term supportive therapy in Brazil. J Clin Periodontol 2006;33(10): Fardal Ø, Johannessen AC, Linden GJ. Tooth loss during maintenance following periodontal treatment in a periodontal practice in Norway. J Clin Periodontol 2004;31(7): Palmer RM, Wilson RF, Hasan AS, Scott DA. Mechanisms of action of environmental factors: tobacco smoking. J Clin Periodontol 2005;32(suppl 6): Johnson GK, Guthmiller JM. The impact of cigarette smoking on periodontal disease and treatment. Periodontol ;44: Kinane DF, Chestnutt IG. Smoking and periodontal disease. Crit Rev Oral Biol Med 2000;11(3): Stavropoulos A, Mardas N, Herrero F, Karring T. Smoking affects the outcome of guided tissue regeneration with bioresorbable membranes: a retrospective analysis of intrabony defects. J Clin Periodontol 2004;31(11): Cortellini P, Bowers GM. Periodontal regeneration of intrabony defects: an evidence-based treatment approach. Int J Periodontics Restorative Dent 1995;15(2): Dawson B, Trapp RG. Basic and Clinical Biostatistics. 3rd ed. New York City: Lange Medical Books-McGraw-Hill; 2001: Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 1992;45(7): Aichelmann-Reidy ME, Yukna RA, Evans GH, Nasr HF, Mayer ET. Clinical evaluation of acellular allograft dermis for the treatment of human gingival recession. J Periodontol 2001;72(8): Barros RR, Novaes AB Jr, Grisi MF, Souza SL, Taba M Jr, Palioto DB. New surgical approach for of localized gingival recession with acellular dermal matrix: a 12-month comparative clinical study. J Esthet Restor Dent 2005;17(3): Berlucchi I, Francetti L, Del Fabbro M, Testori T, Weinstein RL. Enamel matrix proteins (Emdogain) in combination with coronally advanced flap or subepithelial connective tissue graft in the treatment of shallow gingival recessions. Int J Periodontics Restorative Dent 2002;22(6): Berlucchi I, Francetti L, Del Fabbro M, Basso M, Weinstein RL. The influence of anatomical features on the outcome of gingival recessions treated with coronally advanced flap and enamel matrix derivative: a 1-year prospective study. J Periodontol 2005;76(6): Borghetti A, Louise F. Controlled clinical evaluation of the subpedicle connective tissue graft for the coverage of gingival recession. J Periodontol 1994;65(12): Borghetti A, Glise JM, Monnet-Corti V, Dejou J. Comparative clinical study of a bioabsorbable membrane and subepithelial connective tissue graft in the treatment of human gingival recession. J Periodontol 1999;70(2): Bouchard P, Etienne D, Ouhayoun JP, Nilveus R. Subepithelial connective tissue grafts in the treatment of gingival recessions: a comparative study of 2 procedures. J Periodontol 1994;65(10): Bouchard P, Nilveus R, Etienne D. Clinical evaluation of tetracycline HCl conditioning in the treatment of gingival recessions: a comparative study. J Periodontol 1997;68(3): Burkhardt R, Lang NP. Coverage of localized gingival recessions: comparison of micro- and macrosurgical techniques. J Clin Periodontol 2005;32(3): Castellanos A, de la Rosa M, de la Garza M, Caffesse RG. Enamel matrix derivative and coronal flaps to cover marginal tissue recessions. J Periodontol 2006;77(1): Cetiner D, Parlar A, Balofl K, Alpar R. Comparative clinical study of connective tissue graft and two types of bioabsorbable barriers in the treatment of localized gingival recessions. J Periodontol 2003;74(8): Cheung WS, Griffin TJ. A comparative study of with connective tissue and platelet concentrate grafts: 8-month results. J Periodontol 2004;75(12): Cordioli G, Mortarino C, Chierico A, Grusovin MG, Majzoub Z. Comparison of 2 techniques of subepithelial connective tissue graft in the treatment of gingival recessions. J Periodontol 2001;72(11): da Silva RC, Joly JC, de Lima AF, Tatakis DN. Root coverage using the coronally positioned flap with or without a subepithelial connective tissue graft. J Periodontol 2004;75(3): Daniel A, Cheru R. Treatment of localised gingival recession with subpedicle connective tissue graft and free gingival auto graft: a comparative clinical evaluation. J Indian Dent Assoc 1990;61(12): Dembowska E, Drozdzik A. Subepithelial connective tissue graft in the treatment of multiple gingival recession. