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Background:
Systematic Review

A Systematic Review and Meta-Analysis on the Clinical Performance and Longevity of Bioactive Composite Resin Restorations

by
Ahmed A. Holiel
1,2,
Mounir M. Al Nakouzi
2,
Rim Bourgi
2,3,4,*,
Carlos Enrique Cuevas-Suárez
5,*,
Iván Olivares Acosta
6,
Louis Hardan
3,
Naji Kharouf
4,7 and
Youssef Haikel
4,7,8
1
Department of Conservative Dentistry, Faculty of Dentistry, Alexandria University, Alexandria 21532, Egypt
2
Department of Restorative Sciences, Faculty of Dentistry, Beirut Arab University, Beirut 115020, Lebanon
3
Department of Restorative and Esthetic Dentistry, Faculty of Dental Medicine, Saint-Joseph University of Beirut, Beirut 1107 2180, Lebanon
4
Department of Biomaterials and Bioengineering, INSERM UMR_S 1121, University of Strasbourg, 67000 Strasbourg, France
5
Dental Materials Laboratory, Academic Area of Dentistry, Autonomous University of Hidalgo State, San Agustín Tlaxiaca 42160, Mexico
6
Facultad de Ciencias de la Salud Unidad Valle de las Palmas, Universidad Autónoma de Baja California, 7 Blvd Universitario 1000 Valle de Las Palmas, Tijuana 22260, Mexico
7
Department of Endodontics and Conservative Dentistry, Faculty of Dental Medicine, University of Strasbourg, 67000 Strasbourg, France
8
Pôle de Médecine et Chirurgie Bucco-Dentaire, Hôpital Civil, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France
*
Authors to whom correspondence should be addressed.
J. Compos. Sci. 2026, 10(1), 39; https://doi.org/10.3390/jcs10010039
Submission received: 21 November 2025 / Revised: 25 December 2025 / Accepted: 26 December 2025 / Published: 9 January 2026
(This article belongs to the Section Composites Manufacturing and Processing)
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Abstract

Background: Bioactive composite resins combine the esthetic and mechanical properties of resin composites with therapeutic functions such as ion release, remineralization, and caries inhibition. While in vitro studies suggest promising bioactivity, their clinical performance in permanent teeth remains uncertain. Objective: This systematic review and meta-analysis critically appraised randomized controlled trials and prospective clinical studies to determine whether bioactive composites offer superior clinical performance compared to conventional resin composites and glass ionomer-based materials. Methods: Electronic databases (PubMed/MEDLINE, Scopus, Web of Science, Google Scholar) were searched for eligible studies (2018–2025). Clinical outcomes assessed restoration survival, marginal integrity, secondary caries, postoperative sensitivity, and esthetic outcomes (color match). Data were pooled using a random-effects model, and risk of bias was assessed with Cochrane criteria. Results: Twenty-two trials met the inclusion criteria. No significant differences were found between bioactive and control restorations for survival/retention (RD = 0.01; 95% CI, –0.01 to 0.03), marginal adaptation (RD = 0.02; 95% CI, –0.02 to 0.06), secondary caries (RD = 0.01; 95% CI, –0.01 to 0.03), or postoperative sensitivity (RD = 0.01; 95% CI, –0.02 to 0.04), with negligible heterogeneity (I2 = 0–4%). For color match, glass ionomer restorations showed significantly poorer outcomes (RD = –0.23; 95% CI, –0.31 to –0.14; p < 0.00001; I2 = 98%), while conventional resin composites had a slight but significant advantage over bioactive composites (RD = 0.07; 95% CI, 0.02 to 0.12; p = 0.003; I2 = 76%). Most studies presented moderate risk of bias and short-term follow-up (<36 months). Conclusions: Current evidence indicates that bioactive composites perform comparably, but not superior, to conventional restoratives in permanent teeth. The discrepancy between laboratory bioactivity and clinical effectiveness highlights the need for long-term, well-designed clinical trials with standardized outcome reporting.

1. Introduction

Dental caries remains one of the most prevalent oral health conditions worldwide and continues to be a leading cause of tooth structure loss across all age groups. The disease arises from a dynamic imbalance between demineralization and remineralization processes, mediated by cariogenic microorganisms, dietary sugars, and host factors. If not detected and managed early, caries progress to cavitation, ultimately requiring restorative intervention. Despite advances in preventive strategies, the persistence of secondary caries remains a major factor compromising the longevity of restorations [1].
Conventional restorative materials are primarily designed to replace lost tooth structure and restore function and esthetics. Resin composites have become the material of choice due to their esthetics, adhesive properties, and handling versatility. However, they lack biological interaction with surrounding tissues and are prone to marginal degradation, microleakage, and biofilm accumulation, which increase the risk of recurrent caries and restoration failure [2]. These limitations highlight the need for restorative systems that combine the functional and esthetic benefits of composites with therapeutic capabilities.
Bioactive composite resins have emerged as a novel class of restorative materials designed to address these shortcomings. Bioactivity refers to the ability of a material to elicit a beneficial biological response without causing harm [3]. More recently, in dentistry, a material has been considered bioactive if it interacts positively with surrounding tissues while simultaneously fulfilling its primary restorative function. In practice, this is often achieved by incorporating ion-releasing components, such as calcium, phosphate, and fluoride, into resin matrices. These ions can saturate the tooth–restoration interface, buffer acidic challenges, promote remineralization, and exert antibacterial effects [4,5]. For example, fluoride ions inhibit demineralization by facilitating the conversion of hydroxyapatite into the more acid-resistant fluorapatite, while also interfering with bacterial glucosyltransferase activity, thereby reducing biofilm virulence. Clinically, this bioactive potential is expected to enhance restoration longevity, minimize postoperative sensitivity, and reduce the incidence of secondary caries [6].
Several commercially available bioactive composite resins, such as Activa BioACTIVE (Pulpdent, Watertown, MA, USA) and Cention N (Ivoclar Vivadent, Schaan, Liechtenstein), as well as experimental formulations enriched with bioactive glass, hydroxyapatite, or calcium phosphate nanoparticles, have been introduced in restorative dentistry [7,8,9]. While promising in vitro findings have confirmed their ion release and remineralization potential, the extent to which these properties translate into clinical benefits remains unclear [10,11].
Given the increasing clinical adoption of bioactive composite resins, a critical appraisal of available clinical evidence is necessary to determine their performance in real-world settings. This systematic review and meta-analysis, therefore, aimed to synthesize current clinical data on the survival, effectiveness, and overall clinical outcomes of bioactive composite resin restorations, with the goal of guiding evidence-based material selection in restorative practice. The null hypothesis tested was that there are no statistically significant differences between bioactive resin composites and conventional resin composites or alternative restorative materials with respect to restoration retention, marginal adaptation, secondary caries prevention, postoperative sensitivity, and esthetic outcomes (color match).

