Glass half full: Non-invasive bladder biosensors for urinary volume monitoring in the neurogenic pediatric population

Abstract

Purpose

The goal was to elucidate and present the current landscape of bladder biosensor technology for urinary volume monitoring in the management of neurogenic bladder. The need for such technology in managing neurogenic bladder in the pediatric population is discussed, as well as the challenges researchers currently face in advancing individual technologies.

Methods

A literature review including 43 articles discussing bladder biosensor and related technology for continuous urinary volume monitoring was conducted. Articles ranged from original research studies to systematic reviews.

Results

Various continuous bladder urine volume monitoring devices have been proposed and evaluated. These devices utilize principles of ultrasound, electrical impedance tomography, near infrared spectroscopy, pressure biosensor implantation, microwave radar, and frequency modulated continuous wave radar. While several studies have shown promise in correlating device measurements to bladder urinary volume changes, ultimately researchers have not been able to surmount the challenges of optimizing configuration of device components and the impacts of dynamic position, posture, body habitus, bladder location, and urine biochemical properties that demonstrate high interpersonal variability.

Conclusion

The need for developing bladder biosensor technology to provide continuous urine volume monitoring in patients with neurogenic bladder remains great. Transitioning from a time-based clean intermittent catheterization approach to a volume-based approach would possibly improve neurogenic bladder patients’ quality of life. While technologies face limitations that have stalled translation to clinical practice, there is potential to build upon past work to address current challenges and meet this ever-pressing need.

Introduction

Neurogenic bladder is a condition resulting from central and peripheral nervous system lesions such as spina bifida, lumbosacral myelomeningocele, cerebral palsy, spinal cord injury, and more rarely, cerebral and spinal tumors. ¹ Disruptions of neural connections with the lower urinary tract cause problems with bladder storage and emptying, which places children at risk of developing hydronephrosis, vesicoureteral reflux, urinary tract infections (UTIs), and renal scarring which may ultimately progress to end stage renal disease. ² Many children with neurogenic bladder have little to no bladder sensation and thus no awareness of bladder filling or desire to empty at high urine volumes. A normally compliant bladder can accommodate urine with almost no rise in pressure. ³ However, some patients with neurogenic bladder have lower functional volumes and increased pressures.

Patients with neurogenic bladder are monitored every six to 12 months, depending upon age and history, with sonography to surveille the kidneys. In addition, urodynamics are utilized to measure bladder volume and pressure. These values are interpreted and treated by providers to help increase bladder volume and lower pressure with medications, and sometimes surgery, to improve incontinence and protect the kidneys.

Currently, most patients are managed via a time-based regimen of clean intermittent catheterization (CIC) every two to four hours to prevent elevated pressures. ⁴ However, maintaining such a strict schedule can be largely inconvenient and compromise patients’ quality of life. Additionally, patients may have low urine volumes that do not require bladder emptying at time of catheterization or, conversely, experience leakage prior to catheterization. ⁵ As such, some patients tailor their CIC schedule based upon fluid intake and accrued experience with bladder volumes and incontinence. Goals of neurogenic bladder management include optimizing bladder function to prevent injury to the urinary tract, prevention of UTI, and helping patients achieve urinary continence. ⁴ This brief report characterizes the current landscape of continuous bladder urine volume monitoring technology.

Ultrasound

Ultrasound is a modality commonly used across clinical settings to measure urine volume at a single time point. Current ultrasound devices used to measure full bladder volume include the conventional B-mode ultrasound and the BladderScan. However, these devices are limited by their bulky size and high cost, inability to alert patients when a critical threshold for voiding is reached, and requirement for operation by a skilled professional. ⁶ Furthermore, measurements produced by these systems are highly susceptible to positional changes and body habitus. While studies have explored the development of small portable bladder monitors to detect a full bladder, none have been evaluated during natural bladder filling or tested among children.^7–11

Kristiansen et al. evaluated the BladderManager PCI 5000 device, which comprises a single ultrasonic crystal and indicates whether the bladder is empty or full based on the presence of the posterior bladder wall over the pubic symphysis. ¹² In this study, the device was found to underestimate bladder volume with measurements being especially inaccurate among obese patients and female participants, whose bladders were generally located behind the pubic symphysis. A study conducted by Seif et al. evaluated an ultrasound sensor implanted behind the pubic symphysis and measured changes in running time of transmitted signals as bladder anterior-posterior (A-P) diameter changed with urine filling. ¹³ At lower volumes of less than 100 mL, the system generated values that differed largely from true urine volume. However at volumes exceeding 100 mL, there was no significant deviation from true urine volumes. Moreover, the authors speculated that accuracy of the device could decrease with long-term use due to fibrotic tissue changes in areas interfacing with the implanted device.

