Abstract
Introduction/Objectives
To evaluate the effectiveness of bioactive glasses in promoting enamel remineralization.
Data
An electronic search with a complementary gray literature search for in vivo and in vitro research. No language restrictions were applied.
Sources
MEDLINE and EMBASE via OVID, the Cochrane Oral Health Group’s Trials Register, CENTRAL and LILACS
Study selection
One hundred and sixteen studies were identified, of which, eleven met the inclusion criteria and formed the basis of this systematic review. Methodological quality was assessed independently by two reviewers. Factors investigated in the selected articles included the objective and subjective measures of enamel remineralisation; harms, including evidence of damage to the enamel surface; patient satisfaction; and in vitro evidence of enamel remineralisation, using recognized laboratory techniques.
Results
A total of 11 laboratory-based studies were included in this review. The methodological quality was deemed to be high in four, and medium in the remaining studies. Based on the in vitro studies, enamel remineralization improved with bioactive glasses, irrespective of the method of application. Ex vivo signs of remineralization such as increase in enamel hardness, the formation of an enamel-protective layer and reduced intensity of light backscattering were less evident with alternatives including fluoride, and casein phosphopeptide-amorphous calcium phosphate (CPP-ACP).
Conclusions
Based on in vitro findings only, bioactive glasses may be capable of enhancing enamel remineralization in various formulations, compared with other topical remineralizing materials including fluoride, and CPP-ACP. However, clinical research to confirm their effectiveness is now overdue.
Clinical significance
Bioactive glasses have potential utility in promoting enamel remineralization; however, clinical research exploring their clinical effectiveness is required.
1
Introduction
Enamel demineralization is a reversible precursor of overt dental caries and is highly prevalent both among orthodontic and non-orthodontic populations. White spot lesions (WSLs), for example, are a common complication associated with fixed orthodontic treatment, particularly in the presence of poor oral hygiene . Fixed appliances offer retentive areas for accumulation of bacterial plaque. The acidic by-products of cariogenic bacteria are responsible for the subsequent enamel demineralisation and formation of WSLs, which are reported in up to 96% of orthodontic patients . This is further aggravated by the fact that most orthodontic patients are adolescents, who are at increased risk due to the susceptibility of newly- erupting teeth to acid attack .
A number of topical remineralizing agents have been used to inhibit and remineralize enamel and WSLs, in particular . Fluoride has formed the mainstay of enamel remineralization for many decades. It is known to control caries predominantly through its topical effect inhibiting demineralization by forming fluorapatite on the enamel surface. Fluorapatite is less soluble, therefore increasing the resistance of enamel to dissolution relative to hydroxyapatite during acid attack . Various modes and formulations have been used to deliver fluoride such as varnishes, toothpastes, mouth-rinses, solutions, gels and orthodontic adhesives incorporating a source of fluoride.
Convincing evidence of the effectiveness of agents in prevention and reversal of enamel WSLs is limited. Notwithstanding this, a recent Cochrane systematic review reported that the application of fluoride varnish on a 6-weekly basis was effective in preventing WSL formation . This approach, however, is onerous, requires professional input and may be costly. The use of CPP-ACP has been advanced in recent years as an alternative to fluoride to promote remineralisation . The CCP-ACP complex may be applied by means of chewing gum, toothpaste, lozengens, mouth-rinses, or sprays. These complexes adhere to dental biofilm, preventing colonization of bacteria and providing a supersaturated environment of calcium and phosphate . However, clinical research has given disappointing results with little difference in outcome relative to the use of fluoride . Recently, a preventative treatment regimen involving the daily use of CPP-ACP (MI Paste Plus) for 3 minutes daily in a fluoride tray throughout orthodontic treatment has been recommended .
