This review was performed to validate the clinical efficacy of acellular dermal matrix (ADM) for plastic periodontal and implant surgery. Four electronic databases and a manual search were utilized to select randomized clinical trials (RCTs) published until March 2019. Overall, 28 RCTs were included: 25 on teeth and three on implants. For plastic periodontal surgery, ADM exhibited a comparable gingival recession reduction (RecRed) and soft tissue thickness (STT) gain to connective tissue graft (CTG). Subgroup analyses revealed that ADM obtained a similar keratinized tissue width (KTW) gain to CTG within 3–6 months postoperative, but significantly less KTW gain at 1–5 years postoperative ( P = 0.01, mean difference (MD) −0.86 mm). Analyses comparing ADM with free gingival graft (FGG) demonstrated similar RecRed but significantly more KTW/STT gain favouring FGG (KTW: P = 0.01, MD −1.78 mm; STT: P = 0.01, MD −0.77 mm). Significantly more RecRed and KTW/STT gain were verified in ADM + coronally advanced flap/laterally positioned flap compared with these flaps alone (RecRed: P < 0.00001, MD 0.65 mm; KTW: P = 0.001, MD 0.66 mm; STT: P < 0.00001, MD 0.59 mm). Limited data for implant surgery indicated a similar trend as for periodontal surgery. Concerning patient-reported outcomes, ADM achieved favourable aesthetic appearance, alleviation of dentinal hypersensitivity, and less surgical morbidity. In conclusion, ADM exerted comparable clinical efficacy to autogenous tissue for root coverage procedures, with good long-term stability. However, for soft tissue augmentation, ADM exhibited inferior 3–6-month postoperative outcomes compared with FGG and less long-term stability of KTW gain compared with CTG.
Among all the mucogingival deformities, insufficient keratinized tissue and gingival recession are the most prevalent conditions that demand surgical correction . Accordingly, soft tissue augmentation and root coverage procedures are essential parts of plastic surgery protocols. These procedures include coronally or laterally advanced flaps, double papillae repositioned flaps, sub-epithelial connective tissue grafts (CTG), free gingival grafts (FGG), the tunnel technique, and the bilaminar technique of pedicle flaps and grafts or barrier membranes.
Undeniably, autogenous tissue grafts, including the CTG and FGG, remain the gold standard for both soft tissue augmentation and root coverage procedures . Substantial evidence has confirmed that the CTG combined with a coronally advanced flap (CAF) achieves favourable root coverage of recession and that the FGG-based apically positioned flap/vestibuloplasty optimally widens the keratinized tissue zone . Nevertheless, there are some noticeable disadvantages of harvesting autogenous tissue, such as postoperative bleeding and pain/discomfort at the donor site, a restricted supply of tissue, longer operative duration, increased morbidity, and additional expertise of the surgeon .
In order to overcome the drawbacks of autogenous tissue harvesting, several non-vital allograft substitutes have been produced as alternative options for plastic periodontal and implant surgery. An example is acellular dermal matrix (ADM), a dermal allograft derived from human skin . During the processing of AlloDerm, one of the oldest and most utilized ADM products, the epithelium is first eliminated from the cadaveric skin using hypertonic saline and the cells are subsequently extracted using a series of detergents (0.1% glutaraldehyde, 0.5% sodium dodecyl sulphate, and 0.25% trypsin); this is done to prevent an antigenic response/immunological rejection caused by HLA antigenicity, as well as to inactivate viruses . The material is then cryoprotected, freeze-dried, and packaged in a proprietary process for immediate use.
Since its initial use in the 20th century , ADM has been used extensively in various areas of dental practice over the last two decades . In particular, when the donor supply is inadequate and/or the patient is fearful of additional surgery, ADM has been proposed as an alternative option for plastic periodontal and implant surgery . However, there remain concerns regarding the use of ADM, due to the associated ethical issues and the risk of disease transmission. The manufacturer of AlloDerm (LifeCell) states that the donor blood sample is tested for infectious diseases, including HIV and hepatitis B and C viruses. The tissue samples are also screened for microbial contaminants and pathogenic bacteria. Moreover, the patented ADM process (U.S. Patent 5,336,616) demonstrates more than 99.9% viral reduction and that no cells or microbial pathogens are detected using professional tests. Nevertheless, it is difficult to entirely remove all cell remnants; thus there remains a low theoretical risk of disease transmission, which is the case for all preparations derived from allografts.
Although ADM has yielded promising outcomes in numerous trials and its clinical efficacy has been discussed in several standard and commissioned reviews (i.e., European Federation of Periodontology, American Academy of Periodontology, and Cochrane), conclusions about the application of this material are still unclear and controversial. Moreover, evidence on the long-term clinical outcomes and patient-reported outcomes relevant to ADM is of low level. Therefore, the aim of this investigation was to conduct a comprehensive systematic review and meta-analysis with high methodological strength of evidence, focusing on clinical long-term stability and patient-centred parameters, in order to thoroughly verify the clinical efficacy of ADM for plastic periodontal and implant surgery.
