Special Focus on Materials

Review

Advances in Dental Materials
through Nanotechnology:
Facts, Perspectives and
Toxicological Aspects
Gislaine C. Padovani,1 Victor P. Feitosa,2 Salvatore Sauro,2,3
Franklin R. Tay,4 Gabriela Durán,5 Amauri J. Paula,1,* and
Nelson Durán6,7,*
Nanotechnology is currently driving the dental materials industry to substantial
growth, thus reflecting on improvements in materials available for oral prevention and treatment. The present review discusses new developments in nanotechnology applied to dentistry, focusing on the use of nanomaterials for
improving the quality of oral care, the perspectives of research in this arena,
and discussions on safety concerns regarding the use of dental nanomaterials.
Details are provided on the cutting-edge properties (morphological, antibacterial, mechanical, fluorescence, antitumoral, and remineralization and regeneration potential) of polymeric, metallic and inorganic nano-based materials, as
well as their use as nanocluster fillers, in nanocomposites, mouthwashes,
medicines, and biomimetic dental materials. Nanotoxicological aspects, clinical
applications, and perspectives for these nanomaterials are also discussed.
‘Nanodentistry’
Nanotechnology (see Glossary) has induced the generation of innovative and cost-effective
dental materials and devices, enabled the understanding of biomechanical properties of
enamel (e.g., fracture behavior and crack propagation), and contributed to the improvement
of bone-tissue regeneration as well as the diagnosis and prevention of pathologies [1,2]. A
useful definition of nanotechnology with no arbitrary size limitation is: ‘the design, characterization, production/application of structures, devices, and systems by controlled manipulation of size and shape at the nanometer scale (atomic, molecular, scale) that produce
structures, devices, and systems with at least one novel/superior characteristic or property’
[3]. Nevertheless, national and international institutions are looking for an appropriate sizerange definition to generate guidelines for the nanotechnology field – at least one of the
dimensions of the material lie between 1 and 100 nm. The European Commission defines
nanomaterials as those with ‘natural, incidental or manufactured materials containing particles in non-binding states, agglomerates or aggregates in which 50% or more of the total
particles size distribution by number lie in a range between 1 and 100 nm’ [4]. The US FDA
excludes in its definition any naturally-existing substances at small scales, such as microorganisms or proteins [5].

Trends in Biotechnology, November 2015, Vol. 33, No. 11

Trends
Nanotechnology is improving dental
materials and overall oral treatment.
Nanomaterials used in dentistry may
provide mechanical reinforcement,
improve aesthetic aspects, and induce
antimicrobial and therapeutic effects.
Striking recent advances in organic
nanotechnology for dentistry have
come from polymer-based nanomaterials including modified chitosan, polymeric nanogels, and dendrimers.
Emerging nanocomposites for dentistry comprise fillers based mainly on
carbon nanomaterials, nano-silica,
nano-titania, and nano-zirconia.

1
Solid-Biological Interface Group
(SolBIN), Departamento de Física,
Universidade Federal do Ceará,
Fortaleza-CE, Brazil
2
Department of Restorative Dentistry,
Faculdade de Farmácia, Odontologia e
Enfermagem, Universidade Federal do
Ceará, Fortaleza-CE, Brazil
3
Dental Biomaterials and Minimally
Invasive Dentistry, Departamento de
Odontologia, Facultad de Ciencias de
la Salud, Universidad CEU Cardenal
Herrera, Valencia, Spain
4
Department of Endodontics, Georgia
Regents University, College of Dental
Medicine, Augusta, GA, USA
5
Faculdade de Odontologia, Pontifícia
Universidade Católica de Campinas,

http://dx.doi.org/10.1016/j.tibtech.2015.09.005
© 2015 Elsevier Ltd. All rights reserved.