2. Materials and Methods

2.1. Study Design

This systematic review and meta-analysis were conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [12] and the Cochrane Handbook for Systematic Reviews of Interventions [13]. The review protocol was prospectively registered in the PROSPERO database under CRD42023354699 registration number.
The research question was formulated using the Population, Intervention, Comparison, Outcomes, and Study design (PICOS) framework, where the population consisted of patients receiving restorative treatment with direct composite restorations in permanent teeth, the intervention involved bioactive composite resin materials such as Activa BioACTIVE, Cention N, and experimental bioactive resin composites, the comparison was conventional resin composites or alternative restorative materials, the outcomes assessed included clinical performance measures such as restoration survival, failure rates, marginal adaptation, prevention of secondary caries, postoperative sensitivity, and esthetic outcomes (color match), and the eligible study designs included randomized controlled trials, prospective clinical trials, and retrospective cohort studies with clinical follow-up.

2.2. Search Strategy

A comprehensive electronic search was performed in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar to identify relevant clinical studies published from database inception to September 2025. The search strategy combined controlled vocabulary (MeSH terms) and free-text keywords related to bioactive composite resins and clinical outcomes. The detailed PubMed search strategy is presented in Table 1 and was adapted for use in the other databases.

2.3. Study Selection

Two reviewers (A.A.H. and M.N.) independently screened the titles and abstracts of all retrieved records. Full texts of potentially eligible studies were then assessed against the predefined inclusion and exclusion criteria. Studies were included if they met the following criteria: clinical studies (randomized controlled trials, prospective, or retrospective cohort studies) evaluating bioactive composite resin restorations in permanent teeth, with a minimum follow-up period of 6 months, and reporting at least one of the following clinical outcomes: restoration survival, marginal adaptation, secondary caries incidence, postoperative sensitivity, or esthetic outcomes.
Exclusion criteria were narrative or systematic reviews, case reports, pilot studies, editorials, conference abstracts, in vitro or animal studies, and studies investigating bioactive materials other than bioactive resin composites. Any disagreements between reviewers were resolved through discussion or, when necessary, consultation with a third reviewer (R.B.) until consensus was reached.

2.4. Data Extraction

Data were independently extracted by two reviewers (N.K. and C.E.C.-S.) using a standardized form. The following information was collected: study (first author and year), study design (randomized controlled trial, prospective clinical trial, or retrospective cohort study), sample size/number of teeth, baseline caries risk, bioactive composite resin material and manufacturer, comparator material (conventional resin composite or alternative restorative material), follow-up duration, and clinical outcomes reported (restoration survival/failure, marginal adaptation, postoperative sensitivity, secondary caries, and other complications). Extracted data were summarized in structured tables presenting each study’s characteristics, interventions, comparators, clinical outcomes, and key findings. Only clinical studies were included; in vitro and animal studies were excluded from the data extraction process.

2.5. Risk of Bias Assessment

Methodological quality assessment and risk of bias were independently performed for each included study by a blinded examiner using established critical appraisal tools. The quality of randomized clinical trials was evaluated using the modified CONSORT (Consolidated Standards of Reporting Trials) guidelines, the Cochrane Collaboration’s Risk of Bias 2 (RoB 2) tool. Consensus on scoring was achieved through discussion among all reviewers prior to the assessments [14]. For non-randomized prospective and retrospective clinical studies, the ROBINS-I (Risk Of Bias In Non-randomized Studies of Interventions) tool was applied. This tool evaluates bias across seven domains, including confounding, participant selection, intervention classification, deviations from intended interventions, missing data, outcome measurement, and selective reporting. Domains evaluated included confounding, selection bias, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported result [15].

2.6. Certainty of Evidence Assessment

The certainty of evidence for each clinical outcome was evaluated using the GRADE approach [16], considering factors such as study risk of bias, consistency of effect, imprecision, indirectness, and publication bias. Certainty ratings were classified as high, moderate, low, or very low, and detailed justifications for downgrading were reported.

2.7. Data Synthesis

Meta-analyses were conducted using Review Manager Software, version 5.3.5 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). A fixed-effects model was applied to evaluate the incidence of retention loss, secondary caries, and postoperative sensitivity in randomized clinical trials. Restoration longevity was assessed according to the United States Public Health Service (USPHS) and Fédération Dentaire Internationale (FDI) criteria, with outcomes dichotomized as clinically acceptable or unacceptable. Specifically, alpha and bravo ratings were classified as absence of the event (score = 0), whereas charlie and delta ratings were considered presence of the event (score = 1). Statistical heterogeneity across studies was examined using the Cochran Q test and the I2 statistic. A p-value of <0.05 was considered statistically significant.

3. Results

3.1. Search Strategy

The systematic search yielded 2963 records from PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. After removal of 1067 duplicates, 1896 unique records were screened for eligibility. Of these, 1852 records were excluded based on title and abstract screening. A total of 44 full-text articles were then assessed against the predefined inclusion and exclusion criteria. The main reasons for exclusion were in vitro or animal study (n = 2), evaluation of non-composite bioactive restorative materials (e.g., glass ionomer, calcium silicate cements) (n = 6), studies on primary molars (n = 6), and absence of a control group (n = 6), leaving a total of 24 articles. Of these, two studies were not included (inaccessible full text (n = 2) [17,18]). Following full-text assessment, 22 clinical studies evaluating the performance of bioactive composite resin restorations were included in the quantitative synthesis. The study selection process is summarized in the PRISMA flow diagram (Figure 1), detailing records identified, screened, excluded, and included in the final analysis.

