European Polymer Journal 129 (2020) 109604

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European Polymer Journal

journal homepage: www.elsevier.com/locate/europolj

Novel antibacterial and therapeutic dental polymeric composites with the T

capability to self-heal cracks and regain mechanical properties
Shuo Yaoa, Tong Lib, Chuanjian Zhouc, Michael D. Weird, Mary Anne S. Melod, Franklin R. Taye,
⁎
Christopher D. Lynchf, Satoshi Imazatog, Junling Wua, , Hockin H.K. Xud,h,i
a
Department of Prosthodontics, School of Stomatology, Shandong University;Shandong Key Laboratory of Oral Tissue Regeneration; Shandong Engineering Laboratory for
Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
b
Department of Endodontics, Jinan Stomatological Hospital, Jinan 250001, China
c
Research Institute of Polymer Materials, School of Materials Science and Engineering, Shandong University, Jinan 250061, China
d
Department of Advanced Oral Sciences and Therapeutics, School of Dentistry, University of Maryland, Baltimore, MD 21021, USA
e
The Dental College of Georgia, Augusta University, Augusta, GA, USA
f
Restorative Dentistry, University Dental School and Hospital, University College Cork, Wilton, Cork, Ireland
g
Department of Biomaterials Science, Osaka University Graduate School of Dentistry, Osaka, Japan
h
Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
i
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Dental caries (tooth decay) is a prevalent disease. Resin composites have become the most commonly used
Dental composites materials to restore caries due to their direct-filling capability, tooth-colored esthetics, and photo cure-on-de-
Antibacterial mand property. However, it has been reported that the current generation of composite restorations has a re-
Mineral regeneration latively high failure rate due to secondary caries and bulk fracture. Therefore, efforts have been made to develop
Self-healing
a new generation of antibacterial and therapeutic dental polymeric composites to suppress caries and increase
Caries
the longevity of the restorations. These new materials have demonstrated the effects to inhibit the growth of oral
biofilms and plaques, reduce bacterial acid production, regenerate the lost tooth minerals, and self-heal cracks to
regain the load-bearing capabilities. This article reviews the cutting-edge development for this new generation of
dental restorative materials.

1. Introduction was 85.5% and that of amalgam was higher at 94.4% [17,18]. Com-
pared to amalgam, resin composites tend to accumulate more bacterial
Dental polymeric composites are the most popular materials used to biofilms and plaques on their surfaces. These bacteria could secrete
restore tooth caries. In the United States, 70% of all tooth cavity re- organic acids that cause tooth mineral loss and secondary caries. In
storations placed in 2006 used composite materials; furthermore, the clinical applications, microleakages and secondary caries are the
composites usage is increasing with time [1–6]. The merits of compo- leading causes of composite restoration failures [19–25]. Another
sites include the simplicity of usage as compared to indirect restora- reason that causes catastrophic failure of composite restorations is bulk
tions, tooth-colored esthetics, minimally-invasive tooth structure pre- fractures. A continuous application of mechanical loads eventually
parations, adhesion to tooth tissues, adequate mechanical durability, leads to microcrack initiation and accumulation in the restoration
and less cost than other restorations such as ceramics and crowns. In [11,26].
addition, composites have better biosafety than mercury-containing Therefore, researchers have developed novel therapeutic dental
dental amalgams [7–9]. However, a number of studies have reported polymeric composites with oral biofilm-suppression, tooth mineral-re-
higher failure rates and shorter longevity for polymeric composite re- generation and self-healing abilities. The anti-biofilm components
storations when compared to amalgams [6,10–16]. could inhibit plaque formation, and the mineral-regeneration compo-
For example, one study investigated 1748 posterior amalgams and nents could reverse early caries and improve the strength and function
polymeric composite restorations in 8–12 years old children. Overall, of the teeth. The self-healing dental polymeric composites with the
10.1% of all the restorations failed at 7 years. The survival rate of RC ability to autonomically repair the cracks could recover the stress-

⁎
Corresponding author.
E-mail address: doctorwujunling@163.com (J. Wu).

https://doi.org/10.1016/j.eurpolymj.2020.109604
Received 16 February 2020; Received in revised form 6 March 2020; Accepted 7 March 2020
Available online 10 March 2020
0014-3057/ © 2020 Elsevier Ltd. All rights reserved.
S. Yao, et al. European Polymer Journal 129 (2020) 109604

