Immediate Dentin Sealing for Adhesive Cementation of Indirect Restorations: A Systematic Review and Meta-Analysis

Immediate dentin sealing (IDS) involves applying an adhesive system to dentin directly after tooth preparation, before impression. This was considered an alternate to delayed dentin sealing (DDS), a technique in which hybridization is performed following the provisional phase and just before the indirect restoration luting procedure. This study aimed to compare the bond strength of restorations to dentin of the IDS and the DDS techniques throughout a systematic review and meta-analysis. The following PICOS framework was used: population, indirect restorations; intervention, IDS; control, DDS; outcomes, bond strength; and study design, in vitro studies. PubMed (MedLine), The Cochrane Library, ISI Web of Science, Scielo, Scopus, and Embase were screened up to January 2022 by two reviewers (L.H. and R.B.). In vitro papers studying the bond strength to human dentin of the IDS technique compared to the DDS technique were considered. Meta-analyses were carried out by using a software program (Review Manager v5.4.1; The Cochrane Collaboration). Comparisons were made by considering the adhesive used for bonding (two-step etch-and-rinse, three step etch-and-rinse, one-step self-etch, two-step self-etch, and universal adhesives). A total of 3717 papers were retrieved in all databases. After full-text assessment, 22 potentially eligible studies were examined for qualitative analysis, leaving a total of 21 articles for the meta-analysis. For the immediate bond strength, regardless of the adhesive strategy used, the IDS technique improved the bond strength of restorations to the dentin (p < 0.001). Taking into account the subgroup analysis, it seems that the use of the IDS technique with a two-step etch-and-rinse or a one-step self-etch adhesive system does not represent any advantage over the DDS technique (p = 0.07, p = 0.15). On the other hand, for the aged bond strength, regardless of the adhesive strategy used, the IDS technique improved the bond strength of restorations to the dentin (p = 0.001). The subgroups analysis shows that this improvement is observed only when a three-step etch-and-rinse adhesive system (p < 0.001) or when a combination of an adhesive system plus a layer of flowable resin (p = 0.01) is used. The in vitro evidence suggests that the use of the IDS technique improves the bond strength of dentin to resin-based restorations regardless of the adhesive strategy used. The use of a three-step etch-and-rinse adhesive system or the combination of an adhesive system plus a layer of flowable resin seems to considerably enhance the bond strength in the long term.


Introduction
Direct resin composite restorations are most preferred by patients as adequate not only for anterior teeth, but also for posterior teeth. The use of this kind of restoration has increased and a lot of improvements in resin materials formulations and clinical techniques have been developed in recent years [1,2]. Despite this, the performing of large restorations including the proximal region presents challenges for direct resin composite restorations, such as the recovery of an adequate proximal contacts, anatomical form, wear resistance, and marginal adaptation [3,4]. Polymeric or ceramic-based indirect restorations are an effective treatment to resolve these issues. In fact, partial adhesive indirect restorations present multiple advantages when compared with direct restorations, including improved anatomic shape, contour, esthetics, and fracture resistance [5].
Conventional indirect restoration involves a series of complicated procedural steps. These restorations are laboratory fabricated and require at least two appointments: one for preparation and impression/model fabrications, and one for luting [6]. In the first appointment, an impression is immediately taken after tooth preparation, followed by luting a temporary restoration. In the second appointment, once the indirect restoration is fabricated, the temporary restoration is removed, then a bonding agent is applied to the dental substrate; next, for the adhesive luting procedure, a resin luting agent is applied [7]. In this technique, known as delayed dentin sealing (DDS), dentin hybridization is performed following the provisional restorations and just previously to the indirect restoration luting process. This technique has particular drawbacks, as residual temporary cement might persist on the dental surface, and some cement constituents perhaps infiltrate the dental surface [8]. In this fashion, the definitive restoration is commonly not bonded to freshly prepared dentin but quite bonded to contaminated dentin, which could result in hybridization failure and lessened bond strength [9].
In order to prevent this, the immediate dentin sealing (IDS) method has been advised [10,11]. In this procedure, an adhesive system is applied directly to the fresh cut dentin preceding the placement of the provisional phase. IDS demands hybridization of the freshly dentinal surface closely after preparing the tooth and before the luting processes [12,13]. This technique provides adhesion to a freshly cut and uncontaminated dentin, which is ideal for bonding [14,15]. In addition, the technique prevents the bacterial invasion and dentin sensitivity during the provisional phase [16]. Another advantage is that the thickness of the dentin bonding agent is considered before the tooth preparation impression [17].
Theoretically, the method might be performed using any adhesive system, leading to enhanced bond strength when compared to DDS; nevertheless, this was not systematically reviewed. On the other hand, the general procedure proposes the use of two-step selfetch or three-step etch-and-rinse adhesive systems as well [9]; besides this, with recent developments in adhesive dentistry, clinicians have a wide range of adhesive materials available, including two-step etch-and-rinse, three step etch-and-rinse, one-step self-etch, two-step self-etch, and universal adhesives, and the question as to whether all adhesive systems currently available could have an optimal performance for IDS still remains. Considering this, the objective of this study was to systematically review the literature to compare the bond strength of restorations to dentin between the IDS and the DDS techniques. The null hypothesis of the study was that IDS or DDS techniques would provide the same bond strength.

