Application of Copper Nanoparticles in Dentistry

Abstract

Nanoparticles based on metal and metallic oxides have become a novel trend for dental applications. Metal nanoparticles are commonly used in dentistry for their exclusive shape-dependent properties, including their variable nano-sizes and forms, unique distribution, and large surface-area-to-volume ratio. These properties enhance the bio-physio-chemical functionalization, antimicrobial activity, and biocompatibility of the nanoparticles. Copper is an earth-abundant inexpensive metal, and its nanoparticle synthesis is cost effective. Copper nanoparticles readily intermix and bind with other metals, ceramics, and polymers, and they exhibit physiochemical stability in the compounds. Hence, copper nanoparticles are among the commonly used metal nanoparticles in dentistry. Copper nanoparticles have been used to enhance the physical and chemical properties of various dental materials, such as dental amalgam, restorative cements, adhesives, resins, endodontic-irrigation solutions, obturation materials, dental implants, and orthodontic archwires and brackets. The objective of this review is to provide an overview of copper nanoparticles and their applications in dentistry.

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Citation: Xu, V.W.; Nizami, M.Z.I.;
Yin, I.X.; Yu, O.Y.; Lung, C.Y.K.; Chu,
C.H. Application of Copper
Nanoparticles in Dentistry.
Nanomaterials 2022,12, 805.
https://doi.org/10.3390/
nano12050805
Academic Editors: Krasimir Vasilev
and Takuya Kitaoka
Received: 28 January 2022
Accepted: 25 February 2022
Published: 27 February 2022
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4.0/).
nanomaterials
Review
Application of Copper Nanoparticles in Dentistry
Veena Wenqing Xu , Mohammed Zahedul Islam Nizami * , Iris Xiaoxue Yin, Ollie Yiru Yu ,
Christie Ying Kei Lung and Chun Hung Chu
Faculty of Dentistry, University of Hong Kong, Hong Kong 999077, China; u3008489@connect.hku.hk (V.W.X.);
irisxyin@hku.hk (I.X.Y.); ollieyu@hku.hk (O.Y.Y.); yklung@graduate.hku.hk (C.Y.K.L.); chchu@hku.hk (C.H.C.)
*Correspondence: nizami01@hku.hk
Abstract:
Nanoparticles based on metal and metallic oxides have become a novel trend for dental
applications. Metal nanoparticles are commonly used in dentistry for their exclusive shape-dependent
properties, including their variable nano-sizes and forms, unique distribution, and large surface-area-
to-volume ratio. These properties enhance the bio-physio-chemical functionalization, antimicrobial
activity, and biocompatibility of the nanoparticles. Copper is an earth-abundant inexpensive metal,
and its nanoparticle synthesis is cost effective. Copper nanoparticles readily intermix and bind with
other metals, ceramics, and polymers, and they exhibit physiochemical stability in the compounds.
Hence, copper nanoparticles are among the commonly used metal nanoparticles in dentistry. Copper
nanoparticles have been used to enhance the physical and chemical properties of various dental
materials, such as dental amalgam, restorative cements, adhesives, resins, endodontic-irrigation
solutions, obturation materials, dental implants, and orthodontic archwires and brackets. The
objective of this review is to provide an overview of copper nanoparticles and their applications
in dentistry.
Keywords: copper nanoparticles; antimicrobial; dentistry
1. Introduction
Copper is a popular element in medical and dental research due to its antimicrobial
properties and low toxicity [
1
,
2
]. The antimicrobial activities are induced by either copper’s
metal ions or the oxidized cupric ions derived from copper nanoparticles (1–100 nm).
Moreover, copper is readily available for the synthesis of copper nanoparticles, so it is
cost effective [
3
]. Copper nanoparticles can be processed either naturally or via chemical
synthesis [
4
–
7
]. In addition, they can easily oxidize in air or water and produce copper oxide
nanoparticles. Like most metal nanoparticles that are commonly used in dentistry, copper
particles have variable nano-sizes and forms, a unique distribution, and a large surface-
area-to-volume ratio. These properties enhance the bio-physio-chemical functionalization,
antimicrobial activity, and biocompatibility of the nanoparticles. Reports have shown
that copper oxide nanoparticles are antimicrobial and inhibit biofilm formation [
8
,
9
]. The
high surface-area-to-volume ratio of copper nanoparticles enhances their antimicrobial
ability [
10
]. These nanoparticles’ antibacterial activities have been widely investigated,
although the exact mechanism of copper nanoparticles against microbes is not
clear [11–13]
.
