Journal of Controlled Release xxx (2017) xxx-xxx

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Journal of Controlled Release

journal homepage: www.elsevier.com

F
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Review article

Antibacterial glass-ionomer cement restorative materials: A critical review on the

current status of extended release formulations
Tahereh Mohammadi Hafshejania⁠ , Ali Zamaniana⁠ , Jayarama Reddy Venugopalb⁠ , Zahra Rezvania⁠ ,

PR
Farshid Sefatc⁠ ,⁠ d⁠ ,⁠ e⁠ , Mohammad Reza Saebf⁠ , Henri Vahabig⁠ , Payam Zarrintajh⁠ , Masoud Mozafaria⁠ ,⁠ ⁎⁠
a
Bioengineering Research Group, Nanotechnology and Advanced Materials Department, Materials and Energy Research Center (MERC), P.O. Box 14155-4777, Tehran, Iran
b
Center for Nanofibers and Nanotechnology and Department of Mechanical Engineering, National University of Singapore, Singapore 117576, Singapore
c
Department of Materials Science and Engineering, Kroto Research Institute, North Campus, University of Sheffield, Broad Lane, Sheffield, UK
d
Institute of Pharmaceutical Innovation (IPI), University of Bradford, Bradford, West Yorkshire, UK
e
School of Engineering, Design and Technology-Medical Engineering, University of Bradford, Bradford, West Yorkshire, UK
f
Department of Resin and Additives, Institute for Color Science and Technology, P.O. Box 16765-654, Tehran, Iran

D
g
Université de Lorraine, Laboratoire MOPS E.A. 4423, Metz F-57070, France
h
School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran
TE
ARTICLE INFO ABSTRACT

Keywords: Glass-ionomer cements (GICs) have been widely used for over forty years, because of their desirable properties
Glass ionomer cement in dentistry. The most important advantages of the GICs are associated with their ability to release long-term
Antibacterial antimicrobial agents. However, GICs used as restorative materials have still lots of challenges due to their sec-
Controlled release ondary caries and low mechanical properties. Recent studies showed that the fluoride-releasing activity of con-
Caries
EC

ventional GICs is inadequate for effectual antibacterial conservation in many cases. Therefore, many efforts have
been proposed to modify the antibacterial features of GICs in order to prevent the secondary caries. Particularly,
for achieving this goal GICs were incorporated into various biomaterials possessing antibacterial activities. The
scope of this review is to assess systematically the extant researches addressing the antibacterial modifications in
GICs in order to provide with an authoritative, at the same time in-depth understanding of controlled antibacte-
rial release in this class of biomaterials. It also gives a whole perspective on the future developments of GICs and
challenges related to antibacterial GICs.
RR

including host ability and adjustment immune functions play important

1. The importance of controlled antibacterial release in roles [4]. Many studies have shown the dependency of etiology of den-
glass-ionomer cements (GICs) tal cavities on bacterial metabolism [5–7]. Several strains of oral strep-
tococci may lead to the formation of dental plaque biofilms that play
Dental caries are known as one of the most intense oral infected ill- an important role in the growth of cavities. It has been agreed that
CO

ness. Therefore, so many attempts have been made to treat such defects
[1]. Globally, around 60–90% of school's children and about 100% of
adults have dental cavities [2]. The main factors affecting dental caries
are bacteria, food consumption, and the weakness of host. In the fer-
mentation of carbohydrates, acid levels are increased [3]. For keeping
the balance among disease and health, the protecting features of saliva
UN
during adsorption and passive transport of oral bacteria molecules to
the surface of tooth, the growth of the biofilm eventuates in the first
four hours [8,9]. According to many researches, the formation of sta-
ble biofilm has a critical impact on the caries pathogenesis [10–12].
Moreover, it has been reported that the demineralization of tooth hard
tissue caused by the cariogenic bacteria leads to formation of biofilms,

Abbreviations: Glass ionomer cement, GIC; Chlorhexidine, CHX; Epigallocatechin-3-gallate, EGCG; Poly(quaternary ammonium salt), PQAS; Light cured, LC; Quaternary am-
monium salt, QAS; Quaternary phosphonium salt, QPS; Poly acrylic acid, PAA; Acrylic acid, AA; 3,4-Dichloro-5-hydroxy-2(5H)-furanone, DHF; 2,20-Azobisisobutyronitrile, AIBN;
3,4-Dichloro-5-(1,3-glycerol ethylene glycolatemethacrylate)-2-furanone, DGEGM; 3,4-Dichloro-5-(hydroxyacetic acid)-2-furanone, DHAF; Glucosyltransferase enzymes, GTFs; Ethanolic
extract of propolis, EEP; Resin modified glass ionomer cement, RMGIC; Salvadora persica extract, SPE; Bioactive glass, BAG; Titanium dioxide, TiO2⁠ ; Not available, NA; Streptococcus
mutans, S. mutans; Compressive strength, CS; Strontium, Sr; Glass-ionomer, GI.
⁎ Corresponding author.

Email address: mozafari.masoud@gmail.com (M. Mozafari)