3.2. Study Characteristics

The included clinical studies comprised randomized controlled trials (RCTs) and a prospective clinical trial evaluating bioactive composite resin restorations in permanent teeth. Follow-up periods ranged from 6 months to 5 years, and most studies assessed single- or multiple-surface restorations in anterior and posterior teeth. A summary of the key study characteristics is presented in Table 2. Information includes study design, material type, comparator, sample size, follow-up duration, and clinical outcomes. All studies reported at least one of the prespecified outcomes: restoration survival, marginal adaptation, postoperative sensitivity, or incidence of secondary caries.

3.3. Descriptive Analysis

The 22 included clinical studies were published between 2018 and 2025 across different countries, Egypt [7,8,23,24,25,31,32,33,35,36,37,38], Turkey [21,28,29], India [20,27], China [34], and multi-center or regional contributions from other countries [19,22,26,30]. The study designs were primarily RCTs [7,8,19,20,21,24,25,27,28,29,30,31,32,33,34,35,36,38], with a few split-mouth [22,23,37] and comparative trials [26]. Sample sizes ranged from 26 restorations [31] to 300 restorations [21], with most trials enrolling between 12 and 67 patients. A variety of cavity classes were investigated. Class I restorations were evaluated in several studies [8,25,27,38], while Class II restorations were assessed in others [20,23,28,33]. Class V cervical lesions were frequently studied [7,22,24,32,35,36,37], reflecting the clinical challenge of bonding in these areas. Some trials investigated both Class I and II restorations [19,29,30,31,34], while others included Non-Carious Cervical Lesions (NCCLs) or abfraction lesions [21,26]. This diversity reflects attempts to evaluate bioactive composites in different stress-bearing and non-stress-bearing clinical conditions. Only seven of the included studies explicitly reported baseline caries-risk information or selected participants by caries risk [7,19,23,25,32,35,36]. Assessment methods were heterogeneous (ADA tool, CAMBRA, clinician estimate, color-coded questionnaire).
In terms of materials tested, Activa BioACTIVE composite (Pulpdent, Watertown, MA, USA) was the most extensively studied, reported in multiple trials across different cavity classes [19,20,23,24,25]. Cention N (alkasite, Ivoclar Vivadent, Liechtenstein) was also widely investigated in Class I and II restorations as well as cervical lesions [7,8,25,27,28,30,38]. Giomer-based composites (Beautifil II LS, Beautifil Flow, Shofu Inc.) were assessed in several studies [21,22,26,27,31,34,35,36,37]. In addition, newer bioactive formulations such as Activa Presto (Pulpdent, Watertown, MA, USA) [32,33] and self-adhesive bulk-fill composites (Surefil One, Dentsply Sirona, Charlotte, NC, USA) [37] were included. Comparators varied and included conventional nanohybrid composites [8,19,20,21,22,26,27,28,29,30,31,34,37], Resin-Modified Glass Ionomer (RMGI) or Glass Ionomer Cement (GIC) (Fuji II LC, GC America Inc., Alsip, IL, USA) [24,26,31,32,35,36], bulk-fill glass hybrid materials such as Equia Forte (GC, Tokyo, Japan) [23,38], and other newer restorative systems [21,25,33,38].
All included studies reported follow-up durations ranging from 6 to 12 months, with most providing 12-month evaluations. Some studies extended their assessments to 18–36 months [7,8,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38], and one study reported long-term outcomes up to 8 years [34]. Clinical outcomes commonly assessed included restoration survival/retention, marginal adaptation, marginal discoloration, color match, postoperative sensitivity, secondary caries, esthetics, wear, and anatomical form. Evaluation criteria were mostly based on modified USPHS standards [19,20,21,23,24,28,31,32,34,37,38], with some studies employing FDI criteria [8,25,29,35].
In terms of findings, Activa BioACTIVE generally demonstrated acceptable short-term clinical performance, although high failure rates were observed in Class II cavities when used without adhesive pretreatment [19]. For Class I and II restorations, Activa performed comparably to nanohybrid composites over 6–12 months [20,23,28]. Cention N (alkasite) was reported as a viable alternative to conventional composites in occlusal and proximal restorations, with similar survival and marginal adaptation [25,27,28,29], although adhesive pretreatment was shown to improve outcomes [19]. Giomer-based materials also showed favorable performance, with similar survival and marginal adaptation to nanohybrid composites across short- and long-term follow-ups [29,31,34]. Activa Presto, however, presented some limitations, including slight gingival inflammation and color mismatch, though overall clinical performance remained acceptable [32,33]. Newer materials such as self-adhesive bulk-fill composites [37] and comparative evaluations against zirconia-reinforced glass ionomer [38] also showed satisfactory outcomes, suggesting expanding options for bioactive restorative approaches.
Overall, despite variations in design, materials, and outcomes, most included trials demonstrated that bioactive composite resins (Activa, Cention N, Giomer, and Activa Presto) performed comparably to conventional resin composites or alternative restorative materials in short- to medium-term follow-up. Longer-term studies, such as the 8-year trial by Tian et al. [34], confirmed the durability of giomer restorations, further supporting their clinical viability.

3.4. Risk of Bias of Included Studies

The methodological quality and risk of bias of the 22 included clinical studies were evaluated using risk-of-bias tools appropriate to study design. Randomized controlled trials were assessed using the Cochrane Risk of Bias 2 (RoB 2) tool across five domains (D1–D5), whereas the non-randomized clinical study was evaluated using the ROBINS-I tool. Based on the RoB 2 assessment, six randomized studies were classified as having a low risk of bias across all domains [8,23,24,25,28,33]. Fifteen randomized studies were rated as having “some concerns” in one or more domains, mainly due to limitations in randomization procedures, lack of blinding, or incomplete outcome data [7,19,20,21,22,27,29,30,31,32,34,35,36,37,38]. A detailed summary of the domain-specific risk of bias for randomized trials is presented in Figure 2. The methodological quality of the non-randomized study by Costăchel et al. [26] was assessed using the ROBINS-I tool and rated as moderate overall risk of bias. Moderate risk was noted for confounding and participant selection due to non-random allocation and patient withdrawal. Missing data were also moderate. Classification of interventions, deviations from intended interventions, outcome measurement, and selection of reported results were low risk due to clear protocols, adherence to interventions, blinded assessors, and complete outcome reporting.

