Nanomaterials 10 00140 v3

nanomaterials
Review
Nanoparticles as Anti-Microbial, Anti-Inflammatory,
and Remineralizing Agents in Oral Care Cosmetics: A
Review of the Current Situation
Florence Carrouel 1, * , Stephane Viennot 1 , Livia Ottolenghi 2 , Cedric Gaillard 3 and
Denis Bourgeois 1
1 Laboratory “Systemic Health Care”, University of Lyon, University Claude Bernard Lyon 1, EA4129,
69008 Lyon, France; [email protected] (S.V.); [email protected] (D.B.)
2 Department of Oral and Maxillo-facial Sciences, Sapienza University of Rome, 00185 Rome, Italy;
[email protected]
3 Institut national de Recherche en Agriculture, Alimentation et Environnement (INRAE), Unité de Recherche
1268 Biopolymères Interactions Assemblages (BIA), 44316 Nantes, France; [email protected]
* Correspondence: [email protected]; Tel.: +33-4-78-78-57-44

Received: 6 December 2019; Accepted: 10 January 2020; Published: 13 January 2020
Abstract: Many investigations have pointed out widespread use of medical nanosystems in various
domains of dentistry such as prevention, prognosis, care, tissue regeneration, and restoration.
The progress of oral medicine nanosystems for individual prophylaxis is significant for ensuring
bacterial symbiosis and high-quality oral health. Nanomaterials in oral cosmetics are used in
toothpaste and other mouthwash to improve oral healthcare performance. These processes cover
nanoparticles and nanoparticle-based materials, especially domains of application related to biofilm
management in cariology and periodontology. Likewise, nanoparticles have been integrated in
diverse cosmetic produces for the care of enamel remineralization and dental hypersensitivity. This
review summarizes the indications and applications of several widely employed nanoparticles in
oral cosmetics, and describes the potential clinical implementation of nanoparticles as anti-microbial,
anti-inflammatory, and remineralizing agents in the prevention of dental caries, hypersensitivity,
and periodontitis.
Keywords: nanoparticles; oral cosmetics; toothpaste; mouthwash; biofilm; caries; periodontology;

hypersensitivity
1. Introduction
A nanomaterial is defined as “an insoluble or biopersistant and intentionally manufactured
material with one or more external dimensions, or an internal structure, on the scale from 1 nm to
100 nm” [1]. To date, nanotechnologies and nanomaterials have been extensively employed and
the potential for growth in nanomedicine appears significant. Three principal fields of application
are particularly targeted: diagnosis, drug administration, and regenerative medicine [2]. The main
domains of nanoparticles in the field of dentistry globally may involve the teeth-whitening, polishing
pastes for the enamel surface, dental implant coatings, dental filling, antisensitivity agents, and the
prevention of caries [3,4].
One sector is particularly relevant to consumers: cosmetics, much of which is based on
nanoparticles (NP). Cosmetics is specified as whatever substance or preparation is planned to be in
contact with external parts of the human body or with mucous membranes and teeth of the buccal
cavity with a view, principally or exclusively, to changing their appearance, cleaning them, flavoring
them, balancing body odors, keeping them or preserving them in a healthy condition [5].
Nanomaterials 2020, 10, 140; doi:10.3390/nano10010140 www.mdpi.com/journal/nanomaterials

Nanomaterials 2020, 10, 140 2 of 32
Toothpaste is a cosmetic hygiene product requiring daily use. In the oral care market, toothpaste
is the biggest part. The toothpaste market was estimated in 2018 to be worth USD 26.1 billion, and it is
predicted to reach USD 37.0 billion by 2024 [6]. Various forms of toothpaste, such as pastes, powder,
and gels, give more choice to consumers, thus propelling demand [7]. High product usage across
all age groups and income is the prime element driving this segment. The use of cosmetic products
containing nano-objects, such as dentifrices containing titanium dioxide NPs, is commonly used in
periodontal health.
Mouthwash is expected to show profitable growth in the coming years because of the growing
professional recognition of biofilm disorganization, and their increasing use by consumers linked
to oral quality of life. The provision of flavored mouthwash associated with components labeled
as natural should increase demand. The persistence of oral disorders such as periodontal disease,
interdental bleeding, halitosis, and gingivitis, as well as the management of older people’s prostheses,
should also contribute to the demand for medicated and non-medicated mouthwash.
It is rational to question the progress made by these NPs compared to existing technologies as
well as the interest in the massive use of NPs in recent years in oral health cosmetic products. Some
properties of nanoscale objects can confer specific behaviors, amplifying, in some cases, their chemical
reactivity, their electronic or magnetic behavior, or their potential for penetration of living organisms.
The knowledge and practices of nanotechnology in the field of oral hygiene products are progressing
due to the emergence of new technologies that contribute to the improvement of the quality of care
and broadening of the field of application of dentifrices and mouthwash.
In 2018, a catalog of all nanomaterials included in cosmetic products available on the market was
produced by the European Commission. The catalog listed both nanomaterials used as preservatives,
UV-filters, and colorants specifying reasonably predictable exposure conditions and the categories
of cosmetics [8]. Of the 29 nanomaterials listed in this catalog, 3 were identified as colorants, 4 as
UV-filters, and 22 as “other” functions, including oral hygiene products. These diverse nanomaterials
have a major impact in individual prophylaxis, the prevention of caries, and periodontitis, as well as
the quality of life of consumers.
A systematic literature search was conducted on three databases, namely PubMed, Web of
Science, and Scopus. Articles in these databases were searched using the keywords (“nanoparticle” OR
“nanomaterial” OR “nanotechnology”) AND (“nanoparticle” OR “nanomaterial” OR “nanotechnology”)
AND (“toothpaste” OR “dentifrice” OR “oral care” OR “mouthwash” OR “mouthrinse”) AND (“metal”
OR “metal oxide” OR “silver” OR “gold” OR “zinc” OR “titaniumdioxide” OR “copper oxide” OR
“chlorhexidine” OR “ferumoxytol” OR “Scutellaria baicalensis” OR “chitosan” OR “hydroxyapatite” OR
“Casein phosphopeptide–amorphous calcium phosphate” OR “bioactive glass”) AND (“anti-bacterial”
OR “anti-microbial” AND “anti-inflammatory” OR “remineralization”). The research timeframe was
from 2000 to December 2019. The selection procedure was performed by two reviewers, who evaluated
the titles and abstracts of the articles identified in the electronic databases.
Our article provides a synthesis of the progress made by nanomaterials and their use in the oral
hygiene market as anti-microbial and remineralizing agents in oral care cosmetics. It presents the
main current knowledge of the biological and physico-chemical effects of nanomaterials. However,
the health consequences of exposure to nanomaterials of cosmetic origin are not addressed. This
inventory is not intended to be a complete catalog, but wants to point out that nanotechnologies in
dental hygiene products touch a wide spectrum of applications, ranging from traditional toothpaste
and mouthwash through remineralizing, bactericidal, or bacteriostatic agents.
2. Properties and Structural Features of Nanosystems (Nanomaterials and Nanoparticles)

