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26 April 2026: Meta-Analysis  

Influence of Operative Techniques on Clinical and Laboratory Outcomes in Class II Resin-Based Composite Restorations: A Systematic Review

Bassam Zidane ORCID logo ABCDEF 1*

DOI: 10.12659/MSM.951980

Med Sci Monit 2026; 32:e951980

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Abstract

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BACKGROUND: Operative technique is a major determinant of the long-term success of Class II resin-based composite restorations. Variations in adhesive strategy, layering approach, matrix system, and curing protocol influence marginal integrity, polymerization stress, postoperative sensitivity, and secondary caries. Because resin-based composite placement is technique-sensitive, synthesizing evidence on how specific operative steps affect outcomes is essential. This systematic review evaluated the influence of operative techniques on the clinical and laboratory performance of Class II resin-based composite restorations.

MATERIAL AND METHODS: A comprehensive search of PubMed, Cochrane Library, and Embase identified 57 records. After duplicate removal and screening, 21 studies were included (11 randomized controlled trials and 10 in vitro investigations). Techniques assessed were adhesive protocols, layering strategies, matrix systems, and curing methods. Data extraction focused on restoration longevity, marginal adaptation, postoperative sensitivity, and secondary caries. Risk of bias was evaluated using the Cochrane tool for randomized trials and modified CONSORT/Joanna Briggs Institute criteria for in vitro studies. Meta-analysis was not feasible because of heterogeneity.

RESULTS: Multi-step adhesive approaches showed the highest 5-year survival (up to 91%) and lower secondary caries rates. Incremental layering reduced postoperative sensitivity and improved marginal adaptation. Sectional matrices produced tighter proximal contacts (76% vs 42%), while soft-start curing reduced marginal gap formation (112 µm to 45 µm). One-step adhesives and uncontrolled bulk-fill placement showed higher failure and hypersensitivity.

CONCLUSIONS: Multi-step adhesives, incremental layering, sectional matrices, and soft-start curing provide the most favorable outcomes and support technique standardization in clinical practice.

Keywords: Dental Restoration, Permanent, Matrix Bands, Composite Dental Resin, Dental Cavity Preparation, BOND-1 Adhesive

Introduction

Resin-based composites are currently the primary material used for Class II posterior restorations because of their adhesive capability, minimally invasive approach, and favorable aesthetic and mechanical properties. With their widespread clinical adoption, the long-term success of these restorations is increasingly determined not only by material properties but also by the precision of the operative technique [1].The clinical success of these restorations is closely tied to a number of interdependent operative factors – including the type of adhesive system, matrix technique, placement method, and polymerization protocol [2,3].

Improper technique during any stage of the restoration process can compromise marginal integrity, increase polymerization stress, and lead to the development of secondary caries, postoperative sensitivity, or even restoration failure [4]. For example, failure to achieve tight proximal contact can lead to food impaction, while insufficient curing can compromise the mechanical properties of the composite and the hybrid layer formed with dentin [5]. The influence of incremental and bulk-fill placement techniques on polymerization shrinkage and void formation has been widely investigated in laboratory studies, whereas clinical evidence remains less consistent, particularly for contemporary bulk-fill materials [6]. In addition to placement strategy, these phenomena are affected by multiple interacting factors, including material composition, cavity configuration, and light-curing protocols. Therefore, restoration longevity reflects the combined effect of material-related and technique-related variables rather than a single operative step alone [7]. Over the last 2 decades, a wide array of materials and operative approaches have been introduced to improve clinical outcomes, including sectional matrix systems for better contact adaptation [8], soft-start or ramped curing to reduce marginal stress [9], and selective enamel etching to enhance bonding while maintaining dentin integrity [10]. In addition to these developments, the operative techniques used in Class II restorations can be broadly grouped into 4 domains: adhesive protocols, layering strategies, matrix systems, and curing methods. Adhesive protocols, such as etch-and-rinse, self-etch, and selective enamel etching, differ in how they condition enamel and dentin to create an effective hybrid layer. Layering strategies range from incremental placement, which helps to control polymerization stress, to bulk-fill approaches that allow deeper increments with simplified clinical steps. Matrix systems influence proximal contact and contour, while curing methods affect the kinetics of polymerization and stress development. These technique-related variables interact and collectively influence mechanical performance, biological response, and long-term clinical outcomes.

