Collagen Tubular Airway-on-Chip for Extended Epithelial Culture and Investigation of Ventilation Dynamics

Abstract The lower respiratory tract is a hierarchical network of compliant tubular structures that are made from extracellular matrix proteins with a wall lined by an epithelium. While microfluidic airway-on-a-chip models incorporate the effects of shear and stretch on the epithelium, week-long air-liquid-interface (ALI) culture remains limited to static conditions. The circular cross-section and substrate compliance associated with intact airways have yet to be recapitulated to allow studies of epithelial injuries under physiological and ventilation conditions. To overcome these limitations, we present a collagen tube-based airway model. Sustaining a functional human bronchial epithelium during two-week perfusion is accomplished by continuously supplying warm, humid air at the apical side and culture medium at the basal side. The model faithfully recapitulates human airways in size, composition, and mechanical microenvironment, allowing for the first time dynamic studies of elastocapillary phenomena associated with regular breathing as well as mechanical ventilation, along with the impact on epithelial cells. Findings reveal the epithelium to become increasingly damaged when subjected to repetitive collapse and reopening as opposed to overdistension and suggest expiratory flow resistance to reduce atelectasis. We expect the model to find broad potential applications in organ-on-a-chip applications for various tubular tissues.