Is the time right for a new initiative in mathematical modeling of the lower urinary tract? ICI-RS 2023.

INTRODUCTION: A session at the 2023 International Consultation on Incontinence - Research Society (ICI-RS) held in Bristol, UK, focused on the question: Is the time right for a new initiative in mathematical modeling of the lower urinary tract (LUT)? The LUT is a complex system, comprising various synergetic components (i.e., bladder, urethra, neural control), each with its own dynamic functioning and high interindividual variability. This has led to a variety of different types of models for different purposes, each with advantages and disadvantages. METHODS: When addressing the LUT, the modeling approach should be selected and sized according to the specific purpose, the targeted level of detail, and the available computational resources. Four areas were selected as examples to discuss: utility of nomograms in clinical use, value of fluid mechanical modeling, applications of models to simplify urodynamics, and utility of statistical models. RESULTS: A brief literature review is provided along with discussion of the merits of different types of models for different applications. Remaining research questions are provided. CONCLUSIONS: Inadequacies in current (outdated) models of the LUT as well as recent advances in computing power (e.g., quantum computing) and methods (e.g., artificial intelligence/machine learning), would dictate that the answer is an emphatic "Yes, the time is right for a new initiative in mathematical modeling of the LUT."

Cardiac electrophysiology catheters for electrophysiological assessments of the lower urinary tract-A proof of concept ex vivo study in viable ureters.

AIMS: To explore the feasibility of minimally invasive catheter-based electrophysiology studies in the urinary tract. This is a well-known method used in cardiology to investigate and treat arrhythmias. METHODS: We developed an experimental platform which allows electrophysiological recordings with cardiac catheters and conventional needle electrodes in ex vivo pig ureters. The action potential was triggered by a stimulating electrode. We considered 13 porcine ureters (freshly collected and harvested in organ bath), 7 of which were used to optimize the setup and define the stimulation parameters; we performed the recordings in the remaining six ureters. The electrical propagation of the generated action potential was tracked with multiple sensing electrodes, from which propagation directions, velocities, refractory periods, and pacing thresholds were extracted. RESULTS: We recorded propagating electrical activity in four ureters using needle electrodes and in two ureters using cardiac catheters. Propagation velocities for forward direction (from kidney to bladder) derived by the two methods were similar (15.1 ± 2.6 mm/s for cardiac catheters, 15.6 ± 2.3 mm/s for needle recordings). Pacing thresholds, activation patters, and refractory times were provided for the ureteric smooth muscle. Retrograde propagations and corresponding velocities were also observed and measured. CONCLUSIONS: This study is a proof-of-concept showing that electrical activity can be measured "from the inside" of urinary cavities using catheters and that obtained results are comparable with the more invasive needle recordings. Catheter-based electrophysiology may allow, in the clinical setting, for: i) a more differentiated understanding of urological disorders such as overactive bladder and ii) new therapeutic approaches (e.g., targeted tissue ablation).

Detection and quantification of overactive bladder activity in patients: Can we make it better and automatic?

AIMS: To explore the use of time-frequency analysis as an analytical tool to automatically detect pattern changes in bladder pressure recordings of patients with overactive bladder (OAB). To provide quantitative data on the bladder's non-voiding activity which could improve the current diagnosis and potentially the treatment of OAB. METHODS: We developed an algorithm, based on time-frequency analysis, to analyze bladder pressure during the filling phase of urodynamic studies. The algorithm was used to generate a bladder overactivity index (BOI) for a quantitative estimation of the average bladder non-voiding-activity. We tested the algorithm with one control group and two groups of patients with OAB symptoms: one group with detrusor overactivity (DO), assessed by an experienced urologist (OAB-with-DO group), and another group for which detrusor overactivity was not diagnosed (OAB-without-DO group). RESULTS: The algorithm identified diagnostically significant data on the bladder non-voiding activity in a specified frequency range. BOI was significantly higher for both OAB groups compared to the control group: the median value of BOI was twice as big in OAB-without-DO and more than four times higher in OAB-with-DO compared to control group. Moreover the algorithm was successfully tested to detect episodes of detrusor overactivity. CONCLUSIONS: We have shown that a simple algorithm, based on time-frequency analysis of bladder pressure, may be a promising tool in the clinical setting. The algorithm can provide quantitative data on non-voiding bladder activity in patients and quantify the changes according to phenotype. Moreover the algorithm can detect DO, showing potential for triggering conditional bladder stimulation.

