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Hair cells are transducers found found in the inner ear of vertebrates. They convert a mechanical signal, detected by the deflection of a bundle of cilia extending from their top surface, into an electrochemical signal. This dissertation studies the mechanical influence of the structure and materials on the function of the cells. I introduce two methods to conduct the mechanical analysis. The first uses strength of materials formulae to solve the simplified hair cell bundle models. The second is a finite element analysis, used to better account for the observed complexity of the structure. I then use these two techniques to build a fundamental understanding of the hair cell bundle structure. By first studying simplified models, then adding complexity, the effects of geometric and material variation can be deduced. I then study three actual bundles. These are all taken from vestibular organs of turtles, two from the posterior semicircular canal and one from the utricle. I present estimations of stiffness, tip link tensions, and nonlinear response. Finally, I investigate a single cilium forced by a fluid flow. The problem is solved by finite difference technique. Three different initial conditions are solved. / Ph. D.

This research details the creation and characterization of a new biomimetic artificial inner hair cell sensor in an artificial cochlear environment. Designed to mimic the fluid flows around the inner hair cells of the human cochlea, the artificial cochlear environment produces controlled, linear sinusoidal fluid flows with frequencies between 25 and 400 Hz. The lipid bilayer-based artificial inner hair cell generates current through changes in the bilayer's capacitance. This capacitance change occurs as the sensor's artificial stereocilium transfers the force in the fluid flow to the bilayer. Frequency tuning tests are performed to characterize the artificial inner hair cell's response to a linear chirp signal from 1 to 400 Hz. The artificial inner hair cell's response peaks at a resonant frequency of approximately 83 Hz throughout most of the tests. Modelling the artificial stereocilium as a pinned free beam with a rotational spring at the pinned end yields a rotational spring stiffness of 177*10^-6 Nm/rad. Results with 0 mV potential applied across the bilayer indicate that current generation at 0 mV likely comes from other sources besides the bilayer. Increasing the voltage potential increases the broadband power output of the system, with an approximately linear relationship. A final test keeps the fluid flow frequency constant and varies the fluid velocity and applied voltage potential. Manipulation of the applied voltage potential results in a fluid velocity to RMS current relationship reminiscent of the variable sensitivity of the human cochlea. / Master of Science

Computational fluid dynamics and finite element analysis were employed to study vestibular hair cell bundle mechanics under physiologic stimulus conditions. CFD was performed using ANSYS CFX and FEA utilized a custom MATLAB model. Nine varieties of hair cell bundles were modeled using tip-forcing only (commonly used experimentally), fluid-flow only (physiologic for free-standing bundles), and combined loading (physiologic for bundles with tip attachments) conditions to determine how the bundles behaved in each case. The bundles differed in the heights of their components, their length and width, and their number of steriocilia. Tip links were modeled to determine ion-channel opening behavior. Results show that positive pressures, negative pressures, and shear stresses on the exterior of the bundles are of comparable magnitude. Under combined loading, some bundles experienced very high suction pressures on their interior. The bundles with tall steriocilia are hindered by the endolymph while those with short steriocilia and much taller kinocilia are assisted by the fluid flow. Each bundle type has a different range over which it is most sensitive so that the bundles cumulatively cover a very large range of stimuli; the order in which bundles respond from smallest stimulus magnitude to largest is free-standing extrastriolar bundles, attached striolar bundles, attached extrastriolar bundles, and free-standing extrastriolar bundles. A short examination of off-axis loading shows that the prevailing theory suggesting that bundle response is proportional to the cosine of the angle between the stimulus direction and the bundle's direction of maximum excitation is incorrect. / Ph. D.

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<p>Age-related hearing loss is an acute health problem affecting people worldwide, often arising due to defects in the proper functioning of sensory hair cells in the inner ear. The apical surface of sensory hair cells contains actin-based protrusions known as stereocilia, which detect sound and head movements. Since hair cells are not regenerated in mammals, it is important to maintain the functioning of stereocilia for the life of an organism to maintain hearing ability. The actin filaments within a stereocilium are extensively crosslinked by various actin crosslinking proteins, which are important for stereocilia development and maintenance. Multiple studies have shown that the stereocilia actin core is exceptionally stable whereas actin is dynamic only at the tips of stereocilia. However, whether the actin crosslinking proteins, which are nearly as abundant as actin itself, are similarly stable or can freely move in and out of the core remains unknown. Loss or mutation of crosslinkers like plastin-1, fascin-2, and XIRP2 causes progressive hearing loss along with stereocilia degeneration while loss of espin prevents stereocilia from even developing properly. Do these phenotypes stem from an unstable stereocilia core? Does crosslinking confer stability to the core? To address these questions, we generated novel transgenic reporter lines to monitor the dynamics of actin in mice carrying fascin-2R109H mutation and espin null mice and also to study the dynamics of actin crosslinkers, in vivo and ex-vivo. We established that actin crosslinkers readily exchange within the highly stable F-actin structure of the stereocilia core. In addition, we determined that stereocilia degeneration in mice carrying fascin-2R109H mutation and espin null mice could possibly occur due to a less stable actin core. These studies suggest that dynamic crosslinks stabilize the core to maintain proper stereocilia functioning. Future work warrants understanding the reason behind the importance of dynamic crosslinks within a stable stereocilia core. Actin stability not only depends on actin crosslinkers, but also on actin filament composition as evident from distinct stereocilia degeneration and progressive hearing loss patterns in hair-cell specific knockout of actin isoforms. Although beta- and gamma- actin polypeptide sequences differ by only 14 four amino acids, whether the latter determine the unique function of each cytoplasmic actin isoform was previously unknown. Here we determined that these four critical amino acids determine the unique functional importance of beta-actin isoform in sensory hair cells. Taken together, our study demonstrates that actin cytoskeletal proteins are important for the morphogenesis and</p> <p>maintenance of stereocilia.</p>