materials

Review
Mechanisms of Bioactive Glass on Caries
Management: A Review
Lin Lu Dai 1 , May Lei Mei 2 , Chun Hung Chu 1 and Edward Chin Man Lo 1, *
1 Faculty of Dentistry, University of Hong Kong, Pok Fu Lam, Hong Kong; [email protected] (L.L.D.);
[email protected] (C.H.C.)
2 Faculty of Dentistry, University of Otago, 9054 Dunedin, New Zealand; [email protected]
* Correspondence: [email protected]; Tel.: +85-228-590-292




Received: 29 October 2019; Accepted: 10 December 2019; Published: 12 December 2019


Abstract: This review investigates the mechanisms of bioactive glass on the management of
dental caries. Four databases (PubMed, Web of Science, EMBASE (via Ovid), Medline (via Ovid))
were systematically searched using broad keywords and terms to identify the literature pertaining
to the management of dental caries using “bioactive glass”. Titles and abstracts were scrutinized
to determine the need for full-text screening. Data were extracted from the included articles
regarding the mechanisms of bioactive glass on dental caries management, including the aspect of
remineralizing effect on enamel and dentine caries, and antimicrobial effect on cariogenic bacteria.
After removal of duplicates, 1992 articles were identified for screening of the titles and abstracts.
The full texts of 49 publications were scrutinized and 23 were finally included in this review.
Four articles focused on the antimicrobial effect of bioactive glass. Twelve papers discussed the effect
of bioactive glass on demineralized enamel, while 9 articles investigated the effect of bioactive glass
on demineralized dentine. In conclusion, bioactive glass can remineralize caries and form apatite on
the surface of enamel and dentine. In addition, bioactive glass has an antibacterial effect on cariogenic
bacteria of which may help to prevent and arrest dental caries.

Keywords: bioactive glass; mechanism; caries; review

1. Introduction
Dental caries is a prevalent oral disease worldwide and can occur in both primary and permanent
dentitions throughout an individual’s life. It is a biofilm-mediated disease, resulting in mineral loss
and destruction of dental hard tissues. Cariogenic bacteria will produce acids, causing prolonged
periods of low pH environment in the oral cavity which leads to demineralization of dental hard
tissues [1]. The process of dental caries starts with chemical dissolution of enamel and dentine caused
by the acids produced by the bacteria that adhere onto the tooth surface. If sufficient time is allowed
for progression, the carious lesions on the surface will progress to cavity formation in the affected
tooth [2,3].
The current approaches of caries management aim to 1) stop or control the progression of caries, 2)
preserve dental hard tissue as much as possible, and 3) avoid the re-restoration process [4]. Management
of carious lesions with varying severity is outlined below. For initial lesions, nonsurgical approaches are
commonly used. Fluoride-containing products are delivered in different forms onto teeth to promote
remineralization and the mineral contents of the lesions are recovered by penetration of calcium and
phosphate from a higher concentration into the lesions. Casein phosphopeptide–amorphous calcium
phosphate (CPP-ACP) is a stabilized system of Ca–P that has superior remineralization potential on
carious lesions. A modification is to add fluoride into the system (CPP-ACPF), which can improve
the remineralization efficacy compared to that of the original system [5]. The approaches listed above