3.5. Evidence Quality

The certainty of evidence for clinical outcomes of bioactive composite resins was evaluated using the GRADE approach. Evidence derived from 21 randomized controlled trials provides moderate-certainty evidence that bioactive composites perform comparably to conventional resin composites and glass ionomer–based materials with respect to restoration survival/retention, marginal adaptation, secondary caries incidence, and postoperative sensitivity (Table 3). Downgrading was primarily due to some concerns regarding risk of bias (e.g., limitations in randomization, lack of blinding, incomplete outcome data) and imprecision related to modest sample sizes and limited numbers of clinical events. For esthetic outcomes (color match), certainty was rated as low due to serious inconsistency and heterogeneity in assessment methods. While conventional resin composites demonstrated a slight esthetic advantage over bioactive composites, confidence in this estimate remains limited. Overall, bioactive composites demonstrate similar short- to medium-term clinical performance to conventional materials, but not superior performance.
Jcs 10 00039 g002
Figure 2. Summary results of the application of the Cochrane Collaboration tool to assess the risk of bias in randomized controlled trials included in reviews (Rob 2) [7,8,19,20,21,22,23,24,25,27,28,29,30,31,32,33,34,35,36,37,38].
Figure 2. Summary results of the application of the Cochrane Collaboration tool to assess the risk of bias in randomized controlled trials included in reviews (Rob 2) [7,8,19,20,21,22,23,24,25,27,28,29,30,31,32,33,34,35,36,37,38].
Jcs 10 00039 g002
For the single non-randomized trial [26], the certainty of evidence is low. Despite showing good clinical behavior in abfraction lesions over 24 months, limitations include moderate risk of bias (potential confounding, non-random allocation, incomplete outcome data) and imprecision related to the small sample size and limited number of clinical events. These findings should be interpreted cautiously and considered supportive or hypothesis-generating rather than confirmatory.

3.6. Meta-Analysis

A meta-analysis of the 22 randomized clinical trials [7,8,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38] was conducted, with separate analyses for retention loss, marginal adaptation, secondary caries, postoperative sensitivity, and color match.
For restoration survival and retention (Figure 3), regardless of whether the restorative material was bioactive or not, no statistically significant difference was observed between the intervention and control groups (p > 0.05). The overall pooled analysis confirmed comparable retention rates between bioactive and control restorations (RD = 0.01; 95% CI, –0.01 to 0.03; p = 0.86 for glass ionomer and p = 0.18 for resin composite), with no heterogeneity (I2 = 0%).
In terms of marginal adaptation (Figure 4), no significant difference was detected between bioactive materials and controls. For the glass ionomer subgroup, outcomes were comparable (RD = −0.01; 95% CI, −0.08 to 0.05; p = 0.63; I2 = 0%), while the resin composite subgroup also showed no significant difference (RD = 0.04; 95% CI, −0.02 to 0.09; p = 0.19; I2 = 35%). The overall pooled analysis indicated equivalent performance between groups (RD = 0.02; 95% CI, −0.02 to 0.06; p = 0.37), with very low heterogeneity (I2 = 4%). Subgroup comparison confirmed no material-specific effect (Chi2 = 1.48; p = 0.22).
Similarly, the analysis of secondary caries (Figure 5) demonstrated no statistically significant difference between the intervention group (bioactive material) and the control group, regardless of the material used. In the glass ionomer subgroup, no significant difference was observed (RD = −0.01; 95% CI, −0.04 to 0.03; p = 0.72; I2 = 0%). Similarly, the resin composite subgroup showed no significant difference (RD = 0.01; 95% CI, −0.01 to 0.04; p = 0.31; I2 = 0%). The overall pooled analysis confirmed equivalent outcomes between groups (RD = 0.01; 95% CI, −0.01 to 0.03; p = 0.44), with no heterogeneity across studies (I2 = 0%). Subgroup comparison revealed no material-specific effect (Chi2 = 0.75; p = 0.39).
Consistent findings were obtained for postoperative sensitivity (Figure 6). No significant differences were detected between bioactive composites and glass ionomers (RD = 0.01; 95% CI, −0.04 to 0.05; p = 0.78) or between bioactive and conventional resin composites (RD = 0.01; 95% CI, −0.02 to 0.04; p = 0.55). Heterogeneity was negligible (I2 = 0%), and subgroup analysis confirmed the absence of material-specific effects (Chi2 = 0.00; p = 0.95).
In contrast, analysis of color match (Figure 7) revealed significant subgroup differences. Glass ionomer restorations showed substantially poorer outcomes compared with bioactive composites (RD = −0.23; 95% CI, −0.31 to −0.14; p < 0.00001; I2 = 98%), while conventional resin composites exhibited a slight but statistically significant advantage over bioactive composites (RD = 0.07; 95% CI, 0.02 to 0.12; p = 0.003; I2 = 76%). Subgroup comparison confirmed a significant material-specific effect (Chi2 = 34.09; p < 0.00001).