Copper nanoparticles have demonstrated higher bactericidal activity against E. coli, B.
subtilis, and S. aureus compared with silver nanoparticles, which are one of the nanoparticles
commonly used nanoparticles in biomedical research [14,15].
Researchers want to develop dental materials that have antimicrobial properties to
prevent oral infection. Copper nanoparticles exhibit antimicrobial activities and other
metallic properties associated with dental applications. Preparing these nanoparticle
composites with existing dental materials is easy and is said to be physiochemically stable.
Still, they have a very limited clinical application. In dentistry, copper nanoparticles
have mostly been studied as a modifier in amalgam and antimicrobial agents. Recently,
Nanomaterials 2022,12, 805. https://doi.org/10.3390/nano12050805 https://www.mdpi.com/journal/nanomaterials

Nanomaterials 2022,12, 805 2 of 15
several dental materials were studied with regard to copper nanoparticles, and it was
reported that copper nanoparticles can be added to dental cements, restorative materials,
adhesives, resins, irrigating solutions, obturations, orthodontic archwires and brackets,
implant surface coatings, and the bone regeneration process [
15
–
20
]. The results were
impressive but a bit ambiguous for clinical applications.
A search in PubMed using ((copper nanoparticles) AND (dentistry OR dental)) found
no relevant review articles. The aim of this review is to highlight the research directions,
their outcomes, and the feasibility of future studies. Therefore, we performed a systematic
search of the publications in English and included the maximum number of works in the
literature. We searched three common databases, namely, EMBASE, Google Scholar, and
MEDLINE. In the search, the keywords were (copper OR (copper nanoparticles) OR (copper
nanocomposite)) AND (dentistry OR (dental material)). These keywords covered as much
information about copper nanoparticles in dentistry as possible without overlooking related
research. This review includes all publications on the application of copper nanoparticles
in dentistry. Abstracts, editorials, and letters to the editor were excluded. Among the
vast number of articles reviewed, we have summarized the dental materials with copper
nanoparticles into four main categories. They are metals and alloys, polymers and resins,
restorative cements, and miscellaneous dental materials.
2. Antibacterial Mechanism of Copper Nanoparticles
Copper is a well-established antimicrobial and anti-inflammatory agent with a long
history of medicinal applications [
21
,
22
]. The nano-sized particles and high surface-area-to-
volume ratio allow copper nanoparticles to exhibit broad-spectrum antibacterial and antivi-
ral activities [
12
]. Copper nanoparticles may have a similar mode of action as other metal
nanoparticles. Although several studies have shown that copper-nanoparticle-containing
materials demonstrate antibacterial activity and biocompatibility, related antibacterial
mechanisms are not inclusive [
23
]. A few studies were conducted in an attempt to ex-
plore the antibacterial mechanism of copper nanoparticles. Mainly, three hypothetical
mechanisms were commonly described. First, copper nanoparticles accumulate in the
bacterial membrane and change its permeability. They then remove membrane proteins,
lipopolysaccharides, and intracellular biomolecules and cause the dissipation of the proton-
motive energy around the plasma membrane [
24
–
26
]. Second, reactive oxygen species
from nanoparticles (in the form of nanoparticles or ions) process post-oxidative dam-
age in cellular structures [
27
–
30
]. Third, cells’ uptake of ions (generated via nanoparti-
cles) decreases intracellular adenosine triphosphate production and deoxyribonucleic acid
(DNA) replication [31–34].
Studies demonstrated that the carboxyl group of bacterial lipoproteins has a negative
charge that attracts positive copper ions. After binding with copper ions, bacterial cell
membranes and their permeability change, and copper ions enter the cells. When they
merge with phosphorus- and sulfur-containing biomolecules (i.e., DNA), the copper ions
alter the cell structures and cell proteins. This alteration inhibits the cell’s biochemical
processes and causes cell death [
35
,
36
]. However, copper ions inhibit enzymatic activity.