A study conducted by van Leuteren et al. evaluated the wearable SENS-U device, which uses four ultrasound transducers to estimate bladder urine volume status and notifies users when the bladder is full. In a population of 30 children, the device successfully alerted users when their bladder was full 90% of the time. ¹⁴ Van Leuteren et al. developed a similarly wearable and wireless URIKA device, which estimates A-P bladder dimension and alerts patients when the A-P diameter reaches a critical threshold. In this study, the device measured properly in 13 out of 14 children with dysfunctional voiding and concluded that their device could sense a full bladder with a detection rate of 71% using a 5.03 cm threshold. ⁶

Fournelle et al. developed MoUsE, a newer portable ultrasound device, consisting of 32 transmitters and receivers allowing for dynamic bladder reconstruction and imaging. ¹⁵ While the authors deemed adequate sensitivity when testing the device in four human volunteers, they suggested further improvement of the device for precise bladder urinary volume measurements.

Biosensor implants

Implantable bladder biosensors were developed as an alternative to noninvasive monitoring methods using sound or electromagnetic radiation which may be inaccurate due to interfering interactions with adjacent tissue and fluids. ¹⁶ Several types of biosensor implant systems have been developed. A system developed by Dreher et al. utilized a transmitter reed switch and magnet sutured to the bladder detrusor muscle. ¹⁷ As bladder volume increases, the distance between the magnet and reed switch similarly increases, activating a telemetry oscillator. However, this system was not readily applicable to patients with neurogenic bladders subject to chronic overdistension and poor detrusor muscle contractility. ¹⁸ A study testing a similar system by Woltjen et al. found that implantation could trigger a local inflammatory and fibrotic process that would influence bladder wall compliance and thus interfere with sensor readings. Additionally, any system that uses magnets is subject to accuracy errors due to Earth's ubiquitous magnetic fields, which affect measuring performance. ¹⁹

Wang et al. designed a permanent magnet system, which migrated cranially with an increase in bladder volume and caudally with a decrease in volume. ²⁰ Changes in the magnet position subsequently changed the direction of the magnet field where the central fulcrum of the sensor was located. When the system's hand turned to connect with the fulcrum, the sensor circuit would close and alert the patient to urinate. When testing this system on an animal model, the authors found that the mean filling volume that triggered the sensor to sound was 148 mL with a standard deviation of less than 15 mL (10%). While potentially promising, Wang et al. suggested that implantation of such a device could be invasive, and similar to other studies, patients would need to avoid objects causing strong magnetic fields. Lee et al. evaluated a monitoring device applying microelectromechanical systems engineering in a small animal model and found that between filling volumes of 0.6 mL and 1.8 mL, there was no statistical difference between measured and true urine volumes. ²¹ However, outside of this range, the device tended to overestimate urine volume. Many patients with neurogenic bladder require magnetic resonance imaging (MRI) of the brain and other body parts. Metal, and particularly magnetic implants, can move when exposed to the powerful magnetic fields of MRI scanners. These issues have not been addressed.

Biosensor implants that monitor pressure, rather than volume, have been proposed as an alternative means of long-term monitoring. One such device developed by Kim et al. used an acoustic signal produced by an outside speaker to cause a material called piezoelectric ceramic to vibrate, allowing transmission and measurement of the signal. ²² However, pressure-monitoring implants are potentially detrimental to patients due to sustained bladder pressures that may injure the upper urinary tract. ²³ Additionally, the pressure threshold at which the alarm is triggered occurs very close to a point of urinary leakage for neurogenic bladder patients, who may not have sufficient time to catheterize before leakage occurs.

Bioelectrical impedance tomography

As part of bioelectrical or electrical impedance tomography (EIT), electrodes are placed around the body, and a small alternating current (AC) is injected into two of these electrodes. ²⁴ Resulting surface voltages are measured between the remaining electrodes and provide information about cross-sectional impedance, which is ultimately mapped to an image. ²² Using EIT, Sharma et al. demonstrated the ability to accurately estimate bladder boundaries via a gravitational search algorithm when urine conductivity distribution was known prior. ²⁴ An earlier study demonstrated a strong negative correlation between bladder volume and lower abdomen impedance. ²⁵ This technology is currently used to determine lung air flow due to air being a good isolator. ²⁴ However, given that urine has almost an equivalent electrical conductivity as adjacent tissue, estimates of bladder volume may be inaccurate. When comparing EIT with ultrasonographic measurements in nine paraplegic patients, Leonhauser et al. found that EIT measurements were more accurate than standard sonographic measurement techniques. However, when estimating residual urine, mean error for EIT was higher than other modalities. ²⁶ Ultimately, no correlation could be made between measured impedance and bladder urinary volume.

Noguchi et al. built a urinary bladder volume measurement circuit using a four-terminal system. Their circuit used small phase difference measurements and could determine change in impedance in relation to urine volume and change in phase difference corresponding to bladder shape. ²⁷ Small phase difference measurement allows optimal accuracy but in return, requires fine amplitude adjustment which is susceptible to operator error. After testing on one human participant, the authors observed a tendency for both impedance and phase difference to increase after urination and decrease shortly after.

Vafi et al. demonstrated a consistent correlation between bio-impedance measured data and urine volume in each of five porcine bladders and proposed development of a battery-powered device that can be placed in a patient's lower abdomen. ⁵ They raise the potential for connecting bladder biosensor technology to advanced alert mechanisms including smart device notifications, ringtones, and vibrating devices that turn off as bladder urine volume decreases.

