A Wearable Dual-Mode Probe for Image-Guided Closed-Loop Ultrasound Neuromodulation.

Low-intensity focused ultrasound (FUS) is an emerging non-invasive and spatially/temporally precise method for modulating the firing rates and patterns of peripheral nerves. This paper describes an image-guided platform for chronic and patient-specific FUS neuromodulation. The system uses custom wearable probes containing separate ultrasound imaging and modulation transducer arrays realized using piezoelectric transducers assembled on a flexible printed circuit board (PCB). Dual-mode probes operating around 4 MHz (imaging) and 1.3 MHz (modulation) were fabricated and tested on tissue phantoms. The resulting B-mode images were analyzed using a template-matching algorithm to estimate the location of the target nerve and then direct the modulation beam toward the target. The ultrasound transmit voltage used to excite the modulation array was optimized in real-time by automatically regulating functional feedback signals (the average rates of emulated muscle twitches detected by an on-board motion sensor) through a proportional and integral (PI) controller, thus providing robustness to inter-subject variability and probe positioning errors. The proposed closed-loop neuromodulation paradigm was experimentally demonstrated in vitro using an active tissue phantom that integrates models of the posterior tibial nerve and nearby blood vessels together with embedded sensors and actuators.

Wireless and Catheter-Free Bladder Pressure and Volume Sensor.

Continuous monitoring of bladder activity during normal daily activities would improve clinical diagnostics and understanding of the mechanisms underlying bladder function, or help validate how differing neuromodulation strategies affect the bladder. This work describes a urological monitor of conscious activity (UroMOCA). The UroMOCA included a pressure sensor, urine impedance-sensing electrodes, and wireless battery recharge and data transmission circuitry. Components were assembled on a circuit board and encapsulated with an epoxy/silicone molded package that allowed Pt-Ir electrode feedthrough for urine contact. Packaged UroMOCAs measured 12 × 18 × 6 mm. UroMOCAs continuously transmitted data from all onboard sensors at 10 Hz at 30 cm range, and ran for up to 44 hours between wireless recharges. After in vitro calibration, implantations were performed in 11 animals. Animals carried the device for 28 days, enabling many observations of bladder behavior during natural, conscious behavior. In vivo testing confirmed the UroMOCA did not impact bladder function after a two-week healing period. Pressure data in vivo were highly correlated to a reference catheter used during an anesthetized follow-up. Static volume sensor data were less accurate, but demonstrated reliable detection of bladder volume decreases, and distinguished between voiding and non-voiding bladder events.

Assessing Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury: Animal Models in Preclinical Neuro-Urology Research.

Neurogenic bladder dysfunction is a condition that affects both bladder storage and voiding function and remains one of the leading causes of morbidity after spinal cord injury (SCI). The vast majority of individuals with severe SCI develop neurogenic lower urinary tract dysfunction (NLUTD), with symptoms ranging from neurogenic detrusor overactivity, detrusor sphincter dyssynergia, or sphincter underactivity depending on the location and extent of the spinal lesion. Animal models are critical to our fundamental understanding of lower urinary tract function and its dysfunction after SCI, in addition to providing a platform for the assessment of potential therapies. Given the need to develop and evaluate novel assessment tools, as well as therapeutic approaches in animal models of SCI prior to human translation, urodynamics assessment techniques have been implemented to measure NLUTD function in a variety of animals, including rats, mice, cats, dogs and pigs. In this narrative review, we summarize the literature on the use of animal models for cystometry testing in the assessment of SCI-related NLUTD. We also discuss the advantages and disadvantages of various animal models, and opportunities for future research.

A Flexible Implant for Multi-Day Monitoring of Colon Segment Activity.