More recently, a bioactive glass (45S5) has been developed for dental use and applied in a plethora of studies to remineralize WSLs . This glass has shown promise in inducing apatite formation when brought into contact with saliva or any physiological fluid. These apatites constitute either hydroxyapatites , or fluorapatites , if fluoride was incorporated into the chemical composition of the glass structure. Fluoride-containing glasses have ‘smart’ properties, with increased remineralization activity in low pH environments . Consequently, it has variously been added to tooth-paste, prophylactic gels and dental materials to treat enamel demineralization. Nevertheless, there is limited research in relation to the effectiveness of bioactive glasses in inducing remineralization. The current systematic review therefore aims to evaluate the effectiveness of bioactive glasses in inducing enamel remineralization compared to competing topical treatment including fluoride and CPP-ACP.
2
Materials and methods
2.1
Search methodology
This systematic review was conducted in accordance with the PRISMA guidelines based on a pre-defined, unpublished protocol. The research question was: How effective are bioactive glasses in inducing enamel remineralization in comparison to placebo or other topical treatments. The following selection criteria were applied:
Participants: Prospective clinical studies including randomized and non-randomized designs. In vitro studies involving assessment of enamel demineralization utilizing human teeth were also to be included.
Interventions: Use of bioactive glasses in any formulation
Comparators: Untreated control or alternative intervention to address enamel demineralization including fluoride and CPP-ACP
Outcomes: Clinical and in vitro measures of enamel remineralization
A comprehensive literature search was performed without language or date restrictions. The following databases were screened: PubMed/Medline (PubMed, www.ncbi.nlm.nih.gov ), EMBASE via OVID, the Cochrane Oral Health Group’s Trials Register (February 2017), the Cochrane Central Register of Controlled Trials (CENTRAL The Cochrane Library Issue 1, 2017), Literature in the Health Sciences in Latin America and the Caribbean (LILACS, February 2017). Unpublished literatures were searched using ClinicalTrials.gov ( www.clinicaltrials.gov ) and the National Research Register ( www.controlled-trials.com ) using the terms ‘dental’ and ‘dentistry’. After identifying the potential eligible studies in the above databases, these studies were imported into Endnote ×7 software (Thompson Reuters, Philadelphia, PA, USA) to remove duplicates. In addition, the reference lists of included studies were assessed to identify further potentially eligible studies.
2.2
Study selection
The titles and abstracts of all articles identified by the electronic search were read and assessed by two authors (AT, PSF). The full text article was retrieved if the title and abstract were deemed ambiguous or when no abstract was available. All studies, which unrelated to bioactive glasses or enamel remineralization, were excluded initially on the basis of the titles and abstracts of these studies.
2.3
Data extraction
One author (AT) extracted the data using a pre-piloted data collection form, and a second author (PSF) verified data extraction independently for completeness and accuracy. Data obtained included number of teeth used, tooth type, demineralization protocol, remineralization procedures and control conditions; and approach to outcome analysis. Any potential conflict was resolved by joint discussion between the two authors.
2.4
Study quality assessment
The methodological quality of each included study was assessed independently by two authors (AT, PSF). If randomized studies were identified, the risk of bias was to be assessed using the Cochrane risk of bias tool with ROBINS-I used for non-randomized interventional designs. The methodological quality of the in vitro studies was to be evaluated using an accepted quality assessment tool for dental in vitro studies . Specifically, studies were evaluated according to the description of randomization of teeth, presence of caries, blinding of the examiner, statistical analysis, the presence of a control group, sample preparation, outcome measures used and sample size calculation. Where the parameter was reported clearly the domain was scored as “Yes”. If it was not possible to find the information, it was graded as “No”. Studies that reported one to three items were classified as having a low methodological quality, four or five items as medium methodological quality and six to eight items as having high methodological quality.
Meta-analysis was to be considered if sufficient studies of high or moderate methodological quality with clinical homogeneity existed. Statistical heterogeneity was to be assessed using a chi-squared test and quantified on the basis of an I-squared statistic. The existence of publication bias was to be assessed if sufficient (>10) clinical studies were included within a meta -analysis.
2
Materials and methods
2.1
Search methodology
This systematic review was conducted in accordance with the PRISMA guidelines based on a pre-defined, unpublished protocol. The research question was: How effective are bioactive glasses in inducing enamel remineralization in comparison to placebo or other topical treatments. The following selection criteria were applied:
Participants: Prospective clinical studies including randomized and non-randomized designs. In vitro studies involving assessment of enamel demineralization utilizing human teeth were also to be included.