621

Vol. Zinc ions exhibit effective antibacterial activity and this effect is higher when zinc oxide 622 Trends in Biotechnology.. such that nanoparticles larger than 50 nm cannot penetrate the biofilm [23]. zirconia. chitosan). The propensity of research activity in this area is reflected by the number of patent applications (151) over the past decade [8]. SiO2 NPs. and (iii) inorganic nano-based materials (e. hydroxyapatite. The incorporation of a myriad of nanoparticles into dental materials (e. This review provides a discussion on the state-of the-art in nanodentistry together with the most recent advances in this field. silver. properties. Antimicrobial Dental Nanomaterials Silver Nanoparticles (AgNPs) Silver-based nanomaterials are effective against biofilms [17–19] because they can attack multiple sites within the cell at a very low concentration (0.26]. Universidade Estadual de Campinas (UNICAMP). UNICAMP. 23 nm. quartz. defined as the ‘science and technology of diagnosing.g. (ii) metallic (e. Although an overall perspective of nanotechnology has been presented in recent reviews [7. g.J.. Intituto de Química.. titanium dioxide (TiO2). 33.. November 2015.9–16]. followed by AgNPs. possibly due to the presence of carboxyl and phosphoryl groups on the bacteria surface that render the cell surface electronegative [24]. silica. duran@iqm. 11 Campinas-SP. nanogels.g. treating and preventing oral and dental diseases. 14 nm) on Streptococcus mutans [20]. preserving and improving dental health using nanostructured materials’ [7]. and mechanisms through which nanomaterials act when they are utilized in dental materials.32]. No. Because of growing concerns about environmental and human exposure to nanomaterials. dendrimers. 60 nm. proteoglycans present inside the bacteria cells and on the membrane appear to act as binding sites for AgNPs and silver ions [21].g. and inflammation [25. human skin carcinoma [30] and human epidermal keratinocytes [31]. Brazil *Correspondence: amaurijp@gmail. silver ions can interact with sulfuryl groups during protein synthesis. Other in vivo studies demonstrated the influence of these nanoparticles on oxidative stress processes. zinc oxide) represents an innovation by manufacturers to improve the chemical and physical properties of these materials [6]. such as: (i) diffusion of nanoparticles into a plaque biofilm exhibits an inverse relationship between size and effectiveness. nanocarbons). thereby interfering with the replication of bacterial DNA (Figure 1) [22]. copper). Zinc Oxide-Based Nanoparticles (ZnONPs) Zinc has been also used in dentistry for many years as the major filler component of dental cements. relieving pain. solid lipids. Brazil 6 Laboratory of Biological Chemistry.Dental materials have evolved with the advent of nanotechnological research focusing on the production and application of nanoparticles with high-quality structural characteristics. as well as toxicological aspects of the use of nanomaterials in dentistry. quantum dots. this review also provides discussion of the toxicological aspects of the use of nanomaterials in dentistry. myocardial infarction.5–1. Durán). silver. colloidal silica. titanium dioxide. The toxicity of AgNPs was found to be directly related to the activity of free Ag ions released into the medium [25. Campinas-SP. In dentistry. This area of research has been coined ‘nanodentistry’. On the antibacterial mechanism of silver nanoparticles. fundamental aspects must be considered during the preparation of AgNPs.com (A. with consequent accumulation in the brain [27].br (N. polyethylene glycol. hepatic cells [29]. Brazil 7 NanoBioss. Paula). A comparative study evaluated the antibacterial effects of chlorhexidine. little discussion has been provided on the characteristics. and demonstrated that AgNO3 had the most efficient bactericidal effect.0%) to prevent bacterial growth (Box 1). thrombosis. . A further concern exists regarding the capacity of AgNPs to cross the blood–brain barrier through trans-synaptic transport. Campinas-SP. In vitro studies showed that AgNPs decrease mitochondrial function in murine neuroblastoma cells [28]. Intituto de Química.unicamp. and (ii) negatively charged nanoparticles have difficulty in diffusing through the biofilm. and silicon dioxide (SiO2) nanoparticles (AgNPs. Furthermore. gold. TiO2 NPs. zirconia. Nanodentistry is reviewed here from the scientific and technological perspectives by following a property–function–application basis that addresses most of the recent advances on the use of (i) polymeric (e.