Monitoring of colon activity is currently limited to tethered systems like anorectal manometry. These systems have significant drawbacks, but fundamentally limit the observation time of colon activity, reducing the likelihood of detecting specific clinical events. While significant technological advancement has been directed to mobile sensor capsules, this work describes the development and feasibility of a stationary sensor for describing the coordinated activity between neighboring segments of the colon. Unlike wireless capsules, this device remains in position and measures propagating pressure waves and impedances between colon segments to describe activity and motility. This low-power, flexible, wireless sensor-the colon monitor to capture activity (ColoMOCA) was validated in situ and in vivo over seven days of implantation. The ColoMOCA diameter was similar to common endoscopes to allow for minimally invasive diagnostic placement. The ColoMOCA included two pressure sensors, and three impedance-sensing electrodes arranged to describe the differential pressures and motility between adjacent colon segments. To prevent damage after placement in the colon, the ColoMOCA was fabricated with a flexible polyimide circuit board and a silicone rubber housing. The resulting device was highly flexible and suitable for surgical attachment to the colon wall. In vivo testing performed in eleven animals demonstrated suitability of both short term (less than 3 hours) and 7-day implantations. Data collected wirelessly from animal experiments demonstrated the ColoMOCA described colon activity similarly to wired catheters and allowed untethered, conscious monitoring of organ behavior.

First in Human Subjects Testing of the UroMonitor: A Catheter-free Wireless Ambulatory Bladder Pressure Monitor.

PURPOSE: Urodynamics is the standard method of diagnosing bladder dysfunction, but involves catheters and retrograde bladder filling. With these artificial conditions, urodynamics cannot always reproduce patient complaints. We have developed a wireless, catheter-free intravesical pressure sensor, the UroMonitor, which enables catheter-free telemetric ambulatory bladder monitoring. The purpose of this study was twofold: to evaluate accuracy of UroMonitor pressure data, and assess safety and feasibility of use in humans. MATERIALS AND METHODS: Eleven adult female patients undergoing urodynamics for overactive bladder symptoms were enrolled. After baseline urodynamics, the UroMonitor was transurethrally inserted into the bladder and position was confirmed cystoscopically. A second urodynamics was then performed with the UroMonitor simultaneously transmitting bladder pressure. Following removal of urodynamics catheters, the UroMonitor transmitted bladder pressure during ambulation and voiding in private. Visual analogue pain scales (0-5) were used to assess patient discomfort. RESULTS: The UroMonitor did not significantly alter capacity, sensation, or flow during urodynamics. The UroMonitor was also easily inserted and removed in all subjects. The UroMonitor reproduced bladder pressure, capturing 98% (85/87) of voiding and nonvoiding urodynamic events. All subjects voided with only the UroMonitor in place with low post-void residual volume. Median ambulatory pain score with the UroMonitor was rated 0 (0-2). There were no post-procedural infections or changes to voiding behavior. CONCLUSIONS: The UroMonitor is the first device to enable catheter-free telemetric ambulatory bladder pressure monitoring in humans. The UroMonitor appears safe and well tolerated, does not impede lower urinary tract function, and can reliably identify bladder events compared to urodynamics.

Detrusor Pressure Estimation from Single-Channel Urodynamics.

Urodynamics is the current gold-standard for diagnosing lower urinary tract dysfunction, but uses non-physiologically fast, retrograde cystometric filling to obtain a brief snapshot of bladder function. Ambulatory urodynamics allows physicians to evaluate bladder function during natural filling over longer periods of time, but artifacts generated from patient movement necessitate the use of an abdominal pressure sensor, which makes long-term monitoring and feedback for closed-loop treatment impractical. In this paper, we analyze the characteristics of single-channel bladder pressure signals from human and feline datasets, and present an algorithm designed to estimate detrusor pressure, which is useful for diagnosis and treatment. We utilize multiresolution analysis techniques to maximize the attenuation of probable abdominal pressure components in the vesical pressure signal. Results indicate a strong correlation, averaging 0.895 ± 0.121 (N = 40) and 0.812 ± 0.113 (N = 16) between the estimated detrusor pressure obtained by the proposed method and recorded urodynamic data from human and feline subjects, respectively. Clinical Relevance- This work establishes that signal pro-cessing techniques may be applied to vesical pressure alone to accurately reconstruct pressures generated independently by the detrusor muscle. This is relevant for emerging sensors that measure vesical pressure alone or for data analysis of bladder pressure in ambulatory subjects which contains significant abdominal pressure artifacts.

Brain-Derived Neurotrophic Factor Is an Important Therapeutic Factor in Mesenchymal Stem Cell Secretions for Treatment of Traumatic Peripheral Pelvic Injuries.