Materials 2019, 12, 4183; doi:10.3390/ma12244183 www.mdpi.com/journal/materials

Materials 2019, 12, 4183 2 of 14

are mainly due to their remineralization effect on the tooth surface. Some anticaries agents possess
antibacterial properties, which can inhibit the growth of cariogenic bacteria. Chlorhexidine (CHX)
is a type of antibacterial agent which can reduce the Streptococcus mutans level in the oral cavity [6].
Triclosan, which can affect the acid production of biofilm, is another anticaries agent. Previous studies
have shown that amino acid arginine has an anticaries effect because of its effect on oral biofilms.
Furthermore, xylitol is a natural substitute for sugar and has antibacterial potential on dental caries.
Similarly to the other two previously mentioned agents, they possess the ability to control bacterial
level, thus promoting the process of remineralization [3,5].
Placement of pit and fissure sealant is another minimally invasive therapy for managing initial
lesions of the tooth surface. For moderate lesions, mechanical blocking or sealing off the lesion is an
effective method to arrest caries after applying resin-based fissure sealant. Topical application of silver
diamine fluoride (SDF) is an alternative way to arrest moderate carious lesions due to its antibacterial
effect and remineralization effect [2,3]. Besides, the classic standard treatment of extensive lesions
is removing all the demineralized tissues of the tooth and placing dental restorative material like
composite resin to fill up the prepared cavity. In a recent development, stepwise or partial removal of
caries is a new trend to preserve more dental tissues and it can reduce the incidence of pulpal exposure
and favor the formation of tertiary dentine after restoration [2,3]. For the restorative method mentioned
above, various materials are used. These include chemically bonded ceramic cements set by acid–base
reaction, such as zinc phosphate, silicate, polycarboxylate, and glass ionomers. Composite resin is
another type of cement that is set by a polymerization reaction. In addition, resin-modified glass
ionomer cement is made by combining the two reactions [7].
Bioactive glass is a relatively new agent with an ability to heal bone defects caused by trauma or
diseases and lead to bone regeneration. It has been applied in many healthcare fields. The first bioactive
glass introduced in 1969 was a sodium, calcium, and phosphorus silicate glass. Currently, there are
different types of bioactive glass, such as silicate-based glass and phosphate-based glass. Bioactive glass
is an excellent material from the perspective of material properties. Because of its bioactivity and
biocompatibility, the basic concept of applying bioactive glass in bone repair is to use a scaffold to act
as a 3-dimensional template to guide bone regeneration [8]. It has been applied in wide-ranging fields,
especially in the use of bone grafts, scaffold, disinfectant of the dental root canal and coating materials
of dental implants [9]. The main advantage of bioactive glass in bone augmentation and repair is its
high reactivity when in contact with bone surface and the most well-known capability of bioactive glass
is the bonding ability to bone as well as stimulation of bone growth [10]. Firstly, when the material is
in contact with an aqueous solution, the particles will change to mesoporous shape. Then, the particles
will form an enrichment layer to produce an apatite-like layer on bone surface, similar to the component
of bone or other hard tissues [11]. The formation of a hydroxyapatite (HA) layer involves the exchange
of ions between the bioactive glass and the bone surface. The deposition of bone-like precipitates
on bone surface plays a key role in the healing of bone defects [9]. The action on tooth is similar to
that on bone. Bioactive glass can mineralize dentine tubules to relieve tooth sensitivity. The process
is as follows: The glass material dissolves into an aqueous solution, followed by a pH rise. The pH
rise promotes precipitation of hydroxyapatite (HA), the main component of mineralized enamel
and dentine. Calcium and phosphate ions from bioactive glass and mineralizing agents in saliva
may enhance the process of mineralization [8]. The most successful commercial product derived
from a type of noncrystalline amorphous bioactive glass (Bioglass 45S5) with the name of NovaMin
(GlaxoSmithKline, UK) is used in dentine repairing toothpaste, which can relieve the symptoms of
dentine hypersensitivity. Bioglass 45S5 is silica-based and composed of 45 wt% SiO2 , 24.5 wt% CaO,
24.5 wt% Na2 O, and 6.0 wt% P2 O5 . It can appear in the form of particulates or granules [12–14].
Although studies have shown that bioactive glass has an ability to promote regeneration of
bone and mineralization of dental hard tissues, it is not known whether bioactive glass is effective
in preventing and arresting dental caries. Literature reviews conducted so far focus mainly on the
mechanisms of bioactive glass on bone regeneration, tissue engineering, or dentine hypersensitivity,
Materials 2019, 12, 4183 3 of 14

and very few have reviewed the mechanisms of action of bioactive glass on caries management.
The purpose of this study was to review the literature on the actions of bioactive glass on dental caries
management regarding its effects on the caries process and cariogenic bacteria.

2. Materials and Methods

2.1. Searching Strategy

The literature search was conducted on four databases, namely PubMed, Web of Science, EMBASE
(via Ovid), and Medline (via Ovid). Articles in these databases were searched using the keywords
(“bioglass” OR “bioactive glass” OR “bioceramic”) AND (“dentistry” OR “dental caries”).

2.2. Study Inclusion and Exclusion

The lists of publications from the four databases were checked to remove duplications. Afterwards,
the titles and abstracts of the identified articles were screened. This review aimed to summarize
the mechanisms of bioactive glass on caries management. The inclusion and exclusion criteria were
as follows.

2.2.1. Inclusion Criteria:

1. Laboratory studies
2. Studies related to the antimicrobial effect of bioactive glass
3. Studies on the remineralization effect of bioactive glass on dental hard tissues (enamel and dentine)

2.2.2. Exclusion Criteria:

1. Studies on root canal therapy and pulp regeneration
2. Studies on periodontal disease
3. Studies on orthodontic treatment
4. Studies on tissue engineering
5. Studies on bioactive composites or other bioactive materials

Two reviewers independently performed the screening to select potentially relevant articles.
An independent reviewer was consulted on studies that were not able to be determined. The information
extracted after reading the full text of the selected articles included basic publication details
(authors and year), methods and materials used, measurement of outcomes, and main results.

3. Results
A total of 1992 potentially eligible articles published up to July 2019 (1051 articles in PubMed,
437 in Medline, 253 in Web of Science, and 251 in Embase) were identified (Figure 1). After checking
for duplications, 748 records were removed. For the remaining 1244 articles, titles and abstracts
were screened and they were classified into randomized clinical trial (RCT), case report, literature
review, and laboratory study. Only laboratory studies were selected, and studies not related to the
mechanisms of bioactive glass on caries management were excluded. Full-text readings were carried
out on 49 articles and only 23 articles met the study eligibility criteria to be included in the final review.
Among these 23 publications, there were 4 studies which examined the action of bioactive glass on
cariogenic bacteria (Table 1), 12 studies focused on the remineralizing effect of bioactive glass on enamel
(Table 2), while 9 studies investigated the effect of bioactive glass on dentine mineral contents (Table 3).
Materials 2019, 12, 4183 4 of 14
Materials 2019, 12, x FOR PEER REVIEW 4 of 16

Database (keywords)
PubMed, Medline (via Ovid), Web of Science, Embase (via Ovid)
(Bioglass OR Bioactive glass OR Bioceramic) AND (Dentistry OR
Dental caries)

Records identified through database searching

(n = 1992)
PubMed (n = 1051), Medline (n = 437), Web of Science (n = 253),
Embase (n = 251)

Duplicate records
(n = 748)

Records screened by titles and abstracts for

relevance
(n=1244)
Records excluded (n = 1195)
Publications which were not related to the
mechanism of bioactive glass on caries
management such as reviews, case reports, and
clinical trials.

