Nanoparticles in Dentistry—Current Literature Review

Abstract

Interest in the topic of nanoparticles (NPs) and nanomaterials used in dentistry is growing in research as well as clinical settings. In recent years, an increasing number of nanomaterials have been developed and tested, enabling novel solutions unavailable in dentistry before. The aim of the article is to review the current status of knowledge regarding NPs used in modern dentistry. The analysis was made using Science Direct, PubMed and Scopus databases, and articles were selected based on relevance and topicality. The exclusion criteria determining timeliness consisted of a selection of essential works on this topic no older than 2017. Regarding appropriateness, only studies on nanoparticles in the field of dentistry were considered, and were categorized into three subtopics: antimicrobial NPs, therapeutic NPs, material property improving NPs. Each category was further divided into specific groups focusing on the clinical use of the particles. Inside every section, analysis concerning the current state of knowledge about the use and properties of nanoparticles within specific material groups was conducted. Additionally, within this article, common and rising trends in the NPs field were analyzed; additionally, based on novel NPs approaches, possible future applications and dangers were considered.

1. Introduction

Nanoparticles are routinely defined as ultrafine units with dimensions between about 1 and 100 nm (nm; 1 nm = 10⁹ m) that show properties that are not found in bulk samples of the same material [1]. Nanoparticles exist in the natural world and are also created as a result of human activities. Because of their submicroscopic size, they have unique material characteristics, and manufactured nanoparticles may find practical applications in a variety of areas, including medicine, engineering, catalysis and environmental remediation [2]. Some research is suggesting that novel size-dependent properties alone, rather than particle size, should be the primary criterion in any definition of nanoparticles [1]. The unique properties of NPs, including their surface to volume ratio, antibacterial action, physical, mechanical, and biological characteristics and unique particle size have rendered them effective vehicles for dental applications [3]. Although inorganic nanoparticles provide the opportunity to localize bioactive agents to the target sites and protect them from degradation through acute toxicity mechanisms, the long-term toxicity of such materials can present serious health dangers [4]. This and further interest in the use of NPs calls for deeper understanding of the topic and special care in designing research involving them.

The shape and size of these particles influences the physicochemical properties of a substance, which in turn impacts their absorption characteristics [5]. Nanomaterials have unique structures and properties that distinguish them from other materials. In the dental field, nanoparticles have a variety of applications, such as nanocomposites, antimicrobial nanomaterials and bio-mineralization systems. Until recently, the main purpose of using nanotechnologies in dental materials was to achieve better mechanical properties, higher abrasion resistance, less shrinkage and improved optical and aesthetic properties only [6]. Nowadays, it is known that they also present a number of desirable bioactive or antimicrobial properties. For example, in the endodontic field alone, nanoparticles are used in a variety of applications including tissue regeneration, drug delivery systems and antimicrobial administration, mainly aimed at improving overall oral health, particularly by eliminating biofilms and bacteria [7]. Currently, there are also possibilities to merge some of those applications together; for instance, the use of nanoparticles in protein-repellent adhesives (2-methacryloyloxyethyl phosphorylcholine and dimethylamino dodecyl methacrylate) allows for reduction in biofilm accumulation, restoration of a safe level of oral pH (6.5) and promotion of remineralization, as well as overall improved material durability [8]. Thanks to understanding of physical principles, their strengths, limitations and their specific benefits, there is potential to further improve dental nanomaterials and overcome some flaws in currently available products [9].

2. Materials and Methods

The aim of the article is to review the current status of knowledge regarding nanoparticles (NPs) used in dentistry. The analysis was made using Science Direct, PubMed and Scopus databases (databases’ search date: 17.02.2022) and out of over 8885 articles related to the topic, 93 articles were selected based on topicality and relevance (

Table 1. Compilation of topic-related articles found in Science Direct database.

Science Direct	Search Limited to Publication Date
Keywords	20 Years and 2 Months	10 Years and 2 Months	5 Years and 2 Months	2 Months
Nanoparticles AND dentistry	5580	5134	3897	323
Nanotechnology AND dentistry	2443	2170	1612	123
Nanoparticles AND dentistry AND antimicrobial	1994	1917	1585	150
Nanoparticles AND dentistry AND therapeutic	2268	2103	1694	161
Nanoparticles AND dentistry AND reinforcement	718	680	541	40

,

Table 2. Compilation of topic-related articles found in PubMed database.

PubMed	Search Limited to Publication Date
Keywords	20 Years and 2 Months	10 Years and 2 Months	5 Years and 2 Months	2 Months
Nanoparticles AND dentistry	3062	2835	2155	71
Nanotechnology AND dentistry	1187	1001	710	24
Nanoparticles AND dentistry AND antimicrobial	857	834	663	12
Nanoparticles AND dentistry AND therapeutic	1011	936	726	22
Nanoparticles AND dentistry AND reinforcement	150	132	103	4

and

Table 3. Compilation of topic-related articles found in SCOPUS database (data from 2 months were not available in the search).

SCOPUS	Search Limited to Publication Date
Keywords	20 Years	10 Years	5 Years
Nanoparticles AND dentistry	243	216	168
Nanotechnology AND dentistry	183	151	106
Nanoparticles AND dentistry AND antimicrobial	0	0	0
Nanoparticles AND dentistry AND therapeutic	0	0	0
Nanoparticles AND dentistry AND reinforcement	0	0	0

).

The functions of NPs as a part of particular dental material described in selected articles were categorized into three functional subgroups: antimicrobial NPs, therapeutic NPs, material property improving NPs.

Each category was further divided into specific groups focusing on the function and mechanism of action of the nanoparticles.

• Antimicrobial functions of NPs:

  ○

  Antibacterial and antifungal function

  ○

  Antiviral

  ○

  Multiple/simultaneous mechanism

• Property improvement functions of NPs:

  ○

  Reinforcement

  ○

  Wear protection

• Therapeutic functions of NPs:

  ○

  Anti-caries

  ○

  Antibiofilm

  ○

  Anti-inflammatory

  ○

  Whitening

  ○

  Regeneration

Inside every section, analysis concerning the current state of knowledge about properties, the mechanism of action and the purpose of use of a particular nanoparticle group was conducted. Additionally, within this article, common and rising trends in the NPs field were analyzed; additionally, based on novel NPs approaches, possible future applications and dangers were considered.

