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Functional Fillers for Dental Resin Composites

Yazi Wang , Meifang Zhu , X.X. Zhu

PII: S1742-7061(20)30706-6
DOI: https://doi.org/10.1016/j.actbio.2020.12.001
Reference: ACTBIO 7069

To appear in: Acta Biomaterialia

Received date: 26 September 2020

Revised date: 30 November 2020
Accepted date: 1 December 2020

Please cite this article as: Yazi Wang , Meifang Zhu , X.X. Zhu , Functional Fillers for Dental Resin
Composites, Acta Biomaterialia (2020), doi: https://doi.org/10.1016/j.actbio.2020.12.001

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Functional Fillers for Dental Resin Composites

Yazi Wang a,b, Meifang Zhu a,*, X. X. Zhu b,*

a
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College
of Materials Science and Engineering, Donghua University, Shanghai 201620, China

b
Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-ville,
Montréal, Québec, H3C 3J7, Canada

*Corresponding authors. E-mail: zhumf@dhu.edu.cn; julian.zhu@umontreal.ca.

Abstract

Dental resin composites (DRCs) are popular materials to repair caries. Although various
types of DRCs with different characteristics have been developed, restoration failures still
exist. Bulk fracture and secondary caries have been considered as main causes for the failure
of composites restoration. To address these problems, various fillers with specific functions
have been introduced and studied. Some fillers with specific morphologies such as whisker,
fiber, and nanotube, have been used to increase the mechanical properties of DRCs, and other
fillers releasing ions such as Ag+, Ca2+, and F-, have been used to inhibit the secondary caries.
These functional fillers are helpful to improve the performances and lifespan of DRCs. In this
article, we firstly introduce the composition and development of DRCs, then review and
discuss the functional fillers classified according to their roles in the DRCs, finally give a
summary on the current research and predict the trend of future development.

Keywords

Dental resin composites, Reinforcing, Antibacterial, Remineralizing, Self-healing,

Radiopaque, aesthetic

1 Introduction
Dental caries, a common oral disease, has been listed as the third largest non-infectious
disease in the world by World Health Organization. Amalgam is an early dental filling
1
material for caries. It possesses excellent mechanical properties and long service life, meeting
people's basic demand for chewing. With the improvement of the quality of life, people have
put forward higher requirements on the properties of dental restorative materials. A concept
of minimally invasive treatment has been widely accepted by dentists, which advocates that
the healthy dental tissues should be conserved as much as possible when restored. However,
due to a lack of adhesion to teeth substrate, the amalgam treatment has to adopt a strictly
geometric cavity preparation for mechanical retention, which may remove some healthy
tissues. [1-3] Besides, other disadvantages of amalgam, such as the mismatch of appearance
with natural teeth, toxicity of mercury, and environmental pollution, also limit its extensive
application. [4-6]

Since Bowen introduced bisphenol A glycerolate dimethacrylate (BisGMA) in 1962, [7,

8] methacrylate-based dental resin composites (DRCs) have been gradually replacing the
amalgam. Several types of DRCs with different characteristics have been developed.
Flowable composites introduced in 1990’s are usually used for the repair of low-stress areas
of teeth. They possess low viscosity, good fluidity, and reduced elastic modulus because of
20 ~ 25% lower filler loading than other DRCs. [9, 10] On the contrary, packable composites
possess thicker consistency and better mechanical properties resulting from a higher loading
and size distribution of filler, which are widely used for the restoration of posterior teeth. [11,
12] For conventional DRCs, an incremental layering technique is usually adopted when
filling the deep caries cavity, but it is time-consuming and may introduce defects and
contaminants between layers. To address this problem, “bulk-fill” composites were
developed through increasing the translucency, using more efficient photoinitiators, and so
on. Their maximum filling thickness at a time is up to 4 mm, higher than previous thickness
of 2 mm. Besides, the “bulk-fill” composites have low and high viscosity types. [13-15] To
further simplify the restorative process, new self-adhesive composites have also been
developed, whose formulations contain special monomers capable of chemically bonding to
hydroxyapatite. They combine the characteristics of adhesives and composites and are

2
expected to be used directly without a separate adhesive, but their bonding capability is not
yet ideal and should be further improved for clinical use. [16, 17]

Although various types of DRCs have been developed and each type has its own
characteristics, there are still some problems such as bulk fracture and secondary caries.
[18-20] To further improve the performances and lifetime of DRCs, a great deal of efforts
have been made, including the synthesis of newly low-shrinkage and bio-safe monomers,
[21-23] the introduction of reinforced and functional fillers, [24-27] and the development of
colorless and low-toxic photoinitiators. [28, 29] In particular, a variety of functional fillers
have been widely investigated in the DRCs, which can significantly improve the original
performances or endow new functions of DRCs. In this article, we will emphatically review
and discuss the influence of functional fillers on the performances of DRCs.

2 Composition and development of DRCs

The common DRCs are mainly comprised of three components, namely resin monomers
(mixture of monomers), inorganic fillers, and photoinitiator system. [30]

2.1 Resin monomers

The monomers containing methacrylate, acrylate, or allylic groups can photopolymerize
to form a three-dimensional network structure to envelope the filler. [31, 32] There have been
recent reviews on the subject of dental monomers and resins. [33, 34] The most commonly
used dental monomers include bisphenol A glycerolate dimethacrylate (BisGMA), urethane
dimethacrylate (UDMA), and triethylene glycol dimethacrylate (TEGDMA) (Fig. 1).
BisGMA and UDMA possess good mechanical properties, but their viscosities are high,
making them difficult to mix with fillers and leading to a non-ideal filler loading. TEGDMA
has a low viscosity and is usually used as a diluent to combine with BisGMA or UDMA. It
also has two double bonds but a lower molecular weight, resulting in a larger polymerization
shrinkage. [34-36] Therefore, it is necessary to optimize the composition and ratio of resin
monomers so as to find a balance in viscosity, mechanical properties, polymerization
shrinkage, and other properties of DRCs. Other types of monomers with special properties
3
such as low polymerization shrinkage, [22, 37, 38] antibacterial property, [39-41] and
biosafety [23, 42, 43] have also been investigated, which will not be discussed in this review.