Full-text articles assessed for eligibility

(n = 49)

Records added from references (n = 0)

Full-text articles excluded (n = 26)

1) Studies on the different agents containing
bioactive glass, not bioactive glass itself
Full-text articles included for evaluation 2) Studies on erosion of enamel and dentine, not
artificial caries lesions
(n = 23)

Studies examining bioactive glass on

1) Cariogenic bacteria (n = 4)
2) Mineral contents in enamel (n = 12)
3) Mineral contents in dentine (n = 9)

Figure 1. Flowchart of literature search of bioactive glass.

Materials 2019, 12, 4183 5 of 14

Table 1. Summary of studies on antimicrobial effect of bioactive glass.

Author (Year) Methods Main Findings

MIC and MBC were determined to
The MBC and MIC of bioactive
test the antibacterial effect of a
Xu et al. (2015) [15] glass was 37.5 and
bioactive glass against
18.75 mg/mL, respectively.
Streptococcus mutans.
Three methods (agar diffusion,
direct contact, and MIC) were
The MIC of Biosilicate ranged
used to determine the antibacterial
from ≤ 2.5 mg/mL to 20 mg/mL in
effect of a bioactive glass-ceramic
different bacterial species. The best
(Biosilicate) against a wide
Martins et al. (2011) [16] antibacterial effect of Biosilicate
spectrum of bacteria. The assessed
was against S. mutans (inhibition
cariogenic species were
halo: 19.0 ± 2.0 mm) and S. mutans
Streptococcus mutans,
clinical isolate (MIC ≤ 2.5 mg/mL).
Lactobacillus casei,
Actinomyces naeslundii).
The increasing density of
Light absorbance was used to
silver-doped bioglass MSN
evaluate the antibacterial effect of
Jung et al. (2018) [17] induced reduction of
silver-doped bioglass MSN against
light absorbance. It illustrated that
Lactobacillus casei.
bacterial growth was inhibited.
Both the MIC of Bioglass and
Biosilicate against S. mutans were
4mg/mL, which was the same as
Agar dilution method was used to
the MIC against L. casei. Bio-FP
determine the MIC values.
doped with different cations had
Siqueira et al. (2019) [18] The assessed cariogenic species
different MIC against S. mutans
were Streptococcus mutans and
and L. casei: Ag (8 and 4 mg/mL),
Lactobacillus casei.
Mg (2 and 4 mg/mL), Sr (2 and
4 mg/mL), Zn (2 and 4 mg/mL),
Ga (2 and 4 mg/mL).
CFU, colony-forming units; MIC: minimal inhibitory concentration; MBC: minimal bactericidal concentration; TCS,
triclosan; MSN, mesoporous silica nanoparticle.

Table 2. Summary of effect of bioactive glass on enamel mineral content.

Author (Year) Methods Main Findings

Demineralized enamel was treated
Microhardness of dentine treated
with ACP-CPP and BAG, followed
with ACP-CPP and BAG both
by microhardness test. BAG and
increased but showed no
ACP-CPP were applied on
Palaniswamy et al. (2015) [19] significant difference between the
samples for 10 days in the first
1st and 2nd remineralization cycles
remineralization cycle and applied
(BAG after 10 days: 346 ± 45; BAG
for another 5 days in the second
after 15 days: 363 ± 65).
remineralizing cycle.
Demineralized teeth were
Lesion depth after
allocated into five groups as
remineralization in SHY-NM
follows: fluoridated toothpaste,
Rajan et al. (2015) [20] group showed the least mean
CPP-ACPF, ReminPro, SHY-NM
score of 987 µm compared to
and control group. Micro-CT was
other groups.
used to measure lesion depth.
Enamel samples with artificial
Microhardness recovery rate of
lesions were treated with
enamel treated with peptide was
CPP-ACP, BAG, ReminPro,
Soares et al. (2017) [21] the highest (62.1%), followed by
and self-assembling peptide.
CPP-ACPF (48.4%) and BAG
The recovery rate of
group (28.8%).
microhardness was assessed.
Materials 2019, 12, 4183 6 of 14

Table 2. Cont.

