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Engineered nanomaterials offer numerous benefits to society ranging from environmental remediation to biomedical applications such as drug or vaccine delivery as well as clean and cost-effective energy production and storage, and the promise of a more sustainable way of life. However, as nanomaterials of increasing sophistication enter the market, close attention to potential adverse effects on human health and the environment is needed. Here a critical perspective on nanotoxicological research is provided; the authors argue that it is time to leverage the knowledge regarding the biological interactions of nanomaterials to achieve a more comprehensive understanding of the human health and environmental impacts of these materials. Moreover, it is posited that nanomaterials behave like biological entities and that they should be regulated as such.

Background: Sustainability aspects have become a main criterion for design next to performance of material and product. Particularly the emerging field of energy storage and conversion is striving towards more sustainable solutions. However, implementing sustainability considerations during the design and development phase of energy materials and products is challenging due to the complexity and broadness of the different dimensions of sustainability. Results: Here, we demonstrate that by using the principles of Safe-and-Sustainable-by-Design (SSbD), a concept can be formulated. This concept served as the basis for selecting and evaluating criteria and performance parameters aimed at enhancing the safety and sustainability aspects of redox active molecules in an organic redox flow battery. Following an iterative approach, the collected data provided valuable insights enabling us to fine-tune and enhance the materials and processes in alignment with the identified parameters. (Social) life cycle assessment focused on the workflow from sourcing, processing and generation of intermediate products to the quinone used in the redox flow batteries and revealed important insights, highlighting critical steps in the process chain. Additionally, we identified two specific points of intervention regarding solvent and quinone choice, based on sustainability parameters. The proposed solvent change resulted in a greener alternative [changed from tetrahydrofuran (THF) to 2-methyl-tetrahydrofuran (MTHF)], and the ecotoxicity testing revealed MGQ and MHQS to be improved options. However, we also faced severe challenges regarding access to reliable LCA data on the raw material sourcing. Conclusion: Taken together, the modified designs led to safer and more sustainable redox active materials for both humans and the environment at lab scale. Implementing the results mentioned above to further expedite the technology will ultimately pave the way to more sustainable energy storage applications. This study proved the value of implementing of an SSbD concept in battery development is the main result of this study. [ABSTRACT FROM AUTHOR]

Abstract Background Sustainability aspects have become a main criterion for design next to performance of material and product. Particularly the emerging field of energy storage and conversion is striving towards more sustainable solutions. However, implementing sustainability considerations during the design and development phase of energy materials and products is challenging due to the complexity and broadness of the different dimensions of sustainability. Results Here, we demonstrate that by using the principles of Safe-and-Sustainable-by-Design (SSbD), a concept can be formulated. This concept served as the basis for selecting and evaluating criteria and performance parameters aimed at enhancing the safety and sustainability aspects of redox active molecules in an organic redox flow battery. Following an iterative approach, the collected data provided valuable insights enabling us to fine-tune and enhance the materials and processes in alignment with the identified parameters. (Social) life cycle assessment focused on the workflow from sourcing, processing and generation of intermediate products to the quinone used in the redox flow batteries and revealed important insights, highlighting critical steps in the process chain. Additionally, we identified two specific points of intervention regarding solvent and quinone choice, based on sustainability parameters. The proposed solvent change resulted in a greener alternative [changed from tetrahydrofuran (THF) to 2-methyl-tetrahydrofuran (MTHF)], and the ecotoxicity testing revealed MGQ and MHQS to be improved options. However, we also faced severe challenges regarding access to reliable LCA data on the raw material sourcing. Conclusion Taken together, the modified designs led to safer and more sustainable redox active materials for both humans and the environment at lab scale. Implementing the results mentioned above to further expedite the technology will ultimately pave the way to more sustainable energy storage applications. This study proved the value of implementing of an SSbD concept in battery development is the main result of this study.

The adoption of innovative advanced materials holds vast potential, contingent upon addressing safety and sustainability concerns. The European Commission advocates the integration of Safe and Sustainable by Design (SSbD) principles early in the innovation process to streamline market introduction and mitigate costs. Within this framework, encompassing ecological, social, and economic factors is paramount. The NanoSafety Cluster (NSC) delineates key safety and sustainability areas, pinpointing unresolved issues and research gaps to steer the development of safe(r) materials. Leveraging FAIR data management and integration, alongside the alignment of regulatory aspects, fosters informed decision-making and innovation. Integrating circularity and sustainability mandates clear guidance, ensuring responsible innovation at every stage. Collaboration among stakeholders, anticipation of regulatory demands, and a commitment to sustainability are pivotal for translating SSbD into tangible advancements. Harmonizing standards and test guidelines, along with regulatory preparedness through an exchange platform, is imperative for governance and market readiness. By adhering to these principles, the effective and sustainable deployment of innovative materials can be realized, propelling positive transformation and societal acceptance.