O O

O O O O
OH OH

(MW: 512 g/mol; η: 5×102 ~ 8×102 Pa·s)

BisGMA

O O
H
O N O
O N O
H
O O

(MW: 470 g/mol; η: 5 ~ 10 Pa·s)

UDMA

O
O O
O O
O

(MW: 286 g/mol; η: 0.1 Pa·s)

TEGDMA

Fig. 1 Commonly-used dental monomers. “MW” and “η” indicate molecular weight and viscosity,

respectively. [44]

2.2 Inorganic fillers

The fillers used in the DRCs are usually inorganic particles. Among these inorganic
particles, silicon dioxide (SiO2) has been widely applied in the DRCs, which usually acts as a
main filler due to its matched refractive index with resin matrix, good stability and

4
mechanical properties, and easy production, etc. [30] Due to the weak interfacial interaction
between the resin matrix and the fillers, these inorganic particles usually need to be modified
by silane coupling agents. [45] The early DRCs labeled “macrofill” composites were filled by
large particles with a size of 10 ~ 50 μm, which possessed poor polishability and aesthetics
(Fig. 2). [46] Since then, decreasing the size of particles has become a trend. Various types of
DRCs with different size and distribution of particles have been developed successively,
including microfill (0.01 ~ 0.1 μm, late 1970’s), hybrid (0.01 ~ 5 μm, early 1980’s),
microhybrid (0.01 ~ 1 μm, middle 1990’s), nanofill (0.01 ~ 0.04 μm, ~2000), and nanohybrid
(0.01 ~ 1 μm, ~2000). [46, 47] It should be noted that the DRCs are often filled by particles
of nanometer sizes less than a micron and they have been known by the term “microfill”
composites, probably because the term “nano” was not often used initially at that time. [46]
Besides, the boundary between microhybrid and nanohybrid is unclear, because both contain
micro- and nano- particles and possess similar size distribution of particles. [47]

Fig. 2 Large voids are left when the particles fall off from the macrofill composites (left), showing

poor polishability and aesthetics; small voids are left when the particles fall off from the nanofill

composites (right), showing good polishability and aesthetics.

5
2.3 Photoinitiator system
Camphorquinone (CQ)/amine is the most popular photoinitiator system used in dental
materials, in which CQ acts as a photoinitiator and the amine acts as a co-initiator. The
common amines include ethyl 4-dimethylaminobenzoate (4-EDMAB), aliphatic amine
(2-(dimethylamino)ethyl methacrylate (DMAEMA), etc. [48] The photoinitiation mechanism
of CQ/amine is so-called “hydrogen abstraction”. When irradiated by blue light, CQ with an
absorbance range of 360 ~ 510 nm (λmax ≈ 468 nm) is activated, and then interact with amine
which acts as hydrogen donor to generate an α-aminoalkyl radical and a CQ-ketyl radical,
and the former initiates the polymerization of methacrylate monomers (Fig. 3). [28, 49, 50]
However, the CQ/amine system also has some shortcomings, such as the toxicity of amine
and the color of CQ. [48] Other photoinitiators such as phenylbis
(2,4,6-trimethylbenzoyl)-phosphine oxide [51] and tetraacylgermanes [52] have also been
investigated, which were expected to substitute the CQ/amine system.

Fig. 3 Photoinitiation mechanism of CQ with tertiary amine. [49, 50]

6
2.4 Optimization of formula
The commercial DRCs usually contain 70 ~ 80 wt% inorganic particles and 20 ~ 30
wt% resin monomers. [53] The role of dental fillers can endow DRCs good mechanical
properties, and reduced polymerization shrinkage and water absorption, etc. [54] A common
method to improve the performances of DRCs is to optimize the formula of dental fillers.
Maximizing the filler loading has become a goal both in industry and academia. The
maximum filler loading is closely related to the size of inorganic particles. The smaller
particles usually possess a larger specific surface area, therefore a lower filler loading. [55] A
theoretical calculation and practical experiment have confirmed that the maximum filler
loading is hard to be further increased when filling the DRCs with particles of the same size.
However, there will inevitably be gaps between these particles, providing a space to
accommodate smaller secondary particles (Fig. 4). The combination of particles of different
sizes can improve the packing density and therefore the performances of DRCs. [56, 57]

Fig. 4 Close-packed structures in DRCs. [56]

3 Functional fillers
Current commercial DRCs are still lack of functions. Researchers have been trying to
improve the comprehensive performances of DRCs through the introduction of functional
fillers. In this review, these functional fillers are classified into reinforcing, antibacterial,
remineralizing, self-healing, radiopaque, and aesthetic, according to their roles in the DRCs
(Fig. 5).
7
 Fig. 5 Various types of functional fillers.

3.1 Reinforcing fillers

Traditional dental fillers are usually spherical or irregularly granular, these particles are
easy to debond from the resin matrix during long-term chewing, failing stress transfer from
matrix to fillers. Bulk fracture has always been an important reason for the failure of
composites restoration. New fillers with special morphologies such as whisker, fiber,
nanotube, and pore structure have been developed to improve the mechanical properties of
DRCs.

