Biophysical Cues on Human Lung Defense: From Airway Remodeling to Mucosal Drug Delivery

Muco-obstructive lung diseases is a group of airway diseases, such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), characterized by thick mucus plug obstructing the airway. The thick mucus also induced chronic inflammation in the airway and causes fibrosis of the airway. Therefore, increased mucus osmotic pressure and heightened airway stiffness are two prominent altered biophysical properties commonly present in muco-obstructive lung diseases. However, it remains incompletely understood how these altered biophysical properties interact with the airway epithelium, which act as the first-line defense of the lung. Understanding the intricate dynamics between altered biophysical cues and the airway epithelium is essential to understanding the pathogenesis of muco-obstructive lung diseases.

This dissertation starts by delving into the impact of pathological osmotic pressure on airway basal cells, the airway stem cells responsible for differentiating into and replenishing injured or dead airway epithelial cells. Human bronchial epithelial cells (HBECs) are subjected to various osmotic pressures. Findings reveal that pathological osmotic pressure promotes airway basal cell migration, induces goblet cell metaplasia, and impairs ciliogenesis. These results shed light on how pathological osmotic pressure influences airway basal cell behavior and fate, offering insights into potential disease mechanisms.

Furthermore, this study moves on to investigate how the stiffness of the airway impacts epithelial cell activities. Traditional air-liquid interface (ALI) systems have fixed substrate stiffness and fail to mimic substrate stiffness. Therefore, a gel-ALI system is designed by coating the ALI insert with a hydrogel of tunable stiffness to model healthy and fibrotic lung tissues. Optimal gel thickness is determined to ensure nutrient transport and HBEC proliferation and differentiation. Notably, HBECs exhibit enhanced migration on hydrogel substrates matching fibrotic lung tissue stiffness. Thus, using the gel-ALI system, it is demonstrated that pathological substrate stiffness induces unjamming of the airway epithelium.

Lastly, to treat muco-obstructive pulmonary disease, effective drug delivery in the airway faces multiple barriers such as drugs retention in mucus, trapping in the periciliary space, and removal by mucociliary clearance. To enhance drug delivery, a bottlebrush polyethylene glycol (PEG-BB) nanocarrier is engineered to translocate across airway barriers. Designed with a densely grafted, anisotropic structure, PEG-BB nanocarriers penetrate endogenous airway mucus and periciliary brush layers through molecular structure enhanced endocytosis. These findings underscore the potential of large, wormlike bottlebrush PEG polymers as carriers for pulmonary and mucosal drug delivery, offering promise for therapeutic applications in lung diseases.