Nanosized systems are of a great interest mainly due to their exceptional surface-to-volume
ratio and following distinctive optical, physical, and chemical properties, and to their increased
bioavailability towards cells and tissues [9,10]. The nanosystems classically used in oral care cosmetics
can be globally classified regarding their composition and structure. Nanosystem composition can
be inorganic (metals, oxides, or calcium/phosphate (Ca/P) salts), organic (chitosan NPs) [11,12],
phosphatidylcholin/cholesterol liposomes [13], or inorganic–organic hybrids (silica NPs encapsulated
chlorhexidine (CHX); colloidal hexametaphosphate salt of CHX)). The nanostructured materials, often
called nanomaterials, are defined as solid systems with nanodomains embedded in a large, dense
matrix. Such structure must be distinguished from “free” NPs often synthesized as stable dispersed
colloids. Both are used in oral care cosmetics that include either dense materials such as toothpaste,
or liquid dispersed systems, such as mouthwash, for which ingredient stability during processing and
ageing is a key point. The vertebrate bone, which is well known for its exceptional biocompatibility
properties, is a perfect example of a natural nanostructured system with hydroxyapatite organized as
nanocrystals embedded in collagen fibrils [14]. Please note that all oral care applications have so far
been described, to our knowledge, by using only pure NPs, as they need an intermediate dense or liquid
system to keep them from aggregation that reduces the benefit of the nanosized effect. The relative
recent capacity to synthesize purified “free” NPs allows the design of new performing systems with
innovative physico-chemical and bifunctional properties, along with biocompatibility.
NP morphology and size distribution may also be key factors for innovative oral care applications,
as they are described as strategical parameters in other application fields dealing with nanometer-size
particles [15–18]. Indeed, the expected nanometer-size effect on NP properties is generally claimed to
be more efficient, since the size distribution is narrow, and the shape is homogeneous. Size distribution
and shapes are highly associated with synthetic routes and chemical compositions of the NPs. For a
unique NPs composition, various morphologies can be produced: nanospheres, nanorods, necklaces,
nanoprisms, nanostars, or nanowires for the most common ones. Transmission or scanning electron
microscopy, as well as scanning probe microscopy, are the tools of choice to analyze NPs following
synthesis. Also, dynamic light-scattering can be used to characterize the average particle diameter and
polydispersity index of aqueous NP dispersions.
The stability of NPs, from synthesis to sterilization, storage processes, and use in biological
environment, are also of interest regarding the availability to maintain nanosized distribution after
synthesis and purification steps [19–22]. For example, consecutively to their synthesis and stabilization
in a liquid environment, free drying or lyophilization, which is conventionally used to store NPs in
a dried state, is well known to enhance more or fewer aggregation-irreversible mechanisms [23–26].
Then, the in situ characterization of NPs in the final product may be of great interest, as well as
their characterization in the biological environment, where interaction takes place with the biological
substances (proteins, membrane phospholipids, solid minerals (tooth, done), ions, pH, enzymes, etc.).
Therefore, the relevant properties in the achieved products (toothpaste and mouthwash) are
dependent mainly on the nanosized dimension [3,4,12,27–34]. However, to our knowledge, no studies
have focused on NPs ageing or reorganization in relation to their stability in the oral care field. An
important aspect to keep in mind when surveying the clinical application of NPs is the ageing of
NPs between synthesis and their distribution in oral care products after incorporation within other
ingredients. The evolution of size distribution by ageing of NPs, and the consecutive variation of their
properties, is dependent on synthesis and purification protocols, as well as conditions of storage and
the process of incorporation in the liquids or pastes. A prospective exploration of this point may be
relevant for a complete understanding of the real impact of nanometer size of additive NPs on the final
oral care product.
3. Nanoparticles as Anti-Microbial and Anti-Inflammatory Agents in Oral Care Products

In 2017, oral disorders affected 3.47 billion people in the world and represented one of the three
most common causes of global diseases [35]. Among the oral diseases, the most prevalent were dental
caries and periodontitis. Together, they represent the most common infectious human disease in the
world [36].
Even if caries and periodontitis are multifactorial diseases, the main etiological factor is the
presence of pathogenic bacteria. These bacteria are organized within an extracellular matrix to form a
bacterial biofilm [37]. In the biofilm, the bacteria are assembled to form a barrier that resists antibiotics
and promotes chronic systemic infections [29,38]. Also, bacteria are 1000 times more resistant to
anti-microbial treatment than planktonic organisms [39]. Moreover, in biofilms, bacteria can escape the
immune system by producing superantigens [40].
To combat these bacterial infections, metal, metal oxide, and other NPs appear to be promising
alternatives due to their distinct physio-chemical properties (Table 1). Even if some materials have
a naturally anti-bacterial activity, their anti-bacterial activity is increased when their dimensions are
reduced to the nanometer regime. This is attributed to the physical structure of NPs and to the
increased surface-to-volume ratio that permits them to interact and penetrate bacteria [41].
Table 1. Classification of nanoparticles contained in oral care products according to their action.
Nanoparticles
Anti-microbial Anti-inflammatory Remineralizing
Oxide Oxide Hydroxyapatite
Silver Silver Casein phosphopeptide–amorphous Calcium phosphate
Gold Gold Tin chitosan
Tin/Fluor chitosan
Metal oxide Metal oxide
Bioactive glass
Zinc oxide Zinc oxide
Titanium dioxide Titanium dioxide
1. 常见希腊字体斜体
Copper oxide
Chlorhexidine 2. 字体颜色
Ferumoxytol
Scutellaria baicalensis
3. <mo>-<mo> 替换 <mo>−<mo>
Chitosan
Bioactive glass 4. . <sec> <title>references
5. Colspan=”2”
3.1. Nanoparticles of Metals or Metal Oxides
<sup>-</sup> <sup>–</sup> 替换 2212；
Several metal or metal oxide NPs, such as gold (Au) NPs, silver (Ag) NPs, zinc oxide (ZnO)
i.e.,dioxides
NPs, titanium e.g., (TiO2 ) NPs, copper oxide (CuO) NPs, and magnesium oxide (MgO) NPs, are
known to have anti-microbial activities against both Gram-positive and Gram-negative bacteria and/or
Invest.</source> to Investig.</source>
anti-inflammatory properties (Figure 1) [42].
Figure 1. Action of nanoparticles (NPs) contained in oral care products.

3.1.1. Anti-Microbial and Anti-Inflammatory Mechanism

To act as a anti-microbial agent, metal and metal oxide NPs must establish contact with
bacteria via Van der Waals forces [43], electrostatic interactions [44], hydrophobic interactions [45],
and receptor-ligands [46]. Then, the NPs pass through the bacterial membrane and organize
themselves along the metabolic pathway that modifies the structure and function of the cell membrane.
The interaction between NPs and bacterial components (enzymes, ribosomes, lysosomes, and DNA)
will then cause oxidative stress and heterogeneous alterations, modifying the permeability of the cell
membrane, disrupting the electrolyte balance, inhibiting certain enzymes, deactivating proteins and
modifying gene expression [38,47,48]. Metal and metal oxide NPs use three mechanisms of action:
metal ion release [49], oxidative stress [50], and non-oxidative mechanisms [51].
NPs act against bacteria mainly by producing reactive oxygen species (ROS) such as the hydroxyl
radical (OH), the superoxide radical (O− ), the hydrogen peroxide (H2 O2 ), and the singlet oxygen
(O2 ). In physiological conditions, the ROS are the product of oxygen metabolism and play a
major role in cell signaling and cellular homeostasis [52]. However, if an inequality between the
production and the elimination of ROS occurs, and if ROS are overproduced, then oxidative stress
is observed [53]. The oxidative stress can provoke peroxidation, alter proteins, inhibit enzymes,
and damage RNA/DNA [54,55]. The permeability of the bacterial membrane can be altered, which can
deteriorate cell membranes [47,56,57]. Silver NPs are able to form OH, whereas [55] Au, ZnO, and MgO
NPs generate H2 O2 , and TiO2 NPs form both OH and H2 O2 [55].
Metal oxide NPs progressively release metal ions when they are in an aqueous medium. These
metal ions can absorb cell membranes and then interact with functional groups (mercapto (-SH),
carboxyl (-COOH), and amino (-NH) groups) of nucleic acids and proteins. These interactions have
several consequences, including abnormal enzyme activities or modification of the structural cell,
modification of the physiological processes, and inhibition of microorganisms [58]. Polivkova and
colleagues demonstrated that silver nanowires prepared on polyethylene naphthalate released silver
ions in solution and also have anti-bacterial effects [59]. However, other studies suggested that the
main anti-microbial mechanism is not due to the release of metal ions by NPs, because metal ion
solutions only provoke weak anti-bacterial activity [60,61]. In fact, silver NP cores have been found to
preferentially interact in aqueous environments with various ligands to give oxidation, aggregation,
or precipitation states to get a higher thermodynamic stability [62]. Hussein-Al-Ali and colleagues
demonstrated that the interaction between superparamagnetic iron oxide and bacteria is mediated by
penetration through the cell membrane, and through perturbation of the transfer of transmembrane
electrons. Moreover, metal ions can be vectors for transporting anti-microbial substances [30].
Non-oxidative mechanisms can also explain the anti-microbial activity of NPs. Leung and
colleagues proved the anti-microbial activity of three types of MgO NPs against Escherichia coli
(E. coli) [51]. This anti-microbial activity was unrelated to oxidative stress. First, MgO NPs can damage
cell membranes because pores are observed in cell membranes but neither MgO NPs nor magnesium
ions were observed in microorganisms. Secondly, the intracellular ROS are low in quantity. Thirdly,
MgO NP treatment does not induce lipid peroxidation, because the levels of lipopolysaccharide or
phosphatidylethanolamine in the cell walls do not change significantly. Finally, intracellular protein
levels associated with ROS are not affected, but several protein-associated metabolic pathways (amino
acid, nucleotide, and carbohydrate metabolisms) are reduced. [51].
Several metal (silver, gold) and metal oxide (zinc oxide, titanium dioxide) NPs have
anti-inflammatory properties [63]. To act as anti-inflammatory molecules, NPs must enter the
cell through ion channels or pores. Depending on the size of the NPs, different cellular effects are
observed [64]. When small NPs are at higher concentrations, most cell vesicles can endocytose them.
Phagocytosis and macro-pinocytosis are achieved by macrophages and neutrophils [65]. In addition, if
NPs are coated with plasma protein, then the corona protein interacts with the cell-surface receptors of
macrophages or neutrophils [66]. The corona protein acts as a ligand for the M2 macrophage receptors.
The anti-inflammatory macrophages of M2, essential in the assimilation of NP, are then activated.
Finally, neutrophils organize extracellular traps (NETs) around NPs in response to exogenous stimuli
(foreign particles or pathogens) and endogenous stimuli (cholesterol or uric acid). The interaction with
pathogenic microorganisms and the response of inflammatory stimuli influences the formation of these
NETs. The formation of NETs is dependent on RIPK-3 (protein kinase 3) enzymes that interact with
receptors, as well as radicals of ROS [67].
3.1.2. Silver Nanoparticles