http://dx.doi.org/10.1016/j.jconrel.2017.07.041
Received 6 May 2017; Received in revised form 28 July 2017; Accepted 29 July 2017
Available online xxx
0168-3659/ © 2017.
T.M. Hafshejani et al.
and consequently dental caries [13]. Fig. 1 describes how cariogenic
bacteria take action to initiate dental caries.
De Paz. et al. have indicated that S. mutans is the key etiological
player for the initiation of dental caries [15]. It has been generally ac-
cepted that there is a direct association among high amounts of S. mu-
tans and increasing the caries rates [14,16–19]. An extensive range of
carbohydrates may adhere to the tooth surface to form Plaque bacte-
ria like S. mutans and Lactobacillus [20–23]. These acid-producing bacte-
ria result in tooth demineralization because of secondary caries, which
occurs in-between the restoration and the cavity [24]. Thus, for hav-
ing long-term restorations, materials must have antibacterial activities
[25]. Preferable restorative dentistry materials are those preventing bac-
terial growth and surface colonization, and they also should be able to
decrease acid production by microorganisms [26–28]. One of the ma-
jor dental materials applied successfully in regular clinical practice is
glass ionomer cements (GICs) [29–32]. Forty-five years ago, Wilson and
Kent invented GICs. Because of their pioneering work giving such ad-
vantages like release of fluoride, anti-cariogenic features, and direct ad-
hesion to the tooth structure, GICs were mostly used in the dental clinic
[29,30,33].
Furthermore, the resin-modified GICs and older silicate materials
are generally used for fluoride release compared with other systems
[25,34]. Several different mechanisms are playing critical roles in the
anti-cariogenic effects of fluoride. Fluoride mainly affects demineral-
D
ization of dental hard tissues during the decayed process and modi-
fying the pathogenicity of cariogenic bacteria through two key mech-
anisms [35–37]. First, in spite of having many advantages, the exis-
TE
tence of internal cracks and air bubbles in GIC may cause micro leak-
age [38]. Accordingly it was believed that micro leakage has a direct
association with the progress of secondary caries [39,40]. By contrast,
there are diverse ideas about the effects of fluoride on secondary caries.
Even though some studies have shown that fluoride-containing restora-
tions can reduce the risk of this problem [41,42], others failed to ap-
EC
prove the inhibition effects of fluoride after setting. In fact, low pH
values of GICs during the setting process proved to cause leaching of
a higher amount of fluoride as an antibacterial feature [43,44]. This
means that there is relatively no antibacterial activity after the setting
process. Some researchers have reported on the antibacterial effect of
fluoride ion release, which reduces the plaque's acidogenicity to de-
crease the count of S. mutans in biofilm [25,45,46]. Although, recently
RR
some works revealed no link between fluoride release capacity and bac-
terial inhibiting ability [47,48]. Consequently, the bacteria molecules
can affect the interface restoration and dentin by micro leakage to make
secondary caries might improve over time and fail to GIC restoration
CO
UN
Fig. 1. Formation of dental caries by cariogenic bacteria.
2
Journal of Controlled Release xxx (2017) xxx-xxx
[24,47,49]. In the light of the above-mentioned disadvantages, various
additives were proposed to overcome such drawbacks and to enhance
the antibacterial activities of glass ionomer cements. This review aims
to present an overview of them (Table 1).
2. Antibacterial modifications in GICs
F
GICs constituted of fluoride-containing silicate glass and
polyalkenoic acid has antibacterial activity because of their fluoride re-
OO
lease [50]. Nevertheless, some authors believe that glass ionomer ce-
ments antibacterial function is attributed to the GICs low pH through
setting reaction [51,52]. In the other word, the antibacterial activity af-
ter setting was not approved by GICs application. According to a re-
search, similar to the composites, the most prevalent cause to fail GICs
was secondary caries, furthermore specifying that fluoride release could
not necessarily prevent the growth of bacteria toward complete bacter-
PR
ial demolition [53]. Fig. 2 illustrates the roster of the antibacterial ma-
terials and probable defects with restorative materials. Thus, many re-
searches aimed at enhancing the antibacterial activity of GICs. The re-
mainder of this review deals with antibacterial modifications in GICs to
indicate various additives used to improve this property (Table 2).
2.1. Improvement of antibacterial release behavior
One of the fundamental concepts for having long-lasting dental ma-
terials is to control the growth of microbes such as bacteria. Antimi-
crobial polymers are a class of biocides that has become a significant
substitute to existing biocides and even to antibiotics [54]. Cornell and
Dunraruma used the antimicrobial polymers/co-polymers made from
2-methacryloxytroponones to control the growth of bacteria [55]. In
2000, they used sodium fusidate and added it to a GIC composition.
Two years later, CHX has attracted scientists' attention due to its ad-
vantages, which is still applicable in many compositions. During these
years, some polymers have been in the center of attention as antibacter-
ial agents in GICs such as EGCG, triclosan, furanon-modified, and other
kinds of polymers. Such polymers used in GICs to overcome secondary
caries have been in the matter of attention for improvements in antibac-
terial properties. The ability of GIC in adhesion to the base is another
important factor affecting its efficacy. In general, addition of polymers
along with increasing antibacterial features can enhance the adhesion
of GIC to the tooth. Modification of GIC with chitosan was known as a
restorative material with suitable antibacterial feature and adhesion in
this regard [56].
2.1.1. Chlorhexidine containing GICs
Several studies agreed that the addition of chlorhexidine (CHX) in
various forms like chlorhexidine acetate and chlorhexidine gluconate
chlorhexidine hydrochloride into the GICs could affect antibacterial
properties against cariogenic bacteria [57–66]. Antimicrobial activity
of CHX against some gram-positive bacterial species found in the oral
caries has been widely accepted [67]. It may interact with fluoride for
inhibition properties against the bacteria. According to the reports, the
concentration of CHX has a significant impact on the release of fluoride
(higher concentration of CHX is to increase the release of fluoride re-
lease and vice versa). Some studies proved, CHX facilitates the fluoride
release when CHX quantity is higher than 11.5 wt% [64]. It has been
observed that the reduction of fluoride release in a low concentration
of CHX might result in the precipitation of salts with lower solubility
[62]. In addition, some of the studies have exhibited that the incorpo-
ration of CHX often leads to some changes in physical and mechanical
properties [58,60,61,66]. Unlike endowing the antibacterial features of
CHX to GIC, a high dosage of CHX results in the frailty of mechanical
properties, e.g. decreases bonding potential, and increases setting time
T.M. Hafshejani et al. Journal of Controlled Release xxx (2017) xxx-xxx

Table 1
An overview of strategies practiced in controlled antibacterial delivery in GICs.