Traumatic neuromuscular injury to the pudendal nerve and urethra during childbirth does not regenerate well and contributes to stress urinary incontinence in women. Mesenchymal stem cells (MSCs) can improve neuroregeneration via their secretions, or secretome, which includes brain-derived neurotrophic factor (BDNF). In this study, we investigated whether BDNF is a key factor in the secretome of MSCs for the facilitation of functional recovery following a dual simulated childbirth injury. BDNF knockdown (KD) MSCs were created using an anti-BDNF shRNA lentivirus vector. A scrambled sequence was used as a transduction control (scrambled). Cells were cultured for 24 h before media was concentrated 50x to create concentrated conditioned media (CCM) containing MSC secretome. CCM of unmanipulated MSCs was screened for high BDNF expression (high BDNF CCM). Concentrated control media (CM) was created by concentrating media not conditioned by cells. Female Sprague-Dawley rats underwent bilateral pudendal nerve crush and vaginal distension (Injury) or sham injury. One hour and 1 week after injury, sham injured rats received CM, and injured rats received CM, high BDNF CCM, KD CCM, or scrambled CCM (300 µl intraperitoneally). Three weeks after injury, rats underwent leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings. The urethra and pudendal nerve were harvested for anatomical assessment. ANOVA followed by the Student-Newman-Keuls test determined significant differences between groups (p < 0.05). BDNF KD CCM had significantly decreased BDNF concentration compared to scrambled CCM, while the concentration in high BDNF CCM was significantly increased. LPP was significantly decreased in CM and KD CCM treated animals compared to sham injury, but not with scrambled or high BDNF CCM. PNSBP firing rate showed a significant decrease with CM treatment compared to sham injury. Neuromuscular junctions in the urethral sphincter in KD CCM, scrambled CCM, and high BDNF CCM were healthier than CM treated rats. While anatomical and nerve function tests demonstrate regeneration of the pudendal nerve with any CCM treatment, LPP results suggest it takes longer to recover continence with reduced BDNF in CCM. BDNF in MSC CCM is an important factor for the acceleration of recovery from a dual nerve and muscle injury.

A 100-V Withstanding Analog-Front-End for High-Resolution Intravascular Ultrasound Imaging.

Intravascular Ultrasound ultrasonic imaging (IVUS) can microscopically image blood vessels and reveal tissue layers from within the blood vessel lumen. It has high tissue penetration ability for lesion classification and can image through blood. Compared to optical techniques, however, IVUS has lower resolution arising from low acoustic bandwidths which cannot resolve sharp edges. The presented 100-V withstanding Analog-Front-End (AFE) was developed to enable a high resolution, low cost IVUS system using a high-bandwidth focused polymer transducer with 40-MHz center frequency. The fabricated AFE interfaced with the transducer with minimal insertion loss, could withstand and duplex 100-V high voltage pulses and echo signal, and had a total signal chain gain of 9.8 dB. The AFE achieved a signal-to-noise ratio (SNR) of 20.1 dB including the insertion loss of the high-impedance transducer. AFE SNR was limited by input impedance required for high-voltage pulse clamping circuitry, but was sufficient for IVUS echo reception.Clinical Relevance- This work has the potential to enable much higher resolution, and potentially cheaper, IVUS imaging in blood vessels by integrating low-cost acoustic transducers with interface amplifiers directly on the catheter.

Wireless Monitoring of Vascular Pressure Using CB-PDMS Based Flexible Strain Sensor.