Frequency analysis of urinary bladder pre-voiding activity in normal and overactive rat detrusor.

AIMS: To test the hypothesis that voiding in anesthetized rats is preceded by recurrent changes in the pattern of bladder pressure. To explore the use of frequency analysis as an analytical tool for automatically detecting these changes and to provide quantitative data on bladder pre-voiding activity. METHODS: We developed an algorithm, based on frequency analysis, to study bladder pressure during the filling phase in anesthetized rats. Two applications of the algorithm were tested: (i) as a predictor of a voiding contraction with alarms generated which would make conditional nerve stimulation to prevent incontinence possible; and (ii) as a new index to quantify rapid pressure transients in normal and overactive detrusor conditions (i.e., induced by acetic acid instillation into the bladder). RESULTS: The results show that a very high percentage (∼90%) of the alarms was generated by the algorithm within 100 sec before voiding. The index of rapid transients and the bladder volume before voiding were respectively ∼13% less and ∼42% less in acetic acid. CONCLUSIONS: We have shown that a simple algorithm, based on frequency analysis of bladder pressure, can be used to predict voiding and to provide quantitative data on non-voiding bladder activity and its changes due to pathology. Although the results refer to anesthetized rats, they are promising and warrant further urodynamic investigation to identify if similar patterns occur in non-anesthetized rats and in humans.

Dielectric Elastomer Actuator-Based Valveless Impedance-Driven Pumping for Meso- and Macroscale Applications.

Impedance pumps are simple designs that allow the generation or amplification of flow. They are fluid-filled systems based on flexible tubing connected to tubing with different impedances. A periodic off-center compression of the flexible tubing causes the fluid to move and generate flow. Wave reflection at the impedance mismatch is the primary driving mechanism of the flow. In addition to their straightforward design, impedance pumps are bladeless, valveless, and pulsatile. These properties are highly sought after by demanding and challenging applications, such as the biomedical field, as they present less risk of damage, disruption, and obstruction when handling viscous and delicate fluids/matter. In this study, we propose a high-performance impedance-driven pumping concept with embedded actuation based on a multilayered tubular dielectric elastomer. This pumping system is made of three parts, a dielectric elastomer actuator tube, a passive tube, and a rigid ring that binds and decouples the two subsystems. The system is able to generate net fluid flow rates up to 1.35 L/min with an internal pressure of 125 mmHg. The soft simplistic design, self-contained concept, and high performances of these pumping systems could make them disruptive in many challenging meso- and macroscale applications in general and in the biomedical field in particular.

Dielectric elastomer actuator-based valveless pump as Fontan failure assist device: introduction and preliminary study.

OBJECTIVES: Fontan failure refers to a condition in which the Fontan circulation, a surgical procedure used to treat certain congenital heart defects, becomes insufficient, leading to compromised cardiac function and potential complications. This in vitro study therefore investigates the feasibility of bladeless impedance-driven cavopulmonary assist device via dielectric elastomer actuator (DEA) as a means to address Fontan failure. METHODS: A cavopulmonary assist device, constructed using DEA technologies and employing the impedance pump concept, is subjected to in vitro testing within a closed-loop setup. This study aims to assess the device's functionality and performance under controlled conditions, providing valuable insights into its potential application as a cavopulmonary assistive technology. RESULTS: The DEA-based pump, measuring 50 mm in length and 30 mm in diameter, is capable of achieving substantial flow rates within a closed-loop setup, reaching up to 1.20 l/min at an activation frequency of 4 Hz. It also provides a broad range of working internal pressures (<10 to >20 mmHg). Lastly, the properties of the flow (direction, magnitude, etc.) can be controlled by adjusting the input signal parameters (frequency, amplitude, etc.). CONCLUSIONS: In summary, the results suggest that the valveless impedance-driven pump utilizing DEA technology is promising in the context of cavopulmonary assist devices. Further research and development in this area may lead to innovative and potentially more effective solutions for assisting the right heart, ultimately benefiting patients with heart-related health issues overall, with a particular focus on those experiencing Fontan failure.

