Journal of

Functional
Biomaterials

Review
Multiple-Ion Releasing Bioactive Surface Pre-Reacted
Glass-Ionomer (S-PRG) Filler: Innovative Technology for
Dental Treatment and Care
Satoshi Imazato 1, *, Toshiyuki Nakatsuka 2 , Haruaki Kitagawa 1 , Jun-Ichi Sasaki 1 , Satoshi Yamaguchi 1 ,
Shuichi Ito 3 , Hiroki Takeuchi 4 , Ryota Nomura 5 and Kazuhiko Nakano 6

1 Department of Dental Biomaterials, Osaka University Graduate School of Dentistry,

Suita, Osaka 565-0871, Japan; [email protected] (H.K.);
[email protected] (J.-I.S.); [email protected] (S.Y.)
2 Marketing Department, Shofu Inc., 11 Kamitakamatsu-cho, Fukuine, Higashiyama, Kyoto 605-0983, Japan;
[email protected]
3 Division of Clinical Cariology and Endodontology, Department of Oral Rehabilitation, School of Dentistry,
Health Sciences University of Hokkaido, Ishikari, Hokkaido 061-0293, Japan; [email protected]
4 Department of Preventive Dentistry, Osaka University Graduate School of Dentistry, Suita,
Osaka 565-0871, Japan; [email protected]
5 Department of Pediatric Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University,
Hiroshima 734-8553, Japan; [email protected]
6 Department of Pediatric Dentistry, Osaka University Graduate School of Dentistry, Suita,
Osaka 565-0871, Japan; [email protected]
* Correspondence: [email protected]

Abstract: Surface Pre-Reacted Glass-ionomer (S-PRG) filler, which releases strontium (Sr2+ ), bo-
rate (BO3 3− ), fluoride (F− ), sodium (Na+ ), silicate (SiO3 2− ), and aluminum (Al3+ ) ions at high
concentrations, is a unique glass filler that are utilized in dentistry. Because of its multiple-ion
Citation: Imazato, S.; Nakatsuka, T.; releasing characteristics, S-PRG filler exhibits several bioactivities such as tooth strengthening, acid
Kitagawa, H.; Sasaki, J.-I.; Yamaguchi,
neutralization, promotion of mineralization, inhibition of bacteria and fungi, inhibition of matrix
S.; Ito, S.; Takeuchi, H.; Nomura, R.;
metalloproteinases, and enhancement of cell activity. Therefore, S-PRG filler per se and S-PRG
Nakano, K. Multiple-Ion Releasing
filler-containing materials have the potential to be beneficial for various dental treatments and care.
Bioactive Surface Pre-Reacted
Those include restorative treatment, caries prevention/management, vital pulp therapy, endodontic
Glass-Ionomer (S-PRG) Filler:
Innovative Technology for Dental
treatment, prevention/treatment of periodontal disease, prevention of denture stomatitis, and perfo-
Treatment and Care. J. Funct. ration repair/root end filling. This review summarizes bioactive functions exhibited by S-PRG filler
Biomater. 2023, 14, 236. and its possible contribution to oral health.
https://doi.org/10.3390/
jfb14040236 Keywords: dental; bioactive; ion release; glass filler; prevention; S-PRG

Academic Editor: Josette

Camilleri

Received: 17 March 2023 1. Introduction

Revised: 12 April 2023
Patient-oriented dental treatment and care are considered essential. The philosophy
Accepted: 19 April 2023
of restorative treatments has shifted from restoration with aggressive cutting to less in-
Published: 21 April 2023
tervention to preserve sound tooth structure as much as possible. Based on the findings
from many clinical studies, various self/professional care approaches have been gaining
support, and patients can receive more customized oral care. To develop dental treatment
Copyright: © 2023 by the authors.
and care further, novel technologies are needed, and bioactive materials are proposed as
Licensee MDPI, Basel, Switzerland. one such solution [1–5].
This article is an open access article The definition of bioactive materials in dentistry has not been well established. Some
distributed under the terms and researchers focus on functions that promote (re)mineralization or hard tissue formation [6].
conditions of the Creative Commons However, in the life science field, bioactivity refers generally to the functions that positively
Attribution (CC BY) license (https:// interact with living cells and tissues. Therefore, bioactivity useful for restorative/preventive
creativecommons.org/licenses/by/ treatments and care are not so simple just to induce mineralization but can be more diverse
4.0/). to contribute to oral health as listed in Table 1. The mechanism for those effects can be

J. Funct. Biomater. 2023, 14, 236. https://doi.org/10.3390/jfb14040236 https://www.mdpi.com/journal/jfb

 J. Funct. Biomater. 2023, 14, 236 2 of 18

based on biological, chemical, or mixed actions, as described in the policy statement for
bioactive restorative materials proposed by FDI World Dental Federation [7].

Table 1. Bioactive functions for restorative/preventive treatments and care.

Promotion of mineralization/hard tissue formation

Control of bacterial infection
Prevention of inflammation
Promotion of tissue regeneration

Usage of particles that can release specific components is an effective method for
achieving bioactive functions in dental materials [2,4,5]. For example, Surface Pre-Reacted
Glass-ionomer (S-PRG) filler, a fine glass powder which releases multiple ions, is one of
promising technologies. To date, a large number of in vitro and in vivo studies have re-
ported the ability of S-PRG filler and S-PRG filler-containing materials to provide bioactive
effects. In this review, bioactive functions exhibited by S-PRG filler and its benefits for
various dental treatments and care are summarized.

2. What Is S-PRG Filler

S-PRG filler technology was developed by Shofu Inc. and the resin composites incor-
porating S-PRG filler were first commercialized in 2000. S-PRG filler is a three-layered fine
glass particle composed of a SiO2 coating in the outermost layer followed by a pre-reacted
glass-ionomer phase and a glass core (Figure 1A). The pre-reacted glass-ionomer phase is
prepared by spraying a polyacrylic acid that penetrates the SiO2 coating layer and causes
an acid-base reaction with the fluoro-boro-aluminosilicate core glass. Many products con-
taining S-PRG filler are already available on the market, and a series of those materials
are called GIOMER. Three types of S-PRG filler with particle sizes of 3.0, 0.8, and 0.4 µm
J. Funct. Biomater. 2023, 14, x FOR PEER REVIEW 3 of 17
are utilized for different materials among the GIOMER series. In addition to commercial
products, S-PRG filler has been experimentally incorporated into a variety of materials.

Figure 1. Surface
Figure Pre-Reacted
1. Surface Glass-ionomer
Pre-Reacted (S-PRG)
Glass-ionomer filler.filler.
(S-PRG) (A) S-PRG fillerfiller
(A) S-PRG is composed of three
is composed of three
layers: outer SiO2 coating layer, pre-reacted glass-ionomer phase, and inner functional glass core.
layers: outer SiO2 coating layer, pre-reacted glass-ionomer phase, and inner functional glass core.
(B) S-PRG filler releases multiple ions: strontium (Sr2+),2+borate (BO33−), 3fluoride (F−), sodium (Na+),
(B) S-PRG filler releases multiple ions: strontium (Sr ), borate (BO3 − ), fluoride (F− ), sodium (Na+ ),
silicate (SiO3 ), and
2− aluminum (Al ) ions.
3+
silicate (SiO3 2− ), and aluminum (Al3+ ) ions.

