QUINTESSENCE INTERNATIONAL

Angeliki Alexiou Comparison of enamel matrix derivative (Emdogain) and subepithelial connective tissue graft for root coverage in patients with multiple defects: A randomized controlled clinical study

Angeliki Alexiou, DDS, MSc1/Ioannis Vouros, Dr med dent2/Georgios Menexes, BMath, MA, PhD3/Antonis Konstantinidis, Prof DMD, MSc, PhD4

Objective: The purpose of the present study was to compare list. Data were analyzed within the frame of Mixed Linear the clinical efficiency of enamel matrix derivative (EMD) placed Models with the ANOVA method. Results: There were no sta- under a coronally advanced flap (CAF; test group), to a connec- tistically significantly differences observed between test and tive tissue graft (CTG) placed under a CAF (control group), in control groups in regards with the depth of buccal recession patients with multiple recession defects. Method and with a mean REC of 1.82 mm (CTG) and 1.72 mm (EMD) re- Materials: Twelve patients with multiple Miller’s Class I or II spectively. Similarly the mean PPD value was 1.3 mm for both gingival recessions in contralateral quadrants of the maxilla groups at T6, while the respective value for CAL was 1.7 mm were selected. The primary outcome variable was the change (EMD) and 1.8 mm (CTG). Statistically significant differences in depth of the buccal recession (REC), at 6 months (T6) after were observed only for the WKT, which were 3.0 mm and surgery. The secondary outcome parameters included the clin- 3.6 mm for the test and control groups respectively (P < .001) ical attachment level (CAL), the probing pocket depth (PPD), at T6. Conclusion: The use of EMD in conjunction with a CAF and the width of keratinized gingiva (WKT) apical to the reces- resulted in similar results as compared to the CTG plus CAF. sion. Recession defects were randomly divided to the test or (Quintessence Int 2017;48: 381–389; doi: 10.3290/j.qi.a38058) control group by using a computer-generated randomization

Key words: enamel matrix derivative (Emdogain), gingival recessions, root coverage

1 Post-Graduate Student of Periodontology, Dental School, Aristotle University of Mucogingival surgery includes several procedures Thessaloniki, Thessaloniki, Greece; and Private Dental Practice, Thessaloniki, Greece. aimed at correcting defects in morphology, position, 2 Associate Professor, Department of Preventive , Periodontology and 1 Implant Biology, Dental School, Aristotle University of Thessaloniki, Thessaloniki, and dimensions of the gingiva. The ultimate goal of Greece. periodontal plastic surgery is the coverage of the 3 Assistant Professor of Biometry, School of Agriculture, Laboratory of Agronomy, Aristotle University of Thessaloniki, Thessaloniki, Greece. exposed root surface when this condition is related to 4 Professor and Chairman, Department of Preventive Dentistry, Periodontology and esthetic problems, dentinal hypersensitivity, root car- Implant Biology, Dental School, Aristotle University of Thessaloniki, Thessaloniki, ies, or whenever it hinders proper plaque removal.2 Greece. Several procedures have been proven successful Correspondence: Dr Angeliki Alexiou, Gr.Palama 7, 54622 Thessaloniki, Greece. Email: [email protected] and predictable for root coverage, such as coronally