4. Discussion

Despite major advances in restorative composites over recent decades, achieving long-term clinical success remains challenging. This systematic review and meta-analysis synthesized evidence from 22 clinical studies published between 2018 and 2025, evaluating bioactive composite resins in permanent teeth across Class I, II, and V restorations, as well as non-carious cervical and abfraction lesions. The analysis examined whether incorporating bioactive functionality, via ion-releasing fillers, bioactive glass, alkasite chemistries, or giomer technology, offers measurable clinical benefits. The findings indicate that bioactive composites show no statistically significant superiority over conventional resin composites with respect to restoration survival, retention, marginal adaptation, prevention of secondary caries, or postoperative sensitivity, supporting the null hypothesis for these outcomes. However, the null hypothesis was rejected for color match, where a significant difference was observed in favor of conventional composites.
With regard to restoration survival and retention, the most critical indicator of clinical success, the pooled data indicate similar performance between bioactive and conventional resin composites across a range of cavity classes (I, II, and V) and clinical settings. RCTs evaluating products such as Activa™, Cention N, and giomers in both Class I/II and NCCL restorations consistently reported comparable survival outcomes. These clinical findings are consistent with prior RCTs and clinical series showing parity in early-to-medium term survival for ion-releasing resin systems and conventional nanohybrid composites [8,34,39]. Mechanistically, survival and retention are driven primarily by adhesive interface integrity, polymerization stress, occlusal loading, and restorative technique (cavity preparation, incremental placement, curing), rather than by filler chemistry alone. Ion-releasing functionality does not inherently mitigate polymerization shrinkage or improve mechanical resistance to occlusal forces; therefore, equivalent survival is expected when adhesive protocols and restorative techniques are optimized. This mechanistic perspective is supported by laboratory studies demonstrating that ion-releasing fillers can influence ion exchange and surface chemistry but do not necessarily change bulk mechanical behavior under cyclic occlusal loading comparable to conventional composites [40,41].
Restoration survival was generally high for Activa BioACTIVE and Cention N in Class I restorations across short- to medium-term follow-ups (6–36 months) [20,23,25,27,28], while higher failure rates were observed in Class II cavities without adhesive pretreatment, highlighting the importance of proper bonding protocols [19]. Cention N and giomer-based composites achieved survival and marginal adaptation similar to conventional composites, with long-term studies, such as the 8-year evaluation of giomer restorations, confirming durability and sustained performance [34]. Newer formulations, including Activa Presto and self-adhesive bulk-fill composites, demonstrated satisfactory clinical outcomes, though minor limitations such as color mismatch or gingival inflammation were occasionally reported [32,33,37].
Marginal adaptation, another critical determinant of long-term restoration success and a proximate cause of secondary caries, was found to be comparable between bioactive and conventional composites [21,29,31,35]. The pooled analysis revealed no statistically significant differences between groups for either glass ionomer or conventional composites, confirming that overall marginal adaptation is clinically equivalent. Most clinical studies reported acceptable marginal integrity for bioactive formulations, although some noted minor deterioration or discoloration over time [20,21,22,32,33]. Importantly, these changes are rarely translated into restoration failure. The evidence reinforces the multifactorial nature of marginal performance, which is more strongly influenced by adhesive bonding strategy (etch-and-rinse vs. self-etch), polymerization shrinkage dynamics, cavity geometry, and operator technique than by the modest contributions of ion release at the restoration interface. In vitro studies further suggest that adhesive coatings or bonding layers may reduce the reactive surface exposure of ion-releasing fillers (potentially attenuating ion exchange), whereas direct exposure can enhance local reactivity but at the cost of surface durability and esthetic stability [40,42].
Minor marginal deterioration or discoloration has been reported with Activa BioACTIVE, Activa Presto, and alkasite restorations, particularly in cervical or anterior teeth [32,33], but these changes did not compromise overall clinical acceptability. Low-shrinkage giomer formulations demonstrated excellent long-term marginal integrity, underscoring the role of polymerization shrinkage control and material composition in maintaining interface stability [35]. Similarly, marginal discoloration observed in certain alkasite and giomer restorations did not compromise clinical outcomes in the short- to medium-term [7,26].
Secondary caries prevention remains the most debated aspect. In vitro and in situ studies consistently demonstrate fluoride, calcium, phosphate, and other ion release from bioactive composites, as well as their ability to form apatite-like deposits, enhance enamel and dentin remineralization, and exhibit antibacterial activity [4,5,10]. However, these mechanistic findings have not translated into measurable reductions in secondary caries in clinical trials. The reasons for this translational gap are multifactorial. Patient-level factors such as age, salivary composition and flow rate, dietary habits, oral hygiene routines, fluoride exposure, and baseline caries risk, as well as operator- and lesion-specific variables, exert a stronger influence than modest material-derived ion release [43]. These variables can affect plaque accumulation, acid challenge, and remineralization capacity, thereby influencing restoration longevity and secondary caries development. In addition, the magnitude and kinetics of ion release in vivo are highly variable and attenuated by salivary dynamics, pellicle formation, and adhesive coverage, which diminish clinical bioactivity at the restoration margin [40,42]. Finally, the relatively low event rates of secondary caries in well-conducted clinical trials with short to medium follow-up make it statistically difficult to detect modest differences, with larger and longer studies likely needed to reveal meaningful effects [43,44]. Taken together, the evidence suggests that bioactive composites may function as adjunctive anti-caries tools whose benefits are conditional and context-dependent, for instance, in high-risk patients or when used as liners rather than as universally protective restorative solutions [45,46,47].
These conclusions align with prior meta-analyses reporting no significant advantage of bioactive resins over conventional composites in terms of secondary caries or retention, with short follow-up and methodological heterogeneity as limiting factors [43,44]. Notably, earlier reviews also included primary teeth, whereas the present review focused exclusively on permanent dentition and incorporated postoperative sensitivity and esthetic outcomes, strengthening the evidence base.
Postoperative sensitivity, a frequent patient-reported outcome in restorative dentistry, showed no statistically significant difference between bioactive and conventional composites in the pooled analysis. Hypersensitivity after restoration is typically related to dentin thickness, preparation trauma, and the sealing capacity of the adhesive layer. While ion-releasing composites are theoretically capable of occluding dentinal tubules and buffering acidic environments, these properties did not result in measurable differences in sensitivity during the follow-up periods studied. This finding is supported by multiple randomized trials and cohort studies that consistently report low and comparable sensitivity rates across both material classes when standardized bonding protocols are followed [39,48]. These findings suggest that while bioactive composites do not eliminate the risk of postoperative sensitivity, they provide a favorable clinical profile, particularly when appropriate adhesive protocols are applied.
Esthetic performance, color stability, and anatomical form are critical determinants of patient satisfaction. Overall, bioactive composites maintained acceptable levels of color match, surface texture, and anatomical form across clinical studies [24,26,32]. However, the pooled analysis revealed that glass ionomer restorations exhibited significantly poorer color match compared with bioactive composites, underscoring the esthetic advantage of bioactive formulations over traditional glass ionomer. Conversely, conventional resin composites demonstrated a slight but statistically significant advantage over bioactive composites in terms of color match, indicating that while bioactive composites are esthetically acceptable, they may not yet fully match the superior optical integration of contemporary nanohybrid composites in highly esthetic zones. Activa Presto, for example, occasionally exhibited minor color mismatch [32], though these effects did not compromise overall restoration acceptability. Taken together, this meta-analysis highlights that bioactive composites demonstrated clear esthetic advantages over glass ionomers, making them a more reliable alternative in clinical situations where glass ionomer is typically indicated, especially in caries-prone or high-risk patients. However, their slightly inferior color match compared with conventional resin composites suggests that case selection remains critical: bioactive composites may be advantageous where remineralization and biocompatibility are prioritized, whereas conventional resin composites remain preferable in esthetically demanding or mechanically intensive indications.
In terms of functional performance, wear resistance was adequate for most bioactive composites, with Cention N and Activa BioACTIVE showing comparable results to conventional nanohybrid composites in occlusal stress-bearing restorations [23,27,28]. These findings support the utility of bioactive composites in both anterior and posterior teeth, providing functional durability alongside therapeutic potential. Performance variations may be attributed to differences in material composition and curing mechanisms: Activa BioACTIVE contains a urethane dimethacrylate matrix, polyacrylic acid, dimethacrylate phosphate, and silanized fluoro-alumina-silicate (FAS) fillers, supporting both light- and self-curing mechanisms [49,50]. Cention N is a powder-liquid system with reactive alkasite fillers capable of ion release under acidic conditions [50,51], while giomer-based composites incorporate pre-activated FAS fillers coated with silicon dioxide (SiO2) gel, facilitating ionic release and copolymerization with the resin matrix [52]. These differences highlight the importance of selecting materials based on cavity class, occlusal load, and operator experience. Performance variations may also be influenced by curing efficiency. The use of modern polywave light-curing units is critical to ensure adequate polymerization of multi-photoinitiator resin systems, thereby optimizing mechanical properties and long-term clinical performance. Third-generation polywave Light-Emitting Diode (LED) devices, such as the HeptaLux curing light (Xpedent, Guilin, China), provide broad-spectrum wavelength coverage and high irradiance, reducing wavelength compatibility limitations and enhancing depth of cure for polymer-based light-cured restorative materials, including bioactive composites.
From a clinical perspective, these findings suggest several implications for restorative practice. Material selection should emphasize adhesive protocols, handling characteristics, esthetics, wear resistance, and polymerization behavior rather than presumed bioactivity, since survival and retention outcomes remain equivalent. Bioactive composites represent viable alternatives to nanohybrid composites in routine indications such as Class I, small Class II, and selected Class V restorations, but they should not be considered substitutes for comprehensive caries management strategies, which continue to rely on risk assessment, topical fluoride, dietary counseling, and regular recall [34,39]. Their theoretical benefits may hold greater value in high-caries-risk patients, such as those with hyposalivation or high cariogenic challenge, but robust clinical evidence in these populations remains scarce. Moreover, clinicians should recognize that adhesive coatings may diminish surface reactivity and fluoride recharge potential, thereby limiting the extent of bioactivity achievable in practice [53,54].
The strengths of this review include adherence to PRISMA and Cochrane standards, dual independent screening, ROB-2 assessment, prespecified subgroup analyses, and an up-to-date synthesis across multiple cavity classes and clinically relevant outcomes. However, limitations include heterogeneity in study designs (parallel vs. split-mouth), variable follow-up durations, differing evaluation criteria (modified USPHS vs. FDI), inconsistent reporting of operator and adhesive protocols, and generally small sample sizes. Most studies reported only short- to medium-term outcomes (≤3 years), limiting detection of late failures such as wear or fatigue fracture. Low absolute event rates for secondary caries further reduce statistical power. Lack of mechanistic in vivo measures (ion release, localized remineralization) also constrains translational insights. Moreover, variability in baseline caries risk assessment across studies limits the ability to determine whether patient susceptibility modifies the performance of bioactive materials. Underreporting or inconsistent classification of caries risk may obscure true effect differences, especially in high-risk populations where bioactive composites may theoretically confer greater benefit.
Future research should aim to clarify whether bioactive resin composites, including self-cure bulk-fill materials such as Stela (SDI, Bayswater, Victoria, Australia) with potential bioactivity, can provide benefits beyond equivalence through large multicenter RCTs with extended follow-up of at least 5–10 years, ideally stratified by baseline caries risk to increase power for detecting meaningful differences. Standardized outcome measures, including consensus on USPHS or FDI criteria and the integration of objective tools such as micro-computed tomography, quantitative margin analysis, and validated patient-reported outcomes, would improve comparability. Mechanistic sub studies embedded within clinical trials that directly assess in vivo ion release, pH modulation, and localized remineralization would provide much-needed translational evidence. Trials targeting high-risk groups, including xerostomia or radiation-treated patients, may be particularly informative in revealing potential clinical advantages. Additionally, cost-effectiveness studies are needed to evaluate whether bioactive materials reduce lifetime restoration costs, recall frequency, or the need for retreatment.

