Pathways of nanotoxicity: Modes of detection,impact, and challenges

Nanotoxicology has become the subject of intense research for more than two decades. Thousands of articles have been published but the space in understanding the nanotoxicity mechanism and the assessment is still unclear. Recent researches clearly show potential benefits of nanomaterials (NMs) in diagnostics and treatment, targeted drug delivery, and tissue engineering owing to their excellent physicochemical properties. However, these NMs display hazardous health effect then to the greater part of the materials because of small size, large surface area-to-volume ratio, quantum size effects, and environmental factors. Nowadays, a large number of NMs are used in industrial products including several medical applications, consumer, and healthcare products. However, they came into the environment without any safety test. The measurement of toxicity level has become important because of increasing toxic effects on living organisms. New realistic mechanism-based strategies are still needed to determine the toxic effects of NMs. For the assessment of NMs toxicity, reliable and standardized procedures are necessary. This review article provides systematic studies on toxicity of NMs involving manufacturing, environmental factors, eco-toxic and genotoxic effects, some parameters which have been ignored of NMs versus their biological counterparts, cell heterogeneity, and their current challenges and future perspectives.     

Effect of exposure temperature on the cell membrane disruption induced by amorphous silica nanoparticles in erythrocytes,lymphocytes, and malignant melanocytes

It is of great significance to examine carefully the potentially harmful effects of silica-based nanoparticles (NPs) on human body. In the present study, we have investigated the impact of exposure temperatures (4 °C, 15 °C, 26 °C, and 37 °C) on the cell membrane disruption induced by amorphous silica NPs of different primary diameters (28, 55, 88, 156, and 461 nm) in three different types of cells (erythrocytes, Jurkat, and B16F10), where the serum-free culture media were employed for exposure of the cells to the silica NPs. The size- and dose-dependent membranolytic activity of the silica NPs in each cell type at every temperature appeared to be given by a master curve as a function of the NP surface area per suspension volume, regardless of the NP diameter. This silica-induced membranolysis was significantly enhanced by the higher-temperature exposure of each cell type to the silica NPs. Such effects of exposure temperature on the silica-induced membranolysis in non-adherent cells of RBC and Jurkat were quite similar to each other, regardless of their difference in the presence/absence of nucleus and endocytic ability, whereas that for adherent cells of B16F10 was more remarkable. The filterability of erythrocytes also was measured at different temperatures, whereby the effect of temperature on the deformability of cell membranes was estimated. A possible mechanism underlying the effect of exposure temperature on the silica-induced membranolysis was proposed.     

Nanomaterial Transformations in the Environment: Effects of Changing Exposure Forms on Bioaccumulation and Toxicity

In the environment, nanomaterials (NMs) are subject to chemical transformations, such as redox reactions, dissolution, coating degradation, and organic matter, protein, and macromolecule binding, and physical transformations including homo or heteroagglomeration. The combination of these reactions can result in NMs with differing characteristics progressing through a functional fate pathway that leads to the formation of transformed NM functional fate groups with shared properties. To establish the nature of such effects of transformation on NMs, four main types of studies are conducted: 1) chemical aging for transformation of pristine NMs; 2) manipulation of test media to change NM surface properties; 3) aging of pristine NMs water, sediment, or soil; 4) NM aging in waste streams and natural environments. From these studies a paradigm of aging effects on NM uptake and toxicity can be developed. Transformation, especially speciation changes, largely results in reduced potency. Further reactions at the surface resulting in processes, such as ecocorona formation and heteroagglomeration may additionally reduce NM potency. When NMs of differing potency transform and enter environments, common transformation reaction occurring in receiving system may act to reduce the variation in hazard between different initial NMs leading to similar actual hazard under realistic exposure conditions.     

The Nano–Intestine Interaction: Understanding the Location‐Oriented Effects of Engineered Nanomaterials in the Intestine

Engineered nanomaterials (ENMs) are used in food additives, food packages, and therapeutic purposes owing to their useful properties, Therefore, human beings are orally exposed to exogenous nanomaterials frequently, which means the intestine is one of the primary targets of nanomaterials. Consequently, it is of great importance to understand the interaction between nanomaterials and the intestine. When nanomaterials enter into gut lumen, they inevitably interact with various components and thereby display different effects on the intestine based on their locations; these are known as location‐oriented effects (LOE). The intestinal LOE confer a new biological‐effect profile for nanomaterials, which is dependent on the involvement of the following biological processes: nano–mucus interaction, nano–intestinal epithelial cells (IECs) interaction, nano–immune interaction, and nano–microbiota interaction. A deep understanding of NM‐induced LOE will facilitate the design of safer NMs and the development of more efficient nanomedicine for intestine‐related diseases. Herein, recent progress in this field is reviewed in order to better understand the LOE of nanomaterials. The distant effects of nanomaterials coupling with microbiota are also highlighted. Investigation of the interaction of nanomaterials with the intestine will stimulate other new research areas beyond intestinal nanotoxicity.     

