Endoscopic µOCT/DµOCT for Identification and Characterization of Human Olfactory Epithelium In Vivo - Loss of sense of smell is an under-recognized condition that affects approximately 10% of the population. Beyond the inability to sense odors, there is a considerable negative impact on quality of life, nutrition, and safety due to a suppressed ability to detect hazards such as smoke, natural gas, and spoiled food. Olfactory loss is also a feature of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), which show characteristic changes in the olfactory epithelium (OE) prior to symptom onset, making the OE a prime candidate for early detection when treatments are most likely to be effective. Unfortunately, human olfactory mucosa remains a “black box” clinically and from a research standpoint. The OE, which contains the crucial olfactory sensory neurons (OSNs), is indistinguishable from surrounding respiratory epithelium (RE) and from regions of neuronal loss due to injury or age. This inability to identify the OE limits diagnostic and prognostic information for patients presenting with smell loss, prevents accurate biopsy sampling, and confounds both research and patient care. Micro-optical coherence tomography (µOCT) provides high-resolution cross-sectional imaging of nasal RE and its surface ciliary activity, offering a way to differentiate RE from the non-motile cilia of the OE. Previously, we developed an intranasal µOCT probe and demonstrated visualization of ciliated RE in awake, unsedated human subjects, showing differences between cystic fibrosis patients and controls. More recently, we developed dynamic µOCT (DµOCT), which acquires repeated images at the same site to reconstruct frequency signatures of intracellular motion, a proxy for metabolic activity. Early results with 2D and 3D DµOCT in mouse and human olfactory clefts ex vivo show the ability to visualize OE morphology, including ducts, motile versus non-motile cilia, OSNs and their dendrites, and neuronal OE vs. aneuronal OE from functional dynamic contrast. Preliminary data suggest that DµOCT may also be sensitive to neuronal activation, raising the possibility of real-time functional readouts of OSN activity. Here, we propose to advance µOCT/DµOCT by: (1) determining its capacity to distinguish OE from RE with manual and AI algorithms; (2) demonstrating DµOCT visualization of OSN activation; (3) developing a robotically stabilized probe that snaps onto a Hopkins endoscope for image-guided biopsy or detaches for olfactory cleft scanning; and (4) validating this technology for OE discrimination and OSN surface area quantification in patients with smell disorders. “Seeing is believing.” This research will, for the first time, allow clinicians and scientists to view both the structure and function of human OE in real time with a label-free, minimally invasive technique in vivo, propelling the field forward with major implications for understanding olfactory disease, managing smell loss, and enabling early diagnosis of neurodegenerative disease.
