Shedding new light on tissue mechanobiology with multimodal multiphoton nano-rheology microscopy

Mucosal tissues are essential components of our body. For example, in the lung, mucus provides a barrier that entraps foreign pathogens/nanoparticles and is moved into the oesophagus by coordinated ciliary beating of epithelial cells. Mucus viscoelasticity is crucial to this movement, and poor mucociliary clearance correlates with lung diseases. In the living tissue, mucus is changing in space and time, dynamically regulated by neighbouring cells which are heterogeneously organised. However, existing methods cannot measure mucus mechanics at the spatio-temporal scale relevant to nanoparticle transport, correlatively with the behaviour of the cell/tissue environment changing in real time. We propose to develop a transformative multiphoton-microscopy technology that measures mucus viscoelasticity by tracking the trajectories of individual nano-probes with unprecedented nanoscale precision, and correlatively maps the 3D structure and composition of living airway tissues with sub-cellular resolution and molecular chemical specificity. We will apply the technology to healthy and diseased tissues, in response to inflammatory triggers, infections and drugs. This research will unlock new discoveries on how mucus mechanics interconnects to cellular/molecular regulatory pathways, including airways remodelling/fibrosis which is a massive unmet medical need. Beyond the lung, our microscopy technology is applicable to any biofluid-tissue system, enabling wide-ranging discoveries to improve human health.