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positioned flaps, laterally sliding flaps, double papilla CAF (control group), in patients with multiple Miller’s flaps, free gingival grafts, subepithelial connective tis- Class I or II18 buccal gingival recessions in contralateral sue grafts (CTG), guided tissue regeneration, and quadrants of the maxilla. allografts.3-6 Among these procedures, the CTG is con- sidered the “gold standard,” as it has a high predict- METHOD AND MATERIALS ability for root coverage.7 Recent studies8,9 have shown that using a CTG is beneficial when compared to a Twelve patients with at least two Miller’s Class I or II18 coronally advanced flap (CAF) alone, while statistically buccal gingival recessions of ≥ 2 mm depth at teeth in greater recession reduction and probability of com- contralateral quadrants of the maxilla who met the plete root coverage, as well as a greater increase in inclusion/exclusion criteria were recruited among buccal keratinized tissue and better contour evalu- patients seeking treatment in the postgraduate Clinic ation were observed in the CAF when combined with of Periodontology at the Dental School of the Aristotle a CTG. University of Thessaloniki. The participants, ranging in In a randomized controlled clinical trial, Cairo et al10 age from 23 to 60 (mean age 40.1 years), included six demonstrated that even in Miller class III gingival reces- women and six men (Table 1). The study was approved sions with baseline CAL ≤ 3 mm (mesial or distal), there by the Research Ethics Committee of School of Den- is a 57% complete root coverage when CAF with CTG is tistry, Aristotle University of Thessaloniki, Greece (pro- used, against 29% when CAF was used alone. However, tocol number: 21/07-07-2015). this procedure requires a second surgical site that may Heavy smokers (≥ 10 cigarettes per day), patients cause a certain degree of discomfort, increase the risk who were pregnant or lactating, and patients who of postoperative complications, and limit the number presented with systematic disorders and/or under of teeth that can be treated in a single surgery. antibiotic or anti-inflammatory therapy were excluded. Different materials that can be used as a substitute Only defects with identifiable cementoenamel junc- for connective donor tissue are increasingly popular, tion (CEJ) were included in the study. Cases with pros- since they eliminate the disadvantages of the autoge- thetic crowns or restorations and/or the presence of nous donor graft. The enamel matrix derivative (EMD) deep abrasion defects that made the CEJ not identifi- has been evaluated for its potential both in regenera- able were excluded. Situations where no keratinized tion of intrabony defects and in gingival recessions.11-13 tissue apical to the recession defect was detected were A randomized controlled clinical trial14,15 compared the also excluded from the study, taking into account that clinical and histologic efficacy of EMD to subepithelial the use of EMD is not expected to show advantages in connective tissue placed under a CAF in patients with such cases. recession-type defects and there was no significant Before enrolment in the study, all patients com- difference in the percentage of root coverage between pleted a plaque control program.19 Four weeks after the the two groups. The use of EMD is not related with the initial treatment, patients were subjected to a full- disadvantages associated with the CTG, regarding the mouth . The following mea- need of a second surgical approach and the respective surements were performed in the whole dentition: discomfort.14 Also, histologic findings of root coverage • probing pocket depth (PPD) with EMD revealed that EMD enhances periodontal • clinical attachment level (CAL) regeneration.15-17 • The purpose of the present randomized controlled • bleeding scores clinical trial was to compare the clinical efficiency of • plaque scores. EMD placed under a CAF (test group), to the standard The primary outcome variable was the change in technique utilizing a subepithelial CTG placed under a depth of the buccal recession, measured from the CEJ