3.1.1 Whiskers
Whisker fillers can reinforce and toughen composites through crack deflection, bridging,
pinning, and whisker pullout. [58] Xu studied the influence of the amount of silicon nitride
(β-Si3N4) whiskers on the mechanical properties of DRCs. In order to facilitate silanization
and improve the surface roughness of β-Si3N4 whiskers, SiO2 particles were melt and then
bound to the surface of β-Si3N4 whiskers when heated to 800 °C. The flexural modulus and
vickers hardness of the DRCs increased monotonically with the amount of added β-Si3N4
whiskers. The flexural strength and flexural modulus of the whisker-filled DRCs were more
than twice those of conventional SiO2-filled DRCs. [59] The ratio of whiskers and SiO2
particles in the fusion process also influenced the mechanical properties of DRCs, while the
influences on fracture toughness and on flexural strength of DRCs were different. With the
8
increase of the ratio of whiskers, the fracture toughness of DRC increased and finally reached
a plateau, while the flexural strength firstly increased and then decreased. This may be due to
the fact that fracture toughness depends on the ability of a material to prevent the propagation
of a crack, while flexural strength is related to defects on the surface of the material and
inside it. When the ratio of SiO2 particles on the whisker surface was low, entanglement and
agglomeration between whiskers could occur and the defects were formed, which led to a
decreased flexural strength but had less impact on the fracture toughness. [60] Different
whiskers showed characteristic effects on the mechanical properties of DRCs. Silicon nitride
whiskers were helpful to improve the strength and toughness of the material, while silicon
carbide whiskers improved the modulus and hardness of the material. [61]

Liu et al. selected hydroxyapatite (HA) as dental filler, which was bioactive and
biocompatible. The HA whiskers were firstly silanized, followed by the graft of
poly(BisGMA) onto their surface. Compared with the HA whiskers without any treatment
and with only silane treatment, the poly(BisGMA)-grafted HA whiskers showed better
mechanical properties and lower polymerization shrinkage. [62] To address the problem of
aggregation of HA whiskers, urchin-like hydroxyapatite (UHA) fillers were developed (Fig.
6A), which combined features of a whisker and a globule. The morphology of UHA could be
controlled by changing the pH and temperature in a hydrothermal precipitation technique.
These UHA fillers were easier to disperse than HA whiskers. The UHA could insert into the
resin matrix tightly through these spikes (Fig. 6B) and improved the interfacial interaction
between the resin matrix and the fillers. [63, 64] Chen et al. further modified the UHA using
a sol-gel method to obtain a silica coating, followed by silanization with
3-methacryloxypropyl trimethoxysilane (γ-MPS). The silica coating on the UHA surface
could increase the surface roughness and facilitate the contact with γ-MPS, without damaging
the morphology characteristic of UHA. The dispersibility of modified UHA in the resin
matrix was further improved. [65]

9
 Fig. 6 SEM images of UHA particles (A) and fracture surface of DRC filled with UHA (B). [63]

3.1.2 Fibers
Fibers have a higher aspect ratio than whiskers, but their reinforcing and toughening
mechanisms to the matrix are similar. Tian et al. prepared nylon-6/fibrillar silicate
nanocomposite nanofibers. The surface of fibrillated silicate single crystals was rich in Si-OH
groups, which provided convenience for silanization. The silanized silicate single crystals
could be highly oriented along the fiber axis to improve the strength and modulus of the
nanocomposite nanofibers. The flexural strength, flexural modulus, and fracture work of the
material were increased by 23, 25, and 98 %, respectively, when 2 % nanocomposite
nanofibers were added. [66] Lin et al. prepared core-shell electrospun nanofibers with
polyacrylonitrile (PAN) as the core and poly (methyl methacrylate) (PMMA) as the shell.
The PAN core possessed high strength, and the PMMA shell could be partly dissolved in the
dental monomers. After light irradiation, the linear PMMA chains could form physical
entanglement with the matrix network, improving the interaction between the nanofibers and
the resin matrix. Compared with the pure resin, the flexural strength, flexural modulus, and
fracture work of the material were increased by 18.7, 14.1, and 64.8%, respectively, when 7.5
wt % PAN-PMMA nanofibers were added. [67] Sun et al. further imposed a post-draw
treatment on the PAN-PMMA nanofibers to improve orientation and crystallinity of the
nanofibers. The flexural strength, flexural modulus, and fracture work of the material were
increased by 51.6, 64.3, and 152 %, respectively, when 1.2 wt % nanofibers were added. [68]

10
 Glass fibers have been used as a reinforcing filler for the preparation of dental materials,
which possess advantageous characteristics such as good aesthetic property, excellent
reinforcing effect, and acceptable biocompatibility. [69, 70] The reinforcing effect of glass
fibers to the dental materials is related to its aspect ratio, content, and orientation [71, 72].
Among various glass fibers, E-glass and S-glass are the most common ones used in dentistry.
[70] A composition of E-glass is 55.0 wt% SiO2, 14.0 wt% Al2O3, 22.0 wt% CaO, 7.0 wt%
B2O3, 1.0 wt% MgO, 0.5 wt % Na2O, 0.3 wt% K2O, and 0.2 wt% TiO2, while the
composition is different in the S-glass which contains 65.0 wt% SiO2, 25.0 wt% Al2O3, and
10.0 wt% MgO.[73] The S-glass has greater hardness and modulus than E-glass, but its cost
is expensive and the service life is short.[69] The influences of glass fibers on the
performances of DRCs such as wear resistance [74], fracture toughness [75], and
polymerization shrinkage [76, 77] have been investigated. Recently, Cho et al. investigated
the influence of surface modification of short S-glass fibers on the interfacial and mechanical
properties of the dental composites. The S-glass fibers were firstly etched by hydrochloric
acid or sulfuric acid to selectively remove Al2O3 and MgO on the near surface of the fibers
without harming SiO2, then 3-(trimethoxysilyl)propyl methacrylate (TMSPMA), a silane
coupling agent, was anchored on the surface of the etched fibers (Fig. 7). The selective
atomic level metal etching technique increased the surface roughness of the fibers and then
enhanced the interfacial shear bonding between fibers and matrix through the mechanical
interlocking. Besides, abundant hydroxyl groups on the fiber surface were generated after
etching, which was helpful for the formation of strong chemical bonding with silane coupling
agents. Compared with untreated glass fibers, the modified S-glass fibers showed an increase
of 11 ~ 40 % in interfacial shear strength. The flexural strength, modulus, and breaking
energy of composites filled with modified S-glass fibers were also improved. [78]

