The impact and safety of encapsulated nanomaterials as a new alternative against carbapenem resistant bacteria. a systematic review.

The emergence of multi drug resistant bacterial infections has caused a critical problem with implication on hospitalization and mortality rates. This systematic review aims to review the combined antimicrobial effect of nanoparticles attached to the traditionally used antibiotics, to overcome the antibiotic resistance crisis. In this systematic search we focused on preclinical studies that have used animal models, to test and evaluate the effect of nanomaterials added to antibiotics against gram negative bacteria with carbapenem resistance. Where, this newly formed structure has led to significant decrease in bacterial load in animal model serum. Furthermore, by evaluating nanomaterial cytotoxicity and inflammatory markers, promising results were established, where low toxicity indices were presented, supporting the ability of this new pathway to be used as an alternative to abused antibiotics. Our research collected the various data and showed encouraging preclinical one for using nanomaterials with antibiotics. This undeniable route should be considered, due to its ability to contribute to the treatment of multi drug resistant bacterial infections. These findings provide base for future studies and reinforce the need for more evaluation and testing on the safety of nanomaterials against bacterial infections.

Use of the dustiness index in combination with the handling energy factor for exposure modelling of nanomaterials.

The use of modelling tools in the occupational hygiene community has increased in the last years to comply with the different existing regulations. However, limitations still exist mainly due to the difficulty to obtain certain key parameters such as the emission rate, which in the case of powder handling can be estimated using the dustiness index (DI). The goal of this work is to explore the applicability and usability of the DI for emission source characterization and occupational exposure prediction to particles during nanomaterial powder handling. Modelling of occupational exposure concentrations of 13 case scenarios was performed using a two-box model as well as three nano-specific tools (Stoffenmanager nano, NanoSafer and GUIDEnano). The improvement of modelling performance by using a derived handling energy factor (H) was explored. Results show the usability of the DI for emission source characterization and respirable mass exposure modelling of powder handling scenarios of nanomaterials. A clear improvement in modelling outcome was obtained when using derived quartile-3 H factors with, 1) Pearson correlations of 0.88 vs. 0.52 (not using H), and 2) ratio of modelled/measured concentrations ranging from 0.9 to 10 in 75% cases vs. 16.7% of the cases when not using H. Particle number concentrations were generally underpredicted. Using the most conservative H values, predictions with ratios modelled/measured concentrations of 0.4-3.6 were obtained.

Graphene-Based Engineered Living Materials.

With the rise of engineered living materials (ELMs) as innovative, sustainable and smart systems for diverse engineering and biological applications, global interest in advancing ELMs is on the rise. Graphene-based nanostructures can serve as effective tools to fabricate ELMs. By using graphene-based materials as building units and microorganisms as the designers of the end materials, next-generation ELMs can be engineered with the structural properties of graphene-based materials and the inherent properties of the microorganisms. However, some challenges need to be addressed to fully take advantage of graphene-based nanostructures for the design of next-generation ELMs. This work covers the latest advances in the fabrication and application of graphene-based ELMs. Fabrication strategies of graphene-based ELMs are first categorized, followed by a systematic investigation of the advantages and disadvantages within each category. Next, the potential applications of graphene-based ELMs are covered. Moreover, the challenges associated with fabrication of next-generation graphene-based ELMs are identified and discussed. Based on a comprehensive overview of the literature, the primary challenge limiting the integration of graphene-based nanostructures in ELMs is nanotoxicity arising from synthetic and structural parameters. Finally, we present possible design principles to potentially address these challenges.

European nanomaterial legislation in the past 20 years - Closing the final gaps.

