Application of dental nanomaterials: potential toxicity to the central nervous system

Figures & data

Table 1 Summary of the current nanomaterials in the dental field

Major applications	Nanomaterial type	Particle size	Significant characteristics	References
Composite resins	Nano-ZnO	125 nm	Better antibacterial and mechanical properties	Kasraei et al^Citation3
	Nano-silica	7 nm 70 nm	Better mechanical properties	Balos et al^Citation18; Wang et al^Citation12
	Nano-Ca3(PO4)2 and CaF2	112 nm 53 nm	Better stress-bearing capabilities and the inhibition of caries	Xu et al^Citation20
	Nano-TiO2	<20 nm	Improved microhardness and flexural strength	Xia et al^Citation21
Dental adhesives	Nano-HAp	20–70 nm	Better bonding strength to dentin	Wagner et al^Citation24
	Nano-silver and calcium phosphate	<10 nm 112 nm	Improved antibacterial properties	Melo et al^Citation23
	Nano-silica	7 nm	High mechanical strength and good thermostability	Wang et al^Citation22; Habekost et al^Citation25
Root canal fillings	Nano-HAp	–	Better osteogenesis and improved bacteriostatic and antibacterial effects	Jallot et al^Citation26; Krisanapiboon et al^Citation27
Bone repair materials	Nano-HAp	100 nm 20 nm 3 nm	Guiding the regeneration of periodontal and bone tissue	Huber et al^Citation29; Qi et al^Citation28; Yang et al^Citation30
	Nano-ZrO2/HAp composite	70–90 nm/500–1,000 nm	Guiding bone reconstruction	An et al^Citation31
Bioceramics	Nano-ZrO2/Al2O3	–	Better resistance to crack propagation	De Aza et al^Citation32
	Nano-silver	10 nm	Increased fracture toughness and Vickers hardness	Uno et al^Citation33
Silicone elastomer material	Nano-Ti-, Zn-, Ce-oxide	30–40 nm 20 nm 50 nm	Improved mechanical properties	Han et al^Citation34
Denture base materials	Nano-silver	10–20 nm	Better antifungal properties and biocompatibility	Acosta-Torres et al^Citation35
Coating materials for dental implants	Nano-porous alumina	20–200 nm	Good cell adhesion and no adverse effect on cell activity	Karlsson et al^Citation36
	Nano-zirconia/calcium phosphate	360 nm/151 nm	High bioactivity potential and good mechanical stability	Pardun et al^Citation37
	Nano-ZnO	10–100 nm	Better antimicrobial and biocompatible properties	Memarzadeh et al^Citation5
	Nano-HAp	–	Achieving rapid osseointegration	Uezono et al^Citation38
Drug delivery	Nano-silica	150 nm	Sustained and controlled release of anticancer drugs (as drug carriers)	Lebold et al^Citation40
	Polymeric NPs (vitamin E TPGS)	300–1,000 nm	Controlled release of anticancer drugs (as drug carriers)	Mu and Feng^Citation41
Tumor imaging	Superparamagnetic iron oxide NPs	82±4.4 nm	Good superparamagnetic and optical properties	Melancon et al^Citation42

Abbreviations: HAp, hydroxyapatite; NPs, nanoparticles; TPGS, d-alpha-tocopheryl polyethylene glycol 1000 succinate.

Figure 1 Schematic of the blood–brain barrier and the associated components of the neurovascular unit.

Note: Reprinted from Adv Drug Deliv Rev, 64(7), Chen Y, Liu L. Modern methods for delivery of drugs across the blood–brain barrier. 640–665., Copyright (2012), with permission from Elsevier.⁴⁶

Figure 2 Schematic representation of multifunctional NPs as drug carriers across the BBB.

Notes: Drugs can be adsorbed onto the surface of the NP due to the interactions between positive and negative charges (1) and may even be trapped inside its core (2). Different strategies have been applied for the transportation of drugs across the BBB: receptor–ligands for unique recognition and endocytosis (3); tight junction openers for improved intercellular penetration (4); transcytosis enhancers for the promotion of the transport of NP across the membranes (5); surfactants for the enhancement of membrane fluidization (6); efflux system inhibitors for the reduction of drug efflux (7); and local toxicity inducers for the increase in the permeability of the endothelial cells (8). Reproduced with permission of Informa Healthcare. Barbu E, Molnar E, Tsibouklis J, Gorecki DC. The potential for nanoparticle-based drug delivery to the brain: overcoming the blood–brain barrier. Expert Opin Drug Deliv. 6(6):553–565, copyright © 2009, Informa Healthcare.⁵³

Abbreviations: NP, nanoparticle; BBB, blood–brain barrier.