Despite these technological and procedural advances, consensus is lacking regarding the optimal combination of adhesive strategy, placement protocol, matrix system, and curing approach for Class II resin-based composite restorations. This is largely attributable to heterogeneity in the available literature, including differences in study design (randomized clinical trials vs in vitro investigations), restorative materials, cavity configurations, operator experience, follow-up duration, and outcome assessment methods. Such variability limits direct comparison between studies, precludes quantitative synthesis in many cases, and contributes to divergent clinical recommendations [11]. As a result, clinicians must often rely on fragmented evidence when selecting operative protocols.

Although previous reviews have evaluated individual materials or specific operative steps, a comprehensive synthesis that integrates clinical and laboratory evidence to map technique–outcome relationships in contemporary resin-based composite restorations remains limited. In particular, recent developments in bulk-fill materials, universal adhesives, and modified curing strategies have not been collectively assessed in relation to operative technique.

This systematic review aims to address this gap by evaluating the influence of operative techniques on key clinical and laboratory outcomes of Class II resin-based composite restorations. Specifically, we focus on how variations in adhesive protocols, layering strategies, matrix systems, and curing methods affect restoration longevity, marginal adaptation, postoperative sensitivity, and secondary caries formation. By mapping technique–outcome relationships, this review seeks to provide a clinically actionable, evidence-based framework for technique selection in modern adhesive restorative dentistry, thereby enhancing restoration durability and patient-centered outcomes.

Material and Methods

OVERVIEW:

This systematic review was conducted to evaluate the impact of various operative techniques on clinical and laboratory outcomes in Class II resin-based composite restorations. The review adhered to PRISMA guidelines [12] and was prospectively registered in PROSPERO (registration No. CRD420251071249).

RESEARCH QUESTION:

The primary research question guiding this systematic review was to determine how variations in operative techniques – including adhesive protocols, layering strategies, matrix systems, and curing methods – influence the clinical and laboratory outcomes of Class II resin-based composite restorations. This review was structured using a PICO framework to ensure clarity in study selection. The population comprised human teeth restored with Class II resin-based composite restorations in clinical studies and extracted human teeth prepared with standardized Class II cavities in in vitro studies. The interventions evaluated were operative techniques, such as adhesive protocols, layering methods, matrix systems, and curing strategies. Comparators included alternative operative approaches or standard clinical protocols used for comparison within each study. The outcomes assessed were restoration longevity, marginal adaptation, postoperative sensitivity, secondary caries, and laboratory measures, such as microleakage and bond strength.

ELIGIBILITY CRITERIA:

The inclusion and exclusion criteria were defined a priori based on the PICOS framework to ensure consistency during the study selection. Clinical and in vitro studies evaluating operative techniques in Class II composite restorations were eligible. The complete eligibility criteria are summarized in Table 1.

DATA SOURCES AND SEARCH STRATEGY:

A comprehensive literature search was conducted across PubMed, EMBASE, and the Cochrane Library to identify relevant studies published up to March 2024. The search strategy combined MeSH terms and free-text keywords related to “Class II”, “resin-based composite”, “operative technique”, “adhesive systems”, “incremental layering”, “matrix bands”, and “light curing”. Boolean operators (AND, OR) were applied to refine the search. Reference lists of included articles and relevant reviews were also screened manually to identify additional studies. Table 2 presents the detailed search syntax employed in this systematic review. The selection of MEDLINE (via PubMed), Embase, and the Cochrane Library was based on their recognition as the principal databases for systematic reviews in biomedical and dental research, owing to their comprehensive indexing of peer-reviewed clinical and laboratory studies and the availability of controlled vocabulary and advanced search filters [12–14]. Web of Science and Google Scholar were not searched as primary databases, because they function mainly as citation indexing and broad academic search platforms and have been reported to retrieve a high proportion of duplicate and non-clinically relevant records in focused clinical systematic reviews, without a proportional increase in eligible studies [15]. To minimize the risk of missing relevant publications, the reference lists of all included studies and relevant reviews were manually screened. Grey literature was searched through trial registries and open-access repositories.

