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Back to Journal »International Journal of Nanomedicine» Volume 16

Potential transformational applications of nanoparticles in endodontics

Authors: Wong J, Zou T, Lee AHC, Zhang C 

Published on March 9, 2021, the 2021 volume: 16 pages 2087-2106

DOI https://doi.org/10.2147/IJN.S293518

Single anonymous peer review

Editor approved for publication: Dr. Thomas J Webster

Jasmine Wong, Ting Zou, Angeline Hui Cheng Lee, Chengfei Zhang Restorative Dentistry Science (Endodontics), The University of Hong Kong, School of Dentistry, Hong Kong Special Administrative Region Corresponding Author: Chengfei Zhang Restorative Dentistry Science (Endodontics), School of Dentistry, The University of Hong Kong, 3B60 Floor, Prince Philip Dental Hospital, 34 Hospital Road, Sai Ying Pun, Hong Kong Tel 852-2859-0371 Fax 852-2559-9013 Email [email protected] Abstract: Nanotechnology has emerged in different biomedical fields in the past few decades Many possible applications. In particular, the use of nanoparticles in endodontics has aroused great interest due to their unique characteristics. Due to their nano-scale size, nanoparticles have a variety of properties that can enhance the treatment of dental pulp infections, such as enhancing antibacterial activity, increasing reactivity, and the ability to functionalize with other reactive compounds. Effective disinfection and sealing of the root canal system is a sign of successful root canal treatment. However, the presence of bacterial biofilms and resistance to dental pulp disinfectants pose a major challenge to this goal. This encourages research on antibacterial nanoparticle-based irrigation and root canal drugs, which may improve the elimination of dental pulp infections. In addition, photosynthesis functionalized nanoparticles can also be used as an important aid to root canal disinfection strategies. In addition, although there are countless kinds of endodontic fillings on the market to choose from, the "ideal" material has not yet been conceived. This has led to the development of various experimental filler materials and sealants incorporated into nanoparticles, which have a series of favorable physicochemical properties, including enhanced antibacterial efficacy and biological activity. Nanoparticles have also shown promise in the field of regeneration endodontics, such as supporting the release of bioactive molecules and enhancing the biophysical properties of the scaffold. Given the growing research in this field, this article aims to outline the current evidence regarding the potential transformative applications of nanoparticles in endodontics. Keywords: Nanoparticles, Endodontics, Translational Research, Disinfection, Filling, Regeneration Procedure

Nanomaterials are natural, accidental, or synthetic materials that contain particles in an unbound state, aggregates, or agglomerates, where 50% or more of the particles have an external size of 1 nm to 100 nm. 1 Nanomaterials are used according to size, material classification and source of material. 2 Generally, a nanoparticle is composed of three layers: the core, which is the inner and main material of the nanoparticle; the shell, which is the middle layer, which is chemically different from the core; and the surface layer, which is the outer layer, which can pass through the surface. The role is functionalized with other particles. 3 Nanomaterials have obvious advantages because of their nanoscale size and high surface area compared to their bulk counterparts, and they exhibit unique physicochemical properties-2,3 This includes increased reactivity, greater solubility, and bionics Features and the ability to functionalize with other materials (such as drugs, bioactive molecules, and photosynthetic agents). 3-5 In addition, antibacterial nanoparticles can better penetrate biofilms, are effective in smaller doses, and may help reduce the increase in antibiotic use. 6 Many antibacterial nanoparticles have a common mechanism of action. Nanoparticles can penetrate biological membranes and interact electrostatically with bacterial cell walls, resulting in cell membrane damage, increased cell permeability, production of reactive oxygen species, cell function interference, protein damage, DNA damage, and ultimately cell death (Figure 1) ).6-8 Figure 1 The proposed mechanism of action of antibacterial nanoparticles. The nanoparticles penetrate the biofilm and interact electrostatically with the bacterial cell wall. The resulting cell wall and membrane rupture leads to increased cell permeability and leakage of cell components. Nanoparticles can also interfere with cell function, denature proteins, and destabilize ribosomes. Reactive oxygen species (ROS) are produced by membrane-nanoparticle interactions. ROS may interfere with DNA replication, leading to DNA damage, enzyme inactivation, and secondary membrane damage.

Figure 1 The proposed mechanism of action of antibacterial nanoparticles. The nanoparticles penetrate the biofilm and interact electrostatically with the bacterial cell wall. The resulting cell wall and membrane rupture leads to increased cell permeability and leakage of cell components. Nanoparticles can also interfere with cell function, denature proteins, and destabilize ribosomes. Reactive oxygen species (ROS) are produced by membrane-nanoparticle interactions. ROS may interfere with DNA replication, leading to DNA damage, enzyme inactivation, and secondary membrane damage.

In view of the many inherent advantages of nanoparticles, the potential applications of nanoparticles in the fields of medicine and dentistry have aroused great enthusiasm. 5 The term "nanodentistry" was first introduced at the turn of the 21st century. 9 Since then, innovative efforts have led to nanotechnology being incorporated into countless areas of clinical dentistry, such as direct restorative materials, materials for dentures, periodontal treatment, guided tissue regeneration, implant surface modification, and endodontics. 7,10

In the past decade, the use of nanoparticles in endodontics has attracted great attention from researchers. Since its launch, our collective understanding of the field has grown substantially, and new research continues to add to existing knowledge. Therefore, the purpose of this review is to summarize, compile and integrate the current literature on the potential transformational applications of nanoparticles in endodontics. The scope of this article includes an overview of different nanomaterials used in endodontic irrigation strategies, photodynamic therapy, endodontic drugs, sealing materials, and regeneration procedures (Figure 2), as well as their advantages and limitations in a given application Summarize. Figure 2 The potential transformational application of nanoparticles in endodontics.

Figure 2 The potential transformational application of nanoparticles in endodontics.

