10 1016@j Dental 2020 03 020

DENTAL-3527; No.
of Pages 37
ARTICLE IN PRESS
d e n t a l m a t e r i a l s x x x ( 2 0 2 0 ) xxx–xxx
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.intl.elsevierhealth.com/journals/dema
Bioactivity assessment of bioactive glasses for

dental applications: A critical review
Caroline Mocquot a,b,∗ , Nina Attik a,c , Nelly Pradelle-Plasse a,b , Brigitte
Grosgogeat a,c,d , Pierre Colon a,b
a Université de Lyon — Université Claude Bernard Lyon 1, UMR CNRS 5615, Laboratoire des Multimatériaux et
Interfaces, 69372 Lyon Cedex 08, France
b Assistance Publique-Hôpitaux de Paris, Hôpital Rothschild, Service d’Odontologie, Université de Paris, Faculté
dentaire, France
c Université de Lyon, Université Claude Bernard Lyon 1, Faculté d’Odontologie, 69008 Lyon, France
d Hospices civils de Lyon, Service d’Odontologie, 69007 Lyon, France
a r t i c l e i n f o a b s t r a c t
Article history: Objective. In the context of minimally invasive dentistry and tissue conservation, bioac-
Available online xxx tive products are valuable. The aim of this review was to identify, clarify, and classify the
methodologies used to quantify the bioactive glasses bioactivity.
Keywords: Methods. Specific search strategies were performed in electronic databases: PubMed, Embase,
Restorative dentistry Cochrane Library, and Scopus. Papers were selected after a review of their title, abstract,
Enamel and full text. The following data were then examined for final selection: BAG investigated,
Dentin objectives, criteria, methods, and outcomes.
Bioactivity Results. Sixty studies published from 2001 to 2019, were included. The bioactivity of BAG
Bioactive glasses can be evaluated in vitro in contact with solutions, enamel, dentin, or cells. Other stud-
Remineralization ies have conducted in vivo evaluation by BAG contact with dentin and dental pulp. Studies
have used various analysis techniques: evaluation of apatite with or without characteri-
zation or assessment of mechanical properties. Reprecipitation mechanisms and pulp cell
stimulation are treated together through the term ‘bioactivity’.
Significance. Based on these results, we suggested a classification of methodologies for a
better understanding of the bioactive properties of BAG. According to all in vitro studies, BAG
appear to be bioactive materials. No consensus has been reached on the results of in vivo
studies, and no comparison has been conducted between protocols to assess the bioactivity
of other bioactive competitor products.
© 2020 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.
∗
Corresponding author at: Laboratoire des Multimatériaux et Interfaces/Faculté d’Odontologie - Université de Lyon 1, 11 rue Guillaume
Paradin, 69372 Lyon Cedex 08, France.
E-mail addresses: caroline.mocquot@etu.univ-lyon1.fr (C. Mocquot), nina.attik@univ-lyon1.fr (N. Attik).
https://doi.org/10.1016/j.dental.2020.03.020
0109-5641/© 2020 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.
Please cite this article in press as: Mocquot C, et al. Bioactivity assessment of bioactive glasses for dental applications: A critical review. Dent
Mater (2020), https://doi.org/10.1016/j.dental.2020.03.020
DENTAL-3527; No. of Pages 37
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2 d e n t a l m a t e r i a l s x x x ( 2 0 2 0 ) xxx–xxx
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00
2. Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Inclusion and exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3. Paper selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.4. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Study selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00
3.2. Main characteristics of selected articles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.1. BAG investigated . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.2. Comparison with . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.3. Objectives, Criteria, and Methods – Results in terms of objectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Study selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00
4.2. Methodologies linked to biomaterial chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.1. Particles sizes and morphology in relation to the manufacturing method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.2. Glass composition - SiO2 /Na2 O/CaO ratio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.3. Glass composition: adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.4. Bag versus other materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3. Methodologies to assess bioactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3.1. In vitro solution - mechanism of apatite formation on bag surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3.2. In vitro remineralization of enamel and/or dentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3.3. In vitro effect of bag on the mineralization capacity of cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3.4. In vivo remineralization of enamel and/or dentin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00
4.3.5. In vivo evaluation of dentin mineralization and/or dental pulp response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3.6. Association of two categories of methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4. Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
modified to create mesoporous BAG, to change particle size

1. Introduction (nano or micro-scale) or to add additives [6]. BAG are consid-
ered bioactive materials; however, a better definition of the
Minerals ions can be removed from hydroxyapatite (HA) crys- bioactive effect is required to improve formulations or incor-
tals of dental hard tissues, enamel and dentin, in case of poration of particles in scaffolds [7,8].
erosive attack or carious lesions, this process is demineraliza- It is generally accepted that a bioactive material is a mate-
tion. Restoring these mineral ions to the HA crystals is called rial able to induce specific biological activity and stimulate a
remineralization [1]. The contemporary approach to caries beneficial response from the body bonding to the host tissue
management has drastically changed: operative strategies are [5,9]. Regarding BAG, Lebecq et al. defined bioactivity by fol-
abandoned in favor of biologic approaches based on individual lowing the crystalline hydroxy-carbonate apatite (HCA) layer
caries risk, preventive dentistry, and non-invasive or minimal growth on the surface of glass particles [10]. According to
options [2,3]. Remineralization is a non-invasive treatment to other definitions, the bioactivity is the ability to form mineral
preserve dental tissues after an acidic attack. In situ remineral- deposits in biological conditions [11].
ization could occur with a dissolution reprecipitation process In the dental field, the definition of bioactivity depends on
in enamel or in dentin, but new tertiary dentin could also be the clinical use from the ability to induce reprecipitation of
produced by stimulation of pulp cells [4]. BAG are involved in HA on the surface of enamel and dentin to cellular effects
both processes, but some studies have focused only on the first induced by the release of biologically active substances and
mechanism because others have focused on the second mech- ions. There is no consensus on bioactivity’s definition. Vallittu
anism; thus, the term bioactivity for BAG remains unclear. et al. suggested limiting the terms ‘bioactive’ with respect to
BAG were introduced in 1969 by professor Larry Hench (BAG dental materials only to scientifically proven materials and
45S5), the composition was 45% silica (SiO2 ) — 24.5% calcium material combinations that release substantial quantities of
oxide (CaO) — 24.5% sodium oxide (Na2 O) — 6% phosphate ions for specific biomineralization in the clinical environment
(P2 O5 ). Initially, BAG were used for medical application for of the material [12].
their ability to form a bond with bone [5]. Nowadays, the origi- The main objective of this review was to identify and clas-
nal composition (45S5) and manufacturing method of BAG are sify the different methodologies used for the BAG bioactivity
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d e n t a l m a t e r i a l s x x x ( 2 0 2 0 ) xxx–xxx 3
quantification regarding dental hard tissues, to determine the for full analysis. The two authors were also the two reviewers
key parameters considered for these studies and therefore, to and assessed the full text articles independently. Any dis-
influence dental research and clinical practice on an interna- agreement on the eligibility of studies included was resolved
tional basis. through discussion and consensus.
2. Materials and methods 2.4. Data extraction
The website COVIDENCE was used to import references and One author (CM) extracted the data using a prepiloted data col-
view duplicates, titles, abstracts, and full texts. lection form, and a second author (BG) verified data extraction
independently for completeness and accuracy. Data obtained
were as follows: general study details (first author, date of pub-
2.1. Inclusion and exclusion criteria
lication); population: BAG investigated (e.g. glass label, size of
particles if mentioned, technique used to elaborate BAG, BAG’s
To identify relevant studies, the following inclusion and exclu-
composition, comparison with); and the objectives, criteria,
sion criteria were defined.
methods (solutions, time of storage, and analysis), and out-
The search strategy was conducted to include research
comes of studies. Any potential conflict was resolved by a joint
articles that have evaluated the bioactivity of BAG (without
discussion between the two authors.
additives, scaffolds, or other constituents other than SiO2 ,
CaO, Na2 O, or P2 O5 ) with the perspective of dental applica-
tions. BAG with phosphoric acid (PPA) or polyacrylic acid (PAA) 3. Results
were included because these adjunctions were used to mod-
ify the consistency of BAG (from powder to paste) and not the 3.1. Study selection
composition.
The search strategy was conducted to exclude case reports, The initial electronic search using the keyword combination
abstracts, literature review articles, retrospective studies, returned 1077 articles. After the removal of duplicates, 709
editorials, opinions, surveys, guidelines, conferences and records were examined. The title and abstracts of the remain-
commentary articles, and publications in a language different ing 709 papers were screened, and 563 papers were excluded
from English or French. because they were irrelevant to the inclusion criteria. Finally,
The series of inclusion and exclusion criteria were estab- 146 relevant papers were scrutinized by downloading the
lished by a consensus of all authors after discussions and papers and reading the full text. A consensus between the two
while considering the research question—How to evaluate the authors was reached to determine which studies fully fulfilled
bioactivity of bioactive glasses for dental applications?—And the selection criteria. Ninety-eight papers were excluded after
the objectives of the study. reading the full text. Thirteen papers were found from the ref-
erences of the selected papers, and these were also assessed
2.2. Search strategy in a similar manner. Finally, 61 studies were included in this
review (Fig. 1).
Four databases were screened: PubMed, Embase, Cochrane
Library, and Scopus. The references cited in the articles 3.2. Main characteristics of selected articles
included were also checked. The published scientific articles
from May 1999 to January 2020 were systematically assessed A wide range of analysis of bioactivity was presented from
for this review. the included studies. The most common analysis was the for-
Search strategies were developed and performed in the four mation of apatite by in vitro evaluation in solutions. Other
electronic databases. The search terms were divided in three analysis corresponded to enamel and/or dentin remineraliza-
parts: tion in vitro, mineralization ability of cells in vitro, and pulp
capping or pulpotomy in vivo. Data obtained were as follows:
- Teeth, for example, enamel, dentin, dental, dentistry, teeth, BAG investigated, criteria, methods, and main results.
and tooth.
- Bioactive glasses, for example, bioactive glass, bioglass, 3.2.1. BAG investigated
45S5, and nanobioactive glass. The majority of BAG were made by melt-quench (about
- Bioactivity, for example, remineralization, bioactivity, bioac- twenty) and sol–gel techniques (n = 15). There were 4 BAG
tive, and biomineralization. made by the EISA (Evaporation Induced Self-Assembly) pro-
cess and 3 by flame spray synthesis.
2.3. Paper selection The size of particles was not systematically specified.
About twenty studies stipulated that BAG had a micromet-
The titles and abstracts of all articles identified by the elec- ric size, especially 38 or 45 ␮m. Eight BAG had nanometric
tronic search were read and assessed by two authors (CM and size (BGn/nBG/BGNR/NBG), from 10 to 590 nm and included
BG) until January 2020. All titles and abstracts were exam- 34, 20–60, 80–90, 100, 510 nm. Some BAG were mesoporous
ined and selected in accordance with the eligibility criteria. (MBG/MBGs).
Those that appeared to fulfil the inclusion criteria, or with The composition of BAG was mainly traditional BAG 45S5
insufficient data in the title and the abstract, were selected (about thirty). Other studies changed the concentration of SiO,
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Fig. 2 – Number of publications reported for each analysis