Interventions: Use of bioactive glasses in any formulation
Comparators: Untreated control or alternative intervention to address enamel demineralization including fluoride and CPP-ACP
Outcomes: Clinical and in vitro measures of enamel remineralization
A comprehensive literature search was performed without language or date restrictions. The following databases were screened: PubMed/Medline (PubMed, www.ncbi.nlm.nih.gov ), EMBASE via OVID, the Cochrane Oral Health Group’s Trials Register (February 2017), the Cochrane Central Register of Controlled Trials (CENTRAL The Cochrane Library Issue 1, 2017), Literature in the Health Sciences in Latin America and the Caribbean (LILACS, February 2017). Unpublished literatures were searched using ClinicalTrials.gov ( www.clinicaltrials.gov ) and the National Research Register ( www.controlled-trials.com ) using the terms ‘dental’ and ‘dentistry’. After identifying the potential eligible studies in the above databases, these studies were imported into Endnote ×7 software (Thompson Reuters, Philadelphia, PA, USA) to remove duplicates. In addition, the reference lists of included studies were assessed to identify further potentially eligible studies.
2.2
Study selection
The titles and abstracts of all articles identified by the electronic search were read and assessed by two authors (AT, PSF). The full text article was retrieved if the title and abstract were deemed ambiguous or when no abstract was available. All studies, which unrelated to bioactive glasses or enamel remineralization, were excluded initially on the basis of the titles and abstracts of these studies.
2.3
Data extraction
One author (AT) extracted the data using a pre-piloted data collection form, and a second author (PSF) verified data extraction independently for completeness and accuracy. Data obtained included number of teeth used, tooth type, demineralization protocol, remineralization procedures and control conditions; and approach to outcome analysis. Any potential conflict was resolved by joint discussion between the two authors.
2.4
Study quality assessment
The methodological quality of each included study was assessed independently by two authors (AT, PSF). If randomized studies were identified, the risk of bias was to be assessed using the Cochrane risk of bias tool with ROBINS-I used for non-randomized interventional designs. The methodological quality of the in vitro studies was to be evaluated using an accepted quality assessment tool for dental in vitro studies . Specifically, studies were evaluated according to the description of randomization of teeth, presence of caries, blinding of the examiner, statistical analysis, the presence of a control group, sample preparation, outcome measures used and sample size calculation. Where the parameter was reported clearly the domain was scored as “Yes”. If it was not possible to find the information, it was graded as “No”. Studies that reported one to three items were classified as having a low methodological quality, four or five items as medium methodological quality and six to eight items as having high methodological quality.
Meta-analysis was to be considered if sufficient studies of high or moderate methodological quality with clinical homogeneity existed. Statistical heterogeneity was to be assessed using a chi-squared test and quantified on the basis of an I-squared statistic. The existence of publication bias was to be assessed if sufficient (>10) clinical studies were included within a meta -analysis.
3
Results
3.1
Study selection and characteristics
A total of 116 potentially relevant records were identified from the database search ( Fig. 1 ). After the removal of duplicates, 86 records were examined; 72 studies were excluded because they did not meet the eligibility criteria and 14 full-texts were assessed. Of the 14 studies retained for detailed full-text review, 3 were excluded- one review article and two in vitro studies involved bovine tooth samples. A total of 11 studies were included in this review. No clinical studies were identified; therefore, all included studies were laboratory-based. The characteristics of the included studies are summarized in Table 1 .