Polymer GIC type Assay Major outcomes Ref

Chlorhexidine Conventional glass NA In comparison to conventional GI for both cleaned and uncleaned [57]
ionomer dentine samples, less microorganism was observed in CHX containing

F
GI in a 7-day period.
Conventional glass Agar-diffusion CHX quantity had no effect on size of inhibition zones and [58]
ionomer test condensations of CHX release.
For achieving proper antibacterial, physical, and bonding features,

Resin-modified glass-
ionomer
Conventional glass
ionomer (ChemFil
Superior Light Yellow)
OO
synthesis 1% of CHX with diacetate is an optimum content.
Agar diffusion 1.25% CHX considerably enhanced the antibacterial activities. [59]
test Moreover, 1.25% CHX mixture displayed substantial biological and
mechanical activities.
Agar diffusion It has a long term antimicrobial activities against S. mutans and L. [60]
test acidophilus. Moreover, the effectiveness antibacterial activity was
observed in 2.5% diacetate groups.
On the other side, the 1.25 and 2.5% of chlorhexidine diacetate had
considerably lower CS.

PR
Resin modified glass- Agar diffusion In weeks 1–3, substantial decrease in S. mutans numbers was observed. [61]
ionomers test There was no difference in antibacterial activity between the GI with
and without CHX after 4 weeks
Not seriously reduce the physical features
Glass-ionomer cement Agar diffusion An antibacterial effect on mutans streptococci, in vitro [62]
(Aqua-Cem) (glass method An decrease in Fluoride release and antibacterial effect with time
ionomer luting cement) The concentration of CHX had an effect on mechanical features of the
materials
Ketac Molar Easymix GIC Agar diffusion 0.5% concentration of CHX increased the antibacterial activity [63]

D
test The physical-mechanical features remained unchanged.
Glass ionomer cement and CLSM analysis In 24 hour bacterial activities in GICs and RMGICs with CHX are lower [64]
resin modified glass- compared to the conventional GICs and RMGICs
ionomers
Conventional luting Agar diffusion Combining conventional luting cements with 5% CHX and CT present [65]
TE
cements test better antibacterial activity
against SM and LB
GICs and resin-modified OD value Incorporating GICs with CHX can retain its mechanical features, in [66]
GICs addition decrease S. mutans biofilm formation
Epigallocatechin-3-gallate Conventional high- Agar diffusion 0.1% (w/w) EGCG improves mechanical and antibacterial activities. [78]
(EGCG) viscosity glass ionomer test No effect on fluoride ion release
Poly(quaternary Light-curable GICs Acid 3 or 5% CPP–ACP considerably reduced the release of fluoride [105]
EC

ammonium salt) (PQAS) demineralization 3% CPP–ACP improve anticariogenic capacity without affecting its
test on enamel mechanical features
Compared to GIC control, the demineralized enamel with 3 or 5%
CPP–ACP was smaller
Furanone Light-curable GICs NA It demonstrated antibacterial activity against both S. mutans and [88]
Lactobacillus sp.
Human saliva had no effect on the cement antibacterial activity
DGEGM modified cement was biocompatible
RR

An initial reduction in CS.

Triclosan Restorative GICs Agar diffusion More effective against L. acidophilus and S. mutans than Chlorhexidine [93]
test 2.5% of Triclosan was more effective than at lower concentrations
Conventional type II GICs Agar diffusion No effect on the microleakage of the cement [94]
test An enhanced antibacterial property.
Sodium fusidate Restorative grade GICs NA The release of sodium fusidate tested all time [101]
GICs acts as controlled release material for antibacterial sodium
fusidate
CO

[50,68]. It is mainly due to the presence of amines groups in the CHX

molecule. With neutralizing polyacid during salt formation, followed
by decreasing its potential to release ions from the glass structure, the
creation of lower cross-reaction cationic ions/poly-acrylic chains would
be possible. This event roots in the effective does of CHX incorporated
into the GICs; therefore, the best option is the addition of appropriate
UN
2.1.2. Epigallocatechin-3-gallate (EGCG) containing GICs
Although many researchers have demonstrated the effect of incorpo-
rating CHX into the GICs on drug release, the cytotoxic effects and drug
resistance of CHX have not been fully taken into account. The recent
studies indicated that the tendency needs to go toward the use of other

amount of CHX to increase the antibacterial activity without deterio-
rating the physical and mechanical properties of the material. To com-
pensate for this drawback, chitosan was added to the composite struc-
tures exhibiting good antibacterial properties, along with appropriate
mechanical strength [69]. A recent study showed that the release of
CHX from cement could be controlled by adding Zeolite nanoparticles
(ZE NPs). The release profile of CHX-GIC indicated an early burst re-
lease of ∼ 30% of the total CHX during 7 days; however, GICs contain-
ing CHX-loaded ZE NPs presented a continuous release of CHX without
the early burst release in a 4-week period [70]. The chemical structure
of chlorhexidine is shown in Fig. 3.
kinds of additives [71].
Epigallocatechin-3-gallate (EGCG) is the main polyphenol in green
tea that contains health-promoting components such as antioxidant, an-
tidiabetic, anti-inflammatory, and anti-cancer features [72,73]. EGCG
has an antimicrobial function to control oral streptococci and also acts
as a promising cariostatic agent [74]. One of the crucial factors result-
ing in a degradative manner of the demineralized collagen matrix is
the presence of free radicals [75]. The unpaired electrons in oxidants
make them extremely reactive leading to protein structure damaging
[76]. It has been shown that EGCG as an antioxidant has the abil-
ity of neutralizing and potentially damaging the free radicals. It has
been proved that EGCG suppresses salivary and bacterial amylase ac

3
T.M. Hafshejani et al. Journal of Controlled Release xxx (2017) xxx-xxx

tivity that results to reduce carbohydrate metabolism. As acid produc-

tion rate decreases, the growth rate of S. mutans increases through the
alternative effect of EGCG [77]. Enhancement of antibacterial properties
of GIC using EGGG has been investigated by Hu et al. [78]. The chemi-
cal structure of EGCG is illustrated in Fig. 4.
Antibacterial effects of EGCG were found to be attributing to its