Ca10(PO4)6(OH)2] nanoparticles are examples of this group. and showed optimal adhesive properties [116] AgNPs Applied as a coating agent on titanium Implants AgNPs 6 nm in diameter Prevented bacterial proliferation both in vitro and in vivo against specific species such as Escherichia coli and Staphylococcus aureus [117] AgNPs Applied as layer with particle sizes of 9. erythromycin. No. Gold and silver nanoparticles are included in this group. only 34. and N-cetyl-N. Inorganic nanoparticles are mostly used as nanofillers. and environmental studies. and fir balsam Adhesives AgNPs sizes ranging from 1 to 5 nm Provided considerable reduction of the length of adaptation to blade denture. In the grand scheme of things. nanotechnology is related to the engineering of functional systems at an atomic or molecular scale. not in an oxidized state). Dendrimers are also Table 1. polyacrylic acid. Nanotechnology: although not precisely defined. Nanofillers: are reinforcement particles smaller than 100 nm in size which are usually blended with resins to create nanofilled resin composites.. sodium alginate. nanoparticles with improved diffusion capacity into the EPM and broad-spectrum of antimicrobial activities have gained popularity.N.Box 1. Nanotoxicology: currently evaluates the safety of the use of nanomaterials from a multidiscipline paradigm that includes in situ. Antimicrobial Nanomaterials Applied in Dentistry Nanomaterial Method of use Application Details Refs AgNPs (silver nanoparticles) Used in an aqueous composition comprising ethylenediamine tetraacetic acid. This region provides optimal bonding between restorative resins and dentin tissue. Hybrid layer: the interdiffusion region between the polymer matrix and the (partially) demineralized dentin collagen manifested during the application of a dentin adhesive. and chloramphenicol [119–121] AgNPs Inclusion of silver and amorphous calcium phosphate nanoparticles in composites Resin composites Adhesives Calcium phosphate nanoparticles of 100 nm and AgNPs of 3 nm Led to a substantial reduction of the viability and metabolic activity of microcosm biofilms [122. antiseptic cetrimide. and 98 nm on enamel surfaces Antibacterial medicine formulations Led to a substantial antiadherence activity against Streptococcus mutans [118] AgNPs Applied as colloidal suspensions Antibacterial medicine formulations Presented a synergistic effect with other antimicrobials and antibiotics such as chitosan.e. chlorhexidine.. Nanotechnology has required classic toxicological methods to be revisited in view of the quantum size effects and the large surface area-to-volume ratio that are manifested by nanomaterials.g. Incorporation of nanofillers into resin composites enables mechanical strengthening and excellent surface polishing. Inorganic nanoparticles: are mainly based on compounds which comprise elements of the periodic table in an electronic configuration that is different from the configuration of their pure states (e. In this context. Metallic oxides (e. Antimicrobial Nanoparticles against Biofilms Glossary Biofilm resistance has been attributed principally to the protection provided by the extracellular polymeric matrix (EPM). Vol.3. nanotechnology involves the development of high-performance materials or devices within nanometer scales.e. kanamycin. silicon dioxide) and hydroxyapatite [i. 21. Conversely. Polymeric nanoparticles: consist of compounds containing mostly carbon. titanium oxide.3. hydrogen. oxidized metallic elements). such as polyethylene glycol (monomer: C2H4O). caused no toxic action on tissues of denturesupporting area. Metallic nanoparticles: comprise metallic elements of the periodic table present in their pure state (i. and nitrogen organized in basic monomeric chemical structures which are repeated periodically in long molecular chains. which acts as a barrier against diffusion processes. which is not possible with conventional antibiotics. nanoparticles may be able to maintain antimicrobial efficiency in the face of bacterial adaptability.123] AgNPs Stabilized by chitosan in a fluoride solution and applied once per year as a colloidal suspension on decayed primary teeth Mouthwash AgNPs colloidal suspension was able to arrest caries in 66. glycerol.. oxygen. 33.7% of the patients.Ntrimethylammonium bromide Root canal irrigation Efficient against Enterococcus faecalis A 197 A [114] AgNPs Conjugated with calcium phosphate (hydroxyapatite) Adhesives Hydroxyapatite with particle size smaller than 150 nm and AgNPs smaller than 50 nm [115] AgNPs Conjugated with polyvinylpyrrolidone. 11 623 .g. November 2015. Uses of antimicrobial nanomaterials in dentistry are given in Table 1.7% of the patients in control group demonstrated arrested caries in the decayed teeth that were treated with water as the placebo [124] a Trends in Biotechnology.. in vivo. Furthermore. ampicillin.

mutans and Porphyromonas gingivalis through a constant and slow release of zinc ions [132] 624 Trends in Biotechnology.126.127] ZnONPs Incorporated into dental resins Resin composites Adhesives ZnONPs effects were compared to those of AgNPs A more potent antibacterial effect was observed for ZnONP-doped resins compared to resins doped with AgNPs (20 nm) against S. aureus [125] ZnONPs Applied with Ca/PO4based structures Adhesives Cements Favored the remineralization of mineral-depleted dentin. The effect was attributed to the larger particle size of ZnONPs (50 nm) [128] ZnONPs Applied as antibacterial agents (suspensions) for peri-implantitis Antibacterial medicine formulations Implants ZnONPs effects were compared to those of AgNPs Particle size ranging from 10 to 50 nm AgNPs were more efficient than ZnONPs [129] ZnONPs Incorporated into cements Cements Analysis of colony-forming units indicated that all the tested compositions (with and without ZnONPs) exhibited similar anti-biofilm activity [130] TiO2NPs (titanium dioxide or titania) Mixed with a lightcurable orthodontic composite paste Resin composites Adhesives It was able to reduce enamel demineralization and provide antibacterial properties for dental adhesive systems The shear bond strength and the adhesive remnant index for the nanocomposite were similar to those of the control composite [131] TiO2NPs Grown as nanotubes on titanium surfaces and incorporated with ZnONPs Implants Zinc oxide nanoparticles of 20 to 50 nm were bonded to the walls of the TiO2 nanotubes Provided antibacterial activity against S. in which the monomeric chemical structures branch and repeat in a radial fashion in 3D space. Vol. mutans and Lactobacillus. (continued) Nanomaterial Method of use Application Details Refs ZnONPs (zirconium oxide or zirconia) Applied as a coating material along with nano-hydroxyapatite Implants ZnONPs 10 to 120 nm in diameter Prevented infection on dental implants and promoted osteoblast growth Produced a significant antimicrobial effect against S. 33. They are commonly commercialized as visible lightcurable resin composites. Resin-based composites (RBCs): restorative dental composites based predominantly on dimethacrylate resins and inorganic reinforcement particles.Table 1. . providing substantial gains in hardness and modulus of elasticity within the hybrid layer Interfered with matrix metalloproteinase-mediated collagen degradation [6. 11 included in this category. November 2015. No.