Cyclotron production of radioactive CeO(2) nanoparticles and their application for in vitro uptake studies

Nowadays, a wide variety of nanoparticles (NPs) are applied in different fields such as medical science and industry. Due to their large commercial volume, the OECD Working Party on Manufactured Nanomaterials (NMs) has proposed to study a set of 14 nanomaterials, one of which being cerium oxide (CeO(2)). In particular, CeO(2) based NPs are widely used in automotive industry, healthcare, and cosmetics. In this paper, we propose a method for the production of radioactive CeO(2) NPs.We demonstrate that they maintain the same physicochemical characteristics as the “cold” ones in terms of size distribution and Zeta potential; we develop a new protocol to assess their cellular interaction in immortalized mouse fibroblast cell line Balb/3T3, a model for the study of basal cytotoxicity and carcinogenic potential induced by chemicals and in the present case by NPs. Experimental result of this work, which shows a quasi-linear concentration-uptake response of cells, can be useful as a reference dose-uptake curve for explaining effects following biological uptake after exposure to CeO(2) NPs.     

Stimulating effect of silica-containing nanospheres on proliferation of osteoblast-like cells

Silica and silica-based materials have been found widespread application for medical purposes, especially in the fields of bone tissue engineer. Nano-sized silica has been developed too and been considered to be used in bone regeneration. In this study, we observed the biological response of osteoblast-like cells to three kinds of silica nanospheres: SNs-A (30–40 nm), SNs-B (70–80 nm), and Silica/OCP (70–80 nm). Cells treated with three kinds of nanospheres always showed higher cell viability than control cells. ALP activity of cells treated with three kinds of silica nanospheres was higher than that of control cells at early time. Both of the two effects were not in a concentration-dependent manner. Silica/OCP had better effect on MG-63 cell activity and proliferation than SNs-A and SNs-B. The three kinds of silica nano material all have biological validity on osteoblast-like cells, especially Silica/OCP.     

Optical and electrochemical properties of multilayer polyelectrolyte thin films incorporating spherical, gold colloid nanomaterials

Polyelectrolyte multilayer (PEM) films incorporating various types of spherical, gold nanomaterials (NMs) were investigated to assess the existence of electrochemical and/or optical signal enhancement effects directly attributable to embedded NMs and the relationship of these effects to film structure and composition. Specifically, electrostatically assembled films of cationic poly-l-lysine (PLL) and anionic poly(4-styrene sulfonate) (PSS) incorporating one of four types of spherical, gold colloid NMs were constructed on 3-(aminopropyl)trimethoxysilane (3-APTMS)-modified glass substrates for optical studies or 11-mercaptoundecanoic (MUA)-modified gold electrodes for electrochemical studies. The NMs inserted into the PEM films include citrate-stabilized gold nanoparticles, thioctic acid-stabilized gold nanoparticles (TAS-NPs), MUA-modified monolayer protected gold clusters, and hollow gold nanoshells (Au-NSs). Optical sensitivity of the NM-embedded films, in terms of absorbance, surface plasmon band shifts, and the dependence of these optical responses on film thickness, varied depending on the type of NM within the film (e.g., TAS-NPs versus Au-NSs) but exhibited no corresponding electrochemical effects in the diffusional voltammetry of a ferricyanide redox probe. While not correlated to optical responses, the increased Faradaic current achieved during voltammetry at NM-embedded PEM films suggested that electrochemical effects of NMs were less dependent on the type of NMs and were, instead, more related to their location within the film and the electrostatic interactions built into the interfacial chemistry of the films. These results should prove useful for developing strategies constructing thin films with NMs that are specifically designed for optical or electrochemical sensing, taking full advantage of the signal enhancements provided by individual types of NMs.     

