Introduction

Metals are an integral component of various dental restorative and prosthetic materials. Their mechanical properties like elastic modulus, tensile strength, and hardness confer strength and durability to the dental restorations and prostheses, when exposed to functional loads in the oral cavity [1]. The metals applied in dentistry include both noble (e.g., gold (Au), silver (Ag), palladium (Pd), and platinum (Pt)) and base metals (e.g. copper (Cu), zinc (Zn), titanium (Ti), nickel (Ni), chromium (Cr), zirconium (Zr), beryllium (Be), boron (B), and aluminum (Al)) [2]. They may be used alone or in the form of alloys, for restorative and prosthetic purposes.

Lately, nanoparticles (NPs) of metals or their compounds have been incorporated into the dental restorative materials, pulp capping agents, denture-base materials, implants, orthodontic appliances, and oral hygiene aids [3]. Besides improving their physiochemical and mechanical properties, the NPs of metals like Ag, Cu, Au, Ti, and Zn are antibacterial in nature. Therefore, they may be helpful in inhibiting the dental plaque biofilm. In orthodontics, the NP-coated arch wires, adhesives, elastomeric ligatures, temporary anchorage devices, orthodontic wires with shape memory and biofilm control features, and nanometal-coated brackets have been applied [4]. Among them, the NPs of Ag, Au, ZrO2, and TiO have been added to the orthodontic adhesives to increase their compressive, tensile, and shear bond strengths [5, 6]. The NPs of Ag, Cu, and Zn produce an antibacterial and antibiofilm effect when coated on orthodontic brackets [7]. They have also been applied on the stainless steel arch wires to reduce the frictional forces between the wires and the bracket [4, 8].

These NPs are less than 100 nm in diameter which increases their ratio of surface area to volume, chemical reactivity, and biological activity [9]. Their antibacterial effect is mainly attributed to the former and metal-ion release [10]. They even generate reactive oxygen species (ROS) that react with the microbial membranes, damage their structure, and inactivate the bacteria. Furthermore, their unusual crystalline morphologies with a high number of edges and corners, and other potentially reactive sites increase their antibacterial effect [10].

Although metal NPs have better mechanical properties and esthetic outcomes, little is known about their toxicological aspects when functioning for a long time in a living organism [11]. This is specifically true for the restorations incorporating NPs as they may undergo dissolution in the saliva or chemical or physical destruction, erosion from food, wear by chewing, bacterial activity, and variations in temperature and pH [12, 13]. Subsequently, the metal ions released into the oral cavity may enter into systemic circulation through oral fluids and blood vessels. They may be taken up by the cells due to their small particle size and may be localized, undergo degradation and exocytosis [14]. Conversely, they may cause cytotoxicity, genotoxicity, and inflammatory responses [15]. The severity of these reactions is dependent on the size, shape, surface chemistry, and the cell types exposed to the metal ions [15].

As the nanometals have been recently introduced in dentistry and are widely incorporated for improving the antimicrobial and mechanical properties of various dental materials, the present review aims to gain an insight into the applications of nanometals in dentistry. It also describes the plausible toxic implications of these nano metal particles on oral and general health.

Materials and Methods

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed to identify the research publications on applications of nanometals and their oxides in dentistry. Further, articles related to their adverse effects on oral health were also searched. The databases searched were Medline (PubMed), Scopus, and Web of Science. A combination of keywords like “Nanometals” OR “Nano” OR “Silver” OR “Titanium” OR “Gold” OR “Platinum” OR “Palladium” OR “Zinc” OR “Copper” OR “Zirconia” OR “Nickel” OR “Oxides” OR “Toxicity”, AND “Dentistry” were used. They were verified in the titles, abstracts, or keywords during the initial search. It resulted in a total of 572 articles (Fig. 1). The data was screened for duplicates which resulted in 507 articles wherein the titles and abstracts were read. The eligibility criteria were free full-text original articles in English language related to the applications and toxicity of the above nanometals and their compounds in dentistry. Only articles published from 2009 to 2019 were included. Any kind of recommendations, expert statements, reviews, technical reports, case reports, and non-original papers were excluded. Furthermore, only studies reporting incorporation of NPs of metals in the dental materials were included. This resulted in 104 original research articles of which 49 were excluded after reading the full text. Finally, full texts of 55 original studies have been included in the review [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67]. The nanometals used in the dental material, the type of dental material, their surface characterization, size, concentration, mechanism of action and toxic effects, if any, were recorded (Tables 1 and 2).

Fig. 1
figure 1

Evidence search on applications of nanometals in dentistry and their toxic implications

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Table 1 Applications of nano metals and their compounds in dentistry
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Table 2 Evidence related to toxicity of nano metals used in dental materials
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Results

Of the 55 studies that were included in the review, 48 reported the applications of nano metals in dentistry. Among them 42 were in vitro studies, 2 were animal studies while 4 were randomized controlled clinical trials [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. About 5 in vitro and 1 animal study investigated the toxic implications of nanometals used in various dental materials [62,63,64,65,66,67]. The following sections discuss the applications and toxic implications of the nanometals used in dentistry.

Applications of Nanometals in Dentistry

In dentistry, the applications of nanometals range from diagnosis to preventive and therapeutic purposes (Fig. 2). As already stated, they improve the mechanical properties and confer antimicrobial activity to the different materials (Fig. 3). Their applications in dentistry as reported in various studies are summarized as follows (Table 1):

  1. a.