Only English-language publications were included; this may have introduced language bias. The search included studies published up to March 2024. Although previous reviews on specific aspects of Class II composite restorations exist, none integrates clinical and in vitro evidence for operative techniques in a comparative manner or incorporate the substantial advances in bulk-fill materials, universal adhesives, and curing strategies reported between 2018 and 2024. Therefore, an updated synthesis was necessary to reflect contemporary evidence and technique-dependent variations in outcomes.

SELECTION OF STUDIES:

All retrieved records were imported into Zotero reference management software (Corporation for Digital Scholarship, Vienna, Austria), where duplicates were identified using the built-in automatic duplicate detection function and subsequently verified by manual checking to ensure accuracy. A second manual cross-check was performed prior to screening, to minimize the risk of inadvertent removal of eligible studies. Two independent reviewers (XX and YY) screened titles and abstracts for relevance, followed by a full-text assessment based on predefined eligibility criteria. Disagreements were resolved through discussion or consultation with a third reviewer (AB). The study selection process adhered to PRISMA 2020 guidelines and is illustrated in the PRISMA flow diagram (Figure 1).

DATA EXTRACTION:

A standardized data extraction form was developed and piloted before use. Two reviewers (XX and YY) independently extracted data from each included study. Extracted information included study design, year of publication, population characteristics (tooth type or model), specific operative technique(s) evaluated (adhesive system, layering method, matrix type, curing protocol), comparator(s), and outcome measures (longevity, marginal adaptation, postoperative sensitivity, secondary caries, or laboratory analogs such as microleakage and bond strength). Any discrepancies were resolved through consensus or by involving a third reviewer (AB). Inter-reviewer agreement for study selection was high, with a Cohen’s kappa value of 0.87, indicating excellent consistency between reviewers.

RISK OF BIAS ANALYSIS:

The risk of bias for randomized controlled trials (RCTs) and clinical studies was assessed using the Cochrane Risk of Bias 2.0 (RoB 2) tool. This tool evaluates 5 domains, including the randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of the reported result. Each study was classified as either low risk, some concerns, or high risk based on these criteria [16]. For in vitro studies, a modified Joanna Briggs Institute checklist was applied, focusing on sample preparation, standardization of procedures, blinding, and statistical analysis [17]. Two reviewers independently conducted the assessments, with disagreements resolved by discussion.

META-ANALYTIC FEASIBILITY:

Although quantitative synthesis was initially planned, meta-analysis was deemed infeasible because of the substantial heterogeneity across the included studies. Variability in study designs (RCTs, clinical trials, in vitro experiments), operative techniques assessed, outcome measures, follow-up durations, and reporting formats precluded meaningful statistical pooling. Furthermore, inconsistencies in measurement units and a lack of standardized effect estimates limited comparability. Therefore, findings were synthesized qualitatively and mapped to highlight trends and technique–outcome relationships.

Results

STUDY SELECTION:

The initial search yielded 39 records from PubMed, 8 from Cochrane, and 10 from Embase. After the removal of duplicates, 39 unique records remained for screening. Title and abstract screening led to the exclusion of 17 articles for the following reasons: irrelevant intervention (n=5), inappropriate study type (n=9), and full text not available (n=3). Twenty-two articles were assessed in full text. Of these, 1 study was excluded for not meeting the study design criteria, resulting in 21 studies included in the final systematic review: 11 RCTs and clinical studies and 10 in vitro investigations. The study selection process is detailed in the PRISMA flow diagram (Figure 1).

CHARACTERISTICS OF INCLUDED STUDIES:

A total of 21 studies were included in this systematic review, including 11 RCTs and clinical studies [9,18–27], and 10 in vitro investigations [8,28–36]. The clinical studies varied in population demographics, cavity configurations, and follow-up durations, but consistently evaluated operative protocols such as adhesive systems, layering techniques, matrix configurations, and curing strategies in Class II resin-based composite restorations. Table 3 summarizes the key characteristics of the included RCTs and clinical trials, detailing the study population, intervention and comparator arms, and the primary outcomes assessed.

Complementing these, 10 in vitro studies evaluated marginal adaptation, microleakage, polymerization stress, and other laboratory proxies for clinical performance. These studies employed standardized protocols and validated testing methods, such as dye penetration, scanning electron microscopy (SEM), and micro-computed tomography (μCT). Table 4 presents a concise overview of the in vitro study characteristics.