The pre-reacted glass-ionomer phase surrounding the glass core allows the S-PRG filler
to release fluoride ions (F−). Additionally, because specially fabricated fluoro-boro-aluminosilicate
glass is used as the core material, S-PRG filler releases five other ions: strontium (Sr2+ ),
J. Funct. Biomater. 2023, 14, 236 3 of 18

Figure 1. Surface Pre-Reacted Glass-ionomer (S-PRG) filler. (A) S-PRG filler is composed of three
borate (BO3 3− ), sodium (Na+ ), silicate (SiO3 2− ), and aluminum (Al3+ ) ions (Figure 1B). The
layers: outer SiO2 coating layer, pre-reacted glass-ionomer phase, and inner functional glass core.
concentrations of the six ions released into water from S-PRG filler, especially BO3 3− , Sr2+ ,
(B) S-PRG filler releases
andmultiple ions: strontium
F− , are relatively (Sr2+
high [8], much ), borate
greater than (BO
3−), fluoride (F−), sodium (Na+),
those3 liberated from unreacted filler of
silicate (SiO3 ), and aluminum
2− (Alglass-ionomer
conventional 3+ ) ions. cement (Figure 2). Notably, the six ions do not form salts and
are found separately in the eluate.

Figure 2. Comparison of ion release from S-PRG filler and conventional glass-ionomer filler. Release
Figure 2. Comparison of ion release from S-PRG filler and conventional glass-ionomer filler. Release
of ions from S-PRG filler or unreacted filler of conventional glass-ionomer cement was determined
of ions from S-PRG filler afteror unreacted
stirring for 24 h infiller of water
distilled conventional
(mixing ratioglass-ionomer cement
of 1:1). The concentration was determined
of fluoride ions in the
after stirring for 24 h ineluate
distilled water using
was measured (mixing ratioionofelectrode,
a fluoride 1:1). Theandconcentration
those of other ions of fluoride
were measuredions
usinginanthe
eluate was measured using a fluoride ion electrode, and those of other ions were measured using
inductively coupled plasma atomic emission spectrometer.
an inductively coupled3.plasma
Bioactiveatomic
Functions emission
Exhibited spectrometer.
by S-PRG Filler
Owing to the release of multiple ions, S-PRG filler exhibits various bioactive functions,
3. Bioactive Functions Exhibited
which bybelow.
are described S-PRG Filler
Owing to the release
3.1. Toothof multiple ions, S-PRG filler exhibits various bioactive func-
Strengthening
tions, which are describedIonsbelow.
released from S-PRG filler contribute to the strengthening of enamel and dentin,
improving their acid resistance. It is well known that fluoride ions strengthen the tooth
substrate through the formation of fluorapatite. The release of F− from S-PRG filler at high
3.1. Tooth Strengthening
concentrations is effective in providing such effects.
Uo et al. [9] revealed that the strontium content in enamel and dentin became 100 times
Ions released from S-PRG
greater filler contribute
after immersion in the eluateto the strengthening
of S-PRG filler compared withof that
enamel
beforeand dentin,
immersion.
improving their acidIt was
resistance. It is wellthat
further demonstrated known
Al3+ , BOthat
3−
3 , andfluoride
Sr2+ wereions strengthen
taken up the1 htooth
by enamel after of
immersion in the eluate, and Sr showed remarkable incorporation
substrate through the formation of fluorapatite. The release of F from S-PRG filler at high - of up to 7900 ppm after
28 days [10]. Strontium enhances the acid resistance of teeth by converting hydroxyapatite
concentrations is effective in providing
to strontium-apatite such
[11,12]. Uo eteffects.
al. [9] investigated the local structure of Sr taken up by
Uo et al. [9] revealed that the strontium content
teeth using X-ray absorption fine structure in enamel
analysis and that
and determined dentin became
the structure of Sr100
in the enamel and dentin after immersion in the eluate of S-PRG filler was similar to that of
times greater after immersion in the eluate of S-PRG filler compared with that before im-
synthetic Sr-incorporated hydroxyapatite, suggesting that Sr released from S-PRG filler can
mersion. It was further demonstrated
be incorporated that
into the Ca siteAl
of 3+ , BO33−, and Sr2+ were taken up by enamel
hydroxyapatite.
after 1 h of immersion inHiraishi et al. [13]
the eluate, andexamined
Sr showedthe interaction
remarkableof borateincorporation
ions released fromof S-PRG
up to filler
7900
with the apatite of enamel and dentin and revealed that the borate ion adsorbed in the
ppm after 28 days [10].
enamelStrontium
and dentin wasenhances the acid
in a tetra-coordinated resistance
form, of teeth
which possesses a bufferby converting
capacity, helps
protect the tooth structure against acid attacks, and promotes remineralization.
 enamel and dentin was in a tetra-coordinated form, which possesses a buffer capacity,
helps protect the tooth structure against acid attacks, and promotes remineralization.

3.2. Acid Neutralization

J. Funct. Biomater. 2023, 14, 236 4 of 18
S-PRG filler modulates the pH of the surrounding medium and shifts it toward neu-
tral and weak alkaline values [14]. Although further investigations are required to clarify
the acid-buffering3.2. Acid Neutralization
mechanism, the released Sr2+ and Na+ are considered to promote acid
buffering. S-PRG filler modulates the pH of the surrounding medium and shifts it toward
neutral and weak alkaline values [14]. Although further investigations are required to
clarify the acid-buffering mechanism, the released Sr2+ and Na+ are considered to promote
3.3. Promotion of Mineralization
acid buffering.
The S-PRG filler eluate containing Sr2+ at high concentrations can react with other
3.3. Promotion of Mineralization
ions in mineralizable solutions to induce chemical mineralization. The eluate obtained
The S-PRG filler eluate containing Sr2+ at high concentrations can react with other
from S-PRG filler-containing materials promotes mineral deposit formation on the surface
ions in mineralizable solutions to induce chemical mineralization. The eluate obtained
of phosvitin-immobilized
from S-PRG agarose beads (model
filler-containing materialsof demineralized
promotes dentin)
mineral deposit placed
formation on in
the the
surface
mineralizing solution [8] (Figure 3). By micro-area
of phosvitin-immobilized X-ray
agarose beads diffraction
(model analysis,
of demineralized the minerals
dentin) placed in the
that formed with amineralizing solution [8]were
globular structure (Figure 3). By micro-area
determined to beX-ray diffraction analysis, the minerals
apatite.
that formed with a globular structure were determined to be apatite.