11
 Fig. 7 Surface modification procedures of S-glass fibers. [78]

3.1.3 Nanotubes
Single-walled carbon nanotube (SWCNT) has excellent mechanical properties, with
tensile strength of 50 ~ 100 GPa and Young's modulus of 1 ~ 2 TPa. To improve interfacial
compatibility with the resin matrix, Zhang et al. firstly coated SWCNT with a layer of
nano-SiO2, followed by modification using allyltriethoxysilane. The addition of modified
SWCNT improved the mechanical properties of DRC, but it also had an adverse influence on
the aesthetics of the material due to its dark color. [79] Halloysite nanotube (HNT,
Al2Si2O5(OH)4·nH2O) is a natural nanomaterial with characteristics of hollow tubular
structure and high aspect ratio. The elastic modulus of HNT is calculated about 230 ~ 340
GPa. [80] Chen et al. added silanized HNT to DRCs and found that small amounts (1 or
2.5%) of HNT could be dispersed evenly in the matrix and improved the mechanical
properties, while excessive HNT tended to form aggregates. [81] Utilizing the hollow
structure of HNT, Liu et al. loaded silver nanoparticles into HNT and obtained DRC with
excellent antibacterial activity and mechanical properties. The flexural strength of the DRC
was increased by 25% when 3% Ag-HNT was added. [82]

3.1.4 Porous fillers

During long-term clinical service, traditional silane coupling agents can be degraded in
the humid oral environment, which weakens the interfacial bonding between the fillers and
12
the matrix. The porous fillers can form a stable physical interlocking with resin matrix
through the pore structure (Fig. 8), which have been widely investigated. Samuel et al.
prepared mesoporous SiO2 particles using glucose as template and tetraethyl orthosilicate as
precursor. The filler loading of DRC only reached 40 ~ 50 wt%, due to the high specific area
of mesoporous SiO2. Although the filler loading of DRC could be increased through a
combination of nonporous SiO2 and mesoporous SiO2, the mechanical properties of DRC
were still not ideal. [83] Wang et al. synthesized wrinkled mesoporous SiO2 nanoparticles
with a size of ~ 500 nm (Fig. 9) using cetyltrimethylammonium bromide (CTAB) as
template. Compared with nonporous SiO2 nanoparticles similar in size, the wrinkled
mesoporous SiO2 nanoparticles were more conducive to the improvement of flexural strength
and flexural modulus of DRC. [84] However, the high specific area of porous fillers still led
to lower filler loadings of DRC. Recently, rough core-shell SiO2 nanoparticles with a
controllable mesoporous structure were synthesized. The thickness of mesoporous shell could
be adjusted by changing reaction time in an oil-water biphase system. The maximum filler
loading of the rough SiO2 nanoparticles with low specific area was similar to that of
nonporous SiO2 nanoparticles. The DRC filled with the rough SiO2 showed an improvement
of 36.1 and 39.3% in the flexural strength than the DRC filled with nonporous SiO2
nanoparticles and the international standard (ISO 4049-2009), respectively. [85]

Fig. 8 Illustration of DRCs reinforced by particles with interconnected pores (A) and surface pores

(B). [83]

13
Fig. 9 SEM images (A, B, and C) and TEM images (D, E, and F) of wrinkled mesoporous SiO2

nanoparticles (A, B, D, and E) and nonporous SiO2 nanoparticles (C and F). [84]

3.2 Antibacterial fillers

The formation of dental caries is related to the bacteria of mouth. These bacteria
attached to the teeth surface can produce weak organic acids through metabolizing food
residues, causing a decreased pH value at local positions which can lead to the occurrence of
demineralization. [86] Compared with traditional amalgam, DRCs are more likely to
accumulate the bacteria due to the lack of antibacterial property. [87, 88] The antibacterial
fillers such as Ag, ZnO, and chlorhexidine have been tested for use to address this problem.

3.2.1 Silver
Silver nanoparticles have been extensively studied in oral repair materials such as
dentures, [89, 90] adhesive agents, [91, 92] and implants. [93, 94] The antibacterial activity
of silver nanoparticles is mainly contributed to the release of Ag+. The antibacterial
mechanisms of Ag+ have not been clarified completely so far, but it is thought that there are
three ways to kill bacteria, namely damaging the structures of cell wall, inhibiting DNA
replication, and denaturing cytoplasmic enzymes. [95] The antibacterial property of silver is
size-dependent, and the smaller particles with high specific surface area possess significant
antibacterial property even at low dosage. [96] Cheng et al. prepared silver nanoparticles with
a diameter of ~3 nm through an in situ method. Silver 2-ethylhexanoate, an organic silver
14
salt, was dissolved in 2-(tert-butyl) amino ethyl methacrylate (TBAEMA, Fig. 10), followed
by mixing with dental monomers consisting of BisGMA and TEGDMA. When the
monomers underwent photopolymerization, the Ag+ was also reduced to Ag. TBAEMA was
used in this study for two reasons: (1) a coordination bond of Ag-N could be formed between
TBAEMA and silver 2-ethylhexanoate, which improved the solubility of the silver salt in the
dental monomers; (2) the methacrylate group of TBAEMA could participate in the
polymerization of dental monomers. The method of in situ synthesis could avoid the
agglomeration of nanoparticles and the results showed that the flexural strength of the
material did not change significantly. [97] Durner et al. investigated whether the introduction
of silver nanoparticles could affect the amounts of elutable substances from DRCs. They
added different amounts of silver nanoparticles to the commercial DRCs and detected the
substances leaching from the cured samples. The DRC containing silver nanoparticles
released more organic small molecules than that without silver nanoparticles, which might be
an indication that the silver nanoparticles had affected the polymerization. [98] Besides, the
biosafety of silver nanoparticles was also a concern. Excessive silver might accumulate in
some tissues such as skin, liver, and kidneys, potentially affecting human health. [95]

O
N
H
O

Fig. 10 Chemical structure of TBAEMA.