F
contact with bacteria, where GIC with EGCG has not a separate an-
tibacterial activity. Thus, it does not inhibit the biofilm growth. More-
over, it was reported that a surplus of EGCG did not have a special ef-

OO
fect on the release of fluoride. The results have shown that 0.1% (w/
w) EGCG incorporated in GIC improves the mechanical, antibacterial
and better physical properties after 4 h, but this effect was not obvi-
ous after 24 h. The GIC-EGCG composite samples showed higher flex-
ural strength compared to GIC and GIC-CHX samples. The reason might
be related to the presence of many polyphenol groups in the EGCG mol-
ecules resulting a chelation reaction between such phenolic hydroxyl

PR
groups and carboxyl groups of GICs [79]. In addition, EGCG can cause
a high degree of crosslinking in the network of GIC structure, increas-
Fig. 2. Antibacterial materials and probable defects with them.
ing the number of poly-salt bridges and making the structure more

Table 2
An overview of innovative strategies for controlled antibacterial release in GICs.

Other
additive GIC type Assay Major outcomes Ref

D
Propolis Conventional GIC Agar Disk Exhibited antibacterial and antibiofilm efficacy [111]
Diffusion Test The bacterial density was lower in the GIC containing 50% EEP.
In vitro S. MIC values of Turkish propolis for S. mutans were found as 25 μg/mL.
TE mutans Biofilm
Formation
Conventional GIC The broth 25% and 50% EEP activated inhibition of Streptococcus mutans Growth [113]
dilution method Insignificantly enhances the mechanical properties.
Strontium Resin modified glass ionomer cements Growth No remarkable antibacterial activity for only Sr ions [118]
inhibition Fluoride and Sr play an interactive role in the
method development of enamel minerals
NA Agar plate The bacteriocidal action of strontium is more significant than that of [119]
EC

diffusion fluoride
method Significant bacteriocidal activity is seen against A. viscosus only in the
presence of strontium
Salvadora Conventional GIC Agar dilution The antibacterial activity increased by adding higher concentratin of SPE [128]
persica assay No effect on physical properties by adding 1% SPE
(miswak) No results in material distortion by adding 2% and 4% SPE
Zinc sulfate Fuji II Conventional Agar plate Fuji II Light Cure showed maximum inhibition of S. mutans compared to [130]
Fuji II Light Cure diffusion Fuji II conventional and Fuji IX
RR

Fuji IX method There was direct correlation between the release of fluoride and
antibacterial activity. On the other side, there was no correlation
between the release of zinc and antibacterial activity
The synergistic action of the release of fluoride and zinc result in the
antibacterial activity
Conventional and resin modified glass Agar plate The higher the addition of zinc sulfate, the higher the amount of fluoride [157]
ionomer diffusion released 7% zinc sulfate
method caused reduction to DTS and zinc release can enhance the inhibitory
CO

activity of fluoride
Conventional GI showed larger inhibition halo of S. mutans than that of
the RMGI
Conventional and resin modified GI Agar plate Added ZnSO4⁠ showed significant inhibition of S. mutans [132]
diffusion An increase the release of fluoride
method Its solubility enhanced when 10% ZnSO4⁠ was added to the cement
powder
No reduction in flexural strength after 2 days by adding 5 or 10% ZnSO4⁠
Nano Silver Resin-modified glass ionomer cement Direct contact Effective antibacterial activity was observed in combination of Ag-NPs [147]
UN

(RMGIC, GC Fuji, ORTHO LC; GC test (DCT) whereas the adequate bond strength was retained
Corporation, Tokyo, Japan) Agar plate
diffusion
method
Bio glass Conventional cure GIC and resin- OD value A decrease in bacterial colonies significantly by adding BAG [66]
modified light cured GIC Spatial No effect on release of fluoride by adding 10 wt% BAG
distribution and Bactericide CHX had no harmful effect on the micro-hardness and CS
architecture of
biofilm
Titanium Conventional glass ionomer Direct contact 3% (w/w) TiO2⁠ nanoparticles improved mechanical and antibacterial [154]
dioxide test (DCT) properties
nanoparticles Addition of TiO2⁠ nanoparticles does not interfere with the release of
fluoride capacity of GI.