Safe-by-Design (SbD) is a new concept that urges the developers of novel technologies to integrate safety early on in their design process. A SbD approach could—in theory—support the development of safer products and assist a responsible transition to the bioeconomy, via the deployment of safer bio-based and biotechnological alternatives. Despite its prominence in policy discourse, SbD is yet to gain traction in research and innovation practice. In this paper, we examine a frequently stated objection to the initiative of SbD, namely the position that SbD is already common practice in research and industry. We draw upon observations from two case studies: one, a study on the applicability of SbD in the context of bio-based circular materials and, two, a study on stakeholder perceptions of SbD in biotechnology. Interviewed practitioners in both case studies make claims to a strong safety culture in their respective fields and have difficulties differentiating a SbD approach from existing safety practices. Two variations of this argument are discussed: early attentiveness to safety as a strictly formalised practice and early attentiveness as implicit practice. We analyse these perceptions using the theoretical lens of safety culture and contrast them to the aims of SbD. Our analysis indicates that professional identity and professional pride may explain some of the resistance to the initiative of SbD. Nevertheless, SbD could still be advantageous by a) emphasising multidisciplinary approaches to safety and b) offering a (reflective) frame via which implicit attentiveness to safety becomes explicit. [ABSTRACT FROM AUTHOR]

Orthopedic hip implant failure due to adverse events, such as infection, are still a major problem leading to high morbidity and mortality. Over the years, various innovative biomaterials have been investigated to improve safety and functionality of implants. Although novel biomaterials show initial promising results, many fail at the (later) stages of safety testing. We performed a literature review serving as a first step in a Safe-by-Design (SbD) approach. SbD is a strategy which includes safety considerations at early development stages and that streamlines the pre-clinical safety assessment of innovative medical implants. In a SbD approach, the standard safety assessment of medical implants (e.g., ISO10993) is complemented with insights on cell-biomaterial interactions allowing for a better in vivo response prediction. As a first step, these insights are based on existing information from literature. Therefore, in this review, correlations between implant biomaterial surface properties and key biological processes, relevant for the success and safety of titanium hip implants, are investigated. In particular, the influence of biomaterial roughness, wettability and pore size on key biological processes for a hip implant (osseointegration, bacterial adhesion and the immune response) are examined. Although it was found that no ideal combination of properties exist to satisfy the key biological processes simultaneously, the gathered insights provide directions for the development of safe and functional biomaterials. Altogether, an assessment of the different aspects of safety at early development stages within an SbD approach can improve biomaterial functionality and thus safety.

This study introduces a systems-theoretic methodology to meet the requirements of a major national infrastructure for safety and security-based design by enhancing the alignment of stakeholders and actors in the project. Safe-by-Design (SbD) is an engineering concept for risk management that considers safety as much as possible in the design phase. The article presents the results of a case study conducted to investigate the efficacy of recent system safety models and analysis techniques in the major national infrastructure of a Waste-to-Energy (WtE) project under consideration in Iceland. The structures and roles within the system responsible for constructing the WtE plant, given the sustainability and circular economy restrictions, are addressed in the study. Stakeholders' roles and responsibilities are analyzed, yielding their feedback on potential risks and creating a positive image of the project. Also, suitable ways to enter the project and finance it are devised. In essence, this enables the creation of a safety and security-based design approach. Furthermore, detailed documentation of the system model development is presented. The novelty of the study lies in the application of STAM, STPA, and STECA as an SbD approach for a major infrastructure project. Also, the methods discussed here have not been used in a WtE project as far as we know. [ABSTRACT FROM AUTHOR]

Nanosized particles have enticing properties that have received significant attention in recent decades. Polymeric nanoparticles (PNs) are particulates ranging from 1 to 1000 nm that can be loaded with active chemicals that are either entrapped within or surface-adsorbed onto the polymeric core. The term "nanoparticle" refers to both nanocapsules and nanospheres, which differ in morphological aspect. Polymeric nanoparticles have shown technological breakthroughs in the detection and management of many diseases. This review provides an overview of polymers used in PNs for the treatment of cancer and ocular diseases. PNs used for the treatment of different types of cancer and ocular disorders are listed with recent patents. This review also focuses on technological advancements with special reference to the safe-by-design concept. From the literature survey, it was observed that PNs can be used as nanocarriers for the effective delivery of nanomedicines to cancer cells and improve ocular drug delivery. PNs act by increasing solubility, controlling pharmacokinetics, extending release, reducing side effects, and achieving a therapeutic effect with a reduced dose. PNs have shown promising potential in targeting anticancer agents to specific tumor cells by active targeting. This review touches on important considerations, advancements, and challenges of PNs for the treatment of cancer and ocular disorders. [ABSTRACT FROM AUTHOR]

The rate of translational effort of nanomedicine requires strategic planning of nanosafety research in order to enable clinical trials and safe use of nanomedicine in patients. Herein, the experiences that have emerged based on the safety data of classic liposomal formulations in the space of oncology are discussed, along with a description of the new challenges that need to be addressed according to the rapid expansion of nanomedicine platform beyond liposomes. It is valuable to consider the combined use of predictive toxicological assessment supported by deliberate investigation on aspects such as absorption, distribution, metabolism, and excretion (ADME) and toxicokinetic profiles, the risk that may be introduced during nanomanufacture, unique nanomaterials properties, and nonobvious nanosafety endpoints, for example. These efforts will allow the generation of investigational new drug-enabling safety data that can be incorporated into a rational infrastructure for regulatory decision-making. Since the safety assessment relates to nanomaterials, the investigation should cover the important physicochemical properties of the material that may lead to hazards when the nanomedicine product is utilized in humans.