Results and Discussion
A total of 3717 papers were retrieved in all databases. A flowchart designating the study selection process according to the PRISMA Statement is presented in Figure 1. The literature review retrieved 2790 papers for the initial examination after eliminating the duplicates. Afterward, 2760 studies were excluded following reviewing the titles and abstracts, leaving a total of 30 articles to be assessed by full-text evaluation. From these, 8 studies were not considered for the qualitative analysis for various reasons: 4 were clinical studies [18][19][20][21], 2 studies did not evaluate bond strength [22,23], and in 2 studies, there was not a control group using DDS [24,25]. Thus, a total of 22 studies were considered in the qualitative analysis. One study was excluded from the quantitative analysis because data on bond strength were not available [26], giving 21 studies considered for the metaanalysis [12,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46].

Results and Discussion
A total of 3717 papers were retrieved in all databases. A flowchart designating the study selection process according to the PRISMA Statement is presented in Figure 1. The literature review retrieved 2790 papers for the initial examination after eliminating the duplicates. Afterward, 2760 studies were excluded following reviewing the titles and abstracts, leaving a total of 30 articles to be assessed by full-text evaluation. From these, 8 studies were not considered for the qualitative analysis for various reasons: 4 were clinical studies [18][19][20][21], 2 studies did not evaluate bond strength [22,23], and in 2 studies, there was not a control group using DDS [24,25]. Thus, a total of 22 studies were considered in the qualitative analysis. One study was excluded from the quantitative analysis because data on bond strength were not available [26], giving 21 studies considered for the metaanalysis [12,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]. The characteristics of the studies included in this review are summarized in Table 1.  The characteristics of the studies included in this review are summarized in Table 1. The included studies tested several types of adhesives for IDS, including two-step etchand-rinse, three-step etch-and-rinse, one-step self-etch, two-step self-etch, and universal adhesives. The bond strength was evaluated using the micro-tensile or the shear bond strength tests.
A meta-analysis of the 21 in vitro studies was conducted [12,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46], and separate analyses for immediate and aged bond strength were performed. Separate subgroups were analyzed for each aging time considering the type of adhesive used. For the immediate bond strength (Figure 2), regardless of the adhesive strategy used, the IDS technique improved the bond strength of restorations to the dentin (p < 0.001). Taking into account the subgroup analysis, it seems that the use of the IDS technique with a two-step etch-and-rinse or a one-step self-etch adhesive system does not represent any advantage over the DDS technique (p = 0.07, p = 0.15). On the other hand, for the aged bond strength (Figure 3), regardless of the adhesive strategy used, the IDS technique improved the bond strength of restorations to the dentin (p = 0.001). The subgroups analysis shows that this improvement is observed only when a three-step etch-and-rinse adhesive system (p < 0.001) or when a combination of an adhesive system plus a layer of flowable resin (p = 0.01) is used.
Studying the parameters of methodological quality assessment, most of the manuscripts involved were counted with a medium risk of bias (Table 2); though several studies analyzed failed to account for the sample size calculation, single operator, and operator blinded parameters.
A systematic review and meta-analysis was achieved to compare the bond strength of restorations to dentin between the IDS and the DDS techniques. For the immediate and aged bond strength, regardless of the adhesive strategy used, the IDS technique improved the bond strength of restorations to the dentin. Considering this, the null hypothesis proposed in this research was rejected.
Th immediate bond strength was improved when the IDS strategy was used. It seems that the use of the IDS technique with a two-step etch-and-rinse or a one-step self-etch adhesive system does not represent any advantage over the DDS technique. One should bear in mind that applying bonding agents to dentin after preparing dental cavity might increase the bond strength [12]. Furthermore, the resulting hybrid layer (HL) was stable, especially when filled adhesive was applied for IDS [14]. After tooth preparation, IDS reduces the formation of microleakage between dentin surface and restoration, thus lessening bacterial contamination and pulpal sensitivity [15,47]. Consequently, better adaptation of the restoration to the cavity surface could be expected [13]. Nevertheless, by applying the traditional DDS technique, a gap could be formed between the resin and dentin [48]. analyses for immediate and aged bond strength were performed. Separate subgroups were analyzed for each aging time