Novel para-aortic cardiac assistance using a pre-stretched dielectric elastomer actuator.

OBJECTIVES: We propose an evolution of a dielectric elastomer actuator-based cardiac assist device that acts as a counterpulsation system. We introduce a new pre-stretched actuator and implant the device in a graft bypass between the ascending and descending aorta to redirect all blood through the device (ascending aorta clamped). The objective was to evaluate the influence of these changes on the assistance provided to the heart. METHODS: The novel para-aortic device and the new implantation technique were tested in vivo in 5 pigs. We monitored the pressure and flow in the aorta as well as the pressure-volume characteristics of the left ventricle. Different activation timings were tested to identify the optimal device actuation. RESULTS: The proposed device helps reducing the end-diastolic pressure in the aorta by up to 13 ± 4.0% as well as the peak systolic pressure by up to 16 ± 3.6%. The early diastolic pressure was also increased up to 10 ± 3.5%. With different activation, we also showed that the device could increase or decrease the stroke volume. CONCLUSIONS: The new setup and the novel para-aortic device presented here helped improve cardiac assistance compared to previous studies. Moreover, we revealed a new way to assist the heart by actuating the device at different starting time to modify the left ventricular stroke volume and stroke work.

Fluid mechanical performance of ureteral stents: The role of side hole and lumen size.

Ureteral stents are indispensable devices in urological practice to maintain and reinstate the drainage of urine in the upper urinary tract. Most ureteral stents feature openings in the stent wall, referred to as side holes (SHs), which are designed to facilitate urine flux in and out of the stent lumen. However, systematic discussions on the role of SH and stent lumen size in regulating flux and shear stress levels are still lacking. In this study, we leveraged both experimental and numerical methods, using microscopic-Particle Image Velocimetry and Computational Fluid Dynamic models, respectively, to explore the influence of varying SH and lumen diameters. Our results showed that by reducing the SH diameter from 1.1 to 0.4 mm the median wall shear stress levels of the SHs near the ureteropelvic junction and ureterovesical junction increased by over 150 % , even though the flux magnitudes through these SH decreased by about 40 % . All other SHs were associated with low flux and low shear stress levels. Reducing the stent lumen diameter significantly impeded the luminal flow and the flux through SHs. By means of zero-dimensional models and scaling relations, we summarized previous findings on the subject and argued that the design of stent inlet/outlet is key in regulating the flow characteristics described above. Finally, we offered some clinically relevant input in terms of choosing the right stent for the right patient.

Hemodynamic effects of a dielectric elastomer augmented aorta on aortic wave intensity: An in-vivo study.

Dielectric elastomer actuator augmented aorta (DEA) represents a novel approach with high potential for assisting a failing heart. The soft tubular device replaces a section of the aorta and increases its diameter when activated. The hemodynamic interaction between the DEA and the left ventricle (LV) has not been investigated with wave intensity (WI) analysis before. The objective of this study is to investigate the hemodynamic effects of the DEA on the aortic WI pattern. WI was calculated from aortic pressure and flow measured in-vivo in the descending aorta of two pigs implanted with DEAs. The DEAs were tested for different actuation phase shifts (PS). The DEA generated two decompression waves (traveling upstream and downstream of the device) at activation followed by two compression waves at deactivation. Depending on the PS, the end-diastolic pressure (EDP) decreased by 7% (or increased by 5-6%). The average early diastolic pressure augmentation (Pdia¯) increased by 2% (or decreased by 2-3%). The hydraulic work (WH) measured in the aorta decreased by 2% (or increased by 5%). The DEA-generated waves interfered with the LV-generated waves, and the timing of the waves affected the hemodynamic effect of the device. For the best actuation timing the upstream decompression wave arrived just before aortic valve opening and the upstream compression wave arrived just before aortic valve closure leading to a decreased EDP, an increased Pdia¯ and a reduced.WH.

A novel soft cardiac assist device based on a dielectric elastomer augmented aorta: An in vivo study.