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104(3): Cortes Ade Q, Martins AG, Nociti FH Jr, Sallum AW, Casati MZ, Sallum EA. Coronally positioned flap with or without acellular dermal matrix graft in the treatment of Class I gingival recessions: a randomized controlled clinical study. J Periodontol 2004;75(8): de Queiroz Cortes A, Sallum AW, Casati MZ, Nociti FH Jr, Sallum EA. A two-year prospective study of coronally positioned flap with or without acellular dermal matrix graft. J Clin Periodontol 2006; 33(9): Del Pizzo M, Zucchelli G, Modica F, Villa R, Debernardi C. Coronally advanced flap with or without enamel matrix derivative for root coverage: a 2-year study. J Clin Periodontol 2005;32(11): Dodge JR, Greenwell H, Drisko C, Wittwer JW, Yancey J, Rebitski G. Improved bone regeneration and using a resorbable membrane with physically assisted cell migration and DFDBA. Int J Periodontics Restorative Dent 2000;20(4): Duval BT, Maynard JG, Gunsolley JC, Waldrop TC. Treatment of human mucogingival defects utilizing a bioabsorbable membrane with and without a demineralized freeze-dried bone allograft. J Periodontol 2000;71(11): Felipe ME, Andrade PF, Grisi MF, et al. Comparison of two surgical procedures for use of the acellular dermal matrix graft in the treatment of gingival recessions: a randomized controlled clinical study. J Periodontol 2007;78(7): Gupta R, Pandit N, Sharma M. Clinical evaluation of a bioresorbable membrane (polyglactin 910) in the treatment of Miller type II gingival recession. Int J Periodontics Restorative Dent 2006;26(3): Hagewald S, Spahr A, Rompola E, Haller B, Heijl L, Bernimoulin JP. Comparative study of Emdogain and coronally advanced flap technique in the treatment of human gingival recessions: a prospective controlled clinical study. J Clin Periodontol 2002;29(1): Harris RJ. A comparative study of obtained with guided tissue regeneration utilizing a bioabsorbable membrane versus the connective tissue with partial-thickness double pedicle graft. J Periodontol 1997;68(8): Harris RJ. A comparative study of obtained with an acellular dermal matrix versus a connective tissue graft: results of 107 recession defects in 50 consecutively treated patients. Int J Periodontics Restorative Dent 2000;20(1): Harris RJ. Root coverage with connective tissue grafts: an evaluation of short- and long-term results. J Periodontol 2002;73(9): Harris RJ, Miller LH, Harris CR, Miller RJ. A comparison of 304 JADA, Vol March 2009

12 three techniques to obtain on mandibular incisors. J Periodontol 2005;76(10): Henderson RD, Greenwell H, Drisko C, et al. Predictable multiple site using an acellular dermal matrix allograft. J Periodontol 2001;72(5): Hirsch A, Goldstein M, Goultschin J, Boyan BD, Schwartz Z. A 2-year follow-up of using sub-pedicle acellular dermal matrix allografts and subepithelial connective tissue autografts. J Periodontol 2005;76(8): Huang LH, Neiva RE, Soehren SE, Giannobile WV, Wang HL. The effect of platelet-rich plasma on the coronally advanced flap root coverage procedure: a pilot human trial. J Periodontol 2005;76(10): Ito K, Oshio K, Shiomi N, Murai S. A preliminary comparative study of the guided tissue regeneration and free gingival graft procedures for adjacent facial. Quintessence Int 2000;31(5): Jahnke PV, Sandifer JB, Gher ME, Gray JL, Richardson AC. Thick free gingival and connective tissue autografts for. J Periodontol 