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Push‐out bond strength of the calcium silicate‐based endodontic cements in the presence of blood: A systematic review and meta‐analysis of in vitro studies

Abstract Objectives The push‐out bond strength (POBS) of calcium silicate‐based cements (CSCs) to the dentinal wall is considered one of the essential physical properties for clinical success. The presence of blood in the treatment area affects the POBS of these types of cement. This study aimed to evaluate the impact of blood contamination on the bond strength of CSCs and dentinal walls. Material and Methods This systematic review was performed by searching electronic databases (MEDLINE‐PubMed, Scopus, and EMBASE) to include relevant in vitro studies published between 1992 and April 2020. Two reviewers independently evaluated the selected studies and extracted data on the type of studied CSCs, evaluated area of the teeth, sample size, the dimension of a prepared area, slice thickness, storage duration, the setting of the universal testing machine (UTM), effects of blood contamination on POBS of CSCs and their failure modes. The bond strength of evaluated CSCs in studies was used for network meta‐analysis. Results Initial searches identified 292 articles, while only 13 articles met the inclusion criteria. Full texts of these articles were evaluated, and data extraction was performed. The effect of blood contamination on bond strength to the dentinal wall was assessed in various CSCs such as PMTA, Biodentine, and AMTA. The network meta‐analysis results showed that the bond strength of Biodentine was significantly higher than other types of cement in blood presence (p < .05). Conclusions Based on the current systematic review, despite controversies among the result of the different articles and the lack of data for some CSCs like bioaggregate, it could be concluded that the bond strength of Biodentine to the dentinal wall is better than other evaluated CSCs in the presence of blood.


| INTRODUCTION
Root perforations due to iatrogenic or non-iatrogenic causes are among the most common reasons for endodontic failures, with a 9.6% prevalence. These perforations cause the artificial connection between root canal space and periodontium or oral cavity (Bhagya et al., 2018;Mente et al., 2010;VanderWeele et al., 2006).
Considering the connection area, blood and/or saliva could incorporate with root perforation repair materials. Root perforation repair materials should be biocompatible, dimensionally stable, radiopaque, insoluble in the presence of tissue fluids, provide an appropriate seal, and adapt with surrounding dentinal walls (Mente et al., 2010;Saeed Rahimi et al., 2013;Shalan, 2012). In the past, indium foil, gutta-percha, amalgam, zinc oxide, glass ionomers, and calcium hydroxide were used for the perforation treatment (Bhagya et al., 2018;Mente et al., 2010). However, nowadays, calcium silicate-based cements (CSCs) have been used in these cases due to more reported clinical successes (Chan et al., 2020). Mineral Trioxide aggregate is the first generation of CSCs developed more than 25 years ago. The wide range of calcium silicate-based biomaterials used in the endodontic field. These biomaterials could induce mineralization at the dentine interface in the presence of moisture such as blood and saliva.
Over time, various components are added to these biomaterials to improve their physical and clinical properties, such as setting time (Almeida et al., 2014;Chan et al., 2020;Salem Milani et al., 2013).
These materials are often compared with MTA, the most common biomaterial in endodontic, because of its remarkable bond strength with the dentin (Parirokh & Torabinejad, 2010).
During root perforation treatment, CSCs directly contact or mix with blood. This blood contamination has detrimental effects on the physical properties of CSCs. Proper bond strength to dentin is one of the most prominent physical properties, which was considered in evaluating the successful clinical use of endodontic biomaterials ). An ideal root perforation repairing material should not be affected by blood contamination. In addition, this material should remain in place under dislodging forces applied during restorative procedures and functional.
Therefore, many studies focus on the bond strength of these materials in the presence of blood for clinical application (Lotfi et al., 2014;Ratih & Putri, 2017;VanderWeele et al., 2006).
In other words, these biomaterials should keep their proper bonding to the dentinal walls and not displace for providing a proper seal. Biomaterials bond strength with dentin is considered essential criteria for sufficient sealing ability. Insufficient seal causes the leakage of the bacteria and their products, which could lead to treatment failure (Akcay et al., 2016;Lotfi et al., 2013;Roberts et al., 2008).
The push-out test is a standard method for assessing the bond strength. This test measures the interfacial shear strength between two surfaces and shows their adhesive properties and resistance to dislodgement (Collares et al., 2016).
Despite several studies conducted on the effects of blood contamination on the push-out bond strength of CSCs, this systematic review was undertaken to provide comprehensive information about the impact of blood contamination on bond strength between CSCs and dentinal walls.

| Study selection and eligibility criteria
The duplicated data from the three databases were removed. The abstract of all published articles was reviewed and presented as a flowchart. Two reviewers independently evaluated the titles and abstracts of all articles against the below inclusion and exclusion criteria.

