The Detrusor Tension Sensor: A Model for Novel Cystometrics in Overactive Bladder

Virginia Commonwealth University, Richmond VA

Investigators

Linked publications & trials

Abstract

Project Summary: There is growing recognition that overactive bladder (OAB) is not a single clinical entity but may actually represent points on a continuous spectrum. The underlying mechanisms behind the OAB spectrum are poorly understood and likely multifactorial. In addition, the prevalence of OAB is staggering, affects large portions of the adult population, and contributes to significant morbidly and quality of life impact. Multi-channel urodynamics (UDS) have been the gold standard for the evaluation of OAB and other lower urinary tract symptoms for decades. However, UDS are invasive, non-physiologic, and poorly reproducible. In addition, the test provides only limited information regarding the function of the detrusor muscle during the filling phase of the micturition cycle. In our previous R01, we developed ultrasound metrics to improve OAB sub-typing based on bladder biomechanical factors of shape, compliance, and rhythm and showed how these factors can affect the underlying detrusor tension sensor. However, critical research objectives remain and include the: 1) development less- invasive and more physiologic next-generation urodynamics, and 2) development of novel tools to provide improved information about detrusor muscle function and its position on a dynamic elasticity spectrum. Our preliminary data demonstrates how ultrasound can be used to measure biomechanical bladder properties and provide a non-invasive means to quantify bladder wall micromotion. In addition, we have shown how extrinsic strain applied to the bladder wall or intrinsic bladder wall muscle activity work in opposition in the regulation of bladder wall tone, a process that we term the “dynamic elasticity equilibrium.” According to our conceptual model, extrinsic strain acts as a break to acutely decrease detrusor wall tone, and intrinsic muscle activity acts as an accelerator to acutely increase detrusor wall tone. In this proposal, we will use a multi-disciplinary approach combining urology and mechanical engineering to achieve our critical research objectives and test our dynamic equilibrium hypothesis using a pre-clinical approach using in-vitro and in-vivo porcine bladders in two aims which will 1) Develop novel techniques to quantify dynamic elasticity in response to extrinsic strain applied to the bladder wall, and 2) Develop novel techniques to quantify dynamic elasticity in response to intrinsic muscle activity within the bladder wall. Data from these preclinical studies will then be leveraged in future translational studies in human urodynamics. SPECIFIC AIMS: There is growing recognition that overactive bladder (OAB) is not a single clinical entity but may represent points on a continuous spectrum1-3. The underlying mechanisms behind the OAB spectrum are poorly understood and likely multifactorial4. In addition, OAB prevalence is staggering5,6, affects large portions of the population, and contributes to morbidity and quality of life impact7. Multi-channel urodynamics (UDS) have been used for evaluation of OAB and other lower urinary tract symptoms for decades8. However, UDS are invasive9,10, non-physiologic, and poorly reproducible11,12. In addition, UDS provides only limited information regarding the function of the detrusor muscle during the filling phase of the micturition cycle. In our previous R01, we developed ultrasound (US) metrics to improve OAB subtyping based on bladder biomechanical factors of shape13, elasticity14, and rhythm15 and showed how these factors affect the detrusor tension sensor. However, remaining critical research objectives include: 1) development of less-invasive and more physiologic next-generation UDS, and 2) development of novel tools to evaluate detrusor muscle function. Our preliminary data demonstrates how US-UDS can be used to measure bladder shape parameters and non- invasively quantify bladder wall micromotion. In addition, we have shown how extrinsic strain applied to the bladder wall or intrinsic bladder wall muscle activity work in opposition in the regulation of bladder wall tone, a process we term the “dynamic elasticity equilibrium.” According to our conceptual model (Fig1) which is the central hypothesis tested in this proposal, extrinsic strain acts to acutely decrease detrusor wall tone, likely through disruption of passive actin-myosin cross-bridges16-21. In contrast, intrinsic muscle activity, also called detrusor overactivity (DO), micromotion22, autonomous activity22,23, spontaneous activity24,25, or low amplitude rhythmic contractions26, acts to acutely increase detrusor wall tone, likely through cross bridge re- establishment16-21. The overarching goal of our research is improved, non-invasive OAB phenotyping through creation of a mechanistic, biomechanical model relating extrinsic strain and intrinsic muscle activity. In this proposal, we will achieve our critical research objectives and test our dynamic elasticity equilibrium hypothesis using preclinical studies with in-vitro and in-vivo porcine bladders. Per program recommendations for special emphasis, we will prioritize award funding to focus on successful completion of the following two aims: Aim 1: To develop novel techniques to quantify dynamic elasticity in response to extrinsic strain applied to the bladder wall. In this Aim, we will quantify how extrinsic strain applied through repeat filling/passive emptying and compress-release cycles reduces dynamic elasticity. We will employ novel US techniques in in vitro and in vivo porcine bladders to quantify the effects of bladder perimeter strain. We will also create a biomechanical perimeter strain model to relate the effects of extrinsic strain measured with non-invasive US with pressure changes during invasive pressure monitoring. Successful completion will create a biomechanical perimeter strain model for non-invasive prediction of pressure responses to extrinsic strain. Aim 2: To develop novel techniques to quantify dynamic elasticity in response to intrinsic muscle activity within the bladder wall. In this Aim, we will quantify how intrinsic muscle activity of bladder wall micromotion increases dynamic elasticity. We will employ anatomical M-Mode US to quantify regional micromotion and sphericity analysis to quantify global bladder wall micromotion. Porcine bladders will be used to induce graded micromotion increases with prostaglandin E2 (PGE2) and electrical field stimulation (EFS). Results will be used to create a biomechanical micromotion model relating US-measured micromotion to intravesical rhythm using our published Fast Fourier Transform (FFT) technique. Successful completion will create US-techniques for non- invasive quantification of micromotion and a biomechanical micromotion model for non-invasive prediction of spontaneous detrusor rhythm in porcine bladders. Successful completion of his proposal will demonstrate the relationship between extrinsic strain and intrinsic bladder wall micromotion in both in vitro and in vivo porcine bladders. This will provide justification to test our dynamic elasticity hypothesis in future translational urodynamic studies in humans.