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Safety and Biocompatibility of Metallic Nanoparticles

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A special issue of Nanomaterials (ISSN 2079-4991). This special issue belongs to the section "Biology and Medicines".

Deadline for manuscript submissions: closed (14 July 2021) | Viewed by 35023

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Dr. Ivana Vinkovic Vrcek

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Institute for Medical Research and Occupational Health, Analytical Toxicology and Mineral Metabolism Unit, Ksavreska cesta 2, Zagreb, Croatia
Interests: Nanomaterials, nanomedicine, nanosafety, nano-bio interactions, biotransformations, biocompatibility, toxicokinetics/toxicodynamics, ecotoxicity, risk assessment

Special Issue Information

Dear Colleagues,

Nanotechnology, as one of the six key enabling technologies (KETs), boosted the development and application of engineered nanomaterials to meet unmet human needs. The increased relative surface area and the quantum effects of materials at the nanoscale provoke specific and peculiar properties of nanomaterials including wide range of optoelectronic, magnetic, mechanical, photo responsive, catalytic properties, reactivity, and strength that are significantly different from the bulk materials. Among many different types of nanomaterials, metallic nanoparticles (mNPs) are very attractive owing to their simple synthesis and facile surface chemistry that supports wide variety of functionalization features for diverse applications. In spite of huge number of reports and studies published on different aspects of mNPs and enormous investments in nanotechnology, there is still gap between their application and safety assessments. Thus, current innovation processes and risk management for NMs have to be enhanced by the Safe-by-Design (SbD) concept, which is designed to ensure safety for humans and the environment by identifying timely all risks related to the innovation processes and value chain of nanomaterials.

This Special Issue aims to cover all aspects of safe production, safe use and safe disposal of mNPs promoting implementation of the SbD concept. We welcome contributions on

methodologies for design and production of less hazardous mNPs using combination of non-testing predictions together with high-throughput screening tools,
characterisation of mNPs providing the key characteristics that influence the release, exposure, behaviour, effects and subsequent environmental and/or human risks of different forms, types and sizes of mNPs;
transformation pattern and fate of mNPs in different biological or environmental compartments encompassing the conditions, extent and rate of change of mNPs structure and stability throughout the different stages of their life cycle;
dose metrics that define a particular response of mNPs in certain biological or environmental system;
evaluation of exposure risk for workers, consumers and environment by identifying actions for risk mitigation such as life cycle assessment and risk vs. benefit ratio profiling for mNPs.

Dr. Ivana Vinkovic Vrcek
Guest Editor

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Keywords

Safe-by-design
physico-chemical properties
transformation
nano-bio interactions
biocompatibility
safety
life-cycle analysis
risk assessment

Published Papers (10 papers)

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21 pages, 4891 KiB

Open AccessEditor’s ChoiceArticle

Influence of Physicochemical Characteristics and Stability of Gold and Silver Nanoparticles on Biological Effects and Translocation across an Intestinal Barrier—A Case Study from In Vitro to In Silico

by Yvonne Kohl, Michelle Hesler, Roland Drexel, Lukas Kovar, Stephan Dähnhardt-Pfeiffer, Dominik Selzer, Sylvia Wagner, Thorsten Lehr, Hagen von Briesen and Florian Meier

Nanomaterials 2021, 11(6), 1358; https://doi.org/10.3390/nano11061358 - 21 May 2021

Cited by 6 | Viewed by 2670

Abstract

A better understanding of their interaction with cell-based tissue is a fundamental prerequisite towards the safe production and application of engineered nanomaterials. Quantitative experimental data on the correlation between physicochemical characteristics and the interaction and transport of engineered nanomaterials across biological barriers, in particular, is still scarce, thus hampering the development of effective predictive non-testing strategies. Against this background, the presented study investigated the translocation of gold and silver nanoparticles across the gastrointestinal barrier along with related biological effects using an in vitro 3D-triple co-culture cell model. Standardized in vitro assays and quantitative polymerase chain reaction showed no significant influence of the applied nanoparticles on both cell viability and generation of reactive oxygen species. Transmission electron microscopy indicated an intact cell barrier during the translocation study. Single particle ICP-MS revealed a time-dependent increase of translocated nanoparticles independent of their size, shape, surface charge, and stability in cell culture medium. This quantitative data provided the experimental basis for the successful mathematical description of the nanoparticle transport kinetics using a non-linear mixed effects modeling approach. The results of this study may serve as a basis for the development of predictive tools for improved risk assessment of engineered nanomaterials in the future. Full article