5. Conclusions

Bioactive composite resins, including Activa BioACTIVE, Cention N, giomer-based materials, and newer formulations, demonstrate clinical performance comparable to conventional composites in permanent teeth over short- to medium-term follow-up periods. While their bioactive properties offer theoretical advantages, their impact on restoration retention, secondary caries, postoperative sensitivity, and marginal adaptation is not statistically significant within the observed follow-up periods. However, limitations remain in esthetic outcomes, as color match is less favorable in some bioactive formulations over conventional resin composites. Proper material selection, adhesive protocols, and clinical technique remain paramount for ensuring long-term restorative success, positioning bioactive composites as viable alternatives in contemporary restorative dentistry.

Author Contributions

Conceptualization, A.A.H., C.E.C.-S., R.B. and M.M.A.N.; methodology, A.A.H. and M.M.A.N.; software, A.A.H., C.E.C.-S., N.K., L.H., I.O.A., Y.H., R.B. and M.M.A.N.; validation, A.A.H., N.K. and R.B.; formal analysis, A.A.H., L.H., N.K., Y.H., R.B. and M.M.A.N.; investigation, A.A.H. and M.M.A.N.; resources, A.A.H. and M.M.A.N.; data curation, A.A.H. and M.M.A.N.; writing—original draft preparation, A.A.H., L.H., R.B. and N.K.; writing—review and editing, A.A.H., M.M.A.N., N.K., I.O.A., Y.H. and R.B.; visualization, A.A.H. and R.B.; supervision, A.A.H., N.K. and R.B.; project administration, A.A.H.; funding acquisition, N.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. PRISMA 2020 flow diagram of study selection.
Figure 1. PRISMA 2020 flow diagram of study selection.
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Figure 3. Forest plot of the results comparing bioactive composite resins with conventional materials evaluating restoration retention [7,8,19,20,21,22,23,24,25,26,27,28,29,33,34,35,36,37].
Figure 3. Forest plot of the results comparing bioactive composite resins with conventional materials evaluating restoration retention [7,8,19,20,21,22,23,24,25,26,27,28,29,33,34,35,36,37].
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Figure 4. Forest plot comparing bioactive composite resins with conventional materials evaluating marginal adaptation [7,20,22,23,24,26,27,28,30,31,32,33,35,36,37,38].
Figure 4. Forest plot comparing bioactive composite resins with conventional materials evaluating marginal adaptation [7,20,22,23,24,26,27,28,30,31,32,33,35,36,37,38].
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Figure 5. Forest plot comparing bioactive composite resins with conventional materials evaluating secondary caries [7,19,20,22,24,26,27,28,29,30,31,34,35,36,37,38].
Figure 5. Forest plot comparing bioactive composite resins with conventional materials evaluating secondary caries [7,19,20,22,24,26,27,28,29,30,31,34,35,36,37,38].
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Figure 6. Forest plot comparing bioactive composite resins with conventional materials evaluating postoperative sensitivities [7,8,19,20,27,28,29,31,35,38].
Figure 6. Forest plot comparing bioactive composite resins with conventional materials evaluating postoperative sensitivities [7,8,19,20,27,28,29,31,35,38].
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Figure 7. Forest plot comparing bioactive composite resins with conventional materials evaluating color match [7,20,21,22,23,24,26,28,29,30,32,33,35,37].
Figure 7. Forest plot comparing bioactive composite resins with conventional materials evaluating color match [7,20,21,22,23,24,26,28,29,30,32,33,35,37].
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Table 1. Search strategy performed at PubMed and adapted to other databases.
Table 1. Search strategy performed at PubMed and adapted to other databases.
SearchTerms
#1 (Bioactive Composite Resins)“bioactive composite resin” OR “bioactive resin composite” OR “bioactive restorative composite” OR “Activa BioACTIVE” OR “Cention N” OR “bioactive resin”
#2 (Clinical Performance)“clinical trial” OR “clinical evaluation” OR “clinical performance” OR “restoration survival” OR “marginal adaptation” OR “postoperative sensitivity” OR “secondary caries”
#3 (Dentistry Context)“dentistry” OR “restorative dentistry” OR “dental restoration” OR “dental filling”
#4 (Combined)#1 AND #2 AND #3
Table 2. Characteristics of the studies included in the review.
Table 2. Characteristics of the studies included in the review.
Study (Author, Year)Study DesignSample Size/TeethMaterial (Bioactive Composite)ComparatorFollow-UpClinical Outcomes ReportedKey Findings
Van Dijken, 2018 [19]RCTn = 82/group (n = 164), Class I/IIActiva BioACTIVENanofilled resin composite (CeramX)baseline, 6, 12 monthsRetention, postoperative symptoms, secondary cariesActiva BioACTIVE in Class II without adhesive pretreatment had very high failure.
Bhadra, 2019 [20]RCTn = 30/group (n = 60), Class II, permanent molarsActiva BioACTIVENanohybrid composite1 week, 6 months, 1 yearSurvival, marginal adaptationBoth materials successful with acceptable performance at 1-year follow-up.
Türkoğlu, 2020 [21]One-blind clinical trialn = 50/group (n = 300) NCCLs, anterior/posteriorGiomer; CompomerFiltek Ultimate1 week, 3 months, 6 months, 9 months, 12 monthsRetention, secondary caries, anatomic form, surface texture, marginal adaptation/discoloration, color matchGiomer, flowable giomer, and compomer showed unsatisfactory retention but similar other outcomes.
Kang YH, 2021 [22]RCT, split-mouthn = 50/group (n = 98), Class VGiomerNanohybrid composite6 months, 18 monthsSurvival, marginal adaptationSimilar performance; no significant differences.
Eissa, 2021 [23]Split-mouth clinical trialn = 25/group (n = 50), Class II, posteriorActiva BioACTIVEBulk-fill glass hybrid restorativebaseline, 6 months, 12 monthsSurvival, esthetics, wearActiva BioACTIVE higher esthetics and wear resistance; Equia Forte suitable as semi-permanent.