| Authors | Total number of samples | Human tooth type | Sample type | Demineralization protocol | Remineralisation protocol/Control conditions | Storage | Outcome/Analysis technique |
|---|---|---|---|---|---|---|---|
| Bakry et al. | 100 | Third molars | Flat enamel discs | Orange juice (pH 3.85) for 1 h at 20 ºC | –Fluoride gel (20 mg/g, 9000 ppmF, Brand Medico Dental™) applied for 5 min then washed with deionized water | Immersed in remineralization solution (1.5 mM CaCl 2 , 0.9 mM NaH 2 PO 4 , 0.13 M KCl, 5 mM NaN 3 ; pH 7 using HEPES buffer) for 24 h | Vickers hardness number (VHN), SEM images, EDX elemental composition |
| –Fluoride gel (20 mg/g, 9000 ppmF, Brand Medico Dental™) applied for 24 h then left without washing | |||||||
| –Bioactive glass (Novamin™)- phosphoric acid gel | |||||||
| –Control (untreated) | |||||||
| Bakry et al. | 60 | Third molars | Flat enamel blocks | 2.2 mM/L CaCl2, 2.2 mM/L NaH 2 PO 4 , 50 mM/L acetic acid, pH 4.5) for 4 days | –Bioglass (Novamin™) – phosphoric acid gel with no brushing-abrasion | –Remineralizing solution (1.0 mM CaCl 2 , 3.0 mM KH 2 PO 4 , 100 mM acetate, 100 mM NaCl, 0.02%, NaN 3 ; pH 6.3) for 24 h, 7 days and 14 days | SEM images, XRD |
| –Brushing – abrasion after immersion in remineralizing solution for 24 h with no gel | |||||||
| –Both bioglass (Novamin™) –phosphoric-acid gel + brushing-abrasion after immersion in remineralizing solution for 24 h | |||||||
| –Control: Neither gel nor brushing – abrasion was applied | |||||||
| Gjorgievska et al. | Not specified | Molars | Enamel tooth surface | 6% hydroxyl-ethyl cellulose, 0.1 mol/L lactic acid, and 1.0 mol/L NaOH (pH 4.5) for 24 h | –Mirasensitive hap + tooth paste (containing hydroxyapatite) applied for 1 min and then cleaned with a toothbrush for 5 min under copious water spray | SEM images, EDX elemental composition, 3D Stereo Photograph images | |
| –Mirawhite ® tc toothpaste (containing bioglass 45S5) applied for 1 min and then cleaned with a tooth brush for 5 min under copious water spray | |||||||
| –Sensodyne ® toothpaste applied for 1 min and then cleaned with a toothbrush for 5 min under copious water spray | |||||||
| Kohda et al. | 120 | Premolars | Enamel tooth surface after bracket bonding with 4-methacryloxyethyl trimellitic anhydride/methyl meth-acrylate-tri- n -butyl borane-based resin containing various amounts (0–50%) of bioactive glass | 2 mL of demineralizing solution (2 mM calcium chloride and 2 mM sodium dihydrogen phosphate, with 50 mM acetic acid added to pH 4.55) for 4 h at 37 °C followed by remineralization. This cycle was repeated daily for 14 days | 2 mL of remineralizing solution (2 mM CaCl 2 and 2 mM NaH 2 PO 4 with 0.1 M of NaOH added to pH 6.8) for 20 h at 37 °C | Berkovich hardness measurements | |
| Manfred et al. | 50 | Third molars | Enamel surface with brackets bonded with orthodontic adhesive | pH cycling protocol for 14 days: 40 mL of artificial saliva at pH 7.0 [1.5 mmol/L Ca, 0.9 mmol/L PO 4 , 0.15 mol/L KCl, and 20 mmol/L cacodylate buffer) for 18 h, followed by 6 h in 40 mL of buffered artificial caries challenge solution at pH 4.4 (2.0 mmol/L Ca, 2.0 mmol/L PO 4 , 0.075 mol/L acetate]. The cycle was repeated 5 days a week, with teeth remaining in artificial saliva at weekends | Four BAG-Bonds (62 BAG-Bond, 65 BAG-Bond, 81 BAG-Bond, and 85 BAG-Bond) and Transbond-XT used to bond orthodontic brackets | – | Knoop hardness number (KNH) |
