1. Introduction
Within the field of biomedical therapeutics, we can highlight the concept of tissue engineering to refer to the development of procedures and biomaterials that aim to devise new tissues to replace those damaged, following the principles of cellular and molecular biology and taking as a premise the search for “biological solutions for biological problems” [1].
In 2007, the American Association of Endodontists adopted the term “regenerative endodontics” to refer to the concept of tissue engineering applied to the restoration of root canal health, in a way that continuous development of the root and tissues surrounding it is promoted [2].
The introduction of the so-called bioceramic materials meant a great advance for this new paradigm in endodontic therapy [3], given their biocompatible nature and excellent physicochemical properties [4]. Categorized as bioinert, bioactive and biodegradable [5], dentistry-applied bioceramic materials are ceramic materials which share a common characteristic of being specifically designed to fulfil their function; they are able to act as root canal sealers, cements, root repair or filling materials [4]. Applied to vital pulp therapy, bioceramic materials can be used in cases of pulp exposition from trauma, caries or other mechanical causes, as direct pulp cappers [6].
Properties like biocompatibility and bioactivity are to be expected in dentistry-applied bioceramic materials for their use in vital pulp therapy [7]. The first one refers to the “ability to perform as a substrate that will support the appropriate cellular activity, including the facilitation of molecular and mechanical signaling systems, in order to optimize tissue regeneration, without eliciting any undesirable local or systemic responses in the eventual host” [8], while bioactivity goes even further, and is only attributed to those materials which are capable of inducing a desired tissue response from the host [9] by the use of biomimetic approaches [10]. The term differs depending on the field in which it is implemented, being related to the cellular effects induced by biologically active ions and substances released from biomaterials in the field of tissue engineering, but referred to as the biomaterial’s capability of forming hydroxyl apatite mineral on its surface both in vitro and in vivo in the field of biomaterial science [11].
Considering these desirable characteristics of bioceramic materials, it seems convenient to analyze the interaction between human dental pulp stem cells (hDPSCs), which are post-natal stem cells with mesenchymal stem cell (MSCs)-like characteristics, like auto-renewal ability and multilineage differentiation potential [12], and them; as their combined use could mean and advancement in the field of regenerative endodontics.
Cytotoxicity and biocompatibility of a wide range of bioceramic materials towards dental stem cells (DSCs) have been investigated in numerous studies [13,14,15,16,17]; among others. The well-known Pro-Root MTA (Dentsply Tulsa Dental Specialties, Tulsa, OK, USA) has been shown to increase osteoblast, fibroblast, cementoblast, odontoblast and pulp cell differentiation, but its handling difficulty among other limitations encourages for a search for alternative materials [13]. Materials like Biodentine (Septodont, Saint Maurdes-Fosses, France) and TheraCal LC (Bisco Inc., Schaumburg, IL, USA) are examples of bioceramic materials introduced posteriorly in dentistry for their use in vital pulp therapy as blood clot protectors in pulpal revascularization procedures, standing out for their consistency, easier manipulation and tricalcium silicate composition [16].
However, to the best of the authors’ knowledge, there has been no effort to sort and summarize studies analyzing bioactivity of such materials into more homogenous subgroups that would allow for an easier analysis of the evidence.
The aim of this study is to present a systematic review of available literature investigating bioactivity of dentistry-applied bioceramic materials towards dental pulp stem cells; including a bibliometric analysis of such group of studies and a presentation of the parameters used to assess bioactivity, materials studied and summary of results.
2. Materials and Methods
This systematic review was conducted in accordance with the PRISMA guidelines or preferred reporting items for systematic reviews and meta-analyses [18]. Our review was not eligible for registration with PROSPERO, as it did not involve health studies in which participants were people nor animal research studies exclusively.
In terms of the research question, based on the PICO model, our review aimed to assess the current knowledge on dentistry-based bioceramic materials by exploring to what extent they express bioactive properties in in vitro assays and animal studies when exposed to dental pulp stem cells, as opposed to a control or compared to different bioceramic material compositions, for their use in the dentin-pulp complex therapy.
2.1. Inclusion and Exclusion Criteria
Studies assessing bioactivity of one or more bioceramic materials (both commercially available or novel/experimental) towards DPSCs were included in our review. We established bioactivity assessment as any test or measurement for odontogenic, osteogenic, angiogenic and/or mineralization potential of DPSCs exposed both directly or indirectly to bioceramic materials. Studies assessing cytotoxicity and/or biocompatibility alone i.e., cell viability or proliferation were excluded. Studies assessing any other type of stem cell apart from DPSCs were also excluded.
The series of inclusion and exclusion criteria were established by a consensus reached from all authors after discussion, considering the research question and the objectives of the study while aiming for an ample range of results to be provided from the search.
2.2. Search Strategy
2.2.1. Sources of Information
To identify potentially relevant studies, a thorough electronic search was made in PubMed, Web of Science, Scopus, Embase, Cochrane, and Lilacs databases. Study search was performed during October, November and December 2018. In particular cases, the authors of the articles were contacted by email to request missing information. The structured search strategy and data extraction were conducted by an individual examiner.
2.2.2. Search Terms
The search strategy included 6 Mesh (Medical Subject Heading) terms: “Silicate”, “Calcium Silicate”, “Calcium phosphate”, “Calcium aluminosilicate”, “Hydroxyapatite” and “Gene Expression”; and 13 uncontrolled descriptors: “Bioceramic”, “Bioceramics”, “Bioactivity”, “Bioactive”, “Mineralisation”, “Mineralization”, “Differentiation”, “Proliferation”, “Odontogenic”, “Osteogenic”, “Dentinogenic”, “Cementogenic” and “Dental Stem Cells”. Boolean operators (“OR” and “AND”) were used to join search terms related to the search question (Figure 1).
2.2.3. Study Selection
Articles identified using the search terms were exported to RefWorks (ProQuest, MI, USA) to check for duplicates. Once duplicates were discarded, a first screening of record titles and abstracts was carried out according to the previously described inclusion and exclusion criteria. Remaining studies were assessed for eligibility and qualitative synthesis by full-text screening.
2.2.4. Study Data
For the bibliometric analysis, the following variables were recorded for each article: author and year of publication, journal, country, and institution. For the synthesis of study methodology, a summary of the materials and methods of included studies was transcribed by listing the following variables: study type, bioceramic materials used, bioactivity analysis and duration of the analysis. For the synthesis of results, studies were categorized in terms of the significant results found, the duration in which these significant results were found, and their significance level.
2.3. Quality Assessment
The quality of the studies was assessed using a modified CONSORT checklist of items for reporting in vitro studies of dental materials [19] and the ARRIVE guidelines for reporting animal research [20].
3. Results
3.1. Study Selection and Flow Diagram
The search identified 1023 preliminary references related to the bioactivity of bioceramic materials towards dental stem cells, of which 355 were found in PubMed, 473 in Web of Science, 179 in Embase, 15 in Scopus, and 1 in Cochrane databases. Search made in LILACS produced no results. After excluding 203 duplicates, the remaining 820 were screened. Of these, 783 were excluded on reading the title and abstract as they did not fulfil our inclusion criteria. The resulting 37 articles were examined at full-text level, and all of them resulted to be eligible for our review (Figure 2).
3.2. Study Characteristics
3.2.1. Bibliometric Analysis
All corresponding authors of the included studies were associated with an academic institution or university. The distribution of included studies by year of publication, country, and journal is presented in Figure 3.
3.2.2. Bioactivity Analysis
A wide range of analyses of bioactivity were presented from the included studies. The most common analysis was the quantification of the expression of odontogenic, osteogenic and/or angiogenic markers or genes using reverse transcription polymerase reaction (RT-PCR), followed by alkaline phosphatase (ALP) enzyme activity assays and Alizarin Red Staining (ARS) to assess mineralization potential.
Other analyses include western blot, micro-computed tomography (micro-CT), scanning electron microscopy (SEM), attenuated total reflectance-Fourier transform infrared (ATR-FTIR), transmission electron microscopy (TEM), histological analysis, immuno-fluorescence, and immuno-histochemical assays. Bioactivity analyses alongside with their duration and a description of the study associated with them are presented in Table 1.
3.2.3. Study Type
Articles included fell into two main categories in terms of type of study: in vitro, or animal study. In some cases, articles presented both an in vitro and an animal study [26,27,37]. There were two studies which analyzed bioactivity of bioceramic materials towards hDPSCs ex vivo [33,42].
3.2.4. Cell Variant
All studies included used dental pulp stem cells (DPSCs) as their cell variant to assess bioceramic material bioactivity.
3.2.5. Bioceramic Materials Used
Bioceramic materials studied ranged from commercially available (Table 2) to novel or experimental materials (Table 3). A separate category was presented for bioceramic materials which were combined with an additive for their analysis (Table 4).