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periosteal elevator. Any muscular tension was relieved. Table 1 Number of treated recessions and mean Exposed root surfaces were carefully treated with root coverage results gentle root planing. The anatomical interdental N recessions Mean rec papillae were then carefully de-epithelialized. Patient Sex Age (y) CTG EMD CTG EMD In the CAF+CTG-treated site, after measurements 1 Male 43 2 2 2 2.5 were taken from the entire recipient site in order to 2 Female 45 3 3 2.7 1.7 define the palatal donor site incisions, a CTG was har- 3 Female 38 2222vested from the palate as follows: a horizontal incision 4 Male 23 2 2 2.5 3 was placed in the palate 2 to 3 mm from the free gingi- 5 Male 43 2 2 2 2.5 val margin in the premolar to first molar area, and two 6 Male 42 2222 parallel vertical incisions, one superficial and one deep, 7 Female 29 3 3 2.7 2.3 were made and connected mesially and distally. The 8 Male 60 2 2 2 2.5 CTG of thickness 0.5 to 1.0 mm was released at its base 9 Female 45 2 2 2 2 10 Female 34 3 3 2 2 and removed. The graft was designed to provide suffi- 11 Female 36 2 2 2.5 3.5 cient dimensions for covering the exposed root about 12 Male 43 2 2 2.5 2 1 mm beyond the CEJ. Following that, it was stabilized 15 CTG, connective tissue graft; EMD, Emdogain; N recessions, number of recession with resorbable sling suturing 5-0 to the papilla on defects; mean rec, mean recession depth in mm at baseline. either side of the graft and also sutured to the adjacent attached gingiva coronal to the MGJ on either side of the exposed root. Pressure was applied for 2 minutes to the graft after suturing.15 to the most apical extension of the , at 6 In the test group, ethylenediaminetetraacetic acid months (T6) after surgery. The secondary outcome par- (EDTA; PrefGel, Straumann) was applied on the root ameters included the PPD, measured from the gingival surface for 2 minutes before rinsing thoroughly with margin to the bottom of the , the CAL, sterile saline solution.21 EMD (Emdogain, Straumann) defined as the distance from the CEJ to the bottom of was applied immediately on the exposed and condi- the gingival sulcus, and the width of keratinized gingiva tioned root surface after it had been dried.21 The flap (WKT), measured from the most apical extension of the was then coronally sutured using resorbable sling gingival margin to the mucogingival line. Recession suturing 5-0.15 The graft was completely covered by the defects were randomly divided to the test or control flap in all cases (Figs 1 and 2). group by using a computer-generated randomization list (Microsoft Excel 2007).19 The trial was performed Postsurgical protocol according to the declaration of the Helsinki Accords.20 Patients were instructed to avoid any mechanical trauma and tooth brushing for 3 weeks in the surgical Surgical procedures area.15 rinses (0.12%) were prescribed An envelope flap design was used to treat the recession twice daily for 3 weeks for 1 minute. Pain medication defects.2 Following local anesthesia, an intrasulcular prescribed was ibuprofen 600 mg for 4 days. Fourteen incision was performed involving at least one tooth days after the surgery, the sutures were removed.22 mesial and one tooth distal to the teeth with the gingi- Professional plaque control was performed weekly val recessions. Oblique incisions were traced at the during the first 3 weeks. The patients were instructed interdental soft tissue level to achieve a coronal rota- to brush in a roll technique using a soft ,22 tion of the surgical papilla.2 The flap was then raised and were recalled 3 and 6 months after surgery. beyond the (MGJ) with a

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ab Fig 1a Patient from the test group at Fig 1b Oblique incisions and creation of baseline presenting with multiple reces- the new surgical papillae. sions.

c d e Figs 1c and 1d Elevation of full-split-full thickness flap and interdental papillae Fig 1e EDTA application. de-epithelization.

fgh Fig 1f Suture preparation. Fig 1g EMD (Emdogain, Straumann) Fig 1h Coronal advancement of the flap. application.

ij Fig 1i Suture removal after 2 weeks. Fig 1j Healing after 6 months.

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ab Fig 2a Patient from the control group at baseline presenting Fig 2b Oblique incisions and creation of the new surgical with multiple recessions. papillae.

cd e Fig 2c Elevation of full-split-full Figs 2d and 2e Connective tissue graft harvesting. thickness flap and interdental papillae de-epithelization.

fg Fig 2f Connective tissue graft suturing. Fig 2g Coronal advancement of the flap.

hi Fig 2h Suture removal after 2 weeks. Fig 2i Healing after 6 months.

