Biology subjects

O'Malley, J. T.

Publications and source records attributed to O'Malley, J. T..

4 recordsLinked to original sources

bioRxiv2025

Anatomical integrity of the human cochlea estimated with optical coherence tomography for future clinical application

The human cochlea is encased within the otic capsule, the densest bone in the body, posing significant challenges for anatomical imaging of cochlear structures. Because of difficult access and fragility of cochlear structures, our understanding of intracochlear anatomy has historically relied on postmortem histology. We thus have a limited understanding of human cochlear anatomy in its native, unfixed state. Clinical diagnostics for hearing loss, such as audiometry and otoacoustic emissions, offer functional assessments but fail to elucidate the often diverse underlying structural pathologies with any degree of precision. To address the critical need for assessing the human cochlear anatomy and associated pathologies without the risk of traumatizing cochlear structures, we imaged fresh cochleae in situ soon after death through the intact round window membrane with Optical Coherence Tomography (OCT) without inserting instruments inside or opening the cochlea. Micron-resolution OCT cross-sectional images of the human intracochlear structures were acquired and compared with corresponding histology systematically to aid in the identification of fine structural features and possible pathologies. With OCT imaging, we observed varied anatomy of the organ of Corti, and developed a cochlear "integrity" rating system to differentiate healthy appearing cochleae from various pathological states. These results demonstrate the capability of OCT to non-traumatically visualize cochlear integrity, highlighting its potential as a diagnostic tool. This work shows promise in translating the ability to determine the likelihood of existing or lack of hair cells and supporting cells in live patients, which would enable appropriate targeted treatments.

physiology↗

bioRxiv2025

Integrated Histology and Molecular Profiling of Postmortem Human Auditory and Vestibular Organs via a Poly(Methyl Methacrylate)-Based Workflow

Hearing and balance disorders are the most prevalent sensory impairments, affecting hundreds of millions worldwide, yet their underlying cellular and molecular pathologies remain poorly understood. This knowledge gap stems from the inaccessibility of the ears sensory organs--embedded within the temporal bone (TB), the hardest bone in the body--which cannot be biopsied in living patients without causing irreversible damage. Conventional histopathology workflows rely on postmortem en bloc extraction of TBs, followed by lengthy decalcification, celloidin embedding, and manual serial sectioning of these large specimens--a process that takes one to two years, is labor- and cost-intensive, and lacks compatibility with most modern protein, DNA, and RNA assays. Here, we present a rapid, reversible polymethyl methacrylate (rPMMA) workflow that enables advanced molecular histopathology studies on formalin-fixed, calcified TBs. Our protocol uses low-temperature (-40 {degrees}C to +4 {degrees}C) resin embedding, precision near-serial sectioning (10-50 {micro}m) via femtosecond laser microtomy or precision diamond wire sawing, and subsequent deacrylation to fully restore tissue accessibility for high-fidelity histomorphology, multiplexed immunofluorescence, whole-genome sequencing, and in situ mRNA detection (RNAscope) assays. Compared to the gold-standard celloidin workflow, our method reduces processing time and costs by approximately 90% while integrating equivalent histomorphology with advanced molecular assays, providing a new benchmark for multidimensional studies in human hearing and balance pathologies.

pathology↗

bioRxiv2025

Hyperplastic Growth, Not Hydrostatic Distension, in Endolymphatic Hydrops in Humans Challenges the Classic View of Meniere's Disease

Menieres disease (MD), a degenerative inner ear disorder, is characterized by debilitating episodic vertigo "attacks" and hearing fluctuations, progressing to permanent sensory impairment. The prevailing dogma attributes these symptoms to an abnormal inner ear fluid buildup--known as endolymphatic hydrops (EH)--with concomitant rise of fluid pressure and repetitive microtrauma to sensory epithelia. However, this pressure-based mechanism lacks direct experimental evidence and fails to explain key clinical aspects of MD--exposing a critical gap in our disease understanding. To revisit the fundamental nature of EH, we performed 3D reconstructive, machine-learning-enhanced histological analyses and immunohistochemistry on human postmortem inner ear specimens. Contrary to the classic theory, EH-affected epithelia showed no signs of pressure-induced change. Instead, we observed an up to four-to seven-fold increase in epithelial cell number (hyperplasia) in both early and advanced EH stages. Quantification of the hyperplastic epithelial surface area, as well as immunohistochemical localization of key fluid homeostasis-associated proteins in the hyperplastic epithelium suggest this epithelial hyperplasia may actively compensate for cell loss in the endolymphatic sac, a key site of MD pathology. These findings challenge the conventional view of EH as solely a pathological pressure phenomenon, instead revealing an unexpected massive cellular expansion of these epithelia, consistent with a coordinated compensatory cellular response aimed at preserving inner ear fluid homeostasis and function in a compromised environment. This paradigm shift introduces dual beneficial and detrimental roles for EH, and suggests new therapeutic avenues for MD focused on promoting compensatory tissue repair while preventing maladaptive remodeling. Significance StatementFor over a century, the leading explanation for Menieres disease--a debilitating inner ear disorder causing vertigo and hearing loss--has been a buildup of fluid and pressure in the inner ear, analogous to conditions like glaucoma. However, this long-held theory has never been directly proven, and treatments based on reducing this supposed pressure have shown limited success. Our research challenges this traditional view, revealing that the expansion of endolymphatic spaces is not primarily a fluid pressure problem, but secondary to a complex cellular response. This fundamental shift in understanding Menieres disease opens new avenues for developing effective therapies to prevent and treat hearing loss and vertigo attacks.

neuroscience↗

bioRxiv2023

Supporting-cell vs. hair-cell survival in the human cochlea: Implications for regenerative therapies

Animal studies have shown that the supporting-cells surviving in the organ of Corti after cochlear insult can be transdifferentiated into hair cells as a treatment for sensorineural hearing loss. Clinical trials of small-molecule therapeutics have been undertaken, but little is known about how to predict the pattern and degree of supporting-cell survival based on audiogram, hearing loss etiology or any other metric obtainable pre-mortem. To address this, we systematically assessed supporting-cell and hair cell survival, as a function of cochlear location in 274 temporal bone cases from the archives at the Massachusetts Eye and Ear and compared the histopathology with the audiograms and hearing-loss etiologies. Results showed that supporting-cell survival was always significantly greater in the apical half than the basal half of the cochlea, that inner pillars were more robust than outer pillars or Deiters cells, and that total replacement of all supporting cells with a flat epithelium was rare outside of the extreme basal 20% of the cochlea. Supporting cell survival in the basal half of the cochlea was better correlated with the slope of the audiogram than with the mean high-frequency threshold per se: i.e. survival was better with flatter audiograms than with steeply down-sloping audiograms. Cochlear regions with extensive hair cell loss and exceptional supporting cell survival were most common in cases with hearing loss due to ototoxic drugs. Such cases also tended to have less pathology in other functionally critical structures, i.e. spiral ganglion neurons and the stria vascularis. HighlightsO_LISupporting cell survival was systematically assessed in 274 human cochleas C_LIO_LISupporting cell survival was better with flat than with down-sloping audiograms C_LIO_LISupporting cell survival was most robust when hearing loss was from ototoxic drugs C_LIO_LIOtotoxic cases also showed less pathology in other critical cochlear structures C_LIO_LIThe data can inform clinical trials for regeneration via supporting cell conversion C_LI

neuroscience↗