Several synthetic or natural routes have been developed to produce silver NPs [68–70]. To avoid
problems of toxicity during synthesis, biological methods are preferred. The use of bacteria, fungi,
and plants, which do not produce toxic substances in their synthesis are used [71–74]. Plants have
many advantages, as they need simple nutrients to grow and cover large surface areas, are economical,
and are simple to process for Ag NPs synthesis over a range of sizes [75]. In recent years, Ag NPs
have been synthesized from plants such as Terminalia mantaly extracts [70] or Musa acuminata colla
flower [76]. The green synthesis of Ag NPs have also been obtained from vegetables such as Ipomoea
batatas (sweet potato) [77] or from algae such as Botryococcus braunii [78].
Ag NPs are effective against Gram-positive and Gram-negative bacteria, and even against some
antibiotic-resistant strains, but also against viruses and fungi (Table 1) [79–82]. In vitro, Ag NPs have
an anti-microbial effect against Gram-negative bacteria such as Acinetobacter [83], Escherichia [84],
Pseudomonas [85], and Salmonella [86]. These NPs also act against Gram-positive bacteria such as
Bacillus [87], Enterococcus [88], Listeria [89], Staphylococcus [90], and Streptococcus [91]. The anti-bacterial
activity of Ag NPs is influenced by the size of the NP. The biocompatility and the stability increase with
decreasing size of Ag NP. The smaller Ag NPs have higher surface-area-to-volume ratio, which allows
them to penetrate biological surfaces more readily [92–94]. These smaller Ag NPs interact with cell
membranes and disorganize the lipid bilayer, causing the increase of the membrane permeability
and bacterial lysis [95]. Ag NPs smaller than 30 nm demonstrated a strong anti-microbial activity
against Staphylococcus aureus (S. aureus) and Klebseilla pneumonia (K. pseumonia), whereas Ag NPs with
sizes ranging from 5 to 20 nm have a strong anti-microbial activity against S. aureus [96]. Therefore,
small Ag NPs are more toxic than large particles, and even more when they are oxidized [97]. Indeed,
the anti-bacterial activity of small Ag NPs (<10 nm) is mainly due to Ag+ , whereas for large particles
(>15 nm), the anti-microbial activity due to Ag+ is comparable to that of the particles, given that the
release of Ag+ ions is proportional to the exposed nano silver surface area [98].
The morphology of Ag NPs is very important for anti-microbial activity. The colloidal
morphology has higher anti-bacterial activity compared with polygonal, disk, prism, and hierarchical
morphologies [99,100]. The concentration of silver NPs can also impact anti-bacterial activity [101].
Silver NPs smaller than 15 nm and with a concentration of 0.004% w/w have shown maximum
effectiveness in preventing the growth of bacteria that cause unpleasant oral odors and tooth decay [87].
A synergic anti-bacterial effect against Staphylococcus aureus (S. aureus) and E. coli has been
observed, in vitro, by combining Ag NPs with antibiotics such as amoxicillin, penicillin G, clindamycin,
erythromycin, and vancomycin [40]. The conjugation of quinazolinone with Ag NPs demonstrated,
in vitro, a higher anti-bacterial activity against E. coli, Streptococcus pyogenes, Klebsiella pneumoniae
(K. pneumoniae), Bacillus cereus (B. cereus), and Pseudomonas aeruginosa (P. aeruginosa) as compared to
quinazolinone alone [102]. Ag NPs can also inhibit, in vitro, the replication of viruses [81] such as
HIV-1 [103], herpes simplex [104], and influenza [105].
Moreover, Ag NPs have anti-inflammatory properties [63]. For this, Ag NPs (i) decrease
levels of vascular endothelial growth factor; (ii) reduce expression of the hypoxia-inducible factor 1α,
which acts on bacterial destruction and regulates expression of pro-inflammatory genes; (iii) prevent the
hypersecretion of mucins (mucus glycoproteins); and (iv) suppress the production of pro-inflammatory
cytokines such as interleukin-12 and tumor necrosis factor α, and also provoke a decrease in the
expression of the cyclooxygenase-2 gene at higher concentrations [63].
Due to their anti-microbial and anti-inflammatory effects, Ag NPs are used in healthcare products
such as toothpaste, toothbrushes, and mouthwash [106]. The aim of such oral dental care is to fight
against cariogenic and periodontal pathogens.
Ahmed and colleagues evaluated, in vitro, the action of toothpaste with and without Ag NPs
against Streptococcus mutans (S. mutans) [31]. S. mutans is one of the main pathogens known to be
involved in carious lesions [107]. Toothpaste containing Ag NPs had anti-microbial activity against S.
mutans in vitro [31]. Using the agar-well diffusion method, the mean diameter of the zone of inhibition
was measured as 20.14 ± 0.96 mm for this toothpaste, whereas no zone of inhibition was observed with
the toothpaste without Ag NPs. In another in vitro study, Junevičius and colleagues demonstrated that
Ag NP toothpaste had a lower effect against Gram-negative than against Gram-positive bacteria [108].
The minimal inhibitory concentration (MIC) affecting the growth of the fungus Candida albicans (C.
Albicans) was 0.18 g/mL, whereas that affecting the growth of S. aureus, a Gram-positive bacterium, was
0.004 g/mL. For the Gram-negative bacteria, an MIC of 0.15 g/mL was observed for K. pneumoniae and
P. aeruginosa, while no bactericidal effect was observed for E. coli or Proteus mirabilis. This toothpaste
entirely inhibited the growth of Enteroccosus faecalis (E. faecalis) and B. cereus even when the toothpaste
contained the lowest concentration of Ag NPs.
Mouthwash containing CHX is conventionally used for the treatment of plaque-induced
gingivitis [109]. CHX is considered to be the gold standard for avoiding biofilm formation in
addition to mechanical action due to toothbrushing [109]. However, the use of CHX can have various
side effects [109,110]. For this, long-term therapy is not recommended [110]. Therefore, mouthwash
containing Ag NPs could be an interesting alternative. The comparison of Ag NP mouthwash with CHX
mouthwash, in a 6-month controlled clinical study, revealed no significant difference between these two
products. However, a highly significant reduction in plaque index, gingival index, and papilla bleeding
index after 2 and 4 weeks was observed [110]. One previous study had shown that CHX-containing
mouthwash was statistically more effective than Ag NP mouthwash in vitro [111]. These differences
could be explained by the differences in the composition of Ag NPs (a few silver ions contained in
the hydrogen peroxide formulation), a different concentration of CHX (0.2%), and also differences
in methodology (in vivo and in vitro study). Another use of mouthwash containing Ag NPs is to
fight against colonization by certain bacteria resistant to drugs and also by fungi that cause infections
in immunocompromised patients such as oral candidiasis (Candida-associated stomatitis) [112,113].
The in vitro anti-bacterial efficacity of an alcohol-free mouthwash containing a low concentration
of colloidal Ag NPs (50–0.024 µg/mL) was demonstrated by Abadi and colleagues [114]. Using a
challenge test on bacteria and fungi such as S. aureus, S. mutans, P. aeruginosa, E. coli, and C. albicans, they
obtained measures of MIC ranging from 0.78 and 3.12 µg/mL, and measures of minimum bactericidal or
fungicidal concentration (MBC or MFC) ranging between 1.56 and 12.5 µg/mL. At lower concentration
of Ag NPs, the mouthwash killed all microorganisms tested. The addition of 30,000 µg/mL of ethanol
to the mouthwash did not affect anti-bacterial activity.
Ag NPs are also used in impregnated toothbrush to reduce the number of the putative periodontal
pathogens [115,116]. In a randomized controlled trial (RCT), do Nascimento and colleagues compared
the use of toothbrushes with CHX-coated bristles, Ag-coated bristles, or conventional bristles over
30 days [115]. The toothbrush bristles with Ag NPs decreased the individual and total genome
count in the supra- and subgingival biofilm. After 30 days of toothbrushing, the Ag-coated and
CHX-coated bristles were able to reduce or maintain lower levels of bacterial counts of the putative
periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis), Treponema denticola (T. denticola),
Tanerella forsythia (T. forsythia), Prevotella intermedia (P. intermedia), Prevotella nigrescens (P. nigrescens),
Fusobacterium nucleatum (F. nucleatum), and Parvimonas micra. The total genome counts in supragingival
or in subgingival biofilm was not decreased by CHX. However, in supragingival biofilm, CHX reduced
the individual genome counts for most of the target pathogens [115].
Although Ag NPs appear to be very beneficial, one should also consider the adverse effects.
Gaillet and Rouanet indicated that Ag NPs in toothpaste and other products could be responsible
for inflammation of the gastrointestinal tract [117]. The main toxic effects observed were weight loss,
disruption of blood biochemistry, and dysfunction of liver enzymes [117]. However, since toothpaste is
not indicated for systemic use but for topical use, it is unlikely that adverse effects would be observed
in such small quantities.
3.1.3. Gold Nanoparticles

