Mechanical force-induced tissue remodelling in a clinically relevant microphysiological model of asthmatic human lungs.

Abstract

Structural remodelling of living tissues due to mechanical forces is a common occurrence that plays an essential role in development, health and disease, but preclinical investigation of this dynamic process in human-relevant conditions remains a challenge. Here we present a microphysiological system integrated with pneumatically addressable soft actuators to emulate dynamic mechanical loading of mucosal tissues in the human respiratory tract. Using this system, we created a clinically relevant model of airway constriction in distal regions of asthmatic lungs to show compressive force-induced fibrotic airway remodelling. Following in vivo validation, we generated vascularized airway constructs in this model to investigate abnormal vascular remodelling in asthma, revealing airway constriction-induced subepithelial fibrosis as a key contributor to increased vascularity of asthmatic airways. Furthermore, we identified molecular mediators of abnormal airway remodelling through proteomics analysis of our microphysiological system and tested the feasibility of pharmacologically modulating their activity. We believe that our technology provides a useful tool for studying biophysical control and dysregulation of dynamic tissue remodelling in lungs and other mechanically active organs.