They alter DNA or protein synthesis, inactivate their enzymes, and promote hydrogen
peroxide production [
37
]. In addition, nanoparticles denature protein molecules by inter-
acting with their sulfhydryl group [
37
]. At the same time, DNA, ribonucleic acid, proteins,
and cytoplasm leak out through the permeable membrane, causing cell damage that kills
bacteria [38]
. Furthermore, several other hypotheses of possible modes of copper nanopar-
ticle and bacterial interaction exist, such as the permeabilization of the plasma membrane,
the peroxidation of membrane lipids, changes in proteins, the inhibition of protein assem-
bly and activity, and the deformation of nucleic acids [
39
]. In most cases, all of these are
directed in the same way. We believe that further
in vitro
and
in vivo
studies should be
conducted to produce a systematic outline [40].
Many studies investigated copper nanoparticles’ antibacterial activities. However, few
studies reported their antiviral action. They demonstrated that copper nanoparticles target

Nanomaterials 2022,12, 805 3 of 15
the viral genome, especially encoding the genes responsible for viral infections [
21
,
41
].
In addition, some studies showed a similar reactive oxygen species process in the viral
envelope or capsid, which resembles antibacterial activity [
21
]. Viruses are more vulnerable
to injuries induced by copper nanoparticles because, unlike bacteria and fungi, they do
not have a repair mechanism. This leads to instant cell death [
39
]. Processes that cause
the immediate inactivation of microbes upon contact are known as “contact killing” [
42
].
In many studies, researchers have taken advantage of this “contact killing” property and
have created copper-nanoparticle-functionalized antiviral surfaces. Copper nanoparticles
are co-integrated into surface research to increase “contact killing”, as well as to develop
antibacterial and antiviral combination effects [
43
]. Figure 1demonstrates the mechanism
of copper nanoparticles’ antibacterial activities in bacterial cells.
Nanomaterials 2022, 12, x FOR PEER REVIEW 3 of 14
Many studies investigated copper nanoparticles’ antibacterial activities. However,
few studies reported their antiviral action. They demonstrated that copper nanoparticles
target the viral genome, especially encoding the genes responsible for viral infections
[21,41]. In addition, some studies showed a similar reactive oxygen species process in the
viral envelope or capsid, which resembles antibacterial activity [21]. Viruses are more vul-
nerable to injuries induced by copper nanoparticles because, unlike bacteria and fungi,
they do not have a repair mechanism. This leads to instant cell death [39]. Processes that
cause the immediate inactivation of microbes upon contact are known as “contact killing”
[42]. In many studies, researchers have taken advantage of this “contact killing” property
and have created copper-nanoparticle-functionalized antiviral surfaces. Copper nanopar-
ticles are co-integrated into surface research to increase “contact killing”, as well as to
develop antibacterial and antiviral combination effects [43]. Figure 1 demonstrates the
mechanism of copper nanoparticles’ antibacterial activities in bacterial cells.
Figure 1. Antibacterial mechanism of copper nanoparticles.
1. Attach to the cell wall and release copper ions.
2. Adhere to the cell membrane and enter the cell.
3. Disrupt the cell wall and membrane, denature protein, interrupt enzymatic activity, interrupt
deoxyribonucleic acid (DNA) replication, and interrupt adenosine triphosphate (ATP) produc-
tion.
4. Generate reactive oxygen species. Reactive oxygen species further interrupt DNA replication and
initiate the breakdown of DNA, denature ribosomes, and denature protein.
3. Copper Nanoparticles in Dental Materials
Copper nanoparticles present antimicrobial and bio-physio-chemical properties.
They enrich the material pool to minimize the shortage of dental materials in various clin-
ical applications. Generally, copper nanoparticles are used in dental metals and alloys,
dental polymers and resins, dental cements, and miscellaneous dental materials (Table 1).
Figure 1. Antibacterial mechanism of copper nanoparticles.
1. Attach to the cell wall and release copper ions.
2. Adhere to the cell membrane and enter the cell.
3.
Disrupt the cell wall and membrane, denature protein, interrupt enzymatic activity,
interrupt deoxyribonucleic acid (DNA) replication, and interrupt adenosine triphos-
phate (ATP) production.
4.
Generate reactive oxygen species. Reactive oxygen species further interrupt DNA
replication and initiate the breakdown of DNA, denature ribosomes, and
denature protein
.