Exclusion Criteria

After database examination (database search date: 17 February 2022), constantly rising interest in the topic was spotted—especially in recent years—so the exclusion criteria determining timeliness consisted of selecting only essential works for this topic no older than 2017. The exception to this rule was applied to two additional (over the selected 93) articles containing the definition of a nanoparticle, as it has not changed over the past 15 years. Regarding appropriateness, only the studies on nanoparticles in the field of dentistry were considered, and further focus on the antimicrobial, therapeutic and material properties of NPs was emphasized in the chosen studies. Additionally, the studies that were repeated in different databases were reduced.

3. Antimicrobial NPs

3.1. Antibacterial and Antifungal Function

Often, to achieve antibacterial/antifungal properties, specific NPs are incorporated. Those NPs mainly present the ability to damage cellular membranes through membrane penetration and induction of cell lysis, or the ROS scavenging mechanism.

The NPs antibacterial mechanism of action is based on NPs binding to the cell and causing surface charges. This interaction with the peptidoglycan of the cell wall and subsequently with the cell membrane limits protein synthesis, and as a consequence prevents the replication of bacterial DNA. Thus, the antifungal action of NPs is mainly focused on infiltration and lysis of the cell wall.

Through redox reactions, NPs induce a high level of reactive oxygen species (ROS), creating intracellular oxidative stress conditions. If the superoxide and hydroxyl radicals (ROS) are not neutralized by antioxidants, they cause protein degradation and DNA damage and destroy the cell wall. Above all that, ROS, together with simultaneously created reactive nitrogen intermediates (RNI), connect to the lipid membrane of the cell, disturbing the trans-membrane balance and consequently contributing to cell death.

The other reaction involved in induction of cell lysis is centered on nitric oxide-releasing NPs. The reactive nitrogen oxide intermediates (RNOS), formed by interaction of NPs with the cell, enter the reaction with selected bacterial protein amino acids (such as Cys, Met, Tyr, and Phe) and selected DNA chain bases (such as C, A, and G) and lead to their damage. At the same time, RNOS promotes an increase in the concentration of ROS, which in turn increases the destruction of bacterial DNA.

Nanoparticles in the endodontics field have been used in a number of applications including antimicrobial administration, mainly aimed at improving overall oral health, particularly by eliminating biofilms [7]. Research focused on improving photobiological activity showed the superiority of the nanoemulsion of zinc phthalocyanine (ZnPc-NE) free zinc phthalocyanine (ZnPc). Besides, cytotoxicity studies showed that just nanoemulsions alone, without any additions (blank-NE), showed good antimicrobial activity against Enterococcus faecalis and Staphylococcus aureus. Thus, clove oil nanoemulsion can act as a nanocarrier to promote ZnPc photosensitizing activity against pathogenic microorganisms in resistant endodontic infections [10]. Additionally, there are studies reporting the use of samarium-cobalt targets, which work as permanent magnets for nanoparticles’ synthesization through pulsed laser ablation in liquid (PLAL) that could be exploited as a novel method of synthesis for effective small-particle antimicrobials [11]. Another endodontic application of research into gutta percha–sealer–tooth interface revealed that the coating of sealers with a combination of silver NPs and chitosan NPs allows superior antibacterial activity. This is caused by induced oxidative stress and membrane damage to the bacteria; due to this, synthesized alternative filling materials can possibly provide high success rates in root canal therapies in clinical procedures [12]. The addition of NPs can improve not only the properties of materials that are intended to stay in the oral cavity, but also the therapeutic effects of medicaments or irrigants. There were novel attempts to create silver nanoparticles (AgNPs) with a graphene oxide (GO) matrix (Ag-GO) that could effectively act as an endodontic irrigation method. Studies showed that the antimicrobial efficacy of Ag-GO was comparable to that of 2% CHX and 1% NaOCl, which could simplify irrigation the sequence and suppress the risk of formation of a precipitate [13].

In the case of dental prosthetics applications, metal oxides nanomaterials revealed cytotoxicity to Candida and other microbes present in oral biofilms, including the PMMA denture surface. However, they needed to be used in low concentrations in order to not impact the mechanical properties negatively [14].

Another clinical setting with a high risk of infection is dental implant surgery, after which antibiotics are commonly prescribed for prophylaxis of bacterial infections. However, bacteria’s drug resistance may increase the risk of infections, leading to implant failure. Unfortunately, use of regular hydroxyapatite (HA) as scaffolds in implant dentistry has one main issue, namely the accumulation of microorganisms on HA. To overcome this, an antibacterial hydroxyapatite (HAp) scaffold was developed by immobilizing chlorhexidine (CHX)-loaded human serum albumin (HSA) nanoparticles onto implant surfaces. This intervention allowed effective antibacterial activity against S. mutans directly to the implant’s surface [15]. The use of CuO nanoparticles or TiO₂ nanoparticles can also decrease the accumulation of microorganisms including Streptococcus mutans on HA [16]. To increase the antibacterial effect against E. coli and S. aureus even more, porous nanocrystalline hydroxyapatite was impregnated with copper, gold and silver NPs. Although enhancement of antimicrobial abilities occurred, cytotoxicity studies suggested that gold nanoparticle-impregnated HAp has the highest biocompatibility [17].

3.2. Antiviral Function

The primary goal of NPs used for their antiviral properties is to neutralize the virus before it invades the host cells. One of the first steps in viral infection is the initial encounter with host cell receptors. If stopping viral penetration can be achieved at this point through NPs, the infection can be omitted successfully. Unfortunately, this regulatory step can vary between different viruses from nonspecific to very specific pathways. Recently, new nanotechnological strategies to create an antiviral coating that inhibits viral transmission showed additional solutions. A possible mode of action was preventing viral entry into the host cell through anti-transfection action, or through making it impossible to interact with negatively charged DNA and RNA.

Interest in this field concerned carbon dots/quantum carbon dots, graphene oxide (GO) and metal NPs. Positively charged curcumin-derived cationic carbon dots resulted in aggregation of the virus, reducing viral infectivity (with inhibition efficiency over 50% at the concentration of 125 g/mL) through viral cell binding inhibition and the induction of certain changes in viral protein structure.