    Nanometals used in various dental materials

Fig. 2
figure 2

Applications of nanometals in dentistry and mechanism of their plausible toxicity

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Fig. 3
figure 3

Synthesis and antimicrobial effect of nanometals used in dental materials

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The most common nanometals used in the dental materials were Ag, Ti, Cu, Au, Zn, and Zr [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. The Ag and Au were used in their pure form while the nano-oxides of Ti, Zn, Cu, and Zr were employed more often [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. They were incorporated in the composite resins, acrylic denture base resins, endodontic materials, dental implants, restorative cements, and orthodontic brackets and adhesives where they showed improved antimicrobial, mechanical, and regenerative properties which would be discussed in the later section [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. The nanometal particles were incorporated into the following dental materials:

  1. i.

    Restorative materials

The restorative materials like composite resins produce excellent esthetics and load-bearing properties but often undergo failure due to biofilm accumulation, secondary caries, and bulk fracture [68, 69]. Likewise, inadequate instrumentation or microleakage in the filled root canals results in treatment failure [70]. The NPs of Ag, ZnO, and Zr were added to composite resins, cavity varnishes, glass ionomer cement (GIC’s), intracanal medicaments (e.g., calcium hydroxide [Ca (OH)2]), sealers, and root end materials (e.g., Portland cement and mineral trioxide aggregate (MTA)) to overcome these problems [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37].

  1. ii.

    Prosthodontic materials and dental implants

The full mouth rehabilitation for the lost teeth is usually done with the help of acrylic partial/complete dentures or dental implants. The dentures are made of poly methyl metha acrylate (PMMA) resin which has a rough inner surface that favors biofilm accumulation [71]. It promotes colonization by Candida that causes denture stomatitis, specifically in elderly [72]. The dental implants, although a predictable method for oral rehabilitation may undergo failure due to mechanical (e.g., static and dynamic occlusal load) and biological (e.g., biofilm accumulation and invasion) factors [73, 74]. In order to overcome these problems, NPs of Ag, ZrO2, and TiO2 were added to the PMMA or coated on the surfaces of dental implants [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57]. They improved their antimicrobial and mechanical properties as well as favored osseointegration and soft-tissue healing around the dental implants [51,52,53,54,55,56,57].

  1. iii.

    Orthodontic appliances

The orthodontic treatment is often complicated due to the development of white-spot lesions and dentinal caries. The orthodontic brackets act as plaque retentive factors that promote biofilm formation, proliferation of the facultative bacteria, reduced pH, and enamel demineralization [75]. The addition of NPs of Cu and Zn oxides to orthodontic brackets inhibited plaque biofilm and produced an anti-caries effect. Besides increased biofilm formation and caries, frequent de-bonding of the orthodontic brackets often prolongs the treatment time [6]. This was attributed to reduced bond strength of the orthodontic adhesives used to bond the brackets to the tooth surface. The nanofillers of Zr and Ti oxides were added to improve the bond strength [7, 58].

  1. iv.

    Other applications

Some other uses of nanometal particles include oral diagnosis whereby the NPs of Au, Ag, Pt, and Pd were incorporated into the nanobiosensor transduction/bioreception systems. These NPs rapidly reacted with most biological molecules. The NPs of Au specifically enhanced the electronic signals when the analyte was at very low concentrations [76]. They were applied on toothbrushes along with the AgNPs where they enhanced the effects of mechanical plaque control owing to their antibacterial action. This helped in better reduction of periodontal diseases [76]. The AgNPs have also been added to the anticaries components of dentifrices like calcium glycerophosphate [59, 60].

  1. b.

    Surface characterization of nano metal particles in various dental materials

The surface characterization enables determination of size, shape, concentration, and dispersion of the nanometals in various materials. In the research reviewed here, the physical characteristics of metals were analyzed through transmission electron microscopy (TEM), X-ray photon spectroscopy, scanning electron microscopy (SEM), dynamic light scattering, inductively coupled plasma-optical emission spectrometry, UV–Vis spectroscopy, X-ray diffraction, atomic force microscopy, X-ray photon spectroscopy, and field-emission scanning electron microscopy [7, 18, 19, 21, 23, 27, 30, 31, 38, 44,45,46,47,48,49, 51,52,53, 55,56,57, 59,60,61]. Among them, the TEM was most commonly applied [7, 18, 21, 30, 31, 42, 51, 55, 56, 60]. They revealed the following characteristics of the nano metal particles:

  1. i.

    Size

The size, shape, and structure of NPs affects the reactivity, toughness, and other qualities including the optical properties of dental materials. This is significant for materials related to dental aesthetics like composite resins and denture bases. The size of NPs affects the color of these materials due to absorption of light in the visible region.

The size of nanometals ranged from 5 to 260 nm [30, 46]. The average size of AgNPs was between 5 and 100 nm [30, 38, 42]. The nano TiO2 particle size ranged from 10 to 93 nm [51, 53]. Likewise, the size of nano ZnO particles ranged from 20 to 225 nm [55, 61]. The particle size of nano CuO was 37 nm while that of Au was about 18 nm [7, 31]. The particle size of nano Zr and its oxide ranged from 40 to 830 nm [43, 46].

  1. ii.

    Shape and dispersion

The nanometals were mostly spherical in shape [21, 23, 25, 30, 31, 44, 59,60,61], although one study reported triangular configuration [19]. They were evenly dispersed in all the dental materials [19, 21, 23, 25, 30, 31, 49, 59,60,61].

  1. iii.