Author (Year) Methods Main Findings

Percentages of regain of lesion
Teeth with artificial carious lesions depth after remineralization in
were divided into 2 experimental BAG were more in the
groups (sodium fluoride films, experimental groups (NaF films:
Prabhakar et al. (2009) [22] bioactive glass films) and 2 control 67.7% ± 3.8%; and BAG films:
groups (control films placed 73.0% ± 3.0%) than those in the
interproximally and no control groups (control film:
treatment group). 21.1% ± 3.3%; and no treatment:
30.7% ± 2.5%).
Artificial caries lesions were Biosilicate group had higher
formed on enamel fragments and microhardness on enamel surface
either treated with Biosilicate or (265 ± 10 KHN) than APF and
Chinelatti et al. (2017) [23] acidulated phosphate fluoride control group. CLSM also
(APF), or had no treatment displayed shallower lesions in
(control), followed by Biosilicate group when compared
microhardness test. to APF and control group.
Enamel samples with artificial
WSLs were assigned to 4 groups: BAG group illustrated the highest
BAG slurry, PAA-BAG slurry, surface microhardness
Milly et al. (2013) [24] remin solution, and deionized (138 ± 5 KHN), but there were no
water; the surface and significant differences among the
cross-sectional microhardness of other groups.
enamel was assessed.
Demineralized enamel specimens
were divided into 4 groups: (1) no
intervention, (2) only bioglass,
(3) only brushing abrasion
challenge, and (4) bioglass + Hydroxyapatite was detected
brushing abrasion. using XRD on the surface of
After demineralizing and enamel in Group 2 and Group 4
Bakry et al. (2014) [25] application of bioglass, all and these two groups also
specimens were stored in exhibited 100% coverage of
remineralizing medium for 24 h, crystalline structures on
followed by removing the thin enamel surface.
layer of bonding agent on bioglass
in Groups 2 and 4, and then
Groups 3 and 4 were sent to
brushing abrasion challenge.
Artificial enamel WSLs were Intensity increase in BG group was
assigned to BG slurry, BG+PAA, significantly greater when
CS-BG, CS-BG+PAA, remin compared to those without BG.
solution, and deionized CS-BG+PAA group showed the
Zhang et al. (2018) [26] water groups. Microhardness was highest microhardness
assessed and the intensity of (222 ± 38 KHN) of enamel surface.
surface mineral content was Other groups with BG also
measured by Raman exhibited higher microhardness
intensity mapping. than the control group.
BAG group showed significant
Enamels with artificial carious
difference when compared with
lesions were treated with bioactive
control group for elements Ca
glass, fluoride toothpaste,
and P. The mean weight
Narayana et al. (2014) [27] CPP-ACP, or CPP-ACPF and the
percentage of Ca was 40.0% (BAG)
control had no treatment. EDS
and 31.1% (control), while the
was used to test the weight change
percentage of P was 14.0% (BAG)
of different elements.
and 13.2% (control).
Materials 2019, 12, 4183 7 of 14

Table 2. Cont.

Author (Year) Methods Main Findings

Enamel specimens were randomly Mean microhardness values were
distributed into two groups: BAG 372 VHN in BAG group and
Mehta et al. (2014) [28] and CPP-ACP dentifrice. 357 VHN in CPP-ACP group
Vickers microhardness test afterremineralization, but the
was used. difference was not significant.
Microhardness of enamel surface
Demineralized enamels were become higher in PB groups
treated with no treatment, fluoride (175 VHN and 221 VHN) when
varnish, cold plasma, bioglass compared with bioglass groups
EI-Wassefy et al. (2016) [29]
paste, cold plasma + bioglass paste. (153 VHN and 201 VHN) at 30 and
Microhardness was assessed by 50 µm depth, but with no
Vickers hardness tester. significant difference between the
two groups at 70–200 µm depth.
Enamel slabs with artificial WSL
Mean hardness of bioglass group
were assigned into 4 groups:
and chitosan–bioglass group were
bioglass (chitosan pre-treated
56.7 ± 8.7 and 65.1 ± 8.9 KHN,
lesions), chitosan-bioglass slurry,
Zhang et al. (2019) [30] which were significantly higher
remin solution (PC),
than those of NC group
and deionized water (NC).
(12.7 ± 1.3 KHN) and PC group
Subsurface microhardness
(18.6 ± 5.8 KHN).
was assessed.
CPP-ACP, calcium phosphate–casein phosphopeptide; SHY-NM: name of a bioactive glass; HA, hydroxyapatite;
PAA-BAG, bioactive glass containing polyacrylic acid; WSL, white spot lesions; EDS: energy dispersive X-ray
spectroscopy; CLSM, confocal laser scanning microscopy analysis; APF, acidulated phosphate fluoride; XRD,
X-ray diffraction.

Table 3. Summary of effect of bioactive glass on dentine mineral content.

Author (Year) Methods Main Findings

Teeth with root caries were
divided into 4 groups and treated
with different agents The bioglass and fluoride group
(CPP-ACP+fluoride, had the maximum reduction
bioglass+fluoride, fluoride only, (100%) in severity index of root
Sleibi et al. (2018) [31]
no treatment). Severity index of caries and it also had the highest
root caries was evaluated through percentage (60%) increase in
visual–tactile examinations. X-ray mineral deposition.
microtomography was used to
measure mineral change.
Demineralized teeth were treated
with fluoridated toothpaste,
SHY-NM (bioglass) group showed
CPP-ACPF, ReminPro, SHY-NM
Rajan et al. (2015) [20] the lowest mean lesion depth after
(bioglass), and no treatment
remineralization procedure.
(negative control). Lesion depth
was measured after application.
Dentine segments were treated
with bioactive glass (Sylc), NaH
The dentine surface hardness
C2 O4 H2 O, Cavitron Prophy
increased after treated with
Powder, EMS Perio, CPP-ACP,
Sauro et al. (2011) [32] bioactive glass (Sylc). There was
Colgate Sensitive Pro-Relief,
no significant change in Ca and
NUPRO Solution Prophy Paste.
P/O ratios.
Microhardness and EDX
were evaluated.
Materials 2019, 12, 4183 8 of 14

Table 3. Cont.