Negatively charged GO NPs integrated into the material, making it possible to change the polarization of the cellular membrane and deactivate the virus before its penetration. This difference in charge between GO NPs sheets and the virus causes wrapping of the sheet around the virus, and due to the roughness of its surface, simultaneous tearing of the cellular membrane or capsid protein layer. Additionally, the excellent thermal conductivity of these NPs and the high light to heat conversion potential of infrared radiation were proposed as other strategies to capture viral cells and their inactivation.

Metal NPs can interfere with viral infection through various methods:

• by reactive oxygen species (ROS) generation;
• by physical abrasion of the membrane incurred due to interaction with nanoparticles;
• by loss of membrane integrity due to nanoparticle binding; and
• by the release of metal ions from the nanoparticles.

The silver (Ag) NPs seem to be most promising because they present a multifaceted mode of action not limited to a single pathway. Generation of ROS disrupts the cell wall and plasma components, as well as inhibiting viral cell metabolism. Other metal NPs investigated in this subject are Copper (Cu), Cobalt (Co) and Zinc (Zn), but their antiviral abilities are more limited than Ag [18].

3.3. Multiple/Simultaneous Mechanism

An ideal antimicrobial material would combine both antiviral and antibacterial activity.

Those efforts were based on either the NPs-induced ability to link to the DNA, prevention of RNA synthesis, cell membrane damage or an enzymatic inhibition.

Metallic NPs show promising results in this area due to presentation of antibacterial actions, including the production of reactive oxygen species, cation release, biomolecule damages, ATP depletion and membrane interaction, but also due to regulation of gene and protein profiles (transcriptomic and proteomic) also affecting viruses [19].

On the other hand, non-metallic NPs are also very promising antimicrobial adjuvants. Quaternary ammonium polyethylenimine (QA-PEI) nanoparticles are non-toxic and exhibit antibacterial activity. This makes them potential biocidal additives in various dental composite materials, such as dimethacrylate-based restorative materials, dental cements, root canal pastes and orthodontic adhesives, without deteriorating the products’ structures or mechanical properties [20].

Organic-derived NPs like chitosan NPs offer simultaneous antibacterial and antifungal properties, which makes them a promising addition to tissue conditioners which tackles the issue of bacteria and fungi growth on complete dentures [21].

4. Property Improvement Functions

4.1. Reinforcement Function

Due to the similar modes of action and functions of different NPs—the improvement of mechanical properties—this topic was subdivided into particular types of NPs.

The incorporation of CNs into GICs shows reinforcement through fibrillar aggregation of nanoparticles interspersed in the matrix. This results in significantly improved mechanical properties (Maxxion-31.6%; Vidrion R-49.43%; Vitro Molar-37.79%; Ketac Molar Easy Mix-48.78% and Fuji Gold Label 9-32.33%) and increased F-release of all tested GICs [22].

The addition of chitosan NPs to the GICs also results in an increase in fluoride and the induction of moisture during the maturation stage of setting through electrostatic interaction with the carboxylic acid group of the GIC liquid. This also provides supplementary mechanical properties’ enhancement of GICs [23].

Nanodiamonds (ND) are an allotrope of carbon nanoparticles which exhibit superior physical, mechanical, thermal and optical characteristics on their own due to their unique spherical shape which contains a diamond-like structure at the core with a graphitic carbon outer shell. Their qualities and high biocompatibility makes them an attractive additive for the development of multifunctional polymer composites [24]. Use of a trace amount of ND (0.5%), in combination with acrylic resin or composite resin, noticeably improves flexural strength and decreases surface roughness [25].

The nHAp are structurally the closest to natural dental apatite, a main component of the tooth structure. High biocompatibility, and the ability to achieve precise and appropriate morphology, stoichiometry and purity allows seamless improvement of the mechanical and chemical properties of the materials they are incorporated into. Particular interest was established in mechanically improving already bioactive materials such as glass ionomer cements, especially in terms of shear bond strength [26].

Silicon colloidal nanoparticle clusters (SCNCs) can strengthen the structure of inorganic fillers within dental resin composites through the calcination process. Studies have shown enhancement of the flexural properties and hardness of composites. Unfortunately, their addition could decrease overall compressive strength; this is often tackled through use of building blocks made of the silica NPs, or through simultaneous use of another type of filler [27].

The lasting clinical effect of a composite restoration depends on the properties of the dental adhesive. The incorporation of Si nanoparticles (10% and 15%) into the polymeric bonding system increases its bond strength compared with the unmodified adhesive resin, and improves hybrid layer formation within the dentin. However, the addition of Si particles to the adhesive reduced its conversion rate compared with the unfilled adhesive (0% Si-control) [28].

Another solution was proposed by LalehSolhi et al. by adding a Si-containing hybrid nanoparticle of 0.5 wt.% (poly (acrylic acid)-grafted nanoclay/nanosilica, abbreviated as PAA-g–NC–Sil, for adhesive. The bonding system containing PAA-g–NC–Sil showed better dispersion stability and, consequently, the highest shear strength without reducing the degree of conversion compared with the adhesive without fillers [29]. Another application of SiO₂ nanofibers with stabilized silver nanoparticles (SiO₂/Ag) was incorporating them into a composite resin. This modification increased the hardness of the composite, which also retained its flexural strength, even after aging in water for 30 days. The most promising seems to be the addition of silanized nanofibers to the composite (SiO₂/Ag-0.5S) at a concentration of 0.5 wt.%, as such material shows greater inhibition of S. mutans, satisfactory parameters of roughness and flexural strength and better impact strength compared with the control [30].

Nano-inorganic fillers SiO₂, ZrO₂, HA, and Al₂O₃ were added to the tested composites in a constant proportion (40% by weight). The results showed that dental composites reinforced with silica nanoparticles had superior properties compared with other types of prepared nanocomposites in terms of diametrical tensile and compressive strength [31]. The possibility of strengthening PMMA resin for permanent and temporary restorations with pure silica nanoparticles and triethoxy vinyl silane-modified silica nanoparticles was also investigated. The results of the study suggest that both types of nanoparticles, especially at low concentrations, can improve the durability of permanent prosthetic restorations, as they can effectively increase the fracture toughness, elastic modulus and glass transition temperature of PMMA resins [32].