technique of apatite formation in vitro in solutions.
- 4: Laser irradiation.
3.2.3. Objectives, Criteria, and Methods – Results in terms

of objectives
3.2.3.1. Mechanism of apatite formation on BAG surface in vitro
in solutions. The majority of articles evaluated the bioactivity
of BAG in solutions in vitro (Table 1). Simulated body fluid (SBF)
(n = 23) was the main solution used; however, a large part of the
research used Tris buffer solution (TBS) (n = 7) and one study
used Hank’s solution. Two studies used SBF and TBS.
The objectives and criteria of these studies were to evaluate
the formation of apatite in vitro. There was no consensus on
contact time: 15, 20, or 30 min; 1, 3, 4, 6, 8, 9, or 12 h; 1, 2, 3, 5, 7,
9, 17, or 30 days; and 2, 3 or 4 weeks. Studies used the following
analysis techniques:
Fig. 1 – Flow diagram of study identification.
- Microscopic observations: Scanning electron microscopy
(SEM), field emission-SEM (FESEM), and transmission elec-
tron microscopy (TEM).
CaO, Na2 O, or P2 O5 to modify the characteristics and bioactiv-
- Chemical or structural analysis: Energy dispersive X-ray spec-
ity of BAG. Five BAG were made only with SiO2 and CaO: 90 or
troscopy (EDX), Fourier transform infrared spectroscopy
85 or 70 (%)–10 or 15 or 30 (%), respectively. About twenty BAG
(FTIR), X-ray diffraction (XRD), solid state nuclear magnetic
were made without Na2 O.
resonance (NMR), Raman spectroscopy, inductively coupled
plasma (ICP), and UV–vis spectrophotometer.
3.2.2. Comparison with - Association between microscopy and chemical or structural anal-
The BAG without adjuvants were compared with the following: ysis: SEM-EDX.
- 1: Control group (artificial saliva, demineralized water. . .). The main analysis techniques were SEM, FTIR, XRD, and
- 2: BAG with adjuvants (fluoride (n = 9), potassium (n = 2), solid state NMR (Fig. 2).
strontium (n = 2), magnesium (n = 1), zinc (n = 1), bismuth Results lead to the following conclusion: apatite formation
oxide (n = 1), ampicilline (n = 1), siRNA (Small Interfering occurs by contact with BAG and solutions.
Ribonucleic Acid) (n = 1), barium (n = 1). . ..), or scaffolds (chi-
tosan [CS] or polycarbolactone [PCL]). 3.2.3.2. BAG capacity to remineralize enamel and/or dentin
- 3: Oxide alone (ZnO), antiseptic (chlorhexidine [CHX]), in vitro. To evaluate the ability of BAG to remineralize dental
desenziting agents (with oxalate) or bioactive products tissues, 16 studies used human dentin, 9 studies used human
(caseinphosphopeptide-amophouscalciumphosphate [CPP- enamel, and 2 studies bovine enamel in vitro (Table 2).
ACP], stannous fluoride, mineral trioxide aggregate (MTA), The objectives were to assess BAG capacity to remineral-
formocresol, ferric sulfate, BiodentineTM , biosilicate, cal- ize enamel and/or dentin in vitro. Many criteria were used, for
cium phosphate cement, calcium hydroxide [CH], BAG example, mineral changes (Ca/P ratio, presence of Ca, P, Si,
modified with soda lime spherical glass or laser irradiation, O, or Na), surface and subsurface microhardness, roughness,
coating glasses. . .) or restorative materials: dental adhesive, formation of the pellicle layer or globular HA, improve-
glass porcelain system, glass ionomer cement/resin- ment of mechanical properties, surface morphologies, tubular
modified glass ionomer cement (GIC/RMGIC). obstruction for dentin, tubular fluid. No consensus was
Table 1 – Selected articles: In vitro mechanism of apatite formation on BAG surface in solutions. BAG compared with: 1 Control group; 2 BAG with adjuvants; 3 Oxide alone,
antibacterial, desensitizing agents, bioactive, or restorative materials. Analysis: 1 Microscopic observations; 2 Chemical or structural analysis. ( = not specified in the article /
m = minutes; h = hours; d = days; w = weeks; m = months).
References Bag investigated Compared Methods
Main
with Criteria
results
Authors Glass Manufac- Glass composition by mol% Contact Analysis
label turing Interface
Date time
–size methods SiO2 CaO Na2 O P2 O5 1 2 3 1 2
Takadama – 2001 [75] Glass specimen MELT-QUENCH 80 0 20 0 Apatite SBF 12 h – 1, 5, 10, X X Na2 O-SiO2 glass
formation 17, 28 d induced
mineralization of
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apatite on its
surface in the
SBF.
Forsback – S53P4 (<45 m) 53 20 23 4 Silica con- Time up After a short
X TBS X period of
2004 [51] centration to 24 h
immersion, silica
is dissolved from
both types of
glasses, but the
amount of silica
released is much
higher from
Control glass (CG) S53P4 than from
(<45 m) CG.
Lin – 2005 [76] GEL-SILICA SOL–GEL 70 30 0 0 Apatite SBF 20 m - 1, 3, 6, X X After 1 h of SBF
Glasses formation 12, 21.5 h soaking, there
was a significant
increase in the
phosphorus
density of the
phosphorus
species on the
glass surface.
Presumably, an
amorphous layer
with
constituents
similar to HA
had formed on
the glass surface.
5
6
– Table 1 (Continued)
Main
with Criteria
results
Date time
Goudouri – 2009 [77] BG SOL–GEL 60 36 0 4 X Formation of SBF 6, 12, 24, 48 h X X Apatite
apatite formation from
pure BAG is
compared with
dental glass
ceramic
composites
products in SBF
ARTICLE IN PRESS
solutions. Level
of bioactivity is
evaluated
through the
kinetic of apatite
formation.
Porous particles
improved the
level of
bioactivity.
Moawad – 2009 [35] 48S MELT-QUENCH 48 yCaO – zNa2O: y + z = 49.32.7 X Formation of SBF 7d X Diffraction peaks
HA layer for the surface
layer on 48S4F
(4%CaF2 ) glass
are stronger than
those for the
layer on 48S
glass. This
simple
comparison
suggests that the
presence of
fluoride ions
likely enhanced
the bioactivity of
BAG.
Brauer – 2010 [38] GLASS A – 38 m MELT-QUENCH 49.47 23.08 26.38 1.07 X Apatite SBF 3 d – 1, 2 w X Incorporation of
deposition fluoride that
resulted in the
formation of FAp
compared with
fluoride-free
glasses.