3. Copper Nanoparticles in Dental Materials
Copper nanoparticles present antimicrobial and bio-physio-chemical properties. They
enrich the material pool to minimize the shortage of dental materials in various clinical
applications. Generally, copper nanoparticles are used in dental metals and alloys, dental
polymers and resins, dental cements, and miscellaneous dental materials (Table 1).

Nanomaterials 2022,12, 805 4 of 15
Table 1. Properties, applications, and functions of dental materials with copper nanoparticles.
Materials [Reference(s)] Properties Applications Functions
Dental metals and alloys
Copper-coated metal [44,45] Offer antimicrobial properties Denture framework Prevent stomatitis
Copper amalgam alloy [46–49]Improve microstructural
Improve mechanical properties Amalgam restoration Prevent corrosion
Copper-linked alloy [50–56] Offer antimicrobial properties Dental implant Prevent implantitis
Magnesium–copper alloy [57,58] Offer antimicrobial properties Dental implant Prevent implantitis
Titanium–copper alloy [57–71] Offer antimicrobial properties Dental implant Prevent implantitis
Titanium–hydroxyapatite–copper
alloy [72]Offer antimicrobial properties Dental Implant Prevent implantitis
Nickel–titanium–copper alloy
[73–79]
Enhance mechanical properties
Enhance thermal properties
Prevent galvanic corrosion
Reduce alloy aging
Orthodontic bracket
Orthodontic archwire
Facilitate orthodontic
tooth movement
Dental polymers and resins
Copper-nanoparticle-incorporated
acrylic resin [80]Offer antimicrobial properties Denture soft liner Prevent stomatitis
Copper-doped mesoporous
bioactive glass nanosphere acrylic
resin [81]
Facilitate copper-ion release
Offer antimicrobial properties Denture acrylic base Prevent stomatitis
Copper nanoparticles with
adhesive resin [82]Offer antimicrobial properties Dental adhesive Prevent secondary caries
Polyacrylic acid–copper iodide
nanoparticles with adhesive resin [83]Offer antimicrobial properties Dental adhesive Prevent secondary caries
Dental Cements
Copper [84–86] Offer antimicrobial properties Lining materials Prevent secondary caries
Copper(I)-catalysed azide-alkyne
cycloaddition composites [87]Reduce shrinkage stress Composite resin
restoration Prevent secondary caries
Copper nanoparticles incorporated in
glass ionomer cement [88]Offer antimicrobial properties Glass ionomer
restoration Prevent secondary caries
Copper ions releasing blue calcium
phosphate cement [89]
Offer antimicrobial properties
Improve cytocompatibility
Regenerative dental
material Promote bone formation
Functionalized copper phosphate
nanoparticles [90,91]
Increase vascularization
Enhance bone regeneration
Regenerative dental
material Promote bone formation
Copper-modified zinc oxide
phosphate [92]Reduce marginal gap Luting cement Prevent secondary caries
Miscellaneousdental materials
Copper nanoparticles [93–102]Enhance anti-inflammatory
effects Periodontal therapy Prevent inflammation
Copper-based substance [103–107] Offer antimicrobial properties Endodontic irrigation solution
Endodontic paste Prevent apical reinfection
Nano copper-nonstoichiometric
dicalcium silicate [108]
Offer antimicrobial properties
Facilitate tissue regeneration Regenerative dental material Promote bone formation
Copper-doped biphasic calcium
phosphate [109,110]
Improve bone regeneration
Act as a bone substitution Synthetic bone graft material Promote bone formation
Graphene oxide copper
nanocomposite [111]Enhance bone regeneration Regenerative dental material Promote bone formation
3.1. Copper Nanoparticles in Dental Metals and Alloys
Prosthesis-induced inflammatory diseases, such as stomatitis and peri-implantitis,
pose challenges in clinical dentistry. Several strategies have been applied to solve these
problems. However, no specific solution has yet been found. Copper nanoparticles may
play a role in controlling infections. Copper nanoparticles destroy genomic and plasmid
DNA, making them an ideal alternative to antimicrobial surface coatings [
44
]. In addi-
tion, copper nanoparticles’ “contact killing” ability may also be well considered. Copper-

Nanomaterials 2022,12, 805 5 of 15
nanoparticle-incorporated removable and fixed partial denture framework designs could
solve denture-induced stomatitis and oral infections [45].