In recent years, research on NP synthesis has mainly focused on green synthesis using bacteria [73,
118] and plants [119–122]. For example, the marine extremophilic bacteria Pseudoalteromonas was
used to obtain Au NPs with non-cytotoxic, non-genotoxic and non-oxidative stress generated over
a range of concentrations but provoking alterations in DNA methylation and in the expression of
DNA methyltransferase genes [118]. Plants such as Curcuma wenyujin extract [119], Chenopodium
formosanum shell extract [120], Dillenia indica leaf aqueous extract, or Annona muricate leaf extracts were
also used [123]. Au NPs were also obtained using Coffea arabica [124].
Au has a weak anti-microbial effect against many microorganisms such as bacteria and fungi
(Table 1) [123,125–128]. Conjugation with tetracycline [129] or with ampicillin [130] can enhance
anti-bacterial activity. Moreover, Au NPs have anti-inflammatory action by (i) reducing ROS production;
(ii) decreasing lipopolysaccharide-induced cytokine production such as interleukin (IL)-1β, IL-17,
tumor necrosis factor (TNF)-α; and (iii) modulating mitogen-activated protein kinase and phosphatidyl
inositol 3-kinase pathways [63].
The use of Au NPs in oral pathology remains uncommon [125], although they are easily prepared
by the co-precipitation technique and are less toxic than metallic nanomaterials such as Ag NPs [131].
Essentially, as Au is inert, it represents the NP of choice to conjugate with various biomolecules and
ligands to target microorganisms [132]. The effect is similar to the one observed with antibiotics such
as mupirocin [133,134]. Hernández-Sierra and colleagues used NPs of Ag and Au of 25 nm, 80 nm,
and 125 nm average sizes. The results indicate that in vitro, a higher concentration of Au NPs than that
of Ag NPs is required to observe bacteriostatic and bactericidal effects on S. mutans [135]. Similar results
to this study were observed by Junevičius and colleagues [108]. They compared, in vitro, toothpaste
containing Ag NPs and Au NPs and observed that they were less active against Gram-negative than
against Gram-positive bacteria. Moreover, Ag NP-containing toothpaste had a stronger effect on
Gram-negative bacteria and a broader anti-microbial effect compared to toothpaste containing Au NPs.
This lower anti-microbial effect for Au NPs compared with Ag NPs could explain the low use of Au
NPs in oral care products. Au NPs are also used in drug delivery applications [136].
However, Au NPs are also incorporated between toothbrush bristles [125]. In addition to increasing
mechanical elimination of plaque, gold has significantly reduced periodontal disease, because of
its anti-bacterial action [137]. However, to our knowledge, no study concerning the action of the
toothbrush containing the Au NPs bristles was conducted.
Regarding adverse effects of Au NPs, toxicology remains unclear. However, in one review, Jia
and colleagues concluded that according to the range of concentrations, Au NPs are toxic when they
are used in biological systems [138]. In vitro research demonstrated that Au NPs, having penetrated
bacteria, will cause synthesis of ROS. This oxidative stress induces a new cytotoxicity that will damage
DNA, cause cell death by apoptosis and necrosis, and cause cell-cycle arrest. As ROS production is
known as a common mechanism of cytotoxic effects, therefore Au NPs can induce cytotoxic effects [138].
However, recently, Gunduz and colleagues studied the exposition of cultured vascular endothelial
cells to non-lethal Au NPs [139]. They demonstrated that once the maximum number of intracellular
NPs was reached, there was constant depletion but no cell death. This depletion reduced endoplasmic
reticulum stress. This report suggests that in vitro, NPs uptake is actively regulated by cells and the
impact of NPs exposure in the long-term [139]. In vivo, the inhalation of Au NPs by Sprague–Dawley
rats during 6 h/day or 5 days/week for 90 days revealed that dose-related changes were observed only
in the lungs [140]. Therefore, as it is well acknowledged that in vitro and in vivo results can diverge,
other in vivo studies are necessary for more reliable conclusions.
3.1.4. Zinc Oxide Nanoparticles