The current understanding of dental pulp infections indicates that microbial biofilms play a vital role in the development and pathogenesis of periapical periodontitis. 11,12 Therefore, effective chemical mechanical debridement is essential to eliminate root canal infection. However, biofilm bacteria benefit from various factors that help increase their survival rate. For example, the bacteria in the biofilm are protected by a self-produced polymer matrix (EPS), which inhibits the penetration of root canal disinfectants and reduces their effectiveness. 13,14 In addition, anatomically small areas in the root canal system may be inadequately debrided, leading to residual infection. 15 In addition, the irrigation fluid usually cannot reach the depths of the dentinal tubules, 16 leading to the persistence of bacteria, especially Enterococcus faecalis (E. faecalis), which is usually related to after treatment. 17,18 The most commonly used dental pulp irrigant is sodium hypochlorite (NaOCl), the concentration is usually between 0.5% and 5.25%. 19,20 Classical studies often tout its tissue dissolving and antibacterial properties. 21,22 However, the use of NaOCl can have some unfavorable results, such as the decomposition and weakening of the organic dentin matrix, 23 damage to the periapical tissue 24 and the formation of persistent bacteria 25 Chlorhexidine is considered to be corrosive Smaller pulp disinfectants are usually used at a concentration of 2%,19 but their main disadvantages include their inability to degrade necrotic tissue26 and their reduced effectiveness against gram-negative microorganisms. 27 Ethylenediaminetetraacetic acid (EDTA) is a chelating agent commonly used to remove stained layers. 28 It was found that Enterococcus faecalis biofilm is more susceptible to 2.5% NaOCl and 17% EDTA. 29 However, excessive use can lead to demineralization and erosion of dentin, especially when combined with NaOCl. 30 Due to the above-mentioned limitations of current irrigation practices, it is not surprising that people are increasingly interested in nanoparticle-based flushing agents, especially silver nanoparticles (AgNPs), which have been the most studied so far. 31

AgNPs have been extensively studied in the dental field. 10 AgNPs exhibit antibacterial and antifungal properties because of their multi-layered mode of action. By electrostatically interacting with cell membranes and binding to protein thiol groups, AgNPs can destroy cell walls and metabolic processes, inactivate bacterial enzymes, increase cell permeability and generate reactive oxygen species. 7,32 Recently, it has been shown that AgNPs can not only enhance the antifungal effect of antifungal agents, but also enhance the antibacterial effect of antibiotics against a range of bacteria, including antibiotic-resistant strains. 33,34 Synergistic and multimodal antibacterial action greatly reduces the need for high-dose antibiotics, thereby minimizing 33,34 On the other hand, bacteria such as Gram-negative E. coli and Pseudomonas aeruginosa can be exposed to repeated exposures. The production of flagellin rapidly produces resistance to AgNPs, which triggers the aggregation of AgNPs. Nanoparticles. 35

In terms of dental pulp infection, AgNPs have been shown to have antibacterial and anti-biofilm effects against Enterococcus faecalis. 36-38 When used as a rinsing fluid, polyvinyl alcohol (PVA) coated AgNPs are effective against Pseudomonas aeruginosa, Candida albicans and Escherichia coli. Stool. 39 The bactericidal efficacy of positively charged AgNPs was not inhibited by dentin powder after 24 hours. 36 At the same time, it was found that the anti-biofilm and antibacterial properties were enhanced by ultrasonic activation 40 and Nd:YAG laser irradiation, respectively. 41 Surface charge and contact time are important factors that determine its antibacterial performance, because compared with neutral and negatively charged AgNPs, positively charged AgNPs have the lowest minimum inhibitory concentration and are required to inhibit the growth of planktonic Enterococcus faecalis The shortest time. 36 A study reported that the antibacterial activity of AgNPs is equivalent to that of conventional pulp flushing agents, such as 2% chlorhexidine, 1% NaOCl, and 5% NaOCl. 42 H alkai et al. reported that biosynthetic AgNPs are effective against Enterococcus faecalis Its antibacterial activity is similar to that of ampicillin and 2% chlorhexidine. 43 On the other hand, some studies question the efficacy of AgNPs-based irrigants compared with traditional pulp irrigants. After washing for 5 minutes, the AgNPs solution was not as effective as 2% chlorhexidine in reducing the survival of Enterococcus faecalis in the biofilm, and it was only as effective after 15 minutes. 44 In addition, compared with chlorhexidine and AgNPs solutions, NaOCl also exhibits excellent biofilm dissolution and antibacterial properties. 44 Wu et al. suggested that AgNPs may be more suitable as root canal drugs because of their contact and time dependence. They reported that syringe flushing of AgNPs is not as effective as gel application in eliminating biofilms. 37 Studies have shown that the use of AgNPs in combination with graphene oxide can improve stability, prevent aggregation and promote synergistic antibacterial properties. 40,45 In addition, nano-scale graphene oxide also has inherent antibacterial properties against common dental pathogens. 46 According to reports, the AgNPs-graphene oxide system successfully destroyed the biofilm in vitro model, but 2.5% NaOCl is still better than reducing the biofilm volume and microbial cell count. 40 The different results of different studies may be attributed to the different formulations, characteristics and concentrations of AgNP used, as well as different experimental conditions.

Irrigation with AgNPs solution may affect the physical and structural properties of tooth roots. Compared with the use of NaOCl, the fracture resistance of dental pulp treated with AgNPs-based irrigant as the final irrigant is almost doubled. 47 It was found that the solution of AgNPs based on imidazolium can increase the roughness of dentin, which may be a repair material for sealing and 48 canal walls. 48 AgNPs-based irrigants will not negatively affect the hardness and elastic modulus of the dentin 49 or the bond strength and interfacial permeability of resin-bonded glass fiber posts. 50 However, AgNPs may be aesthetically harmful as a result of endodontic treatment because they may contaminate the dentin wall and cause discoloration. 51