Main
with Criteria
results
Date time
Gunawidjaja – 2010 MBG – S85 EISA process 85 10 0 5 Formation of SBF 30 m – 1, 4 h - X The phosphorus
[32] amorphous 1, 3, 7 d content
calcium increased only
phosphate marginally over
layer and the first 4 h of
crystallization SBF exposure
into HCA relative to the
initial value of
S85. The 2
ARTICLE IN PRESS
formations of
ACP and HCA
partially
occurred
simultaneously,
and the former
was most active
over the initial
24 h of SBF
immersion and
the latter
dominating
between 3 and 7
days.
Mohn – 2010 [78] 45S5 – 34 nm FLAME SPRAY 45 24.5 24.5 6 X Formation of SBF 7d X X Radiopaque BAG
SYNTHESIS carbonated with bismuth
hydroxyapatite oxide had higher
in vitro bioactivity
regarding the
formation of
carbonated HA.
Brauer – 2011 [36] GLASS A MELT-QUENCH 48.47 23.08 26.38 1.07 X Apatite TBS 1, 3, 7, 14 d X Glasses formed
formation apatite in TBS.
However, Glass
A.1 (0.94% CaF2 )
showed more
clearly
pronounced
peaks and higher
peak intensities
in XRD compared
with
fluoride-free
glass A.
7
8

Main
with Criteria
results
Date time
Goudouri – 2011 [31] BG SOL–GEL 60 36 0 4 X Apatite SBF 6, 12 h - 1, 2, X X The lower rate of
formation 3, 6, 9 d - 2, 4, bioactivity of the
8, 12, 18 d dental ceramic
with BG in
comparison with
the powdered BG
samples was a
result of the
lower surface
ARTICLE IN PRESS
area of the
specimens
compared with
powdered BG
samples.
Mathew – 2011 [49] MBG EISA process 85 10 0 5 Apatite SBF – TBS 16 h X X HA, and the CaP
formation clusters, were
present in the
pristine MBG
pore walls.
Mneimne A – (<38 m) MELT- 49.47 23.08 26.38 1.07 Apatite 3, 6, 9 h – 1, 3, An increase in
TBS X phosphate or
– 2011 [40] QUENCH deposition 7d
fluoride content
allowed for
apatite
formation at
A2 – (<38 m) 38.14 25.91 29.62 6.33 lower pH.
El-fiqi – 2012 [29] BGn (80–90 nm) SOL–GEL 85 15 0 0 Apatite SBF Different X X A SBF test of the
formation times up to mesoporous BGn
28 d confirmed their
excellent
apatite-forming
ability.
S90 90 10 0 0 The S90 and S85
Gunawidjaja EISA Formation 0.5, 4h -
SBF X MBGs displayed
– 2012 [30] process of HCA 1,3,7 d similar in vitro
behavior,
whereas the
Ca-richer S58
specimen
reacted more
similarly to
S85 85 10 0 5 melt-prepared
bioactive glasses.
Main
with Criteria
results
Date time
S58 58 37 0 5
Gunawidjaja S85 85 10 0 5 Growth of 1, 4, 8, Whereas the TBS
ARTICLE IN PRESS
CaHA – SBF – TBS 16 h – 1, 3, X X grains displayed
– 2012 [33]
Amounts of 7d a 60 ␮m thick
amorphous domain of
CaP and HA almost pure
silica, their SBF
counterparts
verified small but
significant
amounts of Ca
and P throughout
all particles of
diameter >20 ␮m.
This finding is
attributed to the
more extensive
local deposits of
ACP at the MBG
porewalls when
they are
subjected to SBF,
because the
latter medium is
already
supersaturated
with respect to
S58 58 37 0 5 apatite.
9
10
Main
with Criteria
results
Date time
Mačković 45S5 ␮BG – MELT-QUENH 44.97 24.55 24.55 5.99 Apatite 4, 8 h – 1, A higher surface
X SBF X X area and, thus,
- 2012 [25] (10 ␮m) formation 3, 7 d
higher reactivity
of the nBG
particles in
comparison to
␮BG was
ARTICLE IN PRESS
observed.
Investigations
revealed a very
rapid formation
of carbonated
nanocrystalline
hydroxyapatite
after 1 d of
45S5 nBG – FLAME SPRAY 47.8 25.1 22.6 4.6 immersion in
(20–60 nm) SYNTHESIS SBF, for nBG.
Salman – 2012 [42] G1 MELT-QUENCH 48 36 12 4 X Formation of SBF 7, 14, 21 d X X A decrease in the
apatite bioactivity of the
glass ceramic
was observed as
Na2 O was
replaced by K2 O.
Sr and Ca ions in
the apatite layer
formed and were
detected with
SrO/CaO
replacement.
Bachar – 2013 [79] GN0 EXPERIMENTAL 55 13.5 31.5 0 X Apatite layer SBF 15 d X X Crystallinity of
TECHNIQUE formation bioactive apatite
(MELTING layer decreased
MIXTURE) with increasing
nitrogen content,
suggesting that
nitrogen may
slightly decrease
bioactivity.
Main
with Criteria
results
Date time
Farooq – 2013 [80] 45S5 (38–80 ␮m) MELT-QUENCH 46.1 26.9 24.4 2.6 X Apatite TBS 3, 6, 24 h X Glasses formed
formation apatite within 6 h
or less,
suggesting that
ARTICLE IN PRESS
they were highly
bioactive and
capable of
forming apatite
within a few
hours.
Plewinski – 2013 [26] 45S5 MELT-QUENCH 47.3 24.2 22.1 6.2 Apatite SBF 1, 7, 14 d X X Calcium silica
(Amorphous – formation and calcium
crystallized carbonate layers
samples) were found on
amorphous BAG
after 7 and 14 d.
Apatite
formation was
observed only on
the crystallized
45S5 samples
after storage.
Souza – 2013 [44] 45S5 MELT-QUENCH 46.3 26.9 24.3 2.5 X Formation of SBF 4, 8, 16 h - 1, X X Partial
an apatite-like 2, 4, 8, 16 d replacement of
layer CaO by MgO in
the BAG had no
influence on the
kinetic of
precipitation of
the initial ACP
layer when glass
was exposed to
SBF.
11
12
Main
with Criteria
results
Date time
Arepalli -2015 [81] Ba-0 46.1 26.9 24.3 2.6 X Formation of SBF 1, 3, 7, 14, 30 dX X The formation of
HCA layer a hydroxyl
carbonate
apatite layer was
observed on the
ARTICLE IN PRESS
surface of the
barium
containing BAG
after immersion
in SBF. However,
an increase in
barium content
in the glass
samples
decreased the
tendency of
calcite
formation.
Kirsten – 2015 [82] 45S5 45.53 24.88 23.18 6.29 X Surface SBF 1, 3.5, 7, 14, X X 45S5 and BAG
reaction layers 28 d with partial
(HCA) substitution of
Na2 O and CaO by
K2 O and MgO
exhibited an
Si-rich layer of
approximately
20 ␮m and a
CaP-rich layer of
approximately
10 ␮m after 14 d
of storage in SBF.
HCA was found
after 3.5–7 d on
both glasses.

