Abstract
Occlusion of distal airways due to mucus plugs is a key pathological feature common to a wide variety of obstructive pulmonary diseases. Breathing-induced movement of airway mucus plugs along the respiratory tract has been shown to generate abnormally large mechanical stresses, acting as an insult that can incite acute injury to the airway epithelium. Here, we describe a unique microengineering strategy to model this pathophysiological process using a bioinspired microfluidic device. Our system combines an air-liquid interface culture of primary human small airway epithelial cells with a microengineered biomimetic platform to replicate the process of mucus exudation induced by airway constriction that leads to the formation of mucus plugs across the airway lumen. Specifically, we constructed a compartmentalized three-dimensional (3D) microfluidic device in which extracellular matrix hydrogel scaffolds reminiscent of airway stroma were compressed to discharge fluid into the airway compartment and form liquid plugs. We demonstrated that this plug formation process and subsequent movement of liquid plugs through the airway channel can be regulated in a precisely controlled manner. Furthermore, we examined the detrimental effect of plug propagation on the airway epithelium to simulate acute epithelial injury during airway closure. Our system allows for a novel biomimetic approach to modeling a complex and dynamic biophysical microenvironment of diseased human airways and may serve as an enabling platform for mechanistic investigation of key disease processes that drive the progression and exacerbation of obstructive pulmonary diseases.