Introduction: Colorectal cancer is the second most deadly cancer worldwide. Current screening methods have low detection rates and frequently provide false positive results, leading to missed diagnoses or unnecessary colonoscopies. To tackle this issue, the Wageningen UR iGEM team from 2022 developed "Colourectal", a living diagnostic tool for colorectal cancer. Following a synthetic biology approach, the project used an engineered Escherichia coli Nissle 1917 strain capable of binding to tumour cells that detects two distinct cancer biomarkers, and secretes a coloured protein observable in stool. Due to the utilization of genetically modified bacteria in vivo, precautionary biosafety measures were included within a three level safe-by-design strategy. Results: The first genetic safeguard ensured confinement of the living diagnostic to the colon environment by implementing auxotrophy to mucin that is abundant in the colon lining. For this, a synthetic chimeric receptor was generated to ensure expression of essential genes in the presence of mucin. The second strategy limited the viability of the engineered bacteria to the human body, preventing proliferation in open environments. The use of a temperature sensitive kill switch induced bacterial cell death at temperatures below 37°C. The third biocontainment strategy was installed as an emergency kill switch to stop the Colourectal test at any point. By inducing a highly genotoxic response through CRISPR-Cas-mediated DNA degradation, cell death of E. coli Nissle is triggered. Discussion: While the use of engineered microorganisms in human applications is not yet a reality, the safety considerations of our multi-layered strategy provide a framework for the development of future living diagnostic tools. [ABSTRACT FROM AUTHOR]

The Safe-by-Design (SbD) concept aims to facilitate the development of safer materials/products, safer production, and safer use and end-of-life by performing timely SbD interventions to reduce hazard, exposure, or both. Early hazard screening is a crucial first step in this process. In this review, for the first time, commonly used in vitro assays are evaluated for their suitability for SbD hazard testing of nanomaterials (NMs). The goal of SbD hazard testing is identifying hazard warnings in the early stages of innovation. For this purpose, assays should be simple, cost-effective, predictive, robust, and compatible. For several toxicological endpoints, there are indications that commonly used in vitro assays are able to predict hazard warnings. In addition to the evaluation of assays, this review provides insights into the effects of the choice of cell type, exposure and dispersion protocol, and the (in)accurate determination of dose delivered to cells on predictivity. Furthermore, compatibility of assays with challenging advanced materials and NMs released from nano-enabled products (NEPs) during the lifecycle is assessed, as these aspects are crucial for SbD hazard testing. To conclude, hazard screening of NMs is complex and joint efforts between innovators, scientists, and regulators are needed to further improve SbD hazard testing. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (Ag NPs) are among the most widely used metal-based nanomaterials (NMs) and their applications in different products, also as antibacterial additives, are increasing. In the present manuscript, according to an adverse outcome pathway (AOP) approach, we tested two safe-by-design (SbD) newly developed Ag NPs coated with hydroxyethyl cellulose (HEC), namely AgHEC powder and AgHEC solution. These novel Ag NPs were compared to two reference Ag NPs (naked and coated with polyvinylpyrrolidone—PVP). Cell viability, inflammatory response, reactive oxygen species, oxidative DNA damage, cell cycle, and cell–particle interactions were analyzed in the alveolar in vitro model, A549 cells. The results show a different toxicity pattern of the novel Ag NPs compared to reference NPs and that between the two novel NPs, the AgHEC solution is the one with the lower toxicity and to be further developed within the SbD framework. [ABSTRACT FROM AUTHOR]

Phosphorus (P) is a key nutrient for agriculture [...]

The use of silver nanoparticles (NPs) in medical devices is constantly increasing due to their excellent antimicrobial properties. In wound dressings, Ag NPs are commonly added in large excess to exert a long-term and constant antimicrobial effect, provoking an instantaneous release of Ag ions during their use or the persistence of unused NPs in the wound dressing that can cause a release of Ag during the end-of-life of the product. For this reason, a Safe-by-Design procedure has been developed to reduce potential environmental risks while optimizing functionality and costs of wound dressings containing Ag NPs. The SbD procedure is based on ad-hoc criteria (e.g., mechanical strength, antibacterial effect, leaching of Ag from the product immersed in environmental media) and permits to identify the best one among five pre-market alternatives. A ranking of the SbD alternatives was obtained and the safer solution was selected based on the selected SbD criteria. The SbD framework was also applied to commercial wound dressings to compare the SbD alternatives with products already on the market. The iterative procedure permitted to exclude one of the alternatives (based on its low mechanical strength) and proved to be an effective approach that can be replicated to support the ranking, prioritisation, and selection of the most promising options early in the innovation process of nano-enabled medical devices as well as to encourage the production of medical devices safer for the environment.