Materials and methods
Protocol and PICO (participants, intervention, comparison, outcomes) question
The protocol of this systematic review was developed in accordance with the PRISMA Statement (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42019111172).
This review attempted to answer the following focused question: In systemically healthy patients with exposed roots or implants or lack of keratinized tissue (P, population), does ADM-based plastic periodontal and implant surgery (I, intervention), compared to conventional techniques for plastic periodontal and implant surgery (e.g. CAF or laterally positioned flap (LPF) or FGG or CTG + CAF) (C, control), result in a gain of keratinized tissue, resolution of gingival recession, and improved patient-reported outcomes (O, outcomes)?
Only randomized clinical trials (RCTs) of systemically healthy adult patients undergoing ADM-based plastic periodontal or implant surgery, with at least 3 months of follow-up, were eligible for inclusion. Primary clinical parameters (keratinized tissue width (KTW), soft tissue thickness (STT), and reduction of gingival recession (RecRed)) had to be evaluated quantitatively. If multiple studies with the same population were identified, the trial with the longest follow-up duration or with the lowest drop-out rate was selected for meta-analysis. Publications on in vitro studies and those investigating different incisions or surgical variations (e.g. with or without a vertical incision, CAF versus tunnel technique) with the same ADM-based surgical treatment in both groups were excluded. Studies in which it was not possible to identify the effect of ADM alone in plastic periodontal and implant surgery (e.g. those studying a combination of ADM with enamel matrix derivative, platelet-rich plasma, or guided bone regeneration) were also excluded.
Literature search strategy
Relevant RCTs published up until October 2004 that were included in a previous systematic review were identified . Electronic searches of the literature, covering the period November 2004 to March 2019, were performed in the following databases: MEDLINE/PubMed, Google Scholar, Cochrane Library, and Web of Science. Moreover, an additional manual search of relevant journals was conducted ( Fig. 1 ) and attempts were made to search the grey literature and unpublished data on the clinicaltrials.gov website. There was no restriction on publication language. The search terms, selection protocol, and data extraction are given in the Supplementary Material (Appendix S1).
Primary outcomes included KTW gain, STT gain, RecRed, and patient-reported outcomes. Secondary outcomes included mean root coverage, complete root coverage, clinical attachment level gain, probing depth reduction, wounding healing, complications, and clinician-assessed aesthetics.
Two reviewers (WL, ZD) independently assessed the methodological quality of all eligible RCTs with reference to the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The six domains/questions for evaluation included random sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, selected reporting, and other bias . If the study met all criteria, the degree of bias was considered as low risk; if the study was missing fewer than three criteria, the degree of bias was ranked as moderate risk; otherwise (missing three or more criteria), the risk was categorized as high.
The statistical analyses were performed using RevMan 5.3 software (Cochrane Collaboration, Oxford, UK). The mean difference and standard deviation were used to describe the continuous outcomes from each trial, while dichotomous data such as complete root coverage were expressed as risk ratio estimates. Statistical quantitative outcomes were depicted as weighted mean differences (MD) with 95% confidence intervals (CI). In the case of unclear data for the standard deviation, the value was estimated as the square root of the sum of the variances of the measures . The fixed-effects model was used in the event of low heterogeneity, while the random-effects model was used when moderate or high heterogeneity was present. Forest plots were drawn to illustrate the individual effects of comparisons and the global estimation. The unit of analysis was the soft tissue defect site rather than the patient.
Heterogeneity derived from the discrepant treatment effect of each study was evaluated using Cochran’s test . The results of the Q statistic (significant at P < 0.10) and I 2 test (25%: low; 50%: moderate; 75%: high heterogeneity) were utilized to assess the level of heterogeneity . Sensitivity analyses and subgroup analyses were performed when necessary. Considering the power to detect publication bias, those analyses with fewer than 10 studies were not formally assessed ; otherwise publication bias was evaluated via funnel plots. The significant P -value level was defined as 0.05.
Study selection and study characteristics
The electronic search yielded a total of 244 articles after the exclusion of duplicates. Following the reading of titles/abstracts, 60 articles were included in the full-text assessment. Thirty-two of these were excluded for reasons based on the predetermined eligibility criteria (Supplementary Material, Appendix S2). Two trials conducted by Côrtes et al. referred to the same population but with two different follow-up durations (6 months and 5 years, respectively). Hence, the study with the longer follow-up duration was included in the analyses. Finally, 28 RCTs were eligible for statistical analysis, of which 25 were on teeth and three were on implants. A flowchart of the study selection process is displayed in Fig. 1 .
A list of the 28 included RCTs and their respective characteristics is presented in the Supplementary Material (Appendix S3) . Twenty-five studies reported the origin/manufacturer of the ADM, which was consistently found to be AlloDerm (a product of LifeCell).
The selected RCTs conducted ADM-based plastic periodontal or implant surgery and these trials were further divided into the following comparisons: (1) around teeth (three comparisons): ADM versus CTG, ADM versus FGG, ADM + CAF/LPF versus CAF/LPF; (2) around implants (two comparisons): ADM versus CTG, ADM versus FGG.
