A Digital Twin for Designing Bladder Treatment informed by Bladder Outlet Obstruction Mechanobiology (BOOM)

良性前列腺增生（BPH）引起的前列腺肿大会使尿道收缩，导致膀胱炎。 出口梗阻（BOO）是影响衰老的下尿路症状（LUTS）的主要因素 男人BOO气囊能够产生克服出口压力升高所需的高压。 通过增加膀胱平滑肌细胞质量来增加阻力和排尿。然而，长期的上升， 排尿压力引起膀胱壁的进行性机械生物学变化从而导致LUTS， 包括储存和排泄功能障碍随着世界范围内BPH数量的增加， 会增加频率。因此，迫切需要了解为什么30%的前列腺手术 治疗BOO在解决LUTS方面无效，并确定更有效的治疗策略。 我们认为，造成这一认识差距的原因是，对理解的重视不够 膀胱壁变化与排尿/充盈（V-F）功能障碍之间的耦合。事实上，我们目前 缺乏一个完整的三维生物力学模型的整个膀胱V-F过程，即使是健康的膀胱，更不用说 BOO膀胱，因为它经历了几周和几个月的时间尺度上的渐进变化。我们有限 对膀胱生物力学的理解与我们对心脏生物力学的理解形成鲜明对比， 复杂的多尺度，多物理模型的循环填充和排空的心脏腔室， 被开发来了解心脏病和设计患者特定的治疗方法。有希望的是， 利用为其他器官开发的工具和实验/计算方法的机会， 如心脏，以迅速推进膀胱生物力学研究领域向临床影响。 为了满足这一需求，该R 01项目将利用最新的BOO体内和体外研究， 大鼠模型来驱动整个BOO膀胱的数字双胞胎的发育。这些数据和计算机模拟 该模型将使一个机械的了解如何改变BOO膀胱引起进行性膀胱 功能障碍以及如何通过逆转手术和药物治疗来改善这种功能障碍。 治疗目标1的焦点是V-F过程中的功能障碍。尿动力学的三维有限元模型 结合BOO大鼠模型的数据，将用于确定膀胱驱动器的变化 在BOO的每个阶段，V-F循环功能障碍。在目标2中，我们将确定药物治疗如何 可用于改善膀胱功能障碍。膀胱壁的渐进变化将在 使用我们的BOO机械生物学计算框架的周时间尺度。在目标3中，我们将使用动物 数据和数字双胞胎，以确定膀胱对逆转手术反应的机械原因， 关于手术时机和药物干预的功能恢复条件。 我们的长期目标是为医学研究开发数字孪生模型，并将其转化为临床指导 对BPH/BOO相关男性LUTS进行外科干预选择和开发药物治疗。

Prostate enlargement arising from benign prostate hyperplasia (BPH) can constrict the urethra, causing bladder outlet obstruction (BOO), a major contributing factor to the lower urinary tract symptoms (LUTS) that affect aging men. The BOO bladder is capable of generating the elevated pressures necessary to overcome the rise in outlet resistance and void through an increase in bladder smooth muscle cell mass. However, prolonged elevation in voiding pressures induces progressive mechanobiological changes to the bladder wall that lead to LUTS, including storage and voiding dysfunction. With rising numbers of BPH worldwide, prostate surgery to treat BOO will increase in frequency. Therefore, there is an urgent need to understand why 30% of prostrate surgeries to treat BOO are ineffective at resolving LUTS and to identify more effective treatment strategies. We believe the reason for this gap in knowledge is that insufficient attention has been given to understanding the coupling between changes to the bladder wall and voiding/filling (V-F) dysfunction. Indeed, we currently lack a full 3D biomechanical model for the whole bladder V-F process for even healthy bladders, let alone for the BOO bladder as it goes through progressive changes over time scales of weeks and months. Our limited understanding of bladder biomechanics is in sharp contrast to our knowledge of heart biomechanics, for which sophisticated multi-scale, multi-physics models of the cyclic filling and emptying of the heart chambers have been developed to understand cardiac disease and design patient specific treatments. Promisingly, there is opportunity to capitalize on tools and experimental/computational approaches developed for other organs, such as the heart, to rapidly advance the bladder biomechanics research field towards clinical impact. To address this need, this R01 project will make use of state of the art in vivo and in vitro studies of BOO in a rat model to drive the development of a digital twin of the whole BOO bladder. This data and the in silico model will enable a mechanistic understanding of how changes to the BOO bladder cause progressive bladder dysfunction and how this dysfunction can be ameliorated through reversal surgery and pharmacological treatment. The focus of Aim 1 is dysfunction in the V-F process. A 3D finite element model of urodynamics coupled with data from the BOO rat model will be used to determine how changes to the bladder drive dysfunction in the V-F cycle, at each stage of BOO. In Aim 2, we will determine how pharmacological treatment can be used to ameliorate bladder dysfunction. Progressive changes to bladder wall will be modeled over a time scale of weeks using our computational framework for BOO mechanobiology. In Aim 3, we will use animal data and the digital twin to determine mechanistic causes for bladder response to reversal surgery and identify conditions for functional recovery with regards to surgical timing and pharmacological intervention. Our long-term objectives are to develop a digital twin for medical research and translated to the clinic to guide surgical intervention choices and develop pharmacologic treatment for male LUTS associated with BPH/BOO.