    Concentration

The concentration of the NPs varied according to the property of the material which was enhanced, i.e., antimicrobial or mechanical properties. For instance, the AgNPs were commonly used in concentration of 0.1 to 1 w/w% in the composite resins where they produced antibacterial effect and improved their flexural strength, elastic modulus, and shear bond strength [16, 24]. They produced antibacterial effect in bonding agents at 0.05 to 0.1w/w% concentration [16, 17] while the antifungal effect was seen when they were incorporated in the denture base resins at concentrations 2.5, 3 and 5w/w% [38,39,40]. In dental implants antifungal effect was produced at a concentration of 320 ppm [54]. They augmented the antibacterial effect of GICs, intracanal medicaments and dentifrices at concentrations 0.5w/w% [30], 100 ppm concentration [26] and 200 ppm [59], respectively. They increased the surface hardness of a cavity varnish at a concentration of 376.5 μg/ml [28].

The CuO NPs were incorporated in the concentrations 0.01, 0.5, and 1w/w% in the orthodontic adhesive. They enhanced its antibacterial property and shear bond strength [58]. Likewise, 3 to 5w/w% of TiO2 NPs improved the flexural and compressive strengths of GICs [23, 27]. In denture base resins, at 0.4, 0.5 and 1w/w% concentration, these NPs produced antibacterial and antifungal effects [41, 44].

In endodontic sealers and dental implants, the ZnO NPs were used either alone or in combination with Ag and TiO2 NPs to enhance their antimicrobial and mechanical properties [18, 55, 56]. They had a similar effect on composite resins, at 1 and 3w/w% concentrations [20, 25]. The nano Zr and its oxide were widely used in denture base resins, ceramics and restorative cements [6, 36, 37, 42, 43, 45,46,47,48, 50]. Their concentration varied from 1 to 20 w/w% in denture base resins, 30 w/w% in Portland and calcium silicate cements and 0.5 to 1w/w% in orthodontic adhesives [6, 36, 37, 42, 45, 47, 48]. The Zr NPs mainly enhanced the mechanical properties of these materials.

  1. c.

    Synthesis and methods of incorporation of nano metals in the dental materials

The nano metal particles may be synthesized by a top down or a bottom up approach (Fig. 3). The former includes lithographic techniques and etching while the latter consists of sputtering, chemical vapor deposition, sol–gel processes, spray pyrolysis, laser pyrolysis, and atomic/molecular condensation [77]. Lately, a “green synthesis” approach utilizing biological microorganisms like bacteria, fungi, algae, yeast, and plant extracts has been developed to obtain the NPs of metals like Au, Ag, Zn, and ZnO [77].

However, the studies included in this review utilized commercially available and chemically formulated nanometal particles [6, 20, 26, 39, 40, 58]. The AgNPs were prepared by the reduction of silver nitrate (AgNO3) with sodium borohydride, sodium citrate, or ethylene glycol [19, 38, 59, 60]. Besides, photoreduction was also applied on a mixture of AgNO3, tartaric acid, and PAA to obtain them [30]. A mixture of AgNO3 and zinc nitrate (ZnNO3) in gelatin was calcined at different temperatures to obtain ZnO: Ag composite NP powder, which was used as an endodontic sealer [18].

The AgNPs were incorporated with the help of a monomer, 2-(tert-butylamino) ethyl methacrylate (TBAEMA) in the polymeric dental material. This agent improved the solubility of Ag ions in the resin solution and its reactive methacrylate groups integrated with the polymer network upon photopolymerization [16, 17, 19, 24].

The AuNPs were synthesized by the reaction between the chloroauric acid trihydrate and sodium citrate. This resulted in a colloidal solution of AuNPs which was mixed with the calcium phosphate cement [31]. Likewise, a nano thickness film of TiO2 synthesized through the reaction between tetrakis (dimethylamido) titanium (TDMAT) and ozone was deposited on titanium implants using atomic layer deposition (ALD) technique [49]. Additionally, the TiO2 NPs were prepared through a modified sol-gel procedure utilizing titanium tetrabutoxide Ti (OBu) 4 and dimedone as a chelating agent. Some studies included commercially available TiO2 nanopowder in anatase phase [23, 27, 41, 44].

Both commercially available ZnO NPs as well as those synthesized by a modified sol-gel method from gelatin and ZnNO3 at high temperatures (500–700 °C) were used [21, 22, 25]. They were also synthesized from ZnSO4 and ZnCl2 [7, 61]. The CuO NPs were prepared by a reaction between copper acetate, glacial acetic acid, and sodium hydroxide [7]. It resulted in a black precipitate of CuO from which NPs were obtained.

The commercially available ZrO2 NPs (99.9% pure) were incorporated into the PMMA resin, orthodontic adhesives, ceramic restorations, and Portland and calcium silicate cements [6, 36, 37, 42, 43, 45,46,47,48, 50]. They were subjected to salinization process (addition of a silane coupling agent, 3-(trimethoxysilyl) propyl methacrylate (TMSPM) to ZrO2) which rendered their surface reactive and enabled adequate adhesion between the NPs and the resin matrix.

In the dental implants, the AgNP suspensions were either directly deposited on their inner cavity or applied on the surfaces of the titania nanotubes, by soaking the titanium disks in AgNO3 solutions followed by UV light irradiation from a high-pressure Hg lamp [51, 54]. Furthermore, the chemically synthesized AuNPs were deposited on the silanized Ti surface with the help of Au-S bonding. The TiO2 NPs were deposited with the help of a sol gel or anodic treatment and the ZnO NPs (prepared by flame pyrolysis) were deposited with the help of electro hydrodynamic spraying on the dental implants [52,53,54,55,56].