4
T.M. Hafshejani et al.
Fig. 3. Chemical structure of chlorhexidine, C2⁠ 2H3⁠ 0Cl2⁠ N1⁠ 0.
D
Fig. 4. Chemical structure of EGCG, C2⁠ 2H1⁠ 8O1⁠ 1.
TE
complex. In another word, EGCG can act as a spacer when incorporated
with GICs [80].
Moreover, EGCG enhances the human dental pulp cell proliferation
and differentiation, hence, its usage in dentistry can be helpful in re-
generative endodontic therapy [81]. It was reported that the EGCG pre-
EC
vents dental pulp damages by reducing the cytotoxicity of the dental
monomers [82].
2.1.3. Poly(quaternary ammonium salt) (PQAS) in GICs
Dong Xie and his co-workers produced a novel PQAS including
antibacterial GICs [53]. Polymers that contain quaternary ammonium
(QAS)/phosphonium salt (QPS) are known as antimicrobial materials
RR
CO
UN
Fig. 5. Synthesis structure of PQAS followed by tethering QAS onto the polymer poly (AA-co-IA)
5
Journal of Controlled Release xxx (2017) xxx-xxx
and due to their antimicrobial activities have a variety of applications
[72,73]. In both direct polymerizations of monomers including QAS/
QPS groups and covalently combining QAS/QPS with synthetic or nat-
ural polymers, polymeric QAS/QPS could attain a wide range of an-
timicrobial activity because of the inherent feature of the corresponding
QAS/QPS. Antibacterial metabolism of PQAS included 4 steps: (I) ad-
F
sorption to the negatively charged of bacteria cell surface; (II) Cell-pen-
etrating; (III) binding to the cytoplasmic membrane; (IV) disturbance
in the cytoplasmic membrane [83]. In this research, the antibacterial
OO
effects of PQAS on two glass-ionomer cements Fuji II LC and EXPGIC
without PQAS suppressed 20% S. mutans related to the release of flu-
oride have been investigated [25]. This investigation has revealed that
addition of PQAS to samples increased their antibacterial function, sig-
nificantly with an initial compressive strength (CS) decrease. The high
positive charge density may increase antibacterial activity by driving
force and the long alternative chain might intensely interact with the
PR
cytoplasmic membranes [83]. In many studies, have been reported
carboxylic acid groups have a significant impact on GICs setting and
salt-bridge formation. PQAS polymer demonstrated the biocide ability,
which has an effect on the salt-bridge formation by supplying carboxyl
groups. Antibacterial activities of QAS-containing restoratives may de-
crease by human saliva because of the strong electrostatic interactions
that occur between proteins and QAS [84,85]. Since nitrogen has a
higher electronegativity than the phosphorous, due to the feeble-asso-
ciated cations, QPS attachment to the negative bacteria was facilitated
[86]. Synthesis structure of PQAS presented in Fig. 5.
2.1.4. Furanone-modified antibacterial GIC
Apart from acceptable performance of QASs and their functional de-
rivatives, it has been reported that there are possibilities for electro-
static interactions with proteins in the saliva, decreasing the antibac-
terial activity of QAS-containing restorative materials [87]. Weng et
al. recently developed furanone containing poly-acid used to formulate
light-curable GICs. Its derivative has effect on the CS and antibacterial
activities of the formed cements [88]. Furanone derivatives proved to
have potential antitumor activity and antibacterial properties [89,90].
Saliva contains furanone considerably decreases antibacterial activities
of QAS/PQAS-containing materials through contact inhibition [84], but
it did not show any influence on the 3,4-dichloro-5-(1,3-glycerol ethyl-
ene glycolatemethacrylate)-2-furanone (DGEGM)-modified cements be
T.M. Hafshejani et al.
cause these cements do not carry any charge. An aging study conducted
for 30 days revealed that cements might have long-term antibacterial
activities and demonstrated 15 and 26% increases in CS. By adding
(1 − 20)% DGEGM, the S. mutans viability was decreased from 50%
to 3%. In addition, cements containing 5 and 7% DGEGM showing a
(19–28)% decline. According to their results, the DGEGM-containing
polymer provided carboxyl groups (− COOH) with strong attachment
with glass fillers for the salt-bridge formation and did not leach out
of the cement. Halogenated furanone embedded in PLA nanoparticles
showed very good controllable bacteriostatic features, which placed it
in use as a film for desired implantation [91]. Moreover, addition of fu-
ranone derivatives up to 30% exhibited no significant consequence on
mechanical strength [92]. The results obtained from studying the inter-
actions of dental cells with DGEGM-modified cements indicated that af-
ter one day and even seven days, the viability of cells could remain al-
most unchanged, demonstrating that DGEGM was not leachable. Fig. 6
schematically describes the diagram of the synthesis of DGEGM.
2.1.5. Triclosan incorporated glass ionomer cements
The triclosan incorporated GICs has been studied for the effect of
antibacterial activity [93,94]. The aim of these studies was to evalu-
ate the micro leakage of triclosan incorporated GICs. According to the
literature, S. mutans and L. acidophilus can produce a huge amount of
acids and are bearable to acidic environments [95]. In spite of ad-
D
dition various antibacterial agents to GICs, these antibacterial agents
affect the clinical performance of the final material [96]. These ef-
fects were caused by the cationic nature of these materials. Triclosan
TE
5-chloro-2-(-2, 4-dichlorophenoxyl) phenol is a synthetic and anionic
agent with a broad spectrum of antimicrobial activities [97]. It has
been proposed that a material containing triclosan can be an immo-
bilized bactericide, which does not leach out of the carrier mater-
ial, so favoring long term anti-cariogenic activity [98]. The non-re-
leasing bactericide of triclosan leads to be more advantageous than
EC
chlorhexidene, as an antibacterial additive in GICs. It has been re-
ported that 2.5% triclosan added to GIC showed more antimicrobial
activity compare with 2.5% CHX incorpo
RR
CO
UN
Fig. 6. Schematic diagram of the synthesis of DGEGM
6
Journal of Controlled Release xxx (2017) xxx-xxx
rated GIC against Lactobacillus acidophilus and S. mutans, but mechanical
strength of the compoites has taken a similar value [99]. In addition,
its embedding in nanoparticles such as PLA can control the triclosan re-
lease rate [100].
2.1.6. Sodium fusidate added GICs
F
A recent research has studied different types of antimicrobial com-
pounds, specifically sodium salt of fusidic acid [101]. Fusidic acid is
effective mainly in gram-positive bacteria like Staphylococcus species
OO
[102]. In this study, sodium fusidate powder, 1 and 5% by mass percent
was incorporated into the cement to study the antimicrobial activities.
The results showed that GICs have the ability to control the materials
release for the antibacterial composite sodium fusidate. Through the dif-