Figure 3. Mineral induction by eluate

Figure 3. Mineral of S-PRG
induction filler-containing
by eluate adhesive.adhesive.
of S-PRG filler-containing (A) Globular deposit
(A) Globular deposit
formed in the presence of eluate
formed of S-PRG
in the presence filler-containing
of eluate adhesive (Shake
of S-PRG filler-containing adhesiveOne).
(Shake(B) Control.
One). The The
(B) Control.
eluate of S-PRG filler-containing
eluate of S-PRG adhesive promoted
filler-containing adhesive mineral
promotedformation on phosvitin-immobilized
mineral formation on phosvitin-immobilized
agarose beads placed in mineralizing
agarose beads placedsolution consisting
in mineralizing solutionofconsisting
2.24 mMofCaCl 2, 1.34
2.24 mM CaClmM KPO
2 , 1.34 mM4,KPO
1504mM
, 150 mM
KCl, and 10 mM Hepes KCl, at
andpH 7.4. Hepes at pH 7.4.
10 mM

Nemoto et al. [15] reported that the eluate of S-PRG filler upregulated the mRNA
Nemoto et al.expression
[15] reported that the eluate of S-PRG filler upregulated the mRNA
level of the osteogenic differentiation marker (i.e., alkaline phosphatase) in
expression level ofhuman
the osteogenic differentiation
bone marrow-derived marker
stromal cells. (i.e.,
As a alkaline phosphatase)
consequence, in hu-
the S-PRG filler eluate
man bone marrow-derived
promoted the stromal cells. As
mineralization a consequence,
of the the [15].
extracellular matrix S-PRG fillereteluate
Ishigure al. [16] pro-
reported
that the eluate
moted the mineralization of theofextracellular
S-PRG filler promoted the proliferation
matrix [15]. Ishigure etofal.
dental
[16] pulp stem cells
reported thatand
enhanced their alkane phosphatase activity. These results suggest that S-PRG filler can
the eluate of S-PRG filler promoted the proliferation of dental pulp stem cells and en-
biologically promote apatite formation and hard tissue formation, as well as chemically.
hanced their alkane phosphatase activity. These results suggest that S-PRG filler can bio-
logically promote 3.4.
apatite formation
Inhibition and
of Bacteria andhard
Fungi tissue formation, as well as chemically.
Numerous studies have demonstrated antibacterial effects of the S-PRG filler eluate
against bacteria
3.4. Inhibition of Bacteria and Fungiin human saliva and dental plaque, such as streptococci, Enterococcus faecalis,
Actinomyces israelii, Propionibacterium acnes, Porphyromonas gingivalis, and Fusobacterium
Numerous studies have
nucleatum [17].demonstrated antibacterial effects of the S-PRG filler eluate
against bacteria in human Nomura saliva andrevealed
et al. [18] dentalthat
plaque, such
the S-PRG aseluate
filler streptococci, Enterococcus
inhibited Streptococcus mutans
growth in a dose-dependent manner, especially before the logarithmic growth phase. The
growth of S. mutans in the absence of S-PRG filler eluate reached a stationary phase 7 h
after incubation, whereas the time for S. mutans growth was extended in the presence
of S-PRG filler eluate. The ions mainly responsible for such effects are considered to be
 Nomura et al. [18] revealed that the S-PRG filler eluate inhibited Streptococcus mutans
growth in a dose-dependent manner, especially before the logarithmic growth phase. The
growth in a dose-dependent manner, especially before the logarithmic growth phase. The
growth of S. mutans in the absence of S-PRG filler eluate reached a stationary phase 7 h
growth of S. mutans in the absence of S-PRG filler eluate reached a stationary phase 7 h
after incubation, whereas the time for S. mutans growth was extended in the presence of
after incubation, whereas the time for S. mutans growth was extended in the presence of
S-PRG filler eluate. The ions mainly responsible for such effects are considered to be BO33−
S-PRG
J. Funct. Biomater. 2023, filler
14, 236 eluate. The ions mainly responsible for such effects are considered to be BO3
3−
5 of 18
and F−−. Borate ions have been used as a preservative in the ophthalmic field, and fluoride
and F . Borate ions have been used as a preservative in the ophthalmic field, and fluoride
ions at high concentrations are also known to inhibit bacteria. Miki et al. [19] investigated
ions at high concentrations are also known to inhibit bacteria. Miki et al. [19] investigated
S. mutans growth in the presence
3− and −
of Na++, SiO32− , Sr2+, BO33−, Al3+, or F− at the concentrations
S. mutans growthBO in 3the presence of Na , SiO 2−, Sr2+, BO33−, Al3+, or F− at the concentrations
F . Borate ions have been used as a preservative in the ophthalmic field, and
3
released from the experimental resin composites containing S-PRG filler at 55.9 vol% and
released from thefluoride experimental
ions at resin composites containing
high concentrations S-PRGtofiller
are also known at 55.9
inhibit vol%Miki
bacteria. and et al. [19]
determined that BO 33− and F− significantly inhibited the growth. +
investigated S. mutans growth in the presence of Na , SiO 2− , Sr2+ , BO 3− , Al3+ , or F− at
determined that BO3 and F significantly inhibited the growth.
3− − 3 3
Kitagawa et the al. [20] reportedreleasedthat even lowthe concentrations ofcomposites
BO33− or F−−, at which
Kitagawa et al. concentrations
[20] reported that even from low experimental resin
concentrations of BO33− or Fcontaining
, at which S-PRG filler
bacterial growth was at 55.9not affected,
vol% can inhibit
and determined thatS. BO
mutans
3
3 − glucose
and F − metabolism
significantly and
inhibited acid
the pro-
growth.
bacterial growth was not affected, can inhibit S. mutans glucose metabolism and acid 3− orpro-− , at which
duction. A detailed study conducted
Kitagawa byreported
et al. [20] Nomura et even
that al. [18]
lowclarified that the
concentrations eluate
of BO 3 of FS-
duction. A detailed study conducted by Nomura et al. [18] clarified that the eluate of S-
PRG filler prominently bacterialdownregulated
growth was notoperons affected,related
can inhibitto S.S.mutans
mutans sugar
glucosemetabolism,
metabolism and acid
PRG filler prominently downregulated
production. A detailed operons
study conducted related by to S. mutans
Nomura et al. sugar
[18]and metabolism,
clarified thatop-
the eluate of
such as the pdh operon encoding the pyruvate dehydrogenase complex the glg
such as the pdh operon S-PRG encoding
filler the pyruvate
prominently downregulateddehydrogenase
operons complex
related to S.and
mutansthe sugar
glg op-metabolism,
eron encoding a putative glycogen synthase. According to such effects, when cultured
eron encoding a such putative
as theglycogen
pdh operon synthase.
encoding According
the pyruvateto such effects,complex
dehydrogenase when cultured
and the glg operon
with the 20–25% S-PRG filler eluate, glucan synthesis by S. mutans was inhibited (Figure
with the 20–25% encoding S-PRG filler eluate,glycogen
a putative glucan synthase.
synthesisAccordingby S. mutans was
to such inhibited
effects, when(Figure
cultured with the
4), and the biofilm formed
20–25% S-PRG was determined
filler eluate, glucanto be sparse,bywith
synthesis S. less was
mutans extracellular
inhibited matrix4), and the
(Figure
4), and the biofilm formed was determined to be sparse, with less extracellular matrix
(Figure 5). biofilm formed was determined to be sparse, with less extracellular matrix (Figure 5).
(Figure 5).