Safe-by-Design is an approach to engineering that aims to integrate the value of safety in the design and development of new technologies. It does so by integrating knowledge of potential dangers in the design process and developing methods to design undesirable effects out of the innovation. Recent discussions have highlighted several challenges in conceptualizing safety and integrating the value into the design process. Therefore, some have argued to design for the responsibility for safety, instead of for safety itself. However, this idea has not been developed further. In this article, we develop an approach to Safe-by-Design, grounded in care ethics, which builds on the idea of designing for responsibility and can deal with the complexity that is inherent to the conceptualization of safety. We describe five ways in which care ethics contributes to the conceptualization of Safe-by-Design: (1) It suggests the development of 'circles of care' in which stakeholders share the responsibility for safety; (2) it recognizes the importance of considering safety as something that is situated in the surroundings of a technology, instead of as a property of the technology itself; (3) it acknowledges that achieving safety is labour that requires an ongoing commitment; (4) it emphasizes that the way in which we relate to technology impacts its safety; and (5) it recognizes the role of emotions in assessing safety. All these elements combined lead to a broader understanding of safety and a philosophically more substantial and practically more appealing conceptualization of Safe-by-Design. [ABSTRACT FROM AUTHOR]

Emerging applications of biotechnology such as new genomic techniques may give rise to new uncertainties and uncertain risks. Particularly the increased complexity and limited knowledge of possible risks associated with these new techniques, make it currently impossible to perform an adequate environmental risk assessment. As a result, there is a risk that such techniques don’t get beyond experiments demonstrating the proof of principle, stifling their further development and implementation. To break free from this deadlock, we must be able to learn what such uncertainties and uncertain risks entail, and how they should be assessed to ensure safe further development. To shape a responsible learning environment to explore uncertainties and uncertain risks, we have organized five stakeholder workshops. By means of a case about the genetic engineering of plants’ rhizosphere–an application abundant with uncertain risks–we identified tensions between different stakeholder groups and their different estimates of uncertainties and uncertain risks. Based upon derived insights, we developed a tool–a script for researchers to organize a stakeholder workshop–that enables a constructive discussion about emerging risks with a broad range of stakeholders. Thereby, the script provides a step-by-step approach to identify uncertainties, develop anticipatory strategies and adaptations in (experimental) research designs to lower or mitigate the earlier identified uncertainties, and helps to identify knowledge gaps for which (additional) risk research should be set up.

The safe implementation of nanotechnology requires nanomaterial hazard assessment in accordance with the material physicochemical properties that trigger the injury response at the nano/bio interface. Since CuO nanoparticles (NPs) are widely used industrially and their dissolution properties play a major role in hazard potential, we hypothesized that tighter bonding of Cu to Fe by particle doping could constitute a safer-by-design approach through decreased dissolution. Accordingly, we designed a combinatorial library in which CuO was doped with 1-10% Fe in a flame spray pyrolysis reactor. The morphology and structural properties were determined by XRD, BET, Raman spectroscopy, HRTEM, EFTEM, and EELS, which demonstrated a significant reduction in the apical Cu-O bond length while simultaneously increasing the planar bond length (Jahn-Teller distortion). Hazard screening was performed in tissue culture cell lines and zebrafish embryos to discern the change in the hazardous effects of doped vs nondoped particles. This demonstrated that with increased levels of doping there was a progressive decrease in cytotoxicity in BEAS-2B and THP-1 cells, as well as an incremental decrease in the rate of hatching interference in zebrafish embryos. The dissolution profiles were determined and the surface reactions taking place in Holtfreter's solution were validated using cyclic voltammetry measurements to demonstrate that the Cu+/Cu2+ and Fe2+/Fe3+ redox species play a major role in the dissolution process of pure and Fe-doped CuO. Altogether, a safe-by-design strategy was implemented for the toxic CuO particles via Fe doping and has been demonstrated for their safe use in the environment.

While the various physicochemical properties of engineered nanomaterials influence their toxicities, their understanding is still incomplete. A predictive framework is required to develop safe nanomaterials, and a Bayesian network (BN) model based on adverse outcome pathway (AOP) can be utilized for this purpose. In this study, to explore the applicability of the AOP-based BN model in the development of safe nanomaterials, a comparative study was conducted on the change in the probability of toxicity pathways in response to changes in the dimensions and surface functionalization of multi-walled carbon nanotubes (MWCNTs). Based on the results of our previous study, we developed an AOP leading to cell death, and the experimental results were collected in human liver cells (HepG2) and bronchial epithelium cells (Beas-2B). The BN model was trained on these data to identify probabilistic causal relationships between key events. The results indicated that dimensions were the main influencing factor for lung cells, whereas -OH or -COOH surface functionalization and aspect ratio were the main influencing factors for liver cells. Endoplasmic reticulum stress was found to be a more sensitive pathway for dimensional changes, and oxidative stress was a more sensitive pathway for surface functionalization. Overall, our results suggest that the AOP-based BN model can be used to provide a scientific basis for the development of safe nanomaterials. [ABSTRACT FROM AUTHOR]

Attention to environmental issues has become increasingly important in recent years and also massively affects the cosmetics sector. In this context, sunscreens are questioned due to the proven or believed ecotoxicity of organic ultraviolet (UV) filters. This has pushed developers increasingly towards the use of inorganic filters, which can prove difficult to spread with low compliance. We faced the problem by proposing a rational approach based on the evaluation of the morphology of the inorganic material, as the real dimension does not often correspond to the characteristics declared by the producers because the material itself tends to aggregate. A combination of a specially selected inorganic filter is required to formulate Cosmetic Products with a Natural and Sustainable Connotation (CPCNS) standards. [ABSTRACT FROM AUTHOR]