3.3. Quality Assessment
All in vitro studies analyzed using the modified CONSORT checklist [19] (Table 5) presented a structured abstract (item 1) and an introduction which provided information about the background of the bioceramic material and/or bioactivity analysis studied (item 2a). Within the introduction, the majority of studies presented clear objectives and hypotheses (item 2b). Description of methodology as well as of the variables studied was sufficiently clear to allow for replication in all studies (items 3 and 4), but none of them presented a detailed report of the calculation of sample size or random allocation sequence (items 5–9). All studies indicated the statistical method used (item 10), but presented significance level as p values, and not confidence intervals (item 11). Discussions generally included a brief synopsis of the key findings and comparisons with relevant findings from other published studies, but often failed to address the limitations of the studies, which we considered as a reason for non-fulfillment (item 12). Sources of funding (if any) were indicated in the majority of studies (item 13), and indications for access to full trial protocols were obviated in all studies (item 14).
Only three out of the five animal studies analyzed using the ARRIVE guidelines [20] (Table 6) were headed with a sufficiently descriptive title (item 1), but all of them provided a detailed abstract (item 2). All studies provided sufficient scientific background (item 3a) and established clear objectives (item 4) in the introduction, but failed to justify the use of the animal species studied to address the scientific objectives (item 3b). Ethical statements were clear in all studies (item 5), and study design, experimental procedures were detailed enough in all except one (items 6 and 7). Details about the experimental animals and how they were distributed in the study design were included in every study (items 8–11 and 14), but housing and husbandry information was obviated in all cases (item 9). Both experimental outcomes and statistical methods were described in all studies (items 12 and 13). All studies reported the results for each analysis carried out with a measure of precision (item 15), but all of them failed to report baseline data about health status of the animals studied and any adverse effects they could have suffered after the experiment (items 14 and 17). Lastly, items referring to the discussion were fulfilled by all studies (items 18–20).
3.4. Study Tesults
Significant results from included in vitro studies are presented in Table 7, Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, Table 14, Table 15, Table 16 and Table 17, and significant results from included animal research studies are presented in Table 18.
3.4.1. Results for RT-PCR Analysis
Results for bioactivity-related marker expression using RT-PCR comparing a bioceramic material with mineral trioxide aggregate (Nex MTA/PR-MTA/MTA) showed positive significant results for the studied bioceramic materials (Exp. PPL and BD, [22]; Nano-HA, [21]), or mixed results depending on the gene/marker studied (Quick-Set2, [31]) or the concentration of material used (iRoot BP, (56]) [Table 7).
All studies comparing a bioceramic material and an additive with the bioceramic material itself showed positive significant results for the bioceramic material in combination with the additive (GNP-CPC, [25]; SC + LLLI, [30]; CPC-BGN, [32]; hTDM/SC, [33]; MTA-CaCl2 and MTA-Na2HPO4, [46]), except for one case (MTA+UW/PG, [35]) in which the bioceramic material itself produced better results (Table 8).
The majority of studies comparing a bioceramic material and a control showed positive significant results for the bioceramic material (Gel-HA-TCP, [23]; Zn0/1/2/3, [28]; Quick-set2 and PR-MTA, [31]; MTA and BD, [34]; BD, [38]; MTA, [40]; MTA, [43]; MTA, [44]; MTA and Theracal, [49]; MTA and BD, [50]; CaSi-αTCP, [51]; CSP, [54]; Ca3SiO5, [57]), and the rest showed mixed results depending on de gene/marker studied (Exp. PPL, BD and Nex-MTA, [22]; HA-CPC, [26]; SC, [33]; CaP, [41]; FS and BD, [48]) (Table 9).
Studies comparing a bioceramic material and a non-bioceramic material did not show positive significant results for the bioceramic materials studied. One of the studies showed that DDM produced a greater bioactivity-related gene expression than HA-CPC [26]; and the other one showed mixed results for Ca3SiO3, which produced a greater expression of some markers but not others compared to Ca(OH)2 [57] (Table 10).
3.4.2. Results for ARS Staining
Results for ARS staining comparing a bioceramic material with mineral trioxide aggregate (MTA, PR-MTA) showed negative significant results for the studied bioceramic materials (Quick-Set2, [31]; Theracal, [49]) (Table 11).
Both studies comparing a bioceramic material and an additive with the bioceramic material itself showed positive significant results for the bioceramic material in combination with the additive (γION-CPC and αION-CPC, [24]; GNP-CPC, [25]) (Table 12).
All studies comparing a bioceramic material and a control showed positive significant results for the bioceramic materials studied (Gel-HA-TCP, [23]; Zn0/1/2/3, [28]; PR-MTA and Quick-Set2, [31]; BD, Theracal and MTA, [34]; BD, [38]; MTA, [40]; CaP, [41]; FS0.2, [48]; PR-MTA and Theracal, [49]; Ca3SiO5, [57]) (Table 13).
3.4.3. Results for ALP Activity
There was only one study comparing a bioceramic material with MTA in terms of ALP activity, and it produced negative results for the bioceramic material studied (Quick-Set2, [31]). The rest of the studies compared two different biomaterials or different concentrations of the same bioceramic material (Table 14).
All studies comparing a bioceramic material and an additive with the bioceramic material itself showed positive significant results for the bioceramic material in combination with the additive (γION-CPC and αION-CPC, [24]; GNP-CPC, [25]; CPC-BGN, [32]; MTA-CaCl2 and MTA-NA2HPO4, [46]), except for one (SC [30]) (Table 15).
The majority of studies comparing a bioceramic material and a control showed positive significant results for the bioceramic materials studied (Gel-HA-TCP, [23]; Zn0/1/2/3, [28]; PR-MTA and Quick-Set2, [31]; SC, [33]; BD, Theracal and MTA, [34]; BD, [38]; CaP, [41]; CSC, [47]; FS and BD [48]; CSP50/100/200, [54]; Ca3SiO5, [57]). One of them showed mixed results depending on the duration of exposure (MTA, [40]) and the remaining two studies showed negative significant results for the bioceramic materials studied (MTA, [36]; MTAP and MTAF, [52]) (Table 16).
3.4.4. Results for Other Bioactivity-Related Analyses
Western blot analyses showed mixed results for Zn0/1/2/3 compared to a control [28], and a higher expression of bioactivity-related markers by PR-MTA compared to Quick-Set2, and by both of them compared to a control [31]. ATR-FTIR showed positive results for PR-MTA compared to Quick-Set2, and for both of them compared to a control [31]. ELISA showed mixed results for MTA and CEM [39]. Assessment of the level of grey in mineralization nodules using Gene Tool showed positive significant results for PLGA/TCP compared to PLGA/HA and PLGA/CDHA [42]. Lastly, both the TRACP & ALP assay kit (Takahara, Shiga, Japan) and the OC and DSP emzyme-linked immunosorbent assay kit (Thermo Fisher Scientific, Waltham, MA, USA) showed that the addition of polydopamine to PR-MTA produced better results than PR-MTA itself.
4. Discussion
The attractiveness of bioceramic materials for their desirable properties added to their constant development, the demand for new advances and the ampliation of treatment indications results in an overflow of related literature over time. Therefore, it seems convenient to establish an updated and organized vision of the commercially available and experimental dentistry-applied bioceramic materials’ characteristics. With this in mind, the aim of this study was to present a systematic review of available literature investigating bioactivity of these materials towards dental pulp stem cells.
In terms of results, it can be highlighted that the most common method used to assess bioactivity in the included studies was the expression of bioactivity-related markers using reverse transcriptase polymerase chain reaction or RT-PCR. A recent systematic review illustrates this tendency by assessing gene expression of dental pulp cells in response to tricalcium silicate cements [58]. Studies also tended to compare new bioceramic materials with the established mineral trioxide aggregate or the more recently introduced Biodentine, as shown in Table 2, in which they appear as the most studied materials.
The use of additives in combination with bioceramic materials looks promising, in some cases enhancing or positively influencing the material’s results in bioactivity assays in comparison with the bioceramic material itself. For example, positive significant results have been shown for iron oxide [24], gold [25], and bioactive glass [32] nanoparticles in combination with calcium phosphate. However, we need to interpret these results with caution, being able to extrapolate them to clinical practice only when a clear dosage or ratio for the additive and bioceramic material has been established in controlled clinical trials.