People have raised concerns about the cytotoxicity of AgNPs and their aggregation tendency. The cytotoxic effect may be due to the production of reactive oxygen species that trigger a pro-inflammatory host response, the extent of which depends on the concentration, size and aggregation of AgNPs. 52 In addition, the aggregation of AgNPs may also affect the release of Ag ions. 10 Stabilizers (such as imidazole) can prevent the aggregation of AgNPs and inhibit cytotoxicity. 53 Abbaszadegan et al. reported that AgNPs protected by imidazolium-based ionic liquids showed minimal cytotoxicity. 36 Gomes-Filho et al. studied the tissue response of different concentrations of AgNPs dispersions in rats implanted with fibrin-filled polyethylene tubes, and found that lower concentrations of AgNPs have higher biocompatibility. 54 Another in vivo study showed that the tissue response of rats injected with imidazolium-based ionic liquids-protected AgNPs, 2.5% NaOCl or 2% chlorhexidine are all comparable. 55 PVA is similar to only used for stabilizing AgNP, and the obtained washing solution shows good biocompatibility and has no genotoxic effect on fibroblasts. 56 It was found that the use of silica coating to encapsulate AgNPs can improve the stability and prolong the antibacterial activity of the experimental rinsing solution, thereby minimizing the growth of the biofilm at 7 days compared with bare AgNPs, which is regenerated at 2 days with the biofilm. 57 However, before entering clinical research, it is essential to carefully investigate the appropriate use of AgNPs in endodontic treatment and the potential harm to human health and the environment. 10,31

As demonstrated, many studies are devoted to the transformation potential of AgNPs in endodontic irrigation strategies. In order to provide sufficient explanation background, allow comparisons between papers and help assess potential risks, a complete physical and chemical characterization is important. 58,59 This includes but is not limited to average diameter, zeta potential, peak surface plasmon resonance, and concentration. The complete list of the key physicochemical properties of 32,35,36,57 nanomaterials is shown in Table 1.59. For example, Abbaszadegan et al. provided a comprehensive characterization of synthesized AgNPs with negative, neutral and positive surface charges, reporting the plasmon resonance peak at 400 nm , 425 nm and 407 nm, the average size is 7.5 nm, 10.1 nm and 9.0 nm, the concentration is 9.7 x 10-8 mol L-1, 4.0 x 10-8 mol L-1 and 5.7 x 10-8 mol L-1 The and zeta potentials are -38.0 mV, 0.0 mV and 50.0 mV, respectively. 36 In general, many studies investigating AgNPs in the context of root canal irrigation seem to provide partial characterizations, mainly indicating d particle size, concentration, and if the nanoparticles are outsourced, the manufacturing company. 37,39–42,44,47,49–51,54,56 Regardless of the source of the nanoparticles, whether they can be purchased from a third party or synthesized by researchers, it is stated that the relevant physical and chemical properties help to strengthen the nanoparticles in the dental pulp The scientific value of future research applied in science. 7 Table 1 Important physical and chemical properties of nanomaterials

Table 1 Important physical and chemical properties of nanomaterials

Chitosan is a natural organic biopolymer derived from chitin, which can be extracted from crab shells and shrimp shells. Since chitosan is a cationic compound, it exerts its broad-spectrum antibacterial effect by interacting with the negatively charged bacterial cell membrane, thereby increasing its permeability and causing leakage of intracellular components and ultimately cell death. 60 In addition to its antibacterial properties, chitosan also has biodegradability, biocompatibility and chelating ability, making it an attractive alternative to modern root canal irrigants. 61

The chitosan nanoparticle solution was found to have antibacterial properties against Enterococcus faecalis and inhibit the growth of biofilms. 62,63 However, another study found that its antibacterial efficacy may depend on the status of the bacteria, because planktonic bacteria are completely eliminated, and their biofilm counterparts are still there after 72 hours. 64 Chitosan nanoparticles can maintain their antibacterial properties even after 90 days of aging. 64 In addition, its bactericidal effect depends on time, concentration and exposure. 64,65 Antibacterial effects may be hindered by the presence of inhibitors such as pulp residue and bovine serum albumin, but are not affected by dentin, dentin matrix or lipopolysaccharide (LPS). 66 It is reported that conditioning the surface of the root canal with carboxymethyl chitosan can improve disinfection and prevent bacteria from adhering to the dentin before sealing. 67 Another study found that although the surface treatment does not enhance the anti-biofilm effect of the edible chitosan nanoparticle preparation itself, it can still provide additional structural advantages through collagen cross-linking. 68 Several methods have been proposed to enhance the distribution and effects of chitosan nanoparticles in the root canal system, including electrophoresis, 63 diode laser applications, 69 high-intensity focused ultrasound 70 and manual dynamic activation, including in the prepared root canal system. A suitable gutta percha cone is pumped in the tube to generate microbubbles and enhance fluid dynamics. 71

Several studies have demonstrated the ability of chitosan as a chelating agent and may improve the wettability of dentin. 62,72,73 At the same time, chitosan nanoparticles show the potential to stabilize dentin collagen by resisting bacterial collagenase degradation. 74 It has some people believe that traditional chelating agents still have advantages in promoting the penetration of the sealant, because compared with the final rinse using only chitosan nanoparticles, the final rinse of Qmix® or 17% EDTA can allow the sealant to penetrate to the distance. The depth of the dentinal tubules at 5 mm from the cusp was increased by approximately two times. 75 On the other hand, a recent study found that the chitosan-hydroxyapatite precursor nanometer was used before using the tricalcium silicate sealant. The compound conditioning the dentin can significantly increase the average permeability of the sealant to the tubules. 73 Coupled with its antibacterial properties, chitosan nanoparticle solutions appear to be a promising competitor for new irrigation agents, 62,76 although it has been proposed to extend the processing time and contact dependence of irrigation agents based on chitosan nanoparticles. Sex is a limitation, and further research is needed to overcome it. 64