  1. d.

    The biological and mechanical effects of nanometals used in dental materials

The nanometals and their compounds are very similar to atoms due to their nanoscale size. This enables interactions at molecular levels in the biological tissues that surpasses those of micro- or macro-sized particles [76, 78, 79]. They are highly reactive as free surface atoms can form new and strong bonds and also allow the manipulation of NPs in a number of packing configurations [76, 79]. They have a low melting temperature due to high thermal vibrations of surface atoms in comparison with the core atoms [76, 80]. This is specifically useful in constructing porcelain fused to metal crowns, cast post and cores, or denture frameworks [76].

The following properties of nano metal particles were observed in the reviewed literature that make them ideal for use in dental materials:

  1. i.

    Antimicrobial property

In the present review, the Ag NPs were the most commonly applied antimicrobial nano metals followed by TiO2, Zn, ZnO, and CuO [7, 16,17,18,19,20, 22,23,24, 26, 27, 29, 30, 32, 34, 35, 38, 40, 41, 44, 49, 51,52,53,54,55,56, 58,59,60]. The bactericidal activity of nanometals is dependent on their size and shape [73] (Fig. 3). A study reported that smallest nano metal particles with spherical configuration were more bactericidal than the triangular and larger spherical shaped particles [73]. As already stated, in most of the studies the shape of the nano metal particles was spherical and their size ranged from 5 to 260 nm [19, 21, 23, 25, 30, 31, 44, 59,60,61].

In composite resins, PMMA or implants, the NPs of Ag, Zn, and TiO2 enhanced both antimicrobial and mechanical properties [16, 17, 19, 20, 24, 25, 38,39,40,41, 44, 49, 51,52,53,54,55,56]. In orthodontic brackets, adhesives, GIC, dentifrices, varnishes, and base plates they were mainly applied as antimicrobial agents [16,17,18,19,20, 24, 26, 28,29,30, 32,33,34,35, 38,39,40, 51, 54, 59, 60]. In some studies dual metal NPs, like TiO2 with AgNPs and UV irradiation were used to improve the antimicrobial effect [51].

The antimicrobial efficacy of AgNPs is mainly related to their interaction with the peptidoglycan cell walls of bacteria with resultant release of lipopolysaccharides and membrane proteins [81]. Further, their accumulation in the cell membrane increases the membrane permeability causing cell death. This phenomena was specifically useful for killing the microorganisms present in the biofilms. Further, their interactions with the exposed sulfhydryl groups in bacterial proteins prevented DNA replication. They even produced ROS that damaged the bacterial cell membranes [82]. An added benefit of AgNPs was reduced incidence of antimicrobial resistance [83].

In the composite resins, the AgNPs were incorporated in the polymer matrix. The Ag ions slowly oxidized to Ag2O in aerobic conditions. Their release rate was augmented by the acidic environment created by the adhered bacteria [30, 84]. Therefore, these modified composites acted as “smart surface” materials, whereby the concentration of Ag ions was controlled by the bacteria’s pathogenic action [30, 84]. They reduced the CFU’s of Streptococcus mutans (S. mutans) without affecting the dentin shear bond strength [16]. When combined with the NPs of amorphous calcium phosphate (NACP), they reduced biofilm formation, increased the release of calcium and phosphate ions, inhibited caries and promoted re-mineralization of enamel [17, 19, 24]. Likewise, the NPs of ZnO (1%) in composite resins also produced strong bactericidal effect against S. mutans and Lactobacilli [20]. In the GICs, the Ag ions (0.5 w/w%) added to the PAA liquid inhibited the growth of Escherichia coli (E coli) and S. mutans [30, 56]. At 5 w/w% concentration in PMMA, the AgNPs reduced adhesion and biofilm formation by Candida albicans (C. albicans) [38, 40]. Likewise, alongwith Ca (OH)2 intracanal medicaments, they helped in eliminating the Enterococcus faecalis (E. faecalis) from the infected root canals [48]. Addition of nano Ag (1% or 10%) to calcium glycerophosphate or to a colloidal solution of chitosan and fluoride in dentifrices, reduced the levels of ATCC strains of C. albicans and acid production by S. mutans [59, 60]. A combination of ZnO and AgNPs in endodontic sealers effectively controlled the E. faecalis proliferation in root canal space [18]. A coating of Ag, TiO2, and ZnO NPs on the dental implant surfaces prevented biofilm formation by the initial colonizers like C. albicans, Streptococcus sanguis (S. sanguis) and Actinomyces naeslundii (A. naeslundii) [51, 52, 54,55,56]. The antimicrobial effect of AgNPs was also demonstrated in randomized controlled clinical trials included in this review [32,33,34,35].

The CuO NPs in orthodontic adhesives were bactericidal against the S. mutans [7, 58]. Like AgNPs, their bactericidal effect was also related to the production of ROS [85]. The TiO2 NPs were effective against the S. mutans, S. sanguis, A. naeslundii, Lactobacillus acidophilus (L. acidophilus), Candida scotti (C. scotti), and C albicans [23, 27, 41, 44, 49, 52, 56]. They were deposited in situ on the denture base resulting in a smoother hydrophilic surface with increased surface wettability [49]. This inhibited the initial attachment of Candida on the denture base.

The ZnO NPs incorporated in the dental implants showed bactericidal effect against Streptococcus, Staphylococcus, and anaerobes [55, 56]. It was suggested that the ZnO NPs selectively targeted Staphylococcus aureus (S. aureus), and their small particle size increased the penetration into the dentinal tubules [86]. This facilitated elimination of E. faecalis when used in combination with chlorhexidine as an intracanal medicament [22]. Their coating on orthodontic brackets reduced the levels of S. mutans to zero [7]. This was also evident when a combination of CuO and ZnO was incorporated in orthodontic adhesives and brackets [7, 58].