Main
with Criteria
results
Date time
Abbasi – 2016 [83] 58S – (<40 ␮m) SOL–GEL X Formation of SBF 6h - 1, 3, 6, 9 dX X The 58S has a
an apatite layer high surface area
and can release
ions very fast in
the solution
(high bioactivity).
Dental
ceramic/58S BAG
mixtures also
ARTICLE IN PRESS
exhibit high
degrees of
bioactivity
despite the
presence of
leucite with
non-bioactive
behavior.
Wang – 2016 [15] 45S5 X Apatite SBF 1, 5 d X Crystalline
formation apatites were
precipitated on
the
polycarbolactone
(PCL)/submicron
BG (smBG) group
and 45S5
surfaces after
incubation. The
thickness of the
apatite layer on
the PCL/smBG
group was higher
than for the 45S5
samples.
S90 90 10 0 0 ACP 0.25, 1, 4, HCA formation
Mathew – EISA formation/ SBF 8, 24 h - 3, X occurred after 4 h
2017 [84] process conversion 7, 15, 30 d of SBF exposure,
into HCA – except for P-free
Distinct Ca, Si S90 MBG (after
and P 8 h).
contents
S85 85 10 0 5
13
14
Main
with Criteria
results
Date time
S58 58 37 0 5
Anand – 2018 [85] MBG (nano) EXPERIMENTAL 0 Carbonated HA SBF 24, 48 h X X Formation of
TECHNIQUE forming ability hydroxyapatite
layer on different
surfactants was
evaluated:
non-ionic
surfactant
ARTICLE IN PRESS
pluronic and
ionic surfactant
hexadecyltrimethyl-
ammonium
bromide in
contrast with
non-ionic
surfactant
polyethylene
glycol and citric
acid.
Ashok – 2018 [54] BGNR – 45S5 SOL–GEL 45 24.5 24.5 6 X Formation of Hank’s 3, 7 d X X On the 3rd day,
hydroxyl solution the formation of
carbonated the HCA layer is
apatite layer relatively higher
(HCA) in nano hybrids
of BGNR/rGO
(reduced
graphene oxide
sheets)
compared with
that of BGNR.
Similar levels of
HCA formation
in BGNR were
observed only on
the 7th day.
Taha – 2018 [86] 45S5 (SylcTM ) MELT-QUENCH 46.1 26.9 24.4 2.6 X Apatite TBS 1, 3, 6, 9, 24 h X BAG with CaF2
air-abrasion formation formed apatite
faster (6 h) than
45S5 (SylcTM )
(24 h) in TBS.
Table 2 – Selected articles: in vitro BAG remineralization of enamel and/or dentin. BAG compared with: 1 Control group; 2 BAG with adjuvants; 3 Oxide alone, antibacterial,
desensitizing agents, bioactive, or restorative materials; 4 Laser. Analysis: 1 Microscopic observations; 2 Chemical or structural analysis; 3 Mechanical properties evaluation. ( =
not specified in the article / s = seconds; m = minutes; h = hours; d = days; w = weeks; m = months).
References Bag investigated Compared Methods Main
with Criteria results
Authors Glass Manufa- Glass composition by mol%1 Contact Analysis

label cturing Interface
Date time
–size methods SiO2 CaO Na2 O P2 O5 1 2 3 4 1 2 3
Efflandt – 45S5 MELT- 45 24.5 24.5 6 X Apatite Human 5, 21, 42 d X X Ions from
2002 [87] QUENCH formation dentin glass
penetrated
dentin.
Presence of
ARTICLE IN PRESS
apatite at the
interface
between
glass and
dentin was
observed.
Forsback – S53P4 53 20 23 4 Occlude Human Pretreatment
X dentin 14 d X X with BAG
2004 [51] (<45 m) Dentin
tubules – decreased the
Formation degree of
of CaP decalcifica-
tion of dentin
during the
mineraliza-
Control glass tion
(CG) (<45 m) process.
Hassanein – S53P4 53 20 23 4 X Topography of Human 10 d X X BAG has the
2006 [88] the enamel potential to
remineralized and remineralize
areas – Nature of dentin artificial
the compounds carious
deposited – lesions in
Degree of enamel and
remineralization dentin:
formation of
hydroxyap-
atite, sealing
of enamel
pores, and
plugging of
dentinal
tubules.
15
16

Date time
Lee – 2007 DP-BAG SOL–GEL Dentinal Human Percentage of
39.6 40 8.4 12 X X
ARTICLE IN PRESS
with 30% tubule 3d tubular
[21] dentin
PPA occlusion occlusion
with DP-BAG
was
53.2%–65.4%
and
significantly
better than
MELT- Seal & Protect
QUENCH (41.2%).
Schmidlin – S53P4 (≤ 45 X X Improve Human 3w X Hardness and
2007 [45] m) mechanical Dentin elastic
properties – modulus
Higher hardness values of the
dentin
subjacent to
empty
microcavities
and
counterparts
lined were
significantly
higher with
BAG
compared
with the
RMGIC.

Date time
Vollenweider 45S5 NBG – FLAME SPRAY 44.7 27.6 22.8 4.9 X New mineral Human 1, 10, 30 d X X X After
– 2007 [89] 45S5 BG SYNTHESIS precipitated – dentin treatment
(PerioGlas® (NBG) Improve with
90−710 m) mechanical nano-BAG for
properties 10 or 30 d, a
pronounced
ARTICLE IN PRESS
increase in
mineral
content of the
dentin was
observed. A
substantially
higher rem-
ineralization
rate was
induced by
nanometer-
sized vs.
micrometric.
Curtis – 70S30C (0.65 SOL–GEL 70 30 0 0 Tubule Human Treatment
occlusion 24 h X X with
2010 [23] m) dentin
- nanobioglass
Formation resulted in
of an particle
apatite deposition
layer within
tubules and
45S5 (3.30 MELT- 45 24.5 24.5 6 formation of
m) QUENCH apatite rods.
Bakry - 2011 45S5 with 45 24.4 24.5 6 X Tubule orifice Human 24 h X X X 45S5 could
[90] 50% PAA Closure – Recover dentin occlude the
mechanical dentinal
properties tubule
orifices with
calcium
phosphate
crystals.
17
18
References Bag investigated Compared Methods Main results

with Criteria
Date time
45S5 MELT- 44.8 26.5 23.4 5.3 Mineralized Enamel
Dong – Human
QUENCH X layer – 7d X X X surface
2011 [27] enamel
Surface formed a
roughness homogenous,
– Nano- dense
hardness mineralized
and layer with the
Nano- treatment of
reduced 45S and 58 s
ARTICLE IN PRESS
elastic samples. 77S
modulus treatment
showed a
loose and
uneven
remineralized
layer. These
results also
indicated
that the level
of silicon
content of
BAG played a
key role in
dental
58S SOL–GEL 62.8 27.6 0 9.6 enamel rem-
77S SOL–GEL 73.7 16.5 0 9.8 ineralization.
Sauro- 2011 45S5 (SylcTM ) X Dentin Human 24, 48 h X X 45S5 (SylcTM )
[91] permeability – dentin was the only
Hydroxyapatite substance
precipitation (compared with
prophylactic
materials) able
to reduce
dentin
permeability
after
immersion in
remineralising
solution and to
show
hydroxyapatite
precipitation.

Date time
Wang – 2011 BAG (30−90 45 24.5 24.6 5.8 X Mineral variation Human 7d X X Results
[92] m) of the surface – dentin showed a
Apatite significant
ARTICLE IN PRESS
formation – increase of
Roughness of the the mineral
surface matrix area
ratio in
dentin
specimens
treated with
BAG and
M-BAG (with
magnesium).
Both
formulations
have similar
potential in
dentine
remineralization.
Bakry – 2013 45S5 with 45 24.4 24.5 6 X X Dentin Human 24 h X X X Application
[93] 50% PPA permeability – dentin of 45S5 BAG
Examination of paste to
surfaces dentin
(chemical nature occluded
- crystalline patent
structures) dentinal
tubule
orifices with
a layer of
calcium
phosphate
crystals.
19
20

Date time
Gjorgiesvska 45S5 X Observe ion Human 6w X X GIC and BAG
– 2013 [46] exchange layer - dentin underwent
Determine the ion exchange
elemental levels with the
(%) of ions surrounding
ARTICLE IN PRESS
tooth tissue,
confirming
their
bioactivity.
The particle
size of BAG
meant that
cavity
adaptation
was poor.
Smaller
particle size
BAG may
provide a
more
acceptable
result
(<90 m).
Bakry – 2014 45S5 with 45 24.4 24.5 6 X X Improve Human 24 h X X X 45S5 paste
[94] 50% PPA mechanical enamel application
properties of improved the
demineralized microhard-
subsurfaces ness of the
subsurface
eroded
enamel
compared
with the
fluoride and
control
specimens.