ZnO NPs biosynthesis was carried out using plant extracts such as Ocimum tenuiflorum, Trifolium
pretense, or Agathosma betulina [122], Menthaa pulegium leaf extract [141], Crocus Sativus petal extract [142],
or Laurus nobilis plant extract [143]. Another ZnO NP synthesis is the thermal decomposition of
Zn-metal organic frameworks. Hajiashrafi and colleagues prepared ZnO NPs by thermal decomposition
of prepared MOF-5 with and without tri-ethylamine using solution and solvothermal methods [144].
ZnO NPs fight against bacteria [142,145,146], viruses [147], and fungi [148]. The anti-microbial
activity of ZnO NPs (Table 1) depends on synthesis techniques, physico-chemical characteristics,
evaluation tools, and techniques used to generate three-dimensional structures [149,150]. In vitro,
ZnO has anti-bacterial properties that increase when ZnO is in NP form due to the increasing
of surface-area-to-volume ratio [151,152]. It was shown that ZnO NPs were able to damage
E. coli bacteria by cellular internalization with a Gram-negative triple-membrane disorganization
causing increase in membrane permeability [153]. Anti-bacterial effects on Gram-negative and
Gram-positive bacteria have been demonstrated in vitro [142,145,146]. More recently, it was shown
that polyethylenglycol-encapsulated ZnO interacts strongly with the citric acid and lactic acid, leading
to a bacterial inhibition effect against S. aureus and E. coli [142,154], and S. mutans and Lactobacillus in
dental plaque [155]. The anti-microbial effects of ZnO are similar to Ag NPs because the smaller the
NPs are, the larger the surface area becomes. Therefore, the anti-microbial effect becomes stronger
due to its capacity to react with more molecules per unit of surface. However, in vitro, compared
with Ag NPs (0.1 mg/mL), a higher concentration of ZnO NPs (size 15–20 nm; surface area 47 m2 /g)
is necessary to observe growth inhibition (0.5–2.5 mg/mL) and killing effects (>2.5 mg/mL) against
several pathogens [156]. ZnO NPs demonstrated, in vitro, an anti-bacterial activity against bacteria
known to be implicated in gingivitis and periodontitis such as Aggregibacter actinomycetemcomitans
(A. actinomycetemcomitans), P. gingivalis, P. intermedia, and F. nucleatum [157]. ZnO NPs are commonly
used as anti-bacterial agents in oral care products such as toothpaste and mouthwash [158].
Moreover, another interesting property, to fight against gingivitis or caries, is the anti-inflammatory
activity of ZnO NPs in response to pathogens [63]. ZnO NPs reduce inflammation by (i) blocking the
production of pro-inflammatory cytokines such as IL-1β and IL-18 by inhibiting the necrosis factor
kB and caspase 1 in activated mast cells and macrophages; (ii) inhibiting mast cell proliferation by
increasing p53 and decreasing thymic stromal lymphopoietin production related to IL-13, a TH2
cytokine, along with IL-1 and tumor necrosis factor-α; and (iii) suppressing lipopolysaccharide-induced
cyclooxygenase-2 and inducible nitric oxide synthase expression [63,159].
The incorporation of ZnO NPs in toothpaste and mouthwash enables the fighting of gingivitis
due to bactericidal effects [32,160]. Toothpaste containing ZnO has also been demonstrated to have,
on an extracted tooth, a positive effect on the dentin by reducing demineralization [161]. Moreover,
due to its anti-bacterial and anti-gingivitis action, Zn has been incorporated into bioactive glass
toothpaste. Increasing the quantity of Zn in toothpaste could result in a better anti-bacterial and
anti-gingivitis effect [162]. By liquid dilution method, Hernandez-Sierra and colleagues revealed that
the anti-microbial effect of ZnO NPs against S. mutans was lower than of Ag NPs [135]. Although it
has been demonstrated that even if Ag and ZnO NPs have an anti-microbial effect against S. mutans,
their mechanism is still not well known.
Mouthwash containing zinc salts (zinc gluconate, zinc chloride) or ZnO NPs presents high
anti-bacterial activity against S. mutans, in vitro [163,164]. ZnO NPs also act against Streptococcus
sanguis known to be implied in caries and periodontal diseases [165]. The combination of Ag
Nps with ZnO NPs demonstrated a synergistic anti-bacterial effect [166]. Therefore, to control the
formation of dental plaque, very low concentrations of Ag/ZnO NPs are necessary [135]. Mouthwash
containing a low concentration of ZnO NPs have high anti-bacterial activity against Streptococcus
in the mouth [167]. Similar results were obtained by Kachoei and colleagues [167]. They proved,
in vitro, that mouthwash containing Ag/ZnO NPs was an effective anti-microbial agent. Compared to
those containing ZnO NPs, chlorhexidine 0.2% and sodium fluoride 0.05%, mouthwash containing
Ag/ZnO NPs demonstrated a higher anti-microbial activity against S. mutans. Therefore, to avoid
plaque accumulation, mouthwash containing ZnO NPs could replace chlorhexidine 0.2% and sodium
fluoride 0.05%. However, chlorhexidine 0.2% showed higher anti-microbial activity against S. mutans
compared to different concentrations of ZnO NPs [167]. One problem associated with the use of
ZnO NP mouthwash is enamel discoloration. Eslami and colleagues concluded that extracted teeth
immersed in ZnO NPs had the most severe color change, followed by CuO NPs, Ag NPs, TiO2 NPs,
and chlorhexidine, successively [168].
ZnO NPs represent a biologically safe material that does not exhibit toxicity to human cells [152].
Compared with their micron equivalents, ZnO NPs are more toxic for bacteria [169].
3.1.5. Titanium Dioxide Nanoparticles

Recent research focused on the green synthesis of TiO2 NPs using plants such as Azadirachta indica
leaf extract [170], Glycyrrhiza glabra [171], Carica papaya leaves [172], and Cassia fistula [173].
TiO2 is known to possess this anti-microbial activity in vitro (Table 1) [174,175]. It can fight against
bacteria and viruses [176]. TiO2 NPs are of great interest due to their low cost, high stability, high
photocatalytic activity, and reusability [48,177,178]. The bioactivity of TiO2 NPs is linked to the surface
of contact and/or volume that is increased by decreasing the particle size, particularly in this case
the thickness (<100 nm), which authorizes intensified interaction with molecules and proteins of the
cellular membranes and a lesser total of substance [38,179–181]. Compared to Ag and Cu NPs, few
studies on TiO2 anti-bacterial activity have been conducted.
The anti-microbial activity of TiO2 is due to its crystal structure, shape, and size [182]. To ensure the
best anti-microbial activity, the anatase form of TiO2 NPs and the excitation by UV light are necessary.
The photocatalysis of TiO2 NPs provokes: (i) the peroxidation of polyunsaturated phospholipid
component of bacterial lipid membrane; (ii) loss of respiratory activity; and (iii) cell death [183]. Tsuang
and colleagues demonstrated, in vitro, that TiO2 -mediated photocatalytic had microbial activity against
obligate anaerobes (Bacteroides fragilis), facultative anaerobes (E. coli, S. aureus), and obligate aerobes
(P. aeruginosas) [184]. In the absence of UV light, TiO2 NPs of about 18 nm and a surface area of 87 m2 /g
demonstrated a bacteriostatic activity for concentration ranging from 1.0 to 2.5 mg/mL against E. coli
and multi-resistant S. aureus and a bactericidal activity for concentration greater than 2.5 mg/mL.
Against oral pathogens such as A. actinomycetemcomitans, P. gingivalis, P. intermedia, and F. nucleatum,
a bacteriostatic activity is observed, in vitro, for concentrations ranging from 0.25 to 2.5 mg/mL,
and bactericidal activity is demonstrated for concentration greater than 2.5 mg/mL [157].
De Dicastillo and colleagues developed TiO2 NPs from the combination of electrospinning and
atomic layer deposition processes [174]. They obtained spherical, hollow, anti-microbial nanostructures
with a shell of 17 nm thickness. These hollow, calcined TiO2 NPs presented better anti-microbial
activity than commercial TiO2 NPs, against multidrug-resistant bacteria such as Escherichia coli and S.
aureus [174]. The coupling of TiO2 NPs with a second metal strongly modified the photocatalytic and
biocidal activity of the obtained TiO2 -based photocatalysts [185]. The combination of TiO2 and Ag
obtains results in visible light [186,187]. Ag-TiO2 NPs can act against S. mutans [186].
TiO2 can also have an anti-inflammatory action by (i) reducing platelet numbers; and (ii) increasing
thrombin–antithrombin levels [63].
Moreover, TiO2 is an effective whitener used as a pigment in many medical and industrial
products. Komatsu and colleagues proposed the use of TiO2 nanotubes in tooth whitening [188]. They
demonstrated that the use of TiO2 nanotubes in addition to H2 O2 at low concentrations enhanced
whitening. The combination of TiO2 nanotubes with H2 O2 increased the response to visible light [188].
Recent studies indicate that the use of TiO2 NPs can have toxic effects [189–191]. Moreover, Geraets
and colleagues demonstrated that in rats, when oral exposure was repeated, TiO2 NPs can accumulate
in tissue [192]. Rompelberg and colleagues, using analytic methods, concluded that toothpaste (in
young children only) is the product that contributes most to TiO2 intake, but they did not draw a
conclusion concerning the risk of general health [193]. In a review, Baranowska-Wójcik and colleagues
explained that TiO2 NPs in small but regular doses can act on the intestinal mucosa, the heart, the brain,
and other internal organs, which can increase the risk of developing systemic diseases or tumors [194].
3.1.6. Copper Oxide Nanoparticles