Integrating blood cell mechanics,platelet adhesive dynamics and coagulation cascade for modelling thrombus formation in normal and diabetic blood

Normal haemostasis is an important physiological mechanism that prevents excessive bleeding during trauma, whereas the pathological thrombosis especially in diabetics leads to increased incidence of heart attacks and strokes as well as peripheral vascular events. In this work, we propose a new multiscale framework that integrates seamlessly four key components of blood clotting, namely transport of coagulation factors, coagulation kinetics, blood cell mechanics and platelet adhesive dynamics, to model the development of thrombi under physiological and pathological conditions. We implement this framework to simulate platelet adhesion due to the exposure of tissue factor in a three-dimensional microchannel. Our results show that our model can simulate thrombin-mediated platelet activation in the flowing blood, resulting in platelet adhesion to the injury site of the channel wall. Furthermore, we simulate platelet adhesion in diabetic blood, and our results show that both the pathological alterations in the biomechanics of blood cells and changes in the amount of coagulation factors contribute to the excessive platelet adhesion and aggregation in diabetic blood. Taken together, this new framework can be used to probe synergistic mechanisms of thrombus formation under physiological and pathological conditions, and open new directions in modelling complex biological problems that involve several multiscale processes.     

The influence of different preparation methods on the aggregation status of pyrogenic nanosilicas used in concrete

Investigation of the effects of nanosilica materials in cementitious mixtures has attracted considerable research attention due to the very high specific surfaces of these materials. However, high surface area leads to aggregation of these materials due to high surface attraction forces, which could seriously reduce their nano filler effect. In this research the dispersion of pyrogenic nanosilicas in water and parameters influencing it were investigated. The results show that serious aggregation of pyrogenic nanosilicas in water occurs. Increasing the amount of applied forces, particularly the use of ultrasonic waves, has considerable effect in breaking aggregates into smaller aggregates with maximum size up to 0.9 μm. Increasing the pH was found to be very effective in improving dispersion of nanosilicas and through combined use of high pH and applying high levels of energy such as ultrasonic method it is possible to break all the aggregates into primary aggregates with maximum size of about 0.06 μm.     

Integrated metabonomics analysis of the size-response relationship of silica nanoparticles-induced toxicity in mice

Understanding the underlying properties-dependent interactions of nanostructures with biological systems is essential to nanotoxicological research. This study investigates the relationship between particle size and toxicity, and further reveals the mechanism of injury, using silica particles (SP) with diameters of 30, 70, and 300 nm (SP30, SP70, and SP300) as model materials. The biochemical compositions of liver tissues and serum of mice treated with SP30, SP70, and SP300 were analyzed by integrated metabonomics analysis based on gas chromatography-mass spectrometry (GC-MS) and in combination with pattern recognition approaches. Histopathological examinations and serum biochemical analysis were simultaneously performed. The toxicity induced by three different sizes of SP mainly involved hepatocytic necrosis, increased serum aminotransferase, and inflammatory cytokines. Moreover, the toxic effects of SP were dose-dependent for each particle size. The doses of SP30, SP70, and SP300 that were toxic to the liver were 10, 40, and 200 mg kg(-1), respectively. In this study, surface area has a greater effect than particle number on the toxicity of SP30, SP70, and SP300 in the liver. The disturbances in energy metabolism, amino acid metabolism, lipid metabolism, and nucleotide metabolism may be attributable to the hepatotoxicity induced by SP. In addition, no major differences were found in the response of biological systems caused by the different SP sizes among the metabolite profiles. The results suggest that not only nano-sized but also submicro-sized SP can cause similar extents of liver injury, which is dependent on the exposure dose, and the mechanism of toxicity may be almost the same.     

Platelet procoagulant surface as an essential parameter for the in vitro evaluation of the blood compatibility of polymers

Thrombus formation at an artificial surface in contact with blood is the result of the interplay of two tightly linked biological systems, namely blood platelets and blood coagulation. While initiation of the overall process is thought to originate from proenzyme-enzyme conversions at the artificial surface, propagation of the process is only possible when a suitable phospholipid surface is available. The outer leaflet of the plasma membrane of activated platelets is such a surface; it containts negatively charged phospholipids which are normally present in the inner leaflet of the membrane. An examination of the thrombogenicity of materials, therefore, should include a quantitative assay for procoagulant sites at an artificial surface. In the present study we have evaluated polymers, exposed to platelet-rich plasma, for their procoagulant properties by using two sets of assays. With the one set, markers of blood coagulation were assayed (recalcification time of platelet rich plasma and kallikrein-C1-Inhibitor complex formation) and with the other set the surfaces were analysed for platelet adherence and procoagulant sites utilising annexin V, which has a high affinity for negatively charged phopholipids. For the polymers, the fastest rate of contact activation, as determined from kallikrein-C1-Inhibitor generation, was found with polyethylene. In spite of that, the conventional partial thromboplastin time (PTT) could not reveal differences between the various materials. However, when clotting was performed with platelet-rich plasma, it was found that the polymers differed significantly in their clot promoting activities. The shortest clotting time (5 min) was found with polyethylene (PE), and polyvinyl chloride (PVC) gave the longest clotting time (10 min). These findings closely correlated with the amount of procoagulant sites generated at the platelet-rich plasma-polymer interface.     