Yehia, 2022 [24]RCTn = 18/group (n = 36), Class V, anterior/premolarActiva BioACTIVERMGI (Fuji II LC)1 week, 6 months, 12 monthsSurvival, estheticsSuitable as interim restorations; bioactive composite maintained esthetics.
Abdel-Fattah, 2022 [25]RCTn = 15/group (n = 45), Class I, upper/lower molarsActiva BioACTIVE; Bulk-Fill AlkasiteNano-ionomer (Ketac Nano)1 yearFunctional properties, fracture, retention, marginal adaptationAll materials had acceptable clinical performance.
Costachel, 2023 [26]Comparative studyn = 53/group (n = 219), abfraction lesionsGiomerGIC-Fuji bulk, Omnichroma Flowbaseline, 2 months, 6 months, 12 months, 18 months, 24 monthsColor match, marginal discoloration, surface texture, contour, secondary caries, retentionAll materials showed good clinical behavior regardless of additional therapy.
Sharma, 2023 [27]RCTn = 29/group (n = 59), Class I, first permanent molarsBulk-Fill AlkasiteNanohybrid composite1 yearSurvival, marginal adaptationSimilar clinical success; Alkasite viable for occlusal caries.
Oz, 2023 [28]RCTn = 50/group (n = 100), Class II, posteriorBulk-Fill AlkasiteConventional composite (G-ænial Posterior)1 week, 6 months, 12 monthsSurvival, marginal adaptationSimilar clinical success for both materials.
Toz-Akalin, 2024 [29]RCTn = 35/group (n = 70), Class I/II, premolars/molarsLow-shrinkage GiomerNanohybrid composite2 weeks, 6 months, 1 year, 2 years, 3 yearsSurvival, marginal adaptation, surface integritySimilar performance; minor surface deterioration at 3 years.
Al Salamony, 2024 [7]RCTn = 14/group (n = 28), Class V, anterior/premolarBulk-Fill AlkasiteFuji II LC1 week, 6 months, 12 monthsSurvival, marginal integrity, anatomic formAlkasite slightly better marginal integrity; promising alternative.
Bepu, 2024 [30]RCT, pilotn = 15/group (n = 30), Class I/II, first/second molarsAlkasiteBulk-fill composite1 week, 6 months, 17 monthsSurvival, marginal adaptation, wear, color matchGreater anatomical wear and slight color mismatch; acceptable after 17 mo.
El Deriny, 2024 [31]RCTn = 13/group (n = 26), Class I/II, posteriorGiomerNanohybrid compositebaseline, 6 months, 12 months, 18 monthsSurvival, marginal adaptationSimilar clinical performance at 18 months.
El-Gaaly, 2024 [32]RCTn = 17/group (n = 34), Class V, anterior/premolarActiva PrestoFuji II LCbaseline, 6 months, 12 monthsSurvival, marginal adaptation, gingival responseSlight gingival inflammation and color mismatch; overall acceptable.
El-Sayed, 2024 [33]RCTn = 15/group (n = 45), Class II, posteriorActiva Presto; GiomerNanoceramic compositebaseline, 1 month, 3 months, 6 months, 12 monthsSurvival, marginal adaptation, estheticsComparable mechanical properties; Activa Presto slightly inferior esthetics.
Tian, 2024 [34]Double-blinded CTn = 54/group (n = 108), Class I/II, premolar/molarGiomerNanohybrid composite6 months, 18 months, 4 years, 8 yearsSurvival, marginal adaptationSimilar long-term clinical results.
El Ghamrawy, 2025 [35]RCTn = 28/group (n = 56), Class V, maxillary anteriorLow-shrinkage GiomerFuji II LCbaseline, 6 months, 12 monthsSurvival, marginal adaptation, estheticsLow-shrinkage giomer promoted bioactivity, high integrity, excellent esthetics.
El Salamouny, 2025 [8]RCTn = 12/group (n = 36), Class I, posteriorAlkasite with/without adhesiveBulk-fill compositebaseline, 3 months, 6 months, 12 monthsSurvival, marginal staining, postoperative sensitivitySlightly inferior outcomes without adhesive; overall similar performance.
Hendam, 2025 [36]RCTn = 15/group (n = 30), Class VGiomer injectable resinRMGI (Fuji II LC)baseline, 6 months, 12 months, 18 monthsSurvival, marginal adaptation, functional/estheticSimilar clinical properties over 18 months.
El-Shazly, 2025 [37]RCT, split-mouthn = 27/group (n = 54), Class V, incisors/premolars/molarsSelf-adhesive bulk-fill compositeConventional compositebaseline, 6 months, 12 monthsSurvival, marginal integrity, color match, surface roughness, secondary cariesComparable overall performance; Neo-Spectra higher marginal integrity and color match.
Refai, 2025 [38]Clinical trialn = 18/group (n = 54), Class I, posteriorBulk-Fill AlkasiteZirconomer; Bulk-fill glass hybridbaseline, 6 months, 12 monthsSurvival, marginal adaptation, functional/estheticCention N superior, followed by Equia Forte and Zirconomer; all satisfactory.
Table 3. GRADE Summary of evidence for randomized controlled trials evaluating bioactive composite resins.
Table 3. GRADE Summary of evidence for randomized controlled trials evaluating bioactive composite resins.
Clinical OutcomeNo. of Studies (Restorations)Study DesignRisk of BiasInconsistencyIndirectnessImprecisionPublication BiasOverall Certainty of Evidence (GRADE)
Restoration survival/retention (6–36 months)21 (~1483)RCTNot seriousNot seriousNot seriousSerious aNot serious⊕⊕⊕⊝ Moderate
Marginal adaptation (USPHS/FDI; acceptable vs. unacceptable)15 (~1115)RCTNot seriousNot seriousNot seriousSerious aNot serious⊕⊕⊕⊝ Moderate
Secondary caries incidence3 (~518) RCTNot seriousNot seriousNot seriousVery serious bNot serious⊕⊕⊝⊝ Low
Postoperative sensitivity3 (~254) RCTNot seriousNot seriousPossibly serious cSerious aNot serious⊕⊕⊝⊝ Low
Color match/esthetic outcomes9 (~655) RCTNot seriousSeriousNot seriousSerious aNot serious⊕⊕⊝⊝ Low
a Serious imprecision: Total sample sizes were modest, and number of clinical events limited; confidence intervals compatible with both no effect and clinically meaningful benefit or harm. b Very serious imprecision: Secondary caries events were infrequent, leading to wide plausible effect ranges and high uncertainty. c Possible indirectness: Variability in definitions and assessment methods across studies; postoperative sensitivity not always a prespecified primary outcome.
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Holiel, A.A.; M. Al Nakouzi, M.; Bourgi, R.; Cuevas-Suárez, C.E.; Olivares Acosta, I.; Hardan, L.; Kharouf, N.; Haikel, Y. A Systematic Review and Meta-Analysis on the Clinical Performance and Longevity of Bioactive Composite Resin Restorations. J. Compos. Sci. 2026, 10, 39. https://doi.org/10.3390/jcs10010039