In 2004, the potential societal implications related to nanotechnology were highlighted in an influential report by the Royal Society and the Royal Academy of Engineering (RS & RAE). It was made clear that legislation is an important tool to tackle the challenges related to nanomaterials and a list of recommendations were put forward. Shortly after, the European Commission also proposed a list of recommendations on how to handle nanomaterial challenges and adopted the so-called "incremental approach", describing that current legislations should be adapted, where relevant, to handle nanomaterials. Now almost 20 years have passed and it seems relevant to take stock and investigate how legislations have been adapted to tackle nano-specific challenges. In this review, we analyze key pieces of European legislations relevant to nanomaterials and assess to what extent these legislations compare with the original recommendations from 2004 by the RS & RAE and the European Commission. We uncover the cross-cutting challenges that remain and provide recommendations on next steps that should be taken to address the risks of nanomaterials. For each recommendation, we assessed whether it was met to a high, medium or low degree by conducting targeted literature searches at Web of Science, screening legislations, guidance documents, databases etc., and applying expert judgement. We found that >90% of the recommendations put forward in 2004 by the RS & RAE and the European Commission have been either met to a high degree (13 out of 29) or met to a medium degree (14 out of 29). This suggests important advancements in the field of nanosafety. At the same time, it is important to address the concerns still left partly or fully unsolved. Such efforts entail e.g. further development of measuring instruments and standardised characterization and risk assessment methods for nanomaterials, application of a uniform nanomaterial definition, maximization of containment of free nanomaterials until hazards assessed/handled and elimination/minimisation of unintentional nanomaterial emission. Furthermore, we recommend prioritising future efforts to ensure enforcement and implementation of existing nano-specific provisions, as well as revision, where needed, of legislations that currently do not account for nanomaterials, such as the Waste Framework Directive.

MnO2 Nanoflower Integrated Optoelectronic Biointerfaces for Photostimulation of Neurons.

Optoelectronic biointerfaces have gained significant interest for wireless and electrical control of neurons. Three-dimentional (3D) pseudocapacitive nanomaterials with large surface areas and interconnected porous structures have great potential for optoelectronic biointerfaces that can fulfill the requirement of high electrode-electrolyte capacitance to effectively transduce light into stimulating ionic currents. In this study, the integration of 3D manganese dioxide (MnO2 ) nanoflowers into flexible optoelectronic biointerfaces for safe and efficient photostimulation of neurons is demonstrated. MnO2 nanoflowers are grown via chemical bath deposition on the return electrode, which has a MnO2 seed layer deposited via cyclic voltammetry. They facilitate a high interfacial capacitance (larger than 10 mF cm-2 ) and photogenerated charge density (over 20 µC cm-2 ) under low light intensity (1 mW mm-2 ). MnO2 nanoflowers induce safe capacitive currents with reversible Faradaic reactions and do not cause any toxicity on hippocampal neurons in vitro, making them a promising material for biointerfacing with electrogenic cells. Patch-clamp electrophysiology is recorded in the whole-cell configuration of hippocampal neurons, and the optoelectronic biointerfaces trigger repetitive and rapid firing of action potentials in response to light pulse trains. This study points out the potential of electrochemically-deposited 3D pseudocapacitive nanomaterials as a robust building block for optoelectronic control of neurons.

Safety and Biodistribution of Nanoligomers Targeting the SARS-CoV-2 Genome for the Treatment of COVID-19.

As the world braces to enter its fourth year of the coronavirus disease 2019 (COVID-19) pandemic, the need for accessible and effective antiviral therapeutics continues to be felt globally. The recent surge of Omicron variant cases has demonstrated that vaccination and prevention alone cannot quell the spread of highly transmissible variants. A safe and nontoxic therapeutic with an adaptable design to respond to the emergence of new variants is critical for transitioning to the treatment of COVID-19 as an endemic disease. Here, we present a novel compound, called SBCoV202, that specifically and tightly binds the translation initiation site of RNA-dependent RNA polymerase within the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome, inhibiting viral replication. SBCoV202 is a Nanoligomer, a molecule that includes peptide nucleic acid sequences capable of binding viral RNA with single-base-pair specificity to accurately target the viral genome. The compound has been shown to be safe and nontoxic in mice, with favorable biodistribution, and has shown efficacy against SARS-CoV-2 in vitro. Safety and biodistribution were assessed using three separate administration methods, namely, intranasal, intravenous, and intraperitoneal. Safety studies showed the Nanoligomer caused no outward distress, immunogenicity, or organ tissue damage, measured through observation of behavior and body weight, serum levels of cytokines, and histopathology of fixed tissue, respectively. SBCoV202 was evenly biodistributed throughout the body, with most tissues measuring Nanoligomer concentrations well above the compound KD of 3.37 nM. In addition to favorable availability to organs such as the lungs, lymph nodes, liver, and spleen, the compound circulated through the blood and was rapidly cleared through the renal and urinary systems. The favorable biodistribution and lack of immunogenicity and toxicity set Nanoligomers apart from other antisense therapies, while the adaptability of the nucleic acid sequence of Nanoligomers provides a defense against future emergence of drug resistance, making these molecules an attractive potential treatment for COVID-19.