Table 2 Neurotoxicity effects of dental nanomaterials under in vivo conditions

Drug delivery routes	Nanomaterial type	Particle size	Exposure model	Neurotoxicity effects	References
Intravenous injection	Nano-ZnO	30–40 nm	Wistar rats	Increased brain zinc concentrations	Amara et al^Citation67
Intraperitoneal injection	G7 NPs	170±18 nm	C57Bl6 mice	Accumulation in brain areas and special cell populations	Vilella et al^Citation66
Intranasal instillation	Nano-TiO2	40 nm 50 nm	ICR mice	Morphological changes of neurons Disturbance of monoamine neurotransmitter levels	Zhang et al^Citation68
Intratracheal instillation	Nano-TiO2	3 nm	Kunming mice	Brain injury by inducing oxidative stress responses	Li et al^Citation70
Nasal administration	Nano-TiO2	5–6 nm	ICR mice	Oxidative stress in brain Pathological changes of brain cells Changes in genes associated with brain toxicity	Ze et al^Citation71
Nasal instillation	Al NPs	5–100 nm	SD rats	Alteration of gene and protein expression of MAPK and their activity	Kwon et al^Citation72
Oral exposure	Nano-TiO2 Nano-ZnO Nano-Al2O3	<75 nm <100 nm 45 nm	Swiss albino mice	Oxidative stress in brain	Shrivastava et al^Citation74
Intragastric administration	Nano-TiO2	6–7 nm	ICR mice	Accumulation of ROS in the hippocampus Effects on animal behavior	Hu et al^Citation75
Intraperitoneal injection	Fullerene C60 nanocrystals	100 nm	SD rats	Enhanced LTP and spatial memory	Chen et al^Citation80
	Nano-ZnO	20–80 nm	Wistar rats	Damaged spatial cognition capability via over-enhanced LTP	Han et al^Citation81
Intracerebral injection	Nano-MnO2	10 nm	SD rats	Alteration of spatial learning abilities associated with dopaminergic neuronal dysfunction	Li et al^Citation82
Intracerebroventricular injection	Nano-TiO2	9 nm	SD rats	Induction of malaise and general motor retardation	Kim et al^Citation83
Intravenous injection	Nano-TiO2	5 nm	SD rats	Oxidative damage on the offspring brain and depressive-like behaviors in adulthood	Cui et al^Citation84
Intraperitoneal injection	Nano-TiO2	5 nm	Wistar rats	Impaired spatial recognition memory	Hu et al^Citation89

Abbreviations: G7 NPs, glycopeptides-modified poly-lactide-co-glycolide NPs; NPs, nanoparticles; SD, Sprague-Dawley; MAPK, mitogen-activated protein kinases; ROS, reactive oxygen species; LTP, long-term potentiation; ICR, Institute of Cancer Research.

Figure 3 G7 NP distribution in different brain regions and cell populations.

Notes: Confocal microscopy images of brain cryosections in mice sacrificed 6 hours after an intraperitoneal injection of G7 NPs labeled with DAPI (blue), G7 NPs (red), and a number of antibodies (green) Low- (A–D) and high-magnification (E–H) images of the cerebral cortex (A and E), corpus callosum (B and F), choroid plexus (C and G), and subfornical organ (F and H). (E–H) High-magnification images of the dashed squares indicated in (A–D). (I–L) High-magnification images showing single cells from the hippocampal formation.⁶⁶ Scale bar =50 μm (A–D) and 10 μm (E–L). Reprinted from J Control Release, 174, Vilella A, Tosi G, Grabrucker AM, et al. Insight on the fate of CNS-targeted nanoparticles. Part I: Rab5-dependent cell-specific uptake and distribution. 195–201., Copyright (2014), with permission from Elsevier.⁶⁶

Abbreviations: NP, nanoparticle; G7 NPs, glycopeptides-modified poly-lactide-co-glycolide NPs; DAPI, 4′,6-diamidino-2-phenylindole.