(This article belongs to the Special Issue Safety and Biocompatibility of Metallic Nanoparticles)

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17 pages, 2423 KiB

Open AccessArticle

The Role of Polymeric Coatings for a Safe-by-Design Development of Biomedical Gold Nanoparticles Assessed in Zebrafish Embryo

by Pamela Floris, Stefania Garbujo, Gabriele Rolla, Marco Giustra, Lucia Salvioni, Tiziano Catelani, Miriam Colombo, Paride Mantecca and Luisa Fiandra

Nanomaterials 2021, 11(4), 1004; https://doi.org/10.3390/nano11041004 - 14 Apr 2021

Cited by 12 | Viewed by 2889

Abstract

In the biomedical field, gold nanoparticles (GNPs) have attracted the attention of the scientific community thanks to their high potential in both diagnostic and therapeutic applications. The extensive use of GNPs led researchers to investigate their toxicity, identifying stability, size, shape, and surface charge as key properties determining their impact on biological systems, with possible strategies defined to reduce it according to a Safe-by-Design (SbD) approach. The purpose of the present work was to analyze the toxicity of GNPs of various sizes and with different coating polymers on the developing vertebrate model, zebrafish. In particular, increasing concentrations (from 0.001 to 1 nM) of 6 or 15 nm poly-(isobutylene-alt-maleic anhydride)-graft-dodecyl polymer (PMA)- or polyethylene glycol (PEG)-coated GNPs were tested on zebrafish embryos using the fish embryo test (FET). While GNP@PMA did not exert significant toxicity on zebrafish embryos, GNP@PEG induced a significant inhibition of embryo viability, a delay of hatching (with the smaller size NPs), and a higher incidence of malformations, in terms of tail morphology and eye development. Transmission electron microscope analysis evidenced that the more negatively charged GNP@PMA was sequestered by the positive charges of chorion proteins, with a consequent reduction in the amount of NPs able to reach the developing embryo and exert toxicological activity. The mild toxic response observed on embryos directly exposed to GNP@PMA suggest that these NPs are promising in terms of SbD development of gold-based biomedical nanodevices. On the other hand, the almost neutral GNP@PEG, which did not interact with the chorion surface and was free to cross chorion pores, significantly impacted the developing zebrafish. The present study raises concerns about the safety of PEGylated gold nanoparticles and contributes to the debated issue of the free use of this nanotool in medicine and nano-biotechnologies. Full article

(This article belongs to the Special Issue Safety and Biocompatibility of Metallic Nanoparticles)

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14 pages, 627 KiB

Open AccessArticle

Exposure to Ultrafine Particles in the Ferroalloy Industry Using a Logbook Method

by Rikke Bramming Jørgensen, Ida Teresia Kero, Aleksander Blom, Esten Eide Grove and Kristin von Hirsch Svendsen

Nanomaterials 2020, 10(12), 2546; https://doi.org/10.3390/nano10122546 - 17 Dec 2020