PMMA (polymethyl methacrylate) acrylic resin is used to make denture bases, but its mechanical properties may be insufficient for this role. The incorporation of ZrO₂ nanoparticles into the PMMA resin significantly improved flexural strength, flexural modulus (15%, 22%, respectively), fracture toughness and surface hardness, with an optimal zirconia concentration of 3%–5% by weight. However, the distribution of ZrO₂ nanoparticles in the polymer matrix was not uniform, and there were agglomerations that reduced the impact strength [33]. The addition of untreated zirconia nanofillers to PMMA used in 2.5% concentration proved to increase flexural strength and surface hardness; therefore, they can be used for reinforcing dentures and other dental appliances conventionally created from PMMA [34]. Temporary restorations play an important role in protecting the hard and soft tissues of the oral cavity and ensuring function and aesthetics during the preparation of final restorations. Temporary restorations must have sufficient flexural strength to resist chewing deformation and sufficient surface hardness to resist abrasion. In the case of works carried out in the aesthetic zone, color stability is also of great importance. Zirconium nanoparticles have desirable properties, such as high hardness, biocompatibility and white color. For this reason, the addition of zirconia nano to acrylic resins may be a suitable method to improve temporary restorative materials [35].

Silica nanoparticles are the filler types present in almost all commercial dental materials. Particles containing silica are highly reactive to organosilanes and allow simple, effective coupling with the resin phase. However, silica nanoparticles also have some limitations, including radiolucency and poor mechanical properties. Therefore, a question was raised as to whether the use of non-silicate nanoparticles such as zirconia, as a substitution for silica, would actually result in restorative materials with improved properties. The aim of this study was to coat the surface of zirconia nanoparticles with a silica-rich layer (ZRSI) and use the coated nanoparticles to prepare nanohybrid composites. This material showed improved and more stable mechanical properties as compared with nanosilica-based references [36]. The authors of another study followed a similar direction, evaluating the effect of several types of surface treatment of nano si-zirconia fillers on the mechanical properties of the dental resin composite. This surface treatment involved conditioning the nano si-zirconia fillers with MDP phosphate ester monomer to mediate the chemical bond between the zirconia fillers and the resin matrix. The authors also evaluated the cytotoxicity of these composites to ensure the clinical safety of this modification. MDP-conditioned nano-zirconia fillers improve the mechanical properties of resin composites, and are potentially safe for clinical use as they show no significant cellular cytotoxicity [37].

ZnO NPs’ addition can also slightly improve the mechanical and handling properties of GICs, although they are mainly used for possible combination of property improvement and therapeutic functions [38].

The OMMT NPs or nanoclays are mainly used as novel nanofillers intercalated into structures of the nanocomposites. Their main function is the reinforcement and limitation of polymerization shrinkage through extensive filler distribution into the polymer matrix; however, their incorporation into composite resin increases flexural modulus and decreases flexural strength at a high filler loading [39].

To address the challenge of poor resin infiltration of dentin’s conventional total etching during the bonding procedure, products incorporating superparamagnetic iron oxide nanoparticles (SPIONs) were developed. Under the guided magnetic field, SPIONs-doped adhesives increase the bond strength, which surpasses the reduction caused by hydrostatic pulpal pressure. They also improved dentin's adhesion without changing material’s physicochemical properties [40].

Often, to achieve advancement in mechanical properties, different NPs are used; various forms of them are also used. This practice, used in the production of adhesives, is mainly based on the superiority of nanofillers over microfillers in terms of improving the strength of the adhesive layer and the influence of the viscosity, without adversely affecting the material’s polymerization reaction [41]. The use of a combination of high concentrations of nano-ZrO₂, low % nano-SiO₂ and 1 and 1.5 wt.% nano-Al₂O₃ enhanced mechanical properties, improved repair strength and increased the flexural strength of repaired denture bases [42].

4.2. Wear Protection Function

The subject of property improvement through nanoparticle integration would not be complete without mentioning diamond NPs’ ability to smoothen the material surface. The use of those NPs give a unique opportunity to achieve increased wear protection properties. Through a variety of friction and wear tests, nanodiamonds proved to decrease surface roughness. This subject is especially important in dentistry due to everyday use of toothbrushes. Mechanical cleaning of the tooth surface by toothbrush bristles can potentially increase the roughness of the tooth’s surface over time. This phenomenon can lead to increased tissue wear and redeposition of the bacteria. Studies have shown that correct use of a soft-tufted toothbrush in combination with a nanodiamond suspension for oral hygiene applications can provide a protective effect on the enamel and the dentine surfaces, making them smoother, so it is harder for bacteria to adhere [43].

This ability of nanodiamonds was also used to enhance resistance to friction and wear of poly(methylmethacrylate)-based intraoral appliances (such as splints, dental and maxillofacial prosthesis) so they can better withstand the mechanical and microbial impact existent in the harsh environment of the oral cavity. The use of nanodiamonds as fillers not only significantly improved mechanical properties by strengthening the material (11.88%–17.60%); by making its surface smoother, it elevated resistance to the biofilm formation of Streptococcus mutans without any notable impact possibly associated with the functionalization of the nanodiamond particles [44].

5. Therapeutic Functions

5.1. Anti-Caries Function

The literature highlights the number of NPs presenting different modes of action yet achieving the same outcome: a decrease in oral caries. The NPs tackling this problem focus on diminishing Streptococcus mutans populations or inducing teeth remineralization processes [45]. The chitosan- and nanodiamond-modified glass ionomers proved noticeable S. mutans reduction, and as a consequence, the best disruption of its biofilm formation compared with the same GICs without the modification [46,47]. Adversely, silver nanoparticles added to GICs (NanoAg-GIC) presented increased compressive strength of the material and inhibition of E. coli and S. mutans population growth [48]. Furthermore, there were developed materials targeting directly bacterial pathogens. Catalytic nanoparticles (CAT-NP) containing biocompatible Fe₃O₄ and exhibiting peroxidase-like activity trigger extracellular matrix degradation and cause bacterial death within biofilm. They additionally reduce apatite demineralization in acidic conditions [49]. Additionally, the use of glucose-oxidase nanohybrids, which catalyze glucose present in biofilms to increase intrinsic H₂O₂, directly targets Streptococcus mutans (pathogen) without affecting Streptococcus oralis (commensal). Their mode of action was based on iron oxide nanoparticles also with peroxidase-like activity [50].