Date time
Bakry – 2014 45S5 with 45 24.4 24.5 6 X Layer of Human 24 h X X Artificial
[95] 50% PPA hydroxyapatite enamel enamel caries
ARTICLE IN PRESS
crystals lesions
treated with
BAG paste
showed
complete
coverage with
a layer of
brushite
crystals.
Milly – 2014 BAG 45S5 45 24.4 24.6 6 X X Mechanical Human 7d X X X BAG and
[96] slurry (2–6 – properties – enamel PAA-BAG
12 ␮m) – Phosphate surface
PAA-BAG content – treatments
(40 wt%- Morphological enhanced
60 wt%) changes enamel rem-
ineralization:
improved
mechanical
properties,
higher
phosphate
content, and
morphologi-
cal changes
within the
artificial
lesions.
21
22

Date time
Milly – 2015 BAG 45S5 X X Average Human Twice X X X The
[97] slurry (2–6 – roughness – enamel daily pretreatment
ARTICLE IN PRESS
12 ␮m) Optical changes – (5 min per enhanced the
Structural applica- remineraliza-
changes of WSL tion) for tion of WSL
21 d treated with
BAG 45S5
slurry:
increased
mineral
content,
improved
mechanical
properties
and ultra-
structural
changes.
Carvalho – Bio- EXPERIMENTAL
42.3 28.3 22.8 6.6 X X Release of Ca, Na Human 10 min – 24 h X CH had the
2016 [98] Gran + distilledTECHNIQUE and P ions dentin - 7, 14, 21, highest level
water (MELTING 30 d of Ca ions
MIXTURE) release at 30
d. The BAG
released
more Na and
P ions and
presented an
alkaline pH
immediately
and after 30
d.
with Criteria
Date time
El-wassefy – 45S5 with 45 24.4 24.5 6 X X X Changes in the Bovine 24 h X X X Treating
2017 [99] 50% PPA mineral content enamel demineralized
– High enamel with
microhardness cold plasmas
before BAG
application
ensued a
significant high
ARTICLE IN PRESS
mineral
volume
recovery and
microhardness
of
demineralized
region.
Saffarpour – BG (40–90 ␮m) 64 26 0 10 X Chemical Human 7, 14, 21 d X X Dentinal
2017 [43] structure – dentin tubules were
Presence of partially
globular HA occluded by BG
crystals – Tubular and BG
obstruction modified with
5% Strontium,
and they
almost
completely
obstructed
after the use of
BG modified
with 10% Sr.
Addition of 10%
Sr to BG
enhanced
apatite
formation.
Addition of 5%
Sr to BG
stabilized the
apatite lattice
and increased
the
remineralization.
23
24

with Criteria
Date time
TM
Taha – 2018 45S5 (Sylc ) X Intensity of light Human 24 h X X X BAG with CaF2
[37] air- abrasion backscattering – enamel enhanced
Roughness – enamel
Hardness – remineralization
Mineral more effectively
precipitate-like than 45S5.
deposits – Surface
Presence of Ca, P, roughness and
O and Na intensity of light
ARTICLE IN PRESS
backscattering
similar to that of
sound enamel
were observed
following
treatment with
fluoride-
containing
BAG.
Zhang – 2018 BG X X X Change of Human 7d X X X BG+PAA
[100] (Novamin® ) – surface mineral enamel presented
BG content – significantly
(Novamin® )+PAA Improve higher mineral
mechanical regain compared
properties – with negative
Identify the type control on
of newly formed lesions surfaces.
minerals – Chitosan (CS)
Surface improved the
morphologies remineralization
and Ca/P ratio efficacy using
either a BG slurry
alone or BG+PAA
complexes as
both surface and
subsurface
showed an
increased
tendency in
mineral content
assessed and
greatest
hardness
recovery.

Date time
Zhang – 2018 BG X X X Mineral Human 7d X X X Chitosan-BG
[101] (Novamin® ) – content/changes Enamel exhibited
BG – Sub/surface denser
(Novamin® )+PAA microhardness - subsurface
ARTICLE IN PRESS
Formation of structure
pellicle layer than BG, and
in
CS-BG + PAA,
the crystals
were bigger
in size but
were more
enamel-like
compared
with
BG + PAA, as
shown in SEM
observations.
Lee – 2019 BG + PPA SOL–GEL 58 33 0 9 X X Tubules Human 5 min X X BG with PPA
[102] obstructions – dentin prevented the
Formation of HA formation of
– Chemical cracks and
changes in degradation
collagen fibers of collagen
fibers caused
by CO2
irradiation
and
promoted
obliteration
of the
exposed
dentinal
tubules.
25
26
with Criteria
Date time
DionysopoulosBAG 45 24.4 24.6 6 X X Enamel surface Bovine 10 s X X X Surface
– 2019 [103] (Novamin® ) loss – Mechanical enamel pretreatment
45S5 (30−60- properties with BAG 45S5
90 ␮m) reduced
surface loss
after ero-
ARTICLE IN PRESS
sion/abrasion
challenge
compared with
the negative
control group.
Ubaldini 45S5 (BG) 45 24.5 24.5 6 X Chemical Human 30 s X X X BG and
–2020 [48] composition and dentin biosilicate
bond strength of promoted
dentin mineral matrix
ratios increase
in the control
dentin and
bleached
dentin. Both
bioactive
materials
presented a
high remineral-
ization ability
on bleached
dentin surfaces
(improved
dentin’s ability
to chemically
interact with
adhesive
monomers and
consequently
increased the
resin-dentin
bond strength).
ARTICLE IN PRESS
human or rat pulp in vivo (Table 4). The objectives were