层次分析法在爆破安全管理中的应用

工程爆破作业中产生的有害效应和事故,与爆破设计、地形地质条件、防护设施、气候环境、爆破器材、现场作业及施工人员素质等诸多因素有关.应用层次分析法,能够准确找到对爆破安全影响最大的因素,并能对各因素按重要性排序,从而提高安全管理的针对性和有效性.     

The Nanomaterial Metabolite Corona Determined Using a Quantitative Metabolomics Approach: A Pilot Study

Nanomaterials (NMs) are promptly coated with biomolecules in biological systems leading to the formation of the so‐called corona. To date, research has predominantly focused on the protein corona and how it affects NM uptake, distribution, and bioactivity by conferring a biological identity to NMs enabling interactions with receptors to mediate cellular responses. Thus, protein corona studies are now integral to nanosafety assessment. However, a larger class of molecules, the metabolites, which are orders of magnitude smaller than proteins (<1000 Da) and regulate metabolic pathways, has been largely overlooked. This hampers the understanding of the bio–nano interface, development of computational predictions of corona formation, and investigations into uptake or toxicity at the cellular level, including identification of molecular initiating events triggering adverse outcome pathways. Here, a capillary electrophoresis–mass spectrometry based metabolomics approach reveals that pure polar ionogenic metabolite standards differentially adsorb to a range of 6 NMs (SiO₂, 3 TiO₂ with different surface chemistries, and naïve and carboxylated polystyrene NMs). The metabolite corona composition is quantitatively compared using protein‐free and complete plasma samples, revealing that proteins in samples significantly change the composition of the metabolite corona. This key finding provides the basis to include the metabolite corona in future nanosafety endeavors.     

An Assessment of the Impact of SiO2 Nanoparticles of Different Sizes on the Rest/Wake Behavior and the Developmental Profile of Zebrafish Larvae

In this study, zebrafish larvae are introduced as an in vivo platform to examine the neurotoxicity and developmental toxicity associated with continuous exposure to a concentration gradient of different sizes of SiO₂ nanoparticles (15 nm and 50 nm diameter) to determine the dose effect and size effect of SiO₂ nanoparticle (NP)‐induced toxicity. Bovine serum albumin (BSA‐V) is utilized as a stabilizing agent to prevent coagulation of the SiO₂ nanoparticles. To the best of our knowledge, this study is the first to describe locomotor activity assays linking rest/wake behavioral profiles for the purpose of investigating the neurotoxicity of NPs. In addition, developmental toxicological endpoints including mortality, LC₅₀, malformation, and cartilaginous deformity are assessed. The results show a concentration‐dependent increase in behavioral neurotoxicity, mortality, and malformation among larvae treated with the SiO₂ nanoparticles of 15 nm and 50 nm. A comparison of the 15 nm and 50 nm NPs by K‐means clustering analysis demonstrates that the 15 nm NPs have a greater neurotoxic effect than the 50 nm NPs, with the 50 nm NPs exhibiting greater developmental toxicity on the zebrafish larvae than the 15 nm NPs.     

利用膜气液接触器制备纳米材料的研究

利用膜气液接触器制备了纳米CaCO3、SrCO3、Al(OH)3和Al2O3粒子.根据气液反应理论预测了Ca(OH)2浓度、CO2分压等对CO2吸收速率的影响规律,并得到了实验验证.在实验条件下,Ca(OH)2浓度和CO2分压对CaCO3粒子的形貌影响较小,粒径约为70nm.添加PVP和PEG后,粒度降为48nm左右,分散性明显提高.所得SrCO3纳米粒子为球形,粒度均匀,Sr(OH)2浓度对粒子粒度具有明显影响.Al(OH)3粒子为球形,50nm左右,煅烧后得到Al2O3,粒子尺寸增加至70nm左右.反应后用稀盐酸清洗膜使之再生,膜重复使用9次,膜传质系数未见明显降低.     