Cited by 7 | Viewed by 2430

Abstract

Background: It is difficult to assess workers’ exposure to ultrafine particles (UFP) due to the lack of personal sampling equipment available for this particle fraction. The logbook method has been proposed as a general method for exposure assessment. This method measures the time and concentration components of the time-weighted average concentration separately and could be suitable for investigation of UFP exposure. Objectives: In this study, we have assessed workers’ exposure to UFP in a ferrosilicon plant. The main tasks of the furnace workers were identified, and the logbook method was used in combination with stationary measurements of UFP taken as close to the identified task areas as possible. In order to verify the results, respirable particles were collected using stationary sampling in close proximity to the UFP measuring instrument, and personal full-shift sampling of respirable particles was performed simultaneously. Thus, exposure to respirable particles determined using the logbook method could be compared to the results of standard measurement. Methods: The particle number concentration of ultrafine particles was determined using a NanoScan SMPS. Respirable particle concentration and exposure were determined using a sampling train consisting of a pump, filter, filter cassettes, and SKC Cyclone for the respirable fraction. Attendance times for workers at each work location were registered via thorough observations made by the research team. Results: The logbook method for exposure estimation based on stationary sampling equipment made it possible to calculate UFP exposure for workers operating the furnaces at a ferrosilicon plant. The mid-size furnace and the large furnace were evaluated separately. The workers operating the largest furnace were exposed to 1.47 × 10⁴ particles/cm³, while workers operating the mid-size furnace were exposed to 2.06 × 10⁴ particles/cm³, with a mean of 1.74 × 10⁴ particles/cm³. Substantial contributions from the casting area, ladle transport corridor, and both tapping areas were made. Exposure to respirable particles was 2.04 mg/m³ (logbook); 2.26 mg/m³ (personal sampling) for workers operating the large-sized furnace, 3.24 mg/m³ (logbook); 2.44 mg/m³ (personal sampling) for workers operating the medium-sized furnace, and 2.57 mg/m³ (logbook); 2.53 mg/m³(personal sampling) on average of all tappers. The average ratio of these two methods’ results was 1.02, which indicates that the logbook method could be used as a substitute for personal sampling when it is not possible to perform personal sampling, at least within this industry. Conclusions: The logbook method is a useful supplement for exposure assessment of UFP, able to identify the most polluted areas of the workplace and the contribution of different work tasks to the total exposure of workers, enabling companies to take action to reduce exposure. Full article

(This article belongs to the Special Issue Safety and Biocompatibility of Metallic Nanoparticles)

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18 pages, 3532 KiB

Open AccessCommunication

Analysis of the Characteristics and Cytotoxicity of Titanium Dioxide Nanomaterials Following Simulated In Vitro Digestion

by Ana Bettencourt, Lídia M. Gonçalves, Ana C. Gramacho, Adriana Vieira, Dora Rolo, Carla Martins, Ricardo Assunção, Paula Alvito, Maria João Silva and Henriqueta Louro

Nanomaterials 2020, 10(8), 1516; https://doi.org/10.3390/nano10081516 - 2 Aug 2020

Cited by 21 | Viewed by 4931

Abstract

Several metallic nanomaterials (NMs), such as titanium dioxide nanomaterials (TiO₂), present beneficial properties with a broad range of innovative applications. The human population is exposed to TiO₂, particularly by ingestion, due to its increasing use as a food additive and inclusion in dietary supplements and food packaging materials. Whether this oral exposure may lead to adverse local or systemic outcomes has been the subject of research, but studies have generated contradictory results, reflecting differences in the physicochemical properties of the TiO₂ studied, effects of the surrounding matrix, and modifications during digestion. This work aimed to investigate the toxic effects of three different TiO₂ NMs (NM-103, NM-103 and NM-105) on the gastrointestinal tract cells, Caco-2 and HT29-MTX-E12, after the use of the standardized static INFOGEST 2.0 in vitro digestion method to mimic human digestion of TiO₂, contributing to hazard assessment. The results show that, for one of the digested TiO₂ NMs studied (NM-105), a more pronounced toxicity occurs after exposure of HT29-MTX-E12 intestinal cells, as compared to undigested NM, concomitantly with subtle changes in characteristics of the NM. Thus, the inclusion of the digestion simulation in the safety evaluation of ingested NMs through in vitro bioassays can better integrate the modifications that NMs suffer in the organism. It is expected that such an approach will reduce uncertainties in the hazard assessment of ingested NMs for human health. Full article