bearing capability. Together, they provide a new approach to overcome hexametaphosphate (HMP) or polyphosphates (sodium trimetapho-
the current challenges with the ability to substantially increase the sphate (TMP). These composites showed significant antimicrobial ac-
longevity of dental restorations. This article reviews the most recent tivities. Dias et al. [32] added Ag-doped ZnO NPs into a polymer
developments of these novel bioactive composites that not only restore composite. They used various approaches, polymeric precursor and
the decayed tooth structures but also possess therapeutic and self- coprecipitation techniques to produce the ZnO/Ag NPs. They char-
healing functions. acterized them by using thermal decomposition, X-ray diffraction,
scanning electron microscopy (SEM) and specific surface area by N2
2. Anti-biofilm polymeric composites desorption/desorption. Compared with nanoplates, the addition of
ZnO/Ag NPs had stronger biofilm-inhibition and showed no negative
Currently-available dental polymeric composites lack antibacterial effect on the compressive strength of the composite.
properties [27]. Efforts have been devoted to produce novel anti-bio- Recently, Zhang et al. [27] developed a new antibacterial additive, a
film polymeric composites [28]. Leachable antibacterial agents, such as polymer-antibiotic conjugate (PAC). A monomer-antibiotic conjugate
chlorhexidine (CHX), silver, and fluoride were integrated into dental (MAC) was synthesized using an esterification reaction of 2-hydro-
polymers [29]. Among them, silver or silver ion-implanted fillers xyethyl methacrylate (HEMA) and tert-butyloxycarbony (Boc)-pro-
showed a strong antimicrobial activity [29]. Ag ions can lead to cell tected ciprofloxacin (Cip). The Cip-containing PAC was prepared by
death by inactivating the vital enzymes of bacteria and cause bacterial reversible addition-fragmentation chain transfer (RAFT) copolymer-
DNA to fail in its replication property [30,31]. Compared with tradi- ization of the MAC with HEMA. This novel composite consisted of a
tional large particles, metal oxide nanoparticles (NPs) were more ef- commercial resin and PAC additive and demonstrated long-term anti-
fective to both gram-positive and gram-negative bacteria due to their bacterial capability even at a low concentration.
small sizes and high surface areas [32,33]. However, the efficacy of In summary, antibacterial agents in dental polymers can be divided
releasable agents was short-lived due to the initial burst release and the into two categories: Leachable antibacterial agents, and immobilized
diminished release in the long-term [34]. non-releasing contact-killing antibacterial agents. The immobilized
Methacryloyloxydodecylpyridinium bromide (MDPB), a polymeriz- antibacterial agents in dental polymers are not lost over time, and
able antibacterial monomer, was produced by uniting the quaternary hence exert long-term antibacterial effects. However, they can only kill
ammonium dodecylpyridinium with the methacryloyl group [35,36]. bacteria that come in contact with them. Therefore, further study
The inclusion of MDPB into dental polymeric composite suppressed should develop dental polymeric composites that contain both im-
biofilm growth and reduced plaque accumulation. The antibacterial mobilized and leachable agents, in order to inhibit bacteria not only on
agent was immobilized by the polymerization of MDPB and hence was the restoration surface but also possess long-distance killing of cario-
not released or lost over time. This was considered to be meritorious to genic bacteria away from the surface. In addition, further study should
provide a durable long-term anti-biofilm effect [37]. Dental composites develop dental polymeric composites containing leachable antibacterial
contain filler particles and a resin matrix. Both of these parts can be agents that can be recharged to provide long-term antibacterial func-
modified to possess antimicrobial properties [27,38–39]. Indeed, Im- tions.
azato et al. immobilized the bactericide quaternary ammonium in the
pre-polymerized resin fillers, and the fillers containing MDPB had sig- 3. Antibacterial adhesive materials
nificant bacteriostatic effects and were useful for inclusion into various
polymer-based restoratives [40]. Polymeric composites restore caries by bonding to tooth tissues via
The non-releasable anti-biofilm dental polymers kill the bacteria via adhesives [46,47]. Even though adhesives have been significantly im-
a contact-killing mechanism; the inherent drawback of this mechanism proved, the bonded interface remains to be the weakest area of the
is that the antibacterial effect will decrease when a salivary protein resinous restorations [47]. The failure of adhesives could result in mi-
pellicle in the mouth separates the anti-biofilm polymer surface from croleakage, staining and recurrent caries. In return, these situations
the overlaying biofilm [41,42]. Therefore, attempts have been made to would accelerate the degradation and failure of the adhesive. An anti-
combine protein-repellent agent with quaternary ammonium monomer bacterial primer could help to combat biofilms, recurrent caries and kill
(QAMs). Zhang et al. [42] explored the effects of joining 2-methacry- remaining bacteria in the tooth cavity [48–49]. Commercial adhesive
loyloxyethyl phosphorylcholine (MPC) with quaternary ammonium resins are generally made up of monomers of bis-phenol A-glycidyl
dimethylaminohexadecyl methacrylate (DMAHDM) on oral biofilm re- methacrylate (Bis-GMA) and HEMA [50]. It is necessary to develop
sponse. MPC has amphiphilic properties which provide the ability to antibacterial adhesives to inhibit recurrent caries and improve the
repel proteins and inhibit their surface adsorption. DMAHDM, MPC and service life of resinous restorations.
glass particles were added into a dental polymer to develop a compo- Efforts have been made to modify adhesives with QAMs such as
site. The addition of 1.5% DMAHDM + 3% MPC into the composite MDPB, methacryloxyl-ethylcetylammonium chloride (DMAE-CB), qua-
achieved anti-biofilm capabilities and protein-repellency, without re- ternary ammonium methacrylate-modified silica nanoparticles
ducing the stress-bearing capability. Cherchali et al. [43] further in- (QMSNs) and so on [35,37,51–55]. For QAMs, the mode of action is
vestigated this approach, where the MPC and quaternary ammonium that the positive quaternary amine charge (N+) can interact with the
dimethyl-hexadecyl-methacryloxyethyl-ammonium iodide (DHMAI) negatively-charged bacteria cell. This alters the membrane permeability
were mixed into a methacrylate-based polymer composite. They added or surface electrostatic balance of the bacteria, leading to cytoplasmic
DHMAI or MPC either alone or together at different concentrations. The leakage and bacterial death [56,57].
polymer composite with 7.5% DHMAI improved the degree of con- The alkyl chain length (CL) of the QAM makes a great difference in
version and demonstrated a significant bacteriostatic effect, while still the antibacterial effect [58,59]. To determine the effects of CL on the
possessing acceptable stress-bearing abilities. However, the addition of antibacterial property, Zhou et al. [58] incorporated six different QAMs
7.5% MPC to DHMAI did not provide stronger antibacterial activity and (synthesized with CL = 3, 6, 9, 12, 16, 18) into a dental adhesive resin.
decreased the hardness of the polymer composite. The six QAMs are listed in Table 1. They obtained SYTOX green-stained
Recently, Brandão et al. [44] evaluated the antibacterial activity of CLSM images of oral saliva microcosm bacteria early-attachment at 4 h
a modified composite with ZnO nanoparticles (ZnO-NP). The polymer vs. the QAM CL. Incorporating QAMs into Scotchbond multi-purpose
composite incorporating 2–5 wt% ZnO-NP provided antibacterial ac- (SBMP) reduced the bacteria's early-attachment. With the increasing of
tivity, without degrading the physicochemical properties of the com- CL, the bacteria early-attachment was reduced and reached the bottom
posite. Meanwhile, Mendes-Gouvêa et al. [45] synthesized a novel at CL of 16 (Fig. 1A). The colony-forming units (CFU) of dental plaque
composite containing silver nanoparticles (AgNP) with sodium microcosm biofilms on resins cultured for 2 days vs. CL are plotted in