considering the type of adhesive used. For the immediate bond strength (Figure 2), regardless of the adhesive strategy used, the IDS technique improved the bond strength of restorations to the dentin (p < 0.001). Taking into account the subgroup analysis, it seems that the use of the IDS technique with a two-step etchand-rinse or a one-step self-etch adhesive system does not represent any advantage over the DDS technique (p = 0.07, p = 0.15). On the other hand, for the aged bond strength (Figure 3), regardless of the adhesive strategy used, the IDS technique improved the bond strength of restorations to the dentin (p = 0.001). The subgroups analysis shows that this improvement is observed only when a During the conventional bonding process, bonding agents were applied when indirect restorations were seated to the tooth structure in cementation [28]. In an attempt to avoid the incomplete seating of dental restorations, clinically, it is advisable to retain the adhesive resin unpolymerized before the placement of laminate veneer, for example [49]. This could be explained by the fact that polymerized dentin adhesives presented a thickness varying from 60-80 µm to 200-300 µm depending on the tooth surface structure [50,51], though a thickness of fewer than 40 µm was acclaimed before indirect restoration placement [51]. Nonetheless, it is stated that curing resin cement and dentin adhesive agent individually in order displayed superior bond strength than curing both concurrently [50,52]. This comes from the idea that unpolymerized resin-dentin HL collapses when placing the restoration [48,53]. In this manner, efforts were directed towards the optimization of the application of bonding agents [54,55]. This could be possible by applying the adhesive system after preparing the tooth and before taking the impression [56]; thus, this technique is also known as IDS [12]. Further, to demarcate the conventional dentin bonding agent from IDS, it is called DDS [28]. three-step etch-and-rinse adhesive system (p < 0.001) or when a combination of an adhesive system plus a layer of flowable resin (p = 0.01) is used. Studying the parameters of methodological quality assessment, most of the manuscripts involved were counted with a medium risk of bias (Table 2); though several studies analyzed failed to account for the sample size calculation, single operator, and operator blinded parameters.    It is important to define the interdiffusion layer, also called HL, which forms between the adhesive resin and the demineralized dentin, hence, playing a noteworthy role on the retention of the restoration [57][58][59]. This HL was not stable with time due to the degradation process [60]. Once using any type of adhesive systems, uninfiltrated and demineralized dentin structure with exposed collagen networks could be revealed in the HL [61,62]. Bonding systems that possess a hydrophobic resin coating the primer layer play an essential part in lessening dentin permeability [63]. It has been suggested that adequate sealing could be possible when using the IDS with a two-step etch-and-rinse or a one-step self-etch adhesive system, but the complete elimination of marginal microleakage could not be possible [64]. This was unfortunately elucidated by the formation of some porosities within the HL [65]. In addition, these adhesive systems were subjected to outward fluid flow [66]. The inward and outward fluid moves generate the movement of water trees described by Tay et al., which can provide to the degradation of the resinbonded interfaces [67]. This phenomenon could support the finding of this study as these adhesives do not represent any advantage over the DDS technique. There may also be issues with the one-step self-etching adhesives being too hydrophilic, contributing to the increased permeability of the HL, and they may be subject to hydrolysis and chemical decomposition; next, resulting in an incompatibility with chemical or dual-cure composite luting agents [68,69].
Aged bond strength was improved when the IDS strategy was used and this improvement was only detected when a three-step etch-and-rinse adhesive system was used, or when a combination of an adhesive system plus a layer of flowable resin was used. Normally, adequate resin-dentin bonding is immediately reached, yet diminished bonding effectiveness occurs with time due to interfaces degradation [70]. The IDS approach was considered to resist the mechanical loading and heat for a longer period of time, more-over, improved the marginal adaptation between dentin and the restoration [28]. This matches with the discovery of this manuscript, as aged bond strength was perfected with the IDS technique.
Three-step etch-and-rinse adhesive systems were very effective when used correctly, and were the most versatile of all adhesive generations, as they can be used for virtually any bonding protocol (direct, indirect) or photopolymerization (self-cure, dual-cure). These systems were still the standards by which new systems were judged [69,71]. In fact, higher bond strength was achieved by using these systems in an IDS strategy, like the use of Optibond FL (Kerr; Orange, CA, USA), a filled adhesive resin with an ability to form a uniform film thickness of approximately 88 µm. This makes the filled adhesive more suitable for IDS than unfilled adhesive [72]. The filled adhesive was also perceptibly noticeable, a fact that made the assessment of the dentin bonding agents during placement simpler, as well as after surface cleaning preceding the definitive cementation [13,73].