Dental amalgam restoration occupies a unique position in dentistry. These amalgam
alloys are broadly known as low-copper (5% or less copper) and high-copper alloys (13%
to 30% copper). A study reported that through the increasing of their copper density,
conventional dental amalgam alloys improved their microstructural and mechanical prop-
erties. Reports have also revealed the disappearance of the gamma-2 phase in copper
content with more than 20 wt% [
46
]. High-copper amalgams remain the leading materials
in Europe, America, and other advanced markets. A report stated that non-gamma-2
amalgams had superior strength and corrosion resistance properties [
47
]. In addition,
high-copper amalgam alloys showed less marginal deterioration in clinical studies, result-
ing in durable restorations [
48
]. Studies revealed that through the increasing of copper
nanoparticles in amalgam, the gamma-2 phase can be eliminated to increase the amalgam’s
compressive strength [49].
Implant dentistry has always faced the problem of peri-implantitis. Microbial infection
is one of the most common postoperative complications of implant surgery to be resolved.
It is a complex situation, and, apparently, eliminating its occurrence is the only way to
overcome it. However, it is generally impossible to stop the incidence completely. The ad-
vanced biomaterial research confirmed that biofilm formation on the implant surface is the
main cause, and it leads to the serious consequences of implant-related
infections [112,113]
.
In recent decades, studies focused on developing new implant materials or applying var-
ious coatings on existing implants using nanoparticles to inhibit biofilm formation and
to prevent biofilm-related infections. Some studies involved applying antibiotic surface
coatings to metal implants to develop prolonged antimicrobial action [114,115]. However,
this process was not successful due to the unstable bond between the surface coatings
and implants, as well as the risk of antibiotic resistance due to the continuous release of
antibiotics in the body [
116
,
117
]. Many researchers have used copper nanoparticles for the
surface modification of metallic implants [118,119].
Nisshin Steel (Tokyo, Japan) made the first copper-linked antimicrobial stainless steel
for biomedical applications [
113
]. Several studies have reported using copper nanoparticles
as an antimicrobial surface coating on different types of medical-grade stainless steel, such
as 317L stainless steel [
23
,
50
–
53
,
113
], 316L stainless steel [
23
,
54
], 304 stainless steel [
55
],
and 420-copper stainless steel [
56
]. Some studies have reported using copper nanoparticles
for the development of a magnesium–copper alloy as an implant material [57,58]. Several
studies have also reported using copper nanoparticles for the surface modification of
titanium implants [
57
–
63
]. Moreover, some studies have shown that the titanium–copper
alloy exhibits antibacterial and anti-aging properties. The studies have also demonstrated
that these antimicrobial properties could be tuned via changing the copper concentration
of the alloy composition [
64
–
66
]. Another study stated that copper-containing mesoporous
bio-glass reduced bacterial activity and biofilm formation by releasing copper ions [
67
–
69
].
A study reported that copper nanoparticles coating dental implant healing caps in-
hibited bacteria and biofilm formation [
70
]. On the other hand, another report showed
that a copper-bearing titanium alloy implant exhibited anti-infective properties against
oral bacteria. They also demonstrated that a titanium–copper alloy not only inhibited
peri-implant infections but also possessed biocompatibility [
71
]. Copper-nanoparticle
hydroxyapatite is antibacterial. A study reported that a titanium–copper alloy and a
titanium-copper ion-doped hydroxyapatite inhibited oral bacteria [
72
]. A Titanium-copper
alloy reduced the formation of biofilms to prevent implant failure. It was also effective
against implantitis-associated oral bacterial species. Therefore, the study recommended
using a titanium–copper alloy as an alternative for dental implants [
61
]. These are still in
the laboratory stage, and, therefore, further clinical studies should be aimed at validating
the application of copper-nanoparticle-functionalized implants in clinical implant dentistry.
The inclusion of copper nanoparticles in a nickel–titanium alloy offers several benefits
in orthodontic appliances. Copper nanoparticles in archwire reduced loading stress and pro-

Nanomaterials 2022,12, 805 6 of 15
vided a relatively high unloading stress, which increased orthodontic tooth movement and
was explained as a lower stress hysteresis [
73
,
74
]. A study demonstrated that the addition
of copper nanoparticles to metallic orthodontic appliances developed clinical significance
in terms of hyperelasticity, conversion temperature, and load cycling behavior [
73
]. Studies
have furthermore reported that the presence of copper nanoparticles in the nickel–titanium
orthodontic archwire reduced the aging effect and galvanic corrosion [73,75].