Moreover, some materials are aimed to induce remineralization processes. Cements containing amorphous calcium-phosphate nanoparticles showed good bond strength to enamel and continuous calcium and phosphate ion recharge/re-release capability, which induced remineralization reactions. It also increased the local pH, preventing additional harm from cariogenic bacteria [51]. Furthermore, adhesive resins with zinc nanoparticles (ZnNPs) exhibit antimicrobial capacities against aerobic bacteria and proved to be bactericidal against anaerobic bacterial strains (Streptococcus mutans, Streptococcus mitis, and Lactobacillus spp.) through creation of oxidative stress, thus improving material infiltration and enabling remineralization properties [52]. Likewise, Ca-NPs and Zn-NPs used in treated dentin exhibited sealing properties within dentinal tubules, thus decreasing microleakage and strengthening the root dentin by inducing the remineralization process after endodontic treatment [53].

5.2. Antibiofilm Function

5.2.1. Blocking Bacterial Sugar Consumption and Bacteriostatic Function

It was shown that use of hexagonal boron nitride NP (hBN) used in minimum inhibitory concentration exhibits bacterial and fungal sugar-consumption blockage of Streptococcus mutans, Staphylococcus pasteuri and Candida species. Establishing high bacteriostatic abilities favors its use as a potential safe oral care product [54].

Furthermore, it is worth mentioning zein-coated magnesium oxide (zMgO) nanoparticles’ capability to create bacterial inhibition zones when used as dental cement. Their antimicrobial properties against C. albicans and S. aureus, thanks to their high crystalline nature and uniform distribution, show promising results for prosthetic application [55].

5.2.2. Decreasing Expression of FTF and GFT Genes in S. mutans

Adversely, the combination of zinc oxide nanoparticles (ZnO NPs) with hydroxyapatite nanoparticles (HAP NPs) to create Zn-substituted hydroxyapatite nanoparticles (Ca19Zn2(PO4)14 NPs) focuses on targeting bacteria through depressing the FTF (8.15 times) and GFT (8.42 times) genes’ expression. Results show significant impact on S. mutans growth and biofilm formation as well as bacterial adherence, which makes them applicable as dental coatings [56].

5.2.3. Damaging Bacterial DNA and Growth Inhibition of Mature Biofilm

Hafnium oxide nanoparticles (Hf PS NPs) in therapeutic polymeric silane are one of the examples of NPs that are more versatile due to their dual mode of action. Hf PS NPs can penetrate into S. mutans, thus improving caries detection; however, at the same time, they present superior antibacterial properties through damaging bacterial DNA and as a consequence inhibiting the growth of Streptococcus mutans’ mature biofilm without the need for any additional drugs [57].

5.3. Anti-Inflammatory Function

The use of particular NPs instead of conventional anti-inflammatory medication can be very beneficial to patients, simply due to more efficient action and diminished side effects. Consequently, this leads to improvement of the healing processes of damaged tissues by targeting and internalizing proinflammatory cells, releasing ions or by eliminating reactive oxygen species (ROS). Folate-functionalized bioactive glass nanoparticle BGN(F) presents those properties, and thanks to that can substantially down-regulate proinflammatory molecules, including TNF-α, IL-6, iNOS and COX-2, at both gene and protein levels; additionally, it suppresses inflammatory events, such as p38 MAPK, ERK (1/2), SAPK/JANK, IκBα, and NF-κBand, above which it can switch the macrophage polarization from M1 to M2. These profound anti-inflammatory actions consequently accelerate tissue healing [58]. Secondly, coating photosensitizer chlorin e6 onto nanoceria within nanocomposite material allowed the elimination of ROS, achieving simultaneous sterilization and inflammation elimination via a dual directional regulation effect and also the modulation of macrophage polarization from M1 to M2. Utilization of these in periodontal antibacterial photodynamic therapy could overcome the local side effects of standard treatment [59]. Other studies also suggested that incorporation of bioactive chitosan-based nanoparticles (CSnp) in antibiofilm medication upregulated proteins exhibiting antioxidant and immunoregulatory properties. This has proved to have potential beneficiary immunomodulatory effects (reduced pro-inflammatory IL-1β and nitric oxide, enhanced anti-inflammatory IL-10 and TGF-β1) on chronically inflamed periapical tissues, and regulate healing process in the treatment of apical periodontitis [60].

5.4. Whitening Properties

The main nanoparticles exhibiting whitening properties can be divided into three groups: carbide peroxide NPs, nano-hydroxyapatite and nano-encapsulated sodium metabisulfite.

Development of carbamide peroxide polymeric nanoparticles improves the stability and efficacy of most common home dental whitening agents without causing damage to the dental pulp [61]. Nano-hydroxyapatite, apart from its remineralization properties, when added even to mouth rinses over prolonged periods of time presents whitening properties higher than commercial mouth rinses [62]. To accommodate for long application time and post-whitening hypersensitivity, nano-encapsulated sodium metabisulfites were designed. Thanks to liposomal enclosures forming a layer surrounding the enamel surface, they present safer and faster alternatives to current oxidative treatments that provide satisfactory whitening action [63].

5.5. Regeneration Function

5.5.1. Bone Remodeling Function

NPs can play a special role in tissue regeneration processes due to their unique abilities. Organic-related/-based NPs are the main interest in the field of tissue regeneration scaffolds.

The carbon-derivative NPs often considered are carbon nanotubes (CNTs), carbon nanofibers (CNFs) and nanodiamonds (ND). Carbon nanomaterials such as CNTs and CNFs are inherently bioinert, having no osteoinductivity. Effective improvement of their biological properties occurs through the incorporation of CNTs/CNFs into known bioactive compounds such as calcium phosphate (CaP) and bioactive glass (BG). This enables control of cell growth and differentiation. Studies also show that these combinations are more effective than CNFs alone in terms of biocompatibility, tunable degradation ability and controllable osteocompatibility, which makes them more suitable for scaffolds used for bone tissue engineering [64]. In turn, the bioactive glass nanoparticles (BGNPs) are well established in research and have multiple clinical applications in periodontal and bone regeneration due to the mechanism of particle size-regulated bioactivity [65].