Contrary to the metal oxides previously described, few studies exist concerning copper or copper
oxide. A range of Cu and CuO NPs have been obtained from plant extracts such as magnolia,
Syzygium aromaticum, Euphorbia nivulia [122], Triticum aestivum [195], Fusarium solani [196], and Aloe
vera extract [197].
CuO NPs demonstrated anti-bacterial [197] and antifungal [196] activities (Table 1). An inverse
relationship between the size of CuO NPs and the anti-bacterial activity has been established
in vitro [197]. The greatest bactericidal activity was obtained for copper NPs ranging from 1 to
10 nm. CuO is cheaper than Ag, relatively stable in terms of both physical and chemical properties,
and easily mixed with polymers. The physical and chemical characterization of CuO NPs revealed
that CuO NPs synthetized by thermal plasma technology have sizes ranging from 20 to 95 nm and
a mean surface area of 15.7 m2 /g. In suspension, CuO NPs demonstrated their capacity to fight
against a range of bacterial species. However, compared with silver, CuO NPs have lower bactericidal
activity [198]. Cu2 O NPs and CuO NPs have similar anti-bacterial activity [199]. CuO demonstrated
a different anti-bacterial activity against multiple Gram-negative and Gram-positive species such as
P. aeruginosa, methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis, and E. coli [199]. Amiri
and colleagues demonstrated that CuO NPs had a high anti-microbial effect against the examined
dental caries bacterial agents (S. mutans, Lactobacillus acidophilus, and Lactobacillus casei), and lower
effect on three species of candida (C. albicans, Candida krusei, and Candida glabrata) [200].
3.1.7. Other Nanoparticles Used in Oral Care Products and Their Anti-bacterial Activity
• Chlorhexidine NPs
In oral care products, one of the most common anti-microbial agents is CHX (Table 1) [201].
Recently, a novel approach, named nano-encapsulation, has emerged that delivers biologically potent
compounds more effectively to specific targets [202]. Nano-encapsulated drugs can increase overall
biological efficacy through rapid penetration and bioavailability while decreasing potential cytotoxicity,
drug dosage, and the production costs, compared to controls [203].
Seneviratne and colleagues described a novel synthesis of mesoporous silica NPs encapsulated
with pure (non-salt-form) CHX, namely CHX NPs [204]. They coated CHX on mesoporous silica NPs
with inner pore channels of approximately 2.5 nm. The results obtained demonstrated that these
CHX NPs had anti-bacterial effects against both planktonic and biofilm bacteria. Nano-CHX can act
against several oral pathogens such as A. actinomycetemcomitans, E. faecalis, F. nucleatum, S. mutans,
and Streptococcus sobrinus (S. sobrinus) in planktonic modes and in mono-species biofilms, respectively.
Moreover, CHX NPs can inhibit the growth of multi-species oral biofilm composed of S. sobrinus,
P. gingivalis, and F. nucleatum [204].
Barbour and colleagues developed novel anti-microbial NPs based on a hexametaphosphate
salt of CHX [202]. These CHX NPs of size between 20 and 160 nm have colloidal structure and are
highly negatively charged NPs (−50 mV). They are active against MRSA and Pseudomonas aeruginosa
in both planktonic and biofilm conditions. Poly-lactic-co-glycolic acid NPs were also investigated as
CHX biodegradable nanocarriers with gradual CHX release [3]. These new NPs could be added to
toothpaste or mouthwash [202].
• Ferumoxytol
Ferumoxytol NPs can disrupt oral biofilms and avoid caries lesions via intrinsic peroxidase-like
activity. Ferumoxytol NPs penetrate biofilm, bind to bacteria, and produce free radicals from hydrogen
peroxide, provoking in situ death of bacteria because the cell membrane is disrupted, and the
extracellular polymeric substance matrix is degraded. Combinate with low H2 O2 concentrations,
ferumoxytol inhibits biofilm accumulation on natural teeth and avoids acid damage to mineralized
tissue in ex vivo biofilm models [205]. In vivo, in a rodent model with carious disease, topical oral
treatment comprising ferumoxytol and H2 O2 restrained the development of dental caries, avoiding the
occurrence of severe tooth caries. Toothpaste and mouthwash containing ferumoxytol NPs could be an
effective topical treatment of biofilm-induced oral disease [205].
• Scutellaria baicalensis
In traditional Chinese medicine, Scutellaria baicalensis is usually prescribed to treat infectious and
inflammatory diseases [206]. It is used to manage periodontal disease [207]. Its anti-inflammatory,
antioxidative, and immunomodulating action is due to the presence of baicalin, a flavonoid
compound [208,209]. Scutellaria baicalensis has been loaded to magnetic NPs [91,210,211] and chitosan
NPs [212]. These studies demonstrated that the loading of Scutellaria baicalensis on NPs increased the
percentage of drug delivery.
Leung and colleagues analyzed the anti-bacterial activity of the mix of Scutellaria baicalensis NPs
and CHX NPs (ratio 9:1 (w/w)) in both planktonic and biofilm bacteria. The mix was effective on
mono-species biofilms of A. actinomycetemcomitans, F. nucleatum, S. sobrinus, and S. mutans at 24 h. It was
also active against biofilms composed of multi-species such as A. actinomycetemcomitans, P. gingivalis, F.
nucleatum, and S. mutans at 24 h. The author clearly showed a synergistic anti-bacterial action of mixed
NPs on usual oral bacterial biofilms, which may be initiated as a novel anti-microbial factor for clinical
oral care [213].
• Chitosan nanoparticles
Chitosan is an abundant polysaccharide produced by alkaline hydrolysis of chitin, the primary
structural component of the crustaceans, arthropods shells, and fungal cell walls [214]. A large focus
has fallen on this glucosamine unit-based linear biopolymer thanks to its unique cationic global
charge, which no other polysaccharide has [215]. Chitosan showed both a high biocompatibility
and anti-microbial activity against oral biofilms due in part to its positive charge, which facilitates
its adhesion to bacteria cell walls, damaging the cell structure [216]. According to Costa and
colleagues, chitosan proved its ability to destabilize the S. mutans and other oral microorganism
(P. intermedia, C. albicans) biofilm formation and adherence more precisely when incorporated into a
mouthwash [12,217].
Furthermore, chitosan NPs were tested as a low-cost ingredient of dental varnishes for their
anti-microbial activity against S. mutans [11], and as a hybrid chitosan hydrogel for encapsulating Ag
NPs to constitute an alternative for oral anti-microbial control (Table 1) [218]. Chitosan hydrogel was
shown to have bactericide properties similar to chlorhexidine, and can release Ag NPs for two weeks.
Moreover, this human RCT study proved that chitosan-containing polyherbal toothpaste significantly
reduces plaque index and bacterial count [219]. Other studies demonstrated that chitosan toothpaste
can act as an anti-erosive agent [220,221]. For example, Schueter and colleagues, in a human RCT
study, demonstrated that the efficacy of tin or tin and fluoride chitosan toothpaste was of great interest
in the case of erosion or hypersensitivity [221]. In another human RCT, Uysal and colleagues obtained
the same type of results, and proved that toothpaste containing chitosan may reduce demineralization
of enamel in patients presenting poor oral hygiene [222].
4. Nanoparticles as Remineralization Agents

