Assessing renal tissue temperature changes and perfusion effects during laser activation in an in vivo porcine model.

INTRODUCTION: High fluid temperatures have been seen in both in vitro and in vivo studies with laser lithotripsy, yet the thermal distribution within the renal parenchyma has not been well characterized. Additionally, the heat-sink effect of vascular perfusion remains uncertain. Our objectives were twofold: first, to measure renal tissue temperatures in response to laser activation in a calyx, and second, to assess the effect of vascular perfusion on renal tissue temperatures. METHODS: Ureteroscopy was performed in three porcine subjects with a prototype ureteroscope containing a temperature sensor at its tip. A needle with four thermocouples was introduced percutaneously into a kidney with ultrasound guidance to allow temperature measurement in the renal medulla and cortex. Three trials of laser activation (40W) for 60 s were conducted with an irrigation rate of 8 ml/min at room temperature in each subject. After euthanasia, three trials were repeated without vascular perfusion in each subject. RESULTS: Substantial temperature elevation was observed in the renal medulla with thermal dose in two of nine trials exceeding threshold for tissue injury. The temperature decay time (t½) of the non-perfused trials was longer than in the perfused trials. The ratio of t½ between them was greater in the cortex than the medulla. CONCLUSION: High-power laser settings (40W) can induce potentially injurious temperatures in the in vivo porcine kidney, particularly in the medullary region adjacent to the collecting system. Additionally, the influence of vascular perfusion in mitigating thermal risk in this susceptible area appears to be limited.

The impact of siphoning effect on renal pelvis pressure during ureteroscopy using an in vitro kidney and ureter model.

PURPOSE: To experimentally measure renal pelvis pressure (PRP) in an ureteroscopic model when applying a simple hydrodynamic principle, the siphoning effect. METHODS: A 9.5Fr disposable ureteroscope was inserted into a silicone kidney-ureter model with its tip positioned at the renal pelvis. Irrigation was delivered through the ureteroscope at 100 cm above the renal pelvis. A Y-shaped adapter was fitted onto the model's renal pelvis port, accommodating a pressure sensor and a 4 Fr ureteral access catheter (UAC) through each limb. The drainage flowrate through the UAC tip was measured for 60 s each run. The distal tip of the UAC was placed at various heights below or above the center of the renal pelvis to create a siphoning effect. All trials were performed in triplicate for two lengths of 4Fr UACs: 100 cm and 70 cm (modified from 100 cm). RESULTS: PRP was linearly dependent on the height difference from the center of the renal pelvis to the UAC tip for both tested UAC lengths. In our experimental setting, PRP can be reduced by 10 cmH20 simply by lowering the distal tip of a 4 Fr 70 cm UAC positioned alongside the ureteroscope by 19.7 cm. When using a 4 Fr 100 cm UAC, PRP can drop 10 cmH20 by lowering the distal tip of the UAC 23.3 cm below the level of the renal pelvis. CONCLUSION: Implementing the siphoning effect for managing PRP during ureteroscopy could potentially enhance safety and effectiveness.

Change in renal blood flow in response to intrarenal pressure alterations induced by ureteroscopy in an in-vivo porcine model.

INTRODUCTION: High irrigation rates are commonly used during ureteroscopy and can increase intrarenal pressure (IRP) substantially. Concerns have been raised that elevated IRP may diminish renal blood flow (RBF) and perfusion of the kidney. Our objective was to investigate the real-time changes in RBF while increasing IRP during Ureteroscopy (URS) in an in-vivo porcine model. METHODS: Four renal units in two porcine subjects were used in this study, three experimental units and one control. For the experimental units, RBF was measured by placing an ultrasonic flow cuff around the renal artery, while performing ureteroscopy in the same kidney using a prototype ureteroscope with a pressure sensor at its tip. Irrigation was cycled between two rates to achieve targeted IRPs of 30 mmHg and 100 mmHg. A control data set was obtained by placing the ultrasonic flow cuff on the contralateral renal artery while performing ipsilateral URS. RESULTS: At high IRP, RBF was reduced in all three experimental trials by 10-20% but not in the control trial. The percentage change in RBF due to alteration in IRP was internally consistent in each porcine renal unit and independent of slower systemic variation in RBF encountered in both the experimental and control units. CONCLUSION: RBF decreased 10-20% when IRP was increased from 30 to 100 mmHg during ureteroscopy in an in-vivo porcine model. While this reduction in RBF is unlikely to have an appreciable effect on tissue oxygenation, it may impact heat-sink capacity in vulnerable regions of the kidney.

Quantification of outflow resistance for ureteral drainage devices used during ureteroscopy.

PURPOSE: Since renal pelvis pressure is directly related to irrigation flowrate and outflow resistance, knowledge of outflow resistance associated with commonly used drainage devices could help guide the selection of the type and size of ureteral access sheath or catheter for individual ureteroscopic cases. This study aims to quantitatively measure outflow resistance for different drainage devices utilized during ureteroscopy. METHODS: With measured irrigation flowrate and renal pelvis pressure, outflow resistance was calculated using a hydrodynamic formula. After placement of a drainage device into a silicone kidney-ureter model, a disposable ureteroscope with a 9.5-Fr outer diameter was inserted with its tip positioned at the renal pelvis. Irrigation was delivered through the ureteroscope from varying heights above the renal pelvis. Renal pelvis pressure was measured directly from the port of the kidney model using a pressure sensor (Opsens, Canada). Outflow resistance was determined by plotting flowrate versus renal pelvis pressure. All trials were performed in triplicate for each drainage device inserted. RESULTS: Flowrate was linearly dependent on renal pelvis pressure for all drainage devices tested. Outflow resistance values were 0.2, 1.1, 1.4, 3.9, and 6.5 cmH2O/[ml/min] for UAS 13/15 Fr, UAS 11/13 Fr, UAC 6 Fr, UAC 4.8 Fr, and UAC 4.0 Fr, respectively, across the range of commonly used irrigation flowrates. CONCLUSIONS: In this study, outflow resistance of different ureteral drainage devices was quantitatively measured. This knowledge can be useful when selecting which type and size of drainage device to insert to maintain safe renal pelvis pressure during ureteroscopy.