Studies showed that copper–nickel–titanium wires improved mechanical and thermal
properties [
76
,
77
]. The addition of copper nanoparticles increased friction under both wet
and dry conditions [
78
]. Furthermore, a clinical study compared copper–nickel–titanium
archwire and nickel–titanium archwire for correcting mandibular incisor crowding and
found no impact on the correction of the crowding [
79
]. Another study found that the
benefits of the loading pattern of the copper–nickel–titanium wire obtained from the
laboratory were not reflected in the clinical settings. Therefore, further investigations were
suggested to ensure and control these wires’ clinical performance in orthodontic practice.
3.2. Copper Nanoparticles in Dental Polymers and Resins
A heat-cured thermoset denture base with copper oxide nanoparticles is effective to
inhibit the growth of C. albicans, which is mainly responsible for denture stomatitis [
120
].
Moreover, another study found that copper oxide nanoparticles released ions while they
were incorporated into different resin formulations (i.e., heat-cured acrylic resin denture,
chemically cured soft liner, and cream-type adhesive). This ion release could be controlled
and utilized in therapeutic drug delivery for the treatment of oral diseases. However, the re-
lease of these ions may vary. A study showed that the denture base and adhesive had higher
releases compared with the denture liner [
80
]. Researchers may explore the controlled and
optimum therapeutic release of copper ions for an optimum clinical outcome. A study re-
ported copper-doped mesoporous bioactive glass nanosphere-incorporated resin exhibited
antimicrobial properties, mechanical properties, and a better aging resistance effect [
81
]. An
etch-and-rinse adhesive with copper nanoparticles appeared to have antimicrobial activity
and prevented the degradation of the adhesive interface without altering the mechanical
properties [
82
]. Polyacrylic acid-coated copper iodide nanoparticles in another study acted
as an antibacterial additive to adhesive, and their bonding strength or biocompatibility was
not affected [
83
]. Another study showed that copper nanoparticles added to an adhesive
improved the shear bond strength and antibacterial properties without cytotoxicity [121].
3.3. Copper Nanoparticles in Dental Cements
Several
in vitro
studies showed that copper cements developed compressive strength,
solubility, and antibacterial activity, and they were recommended for use as cariostatic
lining under a less soluble restorative material [
84
–
86
]. Some studies also revealed that
copper in restorative materials reduced microorganisms’ growth and viability [
122
] and
improved the bond on the teeth interface [
123
]. Moreover, fluoridated amalgam demon-
strated better caries prevention in both primary and secondary caries adjacent to the
restoration [
124
]. A study reported photo-polymerized copper(I)-catalyzed azide-alkyne
cycloaddition composites to be mechanically strong and highly tough materials. In addition,
they reduced shrinkage stress and generated a modest exothermic reaction [
87
]. Another
study showed that copper nanoparticles added to a commercial glass ionomer developed
antibacterial activity against oral strains [
88
]. On the other hand, blue calcium phosphate
cement with copper ions in another study showed a synergized dual antibacterial effect
and cytocompatibility [
89
]. Many studies have shown that calcium phosphate cement
with copper phosphate nanoparticles could promote vascularized new bone formation
around cancerous bone defects [
90
,
91
]. On the other hand, a copper-modified zinc oxide
phosphate cement showed low surface allocations of copper but no improvement in its
antimicrobial properties [
92
]. Therefore, with this limited study, it is difficult to justify the
clinical application. In light of this, the optimization of copper use in restorative materials

Nanomaterials 2022,12, 805 7 of 15
for clinical applications should be investigated further in relation to the various strains
associated with prosthesis-induced oral infection.
3.4. Copper Nanoparticles in Miscellaneous Dental Materials
Copper is the third-most abundant trace element in the human body [
125
,
126
]. Some
reports stated that the lack of copper had a negative influence on immune cells (i.e.,
neutrophils, macrophages, T cells, and natural killer cells), decreased interleukin-2 produc-
tion, and alternately enhanced proinflammatory cytokine production (e.g., tumor necrosis
factor-
α
, and matrix metalloproteinase-2 and -9), which degraded the collagen and ex-
tracellular matrix components in the periodontal ligament [
93
]. Because copper acts as
a cofactor for metalloenzyme (i.e., superoxide dismutase), which is an essential antioxi-
dant for chronic periodontitis, an optimal level of copper is essential for the prevention of
inflammatory passages [93].
