Active Mechanical Properties of the Uterosacral Ligament: A New Micro-to-Macro Characterization for Prolapse Treatment

盆腔器官脱垂（POP）是一种非常常见的疾病，50岁以上的女性中有一半患有此病，它发生在盆腔器官（如膀胱或子宫）从下腹的正常位置脱落并挤压阴道壁时。患有POP的妇女的生活质量受到严重损害：抑郁、焦虑、社会孤立和性功能障碍是严重的后果。治疗选择从物理治疗到手术干预，但总体成功率很低。鉴于目前手术方法的高发病率和低成功率，需要新的介入方法。到目前为止，子宫、子宫颈和阴道复合体最重要的支持组织是子宫骶韧带（USLs）。这些并不是真正的韧带，但它们是膜状结构，主要由胶原蛋白和平滑肌组成。尽管usl具有重要的支持作用，并且在脱垂的外科手术中广泛使用，但usl的收缩特性仍然未知。该项目的重点是通过提供USL收缩特性的第一个力学特性来填补这一空白。为此，将整合最先进的机械测试和先进的基于光的成像方法。新的数据将指导高保真数学模型的发展，在细胞和组织水平上捕捉usl的活性机制。了解usl在预防和治疗POP方面的作用的进展不可避免地依赖于先进的机械表征工程方法的发展和使用。利用基于USLs新数学模型的计算机模拟，该项目可以从根本上改变目前POP的保守方法和手术程序，最终改善许多妇女的生活质量。参与该项目的本科生和研究生将通过与意大利罗马拉萨皮恩扎大学的交流访问来增加学习经验。学生将获得独特的技能，建立专业网络，并获得跨文化经验，从而在全球工作场所更具竞争力。被称为STEMABILITY的夏令营将被组织起来，为有残疾的高中生提供服务、培训、授权和指导，同时让他们接触科学、技术、数学和工程。该项目的目标是在大鼠模型中描述子宫骶韧带（USLs）的主动和被动特性，然后利用这些信息开发一个包含组织和细胞水平特性的新本构模型，该本构模型可用于骨盆底的精确有限元建模。研究计划分为三个目标。第一个目标是通过进行单轴测试和使用高灵敏度光谱调制干涉法（SMI）和光谱域相位梯度法（SDPG）光学方法测量三维变形，确定从大鼠USL分离的平滑肌细胞的主动和被动力学特性。光学成像技术是唯一能够量化微小（亚纳米）细胞形态变化在收缩期间。第二个目标是通过使用最先进的数字图像相关（DIC）和光学层析成像（OPT）方法进行双轴测试和测量三维变形，量化大鼠USL组织的主动和被动力学特性。第三个目标是通过制定和验证一个新的本构框架来描述和预测经验结果，该框架可以解释USL的主动机械响应。第一步是推导新的本构定律和方程，考虑平滑肌对整体力学行为的贡献。要考虑的机制包括：非线性、各向异性、弹性、粘弹性和主动和被动行为。该格式具有三种配置：1)参考无应力状态，2)主动（由于电或化学刺激）无应力状态，3)主动和被动响应有应力状态。进化规律将从微观机制的描述开始推导，例如，肌动蛋白-肌球蛋白丝滑动，导致肌肉激活。通过对实验数据的曲线拟合得到本构方程的参数。所得的非线性方程组将在有限元计算框架内求解。新的模型框架将用于为阴道穹窿脱垂和子宫脱垂的保守治疗和手术干预提供科学的建议；例如，研究结果对规划骨盆底锻炼、改进用于POP修复的网状移植物以及设计保留USL主动和被动机械特性的手术干预具有重要意义。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Pelvic organ prolapse (POP), which occurs when a pelvic organ--such as the bladder or uterus--drops from its normal place in the lower belly and pushes against the walls of the vagina, is a very common disorder, affecting half of all women over the age of 50. The quality of life of women with POP is severely compromised: depression, anxiety, social isolation, and sexual dysfunction are serious consequences. Treatment options vary from physical therapy to surgical interventions, but the overall success rates are low. Given the high incidence and low success rates of current procedures for POP, new interventional methods are required. By far, the most important supportive tissues of the uterus, cervix, and vagina complex are the uterosacral ligaments (USLs). These are not true ligaments as their name suggests, but they are membrane-like structures that are primarily composed of collagen and smooth muscle. Despite the crucial supportive role of the USLs and their extensive use in surgical procedures for prolapses, the contractile properties of the USLs remain unknown. This project focuses on filling this gap by providing the first mechanical characterization of the contractile properties of the USL. Toward this end, state-of-the-art mechanical testing and advanced light-based imaging methods will be integrated. The new data will guide the development of high fidelity mathematical models that capture the active mechanics of the USLs at the cell and tissue levels. Progress towards understanding the function of the USLs for the prevention and treatment of POP inevitably depends on the development and use of advanced engineering methods for mechanical characterization. Using computer simulations based on the new mathematical models for the USLs, this project can radically change current conservative methods and surgical procedures for POP, ultimately improving the quality of life of many women. The learning experiences of undergraduate and graduate students working on this project will be enhanced by exchange visits with La Sapienza University, Rome, Italy. The students will acquire unique skills, build professional networks, and gain cross-cultural experiences, thus becoming more competitive in the global workplace. Summer camps, called STEMABILITY, will be organized to serve, train, empower, and mentor high school students with disabilities while also exposing them to science, technology, mathematics, and engineering.The goal of this project is to characterize the active and passive properties of the uterosacral ligaments (USLs) in a rat model and then use that information to develop a new constitutive model incorporating tissue and cell-level properties that can be used for accurate finite element modeling of the pelvic floor. The Research Plan is organized under 3 objectives. The first objective is to determine the active and passive mechanical properties of smooth muscle cells isolated from the rat USL by conducting uniaxial tests and measuring three-dimensional deformations using high sensitivity spectral modulation interferometry (SMI) and spectral-domain phase gradient (SDPG) optical methods. The optical imaging techniques are uniquely capable of quantifying minute (subnanometer) cellular morphological changes during contraction. The second objective is to quantify the active and passive mechanical properties of the rat USL tissue by performing biaxial tests and measuring three-dimensional deformations using state-of-the-art digital image correlation (DIC) and optical tomographic imaging (OPT) methods. The third objective is to describe and predict empirical results by formulating and validating a new constitutive framework that accounts for the active mechanical response of the USL. The first step is deriving new constitutive laws and equations that consider the smooth muscle contribution to the overall mechanical behavior. Mechanisms to be considered include: nonlinearity, anisotropy, elasticity, viscoelasticity and active and passive behavior. The format features three configurations: 1) a reference stress-free state, 2) an active(due to electrical or chemical stimulation) without stress state and 3) an active and passive response with stress state. The evolution law will be derived starting from the description of microscopic mechanisms, e.g., actin-myosin filament sliding, that lead to muscle activation. The parameters of the constitutive equations will be obtained via curve-fitting to experimental data. The resulting set of nonlinear equations will be solved within a finite element computational framework. The new modeling framework will be used to provide scientific-based recommendations for both conservative management and surgical intervention for vaginal vault prolapse and uterine prolapse; for example, findings have implications for planning pelvic floor exercises, for improving mesh grafts for POP repair and for designing surgical interventions that preserve the active and passive mechanical properties of the USL.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.