Inclusion criteria:
− Abstract and full text available in English.
− In vitro studies, which evaluated push out bond strength of at least one CSC to the dentinal wall in the presence of blood.

| Risk of bias assessment
The risk of bias assessment was performed based on previous ). The quality assessment of studies was based on the following parameters: sample size calculation, standardization of specimens, randomization, blinding to experimental protocols, standardization of preparation protocol, and data reporting. The items were classified with a low risk of bias when there was no ambiguity. The Moderate risk of bias was used when one of the items was eliminated or indicated ambiguously. The lack of two or more than two items was demonstrated high risks of bias. Also, the statements in the manuscripts were noted in the results.

| Data extraction
EndNoteX9 (Bld 13682) was used to manage references and results. The full text of selected articles was purchased, and data were evaluated by two reviewers and extracted regarding the following data: Name of the author/year of publication, number of samples, type of CSCs, anatomical location of samples, the diameter of the canal or perforated area, sample thickness, diameter and speed of the force rod, incubation time, number of samples per group, removal or non-removal of the smear layer (Table 1), failure mode and the result of the articles due to significant effect of blood contamination on bond strength (Table 2). Moreover, the amounts of bond strength in MPa were extracted from articles for metaanalysis. Requests for data not demonstrated in published articles were sent to the corresponding author three times. If no answer was received, the study was excluded from the analysis.

| Statistical analysis
Studies that reported mean ± SD of push-out bond strength in MPa were evaluated using network meta-analysis. The amounts of bond strengths were considered by GeMTC. The random-effects model was used for Network Meta-Analysis and comparison of bond strength of different CSCs. For each type of cement, a forest plot was used for the graphical representation of the results. The level of confidence interval (CI) was 95%.

| Search results
The initial search results from each database and progression through the search are demonstrated in Figure 1.
Finally, thirteen studies fulfilled the inclusion criteria and were evaluated and reviewed independently by two authors.

| Risk of bias assessment
The quality assessment of manuscripts was demonstrated in Table 1. The risk of bias was high in all of the manuscripts for sample size calculation and blinding because of the lack of details.
None of the evaluated studies used the randomization assignment tool. Only two studies demonstrated disc preparation with a single operator and blood withdrawn procedures (Adl et al., 2019;VanderWeele et al., 2006). The risk of bias assessment for data reporting showed the lack of bond failure results in the Bhagya et al. study despite descriptions in the methods and materials (Bhagya et al., 2018).

| Type of CSCs
ProRoot MTA (PMTA), Biodentine, MTA Angelus, and CEM cement were the most evaluated CSCs in studies, respectively. Moreover, the bond strength of some of the new types of CSCs (EndoSeal MTA, Supra MTA, and MTA Plus) to the dentinal wall was evaluated in three studies (Adl et al., 2019;Aggarwal et al., 2013;Üstün et al., 2015). However, there was a lack of some CSCs such as Bioaggregate in these studies.

| Evaluated area
Furcation perforation in molars was the most evaluated area due to the high prevalence of perforation in this region during root canal treatments or post-space preparation (Arens & Torabinejad, 1996).
Apical root slices were filled with CSCs as root-end filling material in two studies to stimulate apicoectomy clinical situations in the blood presentation (Akcay et al., 2016;Shalabi et al., 2019).

| Sample size
None of the evaluated studies demonstrate sample size calculations clearly. The evaluated dentin slices in each group ranged between five (Ratih & Putri, 2017)
The slice thickness ranged between 1 and 3 mm in reviewed studies.
Only two studies did not mention both the dimension of the prepared area and slice thickness (Aggarwal et al., 2013;Singla et al., 2018).
The incubation duration of samples differed from 1 day to 30 days.
The major reviewed articles evaluated the bond strength at different periods. Most of these studies reported significant increases in bond strength of CSCs by time passing (Adl et al., 2016;Aggarwal et al., 2013;Marquezan et al., 2018;Rahimi et al., 2013;VanderWeele et al., 2006).

| The setting of UTM
Only three studies did not mention the plunger dimension (Bhagya et al., 2018;Singla et al., 2018;VanderWeele et al., 2006). The plunger dimension ranged between 0.5 and 1.5 mm, and the range of load velocity was between 0.2 and 1 mm/min.
Nine studies evaluated the bond strength of Biodentine to the dentinal wall after blood exposure. In three studies, bond strength was notably increased after blood contamination (Shalabi et al., 2019;Singla et al., 2018;Yazdi et al., 2017); while four studies did not report any significant differences before and after blood exposure F I G U R E 1 Flow chart of study selection F I G U R E 2 Forest plots depicting the mean difference (MD) and its 95% confidence interval for comparison types of CSCs. CSC, calcium silicate-based cement Üstün et al., 2015). In spite of these manuscripts, two studies reported the adverse effects of blood contamination on the bond strength of Biodentine (Adl et al., 2019;Akcay et al., 2016).
Among three studies that evaluated bond strength of AMTA, one study indicated notable decreases in bond strength (Singla et al., 2018); while Adl et al. (Adl et al., 2016) and Marquezan et al. (Marquezan et al., 2018) studies reported not significant and increased bond strength of AMTA after blood contamination, respectively.
Comparison of the bond strength of CEM cement after blood contamination was evaluated in three studies, and the results reported incompatible data as well as AMTA (Adl et al., 2016;Saeed Rahimi et al., 2013;Yazdi et al., 2017).
The bond strength of three new CSCs (Retro MTA, Supra MTA, and EndoSeal MTA) to the dentinal wall was evaluated in studies and compared with traditional CSCs. All of these types of cement were not reported any differences in their bond strength before and after blood exposure (Adl et al., 2019;Üstün et al., 2015).