Copper is essential for the development of connective tissue. The elevation of serum
copper has reflected the changes occurring in the periodontal collagen metabolism of
periodontitis patients [
94
]. A study reported an improvement in chronic periodontitis
in diabetic and non-diabetic patients using increased copper ions levels at baseline for
nonsurgical periodontal therapy [
95
]. Several studies have also reported increased copper
ion levels in patients suffering from chronic and aggressive periodontitis, as well as in acute
and chronic gingivitis [
96
–
98
]. A study reported a link between the salivary copper ion
level and periodontitis [
99
]. However, the exact mechanism of the increase in copper in the
plasma and its association with periodontal disease is still unclear and needs to be identified.
Some studies showed the therapeutic application of copper nanoparticles for periodontal
therapy. They demonstrated that copper-nanoparticle-based antimicrobial ions inhibited
bacterial growth. They also observed the controlled and sustained release of bactericidal
copper concentrations for localized periodontal therapy [
100
]. Furthermore, some studies
used copper-nanoparticle-containing composite materials for periodontal therapy. They
used a sodium copper chlorophyllin solution to reduce the production of volatile sulfur
compounds by inhibiting the periodontal anaerobes associated with malodour, and they
recommended using it to improve oral and periodontal health [101].
Another study used copper-calcium hydroxide nanoparticles for treating apical pe-
riodontitis in an endodontically treated tooth, and it recommended using them to treat
periodontitis [
102
]. Researchers have used several copper nanoparticle formulations for
periodontal therapy. However, these nanoparticle formulations are still limited in labora-
tory research, and their effects in clinical applications remain unclear. Further dedicated
research may improve the use of copper nanoparticles in antimicrobial, anti-inflammatory,
and regenerative periodontal therapy.
Endodontic treatment mostly fails due to microbial infections. The inadequate disin-
fection of root canals is a main cause of post-treatment reinfection [
127
]. Studies showed
that bacteria can survive inside the root canal after a careful chemo-mechanical prepara-
tion [
128
]. Copper nanoparticles, due to their ionic compounds, have demonstrated the
potential to produce and capture electrons, as well as to generate radical oxygen species.
These particles have led to toxic hydroxyl radical production and constitute an antimi-
crobial agent in endodontic treatment [
103
,
104
]. On the other hand, copper nanowires
have shown excellent antimicrobial effects against the oral microbes associated with the en-
dodontic systems, so it is suggested that they be considered for root canal disinfection [
105
].
Moreover, a study explained the antibacterial effect of copper sulfate nanoparticles and
proposed further clinical trials for clinical settings [
106
]. Biofilm is resistant to common
intracanal irrigation, antimicrobial drugs, and the host immune response. A study reported
that in such cases, copper hydroxide nanoparticle–based endodontic paste can reduce the
growth and replication time of root canal system–associated oral microbes, which affects the
formation and persistence of biofilm. The researchers suggested using copper hydroxide
nanoparticle–based endodontic paste for the prevention and treatment of biofilm-associated
endodontic infections [107].

Nanomaterials 2022,12, 805 8 of 15
With the progress of multifunctional biomaterials in bone grafting, the possibility
of osteogenesis and angiogenesis has attracted attention in bone and tissue regeneration
research. Inspired by the antibacterial activity of copper ions, a study reported develop-
ing a copper-nanoparticle-based nonstoichiometric dicalcium silicate for infectious bone
repair [
108
]. Another study reported that a copper-doped biphasic calcium phosphate
powder that was made of hydroxyapatite and
β
-tricalcium phosphate powder exhibited
antibacterial activity. In addition, they reported that it had good adherence to bone marrow
cells and maintained good cell viability. Therefore, they recommended it as a promising bio-
ceramic for bone substitution and/or prosthesis coatings [
109
,
110
]. A study reported using
graphene oxide copper nanocomposites for bone regeneration and revealed vascularized
new bone formation [
111
]. Although studies are limited in this field, they are promising.
Clinical studies using copper nanoparticles in various tissue engineering strategies may
result in a new direction of regenerative biomaterials.