which acts as a matrix for the production of antimicrobial periodontal dressings [36]. No. Clinical trial NCT02353611 Clinical trial NCT00299598. It is worth highlighting two important aspects regarding the bio-effects of ZnONPs: (i) the toxicity of these nanoparticles appears to be dose-dependent. Ag > Ag +CuO > Cu2O > CuO > Ag +ZnO > ZnO > TiO2 > WO3. 11 625 . ZnO.gov/). This cytotoxicity of ZnONPs was previously observed for other cell lines such as human Trends in Biotechnology. and E. Candida albicans. in descending order.Table 1. mutans [134] ChitosanNPs Employed in nanohydroxyapatite-coated titanium implants as a chelating agent for calcium ions Implants When human bone-marrow mesenchymal stem cells came into contact with chitosan-pretreated surfaces. 33. [129] ChitosanNPs Conjugated with silver nanoparticles Resin composites Adhesives Silver nanoparticles 5 nm in diameter Displayed high antibacterial activity against S. faecalis. mutans. this toxicity is greatly reduced when these nanoparticles are embedded in sodium-phosphorylated chitosan. which can also inhibit the growth of planktonic bacteria. However. as well as to Ag+CuO and Ag+ZnO composites Resin composites Adhesives Antimicrobial activities of the nanoparticles were. Vol. Despite these promising perspectives. and (ii) coating and functionalization of ZnONPs alter the antibacterial features of zinc compared to the antibacterial activity of the metal in its bulk state. changing the osmotic balance and increasing membrane permeability [33–35]. Zn strongly binds to lipids and proteins. (continued) Nanomaterial Method of use Application Details Refs TiO2NPs Applied in a gel to increase the bleaching efficacy of hydrogen peroxide (H2O2) Bleaching agents In the presence of TiO2NPs the H2O2 concentration could be decreased to 6% with no clinical difference in the bleaching effect compared with H2O2 35% [133] Cu2ONps (cuprous oxide) and CuONPs (cupric oxide) The antimicrobial effects of these compounds were compared with those of silver.54] QAC-based nanostructures Applied as crosslinked quaternary ammonium polyethylenimine (QPEI) nanoparticles incorporated into resin composites Resin composites Presented in vivo antibiofilm activity against salivary bacteria [136] b c a Clinical trial NCT01950546 (http://clinicaltrials. they were able to differentiate into boneforming cells [135] QAC-based nanostructures Applied as a quaternary ammonium compound conjugated to organosilanes and silica nanoparticles. The bactericidal effect of ZnONPs may be attributed to their ability to interact with the cell membrane of several bacterial species. and also to epoxy silicates Resin composites Adhesives Presented antimicrobial activities against S. Actinomyces naeslundii. ZnONPs increase oxidative stress within the bacterial cell because of their ability to generate Zn2+ and reactive oxygen species. [53. and tungsten oxide (WO3) nanoparticles. b c is present as nanoparticles. In addition. November 2015. nanotoxicology results indicate that ZnONPs exhibit significant cytotoxicity on human gingival fibroblasts (HGFs). TiO2.

Silver Nanoparticle (AgNPs) Activity against Bacteria. and chitosan-based nanoparticles. November 2015. the cell membrane. Cu-. Considered together. This involves ROS DNA AgNPs Ag+ Proteins (i) the release of silver ions (Ag+) and the production of reactive oxygen species (ROS). (ii) the accumulation and interaction on the cell membrane. Ti-. However. inoculum 3  105 NIH/3T3 cells [38]. and (iii) bacterial uptake of AgNPs and the consequent generation of ROS and silver ions.Figure 1. cell population growth. whereas membrane mechanisms were evidenced for Zn-. and membrane proteins. 33. 11 . ROS antimicrobial action mechanisms were also evidenced for Zn-. Vol. Titanium Dioxide-Based Nanoparticles (TiO2NPs) TiO2NPs undergo photocatalysis when exposed to near-UV and UVA radiation. It was observed that TiO2NPs induced a concentration-dependent proinflammatory effect on human gingival fibroblasts [42]. cytokinesis-block micronucleus (CBMN). Despite their efficacy as antimicrobial agents along with potential for clinical application. Finally. comet assay. moderate biocompatibility of TiO2-modified glass ionomer cements (GICs) was observed for human oral squamous cell carcinoma cell lines [43]. the safety conditions for the use of TiO2NPs must be determined in the future in terms of their toxicological effects. 626 Trends in Biotechnology. Conversely. thereby causing oxidative cell death [40]. these results indicate that aspects of nanoparticles such as the purity. low cytotoxicity was observed when gastric epithelial (GES-1) and neural stem cells (NSCs) were exposed to ZnONPs [39]. apoptosis by flow cytometry. An important study on the cytotoxicity and genotoxicity of TiO2NPs (from 8 to 20 nm) was performed with assays involving the methyl tetrazolium cytotoxicity assay (MTT). and CuO). may exhibit antibacterial activity through an unknown mechanism [41]. thus affecting its function and permeability. Furthermore. and colloidal stability of TiO2NPs on the cytotoxicity and genotoxicity of human oral cells must be further investigated before these nanoparticles can be adopted for clinical use. producing reactive oxygen species (ROS: mainly H2O2 and OH ) which alter the osmotic equilibrium of bacteria. Biofilm Tooth embryonic lung fibroblasts (HELF) [37] and 3-day transfer. a key aspect to be elucidated is the fact that TiO2.g. TiO2NPs can interfere with phosphorylation. a potential synergistic toxic effect (for the liver and kidney of mice) was observed for ZnONPs when administered with ascorbic acid [39].. TiO2. Conversely. ZnO. and Cu-based nanoparticles (e. morphology. aggregation. even when non-irradiated. structure. which can affect DNA. No. and the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene mutation assay for rat lung alveolar macrophages [44].