To control the risk of caries and dental sensitivity of demineralized enamel, the action the
remineralizing agents is required to restore structure and ensure enamel mechanical feature preservation.
Indeed, the carious process corresponds to the demineralization of hard tissues in the tooth (enamel
and dentine) due to attack from acids produced by bacteria from biofilms of dental plaque [223,224].
In the presence of fermentable carbohydrates, cariogenic bacteria grow and produce acid responsible
for enamel demineralization [225,226]. To avoid caries, it is possible, as previously described, to fight
against bacteria. However, another possibility is to favor the remineralization of tissues (Figure 1) [227].
Another major dental problem is dental erosion which corresponds to a progressive and irreversible loss
of hard dental tissues due to a chemical process i.e., dissolution from acids not involving bacteria [228].
This can induce undesirable effects such as dental tissue loss, aesthetic defects, decreased vertical
dimensions, and functional problems that may impact quality of life [228]. Moreover, the exposure of
dentin, the internal tissue of the tooth, can lead to dental hypersensitivity. Hyperesthesia is related
to the movement of fluids in dentinal tubules. It is characterized by an exaggerated reaction to a
benign stimulus, unrelated to bacteria, and corresponds to a chronic pathology with acute episodes,
specifically acute and brief pain [229].
Due to the fact that fluoride has demonstrated good properties of remineralization [230], few
studies on NPs that have a remineralization effect have been undertaken. The main NPs known and
used to remineralize are hydroxyapatite (HA) NPs (Table 1).
4.1. Hydroxyapatite
The major advantages of hydroxyapatite (HA) NPs are its resemblance to the mineral structure of
teeth, bioactivity, and biocompatibility [231,232]. Indeed, particles are “similar in morphology and
crystal structure to dental apatite” [233]. NPs with a size of 20 nm that correspond to characteristics
of the natural building blocks of enamel had a strong affinity with demineralized surfaces [234,235].
Scanning electron microscopy analysis confirmed that these HA NPs are able to bind to pores created
by demineralization [235]. In vitro, after adhering, HA NPs multiply and organize into microclusters
to form an uniform apatite layer that completely overlaps interprismatic and prismatic enamel [235].
Similar results were observed by Roveri and colleagues with carbonated HA NPs with a size of 100 nm.
HA NPs covered the demineralized enamel surfaces that fluoridated toothpaste more effectively [236].
Treatment with HA NPs exhibited a surface-to-Ca/P ratio similar to that of biological enamel and
synthetic nanohydroxyapatite used, indicating an apatite coating deposition on the demineralized
enamel surface [235]. Chen and colleagues described the mechanism of enamel prism formation with
HA NPs [237]. The proteins of the enamel (mainly amelogenin and amelogenin fragments) change
enamel crystals. Negatively charged carboxy-terminal hydrophilic parts of amelogenin protein bind
to the charged surface of the enamel crystal. The surface of the crystal becomes hydrophobic either
because the hydrophobic part of amelogenin is exposed or because the charged part of the nanospheres
is digested. Thus, the hydrophobic HA NPs can gather together to form a thermodynamically stable
prism structure such as the one observed in the enamel [237].
HA NPs have been integrated into products for oral care such as dentifrices and mouthwash to
reduce or delete dental sensitivity by obstructing open dentinal tubules on the surface of the dentin
and connected to the pulp, or for the purpose of promoting the remineralization of enamel by replacing
calcium and phosphate ions in the areas from which minerals dissolved, restoring its integrity and
shine [238–241]. In 2006, in Europe, HA NP dentifrice was instituted to facilitate remineralization and
restoration of enamel [179]. In accordance with the producer, the maximal incorporation of this 15.5%
HA NP aqueous suspension oral care ingredient is 20% in a dentifrice and 10% in a mouthwash [241].
Kani and colleagues were the first to prove, in one human RCT study, the advantage of using HA
NPs toothpaste to remineralize [242]. They compared the use of 5% HA NP toothpaste with the use of
the same toothpaste without HA NPs for 3 years. The caries incidence decreased by 56% in children
brushing with a HA NP toothpaste compared to the group brushing with a control toothpaste [242].
Several in vitro studies reported the efficacity of HA NPs in the remineralizing process [240,243–245].
HA NP toothpaste as remineralizing paste showed better results when compared to toothpaste
containing calcium and potassium ions and sodium nitrate [246]. In vitro, HA NPs appeared to
be greater desensitizing agents than novamin and proargin, which are known to be desensitizing
agents [247]. Moreover, several RCTs demonstrated the efficiency of HA NP toothpaste in reducing
dentine hypersensitivity and stimulating a remineralizing mechanism [33,238,239,248–251]. Therefore,
the decreasing of dentine hypersensitivity can be explained by the fact that the deposition of HA NPs
produces a remineralizing effect on the enamel surface [236,252]. Bossù and colleagues confirmed,
in vitro and in vivo, these results by demonstrating that HA NPs contained in toothpaste promote
enamel regeneration with a biomimetic film similar in terms of morphology and structure to the biologic
hydroxyapatite of the enamel [252]. A coating of a new layer of apatite is deposited, which contains
fewer particles than the natural enamel. Moreover, due to the chemical bonds between the synthetic
and natural crystals of the enamel, this new layer of apatite shows resistance to toothbrushing [252].
In one human RCT study, Browning and colleagues demonstrated that HA NPs can help to treat
dental hypersensitivity after teeth-whitening. Indeed, for 14 days, subjects used a hydrogen peroxide
gel and brushed their teeth with a dentifrice containing HA NPs. Fewer subjects using HA NP
toothpaste suffered hypersensitivity than subjects who did not use the HA NP toothpaste and, and the
hypersensitivity persisted for fewer days [253]. Another property of HA NP toothpaste is its positive
effect on teeth-whitening and brightness [254,255].
Due to these properties of remineralization and desensitization, HA NPs could be an interesting
alternative to fluoride toothpaste, which is recommended to prevent caries [256]. Its use led to
a decrease in caries in industrialized countries [257], but the daily use of fluoride toothpaste is a
potential source of fluorosis [258]. Moreover, Tschoope and colleagues compared fluoride toothpaste
and HAP NP toothpaste, and demonstrated, in vitro, that the HAP NP toothpaste displayed higher
remineralizing effects on both hard tissues than fluoride toothpaste [259]. The same observations
were obtained by Manchery and colleagues [260]. The use of fluoride toothpaste does not impact the
surface-area-to-Ca/P ratio following demineralization, contrary to the Ca/P ratio observed with the use
of HA NP toothpaste, which is close to biological enamel [235]. Only modification of the structure of
apatite is observed. A partial hydroxyl group is replaced by fluoride ions, whereas the calcium and
phosphate content is not changed [235]. Hill and colleagues proved that use of toothpaste containing
both HA NPs and fluoride had significant benefit in preventing demineralization and promoting the
formation of fluoridated apatite, which is more resistant to acid attack [244]. Moreover, toothpaste
containing HA and Zn NPs demonstrated a greater efficacy than fluoride toothpaste to prevent the
demineralization of enamel induced by acidic products [261]. Due to the presence of Zn, this toothpaste
also decreased the risk of gingivitis and periodontitis [262].
Mouthwash containing HA and Zn NPs have the same effect on enamel and prevent the
multiplication of bacteria in the oral cavity [263,264]. The low number of studies concerning HA NP
mouthwash have focused on its capacity to act on bacterial colonization. Kensche and colleagues
demonstrated that HA NP mouthwash can help control bacterial biofilm formation. They observed,
in situ, an accumulation of HA aggregates and salivary bacteria at the tooth surface. The number
of bacteria that attach to the surface of the pellicle decreased compared with a control mouthwash
and was similar compared with chlorhexidine 0.2% mouthwash [265]. The action of HA NPs is
due more to anti-adhesive capacity than anti-bacterial effect. For one, the attachment of HA NPs to
biofilm bacteria prevents the adhesion of new bacteria. Bacteria that adhere to HA NPs can also be
eliminated by desorption of the complexes composed of HA NPs and the biofilm bacteria surface.
For another, adhesins from the cell wall of saliva bacteria can be blocked by the accumulation of
HA NPs, and bacteria could even be agglutinated by the interaction with the HA microclusters.
Therefore, bacteria would not be able to adhere to the biofilm surface [265]. In vitro, Hannig and
colleagues concluded that mouthwash containing HA and Zn NPs had anti-adherence properties and
anti-bacterial effects against cariogenic bacteria such as S. mutans [263,266].
Despite the good performance of HA NPs, it is essential to ensure that it is not toxic for consumers.
The Scientific Committee on Consumer Safety analyzed the safety of HA NPs as an oral care ingredient,
but the results were not informative enough. Ramis and colleagues proved from in vitro experiments
that no deleterious effects were noticed for human gingival epithelium tissues incubated with HA
NPs at all evaluated time-points and parameters [241]. Moreover, after 7.5 min at 37 ◦ C, the complete
dissolution of 3.1% HA NPs in simulated gastric fluid was observed. These results confirmed the safety
of HA NPs for oral care products [241].
4.2. Casein Phosphopeptide–Amorphous Calcium Phosphate

Calcium phosphate particles dissolved in casein milk protein is a new remineralization method
that creates, in the acidic environment of dental plaque, an amorphous calcium phosphate particle
super-saturation around the tooth that increases the remineralization process [267]. Indeed, the casein
phosphopeptides can stabilize calcium phosphate in solution. The calcium phosphates bind with
phosphoserine residues to form casein phosphopeptide–amorphous calcium phosphate (CPP–ACP)
clusters [268]. These CPP–ACP nanocomplexes are able to localize at the surface of the tooth,
bringing about buffering of the phosphate and calcium free ion activities, and then help maintain
a state of super-saturation with respect to tooth enamel, negating demineralization and enhancing
remineralization [269,270]. Indeed, these CPP–ACP nanocomplexes create a calcium and phosphate
reservoir that can bind to plaque and dental surfaces [268].
Rao and colleagues undertook a clinical trial to assess the efficacy of toothpaste containing CPP
in preventing carious lesions [271]. For 24 months, 150 schoolchildren brushed their teeth with a
given toothpaste. Fifty used toothpaste containing CPP (2% w/w), 50 used toothpaste containing
fluoride (1190 mg/kg) as sodium monofluorophosphate (0.76%), and 50 used a placebo toothpaste
without CPP or fluoride. The conclusions of the study were that CPP can be incorporated into calcium
carbonate-based toothpaste, and that toothpaste containing CPP can help prevent carious lesions. More
recently, several in vitro and in situ studies have demonstrated that toothpaste containing CPP–ACP
nanocomplexes could avoid enamel demineralization produced by soft drinks [272–274]. Moreover,
in case of bleaching protocols, this type of toothpaste can prevent negative changes of roughness
and hardness to enamel [275]. Therefore recently CPP–ACP and fluoride has been recommended as
treatment to remineralize initial caries and white spot lesions [276–279]. However, CPP–ACP compared
to fluoride has a slightly lower potential in the remineralization of early enamel caries [276–279]. An
in vitro study concluded that toothpaste containing CPP–ACP NPs with L. rhamnosus (probiotic strain)
had a potential remineralizing property with a more promising anti-microbial efficiency [280].
4.3. Bioactive Glass