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Clinical measurements foresee any dropouts. The power analysis was done A masked examiner, other than the surgeon, performed with the G*Power v.3 software.25,26 the data recording. Training and calibration was con- ducted prior to the start of the study to ensure intra-ex- RESULTS aminer reproducibility with respect to measurement of the outcome variables.15 Clinical measurements of The averages of all measurements (REC, PPD, CAL, WKT) every recession defect were performed at baseline (T0) in mm at the beginning of the study (T0) in test and and after 6 months (T6) using a to control groups had no statistical differences (Table 2). the nearest 0.5 mm.15 The parameters measured were The primary outcome was the change in depth of buccal recession depth (REC), PPD, CAL, and WKT. the buccal recession defect. When comparing T0 and T6 within the groups, both the control and test groups Statistical analysis showed a statistically significant reduction in REC Data were analyzed within the frame of Mixed Linear (P < .001). At the 6-month examination, 1.72 mm of the Models with the analysis of variance (ANOVA) root surfaces treated with CAG plus subepithelial CTG method.23,24 The model of analysis involved two fixed were covered, whereas 1.82 mm of the root surfaces factors within patients, “Material” (CTG and EMD) and treated with CAF plus EMD were covered with no signif- “Time” (T0 and T6), and one random factor “Teeth” icant difference between the test and control group nested within patients (two to three teeth per patient). (P > .05; Table 3). At 6 months, 79.7% of the root sur- The ANOVA method was used mainly for estimating the faces treated with CAF plus subepithelial CTG were appropriate standard errors involved in the statistical covered, whereas 81.7% of the root surfaces treated comparisons of the mean values. Consequently, ANO- with CAF plus EMD were covered. One hundred per- VA’s analytical results are not presented. Mean values cent root coverage was obtained in 55.6% of cases with were compared with the least significant difference the CAF with the subepithelial CTG and 63% of cases (LSD) criterion. In all statistical hypothesis testing pro- with EMD. cedures the significance level was predetermined at At 6 months (T6) there were no significant differences a = .05. Data in tables are presented in the form in PPD measurements between the two groups, and only mean ± standard error (SE). All statistical analyses were minimal changes were recorded at baseline and 6 performed with the SPSS v15.0 statistical software (IBM). months in both the test and control groups (Table 4). The patient was considered as the unit of statistical The CAL from baseline to 6 months demonstrated a analysis. Recession depth (mm) was the primary out- statistically significant reduction within the control and come of the study. A priori power analysis showed that test group, but no statistically significant difference 11 patients would provide sufficient power (0.80), at between the groups (Table 5). significance level a = .05, for detecting a difference of At baseline, all sites exhibited a WKT ≤ 3 mm. At 6 1 mm (± 1 standard deviation [SD]) between the means months after treatment, a statistically significant differ- of the two materials (CTG and EMD), at 6 months after ence in the WKT was found between the control and the surgery (T6). Minimum sample size determination test groups. There was consistently more keratinized was conducted for a one-tailed paired samples t test tissue observed when the subepithelial CTG (control assuming a Pearson’s correlation of r = 0.3 (conserva- group) was utilized in comparison to the CAF with EMD tive estimation) between split-mouth measurements. (test group), namely that there was an increase of The difference of 1 mm was considered clinically signif- 1.23 mm and 0.58 mm of WKT respectively (Table 6). icant according to previous studies.15 The estimation of No adverse events such as swelling, bleeding, bruising, SD was based on the studies of McGuire and Cochran.15 or sensitivity were observed throughout the duration of Twelve patients were entered in the current study to patient monitoring for both the control and the test group.

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Table 2 Averages of all measurements (REC, PPD, Table 3 Root coverage in mm over time in test and CAL, WKT) in mm at T0 in test and control control group group Time Material REC PPD CAL WKT Material T0 T6 P* CTG 2.15 ± 0.11 1.64 ± 0.11 3.79 ± 0.12 2.35 ± 0.11 CTG 2.15 ± 0.11 0.43 ± 0.09 < .001 EMD 2.25 ± 0.14 1.51 ± 0.11 3.85 ± 0.19 2.42 ± 0.11 EMD 2.25 ± 0.14 0.43 ± 0.10 < .001 P * .603 .321 .785 .672 P† .603 1.000 *P value for the comparison between the two materials CTG, connective tissue; EMD, Emdogain; T0, baseline; T6, 6 months after surgery. CAL, clinical attachment level (mm); CTG, connective tissue graft; EMD, Emdogain; PPD, *P value for the comparison between the two time points. periodontal probing depth (mm); REC, root coverage (mm); WKT, width of keratinized †P value for the comparison between the two materials. tissue (mm).

Table 4 Periodontal probing depth in mm over Table 5 Clinical attachment level in mm over time time in test and control group in test and control group

Time Time Material T0 T6 P* Material T0 T6 P* CTG 1.64 ± 0.11 1.32 ± 0.09 .009 CTG 3.79 ± 0.12 1.75 ± 0.16 < .001 EMD 1.51 ± 0.11 1.26 ± 0.10 .026 EMD 3.85 ± 0.19 1.69 ± 0.15 < .001 P† .321 .510 P† .785 .650

CTG, connective tissue; EMD, Emdogain; T0, baseline; T6, 6 months after surgery. CTG, connective tissue; EMD, Emdogain; T0, baseline; T6, 6 months after surgery. *P value for the comparison between the two time points. *P value for the comparison between the two time points. †P value for the comparison between the two materials. †P value for the comparison between the two materials.