Figure 4. InhibitionFigure
of S. mutans glucan of
4. Inhibition
synthesis
S. mutans
by glucan
S-PRG filler eluate. S. mutans MT8148 (1.0 × 1077 MT8148
S. mutans
Figure 4. Inhibition of S. mutans glucan synthesis by S-PRGsynthesis by S-PRG
filler eluate. filler
S. mutans eluate. (1.0
MT8148 × 10
CFU/mL) was incubated
(1.0 × 10
for
7 18 h at 37 °Cincubated
with the addition of 1%
18 h at 37of◦ C1%
sucrose without (left) or with
CFU/mL) was incubated forCFU/mL) was
18 h at 37 °C with theforaddition with the addition
sucrose withoutof 1% sucrose
(left) or without
with (left) or
(right) the 25% S-PRG filler
withfiller
eluate.
(right)
Arrow:
the 25%
S. mutans
S-PRGS.filler
cell,Arrow:
eluate.
Arrowhead:
S. mutans
glucan formed. glucan formed.
cell, Arrowhead:
(right) the 25% S-PRG eluate. Arrow: mutans cell, Arrowhead: glucan formed.

Figure 5. Inhibition of biofilm formation by S-PRG filler eluate. S. mutans NCTC10449 suspension
Figure 5. InhibitionFigure
of biofilm formation
5. Inhibition by S-PRG
of biofilm fillerbyeluate.
formation S-PRGS. mutans
filler eluate.NCTC10449 suspension
S. mutans NCTC10449 suspension sup-
supplemented with 1% sucrose was incubated for 24 h without (left) or with the 20% S-PRG filler
supplemented withplemented
1% sucrose was
with 1%incubated
sucrose wasfor 24 h without
incubated for 24 h(left) or with
without (left)the 20%the
or with S-PRG filler filler eluate
20% S-PRG
eluate (right). In the presence of the 20% S-PRG filler eluate, S. mutans biofilm formation was in-
eluate (right). In the presence
(right). ofpresence
In the the 20%ofS-PRG
the 20%filler eluate,
S-PRG fillerS. mutans
eluate, biofilmbiofilm
S. mutans formation was was
formation in- inhibited.
hibited.
hibited.
Ions released from S-PRG filler are effective in inhibiting bacteria related to periodontal
disease and suppressing their pathogenic factors. It was reported that the eluate of S-PRG
filler inhibited the growth of P. gingivalis, F. nucleatum, and Aggregatibacter actinomycetemcomitans [21],
and suppressed the hemagglutination and gingipain activity of P. gingivalis [21,22]. It
was also determined that the coaggregation of P. gingivalis and F. nucleatum, essential for
subgingival biofilm formation, can be prevented in the presence of S-PRG filler eluate [22].
J. Funct. Biomater. 2023, 14, 236 6 of 18

Tamura et al. [23] reported that the eluate of S-PRG filler decreased the amount of
hydrogen peroxide and catalase activity in Candida albicans. Furthermore, the S-PRG
filler eluate prevented the growth and biofilm formation of C. albicans and inhibited their
dimorphism conversion. The eluate of S-PRG filler also suppressed the activity to produce
secreted aspartyl proteinases, which are major pathogenic factors of C. albicans.

3.5. Inhibition of Matrix Metalloproteinases

Dentin matrix metalloproteinases (MMP) are a family of host-derived proteolytic
enzymes that are trapped within the dentin matrix and can hydrolyze the organic matrix
of dentin. MMPs break down collagen at the resin–dentin interface and compromise the
durability of dentin bonding. Therefore, many reports are available on application of
MMP inhibitors during bonding procedures to improve the long-term stability of dentin
bonding. The S-PRG filler eluate inhibits the activity of collagen-bound MMPs and dentin
matrix degradation, similar to 2% chlorhexidine digluconate, which is known as a MMP
inhibitor [24]. Salim et al. [25] also reported that the eluate of S-PRG filler showed a reduc-
tion in MMP activity and revealed that F− ions most effectively inhibited the enzymatic
activity among the six ions released from S-PRG filler.

3.6. Enhancement of Cell Activity

Yamaguchi-Ueda et al. [26] examined the effects of various concentrations of S-PRG
filler eluates on the growth and migration of gingival fibroblasts. They revealed that
multiple ions present in the S-PRG filler eluate can stimulate migration of human gingival
fibroblast cells via upregulation of the extracellular signal-regulated kinase 1/2 (ERK 1/2)
signaling pathway. This finding indicates that the ions in the S-PRG filler eluate promoted
cell activity, which may assist in oral wound healing.
Takeuchi et al. [27] reported that the eluate of S-PRG filler inhibited penetration of vir-
ulence factors of P. gingivalis, such as lipopolysaccharide and peptidoglycan, into gingival
epithelial cells. The eluate of S-PRG filler induced the expression of coxsackievirus and
adenovirus receptor (CXADR), a tight barrier of gingival epithelium, in immortalized hu-
man gingival epithelial cells, indicating that the S-PRG filler eluate enhanced the epithelial
barrier function.

4. Benefits of S-PRG Filler for Dental Treatment and Care

Many products containing S-PRG filler are commercially available, such as resin com-
posites, adhesives, resin cements, coating resins, fissure sealants, polishing pastes, and
temporary fillings (Table 2). Additionally, S-PRG filler has been incorporated experimen-
tally into inorganic cements, root canal sealers, denture bases, tissue conditioners, denture
adhesives, toothpastes, varnishes, CAD/CAM composites, and toothbrush filaments. Even
when S-PRG filler is incorporated into resin-based materials with silanization, multiple ions
are released at high concentrations. The capacity for releasing six ions (i.e., Sr2+ , BO3 3− ,
F− , Na+ , SiO3 2− , and Al3+ ) endows the S-PRG filler with various therapeutic effects, which
are useful for restorative treatment, caries prevention/management, vital pulp therapy,
endodontic treatment, prevention/treatment of periodontal disease, prevention of denture
stomatitis, and perforation repair/root end filling. In this regard, S-PRG filler-containing
materials differ from conventional ones that only release ions to promote remineralization,
such as glass-ionomer cements or fluoride-releasing resin composites.

4.1. Restorative Treatment

To develop restorative treatments with preventive effects, S-PRG filler has been incor-
porated in resin composites, adhesives, and resin cements.
A ligand exchange mechanism within the glass-ionomer phase offers S-PRG filler the
ability to release and recharge fluoride ions. The proprietary resin composites containing
S-PRG filler (Beautifil II, Shofu Inc., Kyoto, Japan) release high concentrations of fluoride
ions and can be recharged by exposure to 5000 ppm sodium fluoride solution for 5 min [28].
J. Funct. Biomater. 2023, 14, 236 7 of 18

Table 2. Commercially available materials containing S-PRG filler.