AMA Style

Holiel AA, M. Al Nakouzi M, Bourgi R, Cuevas-Suárez CE, Olivares Acosta I, Hardan L, Kharouf N, Haikel Y. A Systematic Review and Meta-Analysis on the Clinical Performance and Longevity of Bioactive Composite Resin Restorations. Journal of Composites Science. 2026; 10(1):39. https://doi.org/10.3390/jcs10010039

Chicago/Turabian Style

Holiel, Ahmed A., Mounir M. Al Nakouzi, Rim Bourgi, Carlos Enrique Cuevas-Suárez, Iván Olivares Acosta, Louis Hardan, Naji Kharouf, and Youssef Haikel. 2026. "A Systematic Review and Meta-Analysis on the Clinical Performance and Longevity of Bioactive Composite Resin Restorations" Journal of Composites Science 10, no. 1: 39. https://doi.org/10.3390/jcs10010039

APA Style

Holiel, A. A., M. Al Nakouzi, M., Bourgi, R., Cuevas-Suárez, C. E., Olivares Acosta, I., Hardan, L., Kharouf, N., & Haikel, Y. (2026). A Systematic Review and Meta-Analysis on the Clinical Performance and Longevity of Bioactive Composite Resin Restorations. Journal of Composites Science, 10(1), 39. https://doi.org/10.3390/jcs10010039

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