(This article belongs to the Special Issue Safety and Biocompatibility of Metallic Nanoparticles)

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18 pages, 2177 KiB

Open AccessArticle

Surface Stabilization Affects Toxicity of Silver Nanoparticles in Human Peripheral Blood Mononuclear Cells

by Barbara Vuković, Marija Milić, Blaženka Dobrošević, Mirta Milić, Krunoslav Ilić, Ivan Pavičić, Vatroslav Šerić and Ivana Vinković Vrček

Nanomaterials 2020, 10(7), 1390; https://doi.org/10.3390/nano10071390 - 17 Jul 2020

Cited by 23 | Viewed by 2903

Abstract

Silver nanoparticles (AgNPs) are one of the most investigated metal-based nanomaterials. Their biocidal activity boosted their application in both diagnostic and therapeutic medical systems. It is therefore crucial to provide sound evidences for human-related safety of AgNPs. This study aimed to enhance scientific knowledge with regard to biomedical safety of AgNPs by investigating how their different surface properties affect human immune system. Methods: preparation, characterization and stability evaluation was performed for four differently coated AgNPs encompassing neutral, positive and negative agents used for their surface stabilization. Safety aspects were evaluated by testing interaction of AgNPs with fresh human peripheral blood mononuclear cells (hPBMC) by means of particle cellular uptake and their ability to trigger cell death, apoptosis and DNA damages through induction of oxidative stress and damages of mitochondrial membrane. Results: all tested AgNPs altered morphology of freshly isolated hPBMC inducing apoptosis and cell death in a dose- and time-dependent manner. Highest toxicity was observed for positively-charged and protein-coated AgNPs. Cellular uptake of AgNPs was also dose-dependently increased and highest for positively charged AgNPs. Intracellularly, AgNPs induced production of reactive oxygen species (ROS) and damaged mitochondrial membrane. Depending on the dose, all AgNPs exhibited genotoxic potential. Conclusions: this study provides systematic and comprehensive data showing how differently functionalized AgNPs may affect the human immune system. Presented results are a valuable scientific contribution to safety assessment of nanosilver-based blood-contacting medical products. Full article

(This article belongs to the Special Issue Safety and Biocompatibility of Metallic Nanoparticles)

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30 pages, 5357 KiB

Open AccessArticle

Uptake of Cerium Dioxide Nanoparticles and Impact on Viability, Differentiation and Functions of Primary Trophoblast Cells from Human Placenta

by Margaux Nedder, Sonja Boland, Stéphanie Devineau, Amal Zerrad-Saadi, Jasmina Rogozarski, René Lai-Kuen, Ibtissem Baya, Jean Guibourdenche, Francoise Vibert, Audrey Chissey, Sophie Gil, Xavier Coumoul, Thierry Fournier and Ioana Ferecatu

Nanomaterials 2020, 10(7), 1309; https://doi.org/10.3390/nano10071309 - 3 Jul 2020

Cited by 15 | Viewed by 2668

Abstract

The human placenta is at the interface between maternal and fetal circulations, and is crucial for fetal development. The nanoparticles of cerium dioxide (CeO₂ NPs) from air pollution are an unevaluated risk during pregnancy. Assessing the consequences of placenta exposure to CeO₂ NPs could contribute to a better understanding of NPs’ effect on the development and functions of the placenta and pregnancy outcome. We used primary villous cytotrophoblasts purified from term human placenta, with a wide range of CeO₂ NPs concentrations (0.1–101 μg/cm²) and exposure time (24–72 h), to assess trophoblast uptake, toxicity and impact on trophoblast differentiation and endocrine function. We have shown the capacity of both cytotrophoblasts and syncytiotrophoblasts to internalize CeO₂ NPs. CeO₂ NPs affected trophoblast metabolic activity in a dose and time dependency, induced caspase activation and a LDH release in the absence of oxidative stress. CeO₂ NPs decreased the fusion capacity of cytotrophoblasts to form a syncytiotrophoblast and disturbed secretion of the pregnancy hormones hCG, hPL, PlGF, P4 and E2, in accordance with NPs concentration. This is the first study on the impact of CeO₂ NPs using human primary trophoblasts that decrypts their toxicity and impact on placental formation and functions. Full article