Regulatory safety evaluation of nanomedical products: key issues to refine.

Nanotechnologies enable great opportunities for the development and use of innovative (nano)medicines. As is common for scientific and technical developments, recognized safety evaluation methods for regulatory purposes are lagging behind. The specific properties responsible for the desired functioning also hamper the safety evaluation of such products. Pharmacokinetics determination of the active pharmaceutical ingredient as well as the nanomaterial component is crucial. Due to their particulate nature, nanomedicines, similar to all nanomaterials, are primarily removed from the circulation by phagocytizing cells that are part of the immune system. Therefore, the immune system can be potentially a specific target for adverse effects of nanomedicines, and thus needs special attention during the safety evaluation. This DDTR special issue on the results of the REFINE project on a regulatory science framework for nanomedical products presents a highly valuable body of knowledge needed to address regulatory challenges and gaps in currently available testing methods for the safety evaluation of nanomedicines.

Applying Translational Science Approaches to Protect Workers Exposed to Nanomaterials.

Like nanotechnology, translational science is a relatively new and transdisciplinary field. Translational science in occupational safety and health (OSH) focuses on the process of taking scientific knowledge for the protection of workers from the lab to the field (i.e., the worksite/workplace) and back again. Translational science has been conceptualized as having multiple phases of research along a continuum, beyond scientific discovery (T0), to efficacy (T1), to effectiveness (T2), to dissemination and implementation (D&I) (T3), to outcomes and effectiveness research in populations (T4). The translational research process applied to occupational exposure to nanomaterials might involve similar phases. This builds on basic and efficacy research (T0 and T1) in the areas of toxicology, epidemiology, industrial hygiene, medicine and engineering. In T2, research and evidence syntheses and guidance and recommendations to protect workers may be developed and assessed for effectiveness. In T3, emphasis is needed on D&I research to explore the multilevel barriers and facilitators to nanotechnology risk control information/research adoption, use, and sustainment in workplaces. D&I research for nanomaterial exposures should focus on assessing sources of information and evidence to be disseminated /implemented in complex and dynamic workplaces, how policy-makers and employers use this information in diverse contexts to protect workers, how stakeholders inform these critical processes, and what barriers impede and facilitate multilevel decision-making for the protection of nanotechnology workers. The T4 phase focuses on how effective efforts to prevent occupational exposure to nanomaterials along the research continuum contribute to large-scale impact in terms of worker safety, health and wellbeing (T4). Stakeholder input and engagement is critical to all stages of the translational research process. This paper will provide: (1) an illustration of the translational research continuum for occupational exposure to nanomaterials; and (2) a discussion of opportunities for applying D&I science to increase the effectiveness, uptake, integration, sustainability, and impact of interventions to protect the health and wellbeing of workers in the nanotechnology field.

Health and environmental safety of nanomaterials: O Data, Where Art Thou?

Nanotechnology keeps drawing attention due to the great tunable properties of nanomaterials in comparison to their bulk conventional materials. The growth of nanotechnology in combination with the digitization era has led to an increased need of safety related data. In addition to safety, new data-driven paradigms on safe and sustainable by design materials are stressing the necessity of data even more. Data is a fundamental asset to the scientific community in studying and analysing the entire life-cycle of nanomaterials. Unfortunately, data exist in a scattered fashion, in different sources and formats. To our knowledge, there is no study focusing on aspects of actual data-structure knowledge that exists in literature and databases. The purpose of this review research is to transparently and comprehensively, display to the nanoscience community the datasets readily available for machine learning purposes making it convenient and more efficient for the next users such as modellers or data curators to retrieve information. We systematically recorded the features and descriptors available in the datasets and provide synopsised information on their ranges, forms and metrics in the supplementary material.