A crucial component in IDS is the elaboration of an effective resin-to-resin bond between the presented resin coating and the new luting resin. This could be achievable with the use of older adhesive systems (three-step etch-and-rinse adhesive systems) showing their performance at the bonded interface level, in terms of stability, bond strength, and aging [74]. This could be in agreement with the results obtained in this review.
The use of a combination of an adhesive system and a layer of flowable resin seems to improve the adhesive strength [75]. This appears exceptionally principal to the performance of simplified adhesive systems to safeguard the thin bonding interface from oxygen inhibition and preserve IDS coat through the cleaning of the preparation [73]. By doing so, a thick adhesive layer was created. A thick IDS helps in eliminating undercuts and provides a smooth preparation [47]. However, a thin IDS layer is more susceptible when using silica coating, and the dentin might become re-exposed [28].
Additionally, by applying a flowable composite on top of a low film-thickness adhesive, thicker flowable composite may serve as an internal stress absorber, maintaining the integrity of the adhesive interface over time. This may be specifically beneficial in deep proximal boxes of posterior restorations, which will lead to better marginal adaptation at the axial box and critical cervical margins [45,76,77]. Moreover, a previous study [78] showed the importance of protecting the HL with a low stress bulk-fill flowable composite after aging in an oral environment in terms of perfect adaptation and seal. This potential explanation could confirm the long-term performance of applying such a strategy in this research.
The methodological quality assessment showed that most articles involved were categorized with a medium risk of bias, which identifies that the value of the discovery studied can be high. In this manner, it could be highlighted that the sample size calculation, the single operator, and the operator blinding were not designated in most of the articles examined. In addition, failure to describe these factors might increase the probability of finding bias and implementation [79]. In addition, it is worth mentioning that most of the comparisons performed presented a moderate heterogenicity (I 2 ≥ 43.3%), and the reasons for these values of heterogenicity could include differences in the methodological design, like the number of samples tested and bond strength tests used, and differences in the variability outcomes.
From this systematic review and meta-analysis, in vitro evidence was evaluated with regards to comparing by searching in the literature the bond strength of restorations to dentinal surface between two techniques: the IDS and the DDS techniques. The findings of this study should be carefully taken as in clinical practice, a wet environment, masticatory stresses, and pH trigger a rapid degradation of the adhesive-dentin interfaces. This in vitro study offers important information when considering new techniques such as IDS to increase bond to dental tissues.; though they have limitations and do not replace clinical trials.
A recent systematic review and meta-analysis explored if the IDS technique influences postoperative sensitivity in teeth restored with indirect restorations [80] and concluded that there is low-certainty evidence obtained from clinical trials demonstrating that IDS does not reduce postoperative sensitivity in teeth restored with indirect restorations. The low evidence is explained by the fact that only two clinical trials were included in the review, and there were differences in the adhesive strategy and luting agent type used. Summarizing the in vitro evidence collected in this tested review, it should be highlighted that the IDS technique lacks standardization. By analyzing the data presented in this metaanalysis, the use of a three-step etch-and-rinse adhesive followed by a layer of flowable resin could be recommended to ensure the maximum retention of the indirect restoration.
Further examination should be directed, remarkably randomized controlled clinical trials, with the purpose of attaining a better understanding of the performance of IDS technique in the clinical success of indirect restorations to dentin substrate. Next, additional studies measuring cyclic loading and long period effectiveness of IDS should be conducted. Future research is required to investigate more dental adhesives and flowable composite resins to reveal the comparison between diverse materials. It should be also recommended to perform studies with more standardized methods in an effort to reduce the heterogeneity between the studies focusing on this topic and also to establish the ideal protocol for cementing indirect restorations.