Rising pressure within a vascular graft can signal impending failure caused by stenosis or thrombosis, and early detection can improve surgical salvage outcomes. To enable regular graft pressure monitoring, we developed a thin flexible pulsation sensor (FPS) with wireless data readout. A conductive polymer sensing layer is attached to a flexible circuit board and then encapsulated by polydimethylsiloxane (PDMS) for biocompatibility. Due to the FPS' outstanding flexibility in comparison to natural arteries, veins, and synthetic vascular grafts, it can be wrapped around target conduits to monitor blood pressure for short-term surgical and long-term implantation purposes. In this study, we analyze the power spectrum of the FPS data to determine the ideal bandwidth of the wireless FPS device to preserve heart rate and hemodynamic waveforms while rejecting noise. The strain response of FPS wrapped around silicone tube, vascular graft and artery was simulated using COMSOL®, showing a linear relationship between pressure and FPS strain. The optimized bandpass filter of 0.2-10 Hz was simulated and implemented on a flexible polyimide circuit board. The circuit board also included a low- power microcontroller for data conversion and transmission via simple 4-MHz on-off keying. The performance of the prototype was evaluated by recording wireless data from a vascular phantom under different pressure and flow settings. The results indicate that the peak-to-peak FPS voltage responds linearly to RMS blood pressure and systolic-diastolic pressure.Clinical Relevance- Early detection of a failing vascular graft could leverage sensors for near real-time monitoring. The presented wireless flexible sensor measures and transmits vessel distension data as a proxy for internal lumen pressure.

Development of Foot Displacement Detection Algorithm for Power Wheelchair Footplate Pressure and Positioning.

Inadvertent lower extremity displacement (ILED) puts the feet of power wheelchair (PWC) users at great risk of traumatic injury. Because disabled individuals may not be aware of a mis-positioned foot, a real-time system for notification can reduce the risk of injury. To test this concept, we developed a prototype system called FootSafe, capable of real-time detection and classification of foot position. The FootSafe system used an array of force-sensing resistors to monitor foot pressures on the PWC footplate. Data were transmitted via Bluetooth to an iOS app which ran a classifier algorithm to notify the user of ILED. In a pilot trial, FootSafe was tested with seven participants seated in a PWC. Data collected from this trial were used to test the accuracy of classification algorithms. A custom figure of merit (FOM) was created to balance the risk of missed positive and false positive. While a machine-learning algorithm (K nearest neighbors, FOM=0.78) outperformed simpler methods, the simplest algorithm, mean footplate pressure, performed similarly (FOM=0.62). In a real-time classification task, these results suggest that foot position can be estimated using relatively few force sensors and simple algorithms running on mobile hardware.Clinical Relevance- Foot collisions or dragging are severe or life-threatening injuries for people with spinal cord injuries. The FootSafe sensor, iOS app, and classifier algorithm can warn the user of a mis-positioned foot to reduce the incidence of injury.

Acoustic Bruit Transduction Interface for Non-Invasive Vascular Access Monitoring.

Hemodialysis is a treatment for patients suffering from chronic or acute kidney disease, and is administered via an arteriovenous vascular access. One symptom of a dysfunctional vascular access are blood sounds (bruits) produced by turbulent flow. This paper discusses the design and characterization of a multichannel transducer array to capture blood sounds from multiple sites simultaneously. Recorded sounds can be classified by digital signal analysis to categorize severity of dysfunction based on acoustic features. Using a vascular access phantom with 5-80% degree of stenosis and blood mimicking fluid flowing at a rate of 850-1200 mL/min, we analyzed the acoustic properties of blood sounds recorded from a flexible microphone transducer. The signal bandwidth (2.25 kHz) and the dynamic range (60.2 dB) were determined, allowing optimization of a transimpedance transducer interface amplifier.Clinical Relevance-Vascular access stenosis causing turbulent flow produces bruits with spectral content related to degree of stenosis. A flexible microphone recording array could be used for point-of-care monitoring of vascular access function.

Feasibility of Real-Time Conditional Sacral Neuromodulation Using Wireless Bladder Pressure Sensor.

Continuous sacral neuromodulation (SNM) is used to treat overactive bladder, reducing urine leakage and increasing capacity. Conditional SNM applies stimulation in response to changing bladder conditions, and is an opportunity to study neuromodulation effects in various disease states. A key advantage of this approach is saving power consumed by stimulation pulses. This study demonstrated feasibility of automatically applying neuromodulation using a wireless bladder pressure sensor, a real-time control algorithm, and the Medtronic Summit™ RC+S neurostimulation research system. This study tested feasibility of four conditional SNM paradigms over five days in 4 female sheep. Primary outcomes assessed proof of concept of closed-loop system function. While the bladder pressure sensor correlated only weakly to simultaneous catheter-based pressure measurement (correlation 0.26-0.89, median r = 0.52), the sensor and algorithm were accurate enough to automatically trigger SNM appropriately. The neurostimulator executed 98.5% of transmitted stimulation commands with a median latency of 72 ms (n = 1,206), suggesting that rapid decision-making and control is feasible with this platform. On average, bladder capacity increased for continuous SNM and algorithm-controlled paradigms. Some animals responded more strongly to conditional SNM, suggesting that treatment could be individualized. Future research in conditional SNM may elucidate the physiologic underpinnings of differential response and enable clinical translation.

