We propose to develop a novel nanorheology platform to simultaneously map mucus viscoelasticity and mucus flow in situ. Increase in airway mucus complex viscoelastic shear modulus (G*) hinders mucus clearance and is associated with respiratory diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). In the short term, this new platform will provide a more complete biophysical picture of mucociliary clearance and enable better models, leading to new treatment paradigms. In the long term, this platform may be translatable to in vivo mucus monitoring for assessment of disease progression and therapeutic interventions. Our nanorheology platform is based upon dynamic light scattering (DLS) from plasmonic gold nanorods (GNRs) monitored using optical coherence tomography (OCT). Specifically, the cross-polarized light scattering signal from GNRs provides information about their rotational diffusion rate, which is related through a generalized Stokes-Einstein relationship to the G* of the mucus. GNRs are advantageous as rheological probes because their high anisotropy and plasmon-resonance provides a unique optical signal against endogenous mucus light scatterers, and their small size provides a fast rotational DLS signal which allows for more rapid collection of rheological data. Importantly, OCT provides depth-resolved DLS measurements of GNR diffusion, which will enable spatial mapping of heterogeneities in mucus G*, particularly as a function of distance from the periciliary layer. By linking these measurements with OCT- based tracking of mucus flow, it will provide a more complete biophysical picture of mucociliary clearance.
Our first aim i s to validate the DLS-OCT nanorheology technique in controlled complex fluids against standard bead microrheology and bulk rheology. Subsequently, we will validate this technique using non- muco-adherent GNRs in mucus harvested from human bronchi-epithelial (hBE) cultures, and evaluate the response as a function of % solids.
Our second aim i s to employ DLS-OCT to monitor flowing mucus in normal and CF-like hBE model systems, using GNRs delivered by nebulization. We will associate measurements of G* with flow rate measured by speckle-tracking in OCT as a function of distance from the periciliary layer. In addition, we will determin the ability for OCT to monitor ciliary function during simulated hypertonic saline therapy and induced collapse and revival of ciliary activity in these models. By the completion of this study we will have validated DLS-OCT nanorheology against micro- and bulk rheology techniques, and established the sensitivity for mapping G* and quantifying % solids in a flowing mucus system, which will poise the technology for future in vivo studies in murine models of cystic fibrosis.
We propose to develop a new technology to measure the mechanical properties of airway mucus with high resolution in order to better understand mucus thickening in respiratory diseases. This has relevance for chronic obstructive pulmonary disease and cystic fibrosis, and may lead to better methods to diagnose and assess disease progression, as well as for monitoring therapy and developing better methods for drug delivery.
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