fusion mechanism, the release happened for the first 4 and 24 h by 1%
and 5% level of increase, respectively, with dispersion coefficients of
4.49 10−⁠ 8 cm2⁠ s−
⁠ 1 and 3.09 10−
⁠ 8 cm2⁠ s−
⁠ 1 respectively. The controlled
PR
release of sodium fusidate was investigated using alginate, as a disin-
fection material [103]. Moreover, sodium fusidate exhibited the wound
healing properties [104]. The chemical structure of fusidic is shown in
Fig. 7.
2.2. Innovative strategies and opportunities for controlled antibacterial
release in GICs
Many modifications attempted to improve the functions of GICs an-
tibacterial activity. Metals (e.g. Zinc and Strontium from 2003), natural
materials (e.g. Propolis (in 2014) and Salvadora persica (miswak) in
2016), and bioglass in 2012 have been evaluated in an effort to develop
the antibacterial activities of GICs with consideration of physical and
mechanical properties. An overview of the development of innovative
strategies and opportunities in GICs will be discussed followed by a dis-
cussion on obtained results.
2.2.1. Propolis added to GICs
Propolis or bee glue is a resin-like material widely used in medicine
for its antibacterial nature [106]. Some investigations reported that the
T.M. Hafshejani et al.
Fig. 7. Chemical structure of fusidic acid.
GICs containing propolis has antibacterial property against S. mutans
D
[107,108]. In the past, propolis as a natural product mostly used in the
traditional medicine and also included a potential substrate into the top-
ical formulations due to its antioxidant characteristics [109]. Two an-
TE
tibacterial mechanisms have been observed with propolis: (1) antimi-
crobial property against cariogenic bacteria (S. mutans and Streptococcus
sobrinus), (2) prevention of glucosyltransferase enzymes (GTFs) activity
[110]. It has been concluded that propolis extracts have pharmacologic
activities, including prevention of oral diseases [111] and formation
of microorganism within dental biofilm [112]. The results have been
EC
demonstrated according to disk diffusion test, concentrations of propo-
lis do not have any effect on the size of inhibition zones that produced
against S. mutans and the antibacterial activities are independent on the
concentration of EEP. In addition, 25% EEP addition is suitable percent
for development in antibacterial GICs. The cytotoxicity tests proved that
the propolis solutions used against gingival fibroblasts are not affected
and safe [113]. However, adding antibiotics to GIC enhanced antibac-
RR
terial activity. Yesilyurt et al. shown that the antibiotic has a negative
effect on the mechanical properties (compressive and bond strength) of
GIC but it has been found that adding EEP insignificantly enhances the
mechanical properties. Regardless the significant antibacterial feature of
the propolis, its addition to GIC has resulted in compressive mechani-
cal strength decrement and solubility increment, which together cause
CO
failure of the restorative materials [106]. On the other hand, propolis
enhances the micro-hardness and exhibits no effect on micro-leakage
[114]. With increase in EEP amount, composites can become weaken
since EEP in higher doses cannot help GIC network formation. Propolis
containing nano-hydroxyapatite is known because of their appropriate
antibacterial features, at the same time good mechanical strength [115].
For instance, it was reported that propolis quenches the Interleukin-6
expression on inflamed rat dental pulp tissue [116]; while it increases
UN
the expression of VEGF and VIII factor – what is appropriate for revas-
cularization [117].
2.2.2. Incorporation of strontium in GICs
Shorr-Carter et al. studied strontium (Sr) added into GICs for evalu-
ating the antibacterial activity of Sr ions [118,119]. Although the role
of fluoride informed more acid resisting fluorapatite, it has not indi-
cated to affect the release behavior of other ions in the oral system.
According to investigations, strontium physicochemical properties close
7
Journal of Controlled Release xxx (2017) xxx-xxx
to calcium [120,121] for playing a role in dental tissue mineralization.
Previous studies revealed where Sr and fluoride are existent together in
the drinking water supplies, the decrease in dental caries might have oc-
curred [122]. Results of these studies have been indicated that when Sr
is added, a contribution of fluoride to antibacterial activity at low fluo-
ride release greatly enhanced. Even though local pH effects are known
F
to attribute to antibacterial activity, other works have indicated that
the reduction in pH in the region of GICs is due to acidification of the
growth medium as a result of bacterial growth [123]. Surface pre-re-
OO
acted glass ionomer fillers (SPRG) bring about a better ion release like
that of strontium, floride and boron, which cause hindering the en-
dodontic pathogens [124]. Improving the GIC mechanical characteris-
tics is the result of using porous hydroxyl-apatite (HA). There is a clue
that the use of HA leads to mechanical properties enhancement, and
fluoride/strontium ion release [125]. It has been shown that Sr has a
less antibacterial activity; including Sr into RMGIC have an effect on
PR
restoration of a caries resisting enamel surface after bracket removal.
The results of the Sr concentration profiles in enamel exposed to RMGIC
illustrated that the level of Sr considerably enhanced at 5 mm depth
after 20 days' aging and then maintained with a value almost eight
times higher than the control's value. Furthermore, at 15 mm depth the
founded concentration were same at any time. It has been concluded
that the release of Sr was controlled by a diffusion mechanism of the
ions through the matrix.
2.2.3. Salvadora persica (miswak) containing GICs
Salvadora persica tree is one of the most popular natural materi-
als in dentistry, which is frequently utilized for making miswaks. Sal-
vadora persica extract (SPE) generally has a major antibacterial effect
on some of the oral pathogens [126]. Candida albicans as one of these
oral pathogens was used in this study due to its influence on secondary
and dentine carries [127]. This study reported that by adding more con-
centration of SPE the antimicrobial activity significantly improved as
well [128]. The addition of 4% SPE, provide favorable results in the an-
tibacterial experiments particularly regarding the S. mutans, S. sanguis,
and Candida albicans with comparable physical properties with other
commercially available GICs. Using toothbrush and chlorhexidine syner-
gistically increases the antibacterial effects. This conclusion was yielded
over a-six-month clinical trial [129].
2.2.4. Zinc sulfate addition to GICs
In the culture medium Zinc is used to inhibit S. mutans growth
and plaque formation [130]. Antibacterial activity of Zn has been stud-