RISK OF BIAS ASSESSMENTS:

The risk of bias was evaluated separately for RCTs/clinical studies and in vitro investigations. For the 11 RCTs and clinical studies, the Cochrane Risk of Bias Tool (RoB 2.0) was applied. Most studies demonstrated low risk in the domains of random sequence generation and allocation concealment. However, several studies exhibited unclear or high risk in blinding of outcome assessors and reporting of attrition. Notably, blinding of operators was often not feasible due to the procedural nature of operative technique trials. Overall, 5 studies were judged to have a low risk of bias, 4 with some concerns, and 2 with high risk (Table 5).

For the 10 in vitro studies, a customized methodological quality checklist was used, evaluating aspects such as sample standardization, operator blinding, use of control groups, and replicability of procedures. While most studies adequately described their experimental methods, 3 lacked details on blinding, and 2 did not report statistical methods clearly. Nonetheless, 8 of the 10 studies were rated as moderate to high quality, supporting their inclusion in the qualitative synthesis (Table 6).

The risk-of-bias outcomes influenced how the findings were interpreted. Studies with low risk of bias contributed more strongly to the overall conclusions, while studies with some concerns or high risk were interpreted with caution, particularly when limitations such as lack of blinding, unclear allocation processes, or incomplete outcome reporting could influence measures such as marginal adaptation or postoperative sensitivity. Despite these variations, the direction of results remained consistent across studies.

LONGEVITY AND CLINICAL SUCCESS: Across the included clinical studies, various operative techniques were examined for their influence on the longevity of Class II resin-based composite restorations. Incremental layering and selective enamel etching were associated with significantly higher survival rates. For instance, van Dijken et al [25] reported a 90% survival rate at 5 years using a multi-step adhesive and incremental technique, compared with 73% for a bulk-fill approach. Similarly, Attin et al [18] found a statistically significant difference (P<0.05) favoring the incremental group after 3 years. Barabanti et al [21] noted comparable outcomes between bulk-fill and conventional composites, but only when soft-start polymerization and high-performance matrices were used. Matrix type and operator experience were also identified as moderating factors.

MARGINAL ADAPTATION: Marginal adaptation was frequently evaluated through clinical and in vitro metrics, such as dye penetration and marginal gap measurements. Colak et al [22] reported a 76% rate of optimal proximal contacts using sectional matrix systems, vs 42% with circumferential matrices (P=0.001). Attin et al [9] showed a significant reduction in marginal gaps when soft-start polymerization was used (mean gap width: 45 μm vs 112 μm, P<0.01). In vitro studies supported these findings, demonstrating significantly lower microleakage scores with incremental application and high-viscosity matrix support systems [33].

POSTOPERATIVE SENSITIVITY: Postoperative sensitivity was reported in 7 clinical studies. Hoshino et al [26] found that only 8% of patients in the incremental, self-etch group reported any postoperative discomfort, compared with 27% in the total-etch group (P<0.05). Similarly, Attin et al [9] noted that sensitivity scores dropped from 2.4 to 0.9 on a visual analog scale over 2 weeks with proper layering and adhesive technique. A consistent pattern of reduced sensitivity was observed with multi-step adhesives and cavity-sealing strategies, particularly in deeper proximal boxes.

SECONDARY CARIES FORMATION: Only a subset of long-term studies, notably those with over 2-year follow-ups, reported on secondary caries development [6,24]. Techniques that promoted tighter interproximal contact and optimal marginal seals, such as the use of sectional matrices and multi-step adhesives, were correlated with reduced secondary caries incidence. In contrast, simplified single-step adhesives, although faster, showed higher plaque accumulation and caries susceptibility at the margins over time. Light-curing intensity and angle also emerged as contributing factors to marginal breakdown, thereby influencing caries recurrence.

QUALITATIVE SUMMARY: INFLUENCE OF OPERATIVE TECHNIQUES ON CLASS II COMPOSITE OUTCOMES:

Operative technique plays a decisive role in determining the clinical success of Class II resin-based composite restorations. Among adhesive strategies, multi-step adhesive protocols were consistently associated with superior marginal adaptation and long-term survival, compared with simplified approaches. For instance, both Attin et al [9] and Barabanti et al [21] demonstrated enhanced marginal integrity with multi-step or total-etch adhesives. Self-etch adhesives showed moderate improvements in deep proximal boxes, especially regarding postoperative sensitivity reduction [21].