(This article belongs to the Special Issue Safety and Biocompatibility of Metallic Nanoparticles)

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11 pages, 5237 KiB

Open AccessArticle

DNA-Biofunctionalization of CTAC-Capped Gold Nanocubes

by Nicole Slesiona, Sophie Thamm, H. Lisa K. S. Stolle, Viktor Weißenborn, Philipp Müller, Andrea Csáki and Wolfgang Fritzsche

Nanomaterials 2020, 10(6), 1119; https://doi.org/10.3390/nano10061119 - 5 Jun 2020

Cited by 17 | Viewed by 4696

Abstract

Clinical diagnostics and disease control are fields that strongly depend on technologies for rapid, sensitive, and selective detection of biological or chemical analytes. Nanoparticles have become an integral part in various biomedical detection devices and nanotherapeutics. An increasing focus is laid on gold nanoparticles as they express less cytotoxicity, high stability, and hold unique optical properties with the ability of signal transduction of biological recognition events with enhanced analytical performance. Strong electromagnetic field enhancements can be found in close proximity to the nanoparticle that can be exploited to enhance signals for e.g., metal-enhanced fluorescence or Raman spectroscopy. Even stronger field enhancements can be achieved with sharp-edged nanoparticles, which are synthesized with the help of facet blocking agents, such as cetyltrimethylammonium bromide/chloride (CTAB/CTAC). However, chemical modification of the nanoparticle surface is necessary to reduce the particle’s cytotoxicity, stabilize it against aggregation, and to bioconjugate it with biomolecules to increase its biocompatibility and/or specificity for analytical applications. Here, a reliable two-step protocol following a ligand exchange with bis (p-sulfonatophenyl) phenyl phosphine (BSPP) as the intermediate capping-agent is demonstrated, which results in the reliable biofunctionalization of CTAC-capped gold nanocubes with thiol-modified DNA. The functionalized nanocubes have been characterized regarding their electric potential, plasmonic properties, and stability against high concentrations of NaCl and MgCl₂. Full article

(This article belongs to the Special Issue Safety and Biocompatibility of Metallic Nanoparticles)

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20 pages, 2399 KiB

Open AccessArticle

Probing the Mode of Antibacterial Action of Silver Nanoparticles Synthesized by Laser Ablation in Water: What Fluorescence and AFM Data Tell Us

by Lucija Krce, Matilda Šprung, Tomislav Rončević, Ana Maravić, Vedrana Čikeš Čulić, Damjan Blažeka, Nikša Krstulović and Ivica Aviani

Nanomaterials 2020, 10(6), 1040; https://doi.org/10.3390/nano10061040 - 29 May 2020

Cited by 14 | Viewed by 2787

Abstract

We aim to elucidate the mode of antibacterial action of the laser-synthesized silver colloid against Escherichia coli. Membrane integrity was studied by flow cytometry, while the strain viability of the treated culture was determined by plating. The spectrofluorometry was used to obtain the time development of the reactive oxygen species (ROS) inside the nanoparticle-treated bacterial cells. An integrated atomic force and bright-field/fluorescence microscopy system enabled the study of the cell morphology, Young modulus, viability, and integrity before and during the treatment. Upon lethal treatment, not all bacterial cells were shown to be permeabilized and have mostly kept their morphology with an indication of cell lysis. Young modulus of untreated cells was shown to be distinctly bimodal, with randomly distributed softer parts, while treated cells exhibited exponential softening of the stiffer parts in time. Silver nanoparticles and bacteria have shown a masking effect on the raw fluorescence signal through absorbance and scattering. The contribution of cellular ROS in the total fluorescence signal was resolved and it was proven that the ROS level inside the lethally treated cells is not significant. It was found that the laser-synthesized silver nanoparticles mode of antibacterial action includes reduction of the cell’s Young modulus in time and subsequently the cell leakage. Full article

