Dissertations and Theses
Date of Award
2025
Document Type
Dissertation
Department
Biomedical Engineering
First Advisor
Alessandra Carriero
Keywords
osteogenesis imperfecta, brittle bones, hearing loss, middle ear, ossicles, oim mouse model
Abstract
Hearing loss is a common yet understudied manifestation of osteogenesis imperfecta (OI), a hereditary disease of the connective tissues caused by mutations in collagen type I. The hallmark of OI is bone fragility, leading to frequent fractures in childhood that tend to decrease after puberty. Hearing loss in OI often begins in childhood and typically progresses with age. Affecting up to 94% of people with OI, hearing loss often presents bilaterally, and may affect the middle ear, inner ear, or both. No cure exists for OI or OI-hearing loss. While bisphosphonates remain the standard of care for OI, their effects on hearing are poorly understood. Treatments for OI-hearing loss are adapted from the general population but are often less effective. Despite the clinical burden, the mechanisms driving hearing loss in OI remain unknown.
The goal of this dissertation is to explore how collagen type I mutations affect the middle ear ossicles and hearing function. The central hypothesis of this study is that the bone fragility of OI extends to the middle ear ossicles, where poor bone matrix quality predisposes them to fractures and disrupts efficient sound transmission. Additionally, we propose that hearing loss in OI is exacerbated by mechanical stressors, ranging from routine masticatory forces to more acute events such as sudden pressure changes in the ear canal. Furthermore, we hypothesize that bisphosphonate treatment suppresses the abnormal bone remodeling in OI ossicles, preventing structural deterioration and preserving hearing function. To answer these questions, we used the oim/oim mouse model of severe OI type III, and applied synchrotron microtomography, second harmonic generation microscopy, Raman spectroscopy, nanoindentation, X-ray fluorescence microscopy, and auditory brainstem response tests.
Our findings show that while oim/oim ossicles show no alterations in tissue mechanics, composition and collagen fibers organization, they are brittle at the organ level, with thin regions of the malleus and incus highly prone to fracture upon minimal handling. The higher porosity observed in oim/oim ossicles likely contributes to their bone fragility. Additionally, this study found a higher prevalence of incudomalleal joint fractures and widening in oim/oim mice, suggesting that joint instability manifests in the oim/oim ossicular chain. Furthermore, this work determined that oim/oim ossicles are smaller; however, this size reduction does not affect function, as oim/oim mice exhibit hearing comparable to wild-type controls. When evaluating the effects of mechanical stressors, we found that the incudomalleal joint is highly susceptible to damage from acute pressure changes in the ear canal in both WT and oim/oim mice, with increased vulnerability in the oim/oim group. Nevertheless, pressure-induced joint damage did not affect hearing at the most sensitive tested frequencies. Additionally, abnormalities such as bone formations, incudal head fractures, and incudomalleal joint fusions were observed in both WT and oim/oim mice. These abnormalities did not result in functional hearing deficits unless they extended to the footplate, which was associated with frequency-specific hearing loss. Notably, footplate abnormalities were only observed in bisphosphonates-treated oim/oim and wild-type mice. Further studies are needed to determine whether these findings translate to human OI ossicles.
Recommended Citation
Ugarteburu Azcarate, Maialen, "Understanding Hearing Loss in Osteogenesis Imperfecta" (2025). CUNY Academic Works.
https://academicworks.cuny.edu/cc_etds_theses/1252