Author (Year) Methods Main Findings

Demineralized dentine discs were
treated with 3 agents: bioactive BG with 10% strontium showed
glass (BG), BG modified with 5% highest rate of remineralization
Saffarpour et al. (2017) [33]
strontium, BG modified with 10% and completely occluded
strontium and followed by dentinal tubules.
evaluation of morphology.
Dentine discs were treated with
Weight loss was less when discs
bioactive glass S53P4 and control
were pretreated with BAG
Forsback et al. (2004) [34] glass (CG). Weight loss of dentine
(21.0 ± 7.4 µg/mm2 ) than without
discs was measured by weighing
BAG (49.1 ± 6.5 µg/mm2 ).
before and after remineralization.
Demineralizing dentine bars were
applied by nanometric bioactive Dentine specimens treated with
Vollenweider et al. (2007) [35] glass (NBG) and PeriGlas NBG showed apatite depositions
(PG) suspension. SEM was used to on the surface after 10 or 30 days.
observe the dentine surface.
Silver-doped bioglass MSN group
Demineralized dentine discs were
had dentinal tubules completely
divided into four groups: bioglass,
occluded to a depth of 2–3 µm and
Jung et al. (2018) [17] MSN, silver-doped bioglass MSN,
the highest proportion
and no treatment, followed by
(83.4% ± 7.5%) of occluded area
acid resistance test.
after acid challenge.
Root dentine slices were allocated
into four groups: MTA, ERRM, Bioglass 45S5 group showed an
Cardoso et al. (2018) [36]
Bioglass 45S5, and NbG. increase in microhardness.
Microhardness was assessed.
Dentine discs treated with EDTA
Compared to AS and Asp group,
were allocated to 4 groups: AS
BAG group (17.8 ± 2.3) and
(artificial saliva), Asp, BAG,
Zhang et al. (2019) [37] Asp-BAG group (12.5 ± 2.3) had
Asp-BAG, and followed by 6%
significantly higher mineral matrix
citric acid challenge. The mineral
area ratio.
matrix ratio was measured.
EDX, energy dispersive X-ray spectroscopy; Ag-BGN, silver-doped bioactive glass; MSN, mesoporous silica
nanoparticle; DW: deionized water; EDTA, ethylene diamine tetraacetic acid; Asp, DL-aspartic amino; MTA, mineral
trioxide aggregate; ERRM, EndoSequence Root Repair Material; NbG, niobophosphate glass.

3.1. Effect of Bioactive Glass on Cariogenic Bacteria

Table 1 shows the main findings of the four studies that investigated the effect of bioactive
glass on cariogenic bacteria. A study found that the minimal inhibitory concentration (MIC) and
minimal bactericidal concentration (MBC) of bioactive glass powder (45S5; Datsing Bio-Tech Co. Ltd,
Beijing, China) were 18.8 and 37.5 mg/mL, respectively. The study showed that when bioactive glass
dissolved in water, alkaline ions were released to raise the pH of the solution and this could kill
Streptococcus mutans [15]. Another type of bioactive glass-ceramic (Biosilicate) was shown to exhibit
antimicrobial properties that could inhibit a wide spectrum of microorganism. It was found that
Biosilicate possessed antibacterial action against multi-species cariogenic bacteria strains, such as
Streptococcus mutans, Actinomyces naeslundii, Lactobacillus casei, through agar diffusion and direct
contact [16]. Another investigation found that growth of L. casei incubated in a silver-doped bioactive
glass (Ag-BGN@MSN) was inhibited. Silver melted into bioactive glass displays a synergistic effect
on microorganisms as it can inhibit the growth of cariogenic bacteria [17]. A study investigated
cation-doped (Ag, Mg, Sr, Zn, and Ga) bioactive ceramics and revealed a bacterial inhibitory effect on
Streptococcus mutans and Lactobacillus casei with varied MIC [18].
Materials 2019, 12, 4183 9 of 14

