Development of 21st Century Concepts and Tools for Quantifying Urethral Failure Mechanisms that Cause Urinary Incontinence

开发 21 世纪量化导致尿失禁的尿道衰竭机制的概念和工具

• 批准号: 10217124
• 负责人: JAMES Anthony ASHTON-MILLER
• 金额: $ 112.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10217124
• 关键词: 3-Dimensional; Accelerometer; Adult; Affect; Age; American; Anatomy; Assessment tool; Atlases; Bladder; Blood Vessels; Catheters; Cells; Childbirth; Communities; Complex; Computer Models; Data; Development; Diabetes Mellitus; Disease; Distress; Elderly; Elements; Equipment; Event; Failure; Female urethral structure; Genetic; Image; Imaging technology; In Vitro; Incontinence; Individual; Injury; Lead; Maps; Measurement; Measures; Modeling; Morphologic artifacts; Muscle; National Institute of Diabetes and Digestive and Kidney Diseases; Organ; Physiological; Play; Probability; Process; Race; Research; Research Personnel; Resolution; Resources; Role; Scanning; Science; Sensory; Sphincter; Stigmatization; Stress; Stress Urinary Incontinence; Structure; Structure-Activity Relationship; System; Technology; Testing; Time; Ultrasonography; United States National Institutes of Health; Urethra; Urethral sphincter; Urge Incontinence; Urinary Incontinence; Woman; Work; advanced disease; age effect; base; cost; design; elastography; experience; in vivo; intravesical; kinematics; mechanical properties; new therapeutic target; next generation; novel; pressure; sensor; sensor technology; social; stressor; therapeutic target; tool; urinary

Abstract Approximately “one in ten U.S. adults suffer from daily urinary incontinence; most of those affected are women” (NIDDK). Hence 12.6 million American women are afflicted by this distressing and socially stigmatizing problem, at a cost of $88.2 billion dollars annually. Despite the importance of this condition, cure rates in NIH- sponsored trials for stress and urge incontinence remain at 50% or lower. Why? The current conceptual framework on which treatments are based maintains that 1) stress incontinence is caused by poor urethral support, and 2) urge incontinence is caused by abnormal bladder contractility. Paradigm-shifting research by our group shows that the urethral sphincter complex, long overlooked as a causal factor, is responsible for 50% of stress incontinence and also plays a critical role in urge incontinence. Progress in understanding how the urethral closure mechanism works is currently hindered by two factors: 1) current testing strategies that are based on outmoded, simplistic, and artifact-prone 1960s technology, and 2) the lack of a detailed understanding of urethral structure-function relationships needed to guide research. AIM 1: Develop a state-of-the-art battery of urethral sensorimotor and vascular assessment tools: We will produce and validate novel measurement strategies using state-of-the-art sensor and advanced imaging strategies. These tools will include: a) an ultraflexible, microscale, multisite urethral pressure catheter; b) a physiologic urethral sensory testing apparatus; and c) a miniature wearable uroflowmeter and a daily activity monitor. AIM 2: Develop advanced ultrasound imaging equipment and strategies: The structure and function of the urethra is easily accessed by ultrasound, yet strategies and equipment to evaluate it are limited. In this Aim, we will develop: B-mode for dynamic anatomy, Doppler for vascular flow quantification, and elastography for urethral wall mechanical properties to measure real-time urethral kinematics that can be used by AIMS 1 & 3. AIM 3: Develop a multiscale 3D anatomical atlas and high-fidelity urethral multiphysics computer model for simulating how changes in individual structures and the effects of age and disease processes affect urethral function. We will a) produce the first in vitro 3D multiscale probability map and in vivo high-resolution MR scans of the female urethra. These data, along with emerging data from AIMS 1 & 2, will be used to b) create and validate the first finite element multiphysics urethral model that can be used by researchers to investigate how changes in individual urethral structural and functional parameters affect urethral closure pressure. The technical and conceptual tools provided by this work will stimulate research and launch hypothesis testing to clarify how the continence margin is determined and how age, diabetes, childbirth, race, genetics, and other factors affect urethral failure in women. This work will reveal currently unexplored therapeutic targets and bring science to the urethra's critical, but long overlooked, aspect of continence function.

抽象的 大约“美国十分之一的成年人每天尿失禁；大多数受影响的是妇女” （niddk）。因此，有1260万美国妇女受到这种痛苦和社会污名的困扰 问题，每年的成本为882亿美元。尽管这种情况很重要，但可以治愈NIH- 赞助的压力和敦促尿失禁的试验保持在50％或更低。为什么？ 当前的概念框架是基于治疗的维护1）压力尿失禁是 尿道支撑不良以及2）敦促尿失禁是由异常的膀胱收缩性引起的。 我们小组的范式转移研究表明，尿道括约肌综合体长期以来被忽视为 因果因素，导致50％的压力尿失禁，并且在敦促尿失禁中也起着至关重要的作用。 目前，要了解尿道闭合机制的工作原理的进展受到两个因素的阻碍：1） 基于过时，简单和易于人工制品的1960年代技术的当前测试策略，以及2） 缺乏对指导研究所需的尿道结构功能关系的详细理解。 目标1：开发最先进的尿道感觉运动和血管评估工具：我们将 使用最先进的传感器和高级成像制作并验证新颖的测量策略 策略。这些工具将包括：a）超级微观，多站点尿道压导导管； b）a 生理尿道感觉测试设备； c）微型可穿戴尿流和日常活动 监视器。 目标2：开发高级超声成像设备和策略： 超声波很容易进入尿道，但是评估尿道的策略和设备是有限的。在这个目标中，我们 将开发：动态解剖学的B模式，用于血管流量定量的多普勒和弹性图 尿道壁机械性能，用于测量AIM 1和3可以使用的实时尿道运动学。 目标3：开发多尺度3D解剖图集和高保真尿道多物理计算机模型 模拟单个结构的变化以及年龄和疾病过程的影响如何影响尿道 功能。我们将a）产生第一个体外3D多尺度概率图和体内高分辨率MR扫描 女性尿道。这些数据以及来自AIM 1和2的新兴数据将用于b）创建和 验证研究人员可以使用的第一个有限元多物理尿道模型 单个尿道结构和功能参数的变化会影响尿道闭合压力。 这项工作提供的技术和概念工具将刺激研究并启动假设测试 为了阐明如何确定持续性能以及年龄，糖尿病，儿童外生，种族，遗传学和其他如何 因素影响女性的尿道衰竭。这项工作将揭示目前意外的治疗目标，并带来 尿道的批判性但长期以来忽略了连续性功能的科学。