New material compositions being studied also need to be taken into consideration for future investigations, as some of them have shown positive significant results in bioactivity assays. Novel materials like Exp. PPL [22], Gelatin-HA-TCP [23] and Zinc Bioglass (Zn0/1/2/3) [28] have all shown positive significant results for ARS staining and ALP activity assay compared to a control, and more specifically, Exp. PPL has shown a greater expression of DSPP and OCN compared to MTA and a control; Gelatin-HA-TCP has shown a greater expression of RUNX2, OSX and BSP compared to a control; and Zinc Bioglass (Zn0/1/2/3) has shown a greater expression of RUNX2, ON, CON, MEPE, BSP, and BMP-2 compared to a control. So again, in order to extrapolate these results to clinical practice, it would be interesting to carry out further studies investigating these biomaterials in different conditions.
When assessing quality and risk of bias, included studies referred a similar structural pattern. They reported essential data like a sufficient abstract, a clear objective or objectives, a detailed description of methodology, a mention of the statistical tests used and relevant conclusions; but often failed to justify the sample size used, to describe the randomization process used (if any), and most importantly to address the study’s limitations in the discussion. It may be worth noticing for future reviews that a checklist for reporting in vitro studies or “CRIS” guideline is under development [59] to address the need for uniform methodology in the assessment of this type of studies.
The introduction of new bioceramic materials and the use of additives in combination with them calls for updated research in the field. At the current state, bioactivity assessment of these materials towards dental pulp stem cells centers on in vitro assays or animal research at most. For future studies, it could be interesting to explore the mechanisms with which this bioactivity is achieved and move on towards in vivo trials.
5. Conclusions
Quantification of osteogenic, odontogenic and angiogenic markers using reverse transcriptase polymerase chain reaction or RT-PCR is the prevailing method used to evaluate bioceramic material bioactivity towards DPSCs in the current investigative state, followed by alkaline phosphatase (ALP) enzyme activity assays and Alizarin Red Staining (ARS) to assess mineralization potential. Mineral trioxide aggregate and Biodentine are the prevalent reference materials used to compare with newly introduced bioceramic materials. Available literature compares a wide range of bioceramic materials for bioactivity, consisting majorly of in vitro assays. The desirability of this property added to the rapid introduction of new material compositions makes this subject a clear candidate for future research.
Author Contributions
J.L.S. wrote the paper; L.F., C.L., F.J.R.-L. and S.S. supervised the content.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figures and Tables
Enlarge this image.Figure 3. Bibliometric Analysis: distribution of included studies by year of publication (A), country (B) and journal (C). Studies included in the category “other” only appear once for the given bibliometric parameter.
Summary of the methodology of included studies.
| Cell Variant | Study Type | Bioceramics Used | Author | Bioactivity Analysis * | Duration |
|---|---|---|---|---|---|
| hDPSCs | In vitro | MTA, Nano-HA | Hanafy et al. [21] | RT-PCR (Runx2, OCN, ALP, COL1α, OPN); | 21 days |
| ARS | 21 days | ||||
| hDPSCs | In vitro | Exp. PPL, BD, Nex-MTA | Pedano et al. [22] | RT-PCR (OCN, DSPP, ALP) | 4, 10 and 14 days |
| hDPSCs | In vitro | Gelatin-HA-TCP (10:1:1) | Gu et al. [23] | RT-PCR (Runx2, OSX, BSP); | 4, 7 and 14 days |
| ALP activity; | 4, 7 and 14 days | ||||
| ARS | 14 and 21 days | ||||
| hDPSCs | In vitro | aIONP-CPC, bIONP-CPC | Xia et al. [24] | RT-PCR (ALP, COL1α, Runx2, OCN); | 7 and 14 days |
| ALP activity; | 4, 7 and 14 days | ||||
| ARS | 7, 14 and 21 days | ||||
| hDPSCs | In vitro | GNP-CPC | Xia et al. [25] | RT-PCR (ALP, COL1α, Runx2); | 7 and 14 days |
| ALP activity; | 4, 7 and 14 days | ||||
| ARS | 4, 7, 14 and 21 days | ||||
| hDPCSs | In vitro, Animal | HA-TCP | Kyung-Jung et al. [26] | In vitro: RT-PCR (ALP, BSP, OPN, DMP-1, DSPP); | 10 days |
| In vivo: RT-PCR (BSP, OPN, ONT, OCN) | 8 weeks | ||||
| hDPSCs | In vitro, Animal | PCL-BCP | Wongsupa et al. [27] | RT-PCR (Runx2, ALP, OCN, DSPP); | 7, 14 and 21 days |
| Micro-CT; | 2, 4 and 8 weeks | ||||
| Histomorphometric analysis | 2, 4 and 8 weeks | ||||
| hDPSCs | In vitro | Zn0, Zn1, Zn2, Zn3 | Huang et al. [28] | Western blot (DSPP, DMP-1); | 7 and 14 days |
| RT-PCR (Runx2, OCN, BSP, BMP-2, MEPE, ON); | 7 and 14 days | ||||
| ALP activity; | 1, 4, 7 and 10 days | ||||
| ARS | 3, 4 and 5 weeks | ||||
| DPSCs | Animal | HA-TCP | Atalayin et al. [29] | RT-PCR (DSPP, DMP-1, MMP20, PHEX) | 6 and 12 weeks |
| hDPSCs | In vitro | SC | Theocharidou et al. [30] | RT-PCR (DSPP, BMP-2, Runx2, OSX); | 7 and 14 days |
| ALP activity; | 3, 7 and 14 days | ||||
| Mineralization analysis using SEM | 28 days | ||||
| hDPSCs | In vitro | Quick-Set2, PR-MTA | Niu et al. [31] | RT-PCR (Runx2, OSX, ALP, BSP, OCN, DMP-1, DSPP); | 1, 2 and 3 weeks |
| Western blot (DMP-1, DSPP, OCN); | 1, 2 and 3 weeks | ||||
| ALP activity; | 1, 2 and 3 weeks | ||||
| ARS; | 1, 2 and 3 weeks | ||||
| ATR-FTIR; | 1, 2 and 3 weeks | ||||
| TEM | 1, 2 and 3 weeks | ||||
| hDPSCs | In vitro | CPC-BGN | Lee SI et al. [32] | RT-PCR (DMP-1, DSPP, ALP, OPN, OCN, VEGF, (FGF)-2, (VEGFR)-2, VEGFR-1, (PECAM)-1, VE-cadherin; | 7 and 14 days |
| ALP activity; | 7 and 14 days | ||||
| ARS | N/S | ||||
| hDPSCs | In vitro, ex vivo | SC | Bakopoulou et al. [33] | RT-PCR (DSPP, BMP-2, Runx2, OSX, ALP, BGLAP); | 7 and 14 days |
| ALP activity; | 3, 7 and 14 days | ||||
| hDPSCs | In vitro | BD, TheraCal, MTA | Bortoluzzi et al. [34] | RT-PCR (ALP, OCN, BSP, Runx2, DSPP, DMP-1); | 7 days |
| ALP activity; | 14 days | ||||
| ARS | 14 days | ||||
| hDPSCs | In vitro | MTA+UW/PG | Natu et al. [35] | RT-PCR (ALP, OCN, Runx2, DSPP, MEPE); | 7 and 14 days |
| ARS | 7 and 14 days | ||||
| hDPSCs | In vitro | BD, PR-MTA | Widbiller et al. [36] | RT-PCR (COL1α, ALP, DSPP, Runx2); | 7, 14 and 21 days |
| ALP activity | 3, 7 and 14 days | ||||
| hDPSCs | In vitro, Animal | iRoot BP Plus, PR-MTA | Zhu et al. [37] | SEM; | 1, 3 and 7 days |
| ATR-FTIR; | 1, 3 and 7 days | ||||
| microCT; | - | ||||
| Histologic analysis; | - | ||||
