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

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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.