1 INTRODUCTION

Peri-implant soft tissue augmentation interventions are indicated before or after insertion of the final implant-supported prosthesis in sites presenting unfavourable structural features that are associated with or may predispose to the occurrence of inflammatory peri-implant pathosis, soft tissue deformities, and/or sub-optimal aesthetics (Thoma et al., 2018). Depending on their primary therapeutic goal, peri-implant soft tissue augmentation interventions may be broadly classified in two categories: peri-implant soft tissue phenotype modification (Tavelli et al., 2021), and treatment of peri-implant marginal mucosa defects (PMMDs), also known as peri-implant soft tissue dehiscences (Zucchelli et al., 2019).

The peri-implant phenotype has been defined as the morphological and dimensional features characterizing the clinical presentation of the tissues that surround and support osseointegrated implants (Avila-Ortiz et al., 2020). The peri-implant phenotype is constituted by a soft tissue and a bone component. While the peri-implant bone phenotype is primarily determined by the bone thickness (BT), the peri-implant soft tissue phenotype includes three key elements with different clinical and therapeutic implications: the keratinized mucosa width (KMW), the mucosal thickness (MT), and the supracrestal tissue height (STH). On the other hand, PMMDs are alterations of the peri-implant soft tissue architecture characterized by an apical discrepancy of the mucosal margin with respect to its ideal position with or without exposure of transmucosal prosthetic components or the implant fixture surface (Gamborena & Avila-Ortiz, 2021).

Over the past decade, a variety of surgical modalities for peri-implant soft tissue phenotype modification (i.e., augmentation of KMW, MT, and/or STH) and correction of PMMDs using different techniques and graft materials have consolidated or emerged. In parallel, a variety of true and surrogate endpoints of interest (Chambrone & Armitage, 2016) and assessment methods to monitor the results of therapy have also been developed. Research outcomes, also known as endpoints or events, are variables that are recorded during a study to assess the impact that a given intervention or exposure has on the health of a given population. Assessment and interpretation of outcomes is an essential component of research, as this allows testing the validity of the hypothesis (Sanz & Vignoletti, 2014). Standardization of core research outcomes can help in guiding future research, decreasing potential biases, and allowing for more reliable inter-study comparisons and pooled data analyses for the advancement of science and, ultimately, the enhancement of patient care.

The primary objective of this systematic review, which was conducted as part of the Implant Dentistry Core Outcome Sets and Measurements (ID-COSM) initiative, was to identify and report outcome measures and methods of assessment on soft tissue augmentation interventions performed in the context of dental implant therapy reported in clinical studies published in the last 10 years.

2 MATERIALS AND METHODS

The protocol of this review was previously registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the identification code CRD42021252214. This review adheres to the guidelines of the Preferred Reporting Items of Systematic Reviews and Meta-Analyses 2020 statement (Page et al., 2021).

3 RESULTS

3.1 Article selection

The initial database search yielded a total of 14,867 entries, of which 6088 were found in PubMed, 3387 in CENTRAL, and 5392 in EMBASE. Six additional articles were identified through manual search. Following removal of duplicates, 10,572 entries remained. After title and abstract screening, 126 articles were selected for full-text review. Of these 126 articles, 34 were excluded after full-text review. The list of excluded articles and reasons for exclusion are displayed in Table S1. Thus, the final selection comprised 92 articles (see list of selected articles in Supporting Information). A flow chart illustrating the article selection process is depicted in Figure 1. Inter-examiner agreement kappa score for title/abstract review and for full-text review were 0.93 (95% confidence interval [CI]: 0.855–1.0) and 0.78 (95% CI: 0.662–0.921), respectively.

3.2 Study characteristics

Of the 92 selected articles, 4 were published in 2011, 4 in 2012, 6 in 2013, 4 in 2014, 11 in 2015, 8 in 2016, 5 in 2017, 13 in 2018, 11 in 2019, 18 in 2020, and 8 between 1 January and 30 April 2021 (Figure 2). Fifty-seven studies were conducted in an academic (university) setting, 20 were carried out exclusively in a private clinic (of which 2 were multi-centre), 6 multi-centre studies were conducted in both academic and private practice settings, and 1 in a military setting; in 8 articles, this information was not clearly reported. Thirty-nine studies were RCTs, 20 were non-RCTs, and 33 were case series, none of which was reported as being retrospective. For specific bibliographic details, see list of selected articles in Supporting Information. Although some investigations were reported by the authors as cohort studies, critical assessment of the information provided in these articles made it evident that, technically, they were either cases series or clinical trials (RCTs or non-RCTs). Hence, no proper cohort studies were present in the final article selection. Within this selection of 92 articles, a total of 81 distinct clinical studies were identified because some articles were follow-up studies of previous publications or only reported additional data from an already included study.