3.2.2 Zinc oxide

Zinc oxide (ZnO) nanoparticles have attracted extensive attention because of its
broad-spectrum antibacterial property, good safety, and stability. One of the important
antibacterial mechanisms of ZnO nanoparticles is called photocatalytic sterilization. ZnO is a
semiconductor material, whose electronic band structure is composed of a valence band and a
conduction band. When irradiated by ultraviolet or visible light, the electrons in the valence
band absorb energy and then transfer to the conduction band, resulting in the formation of
positive holes in the valence band and the acquirement of free electrons in the conduction
15
band. [99] The positive holes in the valence band can oxidize H2O to form •OH, and the
-
electrons in the conduction band can reduce O2 to form a series of intermediates such as ,

, H2O2, and . The production of these reactive oxygen species (ROS) is an important
reason for the antibacterial activity of ZnO nanoparticles. [99, 100] Obviously, for the
photocatalytic sterilization of ZnO nanoparticles, light irradiation is a requirement. However,
the ROS was also detected under dark conditions, which resulted from the surface defects of
ZnO crystals. These defects helped to capture a lot of electrons which could reduce O2 and
then produce ROS (Formula 1-4): [101]

- -
( ) (1)

- -
(2)

(3)

- -
(4)

Besides, the release of Zn2+ from ZnO nanoparticles and the interaction between
nanoparticles and bacteria were also supposed to be important reasons for the antibacterial
activity. [102]

Unlike Ag, the ZnO nanoparticles have a color similar to natural teeth. Therefore its
introduction to DRCs has less adverse influence on the aesthetics of the materials. The direct
addition of ZnO nanoparticles cannot improve the mechanical properties of DRCs effectively,
Wang et al. prepared cellulose nanocrystal/zinc oxide (CNC/ZnO) nanohybrids through
precipitating Zn2+ on the surface of CNC. The nanohybrids could integrate the reinforcing
effect of CNC and antibacterial function of ZnO nanoparticles together. The mechanical
properties were increased when 2 wt % CNC/ZnO nanohybrids were added. [103] Chen et al.
coated ZnO particles with mesoporous SiO2 to obtain ZnO@m-SiO2 nanoparticles. The
mesoporous structure in these nanoparticles improved the interfacial interaction between the
fillers and the matrix. Compared with the control group without ZnO@m-SiO2, the flexural
16
strength, flexural modulus, and compressive strength of DRC containing 7 wt %
ZnO@m-SiO2 nanoparticles were increased by 121.2, 67.1, and 32.5%, respectively. The
antibacterial rate was greater than 99.9%, and the other properties such as degree of
conversion and depth of cure were not significantly affected. [104]

3.2.3 Chlorhexidine
Chlorhexidine is an organic antibacterial agent (Fig. 11) with low toxicity, which is
considered as a “gold standard” for evaluating antimicrobial agents. [105] Fullriede et al.
developed a pH-responsive release system in which chlorhexidine was loaded into
nanoporous silica nanoparticles, followed by modification with poly(4-vinylpyridine) (PVP).
Under neutral condition, PVP chains enveloped around silica tightly and blocked these pores,
so that chlorhexidine was fixed. Under acidic condition, the pyridine groups on the PVP
chains were protonated and the molecular chains were open due to electrostatic repulsion, so
that chlorhexidine could be released through the nanoporous channel. This study provided a
possibility to realize the controllable and long-term release of chlorhexidine. [106] Luo et al.
developed a chlorhexidine-releasing system induced by near-infrared light. They grew
chlorhexidine microspheres on the surface of gold nanorods. The microspheres were then
coated by a polyelectrolyte to form microcapsules to prevent chlorhexidine from dissolving
fast in water. Once irradiated by near-infrared light, the gold nanorods converted light into
heat to break the microcapsules, resulting in the exposure and dissolution of chlorhexidine.
[107] Luo et al. also developed a chlorhexidine-releasing system controlled by a magnetic
field. They firstly prepared chlorhexidine microspheres containing Fe3O4 nanoparticles,
followed by the mixing with resin monomers. A magnet was then placed in contact with the
resin system to control the distribution of drug within the materials. All materials showed
continuous release behavior, while the materials treated with the magnet had a faster release
rate in the early stage. The cumulative release amount of the material without magnetic
treatment was 4.4 %, while the cumulative release amounts of the material treated with 5 and
10 min were 5.9 and 7.4 %, respectively. [108] These study realized the controllable release
of chlorhexidine, but the practical application may be limited due to the requirement of an

17
external stimulus. Besides, its incompatibility with dental monomers may be also a problem,
which has a potential to weaken the properties of DRCs. [109]

Cl
NH NH
NH NH NH
NH NH NH
NH NH
Cl

Fig. 11 Chemical structure of chlorhexidine.

Other antibacterial agents such as quaternary ammonium compounds have also been
widely investigated in the dental materials. A recent review on the quaternary ammonium
compounds has been made, [110] which will not be discussed here.

3.3 Remineralizing fillers

The component of teeth mineral is not a pure hydroxyapatite [Ca10(PO4)6(OH)2], but a
highly substituted hydroxyapatite, i.e., calcium-deficient carbonated hydroxyapatite
[Ca10-xNax(PO4)6-y(CO3)z(OH)2-uFu]. This is because that during the formation of teeth
mineral, some “impurity” ions from tissue fluids are incorporated into the crystal lattice of
mineral. The major substitution ions are CO32–, Na+, and Mg2+. Due to the presence of CO32–,
the calcium-deficient carbonate hydroxyapatite is more acid-soluble than hydroxyapatite.
[111] The pH value of the oral plaque affects the formation of dental caries. A pH above 6 is
relatively safe, a pH value in the range of 5.5 ~ 6 is potentially cariogenic, while a pH value
in the range of 4 ~ 5.5 is cariogenic. [112] Besides, the rate and degree of dissolution of
minerals also depend on the concentration of ions as shown in Formula (5). [111] A solution
to inhibit the demineralization of teeth is to increase the concentration of these ions such as
calcium, phosphate, and fluoride ions.