Metal oxide nanoparticles have also been studied as potential dental pulp irrigants. Zinc oxide nanoparticles (ZnONPs) are touted for their bactericidal properties, and their mechanism of action is similar to AgNPs. 6 It was found that a flushing agent based on ZnONPs can eliminate floating Enterococcus faecalis and destroy the biofilm matrix while maintaining its antibacterial activity after 90 days of aging. 64 However, compared with plankton equivalents, its antibacterial effect on biofilm bacteria is not so obvious. 64 The combination of AgNPs and ZnONPs in the polymer solution showed better antibacterial activity against Enterococcus faecalis than when used alone, although 2.5% NaOCl was still more effective in reducing colony forming units (CFU). 31 A study reported that compared with 2% chlorhexidine and 5% NaOCl, the ZnONPs-based solution had weaker antibacterial efficacy against Enterococcus faecalis, but the result was not statistically significant. 42 Its use as a final rinse resulted in an increase in the average fracture resistance of the root canal by approximately 400N compared to the treated teeth when using NaOCl. 47 On the other hand, another study reported that after washing with a polymer suspension containing AgNPs and ZnONPs, the push-out bond strength of the dental pulp sealant was negatively affected, which may be due to the deposition of nanoparticles on the dental pulp . The dentin surface reduces the adhesion of the sealant. 77

Magnesium oxide, titanium dioxide, and iron oxide also have antibacterial properties,6,78 although relatively little research has been done on these compounds as potential dental pulp irrigants. Monzavi et al. found that nano-magnesium oxide solution has long-term antibacterial effect against Enterococcus faecalis in vitro and in vitro. 78 It was found that the use of titanium dioxide nanoparticle solution as the final rinse will double the average number of fractures compared to the use of NaOCl, the resistance of the endodontic treatment of the tooth. 47 When hydrogen peroxide is used to synthesize into the washing solution, the iron oxide nanoparticles exhibit peroxidase-like activity, thereby producing anti-biofilm and bactericidal activity against Enterococcus faecalis. 79 However, nanoparticles like AgNPs, metals and metal oxides may also have a certain degree of cytotoxicity. Therefore, risk assessment and biocompatibility studies are essential before conducting in vivo studies. 6

Finally, it is reported that gold nanoparticles are a promising nanomaterial with a large number of biomedical applications. 80 However, their application in endodontics has not been widely studied, which may be due to the preservation of their antibacterial efficacy. 6,31,41 Kushwaha et al. evaluated the effects of AgNPs and gold nanoparticle-based irrigants on the eradication of microorganisms in teeth inoculated with Enterococcus faecalis with or without Nd:YAG laser activation. Although Nd:YAG laser activation did improve the antibacterial activity of gold nanoparticles, the use of AgNPs still resulted in a significant decrease in average CFU. 41 However, gold nanoparticles have been shown to exhibit antibacterial properties in other situations, such as burn wound infections. 81 may be due to differences in microbial composition and the presence of more sensitive pathogens than root canal infections.

Overall, research on nanoparticle-based irrigants may pave the way for new and innovative dental pulp disinfection strategies. Further research is needed to fully clarify the potential of various nanomaterials as dental pulp irrigants. In addition, research should aim to investigate the method of incorporating nanoparticles into flushing solutions, their long-term antibacterial effects and in vivo efficacy, while minimizing any potential negative or adverse effects. 7

Photodynamic therapy involves the combination of light and photosynthesis to induce photochemical reactions. Light of a specific wavelength is used to activate the photosensitizer, generate reactive oxygen species, and produce cytotoxic effects on target cells. 82 Recently, research has focused on exploring disinfection strategies that use functionalized nanoparticles combined with photodynamic therapy to enhance antibacterial properties. Efficacy, encourage lavage and improve the physical properties of dentin. The antibacterial properties of nanoparticles combined with the oxidizing power of photosynthetic agents (such as methylene blue, rose red and indocyanine green) can produce synergistic effects. 83-85 Although there are some limitations, such as the potential for the formation of aggregates of these compounds and the difficulty in penetrating into complex anatomical spaces, 86,87 further research in this field may help optimize the potential of these new disinfection methods.

Shrestha and colleagues have studied the antibacterial potential of rose bengal combined with chitosan in a number of studies, and have achieved promising results. It was found that it not only has anti-biofilm properties, but also has a low level of cytotoxicity. 85 Light-activated Rose Bengal-coupled chitosan nanoparticles can also inactivate endotoxins. 88,89 In the presence of tissue inhibitors, these functionalized nanoparticles show a 50%-65% reduction in planktonic Enterococcus faecalis, and when combined with photoactivation, they can be completely eliminated after 24 hours microorganism. 90 Chitosan has also been used in combination with methylene blue. Compared with chitosan or methylene blue alone, the activation of chitosan with methylene blue light showed a better antibacterial effect on Enterococcus faecalis in infected root canals, although the difference was not statistically significant. 84 Indocyanine green is a photosynthetic agent that has received more attention recently and has been studied in combination with AgNPs and laser activation. This combination can reduce the CFU count of Enterococcus faecalis by 99.12%, which is higher than the reduction of CFU using diode laser alone and AgNP alone, although it is not statistically significant. 83 Another study reported that nano-graphene oxide can serve as a photosynthesis carrier and improve the bioavailability and stability of indocyanine green. 91 Compared with indocyanine green photoactivation alone, indocyanine green photoactivation incorporated into nanographene oxide can increase the anti-biofilm efficacy by 1.3 times. 91

Another benefit of the application of nanoparticles and photosynthesis is that it is possible to improve the physical properties of root dentin. Most of the attention has been focused on chitosan nanoparticles decorated with rose red, because multiple studies have shown that it has the potential to enhance dentin properties. 92-94 The photodynamic activation of rose bengal can enhance collagen cross-linking, and at the same time promote the combination of chitosan nanoparticles and collagenase. 94 It has been found that its application can improve the fatigue resistance of dentin, 92 nanometer hardness and elastic modulus. 93 Therefore, these synergistic effects may help strengthen the structural integrity of weakened dentin. 94

The root canal medication is an antibacterial dressing that is placed during multiple visits for endodontic treatment to help disinfect the root canal system. Because of its proven antibacterial properties, calcium hydroxide is a commonly used endodontic drug in modern endodontics. 95,96 However, subsequent evidence has cast doubt on the effectiveness of calcium hydroxide against refractory pulp infections. 18,65,97 Long-term placement may also lead to 98 other drugs (such as triple antibiotic paste) have become alternatives, especially for regenerative endodontic surgery, although some guidelines question the evidence supporting its routine use, especially considering To the risk of antibiotic resistance. 99 All in all, as researchers use nanoparticles as potential areas for further innovation and development, the pursuit of ideal endodontic dressings continues.

