2024 AIChE Annual Meeting
(40b) Active Microrheology Method to Guide Mucoactive Agent Development
Author
Mucus viscoelasticity is determined by the underlying microstructure formed by the mucin polymer network, which is regulated by several factors including polymer concentration, density of covalent and physical bonds, and hydration. In airway diseases such as asthma and cystic fibrosis, mucus hypersecretion and dehydration results in thick, solid-like mucus that impairs transport, leading to mucus accumulation and blockage of the airway. Mucolytic drugs have been developed to reduce the viscoelasticity of the mucus gel. Reducing agents break down the disulfide bonds between mucins via thiol exchange chemistry. The most commonly used reducing agent drug is N-acetylcysteine; however, its clinical efficacy has been found to be limited due to low activity and a side-effect of bronchoconstriction. Novel reducing agents that are well-tolerated by human patients and effective at breaking down mucin crosslinks are in the process of being developed. Improved understanding of reducing agents effect on mucus material properties is needed to aid in the design of such drugs. Mucus-inspired hydrogels that capture aspects of the dynamic mucin network can help to elucidate the mechanisms of mucus rheology regulation in health and disease. We have demonstrated a magnetic microwire rheometer (MMWR) to measure the changes in material properties of dynamic hydrogels in response to agents that modulate disulfide-crosslinking. In this work, we use the MMWR to compare multiple reducing agents and characterize the degradation of disulfide crosslinked hydrogels as these agents diffuse through the network. While these reducing agents have been investigated via macrorheology methods, we show that the diffusion of these reagents, rather than mixing, into the hydrogel reveals key differences in degradation mechanisms that could have major implications for drug-delivery and efficacy in vivo.