( )

- - -
( - ) ( - ) (5)

18
3.3.1 Calcium orthophosphates
Among calcium orthophosphates (CaP) phases, amorphous calcium phosphate (ACP,
CaxHy(PO4)znH2O) is currently the most studied remineralizing agent. Compared with other
CaP phases, ACP is more water-soluble and easier to release ions in oral environment. ACP
is metastable and can spontaneously convert into HA. Therefore stabilizers such as P2O74- are
usually added during its synthesis. [113] Zhang et al. developed a class of DRC, which could
release and recharge calcium and phosphate ions, using ACP nanoparticles as the
remineralizing filler and pyromellitic glycerol dimethacrylate (PMGDM) and
bis[2-(methacryloyloxy)ethyl] phosphate (BisMEP) as monomers (Fig. 12). The samples
released calcium and phosphate ions in an environment of pH 4, and could recharge when
immersed into solution containing calcium and phosphate ions at pH 7 through the
complexation of acidic groups of PMGDM and BisMEP. The new rechargeable DRC is
hopeful to achieve long-term and sustained release of calcium and phosphate ions. [114]
Recently, a combination of poly (amidoamine) (PAMAM) and dental materials containing
ACP nanoparticles was used to remineralize the dental hard tissues. [115-118] PAMAM
dendrimers are highly branched macromolecules with large numbers of active groups. They
can attract calcium ions through complexation and then induce remineralization, but only
work well in nonacidic media. The ACP nanoparticles can neutralize acids in solution and
release mineral ions. When PAMAM and DRC containing ACP were combined, a layer of
dense needle-like mineral crystals formed on the surface of demineralized dentin and the
hardness of the repaired dentin was similar to that of the healthy dentin. [115]
O HO O
O
O
O O
O
O
O O
O
O
O OH O

PMGDM

19
 O
HO
O
O P O
O
O
O

BisMEP

Fig. 12 Chemical structures of PMGDM and BisMEP.

Other CaP fillers have also been investigated for their remineralizing capacity, including
dicalcium phosphate anhydrous (DCPA, CaHPO4), [119-121] dicalcium phosphate dihydrate
(DCPD, CaHPO4.2H2O), [122-124] tetracalcium phosphate (Ca4(PO4)2O), [125] and
β-tricalcium phosphate (β-Ca3(PO4)2) [126, 127]. The ions release of CaP fillers is related to
size and surface treatment of particles. The CaP filler with small size had higher specific
surface area, showing a faster release rate. However, the silanization treatment improved the
hydrophobicity of particles surface and hence delayed the permeation of water molecules into
the materials, which was not conducive to the release of ions. [121] The mechanical strength
of CaP fillers themselves is poor, the introduction of CaP fillers usually decreases the
strength of materials. [128] One way to solve this problem is to mix reinforcing filler and
CaP filler together. Xu et al. utilized DCPA nanoparticles as remineralizing filler and
nano-silica-fused silicon carbide whiskers as reinforcing filler to prepare DRC. The flexural
strength of prepared DRC was twice higher than that of previous CaP composites. The
released ion concentrations of DCPA-whisker composite matched or exceeded those of
previous CaP composites. [119] Recently, TEGDMA-functionalized DCPD particles were
synthesized and introduced into DRCs. The functionalized layer could increase the
particle-matrix interaction, besides, the relatively hydrophilic characteristic of TEGDMA was
also helpful to the release of ions. [123, 129]. However, another considerable issue is that the
introduction of CaP fillers can increase the water sorption of materials and accelerate the
degradation of the resin matrix. The amount of CaP fillers should be optimized to maintain
the release of ions without seriously sacrificing the mechanical properties of materials. [122,
130]
20
3.3.2 Fluorides
Fluorides have been widely studied as anticariogenic agent in dentistry. [131-133] The
mechanisms to inhibit caries include: preventing demineralization and promoting
remineralization of dental hard tissues, interfering the formation of pellicle and plaque, and
inhibiting the growth and metabolism of microbe. [134] Moreau et al. investigated the effect
of pH values (4, 5.5, and 7) of the solution on the release of F- and mechanical properties of
fluoride-containing dental materials. The lower pH values could cause more F- to release in a
short period of time, which had a positive effect on inhibiting the formation of dental caries.
The mechanical properties of the materials decreased significantly after soaking, but the pH
values of the solution had no significant influence on the mechanical properties of the
materials. [112] To realize the sustainable release of F-, Xu et al. synthesized a
fluorine-containing methacrylate monomer (Fig. 13), which was combined with a
fluorine-releasing filler to prepare DRC. The ternary zirconium (IV) of the monomer acted as
a chelate, capable of sustained release and recharge of F-. This monomer could be
copolymerized with other dental monomers. The new dental monomer facilitated the
penetration of F- within the material through ion exchange, showing a good release efficiency.
[135] Recently, layered double hydroxide and montmorillonite were used in DRCs. They
possess layered structure and ion-exchange capacity, providing convenience for the storage
and recharge of F-. [136, 137]

O O

O O O O
OH O O
O F
O N Zr
O F-H+

Fig. 13 Chemical structure of a fluorine-containing dental monomer. [138]