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S. Yao, et al. European Polymer Journal 129 (2020) 109604

Table 1 Fig. 1B (Total microorganisms), Fig. 1C (total streptococci) and Fig. 1D

QAMs with a series of alkyl chain lengths (CL). (mutans streptococci). The biofilm CFU decreased with increasing the
Tertiary amine Alkyl organo-halide Product CL CL. The CFU at CL of 16 was the lowest, which was decreased by 4 log
when compared to SBMP control. To determine the amine (N+) charge
2-(dimethylamino) ethyl 1-bromopropane (BP) DMAPM 3 density effect, DMAHDM (CL = 16) was added into the SBMP. In-
methacrylate (DMAEMA) 1-bromohexane (BH) DMAHM 6
creasing the DMAHDM content increased the N+ charge density on the
1-bromononane (BN) DMANM 9
1-bromododecane (BDD) DMADDM 12
resin surface. The bacterial early-adhesion to resin surface was reduced
1-bromohexadecane DMAHDM 16 with greater DMAHDM mass fraction in the resin (p < 0.05), as shown
(BHD) in Fig. 1E. Therefore, tailoring and optimizing the CL and the N+
1-bromooctadecane DMAODM 18 charge density is a promising approach to inhibiting biofilms and dental
(BOD)
caries.
The position of the functional groups could also affect the property

Fig. 1. The effects of CL and quaternary amine charge density on the antibacterial activity. (A) Representative confocal laser scanning microscopy (CLSM) images of
SYTOX green-stained microcosm bacteria on resins: SBMP bonding agent containing 10% of QAM with CL of 16. Effect of chain length CL on dental plaque
microcosm biofilm CFU: (B) Total microorganisms, (C) total streptococci, and (D) mutans streptococci. (E) Resin surface area coverage by microcosm bacteria early-
attachment: effect of quaternary amine surface charge density. (Reproduced with permission from Ref. [58], Elsevier, 2013).

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S. Yao, et al. European Polymer Journal 129 (2020) 109604

