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

摘要 大约每十个美国成年人中就有一个患有日常尿失禁；大多数受影响的人是女性。 (NIDDK)。因此，1260万美国妇女受到这种令人痛苦和社会耻辱的折磨 这个问题，每年要花费882亿美元。尽管这种情况很重要，但NIH的治愈率- 赞助的治疗压力和尿失禁的试验仍保持在50%或更低。为什么？ 目前治疗所基于的概念框架认为：1)压力性尿失禁 2)急迫性尿失禁是由膀胱收缩功能异常引起的。 我们团队的范式转换研究表明，长期以来被忽视的尿路括约肌复合体是一种 原因因素，负责50%的压力性尿失禁，也在急迫性尿失禁中起着关键作用。 目前，有两个因素阻碍了人们对尿道闭合机制工作原理的理解：1) 当前的测试策略基于过时的、简单化的和容易出现人工制品的20世纪60年代的技术，以及2) 缺乏对尿路结构-功能关系的详细了解，需要指导研究。 目标1：开发最先进的尿路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和验证新的测量策略 战略。这些工具将包括：a)一个超软、微型、多部位的导尿管；b)a) 生理尿路感觉测试仪；c)微型可穿戴式尿流量计和日常活动 监视器。 目标2：开发先进的超声成像设备和策略：结构和功能 超声可以很容易地进入尿路，但评估它的策略和设备有限。为了实现这一目标，我们 将发展：动态解剖的B型，血管血流定量的多普勒，和弹性成像 用于实时测量可用于AIMS 1和3的尿道壁力学特性的尿道壁运动学。 目的3：建立多尺度三维解剖图谱和高保真的尿路多物理计算机模型 模拟个体结构的变化以及年龄和疾病进程的影响如何影响尿路 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磁共振扫描 女性的尿路。这些数据以及来自AIMS 1和2的新兴数据将用于b)创建和 验证第一个有限元多物理尿道模型，研究人员可以用它来研究 个体尿路结构和功能参数的改变会影响尿路闭合压力。 这项工作提供的技术和概念工具将促进研究并启动假设检验 为了阐明可控边界是如何确定的，以及年龄、糖尿病、分娩、种族、遗传等因素是如何确定的 影响女性尿路衰竭的因素。这项工作将揭示目前尚未探索的治疗靶点，并带来 科学对尿路控制功能的关键，但长期以来被忽视的方面。

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.