Safe(r) by design guidelines for the nanotechnology industry.

Expectations for safer and sustainable chemicals and products are growing to comply with the United Nations and European strategies for sustainability. The application of Safe(r) by Design (SbD) in nanotechnology implies an iterative process where functionality, human health and safety, environmental and economic impact and cost are assessed and balanced as early as possible in the innovation process and updated at each step. The EU H2020 NanoReg2 project was the first European project to implement SbD in six companies handling and/or manufacturing nanomaterials (NMs) and nano-enabled products (NEP). The results from this experience have been used to develop these guidelines on the practical application of SbD. The SbD approach foresees the identification, estimation, and reduction of human and environmental risks as early as possible in the development of a NM or NEP, and it is based on three pillars: (i) safer NMs and NEP; (ii) safer use and end of life and (iii) safer industrial production. The presented guidelines include a set of information and tools that will help deciding at each step of the innovation process whether to continue, apply SbD measures or carry out further tests to reduce uncertainty. It does not intend to be a prescriptive protocol where all suggested steps have to be followed to achieve a SbD NM/NEP or process. Rather, the guidelines are designed to identify risks at an early state and information to be considered to identify those risks. Each company adapts the approach to its specific needs and circumstances as company decisions influence the way forward.

Bayesian based similarity assessment of nanomaterials to inform grouping.

Nanoforms can be manufactured in plenty of variants by differing their physicochemical properties and toxicokinetic behaviour which can affect their hazard potential. To avoid testing of each single nanomaterial and nanoform variation and subsequently save resources, grouping and read-across strategies are used to estimate groups of substances, based on carefully selected evidence, that could potentially have similar human health and environmental hazard impact. A novel computational similarity method is presented aiming to compare dose-response curves and identify sets of similar nanoforms. The suggested method estimates the statistical model that best fits the data by leveraging pairwise Bayes Factor analysis to compare pairs of curves and evaluate whether each of the nanoforms is sufficiently similar to all other nanoforms. Pairwise comparisons to benchmark materials are used to define threshold similarity values and set the criteria for identifying groups of nanoforms with comparatively similar toxicity. Applications to use case data are shown to demonstrate that the method can support grouping hypotheses linked to a certain hazard endpoint and route of exposure.

Investigation of the genotoxicity of digested titanium dioxide nanomaterials in human intestinal cells.

The widespread use of titanium dioxide nanomaterials (TiO2 NMs) in food and consumer products such as toothpaste or food contact materials, suggests the relevance of human oral exposure to these nanomaterials (NMs) and raises the possibility of adverse effects in the gastrointestinal tract (GIT). We previously showed that the in vitro digestion of TiO2 NMs may increase their toxicity in intestinal cells. In this work, we analyzed the genotoxicity and the intracellular reactive oxygen species induction by physiologically relevant concentrations of three different TiO2 NMs (NM-102, NM-103 and NM-105) in Caco-2 and HT29-MTX-E12 intestinal cells, while considering the potential influence of the digestion process in the NMs' physiochemical characteristics. The results evidenced a DNA-damaging effect dependent on the NM, more relevant for the rutile/anatase NM-105, possibly due to its lower hydrodynamic size in the cells medium. In addition, the results of the micronucleus assay suggest effects on chromosomal integrity, an indicator of cancer risk, in the HT29-MTX-E12 cells, for all the tested TiO2 NMs, especially after the in vitro digestion. This work supports the evidence for concerns on the use of TiO2 NMs as a food additive, recently reported by EFSA, and for their use in applications in consumer products that may drive human exposure through ingestion.

Machine Learning Models for Predicting Cytotoxicity of Nanomaterials.