of QAMs. To determine the effect of changing the position of the biofilm properties. Furthermore, multifunctional bonding systems are
functional group on the anti-biofilm activity, Liang et al. [51] synthe- attracting more attention, since adhesives with a single particular
sized a new QAM named triethylaminododecyl acrylate (TEADDA), in property can’t solve the complex issues causing resin-dentin bond fail-
which the functional group’s location was different from that of di- ures [46].
methylaminododecyl methacrylate (DMADDM). They determined the
microtensile bond strength and the amine charge density on the ex- 4. Tooth mineral-regenerating dental composites
perimental resin surfaces. Compared with DMADDM, adding TEADDA
into the adhesive had stronger mechanical properties; however, the Caries is a complex disease in which tooth mineral loss and mineral
antibacterial potency was decreased [51]. Therefore, it is important to regeneration happen constantly, either occurring alternatively or si-
tailor and control the processing variables to optimize material prop- multaneously [69,70]. Repeated episodes of demineralization for an
erties. extended period leading to a net loss of mineral, which results in the
Furthermore, chitosan is a natural aminopolysaccharide biopolymer dissolution of dental hard tissues and the occurrence of tooth decay
[60]. Chitosan was shown to have an antibacterial effect against several [71–76]. When examined in electron microcopy, demineralization is
oral pathogens related to periodontitis and the formation of dental shown as crystal dissolution, whereas mineral-regeneration is the re-
plaque, such as Actinobacillus actinomycetemcomitans, Streptococcus precipitation of the partially dissolved minerals, the growth of the
mutans and Porphyromonas gingivalis [61,62]. The mechanism of ca- survived minerals, and the deposition of the newly-formed crystals
tionic antibacterial agents was considered to be the interaction with [69,77–82].
and disruption of the cell envelope [60]. Machado et al. [63] for- The de-and re-mineralization processes are related to the fluctua-
mulated a novel adhesive resin with chitosan and evaluated its im- tions in pH [71]. When the pH is below the critical pH of 5.5, the dental
mediate and long-term physical, chemical and antibacterial properties. hydroxyapatite undergoes dissolution [83]. Cariogenic bacteria such as
This adhesive resin was synthesized using photoinitiators and metha- lactobacilli and mutans streptococci have a terminal pH of 3.9 to 4.1.
crylate monomers. Chitosan or triclosan-loaded chitosan was added at Thus, whether the tooth surface may undergo demineralization de-
2 wt% or 5 wt% into the base resin. The adhesive resin with 5 wt% pending on the buffering capacity of plaque and its degree of super-
triclosan-loaded chitosan showed the strongest antibacterial activity. saturation with respect to calcium (Ca) and phosphate (P) [83]. Hence,
Furthermore, the addition induced dentin/adhesive interface stability an emerging goal of modern dentistry is to develop a novel composite
over time and may have a positive effect on long-term marginal sealing, with mineral-regeneration function to reverse early caries and improve
which requires further study. the strength and function of the teeth [84].
Yan et al. [64] produced chlorhexidine-encapsulated mesoporous Fluoride ions could suppress dental caries development through its
silica-modified dentin adhesive which could increase the longevity of mineral-regeneration effect [85,86]. The effect of fluoride ions in mi-
adhesive restorations. Wang et al. [65] developed a novel adhesive with neral-regeneration has been the “gold standard” when compared with
MPC and DMAHDM addition into a self-etching adhesive. The resin other mineral-regeneration systems [87]. Fluoride could prevent and
greatly inhibited biofilm viability and reduced protein adsorption. arrest caries by inhibiting bacterial metabolism, restraining deminer-
Santos et al. [66] developed methacrylate saccharide-based monomers alization, and enhancing the mineral-regeneration [86,88–90]. Com-
for bonding systems. When being added to adhesives, saccharide me- pared with OH− ions, fluoride fitted better into the hydroxyapatite
thacrylate monomers, chitosan-methacrylate (Chit-MA), glucose-me- lattice. In the presence of fluoride ions, the hydroxyapatite became the
thacrylate (Gluc-MA) and sucrose-methacrylate (Sucr-MA) showed less soluble fluorapatite. This change meant that the critical pH for
promising antibacterial results. Among them, the Sucr-MA group at 1% demineralization dropped by 0.5–1.0 units [87]. For these reasons, a
concentration decreased the bacterial metabolism, had a low cytotoxi- great number of oral care products and restorative materials now
city, and increased the dentin bond strength after storage. In addition, contain fluoride [91]. The source of fluoride ions includes metal
Dutra-Correa et al. [67] incorporated various concentrations of nano- fluorides or hexafluorophosphate salts, such as CaF2, NaF, KPF6, SnF2,
particles of silver (NAg) into the primer of the SBMP bonding system. YbF3 and fluoro-aluminosilicate glass [92].
Even low concentrations of NAg (250 ppm) in the primer improved the Tammaro et al. [93] synthesized a novel fluoride-releasing dental
antibacterial property and preserved the bond strength and the bio- composite that could constantly release fluoride without any initial
compatibility of the adhesive. Zeolites are an ideal carrier for anti- toxic burst effect. Through an ion exchange procedure, the hydrotalcite
bacterial agents. Li et al. [68] synthesized the nanosized EMT zeolites was modified with fluoride ions (LDH-F). Then mixed different con-
with silver ion-exchange. In order to investigate the inhibition of bio- centrations of the LDH-F inorganic particles (0.7, 5, 10, 20 wt%) with a
film formation at the tooth-restoration margin, a dental adhesive con- photoactivated Bis-GMA/trimethylene glycol dimethacrylate
taining Ag + EMT zeolites was investigated, and demonstrated a sig- (TEGDMA) (45/55 wt/wt) matrix. In fact, even added a small con-
nificant reduction in the biofilm CFU counts by nearly 2 orders of centration of the hydrotalcite filler, the experimental composites still
magnitude for all three cariogenic pathogens. Therefore, the adhesive have slow fluoride released, significant improvement of mechanical
containing Ag + EMT zeolites was promising for anti-biofilm and anti- properties, and the ability to promote human dental pulp stem cell
caries clinical applications [68]. differentiation. In addition, another study [94] developed a novel resin
In summary, dental adhesives play a key role in clinical treatment, composite containing LiAl-F layered double hydroxide (LDH) with an
and the bonded interface is the weak link of the restoration. To prolong advantageous anion exchangeable ability. This composite improved the
the service life, researchers synthesized novel adhesives with anti- fluoride ion release and ion recharge efficacy. The ability of bioactive
bacterial properties. Beside the immobilized non- releasing contact- glass (BAG) has also been evaluated. Caluwé et al. [95] indicated that,
killing antibacterial monomers of QAMs, leachable antibacterial agents compared with other BAGs, fluoride-containing BAG could form more
such as Ag ions, NAg and chlorhexidine are also good antibacterial stable fluorapatite showed greater advantages. Mutluay et al. [96] de-
agents for incorporation into adhesive resins to resist bacteria [46]. monstrated that fluoride-containing phosphate-rich BAG incorporated
Zeolites are an ideal carrier for antibacterial agents. The nanosized EMT as micrometer-sized filler in dental composites offered greater bene-
zeolites with silver ion-exchange revealed potential value for anti-bio- ficial effects than Bioglass 45S5 in mineral-regeneration of the demi-
film applications. In addition, as an alternative to synthetic compounds, neralized dentin and reducing the enzyme-mediated degradation.
antimicrobial compounds in natural products are increasingly desired Non-fluoride remineralization systems could achieve mineral-re-
[66]. For example, chitosan has been introduced into dental adhesives generation through the diffusion or delivery of calcium (Ca) and
because of its antibacterial properties. Saccharide methacrylate mono- phosphate (P) ions into the subsurface lesions and boost the saliva and
mers, such as Chit-MA, Gluc-MA and Sucr-MA, showed promising anti- reservoirs’ mineral-regeneration properties. Previous studies used