ND particles allow the improvement of the osteogenicity of osteoblast-like cells when incorporated into scaffolds. Cytotoxic and inflammatory reactions occurred at higher concentrations of NDs; therefore, to ensure safety, researchers are establishing minimum inhibitory concentration [66]. Often, integration of particular NPs with hormones can present additional regeneration properties that can help in postsurgical treatment or prevention of relapse. Injectable estrogen (17β-estradiol (E2))–nanodiamond hydrogel enabled the improvement of bone-building properties and the healing of palatal expansion in patients with cleft lip and/or palate reconstruction [67].

The possibilities of conjugating different NPs do not end there. Nowadays, multiple synthetic and natural structures can be combined to perform at a superior level.

Effective incorporation of carbonated hydroxyapatite (CHAp) into the nanofibrous structure of poly(vinyl alcohol) and chitosan as poly(vinyl alcohol)/chitosan/carbonated hydroxyapatite (PVA/CS/CHAp) proved to increase the modulus of the scaffold. At the same time, increase in CHAp concentrations directly influenced other scaffold properties, decreasing elongation at break and increasing the swelling capacity of scaffold and protein adsorption onto the scaffold which could increase the cell viability of the scaffold. This means that PVA/CS/CHAp has the potential to serve as an alternative scaffold material for superior bone tissue engineering [68]. In the topic of bone remodeling, it is very important to understand and influence the osteoblastic and osteoclastic cell activity, which, in the case of osteoporosis or osteoporotic bone defects, are crucial. Synthesis of Sr-nanocement showed promising results in osteoclastic inhibition, increased bone volume and density, enhanced production of osteopromotive proteins and more populated osteoblasts, and showed reduced signs of osteoclastic bone resorption, proving its profound bone-regenerative potential [69].

5.5.2. Bone Remodeling and Angiogenic Functions

It is vital to address angiogenic properties, especially when the treatment goal is focused on not only osteointegration, but also on restoration of angiogenesis processes within tissues.

This was tackled in one of the attempts to combine the osteoblastic function achieved by external static magnetic field (SMF) and bone formatting magnetic nanocomposite scaffolds created from polycaprolactone/magnetic NPs. The solution remarkably enhanced the new bone formation, which suggested conjugation as a possible regenerative bone-engineering application [70]. Another proposition was the creation of uniquely structured nanohybrids composed of a bioactive inorganic nanoparticle core (hydroxyapatite, bioactive glass, or mesoporous silica) encapsulated in a chitosan shell (Chit@IOC). Use of those components allowed the synthesis of nano units highly resilient to cyclic load and also the stimulation of the anti-inflammatory, pro-angiogenic and osteogenic events of relevant cells for those processes. These features make the aforementioned nanohybrids promising 3D tissue-regenerative platforms [71].

Finally, injectable nanomaterials for bone repair and regeneration, such as calcium phosphate cement (CPC) enriched by mesoporous bioactive glass nanoparticles (BGn), also show promising results. Creation of Si-Ca-(P)-based amorphous nano-islands-networking BGn increased surface area nine times compared with conventional CPC, and induced production of apatite nanocrystallites, absorbing proteins and releasing Si and Ca ions. These effects majorly stimulated the viability, osteogenesis and angiogenesis of studied cells, resulting in bone matrix formation [72].

5.5.3. Bone Remodeling and Remineralization Functions

Further research into bone remodeling led to attempts to combine these properties with the remineralization processes. These ideas led to the development of different forms of hydroxyapatite. Hydroxyapatite-based biomaterials face a set of issues, from problematic preparation to poor mechanical properties or particle size, and morphology issues in drug delivery and brittleness for bone transplantation [73]. Research focused on the use of those particles in NP form allows us to confront those concerns.

Synthetic whitlockite (WH: Ca18Mg2(HPO4)2(PO4)12) nanoparticles allowed the transformation of the early stages of bone regeneration using a continuous supply of PO₄³⁻ and Mg²⁺ under physiological conditions. As a result, mechanically enhanced hydroxyapatite (HAP)-neo served as ‘living bone mineral’ to induce self-healing [74].

Nano-hydroxyapatite (nHAP) in the form of gelatin cryogel was also developed to work as a scaffold for bone regeneration in the treatment of craniofacial deformities, due to its biocompatibility, slow reabsorption and necessary mechanical properties. On the one hand, it has a structure like a sponge, and on the other, its plasticity allows the reconstruction of the three-dimensional bones of the facial skeleton. At the same time, as a scaffold, it can provide support for mesenchymal stem cells and enhance the bone regeneration process [75].

5.5.4. Multifunctional Regeneration in Tissue Engineering

Calcium silicate (CS)-based materials play an important role in the development of endodontic materials that induce bone/cementum tissue regeneration and inhibit bacterial viability. This study shows novel mesoporous CS (MesoCS) nanoparticles that not only help induce bone/cementum tissue regeneration and inhibit bacterial viability, but also have osteogenic and drug-delivery functions. The results indicate that the MesoCS nanoparticles can be used as drug carriers to maintain the sustained release of gentamicin. Moreover, MesoCS-loaded fibroblast growth factor-2 (FGF-2) might stimulate more odontogenic-related proteins than CS because of the FGF-2 release. Based on this work, it can be inferred that MesoCS nanoparticles are potentially useful endodontic materials for biocompatible and osteogenic dental pulp tissue-regenerative materials [76].

In addition to the extremely dynamic development of calcium silicate (CS)-based materials, the challenges posed to tissue engineering by the development of biological substitutes that restore, maintain or improve damaged tissues and organ functionality remain valid.

Regeneration of tooth tissues is hampered by the complexity of their structures, but the progress in nanotechnology enabling a biomimetic approach to the problem gives hope of overcoming these difficulties [77].

Dental implants as a therapeutic option in the rehabilitation of the oral cavity of patients are becoming more and more common. The long-term success of this therapy largely depends on their surface properties and osseointegration. However, the problem of insufficient integration and peri-implantitis still remains, and the modification of implant surfaces and various types of biomaterial coatings are a tool with which it is possible to solve it. The task of the implant coating material is to accelerate the healing process by improving osseointegration and having an antibacterial effect. Therefore, nanotechnological coating materials and implant surface modification techniques to improve biocompatibility and bio-functionality, as well as decrease the risk of retrograde peri-implantitis, are an extremely important and promising topic [78,79].