Materials Type Product Name

BEAUTIFIL II
BEAUTIFIL II LS
BEAUTIFIL Next *
BEAUTIFIL Enamel
Resin composites Packable
BEAUTIFIL Gingiva
BEAUTIFIL-Bulk Restorative
BEAUTIFIL e Posterior
BEAUTIFIL Unishade *
BEAUTIFIL Flow
BEAUTIFIL Flow Plus
BEAUTIFIL Flow Plus X
BEAUTIFIL-Bulk Flowable
BEAUTIFIL Injectable
Flowable
BEAUTIFIL Injectable X
BEAUTIFIL Unishade Flow *
FIT SA
BEAUTIFIL Kids *
BEAUTIFIL Kids SA
BeautiCore Flow Paste *
Core build up
BeautiCore LC *
2-step self-etch FL-Bond II
Adhesives
1-step self-etch Fluoro Bond Shake One *
With adhesive ResiCem EX *
Self-adhesive BeautiCem SA
Resin cements
Veneer cement BeautiCem Veneer
Orthodonitcs BeautiOrtho Bond II *
Preventive PRG Barrier Coat
Teeth coating resins
Esthetic BeautiCoat
Fissure sealants BeautiSealant
For tooth surface PRG Pro-Care Gel α
Cleaning/polishing pastes
For composites PRG CompoGloss
Fillings PRG Protect Seal *
Temporary fillings
Cementing IP Temp Cement *
* only available on Japanese market.

Several studies have demonstrated that resin composites containing S-PRG filler ex-
hibit antibacterial effects against oral bacteria [4,5]. Miki et al. [19] examined the inhibitory
effects of experimental resin composites containing different ratios of S-PRG filler on
S. mutans growth and reported that the specimens containing S-PRG filler at 28.0 vol%
or greater inhibited bacterial growth on their surfaces. They further demonstrated that
the inhibitory effects were mainly attributed to the release of BO3 3− and F− . It was also
reported that the eluate of S-PRG filler suppressed the adherence of S. mutans [22], and thus,
S. mutans biofilm formation was inhibited on the surface of resin composites containing
S-PRG filler (Figure 6). An in situ study assessing plaque accumulation on resin compos-
ites placed in human mouths for 24 h showed significant suppression of dental plaque
maturation on the surface of resin composites containing S-PRG filler [29] (Figure 7).
er. 2023, 14, x FOR PEER REVIEW 8 of 17
ter. 2023, 14, x FOR PEER REVIEW 8 of 17

placed in human mouths for 24 h showed significant suppression of dental plaque matu-
placed
J. Funct. Biomater.
ration inthe
14,
2023,on human
236 mouths
surface forcomposites
of resin 24 h showed significant
containing suppression
S-PRG of (Figure
filler [29] dental plaque
matu-7). 8 of 18
ration on the surface of resin composites containing S-PRG filler [29] (Figure 7).

Figure 6. Inhibitory effects of S. mutans biofilm formation on resin composites containing S-PRG
Figure Figure
6. Inhibitory effects6. Inhibitory effects
of S. mutans of S. mutans
biofilm formationbiofilm
on formation on resin composites
resin composites containing containing
S-PRG S-PRG
filler. Reproduced with permission from Imazato et al. [4]. Copyright: Japanese Society for Dental
filler. Reproduced filler.
with Reproduced
permission with
frompermission
Imazato etfrom Imazato
al. [4]. et al. [4].Japanese
Copyright: Copyright: Japanese
Society for Society
Dentalfor Dental
Materials and Devices.
Materials
Materials and Devices. and Devices.

Figure 7. Plaque
Figure 7. Plaque accumulated accumulated
on resin composites on after
resin placement
composites in after placement
a human mouthin a for
human
24 h.mouth
Re- for 24 h.
Figure 7. with
produced Plaque Reproduced
accumulated
permission with
fromon permission from
resin composites
Imazato Imazato et al.
after placement
et al. [4]. Copyright: [4]. Copyright:
Japanese in aSocietyJapanese
humanfor mouth Society
Dental 24 h. Re- Materials
for Dental
forMaterials
produced
and Devices. and Devices.
with permission from Imazato et al. [4]. Copyright: Japanese Society for Dental Materials
and Devices.
An investigation of demineralization in the tooth structure surrounding filling materi-
An investigation of demineralization
als revealed in the tooth structure
that S-PRG filler-containing resin compositessurrounding
inhibited filling mate-
the demineralization
An investigation
rials revealed thatofS-PRG of demineralization
filler-containing
wall and outer lesions resin in the tooth
composites
in enamel structure
and dentin inhibitedsurrounding filling
the demineralization
and increased mate-
the surrounding tooth
rials revealed that
of wall and outer hardness S-PRG filler-containing
lesions in[30].enamel
Lai etand resin
dentin
al. [31] composites
and increased
investigated inhibited the demineralization
the surrounding tooth
the anti-demineralization effectshard-
of restorations
of wall
ness [30].andLaiouter lesions
et al.using
[31] S-PRGin enamel andanti-demineralization
dentin
filler-containing
investigated the resinand increased
composites the surrounding
(Beautifil
effects II)
of and toothusing
adhesives
restorations hard-
(FL-Bond II) on
ness [30]. Lai et al.
the [31]
rootinvestigated
surfaces. Usingthe anti-demineralization
an oral biofilm reactor
S-PRG filler-containing resin composites (Beautifil II) and adhesives (FL-Bond II) on the and effects
pH of
cycling restorations
artificial using
caries model, they
S-PRG
root surfaces. demonstrated
filler-containing
Using that thereactor
resinbiofilm
an oral composites combination
(Beautifil
and pH of II)
Beautifil IIartificial
and adhesives
cycling and FL-Bond cariesII model,
(FL-Bond exhibited
II) on athe
they cumulative
root surfaces. effectan
Using to inhibit
oral demineralization
biofilm reactor andof root
pH dentin
cycling adjacent to restoration.
artificial caries model, they
demonstrated that the combination of Beautifil II and FL-Bond II exhibited a cumulative
demonstrated It has been reported that S. mutans
II and contains esterases that can potentially degrade
effect to inhibit that the combination
demineralization of Beautifil
of root dentin adjacent FL-Bond II exhibited
to restoration.
resin-based restorative materials [32]. Gautam et al. [33] revealed by in vitro test that
a cumulative
effect It to
hasinhibit
been demineralization
reported that of root dentin adjacent to restoration.
degradation by S. mutans
S. mutans contains
was reducedesterases that can potentially
for resin composites containing S-PRG degrade filler (Beautifil
It has been
resin-based restorative reported
II) compared
that
materials S.
with
mutans
[32]. Gautam
other
contains esterases
et al. [33]
commercial resinrevealed
that
composites.
can
by inOnpotentially
vitro
thetest
other
degrade
that deg-Yoshihara
hand,
resin-based
radation restorative
by S. mutans
et al. wasmaterials
[34] reduced
reported [32].
for Gautam ofetmany
resin composites
production al. [33] revealed
on theby
containing
holes in vitro
S-PRG
surface test(Beautifil
filler
of S-PRG that deg-
filler-containing
radation by S. mutans
II) compared withresin other was reduced
composites
commercial for resin
afterresin
immersion composites
composites.in lactic containing
OnacidtheatotherpH 4.0S-PRG filler
for 3Yoshihara
hand, (Beautifil
days, while etnoal. change in
II) compared
[34] reported with otherintegrity
surface
production commercial
of many resinon
washoles
detected composites.
for
theother Onofthe
conventional
surface other
S-PRG resinhand, Yoshihara
composites.
filler-containing et
Theyresin al.
described that
[34] reported
composites production
after immersionofinmany
lacticholes onpH
acid at the4.0surface of S-PRG
for 3 days, whilefiller-containing resin
no change in surface
composites after immersion in lactic acid at pH 4.0 for 3 days, while no change in surface
J. Funct. Biomater. 2023, 14, 236 9 of 18

such surface alteration was caused by dissolution of S-PRG filler. Although several clinical
studies revealed their excellent performance [35,36], long-term surface durability of S-PRG
filler-containing resin composites remains to be investigated in detail.
Recently, CAD/CAM resin composite blocks containing S-PRG filler have been de-
veloped for the restoration of primary molar teeth. Nakase et al. [37] reported that S-PRG
filler-containing CAD/CAM resin composite blocks demonstrated acceptable physical
properties and wear performance for clinical use. Moreover, an S-PRG filler-containing
CAD/CAM resin composite crown is advantageous for primary tooth restoration because it
can be cemented using a conventional glass-ionomer cement through the chelation reaction
between Sr and polycarboxylic acid [38].