| Failure modes
Nine studies determined the failure modes among 13 reviewed articles. Only four studies reported failure modes before and after blood contamination (Adl et al., 2019;Marquezan et al., 2018;Shalabi et al., 2019;Üstün et al., 2015). The differences in failure mode pattern before and after blood exposure were only reported in two studies for Biodentine (Marquezan et al., 2018;Shalabi et al., 2019).
One study mainly showed adhesive failure mode for Biodentine after blood contamination (Shalabi et al., 2019); while the other reported mainly mixed failure mode (Marquezan et al., 2018). However, the primary failure mode for Biodentine in the absence of blood contamination was cohesive in both studies.

| Meta-analysis
The bond strength of evaluated CSCs in blood presence was extracted, and network meta-analysis was performed on the data. The network meta-analysis results and comparison between endodontic cements were represented by the forest plot diagram in Figure 2.
Based on these results, the bond strength of Biodentine in blood presence was better than other cements. The mean difference be- close contact between the material and the dentinal wall, which determined sealing ability and resistance against occlusal forces and mechanical forces of condensation of restorative materials (Adl et al., 2019;Lotfi et al., 2013;Samiei et al., 2017). CSCs increasingly were used in endodontics for vital pulp treatment, apicoectomy, and perforation treatment. Contamination with blood occurs during most of these procedures, and CSCs are applied in the presence of blood.
Therefore, the properties of these materials should not be affected after exposure to the blood (Prati & Gandolfi, 2015;Singla et al., 2018). Remaining in place and providing appropriate bonds with surrounding dentin in the presence of blood is necessary for successful clinical outcomes. Different studies have been evaluating the bond strength of CSCs since introducing MTA as the first member of these types of cement (Han et al., 2015;Sluyk et al., 1998).
However, few studies simulated the clinical situation in laboratory studies and evaluated the effects of blood contamination on the dislocation resistance between dentin and CSCs. After reviewing these manuscripts, the controversy in the results of these articles was identified. Moreover, significant amounts of variation in the test setup and conduction were observed. The unheterogeneity in the evaluated area and sample preparation could cause these controversies.
PMTA was the most common material in reviewed studies, which have been evaluated since 2006 in VanderWeele et al.'s study (VanderWeele et al., 2006). In most of the studies, the bond strength of this cement to the dentinal wall decreased in the presence of blood.
However, the results of the three studies were in contrast to those manuscripts (Bhagya et al., 2018;Üstün et al., 2015;Yazdi et al., 2017).
The differences in evaluated area, sample size, sample preparation protocols, and even setting of UTM were shown in these studies.
Biodentine is another CSCs, which showed greater bond strength compared with MTA in most studies (Akcay et al., 2016;Bhagya et al., 2018;EL-Ma'aita et al., 2013;Elnaghy, 2014;Guneser et al., 2013;Marquezan et al., 2018;Yazdi et al., 2017). Moreover, it seems that the bond strength of Biodentine is not affected by acidic PH and blood contamination (Aggarwal et al., 2013;Marquezan et al., 2018;Singla et al., 2018;Üstün et al., 2015). However, two studies showed a reduction in bond strength of this cement after exposure to blood. The results of this evaluation for three studies, which used CEM cement, are contradictory. This contradiction could happen due to different evaluating areas and incubation periods in these studies. The bond strength of three new CSCs was evaluated and compared with traditional CSCs. The results of these studies reported no differences in bond strength of these types of cement before and after exposure to the blood (Adl et al., 2019;Akcay et al., 2016).
The network meta-analysis results confirmed the better bond strength of Biodentine compared to other ones. Based on this systematic review and network meta-analysis, the authors suggested that Biodentine has reported a better bond than CSCs; therefore, it could be more appropriate in apicoectomy and perforation treatments. Furthermore, the new CSCs should be evaluated in future studies.

| CONCLUSION
Based on the results of this systematic review, despite controversies among the result of the different manuscripts and the lack of data for some CSCs like Bioaggregate, the bond strength of Biodentine to the dentinal wall is higher than other CSCs. Therefore, Biodentine may be advantageous, especially for challenging clinical endodontic treatments such as apicoectomy and perforations in the presence of excessive blood.

ACKNOWLEDGMENT
The authors thankfully acknowledge The Dental and Periodontal Research Center of Tabriz University of Medical Sciences. This research received no funding.

CONFLICTS OF INTEREST
The authors declare no conflicts of interests.

AUTHOR CONTRIBUTIONS
Writing-original draft preparation, conceptualization, methodology, data extraction: Mahdieh Alipour. Meta-analysis and methodology: Leili Faraji Gavgani. Conceptualization, supervision, review, and editing: Negin Ghasemi. All authors have read and agreed to the published version of the manuscript.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created, and all analyses were reported in this study.