Table 6 Width of keratinized tissue in mm over time in test and control group became very popular in the 1990s, and among these Time procedures the CAF together with CTG is considered P Material T0 T6 * the gold standard for the treatment of gingival reces- CTG 2.35 ± 0.11 3.58 ± 0.10 < .001 sion defects.10 EMD 2.42 ± 0.11 3.00 ± 0.00 < .001 The present study evaluated the efficacy of adding P† .672 < .001 CTG or EMD to a CAF for the treatment of multiple Mill- CTG, connective tissue; EMD, Emdogain; T0, baseline; T6, 6 months after surgery. *P value for the comparison between the two time points. er’s Class I or II18 buccal gingival recessions in contralat- †P value for the comparison between the two materials. eral quadrants of the maxilla. The 6-month results demonstrated a significant reduction of REC and CAL for both the test and control groups. However, statisti- cally no significant differences between test and con- DISCUSSION trol groups were observed for the depth of buccal recession, with mean REC 1.82 mm and 1.72 mm re- Recession defects around teeth are treated to resolve spectively. Similarly, the mean PDD was 1.3 mm for a variety of patient-centered concerns.27 In the 1970s both groups at T6 and mean CAL was 1.7 mm and and 1980s, gold standard procedures were considered 1.8 mm respectively. On the other hand, the CTG group the (FGG) and the laterally pos- demonstrated significantly superior results compared itioned flap (LPF).28 In the late 1980s, a complete with the EMD group in terms of the WKT, which were description of the CAF procedure was presented, her- 3.0 mm and 3.6 mm for the test and control group re- alding a new era of treatment.29 The latter technique spectively, 6 months after treatment (P < .001).

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An increase in KT would be a positive additional advantageous for the healing process after periodontal effect of the procedure, and ideally this increase should plastic surgery.35,36 restore the normal topographic dimensions of the KT Although the present study lacks data concerning and the alveolar mucosa. Usually the subepithelial CTG the histologic effect of EMD, if the histologic findings of can lead to an increase of the KT zone. Furthermore, in previous studies that demonstrated that the use of case the clinician ends up with excessive dimensions of EMD leads to actual regeneration15,37 are accepted, then keratinized soft tissues, an additional of EMD should be considered a more advantageous treat- the soft tissue should be performed for the correction ment option for recession coverage in terms of morbid- of surface irregularities. ity, compared with the almost universal use of CTG. The treatment of recessions with CAF in conjunc- Recently, the adsorption of amelogenins by various tion with EMD seems to lead to a more physiologic regenerative materials under various conditions was mucogingival relationship, where the increase of the KT studied by Miron et al,38 who showed that the commer- is likely due to the realignment of the MGJ that takes cially prevalent gel EMD adsorbs much less protein place over time,14 or a possible altered expression of content compared with a liquid formulation of EMD. keratinocytes resulting from promotion by enamel Their findings gave rise to the performance of a series matrix proteins.30 of studies,39,40 investigating a new material that con- One limitation of the study could be that the soft tains EMD with improved physical-chemical properties tissue thickness was not assessed, as there are no evi- and specially determined for combination with graft dence-based data in the literature demonstrating that materials.40 This issue needs further investigation and the use of EMD may affect this parameter. Only a few could be the subject of future research aimed at the studies exist,31 and more research is needed in order to improvement of EMD formulations for utilization in safely include this variable in a study at a future time. root coverage. In agreement with the findings of the present study, a number of trials have reported similar results in terms of reduction of buccal recession32-34 by using EMD in CONCLUSION conjunction with CAF. McGuire and Nunn14 also The findings of the present study indicate that the use showed, in a clinical trial, that the addition of EMD to of EMD can lead to similar clinical results as use of a the CAF resulted in a root coverage similar to that of subepithelial CTG in conjunction with a CAF. the subepithlial CTG, but without the morbidity associ- ated with the donor site surgery. In their histologic evaluation it was suggested that EMD leads to forma- REFERENCES tion of new , organizing periodontal liga- 1. Friedman N, Levine HL. Mucogingival surgery: current status. J Periodontol ment fibers, and islands of condensing bone.15 1964;35: 5–21. 32 2. Zucchelli G, De Sanctis M. Long-term outcome following treatment of multi- Similarly, Sayar et al evaluated the efficacy of EMD ple Miller class I and II recession defects in esthetic areas of the mouth. J in conjunction with CAF against CAF plus CTG. The Periodontol 2005;76:2286–2292. 3. De Sanctis M, Zucchelli G. Coronally advanced flap: a modified surgical ap- average percentages of root coverage were 55% and proach for isolated recession-type defects: three-year results. J Clin Periodon- 63.3% respectively, which implies a significant reduc- tol 2007;34:262–268. 4. Zucchelli G, Cesari C, Amore C, Montebugnoli L, De Sanctis M. Laterally tion within the two groups, but no statistical significant moved, coronally advanced flap: a modified surgical approach for isolated difference between them. The low patient morbidity recession-type defects. J Periodontol 2004;75:1734–1741. and the simpler procedure of using EMD instead of CTG 5. Nabers J. Free gingival grafts. Periodontics 1966;4:243–245. 6. Cortellini P, Pini Prato G. Coronally advanced flap and combination therapy for are emphasized. A recent meta-analysis also empha- root coverage. Clinical strategies based on scientific evidence and clinical sized the benefits of EMD in the soft tissue wound experience. Periodontol 2000 2012;59:158–184. 7. Langer B, Langer L. Subepithelial connective tissue graft technique for root healing and its potential in PPD reduction, which is coverage. J Periodontol 1985;56:715–720.

