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

摘要 大约“十分之一的美国成年人患有每日尿失禁;大多数受影响的人是女性” （NIDDK）.因此，1260万美国妇女受到这种痛苦和社会耻辱的折磨。 问题，每年花费882亿美元。尽管这种情况很重要，但NIH的治愈率- 压力性和急迫性尿失禁的赞助试验保持在50%或更低。为什么？为什么？ 目前的概念框架，治疗的基础上，坚持认为：1）压力性尿失禁， 由尿道支撑不良引起，和2）急迫性尿失禁由异常膀胱收缩性引起。 我们小组的范式转换研究表明，长期被忽视的尿道括约肌复合体是一种 压力性尿失禁的病因，占50%，也在急迫性尿失禁中起着关键作用。 了解尿道闭合机制如何工作的进展目前受到两个因素的阻碍：1） 当前的测试策略是基于过时的、简单的和容易产生伪影的20世纪60年代的技术，以及2） 缺乏对尿道结构-功能关系的详细了解来指导研究。 目的1：开发一套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先进的成像技术，制定并验证新型测量策略 战略布局这些工具将包括：a）超柔性、微型、多部位尿道压力导管; B） 生理尿道感觉测试设备;以及c）微型可穿戴尿流量计和日常活动 监视器. 目的2：开发先进的超声成像设备和策略： 尿道很容易通过超声进入，但是评估它的策略和设备是有限的。在这个目标中，我们 将开发：用于动态解剖的B模式，用于血管流量定量的多普勒，以及用于 尿道壁机械特性，以测量AIMS 1和3可使用的实时尿道运动学。 目的3：开发多尺度3D解剖图谱和高保真度尿道多物理计算机模型， 模拟个体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）制作第一个体外3D多尺度概率图和体内高分辨率MR扫描 女性的尿道这些数据，沿着来自AIMS 1和2的新数据，将用于B）创建和 验证第一个有限元多物理尿道模型，可用于研究人员调查如何 个体尿道结构和功能参数的变化影响尿道闭合压力。 这项工作提供的技术和概念工具将刺激研究和启动假设检验 为了阐明如何确定年龄、糖尿病、分娩、种族、遗传学和其他因素， 影响女性尿道衰竭的因素。这项工作将揭示目前尚未探索的治疗靶点， 尿道的重要性，但长期被忽视，尿道功能方面的科学。

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.