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S. Yao, et al. European Polymer Journal 129 (2020) 109604

Fig. 2. Rechargeable dental composite with NACP. (A) Nanoparticles of amorphous calcium phosphate (NACP) synthesized via a spray-drying technique. (B, C) The
Ca and P ion re-release of the three NACP nanocomposites. (D, E) The Ca and P ion re-release after six recharge/re-release cycles without further recharge.
(Reproduced with permission from Ref. [102], Elsevier, 2011, and Ref. [98], Elsevier, 2016).

amorphous calcium phosphate (ACP), nanoparticles of amorphous pH and may be invalid in an acid-challenge environment in the mouths.
calcium phosphate (NACP), tricalcium phosphate (CaP) and so on Poly(amidoamine) (PAMAM) is an excellent nucleation template and
[87,97]. When exposed to a low pH, these materials could deliver Ca could activate the mineral-regeneration process through the absorption
and P ions to neutralize the acid and remineralize the tooth lesions of Ca and P ions via its functional groups [99,105–108]. Therefore, the
[97,98]. The disadvantage of conventional CaP-based polymeric com- combination of NACP and PAMAM achieved triple benefits: excellent
posites was their poor mechanical properties, which were too weak for nucleation templates, superior acid neutralization, and ion release [99].
bulk-filling restorations [99]. Researchers synthesized whisker-re- Liang et al. [109] demonstrated this superior mineral-regeneration ef-
inforced CaP composite and incorporated a barium-glass filler into the ficacy of PAMAM + NACP method. This approach produced great
composite to enhance the stress-bearing capabilities [100–101]. More mechanical properties and induced mineral-regeneration in the demi-
recently, NACP was added into dental polymers [102–104]. Fig. 2A neralized dentin, even in an acid-challenge environment.
shows spray-dried NACP powder with the sizes of about 100 nm. The The ion release from dental composites usually lasted for only a few
NACP nanocomposite not only released high levels of Ca and P ions but months and then the release was diminished over time [98,110–111].
also showed strong mechanical properties, which were twice as strong In order to overcome this problem, Zhang et al. [98] developed a re-
as traditional CaP composites [102]. chargeable CaP dental composite with NACP to achieve long-term in-
Traditional mineral-regeneration methods do not work well at low hibition of tooth decay. They added NACP into three different resin

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S. Yao, et al. European Polymer Journal 129 (2020) 109604

Fig. 3. Self-healing dental composites. (A) Microcapsules showed in the SEM image. (B) SEM image showed the fracture plane of a self-healing material. (C) Field
emission scanning electron microscopy (FESEM) observations of the adhesive/dentin interfaces. The resin tags (white arrow) were longer and more regular as
compared with the control. (D) Micro-tensile bond strength values of five groups. (Reproduced with permission from Ref. [122], Elsevier, 2019, and Ref. [132],
Elsevier, 2011).