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8. Pini-Prato GP, Cairo F, Nieri M, Franceschi D, Rotundo R, Cortellini P. Coronally 24. Page M, Braver S, MacKinnon DP. Levine’s Guide to SPSS for Analysis of Vari- advanced flap versus connective tissue graft in the treatment of multiple ance, 2nd edition. New Jersey: Taylor and Francis, 2003. gingival recessions: a split-mouth study with a 5-year follow-up. J Clin Peri- 25. Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: a flexible statistical power odontol 2010;37:644–650. analysis program for the social, behavioral, and biomedical sciences. Behav 9. Zucchelli G, Mounssif I, Mazzotti C, et al. Coronally advanced flap with and Res Methods 2007;39:175–191. without connective tissue graft for the treatment of multiple gingival reces- 26. Faul F, Erdfelder E, Buchner A, Lang A-G. Statistical power analyses using sions: a comparative short- and long-term controlled randomized clinical trial. G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods J Clin Periodontol 2014;41:396–403. 2009;41: 1149–1160. 10. Cairo F, Cortellini P, Tonetti M, et al. Coronally advanced flap with and without 27. Chambrone L, Tatakis DN. Periodontal soft tissue root coverage procedures: a connective tissue graft for the treatment of single maxillary gingival recession systematic review from the AAP regeneration workshop. J Periodontol with loss of inter-dental attachment. A randomized controlled clinical trial. J 2015;86: S8–S51. Clin Periodontol 2012;39:760–768. 28. Cairo F, Nieri M, Pagliaro U. Efficacy of periodontal plastic surgery procedures 11. Heijl L, Heden G, Svärdström G, Ostgren A. Enamel matrix derivative in the treatment of localized facial gingival recessions. A systematic review. J (EMDOGAIN) in the treatment of intrabony periodontal defects. J Clin Peri- Clin Periodontol 2014;41(Suppl 1):S44–S62. odontol 1997;24(9 Pt 2):705–714. 29. Allen EP, Miller PD. Coronal positioning of existing gingiva: short term results 12. Modica F, Del Pizzo M, Roccuzzo M, Romagnoli R. Coronally advanced flap for in the treatment of shallow marginal tissue recession. J Periodontol 1989;60: the treatment of buccal gingival recessions with and without enamel matrix 316–319. derivative. A split-mouth study. J Periodontol 2000;71:1693–1698. 30. Hägewald S, Spahr A, Rompola E, Haller B, Heijl L, Bernimoulin J-P. Compara- 13. Esposito M, Grusovin MG, Papanikolaou N, Coulthard P, Worthington HV. tive study of Emdogain and coronally advanced flap technique in the treat- Enamel matrix derivative (Emdogain) for periodontal tissue regeneration in ment of human gingival recessions. A prospective controlled clinical study. J intrabony defects. A Cochrane systematic review. Eur J Oral Implantol 2009;2: Clin Periodontol 2002;29:35–41. 247–266. 31. Al-Hezaimi K, Al-Fahad H, O’Neill R, Shuman L, Griffin T. The effect of enamel 14. McGuire M, Nunn M. Evaluation of human recession defects treated with matrix protein on gingival tissue thickness in vivo. Odontology 2012;100: coronally advanced flaps and either enamel matrix derivative or connective 61–66. tissue. Part 1: Comparison of clinical parameters. J Periodontol 2003;74: 32. Sayar F, Akhundi N, Gholami S. Connective tissue graft vs. emdogain: a new 1110–1125. approach to compare the outcomes. Dent Res J (Isfahan) 2013;10:38–45. 