Compared with traditional nanoparticles, calcium hydroxide nanoparticles may have many advantages, such as increased penetration depth, increased surface area in contact with pathogens, excellent solubility, and greater antibacterial activity. 100-102 Several studies have found that nano-calcium hydroxide shows a deeper penetration into dentin 100-103. In addition, compared with traditional calcium hydroxide dressings, nano-calcium hydroxide reduces the microhardness of dentin less. 104 Traditional calcium hydroxide also caused a greater reduction in the microhardness of the dentin. Compared to the application of its nano-sized counterparts, fracture resistance. 101 On the other hand, compared with traditional calcium hydroxide, nano-calcium hydroxide is more cytotoxic, although this finding is not statistically significant. 105

In addition to calcium hydroxide, other types of antibacterial nanoparticles, such as AgNPs and chitosan, have been incorporated or formulated into new root canal drugs. It is reported that the delivery method and storage time of the nanoparticles are important factors affecting the antibacterial potential. 37 For example, AgNPs show better anti-biofilm properties as a drug rather than as a rinse agent. 37 A longer dressing time may produce better results, because 4 weeks of placement results in an increase in the proportion of dead cells in the biofilm of Enterococcus faecalis by approximately 25% compared to 2 weeks of placement. 106 The application of drugs based on chitosan nanoparticles has produced considerable antibacterial properties and has less damage to the strength of dentin than calcium hydroxide, which may be due to the promotion of collagen cross-linking and the neutralization of matrix metalloproteinases effect. 101 However, the same study found that the penetration depth of the sealant into the dentin tubules may be affected due to the tendency of chitosan to agglomerate. 101 A study compared the antibacterial efficacy of nanoparticle chitosan and poly(lactic-co-ethylene glycol) ic) acid (PLGA) as a potential in-tube antibiotic delivery agent, the latter showed better performance within 2 weeks Continuous antibacterial effect. 107

Root canal dressings require certain physical and chemical properties so that they can remain in the root canal system while ideally maintaining a certain level of antibacterial activity. These characteristics will be affected by the choice of carrier. 108 Hydroxyethyl cellulose, polyethylene glycol, and carbomer were evaluated as carriers for AgNPs. Although all of these resulted in stable formulations, hydroxyethyl cellulose has the most promising properties, such as uniformity and fluidity. And antibacterial effect. 109 On the other hand, compared with calcium hydroxide and 2% chlorhexidine gel, the antifungal effect of AgNPs-methylcellulose gel was found to be limited. The author believes that the potential reaction between the carrier and AgNPs may be responsible. 110 Another study also hinted at the limitations of viscous carriers in allowing nanoparticles to diffuse, because ZnONPs gels, with or without AgNPs, compared with calcium, the elimination of Enterococcus faecalis significantly reduced the use of hydroxide and chlorhexidine Certainly. 111 The study requires further research to evaluate different formulations of nanoparticle-based in-tube drugs to optimize their disinfection capabilities and minimize interference between materials. 111

Research has explored the concept of introducing nanoparticles to improve the performance of existing drugs (especially calcium hydroxide). It has been suggested that the combination of calcium hydroxide and antibacterial nanoparticles may promote synergistic effects and together lead to enhanced antibacterial properties. 91 When AgNP is added to calcium hydroxide, the antibacterial activity of this combination is more effective than calcium hydroxide, regardless of whether it contains chlorhexidine, and AgNPs alone, 112–114, but there is no significant difference from triple antibiotic paste . 106 Balto et al. commented on the time dependence of these new in-tube drugs, indicating that long-term exposure improves the efficacy of anti-biofilms. 106 In addition, no significant color changes in dentin have been observed in several studies. 106,115 It has also been reported that the combination of calcium hydroxide and ZnONPs exhibits higher antibacterial efficacy than ZnONPs alone. 116 Another study found that this paired antibacterial properties further enhanced the addition of chlorhexidine. 117

The interest in nanoparticulate calcium silicate compounds with internal porous structures stems from their biological activity, biocompatibility, and osteogenic properties, as well as their potential as drug carriers. 118 Porous calcium silicate nanospheres can penetrate the dentin tubules and enhance mineralization, establishing a good foundation for the development of new root canal dressings. 118 With the addition of AgNPs, mesoporous calcium silicate nanoparticles showed sustained release of Ag ions and inhibited the colonization of Enterococcus faecalis. 119,120 Other studies have found that AgNPs and nano-zinc and mesoporous calcium silicate combined nanoparticles exhibit good anti-biofilm efficacy, minimal cytotoxicity, 121 sustained ion release, dentin tubule infiltration, and changes in dentin mechanical properties can be ignored Excluding. 122 The directness of these compounds may be attributed to the mesoporous structure, which enables these compounds to carry antimicrobial nanoparticles and support their sustained release. 120,123 Bioactive glasses also have antibacterial properties because they can change the alkalinity of the environment. 124 Waltimo et al. found that nanoparticle bioactive glass releases more alkaline substances and therefore has higher antibacterial activity compared to its micron equivalents. 124 However, this alkalinity may affect the physical properties of dentin The impact was caused because a study reported that the application of nanoparticle bioactive glass resulted in a 20% reduction in bending strength compared to a saline control, although it was not statistically significant. 125 Given that radiopacity is an important feature of dental pulp sealants, nano-bioactive glass is modified with bismuth oxide to improve radiopacity while maintaining biological activity. 126 In addition to the potential use as a disinfectant in the root canal, several authors also advocate the development of calcium silicate nanoparticles into a new type of root canal sea 121,122,126

After adequate cleaning and shaping, it is important to seal the root canal system to prevent bacterial entry and reduce the risk of recontamination. 127 Therefore, an ideal dental pulp filling material should not only have sufficient physical and chemical properties, such as dimensional stability, radiopacity, moisture resistance and non-toxicity, but it should also exhibit some antibacterial effects against potentially viable bacteria in the root canal. characteristic. 128,129 In addition, the biological activity and remineralization potential can provide additional benefits by strengthening root dentin and promoting root canal sealing materials. 130 However, the most commonly used packing materials, gutta-perchas, are inert, and commercially available dental pulp sealants also have one A series of shortcomings, including temporary antibacterial activity and lack of adhesion to the tooth root. 128,131,132 In order to overcome the many limitations of var, researchers have used nanoparticles as a means to improve existing sealants and develop new sealants.