Quality assessment and publication bias
The results of the quality assessment for the RCTs included are shown in the Supplementary Material (Appendix S4). In summary, four RCTs had a low risk of bias, 14 a moderate risk, and 10 a high risk. Funnel plots revealed consistent symmetry, which indicated a low risk of publication bias (Supplementary Material, Appendix S5).
Results of the meta-analyses of primary outcomes
A total of 750 soft tissue deficient sites in 511 patients included in 28 eligible RCTs were assigned to specific comparisons for quantitative analysis and estimation of the effect size of all the parameters of interest.
Analysis of plastic periodontal surgery—KTW gain
The comparison of ADM versus CTG around teeth (17 studies) included 16 trials using graft material combined with CAF [Au?1] and one trial with a double papillary flap . The result indicated a significant mean difference of 0.46 mm favouring CTG ( P = 0.002, 95% CI −0.75 to −0.17 mm; χ 2 = 43.02 (df = 16), P = 0.0003, I 2 = 63%) ( Fig. 2 A). The sensitivity analysis excluding low-quality studies revealed similar heterogeneity, but no significant difference between the groups ( P = 0.30) (Supplementary Material, Appendix S6A).
Due to the substantial heterogeneity of the data and inconsistent follow-up durations, subgroup analyses were conducted. Subgroup one comprised 14 studies reporting KTW at 3–6 months postoperative; the meta-analysis revealed a borderline significant difference favouring CTG ( P = 0.04, MD −0.30 mm, 95% CI −0.60 to −0.01 mm; χ = 26.87 (df = 13), P = 0.01, I 2 = 52%) ( Fig. 2 B). However, analysis of the eight high- and moderate-quality studies of subgroup one exhibited no significant difference ( P = 0.89) with low heterogeneity (χ 2 = 8.87 (df = 7), P = 0.26, I 2 = 21%) (Supplementary Material, Appendix S6B). Subgroup two comprised four studies recording KTW at 1–5 years postoperative; the results demonstrated significantly more KTW gain with CTG despite considerable heterogeneity ( P = 0.01, MD −0.86 mm, 95% CI −1.54 to −0.17 mm; χ 2 = 11.91 (df = 3), P = 0.008, I = 75%) ( Fig. 2 C). Sensitivity analysis revealed that the large heterogeneity was mainly derived from one study , without alteration of the result (Supplementary Material, Appendix S6C).
Only three studies compared ADM versus FGG around teeth. The results indicated a significant difference favouring FGG ( P = 0.01, MD −1.78 mm, 95% CI −3.16 to −0.40 mm; χ 2 = 18.40 (df = 2), P = 0.0001, I 2 = 89%) ( Fig. 2 D). In detail, two studies favoured FGG, while the other study showed a similar result. Regarding the surgical technique, all relevant studies performed open graft healing with subtle differences . In two studies , ADM was left completely exposed, whereas in the other study , it was partially covered by a split-thickness flap.
Seven studies compared ADM + CAF/LPF versus CAF/LPF around teeth (six studies combined ADM and CAF and one study combined ADM and LPF). The results showed a significant difference of 0.66 mm favouring ADM + CAF/LPF ( P = 0.001, 95% CI 0.26 to 1.05 mm; χ 2 = 18.77 (df = 6), P = 0.005, I 2 = 68%) ( Fig. 2 E). Bearing in mind that moderate heterogeneity may be derived from inconsistent flap techniques, a subgroup analysis was performed, in which the results revealed a significantly greater KTW gain with ADM + CAF compared with CAF alone ( P = 0.0001, MD 0.44 mm, 95% CI 0.21 to 0.67 mm; χ 2 = 1.20 (df = 5), P = 0.94, I 2 = 0%) (Supplementary Material, Appendix S6D).
Analysis of plastic periodontal surgery—STT gain
Three studies on teeth compared ADM with CTG, which resulted in no statistically significant difference in STT gain ( P = 0.31; χ 2 = 4.91 (df = 2), P = 0.09, I 2 = 59%) ( Fig. 3 A). Three studies compared ADM + CAF/LPF with CAF/LPF around teeth, indicating a superior result favouring ADM + CAF ( P < 0.00001, MD 0.59 mm, 95% CI 0.50 to 0.68 mm; χ 2 = 7.46 (df = 2), P = 0.02, I 2 = 73%) ( Fig. 3 B). In all studies included in this analysis, ADM + CAF/LPF displayed significantly more STT gain than CAF/LPF alone. Only one study compared ADM versus FGG ( Fig. 3 C), and STT was evaluated using an ultrasound device positioned 1 mm apical to the gingival margin . This study revealed a significant intergroup difference ( P = 0.01), in which the STT gain was 0.42 mm in the ADM group and 1.19 mm in the FGG group at 6 months postoperative (MD −0.77 mm, 95% CI −1.37 to −0.17 mm).