Airway Mucus Rheology: Physical Insights for Navigating through Health to Pathology and Clinical Applications

TL;DR

This review addresses how airway mucus rheology governs mucociliary clearance and how disease alters this rheology, contributing to airway obstruction and infection. It synthesizes macrorheology and microrheology across physiological and pathological states, covering measurement techniques (SAOS, LAOS, creep, extensional rheology) and microrheology methods (PTM, FRAP, OT, MT, LF-NMR, microfluidics). Key contributions include detailing how mucus composition (notably MUC5AC/MUC5B and DNA/actin networks) shifts viscoelastic properties, illustrating the impact on clearance and drug delivery, and highlighting the potential of rheology-based diagnostics and therapeutics. The practical significance lies in informing mucolytic strategies, nanoparticle drug design, and device-based treatments, while acknowledging substantial challenges in sample variability, measurement standardization, and clinical translation. Integrating insights across length scales offers a path toward better diagnosis, treatment, and management of chronic respiratory diseases.

Abstract

Airway mucus is a complex gel with an anisotropic three-dimensional network structure. As a crucial component of the respiratory defense barrier, it plays a vital role in maintaining airway hydration and supporting the function of airway epithelial cells. Through linear and nonlinear rheological mechanisms such as ciliary motion and coughing, airway mucus expels foreign pathogens and toxic nano- and microparticles while selectively allowing the passage of specific nutrients and proteins. These protective and clearance functions depend on the proper rheological properties of mucus under normal physiological conditions. However, in respiratory disease such as CF, COPD, asthma, and COVID-19, excessive mucus secretion is often accompanied by abnormal rheological behaviors. This leads to impaired mucus flow, airway obstruction, and potentially life-threatening conditions. Therefore, this review examines the rheological behaviors of airway mucus in relation to health and disease, focusing on both macrorheology and microrheology. The review highlights those changes in the chemical composition and microstructure of airway mucus, especially under pathological conditions, that can significantly alter its rheological behavior. Rheological parameters can also serve as biological indicators to study the role of mucus in clearance functions and aid in developing pulmonary drug delivery systems. By integrating findings from both macro- and microrheological studies, this review aims to enhance our understanding of the complex behavior of airway mucus, supporting better diagnosis, treatment, and management of chronic respiratory diseases.

Figures (17)

• Figure 1: (a) Healthy mucociliary clearance system, (b) impaired mucociliary clearance system, (c) synchronous metachronal movement of cilia, (d) vicious cycle during pathological progress.
• Figure 2: Schematic of airway and mucus in normal and pathological state. (a) Macro to micro airway structure, (b) mucus in normal airway state, (c) mucus in pathological airway state.
• Figure 3: Shear rate dependence of airway mucus viscosity in various conditions. (a) Undiluted CF sputum, adapted from Suk_2009. (b) COPD mucus, adapted from Jory_2022. (c) 2.5 HBE mucus, adapted from Vasquez_2016. (d) Simulated normal (NM) and asthmatic (AM) mucus with 5-mode Giesekus fitting, adapted from Liu_2024.
• Figure 4: Hysteresis loop of shear rate and shear stress obtained through stress ramp-up and -down methods. (a) CF sputum adapted from Tomaiuolo_2014. (b) 2 Actigum™ solution, as simulated airway mucus adapted from Lafforgue_2017a.
• Figure 5: Compliance of airway mucus during creep and recovery experiments. (a) CF sputum, a constant stress (0.7, 3, 6 Pa) applied at 100s and removed at 400s, with strain recovery monitored over the subsequent 600s , adapted from Nielsen_2004. (b) Synthetic normal and asthmatic airway mucus (NM, AM), 1Pa stress applied at 0s, and removed at 600s, with strain recovery monitored over the subsequent 900s, adapted from Liu_2024. (c) Frequency-dependent elastic and viscous moduli ($G’, G"$) for human bronchial epithelial (HBE) mucus, adapted from Tang_2021. (d) Yield stress of mucus from healthy individual in creep test, illustrating strain as a function of time under applied stress, adapted from Jory_2022.