| Double immunofluorescence | - | ||||
| hDPSCs | In vitro | BD | Luo et al. [38] | RT-PCR (OCN, DSPP, DMP1, BSP); | 14 days |
| ALP activity; | 1, 3, 7, 10 and 14 days | ||||
| ARS | 14 days | ||||
| hDPSCs | In vitro | PR-MTA, CEM | Asgary et al. [39] | RT-PCR (FGF4, BMP2, BMP4, TGF-β1, ALP, COL1, DSPP, DMP1); | 1, 3, 7 and 14 days |
| ELISA (FGF4, BMP2, BMP4, TGF-β1); | 1, 3, 7 and 14 days | ||||
| ARS | 14 days | ||||
| iDPSCs | In vitro | MTA | Wang et al. [40] | RT-PCR (ALP, Runx2, OSC, OCN, DSPP); | 3 and 7 days |
| ALP activity; | 3 and 5 days | ||||
| ARS | 14 days | ||||
| hDPSCs | In vitro | CaP granules | Nam et al. [41] | RT-PCR (DSPP, DMP1, COL1, OCN); | 7, 14 and 21 days |
| ALP activity; | 7, 14 and 21 days | ||||
| ARS; | 28 days | ||||
| Western blot | 21 days | ||||
| hDPSCs | In vitro, ex vivo | PLGA/HA, PLGA/CDHA, PLGA/TCP | Zheng et al. [42] | ALP activity; | N/S |
| Von Kossa staining and Gene Tool analysis | 4 and 5 weeks | ||||
| hDPSCs | In vitro | MTA | Zhao et al. [43] | RT-PCR (ALP, DSPP, COL1, OCN, BSP) | 6, 12, 24 and 48 h |
| hDPSCs | In vitro | PR-MTA | Paranjpe et al. [44] | RT-PCR (Runx2, OCN, ALP, DSP) | 1, 4 and 7 days |
| hDPSCs | In vitro | DA0, DA0.5, DA1 | Tu et al. [45] | TRACP & ALP assay kit (Takahara, Shiga, Japan); | 3 and 7 days |
| OC and DSP enzyme-linked immunosorbent assay kits (ThermoFisher Scientific) | 7 and 14 days | ||||
| hDPSCs | In vitro | PR-MTA, MTA-CaCl2, MTA-Na2HPO4 | Kulan et al. [46] | RT-PCR (DSPP, COL1); | 14 and 21 days |
| ALP activity; | 7 and 14 days | ||||
| Von Kossa staining | 21 days | ||||
| hDPSCs | In vitro | CSC | Xu et al. [47] | ALP activity | 10 days |
| hDPSCs | In vitro | iRoot FS, BD at 0.2 and 2 mg/mL | Sun et al. [48] | RT-PCR (COL1, OCN); | 1, 7 and 14 days |
| ALP activity; | 7 and 14 days | ||||
| ARS | 21 days | ||||
| hDPSCs | In vitro | TheraCal, PR-MTA | Lee BN et al. [49] | RT-PCR (DSPP, DMP1); | 1 and 3 days |
| ALP activity; | 7 days | ||||
| ARS | 14 days | ||||
| hDPSCs | In vitro, Animal | BD, MTA | Daltoé et al. [50] | RT-PCR (SPP1, IBSP, DSPP, ALPL, DMP1, Runx2); | 24 and 48 h |
| Immunohistochemical assays for OPN y ALP; | 120 days | ||||
| Indirect immunofluorescence for Runx2; | 120 days | ||||
| hDPSCs | In vitro | CaSi-αTCP, CaSi-DCPD | Gandolfi et al. [51] | RT-PCR (ALP, OCN) | 24 h |
| hDPSCs | In vitro | MTAP, MTAF | Mestieri et al. [52] | ALP activity | 1 and 3 days |
| hDPSCs | In vitro | BCP at a ratio of 20/80, 50/50 y 80/20 | AbdulQader et al. [53] | RT-PCR (COL1A1, BSP, DMP1, DSPP); | 14, 21 and 28 days |
| ALP activity; | 0–3, 3–6, 6–9, 9–12 and 12–15 days | ||||
| hDPSCs | In vitro | CSP | Zhang et al. [54] | RT-PCR (DMP1, DSPP, Runx2, OPN); | 3 and 10 days |
| ALP activity | 3 and 10 days | ||||
| hDPSCs | In vitro | CPC-N, CPC-M | Lee SY et al. [55] | RT-PCR (DMP1, DSPP, OCN, OPM, BSP); | 7 and 14 days |
| ALP activity | 7 and 14 days | ||||
| hDPSCs | In vitro | iRoot BP, MTA diluted at 1:1, 1:2 o 1:5 | Öncel Torun et al. [56] | RT-PCR (BMP, ON, BSP, OPN, DSPP, COL1A1, HO-1) | 24 and 72 h |
| hDPSCs | In vitro | Ca3SiO5 | Peng et al. [57] | RT-PCR (ALP, DSPP, DMP1, COL1, OC) | 4, 7 and 10 days |
| ALP activity; | 4, 7 and 10 days | ||||
| ARS | 30 days |
* Genes or markers studied in RT-PCR appear inside parentheses.
Table 2List of commercially available bioceramic materials studied.
| Material | Abbreviation | Manufacturer | Times Studied |
|---|---|---|---|
| Mineral Trioxide Aggregate | MTA | Angelus Dental Solutions, Londrina, PR, Brazil | 3 |
| Nano-hydroxiapatite | Nano-HA | Sigma-Aldrich, UK | 1 |
| Biodentine (tricalcium silicate) | BD | Septodont, Saint Maurdes-Fosses, France | 7 |
| Nex-Cem MTA | Nex MTA | GC, Tokyo, Japan | 1 |
| Hydroxiapatite-Tricalcium Phosphate | HA-TCP | OSSTEM Implant Co., Ltd., New Zealand | 1 |
| Zimmer, Warsaw, IN, USA | 1 | ||
| N/S | 1 | ||
| ProRoot Mineral Trioxide Aggregate | PR-MTA | Dentsply Tulsa Dental Specialties, Tulsa, OK, USA | 10 |
| Quick-Set2 | - | Primus Consulting, Bradenton, FL, USA | 1 |
| TheraCal LC | TheraCal | Bisco Inc., Schaumburg, IL, USA | 2 |
| iRoot BP Plus | - | Innovative Bioceramix, Vancouver, BC, Canada | 1 |
| Calcium-enriched mixture | CEM | BioniqueDent, Tehran, Iran | 1 |
| Hydroxyapatite | HA | N/S | 1 |
| iRoot Fast Set root repair material | FS | Innovative Bioceramix, Vancouver, BC, Canada | 1 |
| MTA Plus | MTAP | Avalon Biomed Inc., Bradenton, FL, USA | 1 |
| MTA Fillapex | MTAF | Angelus S/A, Londrina, PR, Brazil | 1 |
| FillCanal | FC | Technew, Rio de Janeiro, RJ, Brazil | 1 |
| iRoot BP | iRoot BP | Innovative Bioceramix, Vancouver, BC, Canada | 1 |
N/S: not specified.
Table 3List of experimental/novel bioceramic materials studied.
| Material | Abbreviation | Composition | Times Studied |
|---|---|---|---|
| Calcium-silicate cement containing phosphopullulan | Exp. PPL | 60% portland cement, 20% bismuth oxide, 5% calcium sulfate dehydrate, PPL (5%), other (10%) | 1 |
| Gelatin-hydroxyapatite-tricalcium phosphate scaffold | Gelatin-HA-TCP | Three types of powdered gelatin, HA and TCP at a ratio of 10:1:1 | 1 |
| Poly-ɛ-caprolactane–biphasic calcium phosphate | PCL-BCP | 80% poly-ɛ-caprolactane, 20% biphasic calcium phosphate | 1 |
| Zinc Bioglass | Zn0 | 38.5% SiO2, 26.2% Na2O, 29.0% CaO, 6.3% P2O5, 0% ZnO | 1 |
| Zn1 | 37.0% SiO2, 26.5% Na2O, 29.2% CaO, 6.3% P2O5, 1.0% ZnO | 1 | |
| Zn2 | 35.7% SiO2, 26.7% Na2O, 29.4% CaO, 6.2% P2O5, 2.0% ZnO | 1 | |
| Zn3 | 34.3% SiO2, 27.0% Na2O, 29.6% CaO, 6.1% P2O5, 3.0% ZnO | 1 | |
| Mg-based, Zn-doped bioceramic scaffolds | SC | 60% SiO2; 7.5% MgO; 30% CaO; 2.5% ZnO | 2 |
| Calcium phosphate porous granules | CaP granules | N/S | 1 |
| Gelatin-hydroxyapatite-tricalcium phosphate | Gelatin-HA-TCP | A mixture of 3 types of powdered gelatin, HA and TCP at a ratio of 10:1:1 was added to ultrapure water to form the scaffold | 1 |
| Calcium silicate | CaSi | Dicalcium silicate, tricalcium silicate, tricalcium aluminate, calcium sulfate | 1 |
| Calcium silicate-alpha tricalcium phosphate | CaSi-αTCP | Ca3(PO4)2 | 1 |
| Calcium silicate-dicalcium phosphate dihydrate | CaSi-DCPD | CaHPO4·2H2O | 1 |
| Hydroxyapatite-β-tricalcium phosphate | BCP | Ca5(PO4)3(OH)/ Ca3(PO4)2 at ratios of 20/80, 50/50 and 80/20 | 1 |
| Silicate based Ca7Si2P2O16 bioceramic extract | CSP | Ca7Si2P2O16 diluted at a 200, 100, 50 and 25 mg/mL | 1 |
| Calcium phosphate cements in the form of nano and microparticles | CPC-N, |
α-TCP | 1 |
| Tricalcium silicate | Ca3SiO5 | Ca3SiO5 | 1 |
List of bioceramic materials and additives studied.