15. McGuire MK, Cochran DL. Evaluation of human recession defects treated with 33. Alkan EA, Parlar A. EMD or subepithelial connective tissue graft for the treatment coronally advanced flaps and either enamel matrix derivative or connective of single gingival recessions: a pilot study. J Periodontal Res 2011;46:637–642. tissue. Part 2: Histological evaluation. J Periodontol 2003;74:1126–1135. 34. Zucchelli G, Mazzotti C, Tirone F, Mele M, Bellone P, Mounssif I. The connective 16. Hammarström L, Heijl L, Gestrelius S. Periodontal regeneration in a buccal tissue graft wall technique and enamel matrix derivative to improve root dehiscence model in monkeys after application of enamel matrix proteins. J coverage and clinical attachment levels in Miller Class IV gingival recession. Int Clin Periodontol 1997;24(9 Pt 2):669–677. J Periodontics Restorative Dent 2014;34:601–609. 17. McGuire MK, Scheyer ET, Schupbach P. A prospective, cased-controlled study 35. Cheng G-L, Fu E, Tu Y-K, et al. Root coverage by coronally advanced flap with evaluating the use of enamel matrix derivative on human buccal recession connective tissue graft and/or enamel matrix derivative: a meta-analysis. J defects: a human histologic examination. J Periodontol 2016;87:645–653. Periodontal Res 2015;50:220–230. 18. Miller PD. A classification of marginal tissue recession. Int J Periodontics Re- 36. Graziani F, Gennai S, Cei S, et al. Does enamel matrix derivative application storative Dent 1985;5(2):8–13. provide additional clinical benefits in residual periodontal pockets associated 19. Cardaropoli D, Tamagnone L, Roffredo A, Gaveglio L. Coronally advanced flap with suprabony defects? A systematic review and meta-analysis of random- with and without a xenogenic collagen matrix in the treatment of multiple ized clinical trials. J Clin Periodontol 2014;41:377–386. recessions: a randomized controlled clinical study. Int J Periodontics Restora- 37. Heijl L. Periodontal regeneration with enamel matrix derivative in one human tive Dent 2014;34(Suppl 3):s97–s102. experimental defect. A case report. J Clin Periodontol 1997;24:693–696. 20. World Medical Association Declaration of Helsinki: ethical principles for med- 38. Miron RJ, Bosshardt DD, Buser D, et al. Comparison of the capacity of enamel ical research involving human subjects. JAMA 2013;310:2191–2194. matrix derivative-gel and enamel matrix derivative in liquid formulation to 21. Abolfazli N, Saleh-Saber F, Eskandari A, Lafzi A. A comparative study of the long adsorb to materials. J Periodontol 2015;86:1–18. term results of root coverage with connective tissue graft or enamel matrix 39. Miron RJ, Chandad F, Buser D, Sculean A, Cochran DL, Zhang Y. Effect of protein: 24-month results. Med Oral Patol Oral Cir Bucal 2009;14:E304–E309. enamel matrix derivative liquid on osteoblast and periodontal ligament cell 22. Zucchelli G, De Sanctis M. The coronally advanced flap for the treatment of proliferation and differentiation. J Periodontol 2016;87:91–99 multiple recession defects: a modified surgical approach for the upper anter- 40. Wen B, Li Z, Nie R, et al. Influence of biphasic calcium phosphate surfaces ior teeth. J Int Acad Periodontol 2007;9:96–103. coated with Enamel Matrix Derivative on vertical bone growth in an extra-oral 23. Zar JH. Biostatistical Analysis, 5th edition. Harlow: Pearson Education, 2014. rabbit model. Clin Oral Implants Res 2016;27:1297–1304.

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