Feature of the Week 05/14/2017: Real-Time Monitoring of Mucus Thinning Treatments using Diffusion-Sensitive Optical Coherence Tomography
The airway epithelium is coated with a biopolymeric mucus gel which is responsible for trapping inhaled environmental contaminants that are subsequently removed by mucociliary clearance (MCC). MCC is disrupted under high mucus wt%, causing mucus stagnation, chronic infection and inflammation. Normal mucus hydration by the epithelium is impaired in cystic fibrosis (CF) and COPD resulting in high mucus wt% that leads to halted MCC. Hypertonic saline (HS) treatment is a therapeutic approach to reduce mucus wt% for sustained MCC that has gained popularity due to its relative safety, easy administration, and low cost. However, patient to patient variability, conflicting therapeutic results, and modest global daily improvements in HS therapy suggest the need for better outcome metrics to predict treatment efficacy, aid in the development of improved drug therapies, and enhance precision medicine approaches.
We present a new quantitative method for sensing mucus wt%, diffusion sensitive optical coherence tomography (DS-OCT), that employs gold nanorods (GNRs) to provide real-time measures of respiratory treatment efficacy. DS-OCT uses dynamic light scattering with low coherence interferometry to provide rapid (< 0.2 s) and depth-resolved (4.7 µm) diffusion measurements of gold nanorods (GNRs). Short measurement times of GNR diffusion are achievable due to the small size of the GNRs (~88 × 27 nm) exhibiting a rapid dynamic light scattering signal, and due to ensemble averaging of several particles in a single measurement (10-100 GNRs per coherence volume). Polarized OCT signals from GNRs are easily distinguishable from those of mucus by their shape-dependent optical anisotropy, which we have tuned to exhibit longitudinal and transverse surface plasmon resonances inside and outside of the OCT system wavelength bandwidth (740-860 nm), respectively. The ensemble-averaged translational GNR diffusion (DT), resolved within ~3 coherence volumes, is found and from the co- and cross-polarized light backscattered from GNRs within mucus. GNRs are slowed by intermittent collisions with mucins, making DT is sensitive to the mucus mesh – a measure of mucus wt% – on the size scale of the GNR hydrodynamic diameter (~46 nm). This allows for direct monitoring of changes in DT that are sensitive to nanoporosity with spatial and temporal resolutions of 4.7 µm and 0.2 s. DS-OCT therefore enables us to measure spatially-resolved changes in mucus wt% over time.
In this study, we first established GNR diffusion rates as a robust metric for measuring mucus wt% in both stationary and transporting mucus on human bronchial epithelial cultures (HBEC), and defined a calibration curve used to predict wt% from GNR diffusion measurements. We then used standard OCT to observe the effects of saline treatment on HBEC. Finally, we employed DS-OCT to quantify mucus wt% in real-time during treatment. We demonstrated the applicability of DS-OCT on HBEC during HS treatments to reveal, for the first time, mucus mixing, cellular secretions, and mucus hydration on the micrometer scale that translate to long-term therapeutic effects. In summary, DS-OCT is a previously unavailable assessment tool that enables real-time monitoring of pulmonary disease treatments, taking a critical step toward developing personalized treatments in the clinic.
For more information see recent Article. Courtesy Richard Blackmon from University of North Carolina.