causing adsorption of positively charged polymers on the bacterial cell membrane.47]. nanoparticles present in a composite dental material need to exhibit a hydrophobic characteristic together with a sufficient amount of cationic charge [56]. Vol. antitumor nanoparticles loaded with cisplatin distributed on polyethylene glycol-poly(glutamic acid) showed effective action against oral squamous cell carcinoma. No. The antibacterial effect of chitosan may be attributed to its chemical structure. facilitating diffusion of drugs into tumors. 11 627 . The antibacterial mechanism of QACs has not yet been fully elucidated. This effect may be correlated with the mechanism of destabilization of the bacterial membrane. and reducing side-effects (Figure 2) [57. Nanomaterials and Quaternary Ammonium Compounds (QACs) Nanostructured materials containing low concentrations (1%) of QACs have been recently used in dentistry in view of their antibacterial effects against several species including S. However.5. mutans and Lactobacillus casei [50–54]. the high concentration of copper ions may also cause the formation of reactive species that alter protein synthesis and DNA replication of the microorganisms [45]. and sustained release of the incorporated molecules [60]. with the presence of deacetylated C2 amino groups which become protonated and positively charged at pH <6. Chitosan Nanoparticles Chitosan. solid lipid nanoparticles behave as effective vehicles for hydrophobic or water-labile chemotherapeutics in monolayer-cultured human oral squamous cell carcinoma. Trends in Biotechnology. and (ii) inhibition of mRNA transcription and alteration of protein translation owing to binding of chitosan to the DNA of several microorganisms [40. November 2015. attention must be paid to the purification and processing methods employed for the production of these nanomaterials.46]. a long polymer chain characterized by randomly arranged N-acetyl-glucosamine and glucosamine residues. The lipoteichoic acid present in Gram-positive bacteria acts as a binding site for chitosan. The molecular weight of chitosan appears to be strongly related to the antibacterial activity of the nanoparticles [34. When these ions are replaced with chitosan. has recently been introduced as a potential antibacterial agent for dental applications [46]. Hence. It is well known that Mg2+ or Ca2+ stabilize the outer membrane of bacteria. mainly because of the possible incorporation of toxins and other residues. modification of the cell wall occurs together with alteration of the activity of degradative enzymes. Nanomaterials for Therapeutic Dentistry Polymeric Nanoparticles Nanoparticles also represent a promising strategy for selective and controlled drug delivery into cells and tissues.Copper-Based Nanoparticles (CuNPs) Similar to most of the nanoparticles. 33.40]. Thus. However. QAC nanoparticles must be in contact with bacteria. It is believed that QAC salts may act as highly-active cationic agents.58]. to obtain an effective antibacterial effect. chitosan binds to the membrane of bacterial cells leading to (i) increase in membrane permeability with a concomitant increase in the outward flow of ions and proteins from the microbial cell. chitosan polycations compete with divalent cations and interact with the bacterial cell membrane through electrostatic interactions [49]. thus inducing a uniform drug concentration at the site of injury. a possible explanation is based on the fact that Cu can bind to amine and carboxylic groups on the surface of the microorganism and cause modifications to their cell membranes [34. but with much less renal toxicity compared to the use of cisplatin alone [59]. the mechanism of action of CuNPs remains obscure. with the advantage of improved drug stability. Such interaction would cause significant changes in membrane permeability that eventually result in complete lysis of the bacteria cell membrane [55]. In Gram-negative bacteria. In dentistry. Furthermore. Although little or mild cytotoxicity for chitosan nanoparticles was observed so far [46]. causing alteration of membrane functionality [48]. prevention of proteolytic degradation. In addition.