Although heart transplant is the preferred solution for patients suffering from heart failures, cardiac assist devices remain key substitute therapies. Among them, aortic augmentation using dielectric elastomer actuators (DEAs) might be an alternative technological application for the future. The electrically driven actuator does not require bulky pneumatic elements (such as conventional intra-aortic balloon pumps) and conforms tightly to the aorta thanks to the manufacturing method presented here. In this study, the proposed DEA-based device replaces a section of the aorta and acts as a counterpulsation device. The feasibility and validation of in vivo implantation of the device into the descending aorta in a porcine model, and the level of support provided to the heart are investigated. Additionally, the influence of the activation profile and delay compared to the start of systole is studied. We demonstrate that an activation of the DEA just before the start of systole (30 ms at 100 bpm) and deactivation just after the start of diastole (0-30 ms) leads to an optimal assistance of the heart with a maximum energy provided by the DEA. The end-diastolic and left ventricular pressures were lowered by up to 5% and 1%, respectively, compared to baseline. The early diastolic pressure was augmented in average by up to 2%.

An in vitro bladder model with physiological dynamics: Vesicoureteral reflux alters stent encrustation pattern.

In vitro models are indispensable to study the physio-mechanical characteristics of the urinary tract and to evaluate ureteral stent performances. Yet previous models mimicking the urinary bladder have been limited to static or complicated systems. In this study, we designed a simple in vitro bladder model to simulate the dynamics of filling and voiding. The physio-mechanical condition of the model was verified using a pressure-flow test with different bladder outlet obstruction levels, and a reflux test was performed to qualitatively demonstrate the stent associated vesicoureteral reflux (VUR). Finally, the setup was applied with and without the bladder model to perform encrustation tests with artificial urine on commercially available double-J stents, and the volumes of luminal encrustations were quantified using micro-Computed Tomography and image segmentation. Our results suggest that, VUR is an important factor contributing to the dynamics in the upper urinary tract with indwelling stents, especially in patients with higher bladder outlet obstruction levels. The influence of VUR should be properly addressed in future in vitro studies and clinical analyses.

Effect of Collateral Flow on Catheter-Based Assessment of Cardiac Microvascular Obstruction.

Cardiac microvascular obstruction (MVO) associated with acute myocardial infarction (heart attack) is characterized by partial or complete elimination of perfusion in the myocardial microcirculation. A new catheter-based method (CoFI, Controlled Flow Infusion) has recently been developed to diagnose MVO in the catheterization laboratory during acute therapy of the heart attack. A porcine MVO model demonstrates that CoFI can accurately identify the increased hydraulic resistance of the affected microvascular bed. A benchtop microcirculation model was developed and tuned to reproduce in vivo MVO characteristics. The tuned benchtop model was then used to systematically study the effect of different levels of collateral flow. These experiments showed that measurements obtained in the catheter-based method were adversely affected such that collateral flow may be misinterpreted as MVO. Based on further analysis of the measured data, concepts to mitigate the adverse effects were formulated which allow discrimination between collateral flow and MVO.

Feasibility of a Dielectric Elastomer Augmented Aorta.

Although heart transplantation is a gold standard for severe heart failure, there is a need for alternative effective therapies. A dielectric-elastomer aorta is used to augment the physiological role of the aorta in the human circulatory system. To this end, the authors developed a tubular dielectric elastomer actuator (DEA) able to assist the heart by easing the deformation of the aorta in the systole and by increasing its recoil force in the diastole. In vitro experiments using a pulsatile flow-loop, replicating human physiological flow and pressure conditions, show a reduction of 5.5% (47 mJ per cycle) of the heart energy with this device. Here, the controlled stiffness of the DEA graft, which is usually difficult to exploit for actuators, is perfectly matching the assistance principle. At the same time, the physiological aortic pressure is exploited to offer a prestretch to the DEA which otherwise would require an additional bulky pre-stretching system to reach high performances.

Fluid mechanical modeling of the upper urinary tract.

The upper urinary tract (UUT) consists of kidneys and ureters, and is an integral part of the human urogenital system. Yet malfunctioning and complications of the UUT can happen at all stages of life, attributed to reasons such as congenital anomalies, urinary tract infections, urolithiasis and urothelial cancers, all of which require urological interventions and significantly compromise patients' quality of life. Therefore, many models have been developed to address the relevant scientific and clinical challenges of the UUT. Of all approaches, fluid mechanical modeling serves a pivotal role and various methods have been employed to develop physiologically meaningful models. In this article, we provide an overview on the historical evolution of fluid mechanical models of UUT that utilize theoretical, computational, and experimental approaches. Descriptions of the physiological functionality of each component are also given and the mechanical characterizations associated with the UUT are provided. As such, it is our aim to offer a brief summary of the current knowledge of the subject, and provide a comprehensive introduction for engineers, scientists, and clinicians who are interested in the field of fluid mechanical modeling of UUT. This article is categorized under: Cancer > Biomedical Engineering Infectious Diseases > Biomedical Engineering Reproductive System Diseases > Biomedical Engineering.

