RT Journal Article
SR Electronic
T1 3D printed lung on a chip device with a stretchable nanofibrous membrane for modeling ventilator induced lung injury
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.02.450873
DO 10.1101/2021.07.02.450873
A1 Sinem Tas
A1 Emil Rehnberg
A1 Deniz A. Bölükbas
A1 Jason P. Beech
A1 Liora Nasi Kazado
A1 Isak Svenningsson
A1 Martin Arvidsson
A1 Axel Sandberg
A1 Kajsa A. Dahlgren
A1 Alexander Edthofer
A1 Anna Gustafsson
A1 Hanna Isaksson
A1 Jeffery A. Wood
A1 Jonas O. Tegenfeldt
A1 Darcy E. Wagner
YR 2021
UL http://biorxiv.org/content/early/2021/07/04/2021.07.02.450873.abstract
AB Mechanical ventilation is often required in patients with pulmonary disease to maintain adequate gas exchange. Despite improved knowledge regarding the risks of over ventilating the lung, ventilator induced lung injury (VILI) remains a major clinical problem due to inhomogeneities within the diseased lung itself as well as the need to increase pressure or volume of oxygen to the lung as a life-saving measure. VILI is characterized by increased physical forces exerted within the lung, which results in cell death, inflammation and long-term fibrotic remodeling. Animal models can be used to study VILI, but it is challenging to distinguish the contributions of individual cell types in such a setup. In vitro models, which allow for controlled stretching of specific lung cell types have emerged as a potential option, but these models and the membranes used in them are unable to recapitulate some key features of the lung such as the 3D nanofibrous structure of the alveolar basement membrane while also allowing for cells to be cultured at an air liquid interface (ALI) and undergo increased mechanical stretch that mimics VILI. Here we develop a lung on a chip device with a nanofibrous synthetic membrane to provide ALI conditions and controllable stretching, including injurious stretching mimicking VILI. The lung on a chip device consists of a thin (i.e. ∼20 µm) stretchable poly(caprolactone) (PCL) nanofibrous membrane placed between two channels fabricated in polydimethylsiloxane (PDMS) using 3D printed molds. We demonstrate that this lung on a chip device can be used to induce mechanotrauma in lung epithelial cells due to cyclic pathophysiologic stretch (∼25%) that mimics clinical VILI. Pathophysiologic stretch induces cell injury and subsequently cell death, which results in loss of the epithelial monolayer, a feature mimicking the early stages of VILI. We also validate the potential of our lung on a chip device to be used to explore cellular pathways known to be altered with mechanical stretch and show that pathophysiologic stretch of lung epithelial cells causes nuclear translocation of the mechanotransducers YAP/TAZ. In conclusion, we show that a breathable lung on a chip device with a nanofibrous membrane can be easily fabricated using 3D printing of the lung on a chip molds and that this model can be used to explore pathomechanisms in mechanically induced lung injury.Competing Interest StatementThe authors have declared no competing interest.