It has been explored to use quaternary ammonium compounds as antibacterial compounds in restorative dental materials and as components of root canal sealants. 133,134 In particular, quaternary ammonium polyethyleneimine (QPEI) is a polycationic disinfectant that exhibits broad-spectrum antibacterial and anti-biofilm properties through electrostatic interaction with bacteria. Cell membrane, causing cell damage and leakage of cell components. 135 QPEI nanoparticles are also unique in that they can induce intracellular signals that lead to programmed cell death. 6 In addition, because these compounds can provide long-term antibacterial effects133 When incorporated into epoxy-based sealants, it was found that the addition of QPEI nanoparticles can enhance the antibacterial activity of the sealant. 134,136–138 It has been proposed that QPEI nanoparticles not only improve the integrity of the sealant's bactericidal action film by directly destroying the sealant, but also indirectly act on the remote area of ​​the biofilm, although the exact mechanism has not been elucidated. 137,139 The addition of QPEI nanoparticles to AH PlusTM (an epoxy-based sealant) and Pulp Canal SealerTM (a zinc oxide eugenol-based sealant) was also found to regulate osteoblasts by regulating intracellular signaling pathways The growth and differentiation of osteoclasts and osteoclasts depends on the concentration, bone cell type and sealant used. 140 In addition, studies have shown that the possibility of combining commercially available sealants with QPEI nanoparticles has an adverse effect on the cytotoxicity and physicochemical properties of the sealant (such as solubility, fluidity, compressive strength, and dimensional stability). 134,140,​​141 However, it is reported that the incorporation of QPEI nanoparticles did not significantly improve the antibacterial efficacy of AH PlusTM. 141 Another study reported that the anti-biofilm effect of Enterococcus faecalis AH PlusTM modified with QPEI nanoparticles may be strain-dependent. 142 In contrast, the addition of QPEI nanoparticles to Pulp Canal SealerTM improves the antibacterial and anti-biofilm efficacy of Enterococcus faecalis. 141,142 The conflicting results between the studies may be attributed to the differences in the experimental protocol.143 141,142 In addition, although the addition of QPEI nanoparticles to existing root canal sealants may bring many different benefits, consider the advantages of this nanomaterial Potential disadvantages are also important, such as polymerization shrinkage, solvent adsorption, altered mechanical properties, and cytotoxicity. 144

A number of studies have been devoted to formulating new pulp sealants based on quaternary methacrylic acid quaternary ammonium salt. Dimethylaminohexadecyl methacrylate (DMAHDM) is a long-chain chemical variant that can be fixed in a resin matrix through free radical polymerization to form bonds, thereby prolonging antibacterial efficacy by penetrating and destroying bacterial membranes upon contact. Compared with other antibacterial nanoparticles, the synergistic effect may be able to enhance the antibacterial activity and remineralization potential of these new root canal sealants. A study found that the combination of AgNPs and DMAHDM in a new pulp sealant showed promising anti-E. faecalis and anti-biofilm efficacy, because the new sealant reduced the biofilm CFU by 6 orders of magnitude compared to AH PlusTM. 146 It is reported that an experimental sealant resin containing amorphous calcium phosphate nanoparticles and DMAHDM exhibits anti-biofilm activity and high levels of calcium and phosphate ion release, indicating that it is possible to promote remineralization and strengthen damage The root structure. 147-149 In addition to the development of experimental sealants, another study modified the existing epoxy resin sealants using DMAHDM and AgNPs to improve and extend the antibacterial properties. Although AH PlusTM loses its antibacterial effect on the 7th day, the modified sealant can still maintain its antibacterial properties for up to 14 days. 150

As mentioned earlier, AgNPs have powerful antibacterial properties, but people have raised concerns about their aggregation tendency. Therefore, in order to maximize its potential application as a pulp sealant, nanostructured silver vanadate has been suggested as a means to stabilize AgNPs. 151,152 The combination of nanostructured silver vanadate and AgNPs into a pulp sealant does not seem to have a terrible effect on the physicochemical properties. 153 However, conflicting results have been published regarding its effect on the antibacterial activity of the sealant. One study reported that when the sealant was in a freshly mixed state, no additional antibacterial benefits were obtained,154 while another study reported that the antibacterial properties were enhanced in both the freshly mixed and cured state. 15​​5 In addition, the degree of benefit of containing silver vanadate nanowires decorated with AgNPs may depend on the type of commercial blocking agent and the concentration used. 156 It has been suggested that only higher concentrations of these compounds can enhance the antibacterial activity of the sealant, so more clinically relevant experiments should be conducted to determine cost advantages, such as cytotoxicity and tooth discoloration. 143