1993;64(4): Jepsen K, Heinz B, Halben JH, Jepsen S. Treatment of gingival recession with titanium reinforced barrier membranes versus connective tissue grafts. J Periodontol 1998;69(3): Joly JC, Carvalho AM, da Silva RC, Ciotti DL, Cury PR. Root coverage in isolated gingival recessions using autograft versus allograft: a pilot study. J Periodontol 2007;78(6): Kennedy JE, Bird WC, Palcanis KG, Dorfman HS. A longitudinal evaluation of varying widths of attached gingiva. J Clin Periodontol 1985;12(8): Kimble KM, Eber RM, Soehren S, Shyr Y, Wang HL. Treatment of gingival recession using a collagen membrane with or without the use of demineralized freeze-dried bone allograft for space maintenance. J Periodontol 2004;75(2): Lafzi A, Mostofi Zadeh Farahani R, Abolfazli N, Amid R, Safaiyan A. Effect of connective tissue graft orientation on the outcomes of coronally advanced flap. Clin Oral Investig 2007;11(4): Laney JB, Saunders VG, Garnick JJ. A comparison of two techniques for attaining. J Periodontol 1992;63(1): Leknes KN, Amarante ES, Price DE, Boe OE, Skavland RJ, Lie T. Coronally positioned flap procedures with or without a biodegradable membrane in the treatment of human gingival recession: a 6-year follow-up study. J Clin Periodontol 2005;32(5): Lins LH, de Lima AF, Sallum AW. Root coverage: comparison of coronally positioned flap with and without titanium-reinforced barrier membrane. J Periodontol 2003;74(2): Matarasso S, Cafiero C, Coraggio F, Vaia E, de Paoli S. Guided tissue regeneration versus coronally repositioned flap in the treatment of recession with double papillae. Int J Periodontics Restorative Dent 1998;18(5): McGuire MK, Nunn M. Evaluation of human recession defects treated with coronally advanced flaps and either enamel matrix derivative or connective tissue, part 1: comparison of clinical parameters. J Periodontol 2003;74(8): Modica F, Del Pizzo M, Roccuzzo M, Romagnoli R. Coronally advanced flap for the treatment of buccal gingival recessions with and without enamel matrix derivative: a split-mouth study. J Periodontol 2000;71(11): Moses O, Artzi Z, Sculean A, et al. Comparative study of two root coverage procedure: a 24-month follow-up multicenter study. J Periodontol 2006;77(2): Muller HP, Eger T, Schorb A. Gingival dimensions after with free connective tissue grafts. J Clin Periodontol 1998;25(5): Muller HP, Stahl M, Eger T. Root coverage employing an envelope technique or guided tissue regeneration with a bioabsorbable membrane. J Periodontol 1999;70(7): Nemcovsky CE, Artzi Z, Tal H, Kozlovsky A, Moses O. A multicenter comparative study of two procedures: coronally advanced flap with addition of enamel matrix proteins and subpedicle connective tissue graft. J Periodontol 2004;75(4): Novaes AB Jr, Grisi DC, Molina GO, Souza SL, Taba M Jr, Grisi MF. Comparative 6-month clinical study of a subepithelial connective tissue graft and acellular dermal matrix graft for the treatment of gingival recession. J Periodontol 2001;72(11): Paolantonio M. Treatment of gingival recessions by combined periodontal regenerative technique, guided tissue regeneration, and subpedicle connective tissue graft: a comparative clinical study. J Periodontol 2002;73(1): Paolantonio M, di Murro C, Cattabriga A, Cattabriga M. Subpedicle connective tissue graft versus free gingival graft in the coverage of exposed root surfaces: a 5-year clinical study. J Clin Periodontol 1997;24(1): Paolantonio M, Dolci M, Esposito P, et al. Subpedicle acellular dermal matrix graft and autogenous connective tissue graft in the treatment of gingival recessions: a comparative 1-year clinical study. J Periodontol 2002;73(11): Pilloni A, Paolantonio M, Camargo PM. Root coverage with a coronally positioned flap used in combination with enamel matrix derivative: 