Engineering a High Throughput Lung-on-a-Chip System with Intravascular Shear Stress to Better Represent In Vivo Lung Physiology and Characterize Acute Respiratory Distress Syndrome
Date
2024-08-13
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Abstract
Acute Respiratory Distress Syndrome (ARDS) is an inflammatory condition often requiring mechanical ventilation due to severe lung injury, frequently leading to fatal outcomes. Traditional models, including animal studies and 2D cell cultures, fail to capture the complexities of human lung physiology, limiting our understanding of ARDS. To address these limitations, we developed a sophisticated lung-on-a-chip (LoC) platform integrating human endothelial cells forming microvessels within a fibrin hydrogel containing fibroblasts alongside an alveolar epithelial cell-lined air-liquid interface. We use this novel LoC to investigate ARDS disease mechanisms and drug responses. First, we demonstrate marked microvascular damage and tissue biomechanical changes induced by double-stranded RNA (PolyI:C), a common inflammatory agonist which mimics viral lung infections. Additionally, we identified a clinically available drug that blocks JAK/STAT inflammatory signaling, ruxolitinib, and prevented this lung damage. With the addition of continuous vascular fluid flow (and hence shear stress), we found enhanced vascularization under standard conditions but retained disruption following polyI:C treatment. A computational fluid dynamics model was also used to provide insight into fluid velocities and shear stresses present in the ‘healthy’ LoC, parameters that are difficult to measure using empiric testing. This modeling along with empiric vascular bulk flow and bead velocity measurements, points towards significant intravascular obstruction during viral lung infection. These results significantly advance our understanding of lung physiology and ARDS disease progression, paving the way for novel therapeutic interventions in respiratory health, particularly targeting the pulmonary vasculature.
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Keywords
Lung, Microphysiologic Systems, Organ on Chip
Citation
Volek, K. L. (2024). Engineering a high throughput lung-on-a-chip system with intravascular shear stress to better represent in vivo lung physiology and characterize acute respiratory distress syndrome (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.