Impaired Wound Healing of Alveolar Lung Epithelial Cells in a Breathing Lung-On-A-Chip

• Main Authors: Marcel Felder, Bettina Trueeb, Andreas Oliver Stucki, Sarah Borcard, Janick Daniel Stucki, Bruno Schnyder, Thomas Geiser, Olivier Thierry Guenat
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-01-01
• Series: Frontiers in Bioengineering and Biotechnology
• Subjects: wound healing; organ-on-a-chip; air–blood barrier; cyclic stretch; idiopathic pulmonary fibrosis
• Online Access: https://www.frontiersin.org/article/10.3389/fbioe.2019.00003/full

The lung alveolar region experiences remodeling during several acute and chronic lung diseases, as for instance idiopathic pulmonary fibrosis (IPF), a fatal disease, whose onset is correlated with repetitive microinjuries to the lung alveolar epithelium and abnormal alveolar wound repair. Although a high degree of mechanical stress (>20% linear strain) is thought to potentially induce IPF, the effect of lower, physiological levels of strain (5–12% linear strain) on IPF pathophysiology remains unknown. In this study, we examined the influence of mechanical strain on alveolar epithelial wound healing. For this purpose, we adopted the “organ-on-a-chip” approach, which provides the possibility of reproducing unique aspects of the in vivo cellular microenvironment, in particular its dynamic nature. Our results provide the first demonstration that a wound healing assay can be performed on a breathing lung-on-a-chip equipped with an ultra-thin elastic membrane. We cultured lung alveolar epithelial cells to confluence, the cells were starved for 24 h, and then wounded by scratching with a standard micropipette tip. Wound healing was assessed after 24 h under different concentrations of recombinant human hepatic growth factor (rhHGF) and the application of cyclic mechanical stretch. Physiological cyclic mechanical stretch (10% linear strain, 0.2 Hz) significantly impaired the alveolar epithelial wound healing process relative to culture in static conditions. This impairment could be partially ameliorated by administration of rhHGF. This proof-of-concept study provides a way to study of more complex interactions, such as a co-culture with fibroblasts, endothelial cells, or immune cells, as well as the study of wound healing at an air–liquid interface.