Regeneration of hard tissues infected with bacteria as a result of peri-implantitis is a major challenge, even with high doses of antibiotics or surgical intervention.

In order to promote the multidirectional action necessary in such a situation, i.e., antibacterial, pro-angiogenic and osteopromoting actions, a nanoglass paste made of silicate glass particles (containing Ca, Cu) hardening in contact with an aqueous medium was tested. The ions released in this process (of silicates, calcium and copper) in therapeutically appropriate doses and in a balanced manner (for days or weeks) allowed for the reduction of the inflammatory reaction around the implants and an antibacterial effect against E. coli and S. aureus. The nanoglass paste had osteopromoting and angiogenic effects on endothelial cells in vitro, and on blood vessel formation in vivo.

Based on the above studies, this can be considered a promising form of inorganic biomaterials for the regenerative therapy of hard tissues infected with bacteria [80]. It can be particularly important in the process of osteogenesis in the therapy of craniofacial deformities, which is complex and can be divided into early and late phases, each of which are characterized by a different specificity and dynamics of repair processes.

The study proposed the use of mesoporous bioglass nanoparticles (MBGN) together with methacrylate gelatin (GelMA) if a form of a hydrogel membrane embedded with recombinant human bone morphogenetic protein-2 (rhBMP-2). Early release of rhBMP-2 allowed osteogenic differentiation of the cells. In turn, inorganic ions not only facilitated cell adhesion in the early stage, but also facilitated osteogenic differentiation in the late phase. This GelMA/MBGNs-rhBMP-2 hydrogel showed a promising strategy for the controlled and safer application of bioactive agents such as rhBMP-2 in an artificial periosteum to accelerate the repair of a critical size defect in rat skull bone [81].

6. Trend Analysis

Trend analysis was conducted by subdividing the topic into the main recent trends and future leads, which are promising novel approaches of NPs use in dentistry.

6.1. New Trends–Multifunctionality

The research team, after conducting the analysis, concluded that a few approaches and developments in the NPs field are rising more in popularity than others, especially those which combine more than one beneficial property of NPs in a single solution. Those multipurpose trends that merge abilities from different functional groups were further subdivided, based on performed functions, into:

• Anti-caries function and mechanical properties improvement;
• Antimicrobial function and aesthetic properties improvement;
• Antimicrobial and diagnostic function; and
• Biomimetics.

6.1.1. Anti-Caries Function and Mechanical Properties Improvement

Biofilm accumulation in near proximity to or around composite resin filling margins or orthodontic adhesives can compromise the stability and longevity of the restorations, as well as cause possible progression of undetected secondary caries. One metanalysis compared the addition of the silver-hydroxyapatite, curcumin, curcumin-zinc oxide and titanium oxide NPs into the adhesives, which resulted in the exhibition of excellent antimicrobial potential against cariogenic bacteria with simultaneous maintenance of mechanical properties [82].

As mentioned, Ag NPs allow the incorporation of simultaneous antimicrobial properties, and in combination with other particles improve the mechanical properties of the material. A great example of this double functionality are silica blow spun nanofibers containing silver nanoparticles (SiO₂/Ag) in the form of nanometric SiO₂/Ag fibers incorporated into low-viscosity bulk-fill composite resin. Synthesized material initially did not show extremely remarkable results, but over time showed adequate surface roughness and flexural strength of the material, in addition to the inhibition of S. mutans and increased microhardness. This is an interesting and promising result, considering that dental materials are in constant use within the oral cavity and often, some of the initial properties with time are diminished or lost [30]. Secondly, when Ag NPs were added to glass ionomer cements creating NanoAg-GIC, this allowed the enhancement of antibacterial activity against S. mutans and E. coli, and improved compressive strength by 32%. This solution shows high clinical use potential as a bioactive water-based cement [48].

Moreover, the addition of up to 0.5 wt.% copper nanoparticles may provide antimicrobial properties to etch-and-rinse adhesives, and prevent the degradation of the adhesive interface without reducing the mechanical properties of the formulations [83].

Additionally, similar results were achieved with magnetic nanoparticle-containing adhesives. Under magnetic force, they proved to significantly (by four orders of magnitude) reduce biofilm colony-forming units and increased the biofilm pH from a cariogenic pH 4.5 to safe level of pH 6.9. This shows the possibility of enhancing the resin–tooth bond, strengthening the tooth structures and suppressing secondary caries at the restoration margins in one solution [84].

Furthermore, the implementation of 1.3% mass fraction of ZnO nanoparticles in the synthesized adhesive can add the antibacterial characteristics and prevent biofilm formation without affecting the structural, mechanical, and chemical properties of the adhesive [85]. In addition, zinc-doped NPs are proposed for effective dentin remineralization and tubular occlusion. Zn-NPs also do reduce biofilm formation due to their antibacterial properties. These offer a new strategy for the regeneration of eroded cervical dentin and effective treatment of dentin hypersensitivity [86].

The other example of similar activity combination is the addition of nanodiamonds into polymethyl methacrylate (PMMA) as filler; this allows the enhancement of resistance to friction and wear, as well as the particular improvement of resistance to the formation of Streptococcus mutans biofilms [44]. In another study, this PMMA reinforcement with ND resulted in significant improvement in mechanical properties with the use of as little as 0.1 wt.% ND, resulting in more than a 20% increment in flexural strength over unmodified PMMA. In addition, ND incorporation showed marked resistance to Candida albicans and a considerable reduction in salivary biofilm formation [87].

6.1.2. Antimicrobial Function and Aesthetic Properties Improvement

The superior antimicrobial properties and low cytotoxicity of the dental pulp fibroblasts of silver NPs at low concentrations was already well documented; however, until recently, the unaesthetic appearance of Ag-containing restoration materials was holding back many dentists from offering them to the patients. Creation of AgNPs from green tea (GT) extract and coating their surfaces with silica allowed the synthesis of Ag@SiO₂ nanoparticles, which are bioactive materials that can at the same time be used to fight off S. mutans without compromising aesthetics, and do not exhibit cytotoxicity to the dental pulp [88].

6.1.3. Antimicrobial and Diagnostic Function

A study on hafnium oxide nanoparticles shows the possible combination of antibacterial properties and X-ray contrast enhancement that in the future would allow the increased efficiency of caries treatment using therapeutic polymeric silane with bactericidal properties against Streptococcus mutans. At the same time, dentists could better diagnose caries through molecularly targeted X-ray imaging of S. mutans [57].