The antimicrobial effect of various nanometals was determined with the help of colony forming units (CFUs) and minimal inhibitory concentrations (MIC). The MIC of AgNPs against E. coli, Pseudomonas aeruginosa (P. aeruginosa), and S. aureus were 0.49, 0.975, and 1.95 ppm respectively [19]. Their minimum bactericidal concentration (MBC) and MIC ratio was ≤ 4 which indicated that AgNPs were strongly bactericidal against these organisms [19]. Furthermore, the MIC against the C. albicans and S. mutans was influenced by the type of reducing agent used for preparing the Ag ions, as it affected their concentration [59]. In dentifrices, a 200 ppm concentration of AgNPs was inhibitory for the S. mutans [60].

  1. ii.

    Mechanical properties

The nano metal particles like Ag, ZnO, TiO2, and ZrO2 improved the compressive, flexural and microhardness of various dental materials at a relatively low filler level [6, 16, 23, 24, 27, 28, 30, 36, 39, 42, 43, 45,46,47,48,49,50, 58]. This was related to their nano scale size that increased their surface area. However, incorporation of 5 wt % of AgNPs to PMMA reduced its tensile strength, owing to reduced number of particles per unit area of the matrix and void formation from the entrapped air and moisture [39]. The heterogenous dispersion and agglomeration of the particles produced stress concentration centers that prevented chemical bond formation between the AgNPs and PMMA [39, 87]. Conversely, the AgNPs increased the compressive strength of GIC by 32% when they were homogeneously distributed in the matrix as increased crosslinking between the polymer chains prevented crack propagation [30]. Like AgNPs, the TiO2 NPs also improved the flexural and compressive strengths as well as micro hardness of the GIC [23, 27].

Some studies have demonstrated that incorporation of AgNPs to nano ZnO based endodontic sealers, increased microleakage [18, 21]. This was attributed to the larger particle size of ZnO:Ag composites which could not diffuse into the root bone junction [18, 21]. The microleakage was minimum with ZnO nano-powders calcined at 500 °C [21]. Alternatively, the ZnO NPs increased the microshear bond strength and reduced microleakage of composite resins [25]. They reduced the dentinal fluid flow, increased the complex modulus values at intertubular and peritubular dentin, fastened the active dentin remodeling and tubular occlusion which reduced the dentinal hypersensitivity [28, 61].

The nano Zr significantly increased the flexural strength and surface hardness of the PMMA [42, 43, 45- 48, 50]. This was attributed to the phenomena of “dispersion strengthening” whereby the small, tough, and crystalline Zr NPs, homogeneously distributed in the PMMA matrix, prevented the crack propagation [45, 88]. However, a study showed that a 5 wt% concentration of these NPs reduced the flexural strength due to agglomeration of the untreated nanofillers [47]. Conversely, a 7.5 wt% concentration of nano-ZrO2 when added to the unreinforced resin, increased its flexural strength [43]. It was suggested that the silanization process and the joint’s surface design, played an important role in improving the properties of PMMA [43]. The transformation of ZrO2 from the tetragonal to monoclinic phase, absorbed the energy of crack propagation resulting in “transformation toughening” [43]. It expanded the ZrO2 crystals which placed the crack under compressive stress and arrested its propagation. They even increased the transverse strength of autopolymerized resin. This was related to increased interfacial shear bond between the NPs and the polymeric chains [42, 89]. The maximal transverse strength was recorded with 5 wt% of nano Zr. Conversely, another study reported reduction in transverse strength when various ratios (5, 10, and 20%) of nano-ZrO2 were added to the heat-cured PMMA [47]. It was related to a non-homogenous distribution of the NPs and water sorption in the microcracks within the PMMA matrix. Besides, combination of glass fibers (GFs) with nano ZrO2 (2.5% nano-ZrO2 + 2.5% GFs) increased the flexural strength of PMMA by 45% and impact strength by 51% [50]. An inverse relationship was seen between the concentration of ZrO2 NPs/GFs and the flexural strength. However, addition of ZrO2 NPs to PMMA hindered its translucency due to differences in the optical properties and distribution within the resin matrix [48]. As the ZrO2 NPs were crystalline (high opacity) and formed clusters, the absorbed light was unable to pass resulting in decreased translucency. The difference between the refractive indices of the fillers and matrix affected the refraction and reflection of light at the filler/matrix interface. These effects were inversely proportional to the concentration of ZrO2 NPs.

Besides the PMMA, the ZrO2 NPs improved the compressive strength and radio-opacity of the Portland/MTA cement [36, 37]. The MTA consists of calcium silicate and a radio pacifying agent, the bismuth oxide (Bi2O3) in 4:1 ratio [36]. The Bi2O3 confers high radio-opacity to Portland cement but interferes with its hydration mechanism [36, 90]. It causes precipitation of Ca(OH)2, alters the microstructure of the cement, and increases its porosity and solubility [36]. It is mildly cytotoxic as it interferes with human dental pulp cell growth [36, 91]. The ZrO2 NPs (1:4 ratio) were used as an alternative to Bi2O3 in MTA or Portland cement [36, 37]. It provided adequate radiopacity along with the release of calcium ions and alkaline pH without affecting the hydration reaction [36, 37]. Improved mechanical properties were also seen in yittria reinforced Zr sintered to ceramics [46].