ied for evaluating its effect on GICs [131–133]. Using Zn as an addi-
tive can interfere with the following mechanisms: (I) S. mutans enzy-
matic metabolism; (II) plaque acidogenicity; (III) prevention of plaque
mineralization by controlling dental calculus formation (adsorption of
a Zn-monolayer on apatite crystal) without counteracting the Fluoride
(F) benefited [134]. The release of fluoride and zinc from GICs occurs
via three main mechanisms: 1) a rapid surface elution, 2) diffusion by
cracks, 3) dissolution [135,136]. As results indicated, the chemical com-
positions of samples may have the effective release of Zinc, variable
amounts of Zn present as complexes salts, making it unreachable for
an estimate. Several studies proved that Zinc has an antibacterial ac-
tivity [137,138]. Shashibhushan et al. [131] demonstrated that there
was no connection among the release of Zn and the antibacterial activ-
ity of the three tested cements. The shortage of this correlation among
the release of Zn and the antibacterial activity might be occurred due
to the four main reasons; I) Insufficient Zn release may not be able to
produce growth inhibition, II) The release of Zn as a salt complexes in-
stead of the ionic form, which is needed for the growth prohibition, III)
The components like inorganic salts, amino acids, and proteins that are
used in bacterial culture media may interact with metal ions and mod-
ify their antibacterial activity, and IV) Zn plays an important role in in
T.M. Hafshejani et al.
hibiting both acid production and the growth of S. mutans. Zinc sul-
fide toxicity was applied over a long-term survey and it was observed
that the Zn affects the liver and decreases the mice bode weights [139].
However, the dosage of Zn should be adjusted in dental composite ap-
plications. Moreover, Pranav et al. in 2015 showed that antibacterial ef-
fect of zinc oxide nanoparticles was enhanced with an increase in the
nanoparticles amount (independent from the size of nanoparticles). First
mechanism for this effect could be the absorption of halogens on the
nanoparticles' surfaces, leading to an effective bactericidal activity. An-
other reason is the leaching of Zn ions into the media [140,141].
2.2.5. Nano silver-containing GICs
Silver nanoparticle-including adhesives have demonstrated the
strong antibacterial activities against microcosm biofilms [142], and
Streptococcus mutans [143]. In this study for reinforcing GICs, five differ-
ent weight ratios of the nano-silver base inorganic antibacterial powder
were added to the GICs [144]. The results showed that all fresh silver
nanoparticles-containing tested samples indicated effective antibacter-
ial activity however; the effectiveness of antibacterial agents was lost
during the time of aging. The bacterial inhibition zone 13 mm observed
around the nano‑silver that demonstrates sufficient release of ion silver
into the environment for preventing the bacteria growth. However, be-
cause of a rapid use of available fluoride and silver ions on the surface
of the materials no inhibition zones were observed in the samples aged
D
for two days, one week, and two weeks. Therefore, presence of fluoride
and silver ion in the agar is not an adequate motive to create a bac-
terial inhibition zone. It has been revealed that the internal silver ion
has a capacity to slow releasing activities, which can help to preserve
TE
bond strength for a long period due to active agent release that may
cause vacillation of the matrix and induce weakening of the composites.
To prevent secondary root caries, silver diamine fluoride and phospho-
peptide-amorphous calcium phosphate were added to GIC and showed a
significant effect on property enhancement [145]. Silver-doped HA was
also added to GIC and increased the bacteriostatic properties with no
EC
adverse effect on the compression strength [146]. The careful track of
silver-zeolite incorporation into GICs revealed the antimicrobial effects
of modified cement on S. mutants in vitro and an increase in the com-
pressive strength with 1 wt%. Nevertheless, one of the possible draw-
backs in silver nanoparticles incorporation is color, which can develop a
potential limitation, particularly in using aesthetic brackets [147]. An-
RR
other study compares the antibacterial activities of two different kinds
of zeolite-incorporated GICS containing silver and zinc. The results of
Ag and Zn ion release illustrated however that exactly in the same con-
ditions Zn release was more than Ag release at 0.005 g of Ag-zeolite and
Zn-zeolite. With increment in both additives, the release profile became
almost similar. For both samples, in the first two weeks the level of ion
released enhanced, then became sustain and finally ion concentration in
CO
solution reached an equilibrium state [148].
2.2.6. Bioactive glass (BAG) added GICs
BAGs have great biocompatibility and biological activities demon-
strated in bone and soft tissues (invented in 1971) [149]. The effects
of GICs combined with BAG on S. mutans biofilm formation were re-
cently investigated by Yang et al. [66]. In this research conventional
UN
and resin-modified light-cured GIC and the 77S BAG (SiO2⁠ 79.7%, CaO
16.3%, and P2⁠ O5⁠ 4%) were used. Yli-Urpo et al. demonstrated that
GICs with 10 wt% BAGs can release the same amount of fluoride with-
out BAGs [150]. BAG can raise pH level in an aqueous environment
through leaching out of ions like sodium, calcium, strontium, or mag-
nesium to provide the disinfecting mechanism [149]. However, after
curing the acid-based reaction slows down the development of pH that
prevents the antibacterial effects of BAG that is not suitable as an an-
tibacterial agent. Although releasing of anti-microbial agents from the
8
Journal of Controlled Release xxx (2017) xxx-xxx
materials prevents the bacterial growth it may have a potentially neg-
ative efficacy on mechanical features. Ion release rate has a significant
effect on GIC setting time and mechanical properties [151]. Therefore,
maintaining a good balance among antibacterial activity and mechani-
cal features are essential for the materials. However, incorporating GICs
with bioactive glass affected the CS and it was reduced in this incorpo-
F
ration. This results show that BAG cannot play an proper role as an an-
tibacterial agent, mainly because of its short-term antibacterial activity
compared to the other kind of additives as well as its negative effects on
OO
GICs' mechanical properties. Few methods proved, controlled/sustained
releasing technology may be helpful for optimizing the antibacterial ac-
tivity of incorporating GICs with BAG [152].
2.2.7. Titanium dioxide nanoparticles added into conventional GIC
Introduction of titanium dioxide (TiO2⁠ ) nanoparticles to the conven-
tional GIC may improve the physical and antibacterial features [153].
PR
