Three-dimensional and Multiscale Organ of Corti Biomechanics

描述（由申请人提供）：我们的长期目标是了解支持正常听力的高灵敏度、高频率分辨率和非线性特性的耳蜗机制，这将允许对由各种耳蜗病理、当前干预或未来干预（如耳蜗亚结构再生）引起的这些结构变化进行功能表征。我们的方法是开发基于物理的三维动态计算模型，将新的和现有的关于耳蜗结构和特性、Corti器官结构的尺寸和几何形状以及周围细胞和流体环境特征的信息整合到以前未实现的详细程度。渐近方法和数值方法相结合，可以实现非常快速和有效的计算。大约80个几何参数和材料特性将用于定义耳蜗结构的全面横截面，包括骨架和雷氏膜的毫米尺度，毛细胞体的微米尺度，以及纤毛尖端链接的纳米尺度。这种方法对于整合和理解包括我们在内的几个实验室报告的越来越精确的微观解剖学测量，解释这些结构的动态生物力学相互作用和解决现有问题是必要的。在第一个目标中，将充分考虑线性效应（包括行波的结合）和非线性效应（包括外毛细胞的电运动性的结合）。第二个目标是利用这种建模能力来研究骨传导信号对耳蜗的反应。尽管骨传导刺激在几乎所有耳鼻喉科诊所中都很重要，但目前尚无广泛接受的理论，最近的测量结果难以根据现有理论进行解释，并且之前没有建立基于物理的计算模型。因此，这项建议的完成将构成核心基础，有望从根本上改变我们对耳蜗功能、病理和干预的理解。该结果将适用于理解遗传操作对Corti细胞结构器官的生物力学效应，并提高对高噪声环境中正常听力保护不足的耳蜗骨传导途径的理解。

DESCRIPTION (provided by applicant): Our long-term goal is to understand the cochlear mechanisms that support the high sensitivity, high frequency resolution, and non-linear properties of normal hearing, which will then allow functional characterization of changes to these structures arising from a variety of cochlear pathologies, or from current interventions, or from future interventions such as regeneration of cochlear sub structures. Our approach is to develop physically based, three-dimensional, dynamic computational models that incorporate new and existing information on cochlear structures and properties, dimensions and geometry of structures in the organ of Corti and characteristics of the surrounding cellular and fluid environment to a degree of detail not previously achieved. Asymptotic and numerical methods will be combined for very fast and efficient calculations. Some eighty parameters of geometry and material properties will be used to define a comprehensive cross section of the cochlear structures, including the millimeter scale of the bony shelf and Reissner's membrane, micrometer scale of hair cell soma, and the nanometer scale of the tip links of cilia. This approach is necessary to integrate and understand the increasingly precise microanatomy measures reported by several laboratories including ours, to explain the dynamic biomechanical interaction of these structures and to resolve existing questions. In the first aim, a full model consideration will be given to linear effects including the incorporation of traveling waves and non-linear effects, including incorporation of electromotility of the outer hair cells. The second aim will be to use this modeling capability to investigate cochlear responses from bone conduction signals. Despite the importance of bone conducted stimulation in nearly all otolaryngology clinics, no current theory is widely accepted, recent measurements are difficult to interpret in light of existing theory, and no physically-based computational model has previously been made. The completion of this proposal will therefore form the core foundation that is expected to fundamentally alter our understanding of cochlear function, pathology and intervention. The results will be applicable to understanding the biomechanical effects of genetic manipulations of the organ of Corti cytoarchitecture and improving understanding of bone-conduction pathways to the cochlea in high noise environments where normal hearing protection is inadequate.