Besides, the size of NPs, the technique of their deposition may influence the mechanical properties [49]. For instance, deposition of a nano thickness film of TiO2 on the denture base by ALD technique, improved its wear resistance and decreased the wetting angle to 5° [49].

The TiO2 NPs added at 3 and 5 w/w% concentrations to GIC, significantly enhanced its fracture toughness, compressive and flexural strengths and hardness [23]. A dually modified GIC with chitosan in the liquid phase and TiO2 NPs in the powder phase showed similar effects [27]. However, a previous study reported that incorporation of 7% (w/w) of TiO2 NPs compromised the mechanical properties and adhesion of GIC [23, 92].

  1. iii.

    Bone regeneration

The nanometals may stimulate osseointegration, i.e., formation of a direct connection between living bone and the dental implants [31]. For instance, a study utilizing AuNP-calcium phosphate cement (CPC) scaffold suggested that AuNPs induced osteogenic differentiation of human dental pulp stem cells (hDPSCs) [31]. They improved the wetting, protein adsorption, cell attachment, and spreading properties of CPCs. The AuNP-CPC scaffold enhanced the cell functions and inhibited osteoclast formation. It easily conjugated with Ti and promoted the osteogenic differentiation of other cells like human adipose derived stem cells [57].

Likewise, the sol-gel–derived nanoporous TiO2 coatings enhanced the soft-tissue attachment around implants in both animal and human models [52]. A study showed that the TiO2 deposited by a fast electrochemical anodization treatment produced nano-tubes on the Ti surfaces which enhanced the bone growth, protein adsorption, and cell adhesion [53]. Some studies incorporated AgNPs into these nanotubes which promoted osseointegration [51, 55, 56].

Toxicity Related to Nanometals Used in Dentistry

Although nanometals provide numerous benefits, very little is known about their toxic effects on humans, specifically when incorporated in the dental materials. Evidence from short-term in vitro studies shows that the nano dental materials are non-cytotoxic [62,63,64, 66, 67]. However, these results cannot be generalized. As the dental materials remain functional in the oral cavity for a longer duration, there is a high probability that the NPs from these materials may leach out into the saliva and produce systemic effects [15]. They undergo biodegradation in the oral environment which includes both destruction and dissolution in saliva as well as chemical/physical destruction, wear, and erosion caused by food, chewing, and bacterial activity [93]. Therefore, the material reactivity in the oral cavity is mainly governed by the thermo-dynamic principles and electro-chemical reaction kinetics. Subsequently, when an alloy is placed in the oral cavity, the alloy-saliva system is driven towards a state of thermo-dynamic equilibrium. At this stage, the alloy may remain stable in its elemental form or oxidize into its ionic form (corrosion). The uncharged elements inside the alloy may lose electrons and become positively charged ions which are released into the saliva. They may affect the surrounding tissues or enter the systemic circulation [93]. The same mechanism may be applied to the nano metals used in dental restorations. Therefore, it is imperative to evaluate their long-term toxic effects. Since there were no studies related to this aspect, the following section would describe the factors affecting and mechanism of toxicity induced by nano metal particles. Further the studies evaluating their toxic effects when included in dental materials would be discussed [62,63,64,65,66,67].

Mechanism of Toxicity from Nanometal Particles

The toxicity depends on different parameters like size, surface area, surface characteristics, stability, and routes of exposure resulting in cytotoxicity, genotoxicity, increased inflammation and reticuloendothelial system (RES) toxicity (Fig. 2) [94]. Their adverse effects on different organ systems have been listed in Table 3 [95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111]. These factors were detailed in an earlier study [94].

  1. a)

    Size and surface area of nano metal particles

Table 3 Toxic effects of various nanometals and their compounds on body organs
Full size table

The size of nanometal particles mediates the cell responses, including uptake, cyto-toxicity, ability to penetrate the biological barriers, and immunological responses [112]. As the size decreases, the surface area to volume ratio increases which subsequently increases their reactivity. For instance, the ROS generation and degradation of AgNPs into ions is dependent on their size [113]. It has been reported that a reduction in particle size from 30 to 3 nm increases the number of surface particles from 5 to 50% which subsequently increases their chemical reactivity [94, 114]. These surface atoms affect the cell organelles like mitochondria, lysosomes, nucleus, and genetic material resulting in cytotoxicity and genotoxicity.

Studies have shown that NPs of metals like Ag are easily internalized due to their small size and induce changes in the cell shape and viability [96]. Their active surface stimulates generation of ROS and hydroxyl radicals from lysosomes, leading to increased oxidative stress [113, 115]. The lysosomes become swollen and their membranes rupture due to lipid peroxidation [113, 116]. Eventually, the cathepsins are released into the cytoplasm which activates the lysosome-mediated apoptosis [116]. It has been shown that the AgNPs and Ag ions have preference for the thiol groups [113]. Therefore, the molecules with thiols in the cytoplasm, cell membrane, and inner membrane of mitochondrion, serve as their targets [113, 117]. As a result of lipid peroxidation, the membrane permeability increases and the cytoplasmic contents are leaked out, resulting in cell necrosis. The damage to mitochondrial membrane hinders electron transfer and adenosine triphosphate production which further triggers oxidative stress, and mitochondrion-dependent apoptosis [113, 116, 118]. The nanometer particle size also enables the AgNPs to translocate into the nucleus with the help of nuclear pore complexes [113]. Inside the nucleus they interact with the DNA leading to DNA damage through the direct or indirect mechanisms. The direct DNA damage involves localization of the NP in the nucleus causing mutations while the indirect genotoxicity occurs due to oxidative stress [94, 119]. The latter is related to chronic inflammation caused by activation/recruitment of immune cells, such as macrophages and/or neutrophils by the NPs. The nano metal particles of Ag, Au, and metal oxides like TiO2 and ZnO have been reported to cause DNA damage [94, 119, 120].