(This article belongs to the Special Issue Safety and Biocompatibility of Metallic Nanoparticles)

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17 pages, 2853 KiB

Open AccessArticle

Gold Nanoparticles Induce Oxidative Stress and Apoptosis in Human Kidney Cells

by Maria Enea, Eulália Pereira, Miguel Peixoto de Almeida, Ana Margarida Araújo, Maria de Lourdes Bastos and Helena Carmo

Nanomaterials 2020, 10(5), 995; https://doi.org/10.3390/nano10050995 - 22 May 2020

Cited by 49 | Viewed by 4906

Abstract

Gold nanoparticles (AuNPs) are highly attractive for biomedical applications. Therefore, several in vitro and in vivo studies have addressed their safety evaluation. Nevertheless, there is a lack of knowledge regarding their potential detrimental effect on human kidney. To evaluate this effect, AuNPs with different sizes (13 nm and 60 nm), shapes (spheres and stars), and coated with 11-mercaptoundecanoic acid (MUA) or with sodium citrate, were synthesized, characterized, and their toxicological effects evaluated 24 h after incubation with a proximal tubular cell line derived from normal human kidney (HK-2). After exposure, viability was assessed by the MTT assay. Changes in lysosomal integrity, mitochondrial membrane potential (ΔΨm), reactive species (ROS/RNS), intracellular glutathione (total GSH), and ATP were also evaluated. Apoptosis was investigated through the evaluation of the activity of caspases 3, 8 and 9. Overall, the tested AuNPs targeted mainly the mitochondria in a concentration-dependent manner. The lysosomal integrity was also affected but to a lower extent. The smaller 13 nm nanospheres (both citrate- and MUA-coated) proved to be the most toxic among all types of AuNPs, increasing ROS production and decreasing mitochondrial membrane potential (p ≤ 0.01). For the MUA-coated 13 nm nanospheres, these effects were associated also to increased levels of total glutathione (p ≤ 0.01) and enhanced ATP production (p ≤ 0.05). Programmed cell death was detected through the activation of both extrinsic and intrinsic pathways (caspase 8 and 9) (p ≤ 0.05). We found that the larger 60 nm AuNPs, both nanospheres and nanostars, are apparently less toxic than their smaller counter parts. Considering the results herein presented, it should be taken into consideration that even if renal clearance of the AuNPs is desirable, since it would prevent accumulation and detrimental effects in other organs, a possible intracellular accumulation of AuNPs in kidneys can induce cell damage and later compromise kidney function. Full article

(This article belongs to the Special Issue Safety and Biocompatibility of Metallic Nanoparticles)

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16 pages, 862 KiB

Open AccessDiscussion

To-Do and Not-To-Do in Model Studies of the Uptake, Fate and Metabolism of Metal-Containing Nanoparticles in Plants

by Justyna Wojcieszek, Javier Jiménez-Lamana, Lena Ruzik, Joanna Szpunar and Maciej Jarosz

Nanomaterials 2020, 10(8), 1480; https://doi.org/10.3390/nano10081480 - 28 Jul 2020

Cited by 11 | Viewed by 2688

Abstract

Due to the increasing release of metal-containing nanoparticles into the environment, the investigation of their interactions with plants has become a hot topic for many research fields. However, the obtention of reliable data requires a careful design of experimental model studies. The behavior of nanoparticles has to be comprehensively investigated; their stability in growth media, bioaccumulation and characterization of their physicochemical forms taken-up by plants, identification of the species created following their dissolution/oxidation, and finally, their localization within plant tissues. On the basis of their strong expertise, the authors present guidelines for studies of interactions between metal-containing nanoparticles and plants. Full article

(This article belongs to the Special Issue Safety and Biocompatibility of Metallic Nanoparticles)

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