Role of platelets in blood-biomaterial interactions

Over 2 million cardiovascular procedures are performed annually in the United States. Every one of these procedures requires some period of contact with blood with several different biomaterials used in the manufacture of assist devices or implant devices. In view of the increasing importance of the biomaterials in clinical practice, it would be timely to review briefly physicochemical characterization as well as biological evaluations. Blood compatibility encompasses a variety of events associated with blood interaction with the biomaterials used in various procedures. Two separate coagulation mechanisms are involved (arterial and venous) depending upon the flow characteristics. At least three interacting factors modulate normal hemostasis and the pathogenesis of thromboembolic events. They are the state of activation of coagulation cascade, circulating levels of thrombin and fibrinogen and relative activity of platelets. In this overview we discuss the current concepts on the role of platelets in blood-biomaterial interactions. When blood contacts a biomaterial surface a variety of blood components interact with the surface. Some of the key players in platelet activation on biomaterial surface include fibrinogen and von Willebrand factor. Currently available antiplatelet drugs effectively block aggregation and secretion induced by physiological agonists such as epinephrine, adenosine diphosphate and thromboxane in suspension. However, they do not prevent platelet interaction on biomaterial surfaces. Mechanisms involved in platelet activation in suspension and on surfaces as well as the pharmacology of newer antiplatelet drugs will be discussed.     

Apparatus for preparing mimics of suspended particles in the troposphere and their controlled deposition onto individual lung cells in culture with measurement of downstream biological response

Inhalation exposure to particles <10 microm in size that are suspended in the troposphere (PM10) is a factor in respiratory and cardiovascular diseases. The extent of the injury, local to systemic inflammation, is dependent on the number, size, and composition of the particles to which an individual is exposed. The physical properties of and compounds on PM10 that are responsible for these adverse effects on human health are the subject of intense investigation. Here, we report a laboratory method that involved the creation of 1-120 particles per trial that were of known size and composition, followed by deposition of them directly onto individual human lung cells within a cell culture, and after an incubation period, a downstream biological response was measured. To illustrate this methodology, particles that each contained 50 pg of lipopolysaccharide were created and deposited onto individual cells over a region <0.36 mm2 within a genetically modified A549 cell culture. The biological readout was the relative expression of intercellular cell adhesion molecule 1 after 24 h of incubation using an immunocytochemistry assay. The apparatus and methodology introduced here enables studies at the interface between the relevant but diverse areas of atmospheric particle chemistry and lung cell biology to identify the chemical and physical factors of PM10 that cause/exacerbate respiratory and cardiovascular diseases by triggering various biological pathways.     

Fe70Zr10B20非晶合金的制备及其热稳定性和磁性能研究

采用机械合金化技术制备了Fe70Zr10B2。磁性非晶合金粉末。分析Fe70Zr10B20非晶合金的形成机制、晶化机制：研究Fe70Cr10B20非晶合金不同热处理温度下的磁性及球磨过程中样品的磁性。结果表明：Fe70Cr10B20非晶相的形成是由原子的扩散和晶格崩渍共同作用的结果；Fe70Cr10B20非晶合金的热致晶化模式为一次晶化；球磨过程厦非晶熟处理后样品的磁性与其结构、晶粒尺寸、应力和缺陷等因素有关。     

Biomaterials and Advanced Technologies for Hemostatic Management of Bleeding

Bleeding complications arising from trauma, surgery, and as congenital, disease‐associated, or drug‐induced blood disorders can cause significant morbidities and mortalities in civilian and military populations. Therefore, stoppage of bleeding (hemostasis) is of paramount clinical significance in prophylactic, surgical, and emergency scenarios. For externally accessible injuries, a variety of natural and synthetic biomaterials have undergone robust research, leading to hemostatic technologies including glues, bandages, tamponades, tourniquets, dressings, and procoagulant powders. In contrast, treatment of internal noncompressible hemorrhage still heavily depends on transfusion of whole blood or blood's hemostatic components (platelets, fibrinogen, and coagulation factors). Transfusion of platelets poses significant challenges of limited availability, high cost, contamination risks, short shelf‐life, low portability, performance variability, and immunological side effects, while use of fibrinogen or coagulation factors provides only partial mechanisms for hemostasis. With such considerations, significant interdisciplinary research endeavors have been focused on developing materials and technologies that can be manufactured conveniently, sterilized to minimize contamination and enhance shelf‐life, and administered intravenously to mimic, leverage, and amplify physiological hemostatic mechanisms. Here, a comprehensive review regarding the various topical, intracavitary, and intravenous hemostatic technologies in terms of materials, mechanisms, and state‐of‐art is provided, and challenges and opportunities to help advancement of the field are discussed.