Micro- and Nanotechnologies

Small Airway-on-a-Chip: A Novel Microphysiological System to Model Human Lung Inflammation, Accelerate Drug Development and Enable Inhalation Toxico-analysis

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  Kambez Benam, D.Phil.

  Assistant Professor
  University of Colorado Denver

Lung diseases are a major global health problem with rising incidence and morbidity; they constitute three out of five leading causes of death worldwide (World Health Organization). Lower respiratory infections, chronic obstructive pulmonary disease (COPD) and lung cancers collectively account for over 8 million deaths annually. Unfortunately, development of new therapeutics and advancement in our understanding of inhalation toxico-pathology have been considerably hindered by challenges in studying organ-level complexities of human lung in vitro. Importantly, clinical relevance of widely used animal models of pulmonary disorders is questionable. Here, we applied a microengineering technological approach known as ‘organ-on-chip’ to create a human lung ‘Small Airway-on-a-Chip’ that supports full differentiation of a pseudostratified mucociliary bronchiolar epithelium from normal or diseased donors underlined by a functional microvascular endothelium. Small Airway Chips lined with COPD epithelia recapitulated features of the disease including selective cytokine hypersecretion, increased neutrophil recruitment, and clinical exacerbations by exposure to pathogenic stimuli. Using this robust in vitro approach, it was possible to detect synergistic tissue-tissue communication, identify new biomarkers of disease exacerbation, and measure responses to anti-inflammatory compounds that inhibit cytokine-induced recruitment of circulating neutrophils. In addition, by connecting the Small Airway Chip to a custom-designed and modular electromechanical instrument that ‘breathes’ freshly produced whole cigarette smoke in and out of the chip microchannels, we successfully recreated smoke-induced oxidative stress, identified new ciliary micropathologies, and discovered unique COPD-specific molecular signatures (‘Breathing-Smoking Lung-on-a-Chip’). Moreover, this platform revealed a subtle ciliary damage triggered by acute exposure to electronic cigarette. Therefore, the human Small Airway-on-a-Chip and Breathing-Smoking Lung-on-a-Chip technologies represent new tools to study normal and disease-specific responses of the human lung airway to pathogens and tobacco-related products across molecular, cell, and tissue levels in an organ-relevant context, which can facilitate identification of new clinical biomarkers and potential therapeutic targets.