18-month clinical evaluation. J Periodontol 2006;77(12): Pini Prato G, Tinti C, Vincenzi G, Magnani C, Cortellini P, Clauser C. Guided tissue regeneration versus mucogingival surgery in the treatment of human buccal gingival recession. J Periodontol 1992;63(11): Pini Prato G, Clauser C, Cortellini P, Tinti C, Vincenzi G, Pagliaro U. Guided tissue regeneration versus mucogingival surgery in the treatment of human buccal recessions: a 4-year follow-up study. J Periodontol 1996;67(11): Pini-Prato G, Baldi C, Pagliaro U, et al. Coronally advanced flap procedure for : treatment of root surface root planing versus polishing. J Periodontol 1999;70(9): Pini Prato G, Pagliaro U, Baldi C, et al. Coronally advanced flap procedure for : flap with tension versus flap without tension a randomized controlled clinical study. J Periodontol 2000;71(2): Rahmani ME, Lades MA. Comparative clinical evaluation of acellular dermal matrix allograft and connective tissue graft for the treatment of gingival recession. J Contemp Dent Pract 2006;7(2): Ricci G, Silvestri M, Rasperini G, Cattaneo V. Root coverage: a clinical/statistical comparison between subpedicle connective tissue graft and laterally positioned full thickness flaps. J Esthet Dent 1996; 8(2): Ricci G, Silvestri M, Tinti C, Rasperini G. A clinical/statistical comparison between the subpedicle connective tissue graft method and the guided tissue regeneration technique in. Int J Periodontics Restorative Dent 1996;16(6): Roccuzzo M, Lungo M, Corrente G, Gandolfo S. Comparative study of a bioresorbable and a non-resorbable membrane in the treatment of human buccal gingival recessions. J Periodontol 1996;67(1): Romagna-Genon C. Comparative clinical study of guided tissue regeneration with a bioabsorbable bilayer collagen membrane and subepithelial connective tissue graft. J Periodontol 2001;72(9): Rosetti EP, Marcantonio RA, Rossa C Jr, Chaves ES, Goissis G, Marcantonio E Jr. Treatment of gingival recession: comparative study between subepithelial connective tissue graft and guided tissue regeneration. J Periodontol 2000;71(9): Sallum EA, Casati MZ, Caffesse RG, Funis LP, Nociti Junior FH, Sallum AW. Coronally positioned flap with or without enamel matrix protein derivative for the treatment of gingival recessions. Am J Dent 2003;16(5): Sbordone L, Ramaglia L, Spagnuolo G, De Luca M. A comparative study of free gingival and subepithelial connective tissue grafts. Periodontal Case Rep 1988;10(1): Spahr A, Haegewald S, Tsoulfidou F, et al. Coverage of Miller Class I and II recession defects using enamel matrix proteins versus coronally advanced flap technique: a 2-year report. J Periodontol 2005;76(11): Tolmie PN, Rubins RP, Buck GS, Vagianos V, Lanz JC. The predictability of by way of free gingival autografts and citric acid application: an evaluation by multiple clinicians. Int J Periodontics Restorative Dent 1991;11(4): Tozum TF, Keceli HG, Guncu GN, Hatipoglu H, Sengun D. Treatment of gingival recession: comparison of two techniques of subepithelial connective tissue graft. J Periodontol 2005;76(11): Trabulsi M, Oh TJ, Eber R, Weber D, Wang HL. Effect of enamel matrix derivative on collagen guided tissue regeneration-based root coverage procedure. J Periodontol 2004;75(11): Trombelli L, Schincaglia GP, Scapoli C, Calura G. Healing response of human buccal gingival recessions treated with expanded polytetrafluoroethylene membranes: a retrospective report. J Periodontol 1995;66(1): Trombelli L, Schincaglia GP, Zangari F, Griselli A, Scabbia A, Calura G. Effects of tetracycline HCl conditioning and fibrinfibronectin system application in the treatment of buccal gingival recession with guided tissue regeneration. J Periodontol 1995;66(5): Trombelli L, Scabbia A, Wikesjö UM, Calura G. Fibrin glue JADA, Vol March