The wide application of nanomaterials in consumer and medical products has raised concerns about their potential adverse effects on human health. Thus, more and more biological assessments regarding the toxicity of nanomaterials have been performed. However, the different ways the evaluations were performed, such as the utilized assays, cell lines, and the differences of the produced nanoparticles, make it difficult for scientists to analyze and effectively compare toxicities of nanomaterials. Fortunately, machine learning has emerged as a powerful tool for the prediction of nanotoxicity based on the available data. Among different types of toxicity assessments, nanomaterial cytotoxicity was the focus here because of the high sensitivity of cytotoxicity assessment to different treatments without the need for complicated and time-consuming procedures. In this review, we summarized recent studies that focused on the development of machine learning models for prediction of cytotoxicity of nanomaterials. The goal was to provide insight into predicting potential nanomaterial toxicity and promoting the development of safe nanomaterials.

Potential roles of Kruppel-like factors in mediating adverse vascular effects of nanomaterials: A review.

The development of nanotechnology leads to the exposure of human beings to nanomaterials (NMs), and there is a health concern about the adverse vascular effects of NMs. Current data from epidemiology, controlled human exposure, and animal studies suggested that exposure to NMs could induce cardiopulmonary effects. In support of in vivo findings, in vitro studies showed that direct contact of vascular cells with NMs could induce endothelial cell (EC) activation and promote macrophage foam cell formation, although only limited studies showed that NMs could damage vascular smooth muscle cells and promote their phenotypic switch. It has been proposed that NMs induced adverse vascular effects via different mechanisms, but it is still necessary to understand the upstream events. Kruppel-like factors (KLFs) are a set of C2H2 zinc finger transcription factors (TFs) that can regulate various aspects of vascular biology, but currently, the roles of KLF2 in mediating the adverse vascular effects of NMs have gained little attention by toxicologists. This review summarized current knowledge about the adverse vascular effects of NMs and proposed the potential roles of KLFs in mediating these effects based on available data from toxicological studies as well as the current understanding about KLFs in vascular biology. Finally, the challenges in investigating the role of KLFs in vascular toxicology were also summarized. Considering the important roles of KLFs in vascular biology, further studies are needed to understand the influence of NMs on KLFs and the downstream events.

Investigating the relationship between occupational exposure to nanomaterials and symptoms of nanotechnology companies' employees.

PURPOSE: The increasing use of nanomaterials in academic and industrial environments has raised concerns about the potential effects of these materials on human and the environment. Researches have shown that occupational exposure to nanomaterials can affect employees' health. Many companies are active in the field of nanotechnology in Iran. Therefore, this study was designed and conducted to investigate the relationship between the symptoms of these companies' employees and exposure to nanomaterials. METHODS: The study was conducted among employees of 52 nanotechnology companies in Tehran. For this study, the employees of these companies were categorized in two groups: "exposed" and "non-exposed" to nanomaterials. Data collection tools included the NanoTool method form and a nonspecific symptom questionnaire designed and validated by a team of 19 experts in various fields. Finally, data were analyzed using SPSS.22 software. RESULTS: The results showed that the frequency of cutaneous (such as roughness, itching and redness), respiratory (such as cough, sneezing, and burning throat) and ocular (such as burning, itching and redness) symptoms were higher among the exposed workers to nanomaterials. Examination of the correlation between these symptoms in the two studied groups showed that symptoms with high frequency have a significant relationship with exposure to nanomaterials. CONCLUSIONS: Given the high prevalence of some symptoms among the employees of the studied companies and their association with exposure to nanomaterials, it seems necessary to take control measures to reduce the exposure of employees to nanomaterials and consequently reduce the Investigated symptoms.

How can exposure to engineered nanomaterials influence our epigenetic code? A review of the mechanisms and molecular targets.