| Material | Bioceramic Material Composition | Additive | Additive Composition | Abbreviation | Times Studied |
|---|---|---|---|---|---|
| Calcium phosphate cement | Tetracalcium phosphate Ca4(PO4)2O + dicalcium phosphate anhydrous (CaHPO4) | Iron oxide nanoparticles | Hematite, αFe2O3 | αIONP-CPC | 1 |
| Maghemite, βFe2O3 | βIONP-CPC | ||||
| Calcium phosphate cement | Tetracalcium phosphate Ca4(PO4)2O + dicalcium phosphate anhydrous (CaHPO4) | Gold nanoparticles | Gold (III) chloride trihydrate, sodium citrate tribasic dihydrate | GNP-CPC | 1 |
| Calcium phosphate | α-tricalcium phosphate (Ca3(PO4)2) | Bioactive glass nanoparticles | 85% SiO2, 15% CaO | CPC-BGN | 1 |
| Hydroxyapatite | Ca5(PO4)3(OH) | Poly(lactide-co-glycolide) | - | PLGA/HA | 1 |
| Hydroxiapatite-Calcium carbonate | CaCO3 + Ca5(PO4)3(OH) | Poly(lactide-co-glycolide) | - | PLGA/CDHA | 1 |
| Tricalcium phosphate | Ca3(PO4)2 | Poly(lactide-co-glycolide) | - | PLGA/TCP | 1 |
| Mg-based, Zn-doped bioceramic scaffolds | 60% SiO2; 7.5% MgO; 30% CaO; 2.5% ZnO | Low level laser irradiation | - | SC + LLLI | 1 |
| Premixed C3S/CaCl2 paste | C3S/CaCl2 | Polyethylene glycol | - | CSC | 1 |
| ProRoot MTA | - | Propylene glycol and ultrapure water | - | MTA + UW/PG | 1 |
| ProRoot MTA | - | Polydopamine | 0 mg/mL polydopamine | DA0 | 1 |
| 0.5 mg/mL polydopamine | DA0.5 | 1 | |||
| 1 mg/mL polydopamine | DA1 | 1 | |||
| ProRoot MTA | - | Calcium chloride | CaCl2 | MTA-CaCl2 | 1 |
| ProRoot MTA | - | Sodium phosphate dibasic | Na2HPO4 | MTA-Na2HPO4 | 1 |
Results of the assessment of in vitro studies by the use of the modified CONSORT checklist [19]. Cells marked with an asterisk “*” represent study fulfilment for the given quality assessment parameter. Cells left blank represent non-fulfilment.
| Studies | Modified CONSORT Checklist of Items for Reporting In Vitro Studies of Dental Materials | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2a | 2b | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | |
| Hanafy et al. [21] | * | * | * | * | * | * | |||||||||
| Pedano et al. [22] | * | * | * | * | * | * | * | ||||||||
| Gu et al. [23] | * | * | * | * | * | * | * | * | |||||||
| Xia et al. [24] | * | * | * | * | * | * | * | ||||||||
| Xia et al. [25] | * | * | * | * | * | * | * | * | |||||||
| Kyung-Jung et al. [26] | * | * | * | * | * | * | * | ||||||||
| Wongsupa et al. [27] | * | * | * | * | * | * | * | ||||||||
| Huang et al. [28] | * | * | * | * | * | ||||||||||
| Theocharidou et al. [30] | * | * | * | * | * | * | * | ||||||||
| Niu et al. [31] | * | * | * | * | * | * | * | * | |||||||
| Lee SI et al. [32] | * | * | * | * | * | * | |||||||||
| Bakopoulou et al. [33] | * | * | * | * | * | * | * | ||||||||
| Bortoluzzi et al. [34] | * | * | * | * | * | * | * | * | |||||||
| Natu et al. [35] | * | * | * | * | * | * | * | ||||||||
| Widbiller et al. [36] | * | * | * | * | * | * | * | ||||||||
| Zhu et al. [37] | * | * | * | * | * | * | * | ||||||||
| Luo et al. [38] | * | * | * | * | * | * | * | ||||||||
| Asgary et al. [39] | * | * | * | * | * | * | * | ||||||||
| Wang et al. [40] | * | * | * | * | * | * | * | ||||||||
| Nam et al. [41] | * | * | * | * | * | * | * | ||||||||
| Zheng et al. [42] | * | * | * | * | * | * | * | ||||||||
| Zhao et al. [43] | * | * | * | * | * | * | |||||||||
| Paranjpe et al. [44] | * | * | * | * | * | * | * | ||||||||
| Tu et al. [45] | * | * | * | * | * | * | * | * | |||||||
| Kulan et al. [46] | * | * | * | * | * | * | * | ||||||||
| Xu et al. [47] | * | * | * | * | * | * | * | ||||||||
| Sun et al. [48] | * | * | * | * | * | * | * | * | |||||||
| Lee BN et al. [49] | * | * | * | * | * | * | * | ||||||||
| Daltoé et al. [50] | * | * | * | * | * | * | * | ||||||||
| Gandolfi et al. [51] | * | * | * | * | * | * | * | ||||||||
| Mestieri et al. [52] | * | * | * | * | * | * | * | ||||||||
| AbdulQader et al. [53] | * | * | * | * | * | * | * | * | |||||||
| Zhang et al. [54] | * | * | * | * | * | * | * | ||||||||
| Lee SY et al. [55] | * | * | * | * | * | * | * | ||||||||
| Öncel Torun et al. [56] | * | * | * | * | * | * | |||||||||
| Peng et al. [57] | * | * | * | * | * | * | * | ||||||||
Results of the assessment of animal studies by the use of the ARRIVE guidelines [20].
| Studies | ARRIVE Checklist of Items for Reporting In Vivo Experiments (Animal Research) | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | |
| Kyung-Jung et al. [26] | * | * | * | * | * | * | * | * | * | * | * | * | * | * | * | * | ||||
| Wongsupa et al. [27] | * | * | * | * | * | * | * | * | * | * | * | * | * | * | * | * | * | * | ||
| Atalayin et al. [29] | * | * | * | * | * | * | * | * | * | * | * | * | * | * | * | |||||
| Zhu et al. [37] | * | * | * | * | * | * | * | * | * | * | * | * | * | * | * | |||||
| Daltoé et al. [50] | * | * | * | * | * | * | * | * | * | * | * | * | ||||||||
Summary of the results of included studies showing significant differences between various bioceramic materials or different concentrations of the same bioceramic material for osteogenic, odontogenic and/or angiogenic gene expression.
| Author | Bioceramics Used | Significant Results | Gene | Duration | Significance Level |
|---|---|---|---|---|---|
| Pedano et al. [22] | Exp. PPL, BD, Nex-MTA | Exp. PPL, Biodentine > Nex MTA | DSPP | 10 days | p < 0.05 |
| OCN | 14 days | p < 0.05 | |||
| Biodentine > Nex MTA | DSPP | 14 days | p < 0.05 | ||
| Xia et al. [24] | αIONP-CPC, βIONP-CPC | γION-CPC > αION-CPC | COL1α | 14 days | p < 0.05 |
| Hanafy et al. [21] | MTA, Nano-HA | Nano-HA > MTA | OPN, Runx2, OCN | 21 days | p < 0.05 |
| Niu et al. [31] | Quick-Set2, PR-MTA | Quick-Set2 > PR-MTA | Runx2 | 1 and 2 weeks | p < 0.001 |
| OSX | 2 and 3 weeks | p < 0.001 | |||
| ALP | 3 weeks | p < 0.001 | |||
| BSP | 3 weeks | p < 0.001 | |||
| PR-MTA > Quick-Set2 | ALP | 1 week | p < 0.001 | ||
| OCN | 1, 2 and 3 weeks | p < 0.001 | |||
| DMP-1 | 1, 2 and 3 weeks | p < 0.001 | |||
| DSPP | 2 and 3 weeks | p < 0.001 | |||
| Sun et al. [48] | iRoot FS, BD at 0.2 and 2 mg/mL | FS0.2 > BD0.2 > BD2 > FS2 | COL1 | 7 days | p < 0.05 |
| FS0.2 > FS2 > BD2, BD0.2 | OCN | 7 days | p < 0.05 | ||
| FS0.2 > BD0.2, BD2 > FS2 | COL1 | 14 days | p < 0.05 | ||
| FS0.2, FS2 > BD0.2, BD2 | OCN | 14 days | p < 0.05 | ||
| AbdulQader et al. [53] | BCP at a ratio of 20/80, 50/50 y 80/20 | BCP20 > BCP50-80 | DMP-1, DSPP | 14, 21 and 28 days | p < 0.05 |
| BSP | 21 and 28 days | p < 0.05 | |||
| BCP50 > BCP80 | BSP | 28 days | p < 0.05 | ||
| Öncel Torun et al. [56] | iRoot BP, MTA diluted at 1:1, 1:2 o 1:5 | 1:1MTA > 1:1iRoot BP | OPN, DSPP | 72 h | p < 0.05 |
| HO1, BMP2, BSP | 24 and 72 h | p < 0.05 | |||
| 1:1iRoot BP > 1:1 MTA | DSPP | 24 h | p < 0.05 | ||
| ON, COL1A1 | 24 and 72 h | p < 0.05 | |||
| 1:2MTA > 1:2iRoot BP | BMP2, ON, BSP | 72 h | p < 0.05 | ||
| HO1 | 24 and 72 h | p < 0.05 | |||
| 1:2iRoot BP > 1:2 MTA | OPN | 24 h | p < 0.05 | ||
| DSPP, COL1A1 | 72 h | p < 0.05 | |||
| 1:5MTA > 1:5iRoot BP | HO1, OPN, ON | 72 h | p < 0.05 | ||
| BMP2 | 24 and 72 h | p < 0.05 |
Summary of the results of included studies showing significant differences between a bioceramic material with an additive and the bioceramic material itself for osteogenic, odontogenic and/or angiogenic gene expression.