Transurethral versus suprapubic catheterization to test urethral function in rats.

Transurethral and suprapubic catheterization have both been used to test urethral function in rats; however, it is unknown whether these methods affect urethral function or if the order of catheterization affects the results. The aim of this cross-over designed experiment was to compare the effects of catheterization methods and order on leak point pressure (LPP) testing. LPP and simultaneous external urethral sphincter electromyography (EUS EMG) were recorded in anesthetized female virgin Sprague-Dawley rats in a cross-over design to test the effects of transurethral and suprapubic catheterization. There was no significant difference in peak bladder pressure during LPP testing whether measured with a transurethral or suprapubic catheter. There was no significant difference in peak bladder pressure between the first and second catheter insertions. However, peak EMG firing rate, as well as peak EMG amplitude and EMG amplitude difference between peak and baseline were significantly higher after the first catheter insertion compared to the second insertion, regardless of the catheter method. Our results suggest that route of catheterization does not alter urethral function, e.g. create a functional partial outlet obstruction. Either catheterization method could be used for LPP and/or EUS EMG testing in rats.

Flexible Body-Conformal Ultrasound Patches for Image-Guided Neuromodulation.

The paper presents the design and validation of body-conformal active ultrasound patches with integrated imaging and modulation modalities for image-guided neural therapy. A mechanically-flexible linear 64-element array of piezoelectric transducers with a resonance frequency of 5 MHz was designed for nerve localization. A second 8-element array using larger elements was integrated on the wearable probe for low intensity focused ultrasound neuromodulation at a resonance frequency of 1.3 MHz. Full-wave simulations were used to model the flexible arrays and estimate their generated pressure profiles. A focal depth of 10-20 mm was assumed for beamforming and focusing to support modulation of the vagus, tibial, and other nerves. A strain sensor integrated on the probe provides patient-specific feedback information on array curvature for real-time optimization of focusing and image processing. Each patch also includes high voltage (HV) multiplexers, transmit/receive switches, and pre-amplifiers that simplify connectivity and also improve the signal-to-noise ratio (SNR) of the received echo signals by  âˆ¼ 5 dB. Experimental results from a flexible prototype show a sensitivity of 80 kPa/V with  âˆ¼ 3 MHz bandwidth for the modulation and 20 kPa/V with  âˆ¼ 6 MHz bandwidth for the imaging array. An algorithm for accurate and automatic localization of targeted nerves based on using nearby blood vessels (e.g., the carotid artery) as image markers is also presented.

Flexible, Skin Coupled Microphone Array for Point of Care Vascular Access Monitoring.

Point-of-care screening for hemodialysis vascular access dysfunction requires tools that are objective and efficient. Listening for bruits during physical exam is a subjective examination which can detect stenosis (vascular narrowing) when properly performed. Phonoangiograms (PAGs)-mathematical analysis of bruits-increases the objectivity and sensitivity and permits quantification of stenosis location and degree of stenosis (DOS). This work describes a flexible and body-conformal multi-channel sensor and associated signal processing methods for automated DOS characterization of vascular access. The sensor used an array of thin-film PVDF microphones integrated on polyimide to record bruits at multiple sites along a vascular access. Nonlinear signal processing was used to extract spectral features, and cardiac cycle segmentation was used to improve sensitivity. PAG signal processing algorithms to detect stenosis location and severity are also presented. Experimental results using microphone arrays on a vascular access phantom demonstrated that stenotic lesions were detected within 1 cm of the actual location and graded to three levels (mild, moderate, or severe). Additional PAG features were also used to define a simple binary classifier aimed at patients with failing vascular accesses. The classifier achieved 90% accuracy, 92% specificity, and 91% sensitivity at detecting stenosis greater than 50%. These results suggest that point-of-care screening using microphone arrays can identify at-risk patients using automated signal analysis.