Table 3 In vitro studies of dental nanomaterials with different cell models

Exposure model	Nanomaterial type	Particle size	Cell type	Main research contents	References
BBB	Nano-silica 100 nm 200 nm	50 nm	hCMEC/D3 cells	Cellular accumulation and transcytosis conditions of NPs in brain	Ye et al^Citation94
	Nano-TiO2	21 nm core	HCECs	Cellular uptake and localization, generation of oxidative stress, and DNA-damaging effects in HCECs	Halamoda Kenzaoui et al^Citation96
	PBCA NPs	146 nm	Human BMEC	Cellular uptake and localization	Weiss et al^Citation95
	Silica NPs	30 nm 100 nm 400 nm	Rat BMEC + pericytes	Effects of NPs with different sizes and surface modifications on brain permeability	Hanada et al^Citation97
	Nano-TiO2	25.2 nm	Rat BECs + glial cells	Effects on the integrity of the BBB and NP-induced inflammatory responses of BECs	Brun et al^Citation98
	Magnetic NPs	60 nm	Human BMVEC + AM	Nanocarriers for targeting BDNF across the BBB	Pilakka-Kanthikeel et al^Citation100
	Glucose-coated gold NPs	2 nm core	Peripheral vascular endothelial cells + AM	Transfer rate of NPs across the BBB	Gromnicova et al^Citation101
Neuroglial cells	Nano-ZnO	45 nm	Rat astrocytes	Signaling pathways involved in NP-induced apoptosis in primary astrocytes	Wang et al^Citation107
	Nano-TiO2	<25 nm	Human astrocytoma U87 cells	Cytotoxicity of NPs	Lai et al^Citation109
	Si NPs	150–200 nm	Rat microglia cells	Alterations of microglia functions	Choi et al^Citation77
	Nano-TiO2	<50 nm	Human glial cell U373 and rat glial cell C6	NP-induced oxidative stress and mitochondrial damage in glial cells	Huerta-García et al^Citation111
Neurons	Nano-TiO2	21 nm	Rat PC12 cells	NP-induced oxidative stress and apoptosis in neurons	Liu et al^Citation114
	Nano-TiO2	25 nm	SHSY5Y cells	Cytotoxic and genotoxic effects of NPs on neuronal cells	Valdiglesias et al^Citation115
	Nano-ZnO	30–50 nm	Rat primary neuronal cells	NP-induced cytotoxicity and DNA damage in neurons	Chiang et al^Citation118
	Nano-Ag	50–100 nm	Hippocampal CA1 neurons	Alterations of the action potential of neurons	Liu et al^Citation121

Abbreviations: BBB, blood–brain barrier; hCMEC/D3, human cerebral microvascular endothelial cell line; NPs, nanoparticles; HCECs, human cerebral endothelial cells; PBCA, poly(n-butylcyanoacrylate); BMEC/BMVEC, brain microvascular endothelial cells; BECs, brain endothelial cells; AM, human astrocytes; BDNF, brain-derived neurotrophic factor; U373, human astrocytoma cell line grade III; C6, rat brain glial tumor cell line; PC12 cells, rat pheochromocytoma cells; SHSY5Y cells, human neuroblastoma SHSY5Y cell line.

Figure 4 In vitro cell culture models for the studies on drug and NP transport through the BBB.

Note: Reprinted from Adv Drug Deliv Rev, 64(7), Wong HL, Wu XY, Bendayan R. Nanotechnological advances for the delivery of CNS therapeutics. 686–700., Copyright (2012), with permission from Elsevier.¹⁰³

Abbreviations: NP, nanoparticle; BBB, blood–brain barrier.

Figure 5 Existing problems in assessing the neurotoxicity of NPs.

Note: This scheme summarizes the major limitations of the testing methods and experimental models.

Abbreviations: NPs, nanoparticles; NR, neutral red; ICP-MS, induced coupled plasma mass spectroscopy; EDX, energy-dispersive X-ray spectroscopy; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.

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