6.1.4. Biomimetics

Use of NPs in local drug delivery systems allows for the creation of more efficient treatments of dental caries, simultaneously reducing the possible side effects that adversely could be present in general fluoride administration [89].

6.2. Future Leads

The future leads were considered as novel NPs’ uses or investigations with rising interest throughout the research, but not available as products yet. They were subdivided into following categories:

• Bioactive and nanostructured polymers;
• Modulation of immuno-inflammatory response to control periodontal diseases;
• Drug delivery and biomimetic remineralization of enamel and dentin; and
• Antibacterial functionalized enamel-like structures: fluorapatite NPs.

6.2.1. Bioactive and Nanostructured Polymers: Protein-Repellent, Anti-Biofilm, and Anti-Caries, Remineralization with Fluoride Release

A promising direction for the development of dental polymer composites, bonding agents, cements and coatings and materials that are generally bioinert is the modification that causes their bioactivity and therapeutic effect. Enrichment of materials with agents having the ability to repel protein, e.g., quaternary ammonium methacrylate (QAM) and anti-biofilm and anti-cariogenic silver nanoparticles and phosphate nanoparticles, causes a step change in the classification of materials from inert to active. They inhibit the development of pathogens, reduce or eliminate the production of acids inside the biofilm and raise the pH of the biofilm and restore lost minerals.

Conjugating this type of material modification with other biomimetic materials and releasing and actively replenishing fluoride pull allows the obtainment not only of anti-caries and antibiofilm properties, but also their direction against periodontal pathogens [8].

6.2.2. Modulation of Immuno-Inflammatory Response to Control Periodontal Diseases

Continuing the topic of periodontal disease treatment, it is worth focusing on the modulation of the immune–inflammatory response, as it is crucial for controlling periodontal disease. XuanLi et al. proposed a nanosystem (poly-disulfide/mesoporous silica nanoparticles) to penetrate human gingival epithelial cells (hGECs) and intracellularly controlled release of baicalein, which effectively downregulated the expression of pro-inflammatory cytokines by inhibiting the NF-κB signaling pathway. The synthesized nanosystem can be used as a new multifunctional drug carrier to modulate the immune-inflammatory response in the treatment of periodontal diseases [90].

6.2.3. Drug Delivery and Biomimetic Remineralization of Enamel and Dentin

In the treatment of periodontal diseases, dendrimers, hyperbranched nanoparticle structures with modifications of their surface, can be used. Due to their unique construction with internal hydrophobic and external hydrophilic structures, they can act as drug carriers to the target site and extended release of antimicrobial substances.

The therapeutic use of dendrimers in dentistry may also apply to their use in dental biomaterials for biomimetic remineralization of enamel and dentin and improvement of the mechanical properties of adhesives and the structure of resins. Dendrimers are a good example of a multifunctional nanoparticle structure [91].

6.2.4. Antibacterial Functionalized Enamel-like Structure: Fluorapatite NPs

The construction of an antibacterial functionalized enamel-like structure combining fluorapatite (FAP) nanoparticles with antibacterial low molecular weight polyacrylic acid (LPAA) against Streptococcus mutans is a promising strategy for the development of restorative dental materials [92].

6.3. Cytotoxicity and Risk of NPs

The cytotoxicity of nanomaterials is observed especially when they occur in a free form (not incorporated into the structure of the material), or when they are secreted from it into the tissue environment. This cytotoxic effect of nanoparticles is used in dentistry against bacterial and fungal pathogens resistant to conventional antibiotic therapy. Modification of sealers with nanoparticles to give them antimicrobial activity allows for greater effect through interaction at the molecular level.

Three commercial endodontic sealants with different compositions were modified with nanostructured silver vanadactyl (AgVO₃) and cytotoxicity was assessed. Two of them were found to be cytotoxic both in pure form and with nanoparticles (Sealer 26 and Endometasone N). The AH plus sealant in synergy with the nanomaterial showed the cytotoxicity tested in the cell viability of human gingival fibroblasts (HGF) as the only tested material [93].

On the one hand, NPs give endless therapeutic possibilities; on the other, there is danger of cytotoxicity or triggering an immune response.

An example of the above are magnetic nanoparticles (MNPs), whose addition to dental composites improved the translucency of the material and resistance to abrasion without causing any risk. In turn, the risk of triggering an undesirable immune response may be associated with the use of MNPs in a free form, enriching dental adhesives with anti-biofilm properties, or in the form of drug delivery systems that reduce caries and endo- and periodontal pathologies. Balancing benefits and disadvantages is a challenge for clinicians because, for example, the MNPs described above, despite their cytotoxicity, are characterized by cellular activity limited to the specific target, which reduces the systemic cytotoxicity of the compound. Hence, in recent years, nanoparticles and magnetic forces have been used in dentistry to deliver drugs to prevent and treat dental diseases [94].

7. Conclusions

Over recent years, dental materials and treatment standards were majorly improved thanks to the development of new nano-biomaterials and the incorporation of NPs into already existing solutions [95].

It is very clear that this field will expand, especially due to the fact that:

• Modification of materials with new nanoparticles can result in beneficial effects in more than one aspect, which is standard in the NPs added due to their reinforcement or antimicrobial properties.
• Modification of materials with many nanoparticles allows the achievement of the expected simultaneous multifunctional properties.
• Modification of previously used NPs or the ways they have been used (e.g., Ag NPs encapsulated in SiO₂ NPs) can reduce their disadvantages, which were previously not possible to overcome.
• Due to their different mechanisms of action, NPs could be used to fight off antibiotic-resistant bacterial strains.
• NPs can provide protection against degradation factors in adhesives or ensure stability and efficacy of whitening agents.
• NPs show promising anti-caries results, inhibiting biofilm formation and maturation and concurrently inducing the remineralization processes. Their protective effects on hard tooth tissues are often induced by a biomimetic approach.
• Incorporation of NPs into biomaterials can provide superior immunoregulatory and anti-inflammatory properties without general side effects.
• NPs can provide resistance to wear for tooth tissues as well as intra-oral appliances.
• The use of NPs allows for the creation of new diagnostic tools.