in vivo evaluation of dentin mineralization and/or dental pulp
response. The criteria were the presence or absence of a
dentin bridge associated with the pulp status (no or mild,
moderate, or severe inflammation, necrosis, abscess, resorp-
tion). BAG were compared with Calcium Hydroxide (CH) and
MTA. The contact time extended from 2 weeks to 2 months.
Histological analysis, hematoxylin and eosin staining or Mas-
son’s trichrome were for the technical analysis. BAG was
used in Wang et al., especially the nanoscale version, and
greater induction of pulp cell migration, surface attachment,
proliferation, and odontogenic differentiation were demon-
strated [15]. In Salako et al., BAG induced an inflammatory
Fig. 3 – Number of articles reported for each analysis response at 2 weeks with the resolution of inflammation at
technique of in vitro enamel and/or dentin remineralization. 4 weeks in molars rats [18]. Moreover, MTA performs as an
ideal pulpotomy agent and causes dentin bridge formation
while maintaining normal pulpal histology, compared with
BAG. According to Haghgoo et al., pulp inflammation was
reached on contact time: 10 or 30 s; 5 or 10 min; 1, 2, 3, 5, 7,
observed in BAG samples with dentin bridge formation but
10, 14, 21, 24, or 30 days; and 3 or 6 weeks. To evaluate the abil-
not internal resorption or abscess [19,20]. Unlike the literature,
ity of BAG to remineralize enamel or dentin in vitro, studies
Haghgoo et al. demonstrated MTA and BAG could be used for
used the following analysis techniques:
vital pulp therapy (direct capping) of primary teeth.
Three articles combined two methodologies to assess the
- Microscopic observations: SEM, SEM/three-dimensional bioactivity of BAG:
stereophotographs, FESEM, TEM, and confocal laser
scanning microscopy (CLSM).
- Forsback et al. used TBS and human dentin: both in vitro [51].
- Chemical or structural analysis: EDX, FTIR, XRD, Solid State-
- Wang et al. used hDPCs cells in vitro and molar pulp rats
NMR, ICP-atomic emission spectroscopy, attenuated total
in vivo [13].
reflectance-FTIR (ATR-FTIR), electron microprobe analysis
- Wang et al. used SBF and hDPCs: both in vitro [15].
(EMPA), micro-computed tomography (CT), atomic force
microscope (AFM), thermogravimetric analysis (TG), fluid
filtration/transport system, optical coherence tomography 4. Discussion
(OCT), focused ion beam, profilometry analysis, X-ray pho-
toelectron spectroscopy (XPS), and Raman spectroscopy. 4.1. Study selection
- Association between microscopy and chemical or structural anal-
ysis: SEM-EDX and FESEM-EDX. For study selection, especially search terms, the term ‘glass’
- Evaluation of mechanical properties: Nanoindentation, ultra- was observed in many studies of tricalcium silicates and bio-
microindentation analysis (UMIS), microhardness, and ceramics but not for those of BAG. Additionally, many studies
cryofracture examination. were excluded after the title or abstract screening. Thirteen
studies were observed in the references of other articles, and
Fig. 3 shows the repartition of different analysis tech- many of them were in chemistry and physics reviews; there-
niques. fore, they were not mentioned in the study selection with
According to the studies, BAG were bioactive materials for medical electronic databases.
therapeutic remineralization of dental hard tissues.
4.2. Methodologies linked to biomaterial chemistry
3.2.3.3. In vitro effect of BAG on the mineralization capacity of
cells. Five studies evaluated the bioactivity of BAG in contact 4.2.1. Particles sizes and morphology in relation to the
with cells in vitro (Table 3). manufacturing method
The objectives were to investigate the in vitro effects of BAG The melt-quench and sol–gel processes are the most com-
on the mineralization capacity of cells. The calcium precipita- mon manufacturing techniques for BAG. According to Lee et al.
tion and the matrix mineralization of cells were the criteria. melted glass exhibited a greater size (30–60 ␮m) without pore
Four studies used human dental pulp cells (hDPCs - hDPSCs) formation. The average particle size of sol–gel bioglass was
[13–16] and one study used stem cells derived from deciduous still smaller. Moreover, sol–gel bioglass exhibited a porous
teeth (SHEDs) [17]. The contact time was 21 days to 5 weeks. structure with a large surface area [21,22]. These results
Alizarin red S was used for technical analysis. For all studies, were in accordance with Curtis et al.: melt-derived possessed
BAG increased mineralized nodule formation. an irregular particle morphology and had a mean size of
3.30 ± 0.42 ␮m. The sol–gel bioglass particles were spherical,
3.2.3.4. In vivo evaluation of dentin mineralization and/or den- with a mean size of 0.65 ± 0.19 ␮m [23]. Dentin treated with
tal pulp response. Four studies evaluated the dental pulp melt-derived bioglass exhibited a tightly adherent continuous
response with BAG by using pulp capping or pulpotomy in apatite layer. Treatment with nBAG resulted in particle deposi-
28
Table 3 – Selected articles: In vitro effects of BAG on the mineralization capacity of cells. BAG compared with: 1 Control group; 2 BAG with adjuvants; 3 Oxide alone,
antibacterial, desensitizing agents, bioactive, or restorative materials; 4 Laser. ( = not specified in the article / d = days; w = weeks).
References Bag investigated Compared with: Criteria Methods Main results
Authors Glass label Manufacturing Glass composition by mol% Interface Contact Alizarin
Date – size time red S
SiO2 CaO Na2 O P2 O5 1 2 3 4