4. Biocompatibility Studies of Copper Nanoparticles
The biocompatibility of nanoparticles is an important concern these days. The rapid
growth of nanotechnology is rampant in every research field, including biomedical research.
However, to date, no authentic information exists on the inferences of nanoparticles on
human health [
129
]. Copper is a necessary trace element, and its deficiency is conducive to
various diseases in humans. In addition, it acts as a catalyst cofactor in some redox enzymes
that are essential for broad-spectrum metabolic processes. On the other hand, if the copper
intake exceeds the tolerable limit, it shows toxic effects that lead to cell death [
130
]. Despite
the great potential of the biomedical application of copper nanoparticles, toxicity studies of
these nanoparticles are mostly confined to in vitro studies.
Copper nanoparticles have shown toxic effects on several cell lines [
131
–
137
]. Several
in vitro
studies have been conducted. However, only a few studies reported the
in vivo
toxicity of copper nanoparticles [
138
–
141
]. No information was provided on the bioavail-
ability and excretion data of long-term exposure to copper nanoparticles. Future research is
needed to provide a detailed and systematic overview of both the
in vitro
and the
in vivo
toxicity of copper nanoparticles, as well as their kinetics. Recently, the preliminary inves-
tigation of the biocompatibility of copper nanoparticles showed that they have toxicity
in both humans and the environment [
141
,
142
]. Even though copper is sustained in the
homeostasis of the human body, excess copper showed toxic effects on the kidney and
liver [
142
,
143
]. Although the possible risks of copper nanoparticles have been identified in
human health, their subacute toxicity has not yet been defined.
Copper nanoparticles that are 23.5 nm in size are considered to be class 3 medium toxic
materials, with an LD50 value of 413 mg/kg of body weight. Copper nanoparticles’ toxicity
is related to their ionization [
138
]. Copper nanoparticles lead to ultra-high reactiveness
due to their large surface and active functional ions. They react with hydrogen ions in the
gastric juice and produce a large amount of hydrogen carbonate, and their excretion leads
to kidney disorders. In addition, a study showed that the toxicity of copper nanoparticles
depends on gender. Male mice showed more severe toxic symptoms than females after
being exposed to the same mass of nanoparticles [138]. Another study also identified that
the increased production of reactive oxygen species and reactive nitrogen species plays an
important role in copper nanoparticle-induced organ impairment [144].
The interaction and impact of nanoparticles on cells and tissues have been explained
differently based on their distribution, particle size, and penetration capacity. Studies have
also reported that the variation of the effects depends on the different synthesis methods
of nanoparticles [
145
]. Therefore, with this limited study, it is difficult to bring a gross
scenario. The effect and involvement of nanoparticles should be clearly defined. Thus,
detailed studies focusing on their toxicity, bioavailability, kinetics, and biodistribution
in different organs, including the liver, brain, lung, heart, and spleen, should be further
investigated. Although, some studies described the potentials of copper and other metallic
nanoparticles in specific or different aspects of dental applications, the biosafety was not

Nanomaterials 2022,12, 805 9 of 15
clearly identified [
146
–
148
]. At the same time, the synthesis, the morphological and physic-
ochemical properties of copper nanoparticles, and these properties’ impacts also need to be
explored. Hence, concrete information regarding copper nanoparticles’ biocompatibility
will be in the frame for their future applications.
5. Conclusions
Copper nanoparticles play a dual role in the development of the properties of dental
materials. The inclusion of copper nanoparticles may improve the physio-mechanical
properties and introduce or enhance the antimicrobial activities of various dental materials.
It is expected that researchers and clinicians will focus on the perspective of cost-effective
copper nanoparticles in dentistry. This will reveal potentials and limitations, as well as
open a new door to dental biomaterials research for the use of copper nanoparticles in
clinical dental practice.
Author Contributions:
V.W.X. and M.Z.I.N. equally conceived the conceptual design, interpretation,
and writing—original draft preparation; I.X.Y. and C.Y.K.L. critically commented; and M.Z.I.N.,
O.Y.Y., and C.H.C. revised the draft. All authors have read and agreed to the published version of
the manuscript.
Funding:
This review was funded by the National Natural Science Foundation of China (NSFC)
General Program 81870812.
Conflicts of Interest: The authors declare no conflict of interest.
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