Potential strategies to prevent encrustations on urinary stents and catheters - thinking outside the box: a European network of multidisciplinary research to improve urinary stents (ENIUS) initiative.

Introduction: Urinary stents have been around for the last 4 decades, urinary catheters even longer. They are associated with infections, encrustation, migration, and patient discomfort. Research efforts to improve them have shifted onto molecular and cellular levels. ENIUS brought together translational scientists to improve urinary implants and reduce morbidity.Methods & materials: A working group within the ENIUS network was tasked with assessing future research lines for the improvement of urinary implants.Topics were researched systematically using Embase and PubMed databases. Clinicaltrials.gov was consulted for ongoing trials.Areas covered: Relevant topics were coatings with antibodies, enzymes, biomimetics, bioactive nano-coats, antisense molecules, and engineered tissue. Further, pH sensors, biodegradable metals, bactericidal bacteriophages, nonpathogenic uropathogens, enhanced ureteric peristalsis, electrical charges, and ultrasound to prevent stent encrustations were addressed.Expert opinion: All research lines addressed in this paper seem viable and promising. Some of them have been around for decades but are yet to proceed to clinical application (i.e. tissue engineering). Others are very recent and, at least in urology, still only conceptual (i.e. antisense molecules). Perhaps the most important learning point resulting from this pan-European multidisciplinary effort is that collaboration between all stakeholders is not only fruitful but also truly essential.

Local vs. Global Blood Flow Modulation in Artificial Microvascular Networks: Effects on Red Blood Cell Distribution and Partitioning.

Our understanding of cerebral blood flow (CBF) regulation during functional activation is still limited. Alongside with the accepted role of smooth muscle cells in controlling the arteriolar diameter, a new hypothesis has been recently formulated suggesting that CBF may be modulated by capillary diameter changes mediated by pericytes. In this study, we developed in vitro microvascular network models featuring a valve enabling the dilation of a specific micro-channel. This allowed us to investigate the non-uniform red blood cell (RBC) partitioning at microvascular bifurcations (phase separation) and the hematocrit distribution at rest and for two scenarios modeling capillary and arteriolar dilation. RBC partitioning showed similar phase separation behavior during baseline and activation. Results indicated that the RBCs at diverging bifurcations generally enter the high-flow branch (classical partitioning). Inverse behavior (reverse partitioning) was observed for skewed hematocrit profiles in the parent vessel of bifurcations, especially for high RBC velocity (i.e., arteriolar activation). Moreover, results revealed that a local capillary dilation, as it may be mediated in vivo by pericytes, led to a localized increase of RBC flow and a heterogeneous hematocrit redistribution within the whole network. In case of a global increase of the blood flow, as it may be achieved by dilating an arteriole, a homogeneous increase of RBC flow was observed in the whole network and the RBCs were concentrated along preferential pathways. In conclusion, overall increase of RBC flow could be obtained by arteriolar and capillary dilation, but only capillary dilation was found to alter the perfusion locally and heterogeneously.

Modulation of Bladder Wall Micromotions Alters Intravesical Pressure Activity in the Isolated Bladder.