ZnONPs are also used to formulate new pulp sealants or modify existing zinc oxide eugenol sealants to improve physicochemical and antibacterial properties. 157,158 One of the first studies emphasizing the potential use of nanoparticles in endodontics, including ZnONPs, with or without chitosan nanoparticles, is converted into a zinc oxide-eugenol-based sealant, thereby improving antibacterial properties. 158 Compared with AH 26TM and micro zinc oxide eugenol sealer, sealing with gutta percha and nano zinc oxide eugenol sealant resulted in less tip microleakage. 157 Cytotoxicity According to reports, the nano-zinc oxide eugenol sealant does not exceed other commercially available sealants, such as AH 26TM and PulpdentTM. 159 When incorporated into a polyethylene tube implanted in a rat, the nano-zinc oxide eugenol sealer and Pulp Canal SealerTM and AH 26TM.160 Versiani et al. used different amounts of ZnONPs and found that ZnONPs were used to replace 25% of zinc oxide Powders can improve physical and chemical properties, such as dimensional stability, fluidity, radiopacity, and solubility. 161 A recent study used ZnONPs and AgNPs in combination with an experimental polyurethane acrylate composite sealant, and the results showed better antibacterial activity at lower concentrations than adding any nanoparticle alone. 162

As mentioned earlier, given that the antibacterial properties of chitosan nanoparticles are related to time and contact, these nano-biopolymers must be formulated into new antibacterial pulp sealants. 64,65,68 Several studies have explored the possibility of using chitosan nanoparticles to improve the existing zinc oxide eugenol sealants and improve their antibacterial and anti-biofilm efficacy. 68,158 The combination of chitosan nanoparticles and ZnONP improves the antibacterial film efficacy of Apexit PlusTM, a sealant based on calcium hydroxide, but only the sealant modified with ZnONP can effectively combat the dental pulp isolate strain Enterococcus faecalis. 163 According to reports, the incorporation of chitosan nanoparticles into the epoxy-based sealing agent ThermaSeal PlusTM can improve its antibacterial efficacy. 67 However, when added to the calcium silicate-based sealant MTA fillapexTM, the same degree of improvement was not observed. 67 A possible explanation for var is that different blocking agents have different physicochemical properties, which may interfere with or inhibit any additional antibacterial benefits of chitosan nanoparticles. 67

Polymer nanoparticle carriers have also been used to modify dental pulp filling materials and sealants to improve the sustained and temporary release of antibacterial compounds, while reducing the toxicity of these compounds in their free form. 164 For example, PLGA nanoparticles loaded with experimental root canal sealants added with propolis have antibacterial effects on Enterococcus faecalis, Streptococcus mutans and Candida albicans. 165 Recently, it was discovered that the application of doxycycline-functionalized PolymP-n active nanoparticles can block dentin tubules and exert an anti-biofilm effect on Enterococcus faecalis. 166

In addition to antibacterial effects, nanoparticle-based modifications have been used to enhance other physical and chemical properties of dental pulp sealants, including biological activity and radiopacity. A study found that the inclusion of bioactive glass and hydroxyapatite nanoparticles can enhance the biological activity of epoxy-based sealants. 167 Another study reported that mesoporous calcium silicate nanoparticles can serve as a potential root filling material to provide multiple functions, including drug delivery, biological activity, and bone stimulation. 168 In order to improve the radiopacity of Portland cement-based sealants, Viapiana et al. added niobium oxide or zirconium dioxide in the form of micron or nano-particles. However, according to the specifications established by the International Organization for Standardization, the radiopacity of the improved sealant is insufficient. 169,170

Finally, several studies have investigated the modification of gutta-perchas with nanoparticles. An in vitro study reported that nano-diamond embedded gutta-perchas functionalized with amoxicillin introduced antibacterial properties to this initially inert sealing material. 171 Subsequently, a clinical study used nano-diamond embedded gutta to seal the middle third of the root canal, and it was observed that there was no difference in the treatment effect compared with the control group for up to 6 months. 172 Like most of these innovations, further research is needed to determine the optimal concentration and tailor the synthesis of nanoparticle-based filler materials to provide adequate antibacterial efficacy without compromising physical and chemical properties.

Traditional endodontic treatment involves the cleaning, shaping and sealing of the root canal system. However, since the seminal report by Banchs and Trope, more researchers have turned their attention to regenerative therapy. 173 These strategies aim to restore the shape and function of teeth by eliminating infections, promoting the development and closure of immature root tips, and regeneration. Build pulp vitality. 99,173 Tissue engineering and biological procedures involving stem cells, biologically active molecules, and scaffolds form the basis of regenerative endodontics. 174

Nanoparticle-based carrier systems have been proposed as a method of sustained release of biologically active molecules. 175,176 biologically active molecules are a key component of pulp regeneration treatments because they regulate cell activities such as proliferation, migration and differentiation. 177 Because nanoparticles have enhanced solubility, high surface area to volume ratio and small size, nanoparticle-based carrier systems can improve the dissolution and absorption of bioactive molecules and drugs. 176 Several polymer nanocarriers have been studied in the context of traditional root canal therapy, such as those discussed earlier including chitosan, PLGA and PolymP-n active nanoparticles107,165,166 and regenerative therapy. 178-182 It was found that chitosan nanoparticles loaded with bovine serum albumin can increase the viability of stem cells from the apical papilla (SCAP) and enhance alkaline phosphatase activity. 180 Chitosan nanoparticles loaded with dexamethasone can improve the gene differentiation of dental SCAP. 181 Dentin conditioning with chitosan nanoparticles or chitosan nanoparticles modified with dexamethasone may also reduce the harmful effects of NaOCl and LPS, while stimulating SCAP adhesion, vitality and differentiation. 179,182 Sustained release of dexamethasone wrapped by poly(ε-caprolactone)-forsterite nanocomposite fiber membrane has been reported to promote the osteogenic differentiation and proliferation of human deciduous deciduous tooth stem cells. 178