21
3.3.3 Bioactive glasses
Bioactive glasses (BGs) are a type of biomaterials, which have been widely investigated
for the restoration of both hard and soft tissues. [139] The first BG termed Bioglass 45S5 was
developed by L. Hench in 1969, with a composition of 46.1 mol% SiO2, 26.9 mol% CaO,
24.4 mol% Na2O, and 2.6 mol% P2O5. Various types of BGs have been developed, whose
main components are similar to 45S5 but the concentrations are slightly different. Other
components such as CaF2, K2O, and MgO also appear in some BGs. [140] The BGs have
been widely tested for use in the dentistry such as adhesives, [141, 142] implants, [143] and
pulp capping agents. [144, 145] They have also been introduced into DRCs as fillers for
various purposes such as remineralizing the dentin [146, 147], reducing bacterial penetration
into marginal gaps [148], and neutralizing acid [149]. However, the BGs are hydrophilic,
which tend to aggregate in the hydrophobic resin matrix. The mechanical properties of DRCs
containing BGs can be deteriorated in the humid environment. [150] To avoid this problem,
amphiphilic bioactive raspberry-like composite particles (BRP) were synthesized and used as
fillers for DRC to remineralize the dentin (Fig 14). [151] The BRP possessed hydrophobic
polymer domain compatible with the resin matrix and hydrophilic bioactive domain
promoting mineral precipitation. Compared with composites containing BG, the composites
containing BRP showed improved mechanical properties and lower water sorption and
solubility. When demineralized dentin was treated by composites containing BRP, a dense
mineral layer was formed onto the dentin, but some microparticles were found on the surface
of the dentin treated by composites containing BG (Fig 15). This might be explained that the
poor compatibility between BG and resin matrix resulted in the release of BG in the form of
particles, while the dense mineral formed was due to the ions released from the BRP. [151]
Current research mainly focused on the formation of apatite, but not much on the mechanical
properties of the dentin treated by BGs. It is still questionable whether BGs can remineralize
dentin. [152]

22
Fig. 14 Schematic diagram of the preparation of DRC containing BRP and the subsequent in situ

remineralization on the dentin. [151]

Fig. 15 SEM images of dentin remineralization promoted by three different materials after

immersion in artificial saliva for 30 days. The abbreviations in the figure: BT stands for

23
“Bis-GMA/TEGDMA resin system”, BG for“bioactive glass” and BRP for “bioactive

raspberry-like composite particles”. The arrows point to the BG particles. [151]

3.4 Self-healing fillers

Many natural organisms have the ability to heal nonfatal wounds by themselves.
Inspired this, researchers want to develop smart materials that can sense and repair the
damages spontaneously. [153-155] The self-healing microcapsules were proposed by White
et al. who embedded poly(ureaformaldehyde) (PU) microcapsules containing a healing agent
dicyclopentadiene and Grubbs’ catalyst into epoxy matrix. When the composites suffer a
crack, the propagation of the crack will cause the microcapsules to break, releasing the
dicyclopentadiene. Under capillary action, the dicyclopentadiene flows along the crack and
the polymerization reaction can happen once dicyclopentadiene meets the catalyst distributed
in the matrix. The resultant polymer film acts as an adhesive to bind the crack areas together.
(Fig. 16) [156]

Fig. 16 Schematic diagram of the self-healing of microcapsules. [156]

24
 The service lifetime of DRCs may be prolonged if they can repair damages during
practical application spontaneously. [157, 158] Wertzberger et al. added 2 wt% Grubbs’
catalyst (200 ~ 400 nm) and 5 wt% encapsulated dicyclopentadiene (50 μm) to the DRC
containing 55 wt% silanized glass particles (0.7 μm). The fracture toughness of the DRC
repaired for 7 days could reach 57% of the original fracture toughness. However, the
introduction of self-healing system could decrease the mechanical properties of the DRC.
[159] To replace the potentially toxic and expensive dicyclopentadiene-Grubbs’ catalyst
system, attempts have been made. In one study, TEGDMA, benzoyl peroxide (BPO), and
N,N-dihydroxyethyl-p-toluidine (DHEPT) were used as the healing agent, initiator, and
co-initiator, respectively. TEGDMA can flow and fill the crack due to its relatively low
viscosity. Besides, TEGDMA, BPO, and DHEPT possess acceptable biocompatibility.
[160-163] Wu et al. encapsulated TEGDMA-DHEPT (mass ratio 99:1) in a
urea-formaldehyde resin through in-situ polymerization, then added the microcapsules (70 ±
4 μm) and BP to the DRC. The self-healing efficiency increased with the amount of the
added microcapsules, but the flexural strength and flexural modulus of DRC decreased. [160]
In another study, strontium fluoroaluminosilicate particles were used as the healing powder
and an aqueous solution of polyacrylic acids encapsulated in silica microcapsules was used as
the healing liquid. The silanization treatment of the microcapsules was important, which
improved the interfacial bonding with the resin matrix to ensure that the microcapsules could
rupture successfully once the composite was broke. When the healing powder contacted and
reacted with the healing liquid released from the silica microcapsules, the glass ionomer
cement could be formed to repair the crack. The glass ionomer cement had some advantages
such as good biocompatibility and the ability to release the F-, but the average healing
efficiency of the prepared DRC was only 25%, which should be further increased. [164]

Recently, a new bio self-healing dental composite was proposed using microbially-
induced calcium carbonate precipitation, which is a common biological process. The bacteria
inducing the precipitation of calcium carbonate (CaCO3) was embedded into matrix, along
with necessary substances such as carbon, nitrogen, and calcium source. Once a crack

25
occurred, the moisture and air could penetrate into the matrix and activate the bacteria. The
CaCO3 minerals were finally formed as a result of metabolic activity of the bacteria. The oral
environment with moisture, air, and favorable temperature and pH, provides the possibility
for the bio-precipitation of CaCO3 by bacteria, but more systematic characterization including
mechanical properties and self-healing efficiency of DRCs is needed in the future. [165]

3.5 Radiopaque fillers

The radiopacity is one of the most important properties for DRCs, so that dentists can
diagnose secondary caries and find filling defects. The radiopacity of a DRC is determined by
its composition, thickness, and density. Materials containing elements of high atomic
numbers possess high radiopacity. With the thickness and density of the material, the
radiopacity also increases. [166, 167] Objects with different radiopacity show different
shadows under X-ray (Fig. 17). The material containing elements of high atomic numbers
shows white shadow due to its high X-ray radiopacity, while the caries with hole structure
shows black shadow due to the lower X-ray radiopacity. [168] According to the ISO
4049:2009, at the same thickness, the radiopacity value of DRCs should not be lower than
that of pure aluminum.