Micromotions are phasic contractions of the bladder wall. During urine storage, such phasic activity has little effect on intravesical pressure, however, changed motile activity may underlie urodynamic observations such as detrusor overactivity. The potential for bladder motility to affect pressure reflects a summation of the overall movements, comprising the initiation, propagation, and dissipation components of micromotions. In this study, the influence of initiation of micromotions was investigated using calcium activated chloride channel blocker niflumic acid, and the effect of propagation using blockers of gap junctions. The overall bladder tone was modulated using isoprenaline. Isolated tissue strips and whole bladder preparations from juvenile rats were used. 18ß-glycyrrhetinic acid was used to block gap junctions, reducing the amplitude and frequency of micromotions in in vitro and ex vivo preparations. Niflumic acid reduced the frequency of micromotions but had no effect on the amplitude of pressure fluctuations. Isoprenaline resulted in a reduction in pressure fluctuations and a decrease in pressure baseline. Using visual video data analysis, bladder movement was visible, irrespective of lack of pressure changes, which persisted during bladder relaxation. However, micromotions propagated over shorter distances and the overall bladder tone was reduced. All these results suggest that phasic activity of the bladder can be characterised by a combination of initiation and propagation of movement, and overall bladder tone. At any given moment, intravesical pressure recordings are an integration of these parameters. This synthesis gives insight into the limitations of clinical urodynamics, where intravesical pressure is the key indicator of detrusor activity.

Urethane anesthesia in acute lower urinary tract studies in the male rat.

Urethane is a widely used anesthetic in animal lower urinary tract research. Our objective was to investigate the quality of anesthesia and the correlation between bladder (voiding) contractions, micturition pressure, bladder capacity and urethane dosage and body weight. Urethane was given subcutaneously and/or intraperitoneally (1.0-1.2 g/kg). The bladder was filled with saline and the bladder pressure was recorded continuously. Animals in which the subcutaneous/intraperitoneal ratio was higher needed less urethane. Heavier animals needed less extra urethane. In animals, in which no bladder contractions could be evoked, the total amount of urethane given was similar to that in those that did show contractions. In the animals that did void, the bladder never emptied completely and residual volumes remained. There was no relationship between animal weight or total amount of urethane and mean capacity. Anesthesia lasted up till 14 h, during which bladder (voiding) contractions could be recorded. Considering all results, we conclude that urethane is a well suited anesthetic for acute lower urinary tract physiological research in the intact rat.

Red blood cell phase separation in symmetric and asymmetric microchannel networks: effect of capillary dilation and inflow velocity.

The non-uniform partitioning or phase separation of red blood cells (RBCs) at a diverging bifurcation of a microvascular network is responsible for RBC heterogeneity within the network. The mechanisms controlling RBC heterogeneity are not yet fully understood and there is a need to improve the basic understanding of the phase separation phenomenon. In this context, in vitro experiments can fill the gap between existing in vivo and in silico models as they provide better controllability than in vivo experiments without mathematical idealizations or simplifications inherent to in silico models. In this study, we fabricated simple models of symmetric/asymmetric microvascular networks; we provided quantitative data on the RBC velocity, line density and flux in the daughter branches. In general our results confirmed the tendency of RBCs to enter the daughter branch with higher flow rate (Zweifach-Fung effect); in some cases even inversion of the Zweifach-Fung effect was observed. We showed for the first time a reduction of the Zweifach-Fung effect with increasing flow rate. Moreover capillary dilation was shown to cause an increase of RBC line density and RBC residence time within the dilated capillary underlining the possible role of pericytes in regulating the oxygen supply.

Wave intensity analysis in air-filled flexible vessels.

Wave intensity analysis (WIA) is an analytical technique generally used to investigate the propagation of waves in the cardiovascular system. Despite its increasing usage in the cardiovascular system, to our knowledge WIA has never been applied to the respiratory system. Given the analogies between arteries and airways (i.e. fluid flow in flexible vessels), the aim of this work is to test the applicability of WIA with gas flow instead of liquid flow. The models employed in this study are similar to earlier studies used for arterial investigations. Simultaneous pressure (P) and velocity (U) measurements were initially made in a single tube and then in several flexible tubes connected in series. Wave speed was calculated using the foot-to-foot method (cf), which was used to separate analytically the measured P and U waveforms into their forward and backward components. Further, the data were used to calculate wave intensity, which was also separated into its forward and backward components. Although the measured wave speed was relatively high, the results showed that the onsets and the nature of reflections (compression/expansion) derived with WIA, corresponded well to those anticipated using the theory of waves in liquid-filled elastic tubes. On average the difference between the experimental and theoretical arrival time of reflection was 6.1% and 3.6% for the single vessel and multivessel experiment, respectively. The results suggest that WIA can provide relatively accurate information on reflections in air-filled flexible tubes, warranting further studies to explore the full potential of this technique in the respiratory system.