As we are alive, we must breathe. This process of breathing brings bacterial, viral, and environmental particulates into our lungs. How can the lungs fight against them? Biologists have discovered that, in the airway, particles are trapped by mucus and cleared out from the lung by coordinated cilia beating of airway epithelia, a process that is reminiscent of transporting people on an escalator. The clearance of mucus is the primary innate defense mechanism that protects the lung from inhaled pathogens. It remains a mystery, however, how and why mucus can be transported from the lower to the upper airway against gravity. This active transport phenomenon is ubiquitous among animals ranging from mice to giraffes, which possess radically different airway lengths. Importantly, the failure of this upward transport associates with mucus obstructive lung diseases, including chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis (CF), and the emerging COVID-19. This research aims to understand and restore the active transport of mucus in the lung.

Our approach to studying mucus transport started with engineering a micro-human airway model mimicking the conditions in vivo. Existing studies rely on a closed circular cell culture model, where the beating of cilia must adapt the circular geometry; this inevitably results in a swirl-like motion of mucus. By contrast, in the airway, the mucus is directionally transported. To this end, guided by fluid dynamics and using additive manufacturing, in recent months we had developed a prototype mucus clearance device that successfully captures the geometric and biological features of human airway. This device is inspired by a recently developed technique “lung-on-a-chip,” but different in that it allows a continuous and directional mucus flow, a dynamic exchange of foreign particulates, and the application of pathological triggers. We are exploiting this micro-human airway device to study mucus transport. Integrating soft matter physics, engineering, molecular biology, bioinformatics, and systems biology, we are investigating the interactions between mucus and three indispensable components of the microenvironment: cilia, cells, and bacteria.

We seek to answer three fundamental questions:

• What are the kinds of mucus-cilia interactions required for efficient mucus transport?
• Whether and how mucus-cell interactions induce human airway remodeling?
• How do mucus-bacteria interactions impact mucus transport?