Aside from specific data on the initial and final number of participants, as well as gender and age distribution, specific details pertaining to the type of interventions performed, details on the methods used for the measurement, and timing of assessment of the outcomes reported in the selected articles, as well as additional comments, are available online in the data collection form in Supporting Information.

3.3 RoB assessment

3.3.1 RoB assessment of individual studies

• RCTs

Of the 39 selected RCTs, 14 were categorized as having low RoB, 10 high RoB, and unclear in the remaining 15 (Figure 3a).

• Non-RCTs

All the selected non-RCTs exhibited a high RoB (Figure 3b).

• Case series

Except four studies in which the RoB was fair (Zucchelli et al., 2013; Seyssens et al., 2019; Golmayo et al., 2021; Parvini et al., 2021), all case series were categorized as “poor” (Figure 3c).

3.3.2 RoB assessment of primary outcomes

• RCTs

The RoB associated with the measurement of the primary outcome was categorized as low in 25 RCTs, high in 5 RCTs, and unclear in 9 RCTs (Figure 3a).

• Non-RCTs

The RoB associated with the measurement of the primary outcome was categorized as low in 13 non-RCTs, high in 1 non-RCT, and unclear in 6 non-RCTs (Figure 3b).

• Case series

The RoB associated with the measurement of the primary outcome was categorized as low in 18 case series, high in 14 case series, and unclear in 1 case series (Figure 3c).

The primary outcome was clearly reported in 54 (58.70%) of the 92 selected articles. In the remaining 38 articles, the primary outcome was inferred based on our best judgement (specific comments are included in the data collection form in Supporting Information). Interestingly, examiner calibration for the primary outcome was reported only in 28 of the selected articles (30.43%), 15 of them being RCTs, 5 non-RCTs, and 8 case series. However, beyond that observation, no distinguishable patterns of association between specific types or methodological quality of studies and the choice of primary outcomes were observed.

4 DISCUSSION

The present systematic review mainly revealed the following: (1) An increasing number of publications reported the findings of clinical studies on the topic of soft tissue augmentation in the context of implant therapy over the past 10 years. (2) The most common study type was RCT performed at a university setting. (3) Clinical outcome measures were the most frequently reported outcomes overall. (4) The most frequently reported primary outcomes were facial mucosa thickness and facial KMW, followed by facial mucosal margin position (recession) and STH changes.

The increase in the number of investigations in peri-implant soft tissue augmentation in the past decade is likely due to two main reasons: (1) the recognition of the critical role of the peri-implant soft tissues in the maintenance of peri-implant health and the enhancement of aesthetic outcomes in implant therapy, and (2) the emergence of soft tissue graft substitutes as an alternative to autogenous grafts.

In several classic periodontal investigations on the topic of soft tissue augmentation conducted in the late 1960s and early 1970s, the focus was on understanding the healing process after autogenous oral soft tissue transplantation as well as the development and optimization of surgical interventions (Oliver et al., 1968; Karring, Cumming, et al., 1975; Karring, Lang, & Loe, 1975). In the 2000s, after the consolidation of the fields of mucogingival surgery and implant dentistry, further clinical models were introduced to assess the efficacy of novel soft tissue graft substitutes (as alternatives to autogenous soft tissue grafts that are commonly associated with an increased patient morbidity) for periodontal and peri-implant soft tissue augmentation purposes (Del Pizzo et al., 2002; Griffin et al., 2006; McGuire & Scheyer, 2010; Jung et al., 2011; Thoma et al., 2012). Several clinical studies have demonstrated the suitability of various soft tissue graft substitutes as plausible alternatives to autogenous soft tissue transplants for specific indications (Thoma et al., 2018; Cairo et al., 2019; Fickl et al., 2021; Tavelli et al., 2021).

Assessment and interpretation of outcomes are essential components of clinical research. Broadly, there are two types of clinical research outcomes: primary and secondary. The primary outcome is the most relevant variable to answer the main research question. Depending on their design, number of hypotheses, and objectives, some studies may have more than one primary outcome, as was the case in some of the studies selected in this systematic review. The primary outcome(s) should be used a priori to determine the minimum number of participants required to achieve statistical power and a posteriori to either reject or accept the study hypothesis. Secondary outcomes are supplementary outcomes monitored to help interpret the results of the primary outcome or increase the amount of information obtained through a study (Ferreira & Patino, 2017). Interestingly, clinical studies assessing the performance of soft tissue graft substitutes in peri-implant soft tissue augmentation in the past 10 years have predominantly considered gain of MT or volume and KMW as the primary outcome. Management of peri-implant soft tissue dehiscences and understanding the significance of the STH around dental implants, originally referred to as “peri-implant biologic width” (Berglundh et al., 1991; Berglundh & Lindhe, 1996), have become a relevant topic of research interest in recent years. This would explain why changes in facial mucosal margin position (recession) and STH were also frequently reported as primary outcomes in the selected literature.