4.2. Caries Prevention/Management

The S-PRG filler modulates the pH of the surrounding medium and shifts it toward
neutral and weak alkaline values [14]. Additionally, the release of F− and Sr2+ from S-PRG
filler strengthens the tooth substrate, as described above. These effects are beneficial for
the prevention and management of caries. Many studies have demonstrated that ions
released from S-PRG filler in various materials are taken up by adjacent enamel and dentin
to prevent demineralization, including adhesives [39], endodontic sealers [40], orthodontic
adhesives [41], pit/fissure sealants [42], coating materials [43,44], resinous vanishes [45],
and denture base resins [46].
A resinous coating material containing S-PRG filler (PRG Barrier Coat, Shofu Inc.)
protects the enamel surface from demineralization caused by acidic attack [44,47]. Ions
released from S-PRG filler in PRG Barrier Coat exert acid-neutralizing effects near the
coated surface. Uptake of F and Sr released from PRG Barrier Coat by the tooth substrate
can be effective to inhibit demineralization [48]. Ma at al. [43] demonstrated that PRG
Barrier Coat containing S-PRG filler can protect root surfaces from demineralization by
producing a coating layer with a thickness of approximately 200 µm. It was also shown
that the pH drop in S. mutans clumps caused by glucose on the surface of the PRG Barrier
Coat was reduced, possibly because the glucose metabolism was hindered by the released
ions as well as acid buffering [43].
The incorporation of S-PRG filler into a resin-based pit and fissure sealant provides
acid neutralization capacity without deteriorating the sealing effectiveness [49,50] or the
ability to release and recharge fluoride ions [51]. Some clinical studies demonstrated caries
preventive effects of commercially available S-PRG filler-containing pit/fissure sealant
(BeautiSealant, Shofu Inc.) [52,53]. Penha et al. [53] conducted a randomized clinical trial
to compare the evolution of caries in newly erupted permanent molars and determined
that the S-PRG sealant group presented higher sound teeth predominance compared with
another fluoride-releasing sealant after 12 months.
A polishing paste containing S-PRG filler, including a commercial one containing
5% S-PRG filler (PRG Pro-Care Gel, Shofu Inc.), is useful for controlling caries incidence
and remineralization. Iijima et al. [54] reported that human enamel polished with S-PRG
filler-containing paste, following immersion in the demineralizing solution at pH 4.5,
exhibited greater surface hardness and smoothness than those polished with fluoridated
paste or nano-hydroxyapatite-containing paste. Furthermore, the surface hardness of
demineralized dentin polished with the S-PRG filler-containing paste recovered after
immersion in mineralizing solution for 1 month, indicating that the S-PRG filler-containing
paste can promote dentin remineralization [55]. A recent study revealed that PRG Pro-Care
Gel has a similar potential to remineralize the demineralized root dentin as a 38% silver
diamine fluoride solution [56].
Amaechi et al. [57] examined the effectiveness of experimental toothpastes containing
S-PRG filler in preventing tooth surface demineralization using Featherstone’s pH cycling
model to develop early caries. It was determined that S-PRG filler-containing dentifrice was
more effective in preventing tooth demineralization than 1100 ppm F-containing toothpaste,
highlighting the potential of S-PRG filler to assist individuals at high risk of developing
J. Funct. Biomater. 2023, 14, 236 10 of 18

caries [58]. The potential of S-PRG filler-containing toothpaste to remineralize the deminer-
alized enamel surface has also been shown in situ [59]. Experimental toothpaste containing
5% S-PRG filler showed remineralizing effects similar to those of toothpaste containing
1500 ppm F, even showing greater activity to recover mineral loss in the subsurface regions.
Moecke et al. [60] investigated the remineralizing effects of experimental varnishes
containing S-PRG filler. They revealed that the varnish containing 40% S-PRG filler more
effectively promoted the remineralization of demineralized bovine enamel compared with
the varnish containing 5% sodium fluoride.

4.3. Vital Pulp Therapy

S-PRG filler can promote tertiary dentinogenesis. As pulp capping materials, several
attempts have been made to incorporate S-PRG filler into adhesives [61,62], self-adhesive
resins [63], and inorganic cements [64,65].
Experimental inorganic cement, prepared by mixing S-PRG filler with copolymers
of acrylic acid and tricarboxylic acid, induces complete tertiary dentin formation at 2 and
4 weeks after pulp exposure in rat molars [64]. Strontium released from S-PRG cement was
determined to transfer into the pulpal tissue and contribute to the induction of mineraliza-
tion and dentinogenesis [65]. These functions are based on biological action because the
S-PRG cement enhanced the expression of genes related to osteo/dentinogenic differentia-
tion, such as CXCL-12 and TGF-β1, which contribute to tertiary dentin formation during
the healing process in pulpal tissue [65].
It has been reported that lithium ions can activate the Wnt/β-catenin signaling path-
way and induce dentin formation in pulpotomized teeth [66]. Therefore, trials to add
LiCl to S-PRG cement were conducted, revealing that reparative dentin formation in rat
teeth was enhanced through activation of the Wnt/β-catenin canonical signaling pathway
without adversely affecting the sealing property of the cement [67,68].

4.4. Endodontic Treatment

Apical periodontitis is an infectious disease, and the treatment requires careful bacte-
rial eradication inside filled root canals. However, the complete elimination of bacterial
infection in root canals is difficult to achieve using only mechanical instrumentation, irriga-
tion, and medication. Therefore, endodontic filling materials capable of eliminating residual
bacteria inside root canals have been proposed as a possible solution to this problem. An
experimental zinc oxide-based endodontic sealer containing S-PRG filler demonstrated the
sustained release of multiple ions (i.e., Sr2+ , BO3 3− , F− , Na+ , SiO3 2− , and Al3+ ) [40] and
antibacterial effects against E. faecalis and P. gingivalis [69,70].
The eluate obtained from experimental root canal sealer containing S-PRG filler was
reported to downregulate mRNA expression levels of proinflammatory cytokines, such
as interleukin (IL)-1α, IL-6, and TNF-α, in LPS-stimulated RAW264.7 cells, suggesting its
anti-inflammatory effects [71]. Moreover, an experimental sealer containing S-PRG filler
can promote the healing of periapical lesions in vivo [70,72,73].