Fig. 17 Radiography of a repaired tooth. [168]

Amirouche et al. investigated the influence of filler type (BaO, BaSO4, La2O3, ZrO2,
SrO), filler loading, and monomer composition on the radiopacity of materials. The
radiopacity of pure resin matrix was poor, since the organic monomers only contained C (6),
26
H (1), O (8) elements, which possessed low atomic numbers. The addition of the fillers
significantly improved the radiopacity of the materials, and the type and content of the fillers
had a high influence on the radiopacity of the materials. [169] Wang et al. investigated the
influence of surface modification of ZrO2 nanoparticles on the physical and mechanical
properties of DRCs. The surface of ZrO2 nanoparticles has few hydroxyl groups, not ideal for
silanization. A sol-gel method was adopted to coat the ZrO2 nanoparticles with mesoporous
silica. The silica coating provided large number of hydroxyl groups for silanization. The
presence of mesoporous structure was also helpful to improve the interaction between the
fillers and the resin matrix. In general, the mismatch of refractive index of ZrO2 and resin
matrix could cause a reduced light transmittance. The coating of silica decreased the
mismatch through decreasing the refractive index of nanoparticles. The surface modification
of ZrO2 nanoparticles did not significantly affect the radiopacity of DRC, meeting the
international standard. [170]

3.6 Aesthetic fillers

The mismatch of appearance between restorative materials and teeth is also an important
reason for restoration failure. [171] The appearance of teeth varies widely from a person to
another and from a tooth to another. Even in different regions of one tooth, the appearance
may also be different. The optical properties endowing natural teeth vital appearance involve
color, translucency, fluorescence, and opalescence. Among these, color and translucency are
readily observed, therefore have greater impact on the appearance of teeth. [172]

The color of the human teeth is mainly derived from dentin. Compared with organic
dyes, inorganic pigments are more permanent and stable. [173] To reproduce the color of
natural teeth, a mixture of inorganic pigments with different colors such as yellow, red, white,
and black is commonly used. [172] However, there is little information about the type and
concentration of pigments in the commercial DRCs.

The enamel of natural teeth has translucency, a state between complete transparency and
complete opacity. [174] Ideal DRCs should have translucency similar to that of human

27
enamel. Some metal oxides such as TiO2, Al2O3, and ZrO2 can be used as opacifying agents
to adjust the translucency of DRCs. The opacity of materials increase with the mismatch of
refractive index between opacifying agent and resin matrix. [175] The size of inorganic fillers
can also affect the translucency of DRCs. As the light scattering increase with the size of
particles, smaller-sized particles can produce thus a high transparency. [55, 176]

Fluorescence is a luminescence phenomenon occurring when an object is irradiated by a

light and then spontaneously emits another light with a longer wavelength within 10-8 second
of activation. [177] Both enamel and dentin can occur fluorescence, but the intensity of
fluorescence presented in dentin is stronger than that in enamel, due to much collagen fibers
in dentin. [178] Natural teeth emit a blue fluorescence when exposed in the environment of
ultraviolet light, this is why the teeth appear whiter and brighter in daylight. [179] Some
DRCs lack of fluorescence may match with teeth in appearance under the daylight, but
mismatch under ultraviolet light (Fig. 18A,B). [180] Giving DRCs fluorescence similar to
that of natural teeth can reduce or even eliminate the mismatch. Rare earth oxide (Eu2O3,
Tb4O7, Dy2O3), [181] quantum dots, [182] and fluorescent whitening agent [183] have been
used to tailor the fluorescence of DRCs.

The enamel of natural teeth possesses opalescence. Opalescence is a light scattering

phenomenon that a material appears bluish in reflected light and orange/brown in transmitted
light (Fig. 18C). [184] The opalescence of DRCs can be obtained through the adjustment of
refractive index of the resin matrix and the fillers, and the addition of particles such as TiO2,
Al2O3, and ZrO2. [172]

28
Fig. 18 Teeth of the same person under white (A) and ultraviolet (B) light. The restoration lack of

fluorescence can be distinguished from natural teeth under ultraviolet light, but not under white light.

[180] Demonstration of opalescence in a ceramic restoration (C), which appears brown under

transmitted light and blue under reflected light. [184]

4 Conclusion
As restorative materials for caries, the DRCs need to possess multiple properties so that
they are able to serve in the complicated oral environment for a long time. The introduction
of functional fillers can endow DRCs new functions and/or significantly improve their
original properties usually at low dosages. However, there are still issues worthy of

29
consideration. The reinforcing fillers with special morphology and structure usually lead to a
low filler loading. Therefore a combination of fillers with various sizes and morphologies
may be a good solution to improve the mechanical properties of DRCs. The biocompatibility
of antibacterial fillers should be a concern and systematic biosafety characterization of
antibacterial DRCs should be implemented in the future. Since the remineralizing and
self-healing fillers usually weaken the mechanical properties of DRCs, the added amounts
should be controlled rationally. The aesthetic fillers should possess good stability and
biosafety, and endow the DRCs the appearance of natural teeth whatever light sources. In a
word, the introduction of functional fillers should endow the DRCs significant new properties
without compromising the other properties. The future research trend in the area evolves
toward the development of durable and stable dental materials with improved
biocompatibility and added functions.

5 Author information

Notes

Declaration of Interest Statement

We would like to submit our manuscript for consideration as a review article to be

published in Acta Biomaterialia. This manuscript has not been published previously. It is
free of conflict of interest and has been approved by all authors.

Acknowledgements
The authors acknowledge the financial support from the National Key Research and
Development Program of China (2016YFA0201702/2016YFA0201700) and National
Natural Science Foundation of China (NO. 51733002). YW thanks a scholarship from China
Scholarship Council in support of a research exchange with Université de Montréal. XZ is the

30
member of CQMF funded by FRQNT of Quebec and holder of Canada Research Chair in
Polymeric Biomaterials funded by the Government of Canada.

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