Poly (ethylene glycol) (PEG) is a widely used polymer in a variety of consumer products and in medicine. PEGylation refers to the conjugation of PEG to drugs or nanoparticles to increase circulation time and reduce unwanted host responses. PEG is viewed as being well-tolerated, but previous studies have identified anti-PEG antibodies and so-called pseudoallergic reactions in certain individuals. The increased use of nanoparticles as contrast agents or in drug delivery, along with the introduction of mRNA vaccines encapsulated in PEGylated lipid nanoparticles has brought this issue to the fore. Thus, while these vaccines have proven to be remarkably effective, rare cases of anaphylaxis have been reported, and this has been tentatively ascribed to the PEGylated carriers, which may trigger complement activation in susceptible individuals. Here, we provide a general overview of the use of PEGylated nanoparticles for pharmaceutical applications, and we discuss the activation of the complement cascade that might be caused by PEGylated nanomedicines for a better understanding of these immunological adverse reactions.

The novel chemical strategy for sustainability calls for a Sustainable and Safe-by-Design (SSbD) holistic approach to achieve protection of public health and the environment, industrial relevance, societal empowerment, and regulatory preparedness. Based on it, the ASINA project expands a data-driven Management Methodology (ASINA-SMM) capturing quality, safety, and sustainability criteria across the Nano-Enabled Products’ (NEPs) life cycle. We base the development of this methodology through value chains of highly representative classes of NEPs in the market, namely, (i) self-cleaning/air-purifying/antimicrobial coatings and (ii) nano-structured capsules delivering active phases in cosmetics. These NEPs improve environmental quality and human health/wellness and have innovative competence to industrial sectors such as healthcare, textiles, cosmetics, and medical devices. The purpose of this article is to visually exhibit and explain the ASINA approach, which allows identifying, combining, and addressing the following pillars: environmental impact, techno-economic performance, functionality, and human and environmental safety when developing novel NEPs, at an early stage. A metamodel supports the above by utilizing quality data collected throughout the NEPs’ life cycle, for maximization of functionality (to meet stakeholders needs) and nano-safety (regulatory obligations) and for the minimization of costs (to meet business requirements) and environmental impacts (to achieve sustainability). Furthermore, ASINA explores digitalization opportunities (digital twins) to speed the nano-industry translation into automatic progress towards economic, social, environmental, and governance sustainability.

Nanotoxicology is a relatively new field of research concerning the study and application of nanomaterials to evaluate the potential for harmful effects in parallel with the development of applications. Nanotoxicology as a field spans materials synthesis and characterisation, assessment of fate and behaviour, exposure science, toxicology / ecotoxicology, molecular biology and toxicogenomics, epidemiology, safe and sustainable by design approaches, and chemoinformatics and nanoinformatics, thus requiring scientists to work collaboratively, often outside their core expertise area. This interdisciplinarity can lead to challenges in terms of interpretation and reporting, and calls for a platform for sharing of best-practice in nanotoxicology research. The F1000Research Nanotoxicology collection, introduced via this editorial, will provide a place to share accumulated best practice, via original research reports including no-effects studies, protocols and methods papers, software reports and living systematic reviews, which can be updated as new knowledge emerges or as the domain of applicability of the method, model or software is expanded. This editorial introduces the Nanotoxicology Collection in F1000Research. The aim of the collection is to provide an open access platform for nanotoxicology researchers, to support an improved culture of data sharing and documentation of evolving protocols, biological and computational models, software tools and datasets, that can be applied and built upon to develop predictive models and move towards in silico nanotoxicology and nanoinformatics. Submissions will be assessed for fit to the collection and subjected to the F1000Research open peer review process.

Silver nanoparticles (Ag NPs) are among the most widely used metal-based nanomaterials (NMs) and their applications in different products, also as antibacterial additives, are increasing. In the present manuscript, according to an adverse outcome pathway (AOP) approach, we tested two safe-by-design (SbD) newly developed Ag NPs coated with hydroxyethyl cellulose (HEC), namely AgHEC powder and AgHEC solution. These novel Ag NPs were compared to two reference Ag NPs (naked and coated with polyvinylpyrrolidone—PVP). Cell viability, inflammatory response, reactive oxygen species, oxidative DNA damage, cell cycle, and cell–particle interactions were analyzed in the alveolar in vitro model, A549 cells. The results show a different toxicity pattern of the novel Ag NPs compared to reference NPs and that between the two novel NPs, the AgHEC solution is the one with the lower toxicity and to be further developed within the SbD framework.