3.2. Effect of Bioactive Glass on the Mineral Content of Enamel and Dentine
Table 2 shows the main findings of the 12 published papers that investigated the effect of bioactive
glass on the mineral content of enamel. Demineralized enamel was treated with different types of
bioactive glass. Surface microhardness of the enamel tissue decreased after the demineralization
procedure and increased after application of bioactive glass. The value of microhardness was found
to be higher in bioactive glass group when compared to the control group or application of other
agents [19–21,23,29,38]. A study reported the recovery rate of microhardness on demineralized
enamel surface after treatment with bioactive glass was 28.8% [21]. Further investigation showed
that a combination of bioglass paste and cold plasma had a synergistic effect on increasing the
surface microhardness of demineralized enamel [29]. Apart from assessing microhardness, the mean
carious lesion depth in specimens treated with bioactive glass were significantly lower than those of
specimens without bioactive glass treatment [20,26,38]. A study assessed the percentage of regain in
lesion depth after remineralization and the experimental group with bioactive glass had the highest
regain percentage (73.0 ± 3.0%) of lesion depth in enamel [22]. In addition, energy-dispersive X-ray
spectroscopy (EDX) analysis indicated that Ca/P ratio was higher in the region treated with bioactive
glass than in other regions not covered by bioactive glass particles [26,29,30]. One study found that
compared to just application of deionized water, enamel lesions after treated with two bioactive glass
had significantly higher Ca/P ratios [30].
Table 3 shows the main findings of the nine studies on the effect of bioactive glass on the mineral
content of dentine. Microhardness measurement was a commonly used method to evaluate the
surface of the demineralized dentine. The remineralization process induced an increase in surface
microhardness of carious lesions [32]. In addition, it was found that application of Bioglass 45S5
significantly increased root dentine microhardness [36]. Dentine lesion depth decreased after the
application of bioactive glass in two in vitro studies [17,20]. Another study used visual–tactile
examination to assess the severity of root caries and found that there was a significant reduction in
the group combining bioglass and fluoride and that group also had the highest percentage (60%)
increase in mineral deposition [31]. Dentine discs treated with bioactive glass had significantly higher
mineral matrix area ratio when compared to that of discs in the artificial saliva and DL-aspartic amino
groups [37]. Furthermore, weight loss of dentine slices treated with BAG S53P4, an amorphous glass
with the composition of 53 wt% SiO2 , 23 wt% Na2 O, 20 wt% CaO, and 4 wt% P2 O5 , was less than that
of slices without such treatment [34]. EDX was used in a study to analyze the elements in the occluding
materials within dentine tubules. The results indicated that the ratio of Ca/P of hydroxyapatite was
not significantly different between the bioactive glass and control groups [39].
Apart from the approaches mentioned above, qualitative parameters were also used to measure the
mineralization effect of bioactive glass on enamel and dentine. Most of these studies [25–27,29,33,35,37]
analyzed the morphology of enamel and dentine surface using scanning electron microscopy (SEM).
The deposits newly formed on the surface of dental hard tissue were crystal-like hydroxyapatite (HAP)
and rich in calcium and phosphate with the presence of silica. A layer of mineral formed by the particles
of bioactive glass covered the lesion surface in the remineralized enamel group [24]. Different from that
seen on enamel, a layer of particles of bioactive glass not only deposited on the dentine surface, but also
partially or completely occluded dentine tubules during remineralization [33,39]. Figure 2 shows two
SEM images of demineralized dentine with or without treatment with bioactive glass. After observing
the morphology of the remineralized enamel and dentine, the content of the new deposition was
assessed by X-ray diffraction (XRD) [25]. XRD results showed that the bioactive glass (Ag-BGN@MSN)
particle used had an amorphous two-dimensional hexagonal structure [17]. Another XRD study found
that both nanoparticles and conventional bioactive glass were in amorphous state [35]. Furthermore,
XRD results of another two studies matched the standard diffraction peak of hydroxyapatite crystal
on the enamel and dentine surfaces [31,37]. Strontium-modified bioactive glass displayed a higher
intensity of XRD peaks than that of the original bioactive glass [33]. Another study used a qualitative
method to assess the mineral concentration by using X-ray microtomography. The result showed that
Materials 2019, 12, 4183 10 of 14

the highest percentage increase of mineral content in the lesion area that was treated with bioglass and
fluoride [31]. Raman spectroscopy was another method used in the studies to confirm the content of
remineralized enamel and dentine tissues. The phosphate peak of sound enamel and dentine appeared
in a specific wavelength (around 960 cm−1 ) of Raman spectra, while demineralized hard tissues showed
no peaks. In two studies, the dental tissues treated with bioactive glass displayed the intensity of
phosphate peak [26,32], while another study illustrated that there was a reduction of the intensity of
phosphate peak in demineralized enamel compared to sound enamel [24]. Demineralized dentine
showed phosphate peak after one-day treatment with nanoparticle bioactive glass, but no phosphate
peak appeared after treatment with conventional bioglass, though all the dentine specimens immersed
in the two
Materials types
2019, of bioactive
12, x FOR glass had deposition of apatite on the surface after 10 or 30 days [35].
PEER REVIEW 12 of 16

(a) (b)

images of
Figure 2. SEM images ofthe
themorphology
morphologyofofdemineralized
demineralized dentine:
dentine: (a)(a) 10,000×
10,000× magnification
magnification image
image of
of demineralized
demineralized dentine
dentine treatedtreated with bioactive
with bioactive glass; (b)
glass; (b) 10,000× 10,000× magnification
magnification image of
image of demineralized
demineralized
dentine withoutdentine without
treatment with treatment with bioactive glass.
bioactive glass.