Although the nano metal particles and their oxides are believed to inhibit the production of pro-inflammatory cytokines, their interaction with the immune system cells (leukocytes, neutrophils, monocytes, platelets, dendritic cells and macrophages) may result in pro-inflammatory effects [94]. The NPs like those of Ag may enhance the release of cytokines like interleukin (IL)-1β by inducing inflammasome formation and caspase-1 activation [116]. They were reported to be cytotoxic to human blood monocytes. Stimulation of cell signaling pathways (e.g., nuclear factor kappa–B (NF-κB), mitogen activated protein (MAP)-kinase) accentuates the release of other pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and tumor necrosis factor (TNF)-α) [78, 94] (Fig. 2). The NPs of Au, Ti, Cu, and Zn have also been shown to produce similar effects through activation of these pathways [120,121,122]. The transition metals in metallic NPs may further enhance these processes by inducing Fenton’s and Heiber-Weiss reaction [123, 124]. This phenomena has been reported with the AgNPs. Its apoptotic effects have been attributed to activation of c-Jun N-terminal kinase (JNK) pathway [125]. The ZnO NPs damage the mitochondria as toxic concentrations of Zn ions destabilize the lysosomes. Their internalization or interaction with the cell surface induces toxicity by similar mechanisms [94, 126].

The RES clears the NPs by directing them towards the liver and spleen [127]. They are sequestered or filtered by the kidney. It has been noted that less than 5% of NPs reach the diseased site and the rest are cleared by the liver, spleen, and kidneys [128]. In general, the NPs of about 10 nm size are rapidly filtered out by the kidneys while those larger than 200 nm are cleared by the spleen [129]. The nanometal particles used in the dental materials fall in this range and may have a role in RES toxicity, which needs further verification.

  1. b)

    Surface characteristics

The surface of NPs is one of the important factors determining their toxicity potential as it influences their cellular uptake. The cationic NPs are more reactive when compared with the anionic ones and can be easily taken up by the cells [94, 130, 131]. This is mainly related to the electrostatic attraction between the negatively charged cell membrane glycoproteins and positively charged NPs [115]. They are also more strongly bound to the negatively charged DNA and damage it. Subsequently, the G0/G1 phase of the cell cycle is prolonged [132]. Studies have shown that positively charged AuNPs were easily adsorbed on the cells and were more toxic when compared with their negatively charged counterparts [133].

The positively charged metal NPs have enhanced opsonization potential, i.e., they promote adsorption of proteins including antibodies and complement components, from blood and biological fluids like saliva on their surfaces [132, 134]. These adsorbed proteins form “protein coronas” which affect the surface properties of the NPs [132]. For example, they may alter the surface charge, aggregation characteristics, or size of the NPs [132]. The conformational changes in the proteins may alter or inhibit their functional activities as well. They may either lose their enzymatic action or disturb the biological processes resulting in diseases [132]. Certain techniques have been developed for changing the surface charge of the NPs in order to improve their therapeutic efficacy and reduce toxicity. For example, the NP surfaces and their charges could be modified by grafting differently charged polymers like polyethylene glycol or folic acid to improve their intracellular uptake [135]. The biocompatibility of TiO2 NPs was improved through incorporation of functional NH2 or SH groups [136].

As the nanometal particles used in dental materials are cationic in nature, they may easily penetrate the cells and induce toxicity. They may either stimulate or suppress the immunogenic responses and toxicity in vivo [94, 137].

The shape of NPs also affects their cellular uptake. For instance, rod-shaped AuNPs were readily taken up by the dendritic cells than the spherical- or cubic-shaped particles. This was related to the larger surface volume of rod shaped particles, which may then have increased toxic effects [138].

  1. c)

    Stability of NPs and presence of impurities

The chemically stable NPs are less toxic when compared to the unstable ones. Moreover, NPs with impurities may readily undergo aggregation. This increases their toxicity due to excessive generation of ROS and inflammatory mediators [94]. This was reported with AgNPs in animal studies [139].

  1. d)

    Route of exposure

The exposure route determines the initial interaction of NPs with cells/tissues. The most common routes of exposure include inhalation or direct contact with materials containing NPs [94]. They may reach toxic concentrations in the body which may affect the brain, liver, spleen, lymph nodes, and other organs [94]. Increased exposure to metal oxide NPs (ZnO, TiO2, Al2O3, or CeO2) by aerosol reduced the tidal volume and increased the respiratory rate in mice [140]. The NPs of ZnO and TiO2 may induce nasal irritation. The ZnO NPs may cause significant toxic effect in the airways while TiO2 may result in DNA-strand break.

Toxicity Studies on Nanometal Particles and Their Oxides in Dental Materials

The dental patients as well as the practitioners may be exposed to NPs of metals and their oxides either through accidental or incidental ingestion of the dental materials [141]. Although the dental materials for permanent restorations are investigated for their stability and biocompatibility in oral environment, toxic compounds may be generated through material degradation, or inappropriate application by the clinician [15]. This was reported with the use of dental amalgams and metal alloys used for crown fabrication [142, 143]. However, similar information for dental materials containing nano metal particles is lacking. The NPs generated during treatment may cause systemic toxicity or direct toxicity to the cells/tissue of the oral mucosa. These effects have been evaluated in various in vitro and animal studies that focused on exposure to TiO2, ZrO2, and Ag NPs [62,63,64,65,66,67] (Table 2).