| Author | Bioceramics Used | Significant Results | Gene | Duration | Significance Level |
|---|---|---|---|---|---|
| Xia et al. [24] | αIONP-CPC, βIONP-CPC | γION-CPC, αION-CPC > CPC | COL1α | 7 days | p < 0.01 |
| ALP, Runx2 | 7 and 14 days | p < 0.01 | |||
| OCN | 14 days | p < 0.01 | |||
| Xia et al. [25] | GNP-CPC | GNP-CPC > CPC | COL1α, ALP, Runx2 | 7 and 14 days | p < 0.01 |
| OCN | 14 days | p < 0.01 | |||
| Theocharidou et al. [30] | SC | SC + low level laser treatment > SC | DSPP, BMP-2, OSX, Runx2 | 7 and 14 days | p < 0.05 |
| Lee SI et al. [32] | CPC-BGN | CPC-BGN10% > CPC-BGN5% > CPC-BGN2% | OPN, DSPP, FGF2, VEGF, PECAM-1 | 7 and 14 days | p < 0.05 |
| VEGFR1 | 14 days | p < 0.05 | |||
| CPC-BGN10% > CPC-BGN2% | DMP-1, VEGFR2. VE-cadherin | 7 and 14 days | p < 0.05 | ||
| CPC-BGN2, 5, 10% > CPC-BGN0% | PECAM-1, DSPP | 7 and 14 days | p < 0.05 | ||
| ALP, OPN, DMP-1, VEGF, VEGFR1, VE-cadherin | 14 days | p < 0.05 | |||
| CPC-BGN5, 10% > CPC-BGN0% | FGF2 | 7 and 14 days | p < 0.05 | ||
| OPN, VEGF | 7 days | p < 0.05 | |||
| OCN | 14 days | p < 0.05 | |||
| CPC-BGN10% > CPC-BGN0% | VEGFR2 | 7 and 14 days | p < 0.05 | ||
| DMP-1, VE-cadherin | 7 days | p < 0.05 | |||
| Bakopoulou et al. [33] | SC | hTDM/SC > SC | BMP-2 | 7 and 14 days | p < 0.05 |
| DSPP | 14 days | p < 0.05 | |||
| SC > hTDM | Runx2 | 7 days | p < 0.05 | ||
| Natu et al. [35] | MTA + UW/PG | MTA + UW/PG (100/0) > MTA + UW/PG (50/50) | OCN, DSPP | 14 days | p < 0.05 |
| Kulan et al. [46] | PR-MTA, MTA-CaCl2, MTA-Na2HPO4 | MTA-CaCl2, MTA-Na2HPO4 > PR-MTA + distilled water | COL1, DSPP | 14 and 21 days | p < 0.05 |
Summary of the results of included studies showing significant differences between a bioceramic material and a control for osteogenic, odontogenic and/or angiogenic gene expression.
| Author | Bioceramics Used | Significant Results | Gene | Duration | Significance Level |
|---|---|---|---|---|---|
| Pedano et al. [22] | Exp. PPL, BD, Nex-MTA | Biodentine, Exp. PPL, Nex MTA < control | ALP | 4 and 14 days | p < 0.05 |
| DSPP, OCN | 4 days | p < 0.05 | |||
| Biodentine > control | DSPP, OCN | 10 days | p < 0.05 | ||
| Biodentine, Ex. PPL > control | OCN | 14 days | p < 0.05 | ||
| Gu et al. [23] | Gelatin-HA-TCP (10:1:1) | Gel-HA-TCP > control | Runx2 | 4 days | p < 0.01 |
| OSX | 7 days | p < 0.05 | |||
| BSP | 4 days | p < 0.05 | |||
| Kyung-Jung et al. [26] | HA-TCP | HA-CPC > control | ALP | 10 days | p < 0.05 |
| BSP | 10 days | p < 0.001 | |||
| Control > HA-CPC | OPN, DMP-1 | 10 days | p < 0.01 | ||
| DSPP | 10 days | p < 0.001 | |||
| Huang et al. [28] | Zn0, Zn1, Zn2, Zn3 | Zn1, Zn2 > control | Runx2 | 7 days | p < 0.01 |
| Zn0 > control | 14 days | p < 0.05 | |||
| Zn1, Zn2, Zn3 > control | 14 days | p < 0.01 | |||
| Zn1 > control | ON | 7 days | p < 0.05 | ||
| Zn0, Zn1, Zn2, Zn3 > control | 14 days | p < 0.05 | |||
| Zn0 > control | OCN | 7 days | p < 0.01 | ||
| Zn3 > control | 14 days | p < 0.05 | |||
| Zn0, Zn1, Zn2, Zn3 > control | 14 days | p < 0.01 | |||
| Zn0 > control | MEPE | 7 days | p < 0,05 | ||
| Zn1, Zn2, Zn3 > control | 7 days | p < 0.01 | |||
| Zn0, Zn1, Zn2, Zn3 > control | 14 days | p < 0.01 | |||
| Zn0, Zn1, Zn2, Zn3 > control | BSP | 7 days | p < 0.01 | ||
| Zn0 > control | 14 days | p < 0.05 | |||
| Zn1, Zn2, Zn3 > control | 14 days | p < 0.01 | |||
| Zn1, Zn2, Zn3 > control | BMP-2 | 7 days | p < 0.05 | ||
| Zn0, Zn2, Zn3 > control | 14 days | p < 0.01 | |||
| Zn1 > control | 14 days | p < 0.05 | |||
| Bakopoulou et al. [33] | SC | SC > control | DSPP, BMP-2, BGLAP | 7 and 14 days | p < 0.05 |
| OSX | 14 days | p < 0.05 | |||
| Control > SC | ALP | 7 and 14 days | p < 0.05 | ||
| Runx2 | 14 days | p < 0.05 | |||
| Niu et al. [31] | Quick-Set2, PR-MTA | Quick-Set2, PR-MTA > control | Runx2 | 1 and 2 weeks | p < 0.001 |
| OSX, DSPP | 2 and 3 weeks | p < 0.001 | |||
| ALP | 1 and 3 weeks | p < 0.001 | |||
| BSP | 3 weeks | p < 0.001 | |||
| OCN, DMP-1 | 1, 2 and 3 weeks | p < 0.001 | |||
| Bortoluzzi et al. [34] | BD, TheraCal LC, MTA | Biodentine, MTA > control | ALP, OCN, BSP, DSPP, DMP-1 | 7 days | p < 0.0085 |
| Luo et al. [38] | BD | Biodentine 0.2 mg/mL, Biodentine 2 mg/mL > control | OCN, DSPP, DMP1, BSP | 14 days | p < 0.05 |
| Wang et al. [40] | MTA | MTA > control | OCN | 3 days | P < 0.05 |
| Runx2, OSX, DSPP | 3 and 7 days | p < 0.01 | |||
| ALP, OCN | 7 days | p < 0.01 | |||
| Nam et al. [41] | CaP granules | CaP > control | DSPP, DMP1, OCN | 21 days | p < 0.01 |
| COL1 | 14 days | p < 0.05 | |||
| CaP > control | COL1, OCN, DSPP | 7 days | p < 0.01 | ||
| DMP1 | 14 days | p < 0.05 | |||
| Zhao et al. [43] | MTA | MTA > control | ALP, DSPP, COL1, BSP | 6, 12, 24 and 48 h | p < 0.05 |
| OCN | 12, 24 and 48 h | p < 0.05 | |||
| MTA 0.2 mg/mL, MTA 2 mg/mL > control | ALP, DSPP, COL1, BSP, OCN | 48 h | p < 0.05 | ||
| Paranjpe et al. [44] | MTA | MTA > control | OCN, ALP, DSP | 7 days | p < 0.05 |
| Runx2 | 4 days | p < 0.05 | |||
| Sun et al. [48] | iRoot FS, BD at 0.2 and 2 mg/mL | Control > BD2 | COL1 | 1 and 7 days | p < 0.05 |
| OCN | 7 days | p < 0.05 | |||
| Control > BD0.2, FS0.2, FS2 | COL1 | 7 days | p < 0.05 | ||
| FS0.2 > control | OCN | 7 days | p < 0.05 | ||
| COL1 | 14 days | p < 0.05 | |||
| Lee BN et al. [49] | TheraCal, PR-MTA | PR-MTA > control | DSPP | 1 and 3 days | p < 0.05 |
| DMP | 3 days | p < 0.05 | |||
| Theracal > control | DSPP, DMP | 3 days | p < 0.05 | ||
| Daltoé et al. [50] | BD, MTA | Biodentine, MTA > control | SPP1, ALPL, Runx2 | 48 h | p < 0.05 |
| Gandolfi et al. [51] | CaSi-αTCP, CaSi-DCPD | CaSi-αTCP > control | ALP, OCN | 24 h | p < 0.05 |
| Zhang et al. [54] | CSP diluted at 200, 100, 50 y 25 mg/mL | CSP25, CSP50, CSP100, CSP200 > control | DSPP, DMP1 | 10 days | p < 0.05 |
| Runx2 | 3 and 10 days | p < 0.05 | |||
| CSP50, CSP100, CSP200 > control | DSPP, DMP1, OPN | 3 days | p < 0.05 | ||
| CSP100, CSP200 > control | OPN | 10 days | p < 0.05 | ||
| Peng et al. [57] | Ca3SiO5 | Ca3SiO5 > control | ALP, DSPP | 4, 7 and 10 days | p < 0.05 |
| OC, DMP1 | 7 and 10 days | p < 0.05 |
Summary of the results of included studies showing significant differences between a bioceramic material and a non-bioceramic material for osteogenic, odontogenic and/or angiogenic gene expression.