Data analysis with a focus on primary outcome measures and methods of assessments revealed that clinical methods (e.g., use of periodontal probes, callipers, and endodontic files) were most often employed in the past 10 years. This may be associated with the fact that these traditional methods are part of daily clinical practice and have been used for decades in the field of mucogingival surgeries as part of the conventional clinical examination (Friedman, 1962; Diedrich et al., 1972; Edel, 1974; Bachmann & Bernimoulin, 1980; de Trey & Bernimoulin, 1980). Consequently, clinical assessments served as primary outcome in nearly 60% of the articles selected in the present systematic review. However, while these methods are well established, have been validated, and are associated with low cost and simple logistics, they also are limited to some extent as they do not allow capturing the entire extent of the therapeutic effect of some surgical interventions. This is particularly critical for interventions primarily aimed at modifying the peri-implant soft tissue contour, as clinical measurements based on the use of analogue instruments do not permit a reliable three-dimensional (3D) assessment of the outcomes (e.g., volume changes).

Technological advancements have derived into the implementation of digital assessment methods, such as linear and 3D analyses of STL files obtained from digitization of casts or intra-oral surface scanning (Windisch et al., 2007; Bienz et al., 2017; Pirc et al., 2021). Such analyses accounted for nearly 10% of the methods of choice to assess the primary outcome in the selected articles. The main benefits of digital assessment methods based on STL file analyses are a reduction in measurement errors, higher reproducibility and reliability, and their non-invasiveness (Schneider et al., 2014; Couso-Queiruga et al., 2021). A progressive shift from clinical towards digital imaging methods for assessment of outcomes can be expected in future years in this area of research.

Although PROMs were reported in 30 articles, nearly one-third of the total, in none of the selected studies were they designated as primary outcomes, and in many articles, minimal information about the methodology applied to assess PROMs was provided. Furthermore, PROMs specifically related to patient morbidity (e.g., post-operative pain and discomfort) were inconsistently investigated in studies that involved the use of a soft tissue graft substitute.

It must be noted that frequency of reporting of a specific method and outcome measure does not necessarily correlate with its significance in contemporary clinical research. Therefore, a highly reported clinical outcome per the findings of this systematic review (e.g., PD or PI) should not be automatically considered a core outcome in future research reports related to peri-implant soft tissue augmentation. By the same token, some under-reported outcomes, such as advanced digital imaging analyses and PROMs, should be considered as core outcomes given their methodological advantages and relevance in clinical practice, respectively.

Considering the result of the RoB analyses conducted in this systematic review, no distinguishable patterns of association between specific types or quality of clinical studies and the choice of primary outcomes were observed. It might be speculated that properly designed studies associated with a high level of evidence (e.g., RCTs) would include a more consistent and exhaustive selection of outcomes of interest.

However, this was not observed in the selected literature. This may be attributed to individual preferences by the investigators depending on the study goal, as well as the continuous development and refinement of research methods over time.

Finally, this is the first systematic review focused on comprehensively identifying and reporting outcome measures and methods of assessment on soft tissue augmentation interventions performed in the context of dental implant therapy. Therefore, it is not possible to compare the methods and findings reported here with other similar publications.

5 CONCLUSIONS

Clinical research on soft tissue augmentation in the context of implant therapy has progressively increased over the last decade. Although clinical outcome measures were the most frequently reported outcomes, the continuous development and refinement of assessment methods based on advanced digital imaging, as well as their high reliability and reproducibility, will likely result in an increasing number of studies incorporating the use of such tools in coming years. Moreover, the routine incorporation of PROMs should be recommended in future clinical investigations on this topic, particularly in clinical trials involving the use of a soft tissue graft substitute.

AUTHOR CONTRIBUTIONS

Gustavo Avila-Ortiz and Daniel S. Thoma conceived the idea and initial structure of the systematic review; Leandro Chambrone performed the search; Emilio Couso-Queiruga and Miha Pirc screened the initial entries, selected the articles, and collected the data; Gustavo Avila-Ortiz verified the validity and standardization of collected data; Emilio Couso-Queiruga and Miha Pirc assessed the risk of bias; Leandro Chambrone contributed to the design of the final manuscript and data analysis; Gustavo Avila-Ortiz and Daniel S. Thoma led the writing; Emilio Couso-Queiruga, Miha Pirc, and Leandro Chambrone critically revised the manuscript.

CONFLICT OF INTEREST

The authors have no conflicts of interest to report pertaining to the conduction of this systematic review.