3.3. Effect of
3.3. Effect of Bioactive
Bioactive Glass
Glass on
on the
the Organic
Organic Content
Content of
of Dentine
Dentine
Only
Only two
two studies
studiesmentioned
mentionedchanges
changesininthe
theorganic
organiccontent
contentof dentine.
of dentine.One of them
One found
of them thatthat
found the
dentine remineralized in nanometric bioactive glass suspension, compared to the dentine ®
the dentine remineralized in nanometric bioactive glass suspension, compared to thein dentine
PeioGlasin
(Millipore, Bedford, MA,
PeioGlas® (Millipore, USA),MA,
Bedford, Bioglass
USA),45S5 with particles
Bioglass 45S5 withsize rangingsize
particles from 90 to 710
ranging fromµm90showed
to 710
aµm significantly lower protein content due to the removal of organic contents [35]. As
showed a significantly lower protein content due to the removal of organic contents [35]. As illustrated in
another study,
illustrated Raman spectra
in another study, showed no peakshowed
Raman spectra for hydroxyapatite
no peak for but only a high intensity
hydroxyapatite but onlyof organic
a high
components in the demineralized dentine without treatment by the bioactive glass [32].
intensity of organic components in the demineralized dentine without treatment by the bioactive Lower organic
content indicates
glass [32]. Lower better remineralization.
organic content indicates better remineralization.
4. Discussion
4. Discussion
After screening and analyzing the results of all selected laboratory studies, a number of possible
After screening and analyzing the results of all selected laboratory studies, a number of possible
mechanisms of how bioactive glass act on dental caries were found. The mode of action of bioactive
mechanisms of how bioactive glass act on dental caries were found. The mode of action of bioactive
glass for arresting caries is related to two aspects: 1) the antibacterial properties of bioactive glass on
glass for arresting caries is related to two aspects: 1) the antibacterial properties of bioactive glass on
cariogenic bacteria, and 2) the remineralizing effect on the mineral content of dental hard tissues.
cariogenic bacteria, and 2) the remineralizing effect on the mineral content of dental hard tissues.
In the oral cavity, oral microbiota and dental biofilms are commonly present. Formation of dental
In the oral cavity, oral microbiota and dental biofilms are commonly present. Formation of
plaque (dental biofilm) involves several stages. First, the acquired pellicle on tooth surface provides
dental plaque (dental biofilm) involves several stages. First, the acquired pellicle on tooth surface
sites for bacterial colonizers. The oral microorganisms then grow and form a conditioning film of
provides sites for bacterial colonizers. The oral microorganisms then grow and form a conditioning
bacteria, proteins, and other bacterial products covering the tooth surface. Streptococci, Lactobacilli,
film of bacteria, proteins, and other bacterial products covering the tooth surface. Streptococci,
and Actinomycetes are recognized as the main species of bacteria contributing to caries progression.
Lactobacilli, and Actinomycetes are recognized as the main species of bacteria contributing to caries
Streptococci have high incidence and proportions and in the dental biofilms covering early caries
progression. Streptococci have high incidence and proportions and in the dental biofilms covering
lesions [2]. The key microorganism in initiating and developing dental caries is Streptococcus mutans
early caries lesions [2]. The key microorganism in initiating and developing dental caries is
(S. mutans). Lactobacillus casei (L. casei) is a type of cariogenic bacteria strains that commonly appear in
Streptococcus mutans (S. mutans). Lactobacillus casei (L. casei) is a type of cariogenic bacteria strains that
deep or advanced caries lesions. More recently, another type of acid-producing and acid-tolerating
commonly appear in deep or advanced caries lesions. More recently, another type of acid-producing
species, called Actinomycetes, has been found to be associated with caries [40]. This systematic review
and acid-tolerating species, called Actinomycetes, has been found to be associated with caries [40]. This
systematic review found that very few studies investigated the antimicrobial effect of bioactive glass.
This may be because the most obvious advantage of bioactive glass is its remineralization effect on
bone and teeth rather than its bactericidal efficacy. Xu et al. assayed plaque biofilm of S. mutans and
applied bioactive glass 45S5 at a concentration twice of the minimal bactericidal concentration to
show that the bioactive glass had a great inhibitory effect on S. mutans biofilm [15]. This suggests that
Materials 2019, 12, 4183 11 of 14