Functional nanomaterials (NM) of different size, shape, chemical composition, and surface chemistry are of increasing relevance for many key technologies of the twenty-first century. This includes polymer and silica or silica-coated nanoparticles (NP) with covalently bound surface groups, semiconductor quantum dots (QD), metal and metal oxide NP, and lanthanide-based NP with coordinatively or electrostatically bound ligands, as well as surface-coated nanostructures like micellar encapsulated NP. The surface chemistry can significantly affect the physicochemical properties of NM, their charge, their processability and performance, as well as their impact on human health and the environment. Thus, analytical methods for the characterization of NM surface chemistry regarding chemical identification, quantification, and accessibility of functional groups (FG) and surface ligands bearing such FG are of increasing importance for quality control of NM synthesis up to nanosafety. Here, we provide an overview of analytical methods for FG analysis and quantification with special emphasis on bioanalytically relevant FG broadly utilized for the covalent attachment of biomolecules like proteins, peptides, and oligonucleotides and address method- and material-related challenges and limitations. Analytical techniques reviewed include electrochemical titration methods, optical assays, nuclear magnetic resonance and vibrational spectroscopy, as well as X-ray based and thermal analysis methods, covering the last 5–10 years. Criteria for method classification and evaluation include the need for a signal-generating label, provision of either the total or derivatizable number of FG, need for expensive instrumentation, and suitability for process and production control during NM synthesis and functionalization. [ABSTRACT FROM AUTHOR]

This document discusses the use of nanocomposite metal oxide/hydroxide adsorbents for advanced wastewater treatment and the assessment of their toxicological risk to the aquatic environment. Phosphorus, an important nutrient for agriculture, is often removed from wastewater due to its negative environmental impact. Metal oxide/hydroxide nanocomposites have shown promise in selectively removing phosphorus from wastewater, but their environmental safety is rarely addressed. This study evaluates the ecotoxicological hazard of 10 metal oxide/hydroxide nanocomposites using toxicity tests on marine bacteria and crustaceans. The results indicate that composites containing zinc are harmful to both organisms, while those without zinc are non-toxic. The study provides valuable insights for engineering applications and highlights the importance of considering environmental safety when using nanocomposite adsorbents. [Extracted from the article]

With the increasing production and applications, silver nanoparticles (AgNPs) can be released into the air, water and soil environment, leading to direct exposure to human beings. Embryos and fetuses are more sensitive to environmental pollutants than adults. Thus, the developmental toxicity of AgNPs should be of great concern. However, the targets and molecular mechanisms how prenatal AgNP exposure affects fetal development in mammals are largely unknown. In the current review, the translocation and developmental toxicities of AgNPs upon maternal exposure in mammals are summarized. AgNPs are able to translocate to the fetus, resulting in resorption, growth retardation and histological and functional abnormalities in the fetal central nervous system (CNS), reproductive system, immune system and other systems and organs. A few likely mechanisms, including direct and indirect mechanisms, and knowledge gaps are elucidated. The fundamental physiochemical properties that determine their behaviors are discussed in order to develop safe-by-design nanomaterials for personal care and medical applications. This review aims to advance the understanding of the developmental toxicities of AgNPs for the design of nanomaterials that harbor better biocompatibility.

Few topical products have been developed specifically to treat acute and chronic arthritis and inflammation, using non-steroidal anti-inflammatory drugs (NSAIDs). The lack of dosing accuracy commonly found in locally applied semisolid products for cutaneous use is a critical issue that leads to treatment failure. The aim of the present work is to develop a differentiated and innovative topical patch based on a monolithic hydrogel for ibuprofen skin delivery, in order to provide a safer and accurate way of drug administration along with improved treatment compliance. Topical patches based on hydroxypropylmethylcellulose (HPMC) were optimized in composition, in terms of enhancer and adhesive, supported on a systematic assessment of in vitro release and permeation behavior and adhesion properties. Several mathematical models were used to scrutinize the release mechanisms from the patches. In vitro release kinetics was shown to be mainly driven by diffusion. However, other mechanisms seemed to be also present, supporting the feasibility of using patches for sustained drug delivery. PEG 200 provided the best permeation rate, with a permeation enhancement ratio of ca. 3 times higher, than the commercial reference. The addition of Eudragit L30D 55 to the formulation led to the best adhesion profile, thus achieving a successful development based on a safe-by-design concept.

Gemini surfactants are being proposed as promising eco-friendly replacements of state-of-the-art surfactants, for instance, to synthesize greener nanomaterials. 33738354 2 Kaczerewska O., Sousa I., Martins R., Figueiredo J., Loureiro S., Tedim J. Gemini surfactant as a template agent for the synthesis of more eco-friendly silica nanocapsules. Keywords: green nanotechnology; green chemistry; safe-by-design; sustainability; nanomaterials; nanoparticles; nanoecotoxicology; environmental risk assessment EN green nanotechnology green chemistry safe-by-design sustainability nanomaterials nanoparticles nanoecotoxicology environmental risk assessment 4513 4513 1 05/28/21 20210515 NES 210515 1. [Extracted from the article]