matrices filled with 20% NACP and 50% glass particles. To test the CaP 5. Self-healing dental polymeric composites
ion recharge capability, they immersed the specimens into a flesh so-
lution at pH 4 to exhaust the ion release. The exhausted specimens were It was estimated that 25% or more of all dental polymeric composite
then immersed in a recharge solution. Fig. 2B and Fig. 2C show CaP ion failures were caused by fractures, which were due to microcrack in-
re-release of 6 recharge and re-release cycles. All three groups showed itiation and accumulation [114,115]. Previous studies developed
good CaP ion recharge capability. Their ion re-release amount achieved stronger composites, such as improving the inorganic filler level, using
similar ion concentrations for repeated cycles, indicating that the CaP nanoscale fillers and incorporating whiskers and fibers [116–119].
ion re-release was not decreased with more and more cycles of recharge However, fractures and failures still happen often, thus warranting
over time. After 6 cycles of recharge and re-release, the NACP nano- more research and development efforts.
composites, even without any more recharge, had a continuous release A promising method is the development of dental polymeric com-
of CaP ions for another 42 days, with results in Fig. 2D and Fig. 2E. This posites with self-healing function. Self-healing polymer systems can be
novel rechargeable NACP nanocomposite achieved long-term Ca and P divided into three types, including capsule-based healing systems,
ion release and has great potential to suppress caries for the restora- vascular healing systems, and intrinsic healing systems [120].Recently,
tions. Besides composites, Zhang et al. [112] and Liang et al. [113] microcapsule-based self-healing materials have received much atten-
developed a rechargeable CaP adhesive to provide long-term Ca and P tion [121]. When a microcrack occurs, the flowable healing agent
ions. stored in the microcapsules would be released to the target area via
In conclusion, both fluoride and Ca and P ions could achieve mi- capillary effect. Then the healing agent contacts the catalyst in the
neral-regeneration functions. NACP nanocomposites had strong me- resin, triggering polymerization, which bonds the crack faces together
chanical properties, provided Ca and P ions similar to those in natural [121–125]. In this way, the resin can heal the microcrack and regain
teeth, and could be recharged for long-term effects. In addition, the the load-bearing ability.
NACP recharge method could be applied to dental adhesive resins as In 2001, pioneering research on microcapsule-based self-healing
well. material was reported by White et al. [126]. Using an in situ poly-
merization method, poly (urea-formaldehyde) (PUF) shells were made
to encapsulate the healing agent dicyclopentadiene (DCPD). Micro-
capsules were added into an epoxy matrix with Grubbs’ catalyst

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S. Yao, et al. European Polymer Journal 129 (2020) 109604

Fig. 4. Multifunction self-healing adhesive containing DMAHDM and NACP. (A) A typical SEM image of the microcapsules. Typical fracture surfaces after 12 months
of water immersion: (B) Virgin fracture surface, and (C) the healed and re-fractured surface. (Reproduced with permission from Ref. [152], Elsevier, 2019).

particles. The fracture experiments yielded as much as 75% recovery in Fig. 3D shows the micro-tensile bond strength (μTBS) test values. The
fracture toughness. The SEM image of microcapsules and fracture adhesive with 9 wt% nanocapsules showed the highest microtensile
planes are shown in Fig. 3A and Fig. 3B. Another study [127] for- dentin bond strength of (25.8 ± 4.9) MPa. Adding TEGDMA nano-
mulated a new structural epoxy that achieved more than 90% average capsules into commercial adhesive did not negatively influence the
recovery of its original fracture toughness. In 2010, Wertzberger et al. cellular toxicity, and yielded good biocompatibility which was required
[128] applied White’s self-healing method to a dental polymeric com- in clinical applications.
posite. Despite the highly filled nature of dental composites, these Wu et al. [133] developed a self-healing dental resin composite
specimens were able to recover about 57% of its initial fracture containing microcapsules with PUF shells and TEGDMA-DHEPT (N, N-
toughness. In order to enhance the physical characteristics of the mi- dihydroxyethyl-p-toluidine) healing liquid. Huyang et al. [134] synthe-
crocapsules, Then et al. [129] replaced the urea with 0–5% melamine. sized a new type of self-healing dental composite. Two additional in-
However, the toxicity of DCPD monomer and the high cost of Grubb’s gredients were added in contemporary dental components: a healing
catalyst remained challenges in using them in dental composites clini- powder (strontium fluoro aluminosilicate particles) and a healing liquid
cally [130,131]. (aqueous solutions of polyacrylic acids), encapsulated inside silica mi-
Ouyang et al. [132] synthesized TEGDMA nanocapsules by using crocapsules. In addition, a self-healing dental luting cement was syn-
interfacial polycondensation in a mini-emulsion technique. This type of thesized which achieved more than 60% average recovery of its original
nanocapsules demonstrated a high drug load and could be well dis- fracture toughness [135]. The long-term stability is a major require-
persed in the dental adhesive, due to their smooth surface and well- ment for dental restorative materials. Yahyazadehfar et al. [136]
formed spherical shape. Representative fracture surface features and evaluated the enhancement of long-term stability of self-healing dental
adhesive and dentin interfacial characteristics are shown in Fig. 3C. polymeric composites under monotonic and cyclic loading. The