Evidence suggests that engineered nanomaterials (ENM) can induce epigenetic modifications. In this review, we provide an overview of the epigenetic modulation of gene expression induced by ENM used in a variety of applications: titanium dioxide (TiO2), silver (Ag), gold (Au), silica (SiO2) nanoparticles and carbon-based nanomaterials (CNM). Exposure to these ENM can trigger alterations in cell patterns of DNA methylation, post-transcriptional histone modifications and expression of non-coding RNA. Such effects are dependent on ENM dose and physicochemical properties including size, shape and surface chemistry, as well as on the cell/organism sensitivity. The genes affected are mostly involved in the regulation of the epigenetic machinery itself, as well as in apoptosis, cell cycle, DNA repair and inflammation related pathways, whose long-term alterations might lead to the onset or progression of certain pathologies. In addition, some DNA methylation patterns may be retained as a form of epigenetic memory. Prenatal exposure to ENM may impair the normal development of the offspring by transplacental effects and/or putative transmission of epimutations in imprinting genes. Thus, understanding the impact of ENM on the epigenome is of paramount importance and epigenetic evaluation must be considered when assessing the risk of ENM to human health.

A Review on Conventional and Advanced Methods for Nanotoxicology Evaluation of Engineered Nanomaterials.

Nanotechnology can be defined as the field of science and technology that studies material at nanoscale (1-100 nm). These nanomaterials, especially carbon nanostructure-based composites and biopolymer-based nanocomposites, exhibit excellent chemical, physical, mechanical, electrical, and many other properties beneficial for their application in many consumer products (e.g., industrial, food, pharmaceutical, and medical). The current literature reports that the increased exposure of humans to nanomaterials could toxicologically affect their environment. Hence, this paper aims to present a review on the possible nanotoxicology assays that can be used to evaluate the toxicity of engineered nanomaterials. The different ways humans are exposed to nanomaterials are discussed, and the recent toxicity evaluation approaches of these nanomaterials are critically assessed.

The SCCS scientific advice on the safety of nanomaterials in cosmetics.

The Cosmetic Regulation (EC) No 1223/2009 specifically covers the risk of nanomaterials used in cosmetic products. If there are concerns regarding the safety of a nanomaterial, the European Commission refers it to the SCCS for a scientific opinion. The Commission mandated the SCCS to identify the scientific basis for safety concerns that could be used as a basis for identifying and prioritising nanomaterials for safety assessment, and to revisit previous inconclusive SCCS opinions on nanomaterials to identify any concerns for potential risks to the consumer health. The SCCS Scientific Advice identified the key general aspects of nanomaterials that should raise a safety concern for a safety assessor/manager, so that the nanomaterial(s) in question could be subjected to safety assessment to establish safety to the consumer. The Advice also developed a list of the nanomaterials notified to the Commission for use in cosmetics in an order of priority for safety assessment, and revisited three previous inconclusive opinions on nanomaterials to highlight concerns over consumer safety that merited further safety assessment.

The Antioxidant Supplementation with Filipendula ulmaria Extract Attenuates the Systemic Adverse Effects of Nanosized Calcium Phosphates in Rats.

The aim of this study was to investigate and compare the systemic toxicity of three nanosized calcium phosphates (CaPs): hydroxyapatite (HA), tricalcium phosphate (TCP), and amorphous calcium phosphate (ACP) in rats. Since those metallic compounds are widely used as bone replacement materials, including their use in oral surgery, CaPs were applied (per os) equimollary (17.8 mg/kg, 11 mg/kg, and 9.65 mg/kg b.w., respectively) for 30 days in order to mimic the previously described release rate from dental composites. Also, we employed antioxidant supplementation with Filipendula ulmaria (FU) extract. All the applied CaPs significantly increased serum calcium, triglycerides, LDL, and LDH, while serum levels of testosterone and LH declined, with no alterations in the liver enzymes. The evaluation of oxidative stress markers (in the liver, kidney, and testicle) showed an increase in TBARS values, while SOD and CAT activities and GSH levels were significantly reduced. The relative gene expression of Bax and Bcl-2 was shifted to proapoptotic action, accompanied by intense characteristic histological changes in architecture in all investigated organs. The toxic effects were most prominent in groups treated by ACP. FU administration attenuated the majority of nanosized CaP-induced adverse effects, thus recommending this therapeutic approach to minimize nano-CaP systemic toxicities.