Genetic engineering techniques (e.g., CRISPR-Cas) have led to an increase in biotechnological developments, possibly leading to uncertain risks. The European Union aims to anticipate these by embedding the Precautionary Principle in its regulation for risk management. This principle revolves around taking preventive action in the face of uncertainty and provides guidelines to take precautionary measures when dealing with important values such as health or environmental safety. However, when dealing with ‘new’ technologies, it can be hard for risk managers to estimate the societal or environmental consequences of a biotechnology that might arise once introduced or embedded in society due to that these sometimes do not comply with the established norms within risk assessment. When there is insufficient knowledge, stakeholders active in early developmental stages (e.g., researchers) could provide necessary knowledge by conducting research specifically devoted to what these unknown risks could entail. In theory, the Safe-by-Design (SbD) approach could enable such a controlled learning environment to gradually identify what these uncertain risks are, to which we refer as responsible learning. In this paper, we argue that three conditions need to be present to enable such an environment: (1) regulatory flexibility, (2) co-responsibility between researchers and regulators, and (3) openness towards all stakeholders. If one of these conditions would not be present, the SbD approach cannot be implemented to its fullest potential, thereby limiting an environment for responsible learning and possibly leaving current policy behind to anticipate uncertain risks. [ABSTRACT FROM AUTHOR]

Engineered nanomaterials offer numerous benefits to society ranging from environmental remediation to biomedical applications such as drug or vaccine delivery as well as clean and cost-effective energy production and storage, and the promise of a more sustainable way of life. However, as nanomaterials of increasing sophistication enter the market, close attention to potential adverse effects on human health and the environment is needed. Here a critical perspective on nanotoxicological research is provided; the authors argue that it is time to leverage the knowledge regarding the biological interactions of nanomaterials to achieve a more comprehensive understanding of the human health and environmental impacts of these materials. Moreover, it is posited that nanomaterials behave like biological entities and that they should be regulated as such., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

Safe-by-Design (SbD) concepts foresee the risk identification and reduction as well as uncertainties regarding human health and environmental safety in early stages of product development. The EU’s NANoREG project and further on the H2020 ProSafe initiative, NanoReg2, and CALIBRATE projects have developed a general SbD approach for nanotechnologies (e.g., paints, textiles, etc.). Based on it, the GoNanoBioMat project elaborated a methodological SbD approach (GoNanoBioMat SbD approach) for nanomedicines with a focus on polymeric nanobiomaterials (NBMs) used for drug delivery. NBMs have various advantages such as the potential to increase drug efficacy and bioavailability. However, the nanoscale brings new challenges to product design, manufacturing, and handling. Nanomedicines are costly and require the combination of knowledge from several fields. In this paper, we present the GoNanoBioMat SbD approach, which allows identifying and addressing the relevant safety aspects to address when developing polymeric NBMs during design, characterization, assessment of human health and environmental risk, manufacturing and handling, and combines the nanoscale and medicine field under one approach. Furthermore, regulatory requirements are integrated into the innovation process.

Advanced gene editing techniques such as Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas have increased the pace of developments in the field of industrial biotechnology. Such techniques imply new possibilities when working with living organisms, possibly leading to uncertain risks. In the Netherlands, current policy fails to address these uncertain risks because risk classification is determined process‐wise (i.e., genetically modified organism [GMO] and non‐GMO), there is a strong focus on quantifiable risks, and the linearity within current governance (science–policy–society) hinders iterative communication between stakeholders, leaving limited room to anticipate uncertainties at an early stage of development. A suggested concept to overcome these shortcomings is the Safe‐by‐Design (SbD) approach, which, theoretically, allows stakeholders to iteratively incorporate safety measures throughout a technology's development process, creating a dynamic environment for the anticipation of uncertain risks. Although this concept originates from chemical engineering and is already widely applied in nanotechnology, for the field of biotechnology, there is no agreed upon definition yet. To explore the possibilities of SbD for future governance of biotechnology, we should gain insight in how various stakeholders perceive notions of risk, safety, and inherent safety, and what this implies for the applicability of SbD for risk governance concerning industrial biotechnology. Our empirical research reveals three main themes: (1) diverging expectations with regard to safety and risks, and to establish an acceptable level of risk; (2) different applications of SbD and inherent safety, namely, product‐ and process‐wise; and (3) unclarity in allocating responsibilities to stakeholders in the development process of a biotechnology and within society. [ABSTRACT FROM AUTHOR]

The objective of Safe-by-Design (SbD) is to support the development of safer products and production processes, and enable safe use throughout a materials' life cycle; an intervention at an early stage of innovation can greatly benefit industry by reducing costs associated with the development of products later found to elicit harmful effects. Early hazard screening can support this process, and is needed for all of the expected nanomaterial exposure routes, including inhalation, ingestion and dermal. In this study, we compare in vitro and ex vivo cell models that represent dermal exposures (including HaCaT cells, primary keratinocytes, and reconstructed human epidermis (RhE)), and when possible consider these in the context of regulatory accepted OECD TG for in vitro dermal irritation. Various benchmark nanomaterials were used to assess markers of cell stress in each cell model. In addition, we evaluated different dosing strategies that have been used when applying the OECD TG for dermal irritation in assessment of nanomaterials, and how inconsistencies in the approach used can have considerable impact of the conclusions made. Although we could not demonstrate alignment of all models used, there was an indication that the simpler in vitro cell model aligned more closely with RhE tissue than ex vivo primary keratinocytes, supporting the use of HaCaT cells for screening of dermal toxicity of nanomaterials and in early-stage SbD decision-making. • The in vitro HaCaT cell model provides better support for hazard screening of nanomaterials than primary keratinocytes. • Early-stage safe-by-design decisions can be made with data collected with the in vitro HaCaT cell model. • HaCaT cells correlate more closely with regulatory accepted reconstructed human epidermis than primary keratinocytes. • The nanomaterial dosing strategy can greatly affect the outcome when using the OECD TG for in vitro skin irritation. [ABSTRACT FROM AUTHOR]