found that very few studies investigated the antimicrobial effect of bioactive glass. This may be
because the most obvious advantage of bioactive glass is its remineralization effect on bone and
teeth rather than its bactericidal efficacy. Xu et al. assayed plaque biofilm of S. mutans and applied
bioactive glass 45S5 at a concentration twice of the minimal bactericidal concentration to show that
the bioactive glass had a great inhibitory effect on S. mutans biofilm [15]. This suggests that the
concentration of antimicrobial agent needed for inhibiting biofilm may be many times higher than
that for inhibiting planktonic bacteria. The possible action of bioactive glass acting on cariogenic
bacteria is release of alkaline ions, followed by pH elevation that builds an environment in which
bacteria cannot grow. This is similar to the mechanism of action of arginine, an amino acid, in which
the arginine deiminase system has been identified as a novel technology to prevent initiation of the
dental caries process by increasing pH around the biofilm on tooth surface [3]. Apart from the process
of pH elevation, the presence of antibacterial ions can also control bacterial growth. Cation-doped
bioactive ceramics, such as Ag, Mg, Sr, and Zn, have good inhibitory effect on S. mutans and L. casei [18].
Two literature reviews proposed that silver diamine fluoride (SDF), in which silver ion is the major
antimicrobial agent, is an effective treatment to arrest established dental caries [3,40]. It has been shown
by utilizing bacterial and biofilm models, that SDF can inhibit the growth both Streptococcus mutans
and Actinomyces naeslundii [41]. Therefore, bioactive glass with silver may have additional inhibition
effect against cariogenic bacteria.
The various compositions in bioactive glass have different roles in the remineralization process.
The proportion of calcium and phosphate in dental tissues is identical to that in bone. Phosphate has
a great contribution to hydroxyapatite formation and increases biocompatibility significantly.
Formation of hydroxyapatite layer promotes remineralization in enamel and dentine. The physical
occlusion on the lesion surface begins with the bioactive glass particles exposed to the aqueous
environment, along with ion release and pH elevation [37]. When the biomaterial is exposed to
an aqueous environment, sodium ions will exchange with H+ (hydrogen ions). Meanwhile, Ca2+
(calcium ions) in the particles as well as PO4 3− (phosphate ions) are released from the biomaterial.
Thus, a localized pH rise will allow the precipitates of calcium and phosphate ions, together with
the ions from saliva to form a calcium phosphate (Ca–P) layer on the lesion surface [20]. The silica
network from bioactive glass can react with hydroxyl ions from aqueous solution and form soluble
silanol compounds. It can be observed that the increase in Ca and P content would induce a decrease
in Si content [29]. The newly formed layer displays good resistance to abrasion and transforms
to a hydroxyapatite layer ultimately, which is structurally similar to those of original enamel and
dentine [32].
Topical fluoride has already been proved to be effective in treating dental caries. The mechanism
of fluoride is to inhibit demineralization and promote remineralization, which conducts a similar
procedure with bioactive glass. The fluoride in oral fluid or solution can penetrate along with
the acid at the subsurface and protect the minerals from dissolution, and thus prevents the
demineralization process. After acidic challenge, fluoride will be adsorbed to the demineralized
crystals and attract calcium ions, thus making the solution highly supersaturated with respect to
fluorohydroxyapatite, which can promote the remineralization process [42]. A recent review found
that SDF can inhibit the demineralization and promote remineralization of the mineral content of
enamel and dentine and protect collagen matrix from degradation [40]. An in vitro study showed that
the fluoride in bioactive glass could be switched to fluorapatite on the tooth surface, which leads to
higher resistance to acid dissolution [20]. The precipitation of mineral deposits occurs mostly in the
superficial layer, particularly when fluoride is present [31]. The deposition of a fluoride-contained
mineral layer on dentine surface can occlude dentine tubules and reduce permeability [21].
A study stated that strontium can be a substitution of calcium in bioactive glass which
may show a better bonding ability [9]. Strontium can supply ions for hydroxyapatite formation.
Incorporation of strontium and fluoride can inhibit hydroxyapatite dissolution by the acids produced
by cariogenic bacteria. Strontium can be a substitute for calcium for precipitate formation and
Materials 2019, 12, 4183 12 of 14

it has synergistic caries inhibition effect with fluoride. The remineralization effect can last for
different periods due to the addition of various proportions of strontium into the bioactive glass,
which shows that strontium may be a beneficial factor in preventing caries through remineralizing
dental hard tissues [33]. Besides, nanometric particles of bioactive glass have better remineralization
potential compared to the conventional ones because of its larger surface area and higher Ca/P
ratio [22]. The experiments conducted by Meret showed a greater effect of remineralization on
dentine surface due to the nanosize of bioactive glass [35], while another study also demonstrated
that Biosilicate microparticles were more effective in slowing down progression of caries lesions and
promoting remineralization [38]. Smaller particles may completely block the porosity of enamel and
dentine lesions. These microstructures are capable of penetrating from the tooth surface to the whole
lesion and enhancing the remineralization of carious lesions [24].
An advantageous aspect of bioactive glass is its bioactivity and biocompatibility. Previous studies
adopted the direct contact cell viability method to evaluate the biocompatibility of bioactive glass and
showed a high cell survival rate [43,44]. As a very safe material and based on the merits stated above,
a potential new application of bioactive glass is for dental caries prevention and remineralization of
early caries lesions [45]. Further research should pay more attention to how the bioactive glass work in
treating dental caries in the real oral environment.

5. Conclusions
Based on the findings of the present review, it is concluded that bioactive glass is able to inhibit
the growth of cariogenic bacteria. Bioactive glass can promote remineralization by forming apatite
on the surface of demineralized enamel and dentine. The main mechanisms of bioactive glass for
caries management include an antibacterial effect on cariogenic bacteria, prohibition of mineral
demineralization, and promotion of remineralization.

Author Contributions: L.L.D. conducted the literature search and drafted the manuscript. M.L.M. helped to
design the manuscript structure and double confirmed the including articles. C.H.C. reviewed the article and
gave some suggestions. E.C.M.L. revised and finalized the manuscript of this review.
Funding: This review received no external funding.
Conflicts of Interest: The authors declare no conflict of interests.

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