Li et al. conducted an experiment using a four-electrode configuration on porcine bladders placed in a tank filled with saline solution, with conductivity similar to that of human body fat, and an observational study involving six male volunteers. ²⁸ They found that bladder urinary changes were highly correlated with impedance changes measured by EIT. However, they suggested that numerous factors could decrease the sensitivity of EIT measurements, and identification of bladder area can be an issue. Because urinary volume and conductivity changes in bladder occur slowly, it may be challenging to distinguish corresponding cross-sectional impedance changes. Studies suggest that the sensitivity of impedance measurements decreases when urine volume increases.^29,30 Various studies have elucidated the impact of factors such as central adiposity; proximity of neighboring tissue and organs such as muscles, prostate tissue, and intestines; abdominal muscle contractions; electrode positioning; varying urinary conductivity; and physical movement on EIT measurement.^22,26,28,31 Furthermore, an AC injection may stimulate detrusor contractions, thus causing discomfort for patients. As Li et al. suggest, development of 3D EIT systems which entail more complicated electrode arrangements, and thus more accurate image reconstruction, may help researchers achieve increasingly accurate EIT impedance measurements.

Near-infrared spectroscopy (NIRS)

NIRS involves application of near-infrared light into tissue and analyzing tissue oxygenation and hemodynamics via measuring changes in the concentration of compounds called chromophores that absorb NIR light.^32–34 Changes in oxyhemoglobin and deoxyhemoglobin have been utilized to evaluate bladder function. A pilot study by Macnab et al. of 15 male volunteers demonstrated that changes in chromophore concentration in detrusor muscle could be measured during voiding. ³⁵ Building off these studies, Molavi et al. applied NIR technology to measure changes in bladder urine volume under the assumption that as bladder urine volume rises, light absorption increases, thus causing a decrease in light intensity that returns to the NIRS sensing device. In concordance with their hypothesis, the authors found a consistent decrease in light absorption between pre- and post-void states in each participant at a wavelength of 950 nm. ³⁶ Moreover, Fong et al. built a system consisting of multiple high-power light-emitting diodes with a peak wavelength of 970 nm and evaluated it on one human participant. ³⁷ They found a significant decrease in light intensity when comparing pre- and post-void bladder states, supporting the potential for future clinical trials to evaluate this technology on a larger scale. However, the impacts of differing body wall composition including fat and muscle, bladder shapes, and optode configurations on NIRS measurements remains to be addressed.

Other technologies

Additional technologies for continuous bladder urinary volume monitoring include ultra wideband (UWB), frequency modulated continuous wave (FMCW) radar, and potentiometry. UWB is an imaging modality commonly used for detecting breast cancer. Technicians can create an image based on back-scattered electromagnetic energy emitted from microwave scatterers within the tissue of interest. ³⁸ Krewer et al. conducted a study on male and female pelvis models incorporating different bladder sizes using UWB. They found that antenna movements as small as 1 cm could markedly decrease bladder status classification accuracy, which mirrored past studies concluding that this system would be vulnerable to patient movement.^39,40

FMCW is a newer radar-type device characterized by a probe consisting of small antennas which can be placed on a patient's lower abdomen. The radar transceiver and signal processor are located above the sensing probe and within the patient's waist belt. ⁵ Through this system, the transceiver generates a chirp waveform that interacts with the signal processor, causing phase modulation and a part of the waveform being reflected back toward the transceiver. This produces a frequency value, which can be correlated to urine volume. ⁵ Using MATLAB simulations to simulate signal paths through different organs to the bladder, Vafi et al. mapped urine volume to the frequency domain. ⁵ After conducting an ex-vivo experiment on a porcine bladder, the authors concluded that FMCW radar could be used to monitor urine volume. Of note, it is unknown what impact movement and various patient postures could have on measurements and whether prolonged exposure to high-frequency FMCW could injure adjacent tissue structures.

Chen et al. evaluated a potentiometric system consisting of a power unit, flexible potentiometric module, and a wireless transmission module. ⁴¹ Through this system, the power unit supplies a constant current to the flexible potentiometric and wireless transmission modules. The flexible potentiometer generates a resistance value based on changes in bladder wall length, which is sent by the wireless transmission module. The authors posited that they could correctly capture bladder capacity with an error of less than 3% but noted that the device may be physically too large for surgical implantation in its current state, would require a different power source for long-term implantation, and could cause local tissue irritation.

Conclusion

Current management of neurogenic lower urinary tract dysfunction has significant quality of life implications for patients. Developing continuous bladder urinary volume monitoring devices that can accurately capture bladder volume status and alert patients may reduce the burden of frequent time-based CIC. Ultrasound, pressure/volume-based biosensor implants, EIT, NIRS, microwave radars including UWB and FMCW, and potentiometry have been investigated as potential avenues for bladder biosensor device development. While so far studies have shown promise, there are numerous challenges that make translation of prototype devices to larger scale trials difficult. Nonetheless, such technologies might allow children with neurogenic bladder to protect their kidneys, gain urinary continence, and achieve independence.