Towards a reliable assessment of nanomaterial health effects using advanced biological models and assays

A sound scientific basis is needed to assess the risks to workers and consumers, to inform regulatory bodies and to ensure a responsible development of nanotechnology. Most of the existing laboratory (in vitro) biological models, exposure systems and doses, as well data (in silico) models do not reflect the real-life exposure to nanomaterials (NMs). A significant source for unreliable results is represented by possible interactions of NMs with the reagents and detection systems for toxicity evaluation. The fast pace at which NMs enter the market requires a shift from expensive and ethically doubtful animal testing to innovative, reliable and socially acceptable in vitro and in silico test systems. The aim of NanoBioReal is to establish methods and biological models that reflect real-life exposure and which provide a reliable, robust and efficient platform to evaluate the effects of NMs on human health. Our testing system covers a wide area of biological models, from single cells to three-dimensional (3D) models that simulate tissues and organs. These include air-liquid interface (ALI) models for lung exposure, blood and «organ-on-a-chip» systems (lung and microvasculature-on-a-chip) that measure effects in real-time and can detect relevant effects after both short and longtime exposure. To avoid interferences caused by NMs, we established in this project label-free impedance-based methods to evaluate cytotoxicity and cyclic voltammetry to assess oxidative stress. A set of representative nanomaterials has been produced and physico-chemically characterized. Their in vitro cyto- and geno- toxicity was assessed in 2D cellular models and the results were compared to those obtained using the advanced 3D models and an animal model. Advanced models for lung, vasculature and whole blood exposure have been established and used for toxicity, inflammation, oxidative stress, and barrier integrity testing. A microfluidic setup for label-free live monitoring of cells and 3D biological models was established, optimized and its throughput has been increased. The results obtained in the NanoBioReal project will deliver reliable, robust and relevant biological and in silico-models to support a “safe(r)-by-design” approach to the development of NMs and to address the needs of various stakeholders and regulators. National partners: Dept. of Clinical Dentistry (IKO), Fac. of Medicine, Univ. of Bergen (UiB), Norwegian Inst. for Air Research (NILU), National Inst. of Occupational Health (STAMI), and Norwegian Univ. of Science and Technology (NTNU). Subcontractors: NorGenotech. International partners: Catalan Inst. of Nanoscience and Nanotechnology (ICN2), Univ. of Gdansk. Collaborators: Dept. of Physics and Technology (UiB), Dept. of Electrical Engineering (HVL), NIOM, TkVest and TkØst.

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This proposal answers to the objective of the 5th thematic priority to expand the insight into the impacts of nanomaterials (NMs) on human health by addressing two of the main sources of uncertainty that hamper the assessment of real-life impact of NMs on human health: i) most of the existing in vitro and in silico models do not reflect real life exposure to NMs and ii) potential interferences of NMs with assays or detection systems. The aim of NanoBioReal is to provide solutions to these challenges by delivering i) beyond state of the art advanced biological models, from single-cells to organ-on-a-chip, representing target tissues and organs and ii) innovative realistic, reliable assessment tools integrated into an in vitro and in silico testing toolbox. The NMs selected for testing are relevant for Norwegian conditions and industry and include TiO2, ZnO, SiO2, nano-silver, nano-gold, and widely used polymer-based dental materials containing embedded nanoparticles. The key biological processes and mechanisms that will be investigated are: i) cellular uptake; ii) inflammation, iii) oxidative stress, iv) genotoxicity, DNA damage and DNA repair and v) cell death. At the end of the project a toolbox will be generated integrating reliable, robust, and efficient in-vivo relevant biological models and methods to support a safe-by-design approach to nanomaterial development and to answer the needs for nanomaterial hazard assessment of various end-users, stakeholders and regulators. The outcome of the project will contribute not only to bringing new mechanistic insights into the health impact of NMs, but also to reducing the uncertainty in health hazard and consequently in risk assessment, as well as to replacing animal use, in conformity with the 3R principles (reduce, refine, replace animal use).

Publications from Cristin

Different Sensitivity of Advanced Bronchial and Alveolar Mono- and Coculture Models for Hazard Assessment of Nanomaterials

Decitabine potentiates efficacy of doxorubicin in a preclinical trastuzumab-resistant HER2-positive breast cancer models

Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpression

Advanced Respiratory Models for Hazard Assessment of Nanomaterials—Performance of Mono-, Co- and Tricultures

Thermodynamic parameters at bio-nano interface and nanomaterial toxicity: A case study on BSA interaction with ZnO, SiO2 and TiO2

Genotoxicity of nanomaterials: Advanced in vitro models and high throughput methods for human hazard assessment—a review

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Finner nye metoder for å kartlegge biologiske effekter av nanopartikler

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Label-free Impedance-based Methods for Nanotoxicity Assessment

Validation of an advanced 3D respiratory tri-culture model at the air-liquid interface for hazard assessment of nanomaterials

Monitoring nanoparticle-induced oxidative stress using cyclic voltammetry and fluorescence-based assays

Development of vascular models to study the transport and effect of nanomaterials.

MODERN DENTAL PROSTHETIC MATERIALS AT THE CONFLUENCE OF SCIENCE, TECHNOLOGY AND ART

Genotoxicity assessment of lung cells cultured at the air-liquid interface: comparison of bronchial and alveolar mono- and cocultures

Assessment of nanoparticle-induced oxidative stress using cyclic voltammetry and the convolution technique

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Development of Endothelial Barrier Models for Nanotoxicity Testing

Cyclic Voltammetry to Monitor Total Antioxidant Capacity of In-Vitro Biological Models Exposed to Nanomaterials

Non-invasive impedance-based methods to assess the effects of nanomaterials on human and fish cells

An Advanced In vitro Respiratory Model for Genotoxicity Testing at the Air-Liquid Interface

Micronucleus assay applied to advanced in vitro lung models at ALI for nanotoxicity assessment

Microfluidic-based biomimetic models for toxicological and therapeutic testing of nanoparticles

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