| Author | Bioceramics Used | Other Material Used | Bioactivity Analysis | Significant Results | Gene | Duration | Significance Level |
|---|---|---|---|---|---|---|---|
| Kyung-Jung et al. [26] | HA-TCP | Demineralized dentin matrix | RT-PCR (ALP, BSP, OPN, DMP-1, DSPP) | DDM > HA-CPC | ALP, BSP, OPN | 10 days | p < 0.05 |
| DMP-1 | 10 days | p < 0.01 | |||||
| DSPP | 10 days | p < 0.001 | |||||
| Peng et al. [57] | Ca3SiO5 | Calcium Hydroxide (Ca(OH)2) | RT-PCR (ALP, COL1, OC, DSPP, DMP1) | Ca3SiO5 > Ca(OH)2 | ALP, DSPP | 4, 7 and 10 days | p < 0.05 |
| Ca(OH)2 > Ca3SiO5 | OC, DMP1 | 7 and 10 days | p < 0.05 | ||||
| DMP1 | 4 days | p < 0.05 |
Summary of the results of included studies showing significant differences between various bioceramic materials or different concentrations of the same bioceramic material for ARS staining.
| Author | Bioceramics Used | Significant Results | Duration | Significance Level |
|---|---|---|---|---|
| Xia et al. [24] | αIONP-CPC, βIONP-CPC | γION-CPC > αION-CPC | 14 and 21 days | p < 0.05 |
| Niu et al. [31] | Quick-Set2, PR-MTA | PR-MTA > Quick-Set2 | 2 and 3 weeks | p < 0.001 |
| Lee BN et al. [49] | TheraCal, PR-MTA | PR-MTA > Theracal | 14 days | p < 0.05 |
Summary of the results of included studies showing significant differences between a bioceramic material with an additive and the bioceramic material itself for ARS staining.
| Author | Bioceramics Used | Significant Results | Duration | Significance Level |
|---|---|---|---|---|
| Xia et al. [24] | αIONP-CPC, βIONP-CPC | γION-CPC, αION-CPC > CPC | 7 and 14 days | p < 0.05 |
| Xia et al. [25] | GNP-CPC | GNP-CPC > CPC | 14 and 21 days | p < 0.01 |
Summary of the results of included studies showing significant differences between a bioceramic material and a control for ARS staining.
| Author | Bioceramics Used | Significant Results | Duration | Significance Level |
|---|---|---|---|---|
| Gu et al. [23] | Gelatin-HA-TCP (10:1:1) | Gel-HA-TCP > control | 18 days | p < 0.01 |
| 21 days | p < 0.05 | |||
| Huang et al. [28] | Zn0, Zn1, Zn2, Zn3 | Zn0, Zn1, Zn2, Zn3 > control | 3 weeks | p < 0.05 |
| Zn1, Zn2, Zn3 > control | 4 and 5 weeks | p < 0.05 | ||
| Niu et al. [31] | Quick-Set2, PR-MTA | PR-MTA, Quick-Set2 > control | 1, 2 and 3 weeks | p < 0.001 |
| Bortoluzzi et al. [34] | BD, TheraCal, MTA | Biodentine, TheraCal, MTA > control | 7 and 14 weeks | p < 0.05 |
| Luo et al. [38] | BD | Biodentine 0.2 mg/mL, Biodentine 2 mg/mL > control | 14 days | p < 0.05 |
| Wang et al. [40] | MTA | 0.2 mg/mL MTA > control | 14 days | p < 0.01 |
| Nam et al. [41] | CaP granules | CaP > control | 28 days | p < 0.01 |
| Sun et al. [48] | iRoot FS, BD at 0.2 and 2 mg/mL | FS0.2 > control | 21 days | p < 0.05 |
| Lee BN et al. [49] | TheraCal, PR-MTA | PR-MTA, Theracal > control | 14 days | p < 0.05 |
| Peng et al. [57] | Ca3SiO5 | Ca3SiO5 > control | 30 days | p < 0.05 |
Summary of the results of included studies showing significant differences between various bioceramic materials or different concentrations of the same bioceramic material for ALP activity.
| Author | Bioceramics Used | Significant Results | Duration | Significance Level |
|---|---|---|---|---|
| Xia et al. [24] | αIONP-CPC, βIONP-CPC | γION-CPC > αION-CPC | 14 days | p < 0.05 |
| Niu et al. [31] | Quick-Set2, PR-MTA | PR-MTA > Quick-Set2 | 2 and 3 weeks | p < 0.001 |
| Zheng et al. [42] | PLGA/HA, PLGA/CDHA, PLGA/TCP | PLGA/TCP > PLGA/HA, PLG/CDHA | N/S | p < 0.05 |
| Sun et al. [48] | iRoot FS, BD at 0.2 and 2 mg/mL | FS0.2, FS2, BD0.2 > BD2 | 7 days | p < 0.05 |
| FS0.2 > BD0.2 > BD2, FS2 | 14 days | p < 0.05 | ||
| Mestieri et al. [52] | MTAP, MTAF | MTAP > MTAF | 1 y 3 days | p < 0.05 |
| AbdulQader et al. [53] | BCP at a ratio of 20/80, 50/50 y 80/20 | BCP20 > BCP50, BCP20 | 3–6, 6–9, 9–12 and 12–15 days | p < 0.05 |
| BCP50 > BCP80 | 9–12 and 12–15 days | p < 0.05 | ||
| Lee SY et al. [55] | CPC-N, CPC-M | CPC-N > CPC-M | 7 and 14 days | p < 0.05 |
Summary of the results of included studies showing significant differences between a bioceramic material with an additive and the bioceramic material itself for ALP activity.
| Author | Bioceramics Used | Significant Results | Duration | Significance Level |
|---|---|---|---|---|
| Xia et al. [24] | αIONP-CPC,βIONP-CPC | γION-CPC, αION-CPC > CPC | 7 days | p < 0.05 |
| 14 days | p < 0.01 | |||
| Xia et al. [25] | GNP-CPC | GNP-CPC > CPC | 7 and 14 days | p < 0.01 |
| Theocharidou et al. [30] | SC | SC + LLLI > SC | 7 days | p < 0.05 |
| SC > SC + LLLI | 14 days | p < 0.05 | ||
| Lee SI et al. [32] | CPC-BGN | CPC-BGN2, 5, 10% > CPC-BGN0% | 7 and 14 days | p < 0.05 |
| Kulan et al. [46] | PR-MTA, MTA-CaCl2, MTA-Na2HPO4 | MTA-CaCl2, MTA-Na2HPO4 > PR-MTA + distilled water | N/S | p < 0.01 |
Summary of the results of included studies showing significant differences between a bioceramic material and a control for ALP activity.