4.5. Prevention/Treatment of Periodontal Disease

The S-PRG filler eluate suppresses the activity of periodontitis-related bacteria [21,22]
and inhibits penetration of P. gingivalis virulence factors into gingival epithelial cells [27]. It
also promotes recovery of migration activity in epithelial cells infected with P. gingivalis
(Figure 8). In recent years, several animal studies have verified the ability of S-PRG filler
to help prevent the progression of periodontal disease. Iwamatsu-Kobayashi et al. [74]
investigated the effects against tissue destruction induced in a mouse periodontal disease
model and revealed that periodical dripping of the S-PRG filler eluate suppressed the bone
loss and resulted in greater volume and density of alveolar bone. It has also been reported
that ultrasonic irrigation with S-PRG filler dispersion can improve periodontal parameters,
such as gingival index, bleeding on probing, probing pocket depth, and clinical attachment
level when applied to a periodontal defect in a dog [75,76]. Irrigation with S-PRG filler
 reported that ultrasonic irrigation with S-PRG filler dispersion can improve periodonta
parameters, such as gingival index, bleeding on probing, probing pocket depth, and clin
ical
J. Funct. attachment
Biomater. 2023, 14, 236 level when applied to a periodontal defect in a dog [75,76]. Irrigation 11 of 18 with
S-PRG filler dispersion reduced the ratio of red complex (i.e., Tannerella forsythia, P. gingi
valis, and Treponema denticola)
dispersion among
reduced theofbacterial
the ratio red complexflora in the periodontal
(i.e., Tannerella pocket
forsythia, P. gingivalis, and[76].
Treponema denticola) among the bacterial flora in the periodontal pocket [76].

Figure 8. Recovery of migration

Figure 8. Recoveryactivity in activity
of migration epithelial cells cells
in epithelial by S-PRG
by S-PRG filler eluate.
filler eluate. Human
Human gingivalgingiva
epithelial cells were infected with
epithelial cells wereP.infected
gingivalis,
with P. and their
gingivalis, andmigration
their migrationwas
wasassessed after
assessed after 24culture.
24 h of h of culture
(A) Before culture, (B) after culture without P. gingivalis infection, (C) after culture with P. gingivalis
(A) Before culture, (B) after culture without P. gingivalis infection, (C) after culture with P. gingivali
infection, and (D) after culture with P. gingivalis infection and 1% S-PRG filler eluate.
infection, and (D) after culture with P. gingivalis infection and 1% S-PRG filler eluate.
4.6. Prevention of Denture Stomatitis
A denture base with antifungal effects may be useful for the prevention of denture
4.6. Prevention of Denture Stomatitis
stomatitis. The morphology of C. albicans cells remains in the yeast form in a normal
A denture base resident
withflora, but it growseffects
antifungal from themay
yeast form to the hyphal
be useful formprevention
for the by creating a longer
of dentur
germ tube when grown in an inflammatory environment in a human host [77]. The
stomatitis. The morphology
eluate of S-PRGoffiller
C. albicans cells remains
prevents adherence in the
of C. albicans yeastbase
to denture formresinin a inhibits
and normal resi
dent flora, but it grows from the
the dimorphism yeast form
conversion to the[23].
of C. albicans hyphal form by creating
The incorporation a longer
of S-PRG filler into germ
polymethyl methacrylate-based resin effectively inhibited biofilm formation by C. albicans,
tube when grown within an inflammatory
reduced environment
length of the hyphae [78]. Similar in a human
results have beenhost [77].
reported The
for the eluate of S
addition
PRG filler preventsofadherence
S-PRG filler to of C.materials
other albicans in to
the denture base resin
field of removable and inhibits
prosthodontics, the dimor
such as tissue
conditioners [79,80] and poly(methyl vinyl ether-alt-maleic anhydride)-based denture
phism conversion adhesives
of C. albicans [23]. The incorporation of S-PRG filler into polymethy
[81]. The multiple-ion release characteristics of S-PRG filler may contribute to
methacrylate-based theresin effectively
oral health inhibited
of the elderly population biofilm
by preventingformation
the onset of by
oral C. albicans, with re
candidiasis.
duced length of the hyphae [78]. Similar results have been reported for the addition of S
PRG filler to other materials in the field of removable prosthodontics, such as tissue con
ditioners [79,80] and poly(methyl vinyl ether-alt-maleic anhydride)-based denture adhe
 J. Funct. Biomater. 2023, 14, 236 12 of 18

14, x FOR PEER REVIEW 12 of

4.7. Perforation Repair/Root End Filling
Hirata-Tsuchiya et al. [72] reported that the application of commercially available resin
composites containing S-PRG filler for sealing root perforation can facilitate periodontal
tissue healing and support good clinical outcomes. Inorganic cement containing S-PRG filler
silicate-based cement
exhibits(Figure 9). Considering
excellent cytocompatibility the enhancement
for osteoblastic cells, similar toof cell activity
a calcium by releas
silicate-based
cement (Figure 9). Considering the enhancement of cell activity
ions, S-PRG filler-containing materials may be useful for perforation repair and root e by released ions, S-PRG
filler-containing materials may be useful for perforation repair and root end filling, for
filling, for which which
calcium silicate-based
calcium cements
silicate-based cements have
have been been
widely widely used.
used.

Figure 9. Proliferation
Figureof9.osteoblastic
Proliferation ofcells on the
osteoblastic material
cells surface.
on the material (A)(A)
surface. Experimental S-PRG
Experimental S-PRG ce- ceme
(B) calcium silicate-based cement (ProRoot MTA), (C) reinforced zinc oxide cement, and (D) gla
ment, (B) calcium silicate-based cement (ProRoot MTA), (C) reinforced zinc oxide cement, and
(D) glass-ionomer cement. MC3T3-E1 cells were seeded on the set specimen and cultured for 24 h.
ionomer cement. MC3T3-E1 cells were seeded on the set specimen and cultured for 24 h.
5. Ion Release Profile of S-PRG Filler-Containing Materials
To of
5. Ion Release Profile provide
S-PRGclinical benefits for restorative treatments,
Filler-Containing Materials sustained or controlled release
of active components is essential for agent-releasing bioactive materials. Figure 10 shows
To provide clinical
the releasebenefits for
profile of six ionsrestorative treatments,
from commercially sustained
available S-PRG or controlled
filler-containing resin com- relea
posites, an S-PRG filler-containing resin cement for luting, and an S-PRG filler-containing
of active components is essential for agent-releasing bioactive materials. Figure 10 show
bonding agent in a two-step self-etch adhesive. All materials demonstrated continuous
the release profile of six
release ions
of six from
ions for up tocommercially
440 days, with the available
release of Sr2+S-PRG
and BO3filler-containing
3− at high concen- res
trations for the resin composites and the resin cement. The
composites, an S-PRG filler-containing resin cement for luting, and an S-PRG3−filler-cobonding agent containing
S-PRG filler exhibited a different release pattern and released a large amount of BO3 .
taining bonding Continuous
agent in release
a two-step
of fluorideself-etch adhesive.
for 440 days Allformaterials
was confirmed demonstrated
all restorative materials. co
tinuous release of six ions for up to 440 days, with the release of Sr2+ and BO33− at hi
concentrations for the resin composites and the resin cement. The bonding agent contai
ing S-PRG filler exhibited a different release pattern and released a large amount of BO
Continuous release of fluoride for 440 days was confirmed for all restorative materials.
The ion release profile of a coating resin containing S-PRG filler is depicted in Figu
J.J.Funct.
Funct.Biomater.
Biomater.2023,
2023,14,
14,x236
FOR PEER REVIEW 13 13
ofof1718