Incremental layering outperformed bulk-fill placement in terms of minimizing polymerization stress, improving the marginal seal, and reducing postoperative sensitivity (Hoshino et al [26] and van Dijken et al [37]). Nevertheless, when bulk-fill materials were combined with hybrid top layers and controlled curing (eg, soft-start protocols), results were comparable in short-term performance [22], although long-term data remain limited.

Matrix system selection significantly influenced both the marginal adaptation and contact tightness. Sectional matrices with anatomical separation rings achieved better proximal contacts and reduced microleakage, as seen in Saber et al [8] and Wenckert et al [19], compared with circumferential matrices. Proper matrix adaptation and wedge placement were critical moderating factors.

Curing protocols also played a vital role. Studies employing soft-start polymerization showed reduced gap formation and better stress distribution, whereas aggressive light curing increased marginal defects and compromised seal integrity [32]. Operator-related factors, such as experience, protocol adherence, and matrix handling technique, further influenced clinical outcomes. Notably, several studies indicated that operator variability could confound material-related effects [27,38].

These patterns are visually summarized in Table 7, which maps the strength and direction of associations between operative techniques and key clinical outcomes, including longevity, marginal adaptation, postoperative sensitivity, and secondary caries. In summary, optimized Class II restoration protocols should incorporate selective enamel etching or multi-step adhesives, incremental layering, sectional matrices with proper anatomical support, and soft-start curing protocols. These strategies collectively enhance longevity and marginal adaptation and reduce postoperative complications, as confirmed across multiple included studies.

ASSESSMENT OF META-ANALYTIC FEASIBILITY:

Meta-analysis was not feasible due to significant heterogeneity in operative techniques, outcome measures, and study designs. Variations in adhesive protocols, layering strategies, matrix systems, and curing methods made it difficult to isolate comparable interventions. Outcomes such as marginal adaptation and sensitivity were assessed using different scales and follow-up durations, and essential statistical data (eg, standard deviations) were often missing. Given these inconsistencies, a narrative synthesis with evidence mapping (Table 7) was considered the most appropriate approach.

Discussion

Although several previous reviews have examined individual operative steps or material categories, our review provides added value by integrating clinical and in vitro evidence to map specific technique–outcome relationships in Class II composite restorations. In contrast to earlier literature, this review incorporates recent advancements from 2018 to 2024, directly compares operative techniques with one another, and highlights how operator-dependent variables interact with material properties to influence restoration performance. By synthesizing these dimensions into an evidence-based framework, the present review offers a more clinically actionable understanding of technique-sensitive factors that has not been explicitly addressed in prior studies.

This systematic review examined how operative techniques influence clinical and laboratory outcomes in Class II resin-based composite restorations. The included studies consistently showed that outcomes such as longevity, marginal adaptation, postoperative sensitivity, and secondary caries are shaped not only by material properties but also by the precision with which techniques are executed. This reinforces that clinical success is fundamentally technique-sensitive and dependent on practitioner adherence to evidence-based protocols.

Longevity of restorations was most strongly influenced by adhesive strategy and placement method. Multi-step adhesives, including etch-and-rinse or selective enamel etching protocols, demonstrated superior long-term performance, with van Dijken and Lindberg reporting a 5-year survival rate of 91% using a multi-step approach [37]. These findings align with broader evidence that emphasizes the durability of more comprehensive adhesive systems. Conversely, simplified 1-step self-etch adhesives were associated with reduced bond strength and increased marginal degradation [21,22], consistent with external systematic reviews documenting the limitations of 1-step systems in stress-bearing regions [39]. The contrast between these adhesive strategies highlights the importance of adhesive selection for long-term success.

Marginal adaptation, a key predictor of both longevity and secondary caries, was strongly shaped by adhesive choice, matrix system, and curing method. Studies such as those by Hoshino et al [26] and Attin et al [9] demonstrated that selective enamel etching and soft-start polymerization significantly improved marginal seal by reducing polymerization shrinkage stress. Sectional matrix systems consistently outperformed circumferential bands in producing tighter proximal contacts and fewer overhangs, as observed by Saber et al [8]. These results support laboratory evidence that sectional matrices, when used appropriately, facilitate more anatomical contours and reduce marginal discrepancies [40]. The cumulative findings reinforce that marginal adaptation is a function of coordinated technique choices, rather than material selection alone.