Vascular Pressure-Flow Measurement Using CB-PDMS Flexible Strain Sensor.

Regular monitoring of blood flow and pressure in vascular reconstructions or grafts would provide early warning of graft failure and improve salvage procedures. Based on biocompatible materials, we have developed a new type of thin, flexible pulsation sensor (FPS) which is wrapped around a graft to monitor blood pressure and flow. The FPS uses carbon black (CB) nanoparticles dispersed in polydimethylsiloxane (PDMS) as a piezoresistive sensor layer, which was encapsulated within structural PDMS layers and connected to stainless steel interconnect leads. Because the FPS is more flexible than natural arteries, veins, and synthetic vascular grafts, it can be wrapped around target conduits at the time of surgery and remain implanted for long-term monitoring. In this study, we analyze strain transduction from a blood vessel and characterize the electrical and mechanical response of CB-PDMS from 0-50% strain. An optimum concentration of 14% CB-PDMS was used to fabricate 300-µm thick FPS devices with elastic modulus under 500 kPa, strain range of over 50%, and gauge factor greater than 5. Sensors were tested in vitro on vascular grafts with flows of 0-1,100 mL/min. In vitro testing showed linear output to pulsatile flows and pressures. Cyclic testing demonstrated robust operation over hundreds of cardiac cycles, with ±2.6 mmHg variation in pressure readout. CB-PDMS composite material showed excellent potential in biologic strain sensing applications where a flexible sensor with large maximum strain range is needed.

Bruit-enhancing phonoangiogram filter using sub-band autoregressive linear predictive coding.

Subjective analysis of bruits has long been an element of vascular access physical exams. Digital recordings of blood flow bruits-phonoangiograms (PAGs)-may provide an objective, non-imaging measure of vascular access stenosis. We have analyzed the long-term stability in PAGs from typical dialysis patients with arteriovenous fistulas and grafts and found that typical patients have correlated PAG spectra. PAGs can be analyzed using nonlinear, sub-band frequency-domain linear prediction to produce both bruit-enhanced recordings and a bruit-enhanced power envelope. This approach is novel over prior methods because it adaptively predicts signal envelopes based on physiologic properties of blood flow determined from chronic dialysis recipients. Our results indicate that a generalized bruit-enhancing filter can be developed for dialysis vascular access. Outputs from this filter may be analyzed to determine vascular physiology, including re-stenosis risk.

A Conductance-Based Sensor to Estimate Bladder Volume in Felines.

New research tools are essential to help understand the neural control of the lower urinary tract (LUT). A more nuanced understanding of the neuroanatomy of bladder function could enable new treatment options or neuroprosthesis to eliminate incontinence. Here we describe the design, prototyping and validation of a sensing mechanism for a catheter-free fluid volume estimating system for chronic neurophysiological studies of the lower urinary tract and ambulatory urodynamics. The system consists of two stimulation electrodes, one sensing anode, and a microcontroller for control and recording. The packaged device is small enough to be surgically implanted within the bladder lumen, where it does not inhibit bladder function nor inflict trauma. Benchtop evaluation of the conductance-sensing system in simulated bladder-like conditions has demonstrated that the system can predict intra-vesical fluid volume with $< 5$ mL mean error below 40mL and worst-case mean error of 13mL near full-scale volume. These results indicate that conductance-based volume sensing of the urinary bladder is a feasible method for real-time measurement.

Sensors Selection for Continuous Monitoring of Bowel State and Activity.

New research and diagnosis tools are needed to continuously measure bowel state and activity. We investigated functionality of several sensors in vivo and in vitro. Five sensor types, including pressure, infrared, color, conductivity and capacitance, were tested to validate functionality inside the colon. Initial wired prototypes were tested and calibrated in benchtop testing and then inserted intraluminally into pig colon and rectum in three acute surgical procedures. The results from both benchtop and in-vivo testing correlate and indicate that pressure, conductivity, and capacitance measurements could provide information on the state of the bowel and its activity.