November 2015. drugs can be physically or chemically mixed with the polymer. 11 . Schematic Illustration Representing the Current Use and Perspectives on the Use of Nanomaterials on Therapeutic Dentistry. dendrimer nanoparticles. Carbon Nanomaterials and Quantum Dots Nanocarbon materials (NCs: carbon nanotubes. Vol. In the same context. incorporated in the cavities. graphene. leading to the mucoadhesion in oral carcinomas [63]. it was possible to observe that carbon nanotubes selectively attach to dentin and cementum surfaces by adhering to the exposed collagen fibrils [66]. calcium hydroxide cements have limited antibacterial activity with a plateaued release of OH ions after 1 week [67]. and fullerene) have been widely used in medicine in view of their ability to improve the mechanical properties of specific bio-composites. These materials can be easily modified by adding functional groups to provide colloidal stability in biological media. Similarly to NCs. facilitating the delivery of molecules and promoting sustained release of biological agents [64. Another efficient strategy for drug delivery applications is the use of hydrogels. nanoparticles carrying antibiotics in combination with ZnONPs improved root canal disinfection against E. poly(D. 33. Through the analysis of the morphology of a tooth surface before and after immersion in a suspension of carbon nanotubes. These are important aspects that can improve restorative and endodontic materials. Commercial quantum dots comprise mainly chalcogenide compounds such as CdSe and CdTe.L-lactide-co-glycolide). the application of quantum dots (QDs) represents another significant achievement via nanotechnology.65]. For example. and cellulose acetate phthalate incorporated with triclosan tested in vivo (in dogs) were able to reduce periodontal inflammation sites during bleeding [61]. Quantum dots are semiconductor nanometer-sized monocrystals 628 Trends in Biotechnology. and progressively released from the hydrogel. a composite based on a mesh of hydrophilic polymer chains dispersed in water. and hydrogels. Hydrogels Periodontology Gold nanoparcles Oral cancer management Quantum dots Dendrimers Biomineralizaon Adhesive denstry Nanoparticles of poly(D. faecalis biofilms [62].Nanomaterials Therapeuc nanomaterials in denstry PolyGA– PEG– cisplan Solid lipids Oral cancer management Figure 2. Basically. Synthetic and biological polymers can be chemically and physically managed for the production of solid polymeric nanoparticles. No.L-lactide). Hydrogels are attractive for oral administration because their polymeric chains can interact with glycoproteins of saliva.

thus being applied in head-and-neck cancer diagnosis/detection [68]. nanocomposites and resin-based dental materials containing nanoparticles currently have the highest feasibility for clinical use. November 2015. Application of Resin-Based Composites (RBCS) Incorporated with Nanoparticles for Dental Restorations. (ii) coupling agents (e.. Nanoparcle: SiO2. (iii) organic monomers responsible for the generation of the polymeric matrix. 11 629 . radiosensitizers. Although some of these dental materials are already commercialized. Vol. anbiocs. and drug delivery properties. and pigments are not depicted. and removing fillings prepared with these nanocomposites [71]. Gold Nanoparticles Gold nanoparticles have recently been introduced in a variety of applications in cancer diagnosis and treatment. Several studies reported the synthesis of gold nanorods.. TiO2. organosilanes) that increase nanoparticle bonding to the polymeric matrix. anti-inflammatory... antimicrobial. The basic composition of new nanotechnological RBCs comprises (i) inorganic nanoparticles that provide mechanical. Ca3(PO4)2. E n a m e l Denn that emit high-intensity fluorescence when illuminated by ultraviolet and/or visible light. No. QDs may be combined with antibodies to bind to specific cancer proteins for sensitive detection of cancer cells. there are still concerns regarding the inhalation of released nanoparticles during abrasive procedures such as re-shaping.. and nanospheres [69]. remineralization.. and (iv) other possible bioactive molecules with antimicrobial. Other essential elements present in the RBCs such as photoinitiators.g. photothermal agents. Nanocomposites Considering the variety of nano-based dental materials reported herein. BisGMA.. aesthetic. The main benefits are their low cytotoxicity and wide variety of possible chemical functionalizations. Nanoparcle coupling agent for matrix bonding Resin Adhesive Figure 3. nanocages. or antibiotic properties. 33. Trends in Biotechnology. photoinibitors. concerns still remain on their prolonged retention within cells and difficulty in removal by the kidneys. The use of nanoparticles allows the addition of larger amounts of fillers into dental resin composites compared to those containing microparticles (Figure 3).. generating promising compounds to be used as contrast agents. However. and drug delivery nanocarriers [70]. nanoshells.Key: Bioacve molecules: anmicrobial.. BisEMA. polishing. ZrO2. carbon.. Organic monomers: TEGDMA.