Postoperative sensitivity was most effectively minimized by incremental layering and controlled curing. Hoshino et al [26] documented a clinically meaningful reduction in visual analog scale scores within 2 weeks when incremental techniques were used. Bulk-fill resins, although efficient, showed a greater tendency toward hypersensitivity when not combined with low-stress curing methods [23,32]. These observations align with established concerns that deeper increments and rapid curing can elevate polymerization stress and pulpal temperature, thereby increasing sensitivity [41]. The consistency of these findings across multiple studies underscores the need to balance procedural efficiency with biologically conservative curing strategies.

Secondary caries development was closely tied to the quality of marginal adaptation and adhesive stability. Studies by Saber et al [8] and Barabanti et al [21] demonstrated lower rates of marginal staining and suspected recurrent caries when multi-step adhesives and well-adapted matrices were used. These findings reinforce the concept that a stable, well-sealed tooth–restoration interface is more influential in preventing recurrent caries than the composite’s intrinsic formulation [42]. Poor performance of 1-step adhesives and suboptimal matrix placement, which are both common technique deviations, were frequently associated with increased microleakage and bacterial ingress, highlighting the clinical risks of oversimplified or poorly executed protocols.

Across all outcome domains, operator technique emerged as a consistent moderating factor. Failures were often linked to inadequate adhesive application, improper matrix adaptation, or overly aggressive curing, all of which are modifiable through training. Even when the same materials were used, variability in clinical outcomes frequently reflected differences in procedural precision. This suggests that improving technique standardization may have a greater impact on clinical success than introducing new materials alone.

The evidence mapping matrix (Table 6) consolidates these relationships and demonstrates the directional consistency of findings across heterogeneous study designs. Although methodological differences limited the feasibility of meta-analysis, the convergence of clinical and laboratory evidence shows that specific techniques – particularly selective enamel etching or multi-step adhesives, incremental layering, sectional matrices, and soft-start curing – consistently optimize key outcomes.

Collectively, the findings indicate that successful Class II composite restorations require more than the selection of an appropriate material. They depend on the deliberate integration of evidence-based operative techniques. The synergistic use of selective enamel etching or multi-step adhesives, incremental layering, sectional matrices, and soft-start curing should be considered the procedural foundation for high-quality restorations until more definitive evidence becomes available.

This systematic review has several limitations that should be considered when interpreting the findings. Although a comprehensive search strategy was employed, the exclusion of Web of Science and Google Scholar as primary databases may have resulted in the omission of some relevant studies. In addition, the grey-literature search was limited to trial registries and open-access repositories, and unpublished data, conference abstracts, and theses were not systematically explored, which may have introduced publication bias. The inclusion of RCTs and in vitro studies, while providing a broader understanding of technique–outcome relationships, also introduces inherent differences in study design, outcome assessment, and clinical applicability. Furthermore, considerable variability existed in restorative materials, cavity configurations, follow-up periods, operator experience, and measurement methods, which limited direct comparability between studies and precluded quantitative meta-analysis. The overall interpretation of the evidence may also have been influenced by the methodological quality and risk-of-bias profile of the included studies. The search was restricted to English-language publications and to studies available up to March 2024, which may have introduced language and temporal bias. Finally, because most included clinical studies were conducted in controlled academic or specialist settings, the generalizability of the findings to routine clinical practice should be interpreted with caution.

These findings are consistent with recent literature demonstrating that adhesive selection and microleakage control remain central to restoration performance, with newer evaluations confirming the superior reliability of multi-step adhesive strategies and reduced leakage patterns, compared with that of simplified systems [43,44].

Conclusions

Operative techniques significantly influence the success of Class II resin-based composite restorations. Multi-step adhesives, incremental layering, sectional matrices, and soft-start curing showed consistently better outcomes across key domains when compared with simplified 1-step adhesive systems, unsupported bulk-fill placement techniques, circumferential matrix bands, and high-intensity continuous curing protocols, which were associated with poorer marginal adaptation, higher postoperative sensitivity, and greater risk of secondary caries. Given the heterogeneity among studies, standardization is needed for future trials. Clinicians should adopt evidence-aligned, technique-sensitive approaches for optimal results.

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750