Figure 10. Ion release profile of commercially available S-PRG filler-containing restorative materials.
Cumulative concentrations of ions released from (A) resin composites (Beautifil II), (B) flowable-type
Figure 10. Ion release profile of commercially available S-PRG filler-containing restorative materials.
resin composites (Beautifil Flow Plus), (C) resin cement for luting (ResiCem EX), and (D) bonding
Cumulative concentrations of ions released from (A) resin composites (Beautifil II), (B) flowable-
agent
type in acomposites
resin two-step self-etch adhesive
(Beautifil (FL-Bond
Flow Plus), II). The
(C) resin disc-shaped
cement cured
for luting specimen
(ResiCem EX),(15
andmm diameter,
(D) bond-
1 mm thickness) was immersed in 5 mL of distilled water, which was replaced periodically.
ing agent in a two-step self-etch adhesive (FL-Bond II). The disc-shaped cured specimen (15 mm The
diameter, 1 mm thickness) was immersed in 5 mL of distilled water, which was replaced periodi-of
concentration of fluoride ions in the eluate was measured using a fluoride ion electrode, and those
otherThe
cally. ionsconcentration
were measured using anions
of fluoride inductively coupled
in the eluate wasplasma
measuredatomic emission
using spectrometer.
a fluoride ion electrode,
and those of other ions were measured using an inductively coupled plasma atomic emission spec-
The ion release profile of a coating resin containing S-PRG filler is depicted in Figure 11.
trometer.
The concentrations of all ions released from the coating resin were much greater than those
released from the restorative materials, and a large amount was released within 100 days,
except for Sr2+ , which showed relatively constant release pattern.
J.J. Funct.
Funct. Biomater.
Biomater. 2023,
2023,14,
14,236
x FOR PEER REVIEW 14
14 of 17
of 18

Figure 11. Ion release profile of coating resin containing S-PRG filler. Cumulative concentrations
of ions released from commercial coating resin containing S-PRG filler (PRG Barrier Coat). The
Figure 11. Ion release profile of coating resin containing S-PRG filler. Cumulative concentrations of
disc-shaped cured specimen (15 mm diameter, 1 mm thickness) was immersed in 5 mL of distilled
ions released from commercial coating resin containing S-PRG filler (PRG Barrier Coat). The disc-
water, which was replaced periodically. The concentration of fluoride ions in the eluate was measured
shaped cured specimen (15 mm diameter, 1 mm thickness) was immersed in 5 mL of distilled water,
using
whicha was
fluoride ion electrode,
replaced and those
periodically. of other ions were
The concentration measured
of fluoride ionsusing
in theaneluate
inductively coupled
was measured
plasma atomic emission spectrometer.
using a fluoride ion electrode, and those of other ions were measured using an inductively coupled
plasma atomic emission spectrometer.
6. Conclusions
A large number of in vitro and in vivo (animal) studies have been conducted to assess
6. Conclusions
the bioactive functions exhibited by S-PRG filler and S-PRG filler-containing materials. In
A large number of in vitro and in vivo (animal) studies have been conducted to assess
addition to commercial products containing S-PRG filler, many reports on experimental
the bioactive functions exhibited by S-PRG filler and S-PRG filler-containing materials. In
materials are available. The S-PRG filler has the potential as a bioactive material to con-
addition to commercial products containing S-PRG filler, many reports on experimental
tribute to the success of various dental treatments and care. The main concern is that a
materials are available. The S-PRG filler has the potential as a bioactive material to con-
limited number of clinical studies on the benefits of bioactive functions exhibited by S-PRG
tribute
filler andto S-PRG
the success
filler of various dental
containing treatments
materials and care.
is available. MostThe main
of the concern
evidence is that a
described
limited number of clinical studies on the benefits of bioactive functions
in this review is based on in vitro or animal studies. Although several studies evaluated exhibited by S-
PRG filler and S-PRG filler containing materials is available. Most of the
long-term action of ion-release from S-PRG filler, it is well known that the bench-to-clinic evidence de-
scribed in this review is based on in vitro or animal studies. Although several
translation is not so simple. Future research in clinical settings and their accumulation are studies eval-
uated long-term
expected action
to elucidate of ion-release
further from S-PRG
the practicality filler, it
and efficacy ofisbioactive
well known
S-PRGthat thefor
filler bench-
oral
to-clinic translation
health promotion. is not so simple. Future research in clinical settings and their accumu-
lation are expected to elucidate further the practicality and efficacy of bioactive S-PRG
filler for
Author oral health promotion.
Contributions: Conceptualization, S.I. (Satoshi Imazato), T.N. and K.N.; investigation, S.I.
(Satoshi Imazato), H.K., J.-I.S., H.T. and R.N.; methodology, H.K., S.Y., S.I. (Shuichi Ito) and R.N.;
Author
data Contributions:
curation, Conceptualization,
S.I. (Satoshi Imazato), T.N., H.K., S.I. (Satoshi
H.T. andImazato), T.N. and K.N.; draft
K.N.; writing—original investigation, S.I.
preparation,
(Satoshi
S.I. Imazato),
(Satoshi H.K.,
Imazato), J.-I.S.,
T.N., H.K.H.T.
andand R.N.;writing—review
J.-I.S.; methodology, H.K., and S.Y., S.I. (Shuichi
editing, Ito) and
S.I. (Satoshi R.N.;
Imazato),
data R.N.
S.Y., curation, S.I. (Satoshi
and K.N.; Imazato),
supervision, T.N., H.K.,
S.I. (Satoshi H.T. and
Imazato), K.N.;
S.I. writing—original
(Shuichi Ito) and K.N.;draft preparation,
funding acquisi-
S.I. (Satoshi
tion, Imazato),
S.I. (Satoshi T.N.,and
Imazato) H.K.K.N.
and All
J.-I.S.; writing—review
authors have read andandagreed
editing,toS.I.
the(Satoshi Imazato),
published S.Y.,
version of
R.N.manuscript.
the and K.N.; supervision, S.I. (Satoshi Imazato), S.I. (Shuichi Ito) and K.N.; funding acquisition,
S.I. (Satoshi Imazato) and K.N. All authors have read and agreed to the published version of the
Funding:
manuscript. This work was supported by Grants-in-Aid for Scientific Research (21K19593 to S. Imazato)
from the Japan Society for the Promotion of Science.
Funding: This work was supported by Grants-in-Aid for Scientific Research (21K19593 to S. Ima-
Data
zato) Availability
from the Japan Statement: The
Society for data
the that support
Promotion the findings of this study are available from the
of Science.
corresponding author upon reasonable request.
Data Availability Statement: The data that support the findings of this study are available from the
Conflicts authorThe
of Interest:
corresponding uponauthors declare
reasonable no conflict of interest.
request.

References Conflicts of Interest: The authors declare no conflict of interest.

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