Nanomaterials Conjugated in Cements and Metals Minimally invasive and atraumatic restorative dentistry requires the use of therapeutic restorative materials. Nano-based cements containing nanoparticles of hydroxyapatite demonstrated the ability to induce mineralization-associated gene expression in osteoblasts [88]. Recently. quaternary ammonium dimethacrylate. The benefit of using resin composites containing nanofillers for restorations has been observed in a 2 year clinical study [75]. To achieve this goal. Therapeutic dentin adhesives for atraumatic and minimally-invasive restorative dentistry have also been developed by adding doxycycline-encapsulated nanotubes to dentin adhesives to enhance their antimicrobial potential [79]. the use of nanogels with varying hydrophilicity has enabled the development of highly crosslinked water-compatible polymers that enhance the durability of phase-separated and highly-hydrophilic adhesive resins [83]. providing suitable protein adsorption and cell adhesion/proliferation [90]. 33.73]. 11 . These resin-based composites (RBCs) containing nanoparticles exhibit a high surface free-energy that exerts differential behavior in terms of mechanical and physicochemical properties. especially when using silver nanoparticles. resistance to fracture. It was also shown that inclusion of hydroxyapatite nanoparticles in soft drinks can prevent tooth erosion in athletes [89]. such as an excellent color density.78]. adequate surface brightness. mainly through the evolution towards nanocomposites [72. In addition. calcium phosphate nanoparticles and fluorinated hydroxyapatite nanocrystals have been developed and tested as potential dental filling materials with therapeutic ability to prevent and/or combat dental caries [84. Incorporation of carbon nanotubes into resin composites resulted in significant reduction of polymerization shrinkage associated with methacrylate resins [80]. silane-coupling agents (i.85]. phosphate.e. The resin composite was capable of enhancing enamel/dentin remineralization.. Regarding the biocompatibility of dental materials containing hydroxyapatite nanoparticles. November 2015. Alginate/nano-bioactive glass ceramic composite scaffolds were useful in periodontal regeneration. Furthermore.e. and excellent adherence to dental tissues [73. low polymerization shrinkage. and additional calcium phosphate nanoparticles [77. without changing other fundamental properties of the resins [81. No. dimethylaminohexane methacrylate. cytotoxicity assays have been performed comparing the effect between commercially available nano-based cements and conventional ceramic cement for root-end filling in endodontics.82]. organosilanes) offer the possibility to achieve bonding compatibility with TiO2 and SiO2 nanofillers within the restorative resin matrices.and/or fluoride ions has been created to combat secondary caries [86]. Vol. nanogel particles based on polymers with high molecular weight have been used to reduce polymerization shrinkage and cavity wall stresses associated with polymerization of dental resin composites. Another noteworthy application of nanotechnology may be found in dental implantology [91]. and dimethylaminododecyl methacrylate (antibacterial resin monomer) [76].74]. The development and characterization of a resin composite was performed with nanoparticles of amorphous calcium phosphate. low surface roughness. biocompatibility) to that of mineral trioxide aggregate (MTA) when these cements are placed in contact with human mesenchymal stem cells [87].Resin-Based Composites Containing Nanoparticles and Nanoclusters Resin composites have been refined during the past decade for use in both anterior and posterior regions of the oral cavity. 630 Trends in Biotechnology. It was found that cements with nano-hydroxyapatite exhibit similar characteristics (i.. A dental material containing calcium phosphate nanoparticles and/or other fillers capable of releasing calcium.

they tend to re-precipitate as more complex calcium phosphate compounds such as apatite and/or octacalcium phosphate under appropriate pH and temperature conditions. In dentin collagen remineralization.5 nm 50 nm 20 nm 10-Methacryloyloxydecyl dihydrogen phosphate (MDP) forms nanolayers on enamel and denn (red arrow) Figure 4.95]. November 2015. the use of resin-bonding systems containing specific functional monomers can create self-assembling of bonding nano-layers with calcium/hydroxyapatite present at the resin–dentin interface [94. No.96. These nano-layers were found when using commercial adhesives. with permission. A biomimetic remineralization strategy based on the use of biomimetic analogs of dentin noncollagenous proteins into polymer-stabilized liquid precursors has the potential to remineralize apatite-free collagen matrices.104]. Promising nanostructured-bioactive agents such as polyamidoamine dendrimers (PAMAM) can induce enhanced biomineralization of dentin and enamel. Biomodulation of Dental Tissues through Nanotechnology Different types of dental materials are capable of creating nano-arranged structures. several bioactive fillers capable of releasing calcium and phosphate are currently available. Furthermore. 33. Biomodulation in Dentistry. Nano-layers formed by commercial adhesives containing monomers such as 10-methacryloyloxydecyl dihydrogen phosphate (MDP) can largely increase their bonding properties. These amorphous calcium phosphate nanodroplets were found to be liquid-like and were capable of infiltrating the internal water compartments of collagen fibrils to achieve intrafibrillar remineralization of collagen fibrils (Figure 4) [96].Un mi ne ral ize d Ion-releasing resins and phosphoproteins analogous fib rils PAMAM dendrimers B: Incubated in saliva Enhance biomineralizaon of enamel and denn Co lla ge n 500 nm A: Adsorb on etched enamel Nanolayers 15wt% MDP on enamel Rem ine ral iza o n C: Induce HA remineralizaon 15wt% MDP on denn Adhesive Acidic funconal monomers 100 nm Promote hierarchically organized denn remineralizaon Self-assembly in nanolayers improves denn/enamel bonding 3. 11 631 . thereby demonstrating the suitability of such treatment (Figure 4). Unlike conventional remineralization strategies that require the presence of apatite seed crystallites for epitaxial crystalline growth. from [95. Once these ions are released from the bioactive fillers. the aforementioned biomimetic remineralization strategy based on adoption of nanotechnology principles has the potential to remineralize apatite-free collagen Trends in Biotechnology. poly (lactic acid) combined with carbon nanotubes and calcium phosphate improved the mechanical tensile strength of the polymer and stimulated osteoblastic proliferation and differentiation [93]. Vol. It has been demonstrated that amorphous calcium phosphate may be stabilized by biomimetic analogs of dentin noncollagenous proteins into ‘polymer-stabilized liquid precursors’. Adapted. It is possible to enhance the mechanical properties of hydroxyapatite-coated titanium implants by using carbon nanotubes incorporated in the hydroxyapatite coating [92]. For example.

