Dataset Information

A 3D human lung-on-a-chip model for nanotoxicity testing.

ABSTRACT: The prevalent application of nanoparticles (NPs) has drawn intense concerns about their impact on the environment and human health. Inhalation of NPs is the major route of NP exposure and has led to adverse effects on the lung. It is of great concern to evaluate the potential hazards of nanoparticles for human health during pulmonary exposure. Here, we proposed a novel 3D human lung-on-a-chip model to recreate the organ-level structure and functions of the human lung that allow to us evaluate the pulmonary toxicity of nanoparticles. The lung-on-a-chip consists of three parallel channels for the co-culture of human vascular endothelial cells and human alveolar epithelial cells sandwiching a layer of Matrigel membrane, which recapitulate the key features of the alveolar capillary barrier in the human lung. Cell-cell interaction, cell-matrix interaction and vascular mechanical cues work synergistically to promote the barrier function of the lung-on-a-chip model. TiO2 nanoparticles and ZnO nanoparticles were applied on the lung-on-a-chip to assay their nanotoxicity on both epithelial cells and endothelial cells. Junction protein expression, increased permeability to macromolecules, dose dependent cytotoxicity, ROS production and apoptosis were assayed and compared on the chip. This lung-on-a-chip model indicated its versatile application in human pulmonary health and safety assessment for nanoparticles, environment, food and drugs.

SUBMITTER: Zhang M

PROVIDER: S-EPMC6220735 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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A 3D human lung-on-a-chip model for nanotoxicity testing.

Zhang Min M Xu Cong C Jiang Lei L Qin Jianhua J

Toxicology research 20180811 6

The prevalent application of nanoparticles (NPs) has drawn intense concerns about their impact on the environment and human health. Inhalation of NPs is the major route of NP exposure and has led to adverse effects on the lung. It is of great concern to evaluate the potential hazards of nanoparticles for human health during pulmonary exposure. Here, we proposed a novel 3D human lung-on-a-chip model to recreate the organ-level structure and functions of the human lung that allow to us evaluate th ...[more]

PMID: 30510678

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Project description:BackgroundMulti-walled carbon nanotubes (MWCNT) have been shown to elicit the release of inflammatory and pro-fibrotic mediators, as well as histopathological changes in lungs of exposed animals. Current standards for testing MWCNTs and other nanoparticles (NPs) rely on low-throughput in vivo studies to assess acute and chronic toxicity and potential hazard to humans. Several alternative testing approaches utilizing two-dimensional (2D) in vitro assays to screen engineered NPs have reported conflicting results between in vitro and in vivo assays. Compared to conventional 2D in vitro or in vivo animal model systems, three-dimensional (3D) in vitro platforms have been shown to more closely recapitulate human physiology, providing a relevant, more efficient strategy for evaluating acute toxicity and chronic outcomes in a tiered nanomaterial toxicity testing paradigm.ResultsAs inhalation is an important route of nanomaterial exposure, human lung fibroblasts and epithelial cells were co-cultured with macrophages to form scaffold-free 3D lung microtissues. Microtissues were exposed to multi-walled carbon nanotubes, M120 carbon black nanoparticles or crocidolite asbestos fibers for 4 or 7 days, then collected for characterization of microtissue viability, tissue morphology, and expression of genes and selected proteins associated with inflammation and extracellular matrix remodeling. Our data demonstrate the utility of 3D microtissues in predicting chronic pulmonary endpoints following exposure to MWCNTs or asbestos fibers. These test nanomaterials were incorporated into 3D human lung microtissues as visualized using light microscopy. Differential expression of genes involved in acute inflammation and extracellular matrix remodeling was detected using PCR arrays and confirmed using qRT-PCR analysis and Luminex assays of selected genes and proteins.Conclusion3D lung microtissues provide an alternative testing platform for assessing nanomaterial-induced cell-matrix alterations and delineation of toxicity pathways, moving towards a more predictive and physiologically relevant approach for in vitro NP toxicity testing.

Project description:Background & aimsCholangiocarcinoma (CCA) is a primary liver tumour characterised by a poor prognosis and limited therapeutic options. Available 3D human CCA models fail to faithfully recapitulate the tumour niche. We aimed to develop an innovative patient-specific CCA-on-chip platform.MethodsA CCA tumour microenvironment was recapitulated on a microfluidic three-channel chip using primary CCA cells, cancer-associated fibroblasts (CAFs), endothelial cells, and T cells isolated from CCA specimens (n = 6). CAF and CCA cells were co-cultured in the central channel, flanked by endothelial cells in one lateral channel, recreating a tubular structure. An extensive characterisation of this platform was carried out to investigate its diffusion ability, hydrogel properties, and changes in matrix composition. Cell phenotype and functional properties were assessed.ResultsPrimary cells seeded on the microfluidic device were shown to reproduce the architectural structure and maintain the original phenotype and functional properties. The tumour niche underwent a deep remodelling in the 3D device, with an increase in hydrogel stiffness and extracellular matrix deposition, mimicking in vivo CCA characteristics. T cells were incorporated into the device to assess its reliability for immune cell interaction studies. Higher T cell migration was observed using cells from patients with highly infiltrated tumours. Finally, the drug trial showed the ability of the device to recapitulate different drug responses based on patient characteristics.ConclusionsWe presented a 3D CCA platform that integrates the major non-immune components of the tumour microenvironment and the T cell infiltrate, reflecting the CCA niche. This CCA-on-chip represents a reliable patient-specific 3D platform that will be of help to further elucidate the biological mechanisms involved in CCA and provide an efficient tool for personalised drug testing.Impact and implicationsAn innovative patient-specific cholangiocarcinoma (CCA)-on-chip platform was successfully developed, integrating the major components of the tumour microenvironment (tumour cells, cancer-associated fibroblasts, endothelial cells, and immune infiltrate) and faithfully mimicking the CCA niche. This CCA-on-chip represents a powerful tool for unravelling disease-associated cellular mechanisms in CCA and provides an efficient tool for personalised drug testing.

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A 3D human lung-on-a-chip model for nanotoxicity testing.

Publications

A 3D human lung-on-a-chip model for nanotoxicity testing.

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