TiO2⁠ is an inorganic additive with many effectual features such as bio-
compatibility, non-toxicity and chemical stability [154]. Results of this
study have indicated that glass-ionomer (GI) containing 3, 5, and 7%
(w/w) TiO2⁠ nanoparticles were effectual in preventing the growth of
bacteria. The nano-sized TiO2⁠ particles maximize their bactericidal ef-
fect [155]. Compared to the controlled groups of the materials, GI in-
cluding 3, 5, and 7% (w/w) TiO2⁠ nanoparticles have the same pat-
terns of the release of fluoride ion. This suggests that addition of TiO2⁠
nanoparticles does not affect the releasing capacity of fluoride in the
GI. The GI containing 3 to 5% (w/w) TiO2⁠ nanoparticles enhanced the
mechanical properties compared to the unmodified GI. Although, in
GI containing 7% (w/w) TiO2⁠ nanoparticles a reduction was found in
the mechanical properties due to the inadequate ionomer to maintain
the relatively large amount of TiO2⁠ nanoparticles powders. As the ob-
tained results illustrated, the mechanical strength in TiO2⁠ -containing
GICs was dramatically increased (e.g. enhancement of flexural strength
from 13.57 MPa in GI-control to 23.17 MPa in GI3% (w/w) TiO2⁠ ) com-
pared to other kinds of systems such as zinc-containing GICs (as a re-
sult of adding TiO2⁠ in form of nanoparticles). In this research, among
3, 5, and 7 wt% of TiO2⁠ nanoparticles, GI-including 3 wt% TiO2⁠ NPs
have promising restorative dental materials with developed antibacter-
ial activity. It may be concluded that this GI-containing TiO2⁠ can be a
promising candidate for greater stress-bearing site restorations like Class
I and II. Elsewhere, titanium doped with ZnO was applied as antibac-
terial agent, where bactericide properties of powder were governed by
particle size, crystallinity and microstructure [156].
3. Future perspective
Bacteriostasis materials are the harbingers of promising materials
used in health care. The under developing materials with antibacter-
ial features can hamper the dental cariogenesis and soar the restora-
tive materilas life time in comparison with traditional ones. However,
releasing high amounts of bactericides results in destructive effects on
dental milieu. It is expected to manifest the new generations of restora-
tive materials exposing the antibacterial feature in the bacterial en-
vironments; hence, deleterious effects of them will be minimized. In
another word, antibacterial properties fueled by addition of different
agents are of importance, but it should not deteriorate other charac-
teristics of the composite materials. The applied antibacterial agents
should not impose negative effects on mechanical, physical and chem-
ical properties of dental materials. According to previous researches,
some important factors including antibacterial additive dosage, its ef-
fect on fluoride release, its interaction with chemical composition of
samples, the size and the form of antibacterial agent (e.g. salt com-
plexes, the ionic form, …), the effect of time on its release (controlled/
sustained releasing) and finally its release behavior should be taken
into account in future developments. From this perspective, it is neces
T.M. Hafshejani et al.
sary to develop restorative materials with superb antibacterial proper-
ties and constant release behavior along with acceptable physico-chem-
ical properties. Nevertheless, the determination of the best way in or-
der to increase antibacterial activity is the black box of future develop-
ments. Considering all the mentioned attempts, we can reach to the con-
clusion that when we consider an applicable balance between the an-
tibacterial properties of restorative materials and their mechanical prop-
erties, achieving the best result would be possible. In fact, by chang-
ing the experimental design, we would expect different results, which
may superb antimicrobial activity without compromising the mechani-
cal properties. It is clear that an optimum antibacterial effect could be
the result of sustained-release of antibacterial ions without diverse ef-
fect on fluoride release and mechanical properties. The retention time
and the interaction between fluoride and antibacterial additives have a
direct impact on fluoride release pattern and the anti-cariogenic effect
of GICs. Briefly saying, such effects must be pondered in experimental
design.
One of the main concerns has been the decrement in the mechan-
ical properties of restoratives over time following slow release of low
molecular weight antibacterial additives such as silver ions, zinc ions,
and chlorhexidine. This release would result in short-term efficiency
and might increase the possibility of toxicity to the surrounding tis-
sues. That is why the non-releasing bactericides like triclosan and fura-
none-modified ones have attracted researchers' attentions. In addition,
D
the effect of antibacterial additives on polyacrylic acid - glasses reac-
tion and as a matter of fact, their dose-dependent mechanical properties
is another considerable matter that results in a considerable increase in
the antibacterial ion release. Furthermore, the interaction between pro-
TE
tein macromolecules in saliva and positive charged-antibacterial agents
is vitally important which may lead to the formation of a protein coating
that covers the antibacterial spots on their surfaces. Therefore, attention
was paid toward the selection of a proper additive without having any
interaction with saliva. Finally, for further investigations and develop-
ing new restorative materials, it deemed immensely important to con-
EC
sider all of the above-mentioned limitations of each antibacterial agent.
4. Conclusion
The field of GICs is an important topic of interest in healthcare be-
cause of their unique properties, especially controlled antibacterial re-
RR
lease behavior. Clinical experiences have confirmed that release of fluo-
ride ions is not enough for coping with recurrent caries. Recent studies
aimed to enhance antibacterial activity of GICs using innovative strate-
gies. According to the literature summarized in this paper, several types
of organic and inorganic materials can be added to GICs in order to
enhance their antimicrobial activity. Although antibacterial activity of
GICs is vitally important, this characteristic might prevent secondary
CO
decay and cement failure. Thus, the effect of antibacterial additives on
physical and mechanical properties of GICs should also be reckoned.
The antibacterial features and mechanical properties are the two sides
of the same coin. Overall, by increasing the amount of the additives the
bacteriostatic effect of the composite is increased, but the mechanical
characteristics undergo a deficiency; hence, the amount of the additive
should be optimized to reach the desired restorative materials.
UN
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