| Mehta et al. | 30 | Premolars | Flat enamel surface | 2.2 mM calcium chloride, 2.2 mM sodium phosphate and 0.05 M acetic acid; pH adjusted with 1 M potassium hydroxide to 4.4. Demineralization was performed twice for 3 h of a day with 2-h immersion in a remineralizing solution in between | –BAG containing dentifrice (SHY-NM; Group Pharmaceuticals; India) | Vickers hardness number (VHN) | |
| –CPP-ACP(GC tooth mousse Recaldent; GCcorp; Japan) containing dentifrice | |||||||
| Milly et al. | 52 | Molars | Flat enamel slabs | 8% methylcellulose gel buffered with a lactic acid layer (0.1 mol/L, pH 4.6) for 14 days at 37 °C | –Bioactive glass (Sylc™) slurry prepared with de-ionized water (L/P ratio of 1 g/m) for 7 days at 37°C | SEM images, Knoop hardness Number (KHN), Micro-Raman spectroscopy grey-scale images, surface roughness using non-contact profilometry | |
| –Polyacrylic acid-modified bioactive glass paste prepared with de-ionized for 7 days at 37°C. water (L/P ratio of 1 g/m) | |||||||
| –Remineralisation solution 20 mM Hepes, 130 mM KCl, 1.5 mM CaCl 2 and 0.9 mM KH 2 PO 4 (adjusted to pH 7.0 with KOH) | |||||||
| –Deionized water | |||||||
| – | |||||||
| Milly et al. | 90 | Molars | Flat enamel slabs | 8% methylcellulose gel buffered with a lactic acid layer (0.1 mol/L, pH 4.6) for 14 days at 37°C, followed by surface conditioning via propelling polyacrylic acid-bioactive glass (45S5) powder using air-abrasion for 10 s | –Bioactive glass (45S5) slurry prepared with de-ionized water (L/P ratio of 1 g/m) twice daily for 5 min for 21 days at 37 °C | – | Surface roughness using non-contact profilometry, Knoop hardness number (KHN), intensity of light backscattering using OCT, Raman spectroscopy grey-scale images, SEM images, EDX elemental composition |
| –Polyacrylic acid-modified bioactive glass paste prepared with de-ionized applied twice daily for 5 min for 21 days at 37 °C | |||||||
| Narayana et al. | 20 | Molars | Enamel tooth surface | –pH cycling for 7 days involving immersion in demineralization solution [2 mM Ca(NO 3 ) 2 4H 2 O, 2 mM NaH 2 PO 4 2H 2 O, 0.075 mM acetate buffer for 5 days, followed by 0.02 ppm F (pH 4.7) for 6 h and in remineralized solution (1.5 mM Ca(NO 3 ) 2 4H 2 O, 0.9 mM NaH 2 PO 4 2H 2 O, 150 mM KCl, 0.1 mol/L Tris buffer, 0.03 ppm F pH 7] for 18 h. Samples were maintained only in the remineralized solution for the last 2 days | –Bioactive glass (Novamin) for 10 min | Artificial saliva at 37 °C for 10 days | SEM images, EDX elemental composition |
| –Fluoride toothpaste (Amflor) for 10 min | |||||||
| –CPP-ACP (Tooth mousse) for 10 min | |||||||
| –CPP-ACPF (Tooth mousse plus) for 10 min | |||||||
| –Control (untreated) | |||||||
| Palaniswamy et al. | 20 | Premolars | Enamel tooth surface | 37% phosphoric acid for 20 min | –ACP-CPP (GC Tooth Mousse, Recaldent; GC Corp.; Japan) for 3 min | Artificial saliva for 10 days, and then 15 days | Vickers hardness number (VHN) |
| –BAG (Novamin, Sensodyne Repair and Protect; GlaxoSmithKline; UK) for 1 min | |||||||
| –37% phosphoric acid; Ivoclar Vivadent, | |||||||
| –Natural saliva, | |||||||
| –Deionized water | |||||||
| Pulido et al. | 10 | Molars | Enamel tooth surface | 8% methylcellulose aqueous solution (1500cP, 63 kDa) with an equal volume of 0.1 mol/L of lactic acid, with an adjusted pH with KOH at 4.6 a 37 ºC for a 5-day period | –Bioactive glass (VBio): Biogran® (Biomet 3i™) at a 5 wt% concentration twice daily 2 for 15 days | SEM images, EDX elemental composition | |
| –Stannous fluoride Gel Kam (Colgate Palmolive ® ) 0.4% twice daily for 15 days | |||||||
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