| Author | Bioceramics Used | Significant Results | Duration | Significance Level |
|---|---|---|---|---|
| Gu et al. [23] | Gelatin-HA-TCP (10:1:1) | Gel-HA-TCP > control | 4 days | p < 0.05 |
| 7 and 12 days | p < 0.01 | |||
| Huang et al. [28] | Zn0, Zn1, Zn2, Zn3 | Zn3 > control | 1 day | p < 0.05 |
| Zn0, Zn1, Zn2, Zn3 > control | 7 and 10 days | p < 0.05 | ||
| Niu et al. [31] | Quick-Set2, PR-MTA | PR-MTA, Quick-Set2 > control | 1, 2 and 3 weeks | p < 0.001 |
| Bakopoulou et al. [33] | SC | SC > control | 3, 7 and 14 days | p < 0.05 |
| Bortoluzzi et al. [34] | BD, TheraCal, MTA | Biodentine, MTA, TheraCal > control | 14 days | p < 0.05 |
| Widbiller et al. [36] | BD, PR-MTA | Control > MTA | 3, 7 and 14 days | p < 0.05 |
| Luo et al. [38] | BD | Biodentine 0.2 mg/mL, Biodentine 2 mg/mL > control | 7, 10 and 14 days | p < 0.05 |
| Biodentine 0.2 mg/mL > control | 3 days | p < 0.05 | ||
| Wang et al. [40] | MTA | 0.02 mg/mL MTA > control | 3 days | p < 0.05 |
| 0.2 mg/mL MTA > control | 3 and 5 days | p < 0.01 | ||
| 2 mg/mL MTA > control | 5 days | p < 0.01 | ||
| Control > 20 mg/mL MTA | 3 and 5 days | p < 0.01 | ||
| Nam et al. [41] | CaP granules | CaP > control | 14 and 21 days | p < 0.01 |
| Xu et al. [47] | CSC | CSC > control | 10 days | p < 0.05 |
| Sun et al. [48] | iRoot FS, BD at 0.2 and 2 mg/mL | BD0.2, BD2, FS0.2, FS2 > control | 7 and 14 days | p < 0.05 |
| Lee BN et al. [49] | TheraCal, PR-MTA | MTA > control | 7 days | p < 0.05 |
| Mestieri et al. [52] | MTAP, MTAF | Control > MTAP, MTAF | 1 and 3 days | p < 0.05 |
| Zhang et al. [54] | CSP diluted at 200, 100, 50 y 25 mg/mL | CSP50, CSP100, CSP200 > control | 3 and 10 days | p < 0.05 |
| Peng et al. [57] | Ca3SiO5 | Ca3SiO5 > control | 10 days | p < 0.05 |
Summary of the results of included studies showing significant differences for another bioactivity-related analysis.
| Author | Bioceramics Used | Bioactivity Analysis | Significant Results | Gene | Duration | Significance Level |
|---|---|---|---|---|---|---|
| Huang et al. [28] | Zn0, Zn1, Zn2, Zn3 | Western Blot | Zn0, Zn1, Zn2, Zn3 > control | DSPP | 7 days | p < 0.05 |
| Control > Zn0, Zn1, Zn2, Zn3 | DSPP | 14 days | p < 0.05 | |||
| Zn2, Zn3 > control | DMP-1 | 7 days | p < 0.05 | |||
| Control > Zn0, Zn1, Zn2, Zn3 | DSPP | 14 days | p < 0.05 | |||
| Niu et al. [31] | Quick-Set2, PR-MTA | Western Blot | PR-MTA > Quick-Set2 | DMP-1 DSPP, OCN | 1, 2 and 3 weeks |
p < 0.001 |
| PR-MTA, Quick-Set2 > control | DMP-1 |
1, 2 and 3 weeks |
p < 0.001 |
|||
| PR-MTA > control | OCN | 1, 2 and 3 weeks | p < 0.001 | |||
| ATR-FTIR | PR-MTA > Quick-Set2 | - | 2 and 3 weeks | p < 0.001 | ||
| PR-MTA, Quick-Set2 > control | - | 1, 2 and 3 weeks | p < 0.001 | |||
| Asgary et al. [39] | MTA, CEM | ELISA | MTA > CEM | TFG-β1 | N/S | p < 0.05 |
| CEM > MTA | FGF4 | N/S | p < 0.05 | |||
| Zheng et al. [42] | PLGA/HA, PLGA/CDHA, PLGA/TCP | Gene Tool (level of grey in mineralization nodules analysis) | PLGA/TCP > PLGA/HA, PLG/CDHA | - | 4 weeks | p < 0.05 |
| PLGA/TCP > PLGA/HA | - | 5 weeks | p < 0.05 | |||
| Tu et al. [45] | DA0, DA0.5, DA1 | TRACP & ALP assay kit (Takahara, Shiga, Japan) | DA0.5, DA1 > DA0 | ALP | 7 days | p < 0.05 |
| DA1 > DA0 | ALP | 3 days | p < 0.05 | |||
| DA0.5, DA1 > DA0 | OCN | 7 and 14 days | p < 0.05 | |||
| OC and DSP enzyme-linked immunosorbent assay kits (ThermoFisher Scientific) | DA1 > DA0 | DSP | 7 days | p < 0.05 | ||
| DA0.5, DA1 > DA0 | DSP | 14 days | p < 0.05 |
Summary of the significant results of included studies categorized as animal studies.
| Author | Bioceramics Used | Non-Bioceramic Material Used | In Vivo Assay Description | Bioactivity Analysis | Results | Gene | Duration | Significance Level |
|---|---|---|---|---|---|---|---|---|
| Kyung-Jung et al. [26] | HA-TCP | Demineralized dentin matrix | Ectopic bone fomation in athymic rats with HA-(HA-TCP or DDM) and HDPSCs implanted subcutaneously. | RT-PCR | HA-TCP > DDM | BSP | 8 weeks | p < 0.001 |
| Wongsupa et al. [27] | PCL-BCP | - | Bone formation in 1mm diameter calvarial defects in the parietal bone in 5–6-month-old male New Zealand white rabbits. | Micro-CT | PCL-BCP + hDPSCs > PCL-BCP | - | 4 and 8 weeks | p < 0.01 |
| Hysto-morphometric anaysis | PCL-BCP + hDPSCs > PCL-BCP | - | 2, 4 and 8 weeks | p < 0.01 | ||||
| Atalayin et al. [29] | HA-TCP | L-lactide/DL-lactide copolymer (PLDL), DL-lactide copolymer (PDL) | Odontogenic differentiation of hDPSCs in rats implanted with HA-CPC and hDPSCs subcutaneously. | RT-PCR (DSPP, DMP-1, MMP20, PHEX) | PDL > PLDL, HA/TCP | DSPP | 12 weeks | p < 0.05 |
| PLDL > PDL, HA-TCP | DMP1 | 6 weeks | p < 0.05 | |||||
| HA-TCP > PLDL, PDL | 12 weeks | p < 0.05 | ||||||
| PLDL, HA/TCP > PDL | MMP20 | 6 weeks | p < 0.05 | |||||
| PDL > PLDL, HA/TCP | 12 weeks | p < 0.05 | ||||||
| HA-TCP > PLDL, PDL | PHEX | p < 0.05 | ||||||
| PLDL > PDL, HA-TCP | p < 0.05 | |||||||
| Daltoé et al. [50] | BD, MTA | - | 87 specimens of 2nd and 3rd upper premolars and 2nd, 3rd, and 4th lower premolars from 4 dogs (Beagles), evaluated 120 days after pulpotomy. | Staining for OPN and ALP in mineralized tissue bridge | MTA > BD | OPN | 120 days | p < 0.001 |
| BD > MTA | ALP | 120 days | p < 0.001 | |||||
| Staining for OPN and ALP in pulp tissue | BD > MTA | OPN | 120 days | p < 0.001 |
© 2019 by the authors.
Details
; Rodríguez-Lozano, Francisco Javier 2
; Llena, Carmen 1
; Sauro, Salvatore 3
; Forner, Leopoldo 1
1 Department of Stomatology, Universitat de València, 46010 Valencia, Spain
2 Cellular Therapy and Hematopoietic Transplant Unit, Hematology Department, Virgen de la Arrixaca Clinical University Hospital, IMIB, University of Murcia, 30120 Murcia, Spain; School of Dentistry, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
3 Department of Dentistry, Faculty of Health Sciences, Universidad CEU-Cardenal Herrera, 46115 Alfara del Patriarca (Valencia), Spain; Faculty of Dentistry, Oral & Craniofacial Sciences at King’s College London, Floor 17 Tower Wing, Guy’s Hospital, London SE1 9RT, UK