Predictive toxicity and structure–activity relationships (SARs) are raising interest since the number of nanomaterials has become unmanageable to assess their toxicity with a classical case-by-case approach. Graphene-based materials (GBMs) are among the most promising nanomaterials of this decade and their application might lead to several innovations. However, their toxicity impact needs to be thoroughly assessed. In this regard, we conducted a study on 22 GBMs to investigate their potential SARs by performing a complete physicochemical characterization and in vitro toxicity assessment (on RAW264.7 cells). We used GBMs of variable lateral size (0.5–38 µm), specific surface area (SSA, 30–880 m²/g), and surface oxidation (2–17%). We observed that reduced graphene oxides (RGOs) were more reactive than graphene nanoplatelets (GNPs), potentially highlighting the role of GBM’s surface chemistry and surface defects density in their biological impact. We also observed that for GNPs, a smaller lateral size caused higher cytotoxicity. Lastly, GBMs showing a SSA higher than 200 m²/g were found to induce a higher ROS production. Mechanistic explanations are proposed in the discussion. In conclusion, pairing a full physicochemical characterization with a standardized toxicity assessment of a large set of samples allowed us to clarify SARs and provide an additional step toward safe-by-design GBMs.

Research on plant-nanomaterial interactions has greatly advanced over the past decade. One particularly fascinating discovery encompasses the immunomodulatory effects in plants. Due to the low doses needed and the comparatively low toxicity of many nanomaterials, nanoenabled immunomodulation is environmentally and economically promising for agriculture. It may reduce environmental costs associated with excessive use of chemical pesticides and fertilizers, which can lead to soil and water pollution. Furthermore, nanoenabled strategies can enhance plant resilience against various biotic and abiotic stresses, contributing to the sustainability of agricultural ecosystems and the reduction of crop losses due to environmental factors. While nanoparticle immunomodulatory effects are relatively well-known in animals, they are still to be understood in plants. Here, we provide our perspective on the general components of the plant's immune system, including the signaling pathways, networks, and molecules of relevance for plant nanomodulation. We discuss the recent scientific progress in nanoenabled immunomodulation and nanopriming and lay out key avenues to use plant immunomodulation for agriculture. Reactive oxygen species (ROS), the mitogen-activated protein kinase (MAPK) cascade, and the calcium-dependent protein kinase (CDPK or CPK) pathway are of particular interest due to their interconnected function and significance in the response to biotic and abiotic stress. Additionally, we underscore that understanding the plant hormone salicylic acid is vital for nanoenabled applications to induce systemic acquired resistance. It is suggested that a multidisciplinary approach, incorporating environmental impact assessments and focusing on scalability, can expedite the realization of enhanced crop yields through nanotechnology while fostering a healthier environment.

Nanotechnology is a key enabling technology bringing together chemists, biologists, physicists, and materials science engineers, among others [...]

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.

This review was initiated by the COST action CA15114 AMICI “Anti-Microbial Coating Innovations to prevent infectious diseases,” where one important aspect is to analyze ecotoxicological impacts of antimicrobial coatings (AMCs) to ensure their sustainable use. Scopus database was used to collect scientific literature on the types and uses of AMCs, while market reports were used to collect data on production volumes. Special attention was paid on data obtained for the release of the most prevalent ingredients of AMCs into the aqueous phase that was used as the proxy for their possible ecotoxicological effects. Based on the critical analysis of 2,720 papers, it can be concluded that silver-based AMCs are by far the most studied and used coatings followed by those based on titanium, copper, zinc, chitosan and quaternary ammonium compounds. The literature analysis pointed to biomedicine, followed by marine industry, construction industry (paints), food industry and textiles as the main fields of application of AMCs. The published data on ecotoxicological effects of AMCs was scarce, and also only a small number of the papers provided information on release of antimicrobial ingredients from AMCs. The available release data allowed to conclude that silver, copper and zinc are often released in substantial amounts (up to 100%) from the coatings to the aqueous environment. Chitosan and titanium were mostly not used as active released ingredients in AMCs, but rather as carriers for other release-based antimicrobial ingredients (e.g., conventional antibiotics). While minimizing the prevalence of healthcare-associated infections appeared to be the most prosperous field of AMCs application, the release of environmentally hazardous ingredients of AMCs into hospital wastewaters and thus, also the environmental risks associated with AMCs, comprise currently only a fraction of the release and risks of traditional disinfectants. However, being proactive, while the use of antimicrobial/antifouling coatings could currently pose ecotoxicological effects mainly in marine applications, the broad use of AMCs in other applications like medicine, food packaging and textiles should be postponed until reaching evidences on the (i) profound efficiency of these materials in controlling the spread of pathogenic microbes and (ii) safety of AMCs for the human and ecosystems.