Conclusions
The in vitro evidence suggest that the use of the IDS technique improves the bond strength of dentin to resin-based restorations regardless of the adhesive strategy used. The use of a three-step etch-and-rinse adhesive system or the combination of an adhesive system plus a layer of flowable resin seems to considerably enhance the bond strength in the long term.

Materials and Methods
This systematic review and meta-analysis was performed following the PRISMA 2020 statement [81]. The registration protocol was carried out in the Open Science Framework with the registration number 0000-0002-2759-8984. The following PICOS framework was used: population, indirect restorations; intervention, IDS; control, DDS; outcomes, bond strength; and study design, in vitro studies. The research question was: "Does the use of the IDS technique improve the bonding performance of restorations?"

Literature Search
The literature search was independently conducted by two reviewers (R.B. and L.H.) until 20 January 2022. Six electronic databases were selected to recognize manuscripts that might be included: PubMed (MedLine), The Cochrane Library, ISI Web of Science, Scielo, Scopus, and Embase. The search strategy and keywords used in PubMed are listed in Table 3. The full search strategy for The Cochrane Library, ISI Web of Science and Scielo, Scopus, and EMBASE databases is presented as supplementary material (Tables S1-S4). The reviewers also hand-searched the reference lists of involved manuscripts for identification of supplementary papers. After the initial screening, all articles were introduced into Mendeley Desktop 1.17.11 software (Glyph & Cog, LLC, London, UK) to exclude duplicates.

Study Selection
Two independent reviewers (C.E.C.-S. and R.B.) assessed the titles and abstracts of all the studies. Manuscripts for full-text review were chosen agreeing to the following eligibility criteria: (1) evaluated the bond strength to human dentin of the IDS technique compared to the DDS technique; (2) included a control group with the use of the DDS technique for indirect restorations; (3) published in the English, Spanish, or Portuguese language. Case series, case reports, pilot studies, and reviews were excluded. Full copies of all the possibly appropriate papers were examined. Those that seemed to gather the inclusion criteria or had inadequate data in the title and abstract to make a clear decision were selected for full evaluation. The full-text manuscripts were considered in duplicate by two independent review authors. Any disagreement or discrepancy regarding the eligibility of the included manuscripts was resolved and decided through consensus and agreement by a third reviewer (L.H.). Only papers that satisfied all the eligibility criteria enumerated were included for review.

Data Extraction
Data of relevance from the studies involved were extracted using Microsoft Office Excel 2019 sheets (Microsoft Corporation, Redmond, WA, USA). These data comprised the study and year of publication, the type of tooth, the IDS, the type of cement, the type of restoration, the aging procedures, and the bond strength test used. The corresponding authors of the included studies were connected twice via e-mail to retrieve the lack of information, if any data were somewhat missing. If the investigators did not response within 2 weeks of the first communication, the missing information was not included.

Quality Assessment
The methodological quality of each involved manuscript was performed by two independent authors (L.H. and R.B.), by assessing the description of the following parameters: specimen randomization, single-operator protocol implementation, operator blinded, presence of a control group, standardized samples, failure mode, manufacturer's instructions, and the sample size calculation [82]. If the reviewers stated the parameter, the study received a "YES" for that specific parameter. In the case of missing data, the parameter received a "NO." The risk of bias was classified regarding to the sum of "YES" answers received: 1 to 3 indicated a high bias, 4 to 6 medium, and 7 to 8 indicated a low risk of bias. Through risk of bias assessment, any differences between the reviewers were resolved through conversation by accessing a third researcher (C.E.C.-S.).

Statistical Analysis
Meta-analyses were performed using Review Manager v5.4.1 (The Cochrane Collaboration) software program. The comparisons were performed using the random-effects model, and the standardized mean difference between the bond strength values obtained using the DDS or the IDS technique. Subgroups comparisons were made depending on the adhesive used for bonding (two-step etch-and-rinse, three step etch-and-rinse, one-step self-etch, two-step self-etch, and universal adhesives). In studies where several experimental groups were compared against the same control group, data for the experimental groups (mean, standard deviation, and sample size) were combined for the meta-analysis. Immediate and long-term bond strength data were analyzed separately. Statistical heterogeneity among studies was assessed using the Cochran Q test and the I2 test.