Gong – 2014 45S5 – 1 and MELT-QUENCH 45 24.5 24.5 6 X Matrix hDPCs 21 d X All BG extractions,
[14] 10 m mineral- especially nano-58S,
ization increased mineralized
nodules formation.
58S BG – SOL–GEL 58 33 0 9
2–20 ␮m
Nano-58S BG 58 33 0 9
ARTICLE IN PRESS
– 10−100 nm
Wang – 2014 58Sm SOL–GEL 58 33 0 9 X Calcium hDPCs 4w X Relative calcium
[13] (micro)-BG concen- concentrations
58Sn trations increased significantly
(nano)-BG in the m-BG and n-BG
groups and were
particularly higher in
the n-BG group
compared with the
control group.
Wang – 2016 45S5 X MineralizedhDPCs 4w X More mineralized
[15] nodules nodules were
generated in the
polycarbolactone
(PCL)/submicron BG
(smBG) group than in
45S5 group.
Huang – 2017 Zn0BG MELT-QUENCH 38.5 29 26.2 6.3 X MineralizedhDPSCs 3, 5 w X Formation of
[16] (≤38 m) nodule mineralized nodules
formation was observed in the
and com- 0ZnBG group;
position however, it was higher
in the ZnBG group.
Lopez – 2017 BG SOL–GEL 57 26 0 17 X X X Calcium SHEDs 21 d X Desensitizing agent
[17] precipita- alone or with laser,
tion and BG alone or with
laser, stained
positively with
Alizarin red staining.
BG + laser had
significantly higher
mineral matrix
deposition than BG
alone.
Table 4 – Selected articles: In vivo evaluation of dentin mineralization and/or dental pulp. BAG compared with: 1 Control group; 2 Oxide alone, antibacterial, desensitizing
agents, bioactive, or restorative materials. ( = not specified in the article / w = weeks; m = months).
ReferencesBag investigated Compared Methods
Main
with: Criteria
results
Authors Glass Manufacturing Glass composition by mol% Contact Histological
Label – Interface Analysis
Date methods time
size SiO2 CaO Na2 O P2 O5 1 2
ARTICLE IN PRESS
Salako – S53P4 53 20 23 4 X Inflammation Molars 2, 4 w X BAG induced an
2003 [18] – Necrosis – rats – inflammatory
Cells Pulpo- response at 2 weeks
observations tomy (w) with resolution
– Dentin of inflammation at
bridge 4 w.
formation Most of the 4 w-old
BAG samples
showed regular
pulpal histology,
with some dilated
blood
vessels.Complete
pulpal necrosis of
some specimens.No
dentin bridge
formation.
Haghgoo – BG X Inflammation Primary 60 d X Inflammation was
2007 [19] (Biogran® ) – Necrosis – canine seen in three BAG
Abscess – teeth samples (n = 10) and
Resorption – (direct dentinal bridge in
Dentin bridge pulp seven teeth, but
formation capping) internal resorption
and abscess were
not seen.
29
30
ReferencesBag investigated Compared Methods
Main
with: Criteria
results
Authors Glass Manufacturing Glass composition by mol% Contact Histological
Label – Interface Analysis
Date methods time
size SiO2 CaO Na2 O P2 O5 1 2
Wang – 58Sm SOL–GEL 58 33 0 9 X Mineralized Molars 2, 6 w X 2 w/n-BG group:
2014 [13] (micro)- tissue pulp rats newly generated
ARTICLE IN PRESS
BG formation matrix was observed
58Sn around particles.
(nano)-BG 6 w/n-BG group: new
dentin-like tissue
was formed with
uniform thickness
and well-organized
dentinal tubule
structure.6 w/m-BG
group:
pulpo–dentinal
complex-like tissue
was also generated
(thinner than that in
n-BG group).
Haghgoo – BAG X Pulp statue Primary 2m X In the BAG group,
2016 [20] (Biogran® ) (Inflamma- canine inflammation was
tion, necrosis, teeth observed in 3
abscess, (direct patients (n = 22);
resorption) - pulp internal resorption
Dentin bridge capping) and abscess were
formation not observed.
Dentinal bridge
formation was
observed in 5
patients in the BAG
group (n = 22).
ARTICLE IN PRESS
tion within tubules and formation of apatite rods, which were molecules, drugs, or growth factors could be included in the
tightly adherent to tubule walls and continuous to a measured pores.
depth of 270 ␮m [23]. Other techniques have been used, spe-
cially to create MBG or nBG. For example, EISA (Evaporation
4.2.3. Glass composition: adjuvants
Induced Self-Assembly) combines the sol–gel technique and
Some studies used BAG with adjuvants to conduct compar-
supramolecular chemistry to obtain MBG [24]. Using flame
isons with traditional BAG. Three methodologies were used
spray synthesis, BAG synthesis occurred by combining and
for these assessments: in solution in vitro, remineralization
mixing the corresponding liquid metal precursors and feeding
of enamel and/or dentin in vitro, and mineralization of cell in
the mixture into a flame reactor [25]. According to MačKović
vitro.
et al., nBAG (flame spray synthesis) have a higher surface area
Fluoride was often added to BAG. According to Moawad
and, thus, higher reactivity compared with conventional ␮BAG
et al., the formation of HA and hence bioactivity was signif-
(melt-quench): coprecipitation of nanocrystalline and large
icantly influenced by the mol% of CaF2 in the initial glass
calcite was observed by TEM [25]. In contact with hDPCs, nBAG
composition [35]. Addition of fluoride ions to the glass, by
can induce the mineralization of cells more efficiently com-
maintaining the ratio of all other components constant, main-
pared with regular BAG. Because of the higher specific area,
tains the polymerization of the silicate network, network
n58S released more Si and Ca ions into the medium com-
connectivity, and bioactivity of BAG [36,37]. By contrast, sub-
pared with 58S and 45S5 in a short time [14]. These results
stituting CaO (or Na2 O) for CaF2 increases the polymerization
were confirmed by Wang et al.: in contact with pulp cells,
of the SiO2 network, resulting in decreased solubility, bioactiv-
nBAG increased mineralized nodules formation [13]. nBAG
ity, and even cell compatibility [36]. Incorporation of fluoride
were promising particles for dental applications and might be
resulted in the formation of fluoroapatite (FAp) compared with
a better potential candidate for dentin–pulp complex regen-
fluoride-free glasses [35;38]. This parameter was notable for
eration. In cases of direct pulp capping, a continuous layer of
dental application because FAp was more resistant to acidic
dentin-like tissue was observed.
attack than fluoride, had lower solubility compared with HA,
and was more chemically stable than HA or carbonated HA
4.2.2. Glass composition - SiO2 /Na2 O/CaO ratio
[39,40]. For the oxide addition or substitution, in Nommeots-
BAG 45S5 were used in most studies because of the original
Nomm et al., phosphorous reduction and CaP layer formation
composition of BAG made by Larry Hench in 1969. BAG 45S5
were much faster in SBF containing BAG with K2 O compared
were able to form carbonated HA in solution and to precipitate
with BAG containing K2 O-MgO or K2 O-MgO-SrO [41]. In other
a layer of apatite at the enamel and dentin interfaces. Accord-
studies, BAG with Sr formed apatite to increase dissolution
ing to Plewinski et al., calcium silica and calcium carbonate
resistance and tubules’ obliteration [42,43]. For magnesium,
layers were found on amorphous bioglass 45S5 after 7 and 14
according to Souza et al., partial replacement of CaO by MgO
d (stored in SBF). However, apatite formation after storage was
in the BAG did not influence the rate of precipitation of the
observed only on the crystallized 45S5 samples [26].
initial ACP layer when the glass was exposed to SBF [44].
Dong et al. compared 45SiO2 with 58SiO2 and 77SiO2 (both
without sodium oxide). They found that an enamel surface
formed a homogenous and dense mineralized layer with 4.2.4. Bag versus other materials
the treatment of 45SiO2 and 58SiO2 samples. The average BAG have been compared with RMGIC as liner materials for
thickness was 4 and 2.5 ␮m, respectively. The surface rough- dentin remineralization in vitro. According to Schmidlin et al.,
ness decreased with the increase of silicon content, and the the dentin exposed resulted in significantly higher hardness
mechanical strength of the enamel samples decreased gradu- and elastic modulus values with BAG compared with corre-
ally. BAG with 77SiO2 showed a loose, uneven remineralized sponding dentin RMGIC-interfaces [45]. GIC have been used for
layer, whereas 45SiO2 and 58SiO2 formed a homogenous, comparison with BAG. According to Gjorgievska et al. bioac-
dense mineralized layer on surface enamel [27]. 45SiO2 paste tivity of BAG and GIC were confirmed by ion exchange with
had the best mineralization ability, best mechanical strength, the surrounding tooth tissue [46]. In 2003, bioactivity of BAG
and satisfactory surface roughness [27]. In the included arti- was compared with MTA, formocresol (FC), and ferric sulfate
cles, they were BAG with only SiO2 and CaO; notably, CaO was (FS) [18]. FC and FS are pulpotomy agents; however, their use
fundamental in the first step of HA formation because of an today is uncommon. According to Salako et al. and Haghgoo
exchange with H+ ions [28]. According to Curtis et al. and El- and Ahmadvand, MTA induced less inflammation than BAG
Fiqi et al., it was possible to create nBAG with SiO2 and CaO in contact with dental pulp and formed more dentin bridge
[23,29]. These SiO2 -CaO BAG formed apatite rods emanated [18,47]. MTA was progressively replaced by BiodentineTM in
from within the tubules [23]. According to Gunawidjaja et al., restorative procedures. Based on this review, 1 study compared
90SiO2 -10CaO BAG and 85SiO2 -15CaO BAG displayed similar BAG and BiodentineTM as dentin substitutes [46]. In this study,
in vitro behavior [30]. In other studies, BAG was made with- BiodentineTM performed well as a dentin substitute. The use
out Na2 O, and indeed, high sodium content was unnecessary of BAG was limited to the size of particles (<700 ␮m) to allow
for bioactivity [30–33]. The porosity increased when calcium for a better adaptation to cavity walls. Notably, BAG may also
oxide increased, compared with sodium oxide. Indeed, the be considered for use as dentin substitute [46]. According to
enhanced fluxing in compositions with high sodium inter- Ubaldini et al., BAG and biosilicate promoted increased min-
fered with the textural features by reducing the porosity eral matrix ratios on the bleached and control dentin samples
because of fusion of pores [34]. Porosity was a critical param- using MicroRaman Spectroscopy. Microtensile bond strength
eter to increase surface area and hence bioactivity. Moreover, of dentin resin bonding interfaces was significantly improved
ARTICLE IN PRESS
when the bleached or control dentin surfaces had been cov- AFM, CLSM, CT, EMPA, fluid filtration of dentin, focused ion
ered by BAG and/or biosilicate [48]. beam, nanoindentation, TG, UMIS, or XPS (Fig. 3). Accord-
ing to the studies included, BAG remineralized demineralized
4.3. Methodologies to assess bioactivity enamel:
4.3.1. In vitro solution - mechanism of apatite formation - Improved mechanical properties (mechanical strength, sur-
on bag surface face roughness, microhardness).
Studies used mainly SBF (n = 23) and TBS (n = 7) to assess - Increased mineral content.
the mechanism of apatite formation on BAG surface in vitro. - High mineral volume recovery.
Microscopic observations and chemical or structural analysis - Coverage with a layer of brushite crystals.
allowed for the following conclusion: BAG formed apatite in - Ultrastructural changes.
vitro.
According to Mathew et al., results obtained from BAG after
For the dentin, BAG formed apatite at the interface and
being soaked in SBF or TBS revealed a biomimetically grown
surface layer of calcium phosphate comprising domains of
nanocrystalline HCA [49]. Gunawidjaja et al. observed ACP and - Decreased the degree of decalcification of dentin during the
HCA growth at the surface of BAG in SBF and TBS. When the mineralization process in one study [51].
authors examined the ion release, the TBS grains displayed a - Promoted the increase of mineral matrix ratios and the
60 m thick domain of almost pure silica, and their SBF coun- appearance of new interface peaks, indicating a chemical
terparts were verified as small but had significant amounts interaction.
of Ca and P. This finding is attributed to more extensive local - Remineralized artificially carious dentin.
deposits of ACP at BAG when they are subjected to SBF, because - Allowed deposition in the tubules with obliteration by pre-
the latter medium is already supersatured with respect to cipitation of apatite (increase of the% of tubular occlusion –
apatite [33]. These results were in accordance with the litera- reduce dentin permeability).
ture. - Increased hardness and elastic modulus values of the
For other authors, the choice of SBF solution for testing dentin.
the bone bonding ability of materials was arbitrary, and there
was no correlation between bioactivity in SBF solution and in Precipitations of deposits inside the tubules were a barrier
vivo. The supersaturation of SBF in calcium and phosphate against bacterial penetration and therefore prevented pulp
can induce false-positive results [50]. Mneimne et al. recom- inflammation. Dentin remineralization is more complex than
mended the use of TBS without Ca2+ and PO4 3− because saliva enamel remineralization because dentin has a heterogenous
in the mouth is diluted after liquid uptake and no longer structure. Electronic microscopy could evaluate the inter- or
saturated with these ions [40]. TBS was used to avoid the possi- intrafibrillar remineralization, and mineral formation must
ble interference of phosphate ions during measurement [51]. be assessed by measurements of mechanical properties [58].
However, according to Cerruti et al., TBS solutions and SBF According to the 26 articles in this review, standard BAG
were comparable to evaluate the dissolution of BAG [52]. For appears to be promising agents of remineralization.
Kokubo and Takadama, SBF was useful to predict the bioac- To use BAG in contact with dental hard tissues, the bioactiv-
tivity of a material [53]. One study used Hank’s balanced salt ity of BAG in contact with pulp cells must be assessed. Notably,
solution [54]. According to Gandolfi et al., Hank’s solution can carious lesions increase the permeability of dentin. Permeabil-
be used for cells’ culture; however, it is a solution with a low ity involves the passage of fluids, ions, molecules, particulate
concentration of phosphate and reduced the rate of apatite matter, and bacteria into and through a substance or tissue
precipitation and increased the time required for superficial under different and variable conditions. The permeability of
apatite formation [55]. dentin is essential to support the physiology and reaction pat-
Bioactivity evaluation in solution provides the best incom- terns of the pulp–dentin organ [59]. Enamel carious lesions
plete information because it is irrespective of biological can also lead to a pulp–dentin complex reaction. Notably, the
processes and context. However, for Zadpoor, three quarters examination of enamel lesions and pulp–dentin organs con-
of the in vitro studies of ability successfully predicted in vivo firmed not early odontoblast cell reactions and a difference
performance of the same materials [56]. The ability to form in tertiary dentin formation as a response to slow and active
apatite in solution could be a bioactive parameter [57]. Accord- lesion activity [60]. Enamel is a microporous solid, the car-
ing to some definitions of bioactivity and the description of ious process and response of the dentin–pulp complex can
protocol in articles, the answer is yes. However, because bioac- frequently start before it is breached [61].
tive required a biological reaction induced by BAG, apatite
formation in a solution is the reactivity of BAG and not bioac- 4.3.3. In vitro effect of bag on the mineralization capacity
tivity [52]. of cells
All the studies that assessed the bioactivity of BAG in con-
4.3.2. In vitro remineralization of enamel and/or dentin tact with cells used Alizarin red staining to evaluate matrix
To assess the BAG capacity to remineralize enamel and/or mineralization.
dentin in vitro, the literature used a combination of micro- According to these studies, cells in contact with BAG led to
scopic observations, chemical or structural analysis, and increases in relative calcium concentration and precipitation
evaluation of mechanical properties. One or 2 studies used and increases in mineralized nodules formation.
ARTICLE IN PRESS
Fig. 4 – Methodology classification of BAG bioactive properties for dental applications.
Four studies used human dental pulp cells. These cells may The gold standard technique to quantify changes in the
represent a different population of differentiated and undiffer- mineral content of early carious lesions was transverse micro-
entiated cells with great potential for dental pulp repair and radiography (TMR). However, TMR requires preparation of thin
dentin regeneration. They can be successfully used to evaluate sections and therefore cannot be used to monitor a WSL
new biomaterials for dental applications [62]. undergoing in vivo treatment [60]. This technique can be used
SHEDs were identified as a population of highly prolifera- in situ with removable mid-palatal appliances [67].
tive, clonogenic cells capable of differentiating into a variety Thus, no study investigated the in vivo remineralization
of cell types, for example, neural cells, adipocytes, and odon- capacity of dental tissues by using pure BAG.
toblasts [63].
The other factors used to assess biocompatibility could
be studied to evaluate bioactivity: collagen production,
4.3.5. In vivo evaluation of dentin mineralization and/or
protein expression (DSPP, DMP-1), expression of several
dental pulp response
Histological analyses are required to characterize the bioac-
mineralization-related genes (osteocalcin, osteonectin, osteo-
tivity of BAG in direct or indirect contact with pulp cells.
pontin, and bone sialoprotein) and promotion of alkaline
Pulp inflammation, presence of resorption, dentin bridge
phosphatase. These factors could be responsible for the initia-
formation, and organization of odontoblast-like cells were
tion and modulation of dentin mineralization [13]. Moreover, a
commonly reported.
bioactive product can be toxic. Therefore, Alizarin red staining
According to Salako et al. and Haghgoo and Ahadvand,
is insufficient to predict the behavior of BAG in contact with
BAG induced an inflammatory response from the dental pulp
cells. The in vivo studies were reported as the best means to
[18–20]. Fluctuations in pH can lead to an unfavorable microen-
evaluate the bioactivity of bioactive products [64].
vironment for dental pulp tissues and cause inflammation
and pulp tissue necrosis [71]. Haghgoo et al. demonstrated
formation of a dentin bridge but did not observe internal
4.3.4. In vivo remineralization of enamel and/or dentin resorption and abscess [19,1,20]. According to Wang et al., a
No study of the in vivo remineralization of enamel and/or continuous layer of dentin-like tissue with uniform thickness,
dentin using BAG was observed. A likely explanation for a well-organized dentinal tubule structure, and polarizing
this result is the difficulties of evaluating in vivo remineral- odontoblast-like cells aligned along were generated on the
ization. The International Caries Detection and Assessment nano-BAG layer [13]. These results are in accordance with
System (ICDAS) criteria, optical boundary depth by OCT sys- Salako et al.: BAG can interact with pre-existing odontoblasts
tem, enamel decalcification index, quantitative light-induced and underlying dental pulp cells [18].
fluorescence, and digital photography were mainly used for
visual characterization of in vivo remineralization of white
spot lesions (WSLs) [65,66]. These methods were used as 4.3.6. Association of two categories of methodologies
quantitative methodologies for CPP-ACP but not for pure BAG Three articles combined two categories of methodologies to
[67–70]. assess the bioactivity of BAG:
ARTICLE IN PRESS
- Forsback et al. used in vitro solution and in vitro dentin and rank the impact of different studies and the bioactive
remineralization [51]. According to these assessments of effects.
bioactivity, bioactive glass S53P4 can be used as a therapeu-
tic material for mineralization of dentin and its tubules in a
Funding
physiological environment.
- Wang et al. used in vitro capacity mineralization of cells
and in vivo evaluation of dentin mineralization and/or den- This research received no specific grant from funding agencies
tal pulp response [13]. According to these methodologies, in the public, commercial, or nonprofit sectors.
BAG, especially nano-BAG, induced the odontogenic differ-
entiation and dentin formation of dental pulp cells and is a Acknowledgements
potential material for pulp repair and dentin regeneration.
- Wang et al. used in vitro solution and in vitro capacity min- The authors thank Clémence Agostini, librarian of the
eralization of cells [15]. After incubation in SBF, a crystalline interuniversity health library (Université de Paris), for her assis-
structure precipitated on the surfaces of BAG and in contact tance with the research strategy of the study. The authors also
with cells, and mineralized nodules were generated in the thank Charlène Chevalier (Université Claude Bernard Lyon1) for
BAG group. Both methodologies confirmed the bioactivity of her help for the teeth illustrations of the graphical abstract.
BAG.
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DENTAL-3527; No.