when implanted in loco as a regenerative scaffold. The odontogenic potential of restorative materials was reported to be enhanced by the incorporation of 5-polyamidoamine (PAMAM) dendrimers (G5. therapeutic and biomimetic restorations performed after dentin caries removal and subsequently filled using nanomaterials are not yet completely achievable at the moment. need to be addressed and overcome before new nano-based dental materials are introduced in the market. as well as remineralization of the apatite-sparse superficial layers of caries-affected dentin. resin-sparse regions in hybrid layers created by the application of dentin adhesives to acid-etched dentin. as well as cost-effectiveness. but instead persist in a free state such that they can be immediately available to reach the target? Can new antibacterial nanoparticles be generated with less-heterogeneous release potential and longer antimicrobial effects when incorporated in solid and/or gel biomaterials? Will it be possible in the near future to create smart nano-materials or ‘robotic’ nanoparticles that. resin composites and cements that can be used to replace missing tooth structures. One of the most stimulating perspectives for dental restorative nanomaterials is that nanotechnology can mimic the physicochemical-mechanical properties and the aesthetic properties of dentin and enamel (biomimetics). treatment. November 2015. further research is required with respect to clinical suitability [100]. The anti-inflammatory effects of biologically-active nanostructured multilayer films containing melanocortin peptides (/-melanocyte stimulating hormone. 33. many types of dental materials have been generated through nanotechnology and are available for clinical application. More recently. This is due to replacement of hydroxyapatite crystallites which were lost due to erosion. No. fifth generation) conjugated with fluorescein isothiocyanate and /Vb3-specific cyclic arginine-glycine-aspartic acid (RGD) peptides [102]. The popularity of using dendrimers as additives in dental resin composites can be appreciated by recognizing the number of recently-registered patents on this subject [106–110]. /-MSH) were successfully exploited in dental applications [97]. Vol. or at least of specific tissues such as pulp and periodontal ligament? . However. the clinical feasibility of this strategy is still under investigation and further developments will be necessary to produce a commercial dental material with such nano-based biomodulation. However. A further example of current nanotechnological benefits in dentistry is the biomineralization of dental enamel by means of highly organized nanorod-like crystals of hydroxyapatite and nano-silica [99]. The /-MSH peptides stimulate adhesion and proliferation of human pulp fibroblasts and modulate pulpal inflammation. several particles have been developed with different crystallinity and sizes to remineralize and mimic the physiological structure of tooth enamel. To date. in particular those working in countries not yet industrialized? Will it be possible to create specific therapeutic dental nanoparticles with low toxicological outcomes that cannot agglomerate in nano. Potential applications include remineralization of water-rich.matrices.or micro-clusters. Ceramic as well as silica-rich glass nanoparticles have been 632 Trends in Biotechnology. Using organized micro-architectures based on nanorod-like hydroxyapatite crystals. In preventive dentistry. 11 Outstanding Questions When will the newest nano-dentistry achievements attained so far in diagnosis. PAMAN dendrimers functionalized with carboxylic acid have been used to mimic non-collagenous proteins to promote remineralization of tooth enamel (Figure 4) [103. Initiation of the regenerative process is subsequently performed using the nanostructured film to induce colonization of dental pulp stem cells [98]. in particular. reduction of inflammation is first achieved with the use of /-MSH. and more specifically for pulp connective tissue regeneration.104] and dentin collagen matrices [105]. or attrition [101]. This resulted in the creation of an anti-inflammatory agent for treatment of endodontic lesions. can regulate and favor the self-regeneration of teeth. the use of toothpastes and mouthwashes containing hydroxyapatite nanoparticles has been advocated as promising approaches to promote remineralization and physiological management of dental plaque biofilms. As a multifunctional nano-based material. Concluding Remarks and Future Perspectives There is no doubt that recent developments in nanomaterials and nanotechnology have improved and will further advance dentistry and oral health care in the near future. The morphology and crystallinity aspects play an important role in the specific physicochemical properties of enamel [1]. Nevertheless. and prevention of oral and dental health be adopted in daily practice by dentists. great challenges involving ethics and safety regulations. abrasion.

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