Mass transport in the inner-ear fluid

内耳液体中的质量运输

• 批准号: 10580498
• 负责人: Jong-Hoon Nam
• 金额: $ 54万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580498
• 关键词: Acoustic Stimulation; Acoustics; Adult; Agitation; Animals; Apical; Area; Biophysics; Blood; Body Fluids; Characteristics; Cochlea; Cochlear duct; Cochlear nucleus; Computer Models; Custom; Data; Diffusion; Disease; Distant; Drug Delivery Systems; Drug Targeting; Electric Stimulation; Electrodes; Experimental Designs; Fluid Balance; Frequencies; Gene Delivery; Geometry; Gerbils; Goals; Health; Hearing; Hour; Image; Implant; In Vitro; Individual; Inherited; Injections; Kainic Acid; Labyrinth; Learning; Length; Liquid substance; Location; Lymph; Measures; Mechanical Stimulation; Mechanics; Methods; Microfluidics; Modeling; Molecular; Motion; Neurotoxins; Noise; Noise-Induced Hearing Loss; Operative Surgical Procedures; Optical Coherence Tomography; Outer Hair Cells; Pattern; Perforation; Pharmaceutical Preparations; Phase; Physiological; Public Health; Pump; Quality of life; Radial; Resolution; Rest; Salicylic Acids; Sensorineural Hearing Loss; Series; Site; Source; Stimulus; Structure; Temporal bone structure; Testing; Time; Tissues; United States; age related; base; cell motility; design; experimental study; gene therapy; hearing impairment; improved; in silico; in vivo; inner ear diseases; innovation; insight; mechanotransduction; minimally invasive; models and simulation; neural; novel; physiologic model; prevent hearing loss; response; round window; sound; sound frequency; surgical risk; theories; vibration; virtual

PROJECT SUMMARY The inner-ear fluids, unlike other body fluids, are stationary and isolated from the rest of the body. These characteristics give opportunities and challenges in maintaining inner-ear health and in treating inner- ear diseases. Due to the blood-labyrinth barrier, systemic delivery of drugs to the inner ear is highly inefficient. On the other hand, this isolation is an opportunity—drugs can be delivered locally with minimal off-target concerns. Unfortunately, the potential advantage of local delivery has been difficult to capitalize on because of the labyrinthine geometry of the inner ear. Application of drug at any location of the inner ear labyrinth filled with stationary fluids results in high concentration at the application site without reaching distant locations. A current remedy is to create surgical holes in the temporal bone to allow inner-ear fluids to flow despite the risk of surgical damage. We propose minimally invasive and efficient drug delivery mechanism into the inner ear. Specifically, we will develop a method to use sounds as the agitating source for cochlear drug delivery. Recent data regarding OoC micromechanics are both exciting and controversial because new observations do not fit well into existing frameworks for cochlear biophysics. For example, the outer hair cells are widely-acknowledged as the actuator for cochlear amplification. However, the outer hair cells generate force most efficiently at frequencies below the characteristic frequency at most cochlear locations, raising the possibility of additional functions. The proposed project combines two topics that have previously been investigated independently—mechanics and fluid homeostasis of the OoC. By combining these two subjects, we propose the novel hypothesis that active outer hair cells enhance mass transport along the cochlea. We will test the hypothesis with three aims that combine physiological and computational modeling approaches. For Aim 1, experiments in live animals (gerbil) will be used to characterize the effect of sound and outer-hair-cell motility on mass (neurotoxin) transport along the length of the cochlear duct. Aim 2 experiments will use excised cochlear tissues implanted in a novel micro-fluidic chamber to characterize the OoC peristaltic vibrations due to outer-hair-cell motility. For Aim 3, new biophysical computer models will simulate drug delivery along the cochlea, thereby integrating physiological results from Aims 1 and 2. Approximately one out of five adults in the United States has some degree of hearing loss. Multiple common forms of hereditary, age-related, and noise-induced hearing loss are ascribed to malfunctions of cochlear-fluid homeostasis. By investigating cochlear-fluid homeostasis from an innovative point of view (mechanics), this project will provide an explanation on why hearing of high frequency sound is more vulnerable. In the long term, we have ambition to provide a remedy to delay/prevent hearing losses related to fluid-homeostasis.

项目摘要 与其他体液不同，内耳液体是静止的，与身体的其他部分隔离。 这些特点为保持内耳健康和治疗内耳疾病带来了机遇和挑战。 耳疾病。由于血迷路屏障，药物向内耳的全身递送是非常低效的。 另一方面，这种隔离是一个机会-药物可以在最小脱靶的情况下在当地输送 性问题不幸的是，当地交付的潜在优势一直难以利用，因为 内耳的几何形状在内耳迷路的任何位置应用药物填充 与静止的流体一起使用导致在应用位置处的高浓度，而不会到达远处的位置。一 目前的治疗方法是在颞骨上开一个手术孔，让内耳液体流动， 手术损伤我们提出了微创和有效的药物输送机制进入内耳。 具体来说，我们将开发一种方法，使用声音作为耳蜗药物输送的搅拌源。 最近关于OoC微观力学的数据既令人兴奋又有争议，因为新的 观察结果并不很好地适合耳蜗生物物理学的现有框架。例如，外毛细胞 被广泛认为是用于耳蜗放大的致动器。然而，外毛细胞产生 在大多数耳蜗位置，在低于特征频率的频率下最有效地施力， 额外功能的可能性。拟议的项目结合了以前已被 独立研究了OoC的力学和流体稳态。通过结合这两个主题， 我们提出了新的假设，即活跃的外毛细胞增强了沿耳蜗沿着的质量运输。 我们将测试假设与三个目标，结合联合收割机生理和计算建模 接近。对于目标1，将使用活体动物（沙鼠）实验来表征声音的影响， 外毛细胞运动对质量（神经毒素）沿耳蜗导管长度沿着运输的影响。Aim 2实验 将使用切除的耳蜗组织植入一种新型的微流体室，以表征OoC蠕动 由于外毛细胞运动而产生的振动。对于目标3，新的生物物理计算机模型将模拟药物 沿着耳蜗递送，从而整合来自目标1和2的生理结果。 在美国，大约五分之一的成年人有一定程度的听力损失。多 常见的遗传性、年龄相关性和噪声引起的听力损失归因于 耳蜗液稳态通过从创新的角度研究耳蜗液的动态平衡 （力学），这个项目将提供一个解释，为什么听到高频声音， 脆弱从长远来看，我们的目标是提供一种补救措施，以延迟/预防与听力损失有关的疾病。 体液平衡