Nanoparticles have also been customized to develop various forms of scaffolds, which are another key component of regenerative endodontic treatment. The scaffold is a temporary structure that mimics the extracellular matrix to support the growth and differentiation of stem cells and facilitate the controlled release of drugs and bioactive molecules. 183 They can also be combined with nanocarriers to achieve a variety of biologically active molecule release mechanisms. 175 Chitosan has the advantages of adapting and swelling to adapt to the configuration of different sites and its advantages of being easy to combine with other molecules. 184 Bellamy et al. reported that carboxymethyl chitosan-based scaffolds and transforming growth factor β1 shells Glycan nanoparticles can enhance the vitality, differentiation and migration of SCAP. 185 Similarly, it has been demonstrated that incorporating dexamethasone and bioactive glass nanoparticles into a nanofiber scaffold system can also stimulate the odontogenic differentiation of human dental pulp cells. 186 The addition of bioactive glass nanoparticles can improve the mechanical properties of the scaffold w to promote biological activity and mineralization through the release and deposition of calcium. 187 Another study used cellulose nanocrystals to reinforce hydrogel scaffolds, thereby increasing stiffness and stability. The enhanced hydrogel also contains platelet lysate, which is rich in angiogenesis and chemokines, which may enhance the revascularization and regeneration of dental pulp tissue. 188

Finally, nanoparticles are also used in new methods to evaluate regeneration results. Biz et al. compounded gold nanoparticles with biodegradable organic plastic L-lysine to create compounds that are easily internalized by stem cells. Studies have found that the resulting increase in cell radiopacity allows microtomography to identify the presence of living cells after the regeneration process without causing obvious harmful cytotoxic effects. 189

When investigating the potential transformational applications of nanoparticles, one must be aware of possible adverse effects. 31 Therefore, nanotoxicology has become an area of ​​research focusing on evaluating the hazards associated with contact with nanomaterials. 190 The characteristics that lead to the unique properties of nanoparticles are also responsible for the potential toxicity of oral tissues, general health and the environment. 191 The degree of toxicity depends on many factors, such as material, concentration, exposure time, aggregation, particle size, geometry, and surface charge. 2

Nanoparticle-based endodontic treatment is not without its disadvantages, for example, it may have cytotoxic effects on the periapical and dental pulp tissue. As mentioned earlier, the application of AgNPs has been retained due to potential cytotoxicity. 192 It has been reported that the cytotoxicity of AgNPs-based irrigants to rat tissues is concentration-dependent, because of the longer-lasting inflammation and the dispersion of AgNPs compared with the application of 47 ppm and 23 ppm. 54 These findings were echoed by another study that reported that low concentrations of AgNPs have the least cytotoxicity on L929 murine fibroblasts. 36 According to reports, AgNPs-based irrigation solutions are less cytotoxic than traditional pulp irrigation solutions, such as 3% NaOCl and 17% EDTA, to human gingival fibroblasts. 57 The degree of cytotoxicity does depend on the material, because more favorable interactions are associated with chitosan nanoparticles. 193 Shrestha et al. found that these naturally occurring biopolymers are not cytotoxic to both macrophages88 and fibroblasts. 85 Photo-activated rose bengal combined with chitosan also showed low levels 85,88 In addition, taking into account the possibility of extruding the root apex and directly contacting the periapical tissue, special efforts should be made to ensure that new nanoparticle-based pulp filling materials and Biocompatibility of drugs in the root canal. 20,128 For example, it is well known that calcium hydroxide, a widely used root canal drug, is cytotoxic to periapical tissues, 194 but no significant reduction in cytotoxicity of its nanoparticle equivalent has been found. 100 According to reports, a new type of dental pulp sealant containing QPEI nanoparticles has good biocompatibility, and L929 lysis of fibroblasts has not been observed. 134 Similarly, root filling materials based on mesoporous calcium silicate nanoparticles have no cytotoxic effect on periodontal ligament cells, and even promote osteogenic properties by regulating gene expression. 168

There are many ways to allow nanoparticles to enter the human body, including lung, skin, gastrointestinal and systemic administration. 191 Given that nanoparticles and biomolecules have similar sizes, they are easily absorbed by various organs and tissues, and have been found to accumulate in the lung, liver, and reticuloendothelial system. 195-197 Toxic concentrations can cause damage through reactive oxygen dependent and independent mechanisms. 198 Oxidative stress may play an important role in causing tissue damage through DNA mutations, cytokine release, protein denaturation, lipid peroxidation, and apoptosis. 190,191 For example, it has been reported that AgNPs can induce lung inflammation and damage the alveoli. 199 When exposed to peripheral blood mononuclear cells, high concentrations of AgNPs were found to have potential cytotoxicity and can regulate the expression of cytokines. 200 Organic biopolymer chitosan, on the other hand, is generally considered non-toxic and biocompatible. 61 However, it has been suggested that greater cytotoxicity is related to smaller particle size and higher concentration. 201 QPEI nanoparticles are another frequently studied organic nanomaterial in dentistry. They are added to restorative materials. 202 These examples emphasize the importance of fully understanding the potential health effects of nanoparticles in endodontics before conducting clinical research. importance.

There are also environmental issues associated with the use of nanoparticles. 58 Nanoparticles may accumulate in the environment as pollutants, and given that toxic effects are usually concentration-dependent, bioaccumulation may lead to subsequent systemic toxicity to exposed organisms. 203 A There is a certain degree of uncertainty in the ideal policy for the correct recovery and safe disposal of nanoparticles, because the degree of harmful effects of their biological persistence has not been fully elucidated. 2

In general, the potential adverse effects of using nanoparticles in endodontics cannot be ignored because they may affect the success of treatment, patient health, and the environment. 31 Thoroughly investigate the extent of potential hazards and determine safe application methods to minimize biological and environmental risks while maximizing the therapeutic effect.

Advances in nanotechnology may lead to a new era in the transformation and application of nanoparticles in endodontic treatment. The current literature shows that nanoparticles can be used in a variety of applications in endodontics, such as disinfection strategies, photodynamic therapy, filling materials, and regeneration procedures. Nevertheless, considering that different materials, formulations and combinations will produce different characteristics, both beneficial and disadvantageous, so the "one size fits all" approach should not be used to apply nanoparticles. Therefore, the application of nanoparticles in endodontics has great potential, but there is still a way to go before basic research is transformed into clinical research.

This work was supported by Zhang CF from the Fundamental Research Seed Fund of the University of Hong Kong (201910159019) and the Platform Technology Fund.

The authors declare that they have no conflicts of interest in this work.

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