Short-Wave Infrared Fluorescence Chemical Sensor for Detection of Otitis Media

Abstract

Otitis media (OM) or middle ear infection is one of the most common diseases in young children around the world. The diagnosis of OM is currently performed using an otoscope to detect middle ear fluid and inflammatory changes manifested in the tympanic membrane. However, conventional otoscopy cannot visualize across the tympanic membrane or sample middle ear fluid. This can lead to low diagnostic certainty and overdiagnoses of OM. To improve the diagnosis of OM, we have developed a short-wave infrared (SWIR) otoscope in combination with a protease-cleavable biosensor, 6QC-ICG, which can facilitate the detection of inflammatory proteases in the middle ear with an increase in contrast. 6QC-ICG is a fluorescently quenched probe, which is activated in the presence of cysteine cathepsin proteases that are up-regulated in inflammatory immune cells. Using a preclinical model and custom-built SWIR otomicroscope in this proof-of-concept study, we successfully demonstrated the feasibility of robustly distinguishing inflamed ears from controls (p = 0.0006). The inflamed ears showed an overall signal-to-background ratio of 2.0 with a mean fluorescence of 81 ± 17 AU, while the control ear exhibited a mean fluorescence of 41 ± 11 AU. We envision that these fluorescently quenched probes in conjunction with SWIR imaging tools have the potential to be used as an alternate/adjunct tool for objective diagnosis of OM.

Fluorescence Imaging of Inflammation with Optical Probes

“…When the probe enters the lysosome, the latent lysosomotropic effect will result in fluorophore retention in the lysosome upon cleavage by cysteine cathepsins and detection by fluorescence otoscopy. Reproduced with permission from ref . Copyright 2020 American Chemical Society.…”

“…Traditional otoscopy cannot see the sample of tympanic membrane or middle ear fluid, leading to low diagnostic certainty of OM . Based on the characteristics of high expression of cathepsin in the process of otitis media, Valdez and co-workers designed a biosensor, 6QC-ICG, that can detect the degree of otitis media inflammation by conjugating a fluorescent quenching agent to ICG through a short peptide that can be cleaved by cathepsin (Figure d) . Using a preclinical model and custom-built short-wave infrared otomicroscope, they successfully distinguished inflamed ears from normal ears with 6QC-ICG.…”

Activity-Based Diagnostics: Recent Advances in the Development of Probes for Use with Diverse Detection Modalities

“…(C) 6QC is specifically activated upon LPS-induced inflammation in a murine ear infection model. Image reprinted from ref . Copyright 2020 American Chemical Society.…”

“…As an alternative to LUM015, a cathepsin-activated fluorescent peptide, 6QC (Figure B), with reduced overall size compared to LUM015, was shown to be an effective preclinical agent for imaging of a range of disease states associated with elevated cathepsin activity, such as inflammation in middle-ear infections (Figure C). , Additionally, the 6QC probe is compatible with the clinically approved da Vinci optical guided surgical system . Though the preclinical results are promising, high levels of active cathepsin activity in healthy organs such as the liver and kidneys result in a high background signal, thus potentially limiting the contrast that can be obtained with the 6QC probe in some types of cancer.…”

Low dark current lateral Ge PIN photodetector array with resonant cavity effect for short wave infrared imaging

“…Short-wave infrared (SWIR) imaging has a wide range of prospective applications in industrial inspection [1,2], medical diagnosis [3,4], military reconnaissance [5,6], and other fields thanks to its remarkable detection capabilities including high resolution, high sensitivity, all-weather adaptability, and shimmer night vision. In particular, SWIR imaging, especially at * Authors to whom any correspondence should be addressed.…”