Available online at www.sciencedirect.com

journal homepage: www.intl.elsevierhealth.com/journals/dema

Bioactivity assessment of bioactive glasses for

modified to create mesoporous BAG, to change particle size

2. Materials and methods 2.4. Data extraction

Fig. 2 – Number of publications reported for each analysis

3.2.3. Objectives, Criteria, and Methods – Results in terms

DENTAL-3527; No. of Pages 37

References Bag investigated Compared Methods

References Bag investigated Compared Methods

References Bag investigated Compared Methods

Authors Glass Manufa- Glass composition by mol%1 Contact Analysis

Authors Glass Manufa- Glass composition by mol%1 Contact Analysis

Authors Glass Manufa- Glass composition by mol%1 Contact Analysis

References Bag investigated Compared Methods Main results

Authors Glass Manufa- Glass composition by mol%1 Contact Analysis

Authors Glass Manufa- Glass composition by mol%1 Contact Analysis

Authors Glass Manufa- Glass composition by mol%1 Contact Analysis

Authors Glass Manufa- Glass composition by mol%1 Contact Analysis

References Bag investigated Compared Methods Main results

Authors Glass Manufa- Glass composition by mol%1 Contact Analysis

human or rat pulp in vivo (Table 4). The objectives were

SiO2 CaO Na2 O P2 O5 1 2 3 4

Fig. 4 – Methodology classification of BAG bioactive properties for dental applications.

[1] Abou Neel EA, Aljabo A, Strange A, Ibrahim S, Coathup M,

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