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S. Yao, et al. European Polymer Journal 129 (2020) 109604

Fig. 5. Self-healing and multifunctional adhesive. (A) Dentin shear bond strength results (B) Self-healing efficiency of adhesive resins. (mean ± sd; n = 10)
(Reproduced with permission from Ref. [152], Elsevier, 2019).

addition of 5 wt% microcapsules into the methacrylate silane self- DMAHDM, the lactic acid production and the metabolic activity of
healing dental composites got the best results both of healing efficiency adherent biofilms were reduced to 1% and 4% of that of biofilms on
and fracture toughness. composite control. The biofilm CFU counts dropped by 3 orders of
Furthermore, Chen et al. [137] combined MPC with self-healing magnitude. This novel nanocomposite achieved excellent antibacterial
dental composites and achieved the double function of protein-resistant and remineralization ability, and also possessed great fracture re-
and self-healing properties. The MPC incorporation into the polymeric sistance. Another study [139] synthesized a bioactive root canal sealer
composite reduced substantially the protein adhesion on the polymer using DMAHDM and NACP. This novel material contained 20% NACP
surface (p < 0.05). The self-healing efficiency was 57–71%. This novel and 5% DMAHDM. This new sealer provided great amounts of Ca and P
dental composite with great protein-repellent and crack self-healing ion release which is necessary to remineralization of the tooth roots. In
characteristics provided a novel platform for anti-caries and self-healing addition, another study [19] developed a CaP rechargeable and anti-
dental bioactive materials. biofilm polymeric composite with DMAHDM and NACP. This composite
with long-term remineralization exhibited far less biofilm accumulation
6. Antibacterial and remineralizing polymeric composites and lactic acid synthesis when compared to those on control composite.
Ibrahim et al. [140] developed a dental sealant with NACP and
Efforts were made to develop dental polymeric composites with DMAHDM. Various mass percentage loadings of NACP were in-
double benefits of antibacterial and remineralization abilities. Zhang corporated to investigate the effects on mechanical properties and the
et al. [138] incorporated QAMs with CLs of 3-18 into NACP nano- Ca and P ion release and rechargeability over time. With the increasing
composites and investigated the effects of the CL on the mechanical and of NACP mass fraction, the ion release was increased. The sealant with
biofilm properties. The results indicate that the NACP nanocomposite 20% NACP demonstrated good mechanical properties and desirable
with a CL of 16 showed the strongest antibacterial activity among all handling properties. Furthermore, it displayed high levels of lasting Ca
the tested groups. Wu et al. [103] developed a novel DMAHDM-NACP and P ion release and ion rechargeable features.
nanocomposite and investigated the DMAHDM mass fraction effects on Studies were further performed to add three functional components
biofilm response and fracture toughness. Adding DMAHDM from 0% to to the composite. Li et al. [141] developed a dental polymeric adhesive
3% did not negatively affect fracture toughness (p > 0.1). With 3% containing NACP, DMAHDM, and magnetic nanoparticles. Compared

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S. Yao, et al. European Polymer Journal 129 (2020) 109604

Fig. 6. Dental plaque microcosm biofilm viability grown for 2 days on adhesive resins: (A) MTT assay, and (B) lactic acid production (mean ± sd; n = 6).
(Reproduced with permission from Ref. [152], Elsevier, 2019).

with the commercial adhesive, this novel adhesive under a magnetic inhibition of tooth root caries and recurrent caries with MPC, NACP,
force showed greater dentin bond strength. The new adhesive decreased and DMAHDM. With the triple capability of protein-repellent, re-
the biofilm CFU by 4 log and increased the biofilm pH from 4.5 to 6.9. mineralizing and antibacterial properties, this novel multifunctional
Therefore, this new adhesive has strong potential to strengthen the adhesive was promising to coat tooth roots to prevent root caries for
resin-tooth interfacial bonding, protect the tooth minerals, and greatly senior patients. Another study [144] further investigated the effects of
reduce recurrent caries at the tooth-restoration margins. MPC. They developed a novel ion-rechargeable adhesive with MPC and
Long-term water-aging for 1 year was investigated for the new NACP. Added MPC showed no negative influence on the adhesive
polymers to test their durability. Cheng et al. [142] developed a com- properties and greatly reduced the protein adsorption.
posite with NAg, NACP and quaternary ammonium dimethacrylate In addition, Alijabo et al. [145] synthesized a high strength dental
(QADM). This new composite displayed the capability of reminer- composite. The light-curable composite containing 80 wt% urethane
alization and possessing antibacterial properties. After 1 year of water- dimethacrylate-based liquid which was mingled together with glass
aging, there was no reduction in the antibacterial capability. The dur- particles, as well as 10 wt% CHX and 0, 10, 20 or 40 wt% reactive
able and long-term antibacterial and mechanical properties of NACP- mono- and tricalcium phosphate. Due to the high strength, surface
QADM-NAg composites indicated their potential for use in dental re- antibacterial function and hydroxyapatite precipitation, this novel
storations. composite could decrease the restoration fracture and prevent subsur-
Zhang et al.[143] synthesized a novel bonding system for the face carious disease. Another study [146] reported a novel dental