The occupational exposure may occur in dental laboratories or clinics whereby NPs of metals may be released during the manipulation of the materials [141]. This includes mixing of materials in paste form or milling of the set materials. For instance, peak concentrations of these NP in the aerosol were observed when the dentist was finishing or polishing the set composite restorations on the front teeth without water coolant [141, 144, 145]. It was found that the aerosol mainly contained the nano-sized particles with concentrations above 106 particles/cm3, in the breathing zone of both patient and the dentist [141, 145]. The NPs of metals are rarely released from the set materials in the patient’s oral cavity. However, they may be generated through wear process and swallowed. These NPs apparently reach the intestine from where they may enter into the lymphatic system [141]. The wear rates have been reported to be least for ceramic restorations followed by the composites and GICs [141, 146].

Previous research work has demonstrated that NPs of TiO2 may be absorbed across the lungs and gastrointestinal tract [147]. The Ti NPs may be released from the dental implants into the surrounding periodontal tissues or newly regenerated bone [141, 148,149,150]. A postmortem study showed that highest concentration of Ti NPs generated during or after the insertion of implants was in human mandibular bone (37,700 μg/kg of bone weight at a distance of 556–1587 μm from the implants) [141, 151]. Their concentrations were inversely proportional to the distance from the implants. The sizes of particles ranged between 0.5 and 40 μm in human jaw bone marrow tissues, at distances of 60–700 μm from dental implants [141, 151]. The AgNPs release rate has been found to be 550 μg/l after 168 h [152]. There is also a risk of exposure from environmental contamination due to improper disposal of dental materials containing nanometal particles.

In vivo studies on rodents revealed increased accumulation of nano metals from dental materials in the internal organs which could result in organ pathology. For instance, single oral gavage of TiO2 NPs (25 or 80 nm) caused pathological changes in the liver and kidney of mice; chronic ingestion of colloidal silver solution caused argyria in humans [153, 154]. A recent review suggested that NPs of metals like Au, Ag, and Ti from dental materials could cross the blood-brain barrier or translocate through sensory nerves resulting in neurotoxicity [155].

As the oral epithelium is mostly non-keratinized stratified squamous epithelium, with the exception of gingiva, hard palate and dorsal surface of the tongue, there is a plausibility for direct contact of NPs with the cells and tissues of the oral cavity [15]. They may induce hypersensitivity reactions or inflammation in a vulnerable patient. The Ag, TiO2, ZnO, and Au NPs commonly used in dental materials may slowly dissolve into more toxic ionic forms. However, the studies have reported that these metals were not cytotoxic to the surrounding cells. For instance, a novel AgNPs endodontic irrigant was not cytotoxic to human periodontal ligament stem cells (hPDLSCs) and the mouse fibroblasts over a 48-hperiod [64]. Similarly, Ag NPs incorporated in MTA did not cause any reaction in the rat connective tissue [65]. The GICs containing Zr NPs and microparticles were reported to be non-genotoxic [67]. Although the TiO2 NPs, are considered to be non-cytotoxic, moderate cytotoxicity on human gingival fibroblasts was reported when they were incorporated in an orthodontic adhesive (1% w/w) [63, 66]. However, the cell viability percentages were similar to the unmodified adhesive [63]. Other NPs like those of Au in injectable calcium phosphate cement have been demonstrated inside the hDPSCs and postulated to interfere with the cellular behavior [31].

Recommendations to Reduce Toxicity from Dental Materials Containing Nanometal Particles

As the data on possible adverse reactions derived from metal NPs in dental materials or from manipulation of these materials is sparse, more research is required in this direction. Following suggestions may be helpful in preventing exposure to the metal NPs [141]:

  1. 1.

    The safety regulations for all dental materials should be strictly followed by the dental professionals.

  2. 2.

    The amount of dust generated may be reduced through proper carving of the restorations.

  3. 3.

    Barrier techniques like use of mouth masks or face shields may be helpful in reducing the exposure from aerosol released during handling of set materials.

  4. 4.

    High vacuum suctions or evacuators and coolants should be used when grinding and polishing the restorations intraorally.

  5. 5.

    Effective ventilation in treatment areas prevents accumulation of the particles in the localized environment and hence inhalation.

  6. 6.

    Encapsulated powder/liquid systems should be used to avoid exposure during manipulation of materials.

  7. 7.

    Stability of restorations and prostheses like Ti implants is imperative to prevent leaching of NPs during functional movements in oral cavity.

  8. 8.

    The surface charge of metal NPs may be modified with help of charged polymers like poly (lactic-co-glycolic acid) for targeted drug delivery in oral cavity with minimal toxicity [156].

  9. 9.

    The pulmonary toxicity of metal oxide NPs may be reduced with the help of phosphonate surface passivation [157].

Conclusion

The nanometals and their oxides have numerous applications in dentistry owing to their favorable antimicrobial, mechanical and regenerative properties. However, their potential benefits are often accompanied with the risk for toxicity owing to their nanoscale size and reactivity. Although in vitro studies suggest that these materials are noncytotoxic, there is a dearth of evidence on this aspect. As the current research lacks a unifying protocol for the toxicological profiling of NPs of metals used in dental materials, there is a need for well-designed clinical trials which would evaluate their plausible adverse oro-systemic effects in humans.