Several bioactive glasses (BAG) exist, such as phosphate-based glass and silicate-based glass. BAG
is known to heal bone defects and stimulate bone regeneration [281]. Similar action is observed on the
tooth. Indeed, BAG NPs can decrease tooth sensitivity by mineralizing dentine tubules. First, the BAG
makes contact with an aqueous solution, and the NPs will change to a mesoporous shape. This layer of
NPs allows formation of apatite on the dentine surface. Then, a pH rise provokes the precipitation
of HA. The mineralizing process can be activated by phosphate and calcium ions contained in the
bioactive glass and mineralizing agents from the saliva [282]. Due to larger surface areas and higher
Ca/P ratios, better remineralization and slower progression of carious lesions are observed for BAG
NPs compared to conventional BAGs [283–285].
Due to this remineralizing property, BAG NPs are incorporated into toothpaste to treat dentine
hypersensitivity [286–289]. In vitro studies have demonstrated that BAG NPs could promote mineral
formation on dentin surfaces and they were shown to make dentin more acid-resistant [290,291].
Calcium sodium-phosphosilicate toothpaste was more effective in increasing acid resistance compared
with CCP–ACP NP toothpaste [291]. Rajendran and colleagues showed, in vitro, that toothpaste
containing BAG NPs (calcium sodium-phosphosilicate) was less effective than toothpaste containing
CPP–ACP NPs to remineralize the enamel of carious lesions [292]. Even if the new HA layer formed in
response to the presence of BAG NPs is similar to those of enamel or dentine, it presents better resistance
to abrasion [293]. In vitro, Farooq and colleagues proved that fluoride-containing bioactive glass had
better capacities of remineralization compared to BAG toothpaste and sodium monofluorophosphate
toothpaste [294]. In a randomized clinical trial, Patel and colleagues demonstrated that the 5%
fluorocalcium phosphosilicate-containing bioactive glass toothpaste further reduced hypersensitivity
compared with an 8% arginine and calcium carbonate toothpaste and a placebo toothpaste [295].
Moreover, BAG NPs toothpaste has demonstrated anti-bacterial properties [281]. In their
systematic review, Dai and colleagues explained that very few and only in vitro studies investigated
the anti-microbial effect of BAG NPs because researchers focused on the remineralizing capacities [281].
However, a concentration of BAG NPs twice that of CMB can inhibit S. mutans biofilm [296]. To fight
bacteria, BAG NPs release alkaline ions that cause the pH to rise and thus create an environment in
which bacteria cannot grow.
A higher resistance to acid dissolution is obtained by adding fluoride to BAG, allowing formation
of fluorapatite on the tooth surface [297]. This deposit of fluoroapatite on the dentine surface occludes
dentine tubules and decreases permeability [298]. Strontium can also be added to BAG to increase
bonding capacities [299]. The dissolution of hydroxyapatite by the acid produced by cariogenic bacteria
can be inhibited by the incorporation of strontium and fluoride into BAG. Strontium can replace
calcium for precipitate formation, and it has synergistic caries inhibition effect with fluoride. Therefore,
due to its capacities to remineralize dental hard tissues, strontium can prevent caries lesions [300].
5. Complementary Content
Cosmetic products are placed in contact with external parts of the human body, with mucous
membranes of the oral cavity, and with teeth. The development of nanotechnology has opened up
new perspectives for innovation in oral cosmetics; simultaneously, the use of very small particles
in user products has increased preoccupation about their safety to human health [301,302]. Due to
the potential for modifications related to biokinetic behavior, toxicological effects, and the size of the
physico-chemical properties of materials at the nanometric scale, exposure to NPs through the use
of cosmetic products can constitute a risk of harmful consequences from persistent and insoluble
nanoparticles that can arrive at involuntary sites in the organism and interact with biological entities
close to molecular proportions [303].
In the case of NPs, the chemical composition is not alone in influencing potential toxicity. Other
properties, including size, play a role in this, allowing NPs to escape the body’s defense mechanisms
and to interact with biological constituents [38]. Consequently, the safety-in-use of these produces has
been established by measuring the substances, their toxicity profiles, chemical structures, and exposure
types [303,304]. Specific attention is required for long-term safety considerations, as cosmetic products
can be widely used over a large part of the human lifespan and sensitive groups of the population,
such as children, may be affected [303].
In practice, cosmetic products have seldom been related to severe health hazards, which, however,
does not imply that cosmetics are secure in use per se (SCCS 8th revision). However, among all
cosmetic products, taking an interest in the risks linked to oral exposure to oral cosmetics such as
toothpaste and mouthwash is relevant because they can be inadvertently ingested. If, to assess oral
exposure, the procedure followed is similar to that used for NPs for other cosmetic ingredients [305],
it is considered that the size and agglomeration state of NPs may differ from having low pH in
the stomach and high ionic strength throughout the gastrointestinal tract. NPs can even lose their
nano-specific properties, due to a deterioration or dissolution. For such NPs, properties and effects are
more probably similar to those of the corresponding ions [306,307].
Estimated daily exposure levels for toothpaste in adult and mouthwash cosmetic product types
according to Cosmetics Europe data were described in detail by Hall and colleagues [308]. A literature
overview (2016–2018) of specific cosmetic consumers described exposure data and assessments by
product category, of which three concerned toothpaste [303]. Gomez-Berrada and colleagues evaluated
in French families the consumption and exposure to dentifrice, leaving consumers free to use their own
product at home in accordance with their practices [309]. In 2018, Bernard and colleagues produced a
probabilistic evaluation of the exposure of oral cosmetics using recent data from French consumption
across different age groups [310]. Finally, Strittholt and colleagues, in an RCT study, looked for
whether there was a difference in the amount of toothpaste ingested by children using pea-size dosing
instructions [311].
6. Conclusions
Nanotechnology has brought enormous changes to the field of preventive dentistry. Currently,
these developments are found on a large scale in various activities related to oral prophylaxis.
Currently, oral care products such as toothpastes and mouthwash contain NPs with anti-microbial,
anti-inflammatory, and remineralizing properties. Because of promising results and varied and often
unpublished properties, nanomaterials contain very diverse potentialities, and their uses prompt
multiple perspectives that make it possible for them to be effective. However, the advantages of
NPs are the same reasons that make them dangerous—small size, surface properties, quantum state,
migration, aggregation, mutation, and the creation of free radicals. Therefore, research into NPs is
currently one of the most studied branches of science, due to the almost unlimited fields of application,
and therefore regulatory and safety concerns must be discussed and questioned, especially concerning
the use of hydroxyapatite NPs in oral care products.
Author Contributions: D.B. and F.C. conceived and designed the manuscript. D.B., F.C., C.G., L.O. and S.V.
drafted all the manuscript paragraphs. D.B., F.C., C.G., L.O. and S.V. approved the final version of the manuscript.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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nanomaterials

Keywords: nanoparticles; oral cosmetics; toothpaste; mouthwash; biofilm; caries; periodontology;

Nanomaterials 2020, 10, 140; doi:10.3390/nano10010140 www.mdpi.com/journal/nanomaterials

2. Properties and Structural Features of Nanosystems (Nanomaterials and Nanoparticles)

3. Nanoparticles as Anti-Microbial and Anti-Inflammatory Agents in Oral Care Products

Figure 1. Action of nanoparticles (NPs) contained in oral care products.

3.1.1. Anti-Microbial and Anti-Inflammatory Mechanism

3.1.2. Silver Nanoparticles

3.1.3. Gold Nanoparticles

3.1.4. Zinc Oxide Nanoparticles

3.1.5. Titanium Dioxide Nanoparticles

3.1.6. Copper Oxide Nanoparticles

4. Nanoparticles as Remineralization Agents

4.2. Casein Phosphopeptide–Amorphous Calcium Phosphate

4.3. Bioactive Glass

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