9
S. Yao, et al. European Polymer Journal 129 (2020) 109604

Fig. 7. Dental plaque microcosm biofilm CFU on adhesive resins. (A) (B) total microorganisms, (C) (D) total streptococci, and (E) (F) mutans streptococci
(mean ± sd; n = 6). (Reproduced with permission from Ref. [152], Elsevier, 2019).

polymeric composite containing 20 wt% of urethane dimethacrylate- bioactive composite. These novel composites could increase the long-
based liquid, and 80 wt% glass particles, plus 10 wt% CHX and 0–40 wt evity of restorations through the suppression of secondary caries and
% CaP. Incorporation of 10–20 wt% additives attained extra volumetric remineralizing the dental tissues in the lesions.
expansion to compensate the shrinkage, with desirable mechanical Furthermore, another study [149] synthesized a therapeutic poly-
properties and strong antibacterial and remineralizing abilities. meric composite via MPC, NACP, NAg, DMAHDM and investigated the
BAGs also played a key role in bioactive properties. Chatzistavro effects of combining this composite with PAMAM on mineral-re-
et al. [147] fabricated novel Ag-doped anti-biofilm dental polymeric generation. The composite and PAMAM joint method had excellent root
composites. Ag-doped sol gel-derived bioactive glass (Ag-BG) was dentin mineral-regeneration effects which could induce effective and
added into the polymeric matrix at 5, 10, and 15 wt% filler levels. The complete root dentin mineral-regeneration in an acid-challenge en-
new resin composites with antibacterial and re-mineralizing properties vironment.
could ultimately prevent restoration failure. Another study [148] added
Ag-BG into a flowable composite to develop an antibacterial and

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S. Yao, et al. European Polymer Journal 129 (2020) 109604

7. Composites with triple benefits of self-healing, antibacterial, calcium phosphate systems inhibited demineralization and enhanced
and mineral-regeneration functions mineral-regeneration to reverse early caries and improve the strength
and function of the teeth. Self-healing microcapsules in dental polymers
There has been an increasing number of reports on the development automatically healed the cracks and regained the load-bearing ability.
of bioactive and multifunctional dental materials [97]. Wu et al. [150] Multifunctional composites achieved antibacterial, remineralization
developed a novel self-healing NACP-DMAHDM composite with triple and self-healing functions by incorporating antibacterial agents, re-
benefits of self-healing, remineralizing and antibacterial properties. mineralizing materials and self-healing microcapsules. The combina-
Microcapsules were synthesized using an in situ polymerization tech- tion of novel bioactive and therapeutic agents and nanoparticles is a
nique with PUF shells containing TEGDMA and DHEPT as the healing promising strategy to overcome the existing problems, increase the
solution. The composite consisted of 20% NACP, 35% glass fillers and service time of dental polymeric composites, regenerate minerals and
different concentrations of microcapsules. The composite with 7.5% protect tooth structures.
microcapsules did not compromise the mechanical properties. The self-
healing DMAHDM-NACP composite achieved more than 60% recovery Author contributions
of the virgin fracture toughness and showed strong antibacterial and
mineral-regeneration effects. As a follow-up study, Yue et al. [151] Junling Wu and Hockin H. K. Xu proposed the ideas and designed
developed a self-healing adhesive with antimicrobial and mineral-re- this paper. Shuo Yao, Tong Li and Chuanjian Zhou wrote the first draft.
generation functions. Compared with control commercial resin, this Michael D. Weir, Mary Anne S, Melo, Franklin Tay, Christopher D.
novel self-healing adhesive with NACP and DMAHDM matched the Lynch and Satoshi Imazato provided discussions, revisions and feed-
dentin bond strength, decreased the biofilm acid production and re- back. Junling Wu and Hockin H. K. Xu finalized the manuscript.
duced the biofilm CFU. Autonomous crack-healing efficiency test
showed that this new adhesive attained more than 60% recovery of the Acknowledgments
virgin fracture toughness, thus achieving successful crack-healing.
Furthermore, Wu et al. [152] investigated the effects of water-aging This study was supported by National Natural Science Foundation
for 12 months on dentin bonding, self-healing and antibacterial prop- (NSF) of China 81671032 (JLW).
erties. The adhesive contained 7.5% microcapsules, 10% DMAHDM and
20% NACP. Fig. 4A shows a representative SEM picture of the micro- Declaration of Competing Interest
capsules. After water-aging for 12 months, the micro-
capsules + DMAHDM + NACP group demonstrated no decrease in the The authors declare no conflict of interest.
dentin bond strength and had a high self-healing efficiency. Typical
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