Aberration correction in abdominal histotripsy.

In transabdominal histotripsy, ultrasound pulses are focused on the body to noninvasively destroy soft tissues via cavitation. However, the ability to focus is limited by phase aberration, or decorrelation of the ultrasound pulses due to spatial variation in the speed of sound throughout heterogeneous tissue. Phase aberration shifts, broadens, and weakens the focus, thereby reducing the safety and efficacy of histotripsy therapy. This paper reviews and discusses aberration effects in histotripsy and in related therapeutic ultrasound techniques (e.g., high intensity focused ultrasound), with an emphasis on aberration by soft tissues. Methods for aberration correction are reviewed and can be classified into two groups: model-based methods, which use segmented images of the tissue as input to an acoustic propagation model to predict and compensate phase differences, and signal-based methods, which use a receive-capable therapy array to detect phase differences by sensing acoustic signals backpropagating from the focus. The relative advantages and disadvantages of both groups of methods are discussed. Importantly, model-based methods can correct focal shift, while signal-based methods can restore substantial focal pressure, suggesting that both methods should be combined in a 2-step approach. Aberration correction will be critical to improving histotripsy treatments and expanding the histotripsy treatment envelope to enable non-invasive, non-thermal histotripsy therapy for more patients.

Development of an automated laser drilling algorithm to compare stone ablation patterns from different laser pulse modes.

PURPOSE: To develop a novel automated three-dimensional (3D) laser drilling algorithm to further investigate laser-stone interaction with different laser pulse modes. Comparison of post-ablative lattice architecture combined with mass of stone ablated can provide a more complete understanding of differences between pulse mode. METHODS: A 3D positioner (securing laser fiber) was programmed to create a 5 × 5 grid of drill holes spaced 1 mm apart on 15:5 cylindrical BegoStones. Beginning 0.5 mm above the stone surface, the laser fiber was activated and advanced 2 mm toward and into the stone for all 25 points. Four trials for each pulse mode [short pulse (SP), long pulse (LP), Moses Contact (MC), Moses Distance (MD)] were completed. Outcome measures were assessment of lattice preservation and mass of ablated stone. RESULTS: MC exhibited the greatest lattice preservation and least stone mass ablated (50.5 ± 2.2 mg). SP (69.4 ± 4.3 mg) and MD (70.0 ± 2.6 mg) had the greatest lattice destruction and stone mass ablated. The differences in stone ablated between MC and MD (p = 0.00003), MC and SP (p = 0.0002), and LP and MD (p = 0.004) were statistically significant. CONCLUSIONS: Consistent quantitative and qualitative differences between pulse modes were observed with a novel automated 3D laser drilling algorithm applied to BegoStone. The laser drilling algorithm developed here can be used to further enhance mechanistic understanding of laser-stone interactions and facilitate selection of appropriate laser pulse modes to balance precision and efficiency across the range of laser lithotripsy techniques.

Laser operator duty cycle effect on temperature and thermal dose: in-vitro study.

PURPOSE: High-power laser lithotripsy can elevate temperature within the urinary collecting system and increase risk of thermal injury. Temperature elevation is dependent on power settings and operator duty cycle (ODC)-the percentage of time the laser pedal is depressed. The objective of this study was to quantify temperature and thermal dose resulting from laser activation at different ODC in an in-vitro model. METHODS: Holmium laser energy (1800 J) was delivered at 30 W (0.5 J × 60 Hz) to a fluid filled glass bulb. Room temperature irrigation was applied at 8 ml/min. ODC was evaluated in 10% increments from 50-100%. Bulb fluid temperature was recorded and thermal dose calculated. Time to reach threshold of thermal injury and maximal allowable energy were also determined at each ODC. RESULTS: Upon laser activation, there was an immediate rise in fluid temperature with a "saw-tooth" oscillation superimposed on the curves for 50-90% ODC corresponding to periodic activation of the laser. Higher ODC resulted in greater maximum temperature and thermal dose, with ODC ≥ 70% exceeding threshold. Use of 50% compared to 60% ODC resulted in a tenfold increase in time required to reach threshold of thermal injury and an eightfold increase in maximal allowable energy. CONCLUSIONS: Laser activation at higher ODC produced greater fluid temperature and thermal dose. Time to threshold of thermal injury and maximal allowable energy were dramatically higher for 50% compared to 60% ODC at high-power settings. Proper management of laser ODC can enhance patient safety and optimize stone treatment.

Pulse modulation with Moses technology improves popcorn laser lithotripsy.

PURPOSE: Moses™ technology has been developed to improve holmium laser fragmentation at 1-2 mm distance from the stone. Because popcorn lithotripsy is a non-contact technique, we compared short pulse (SP) and Moses distance (MD) modes in an in vitro model. METHODS: BegoStones were fragmented using a 120 W Ho:YAG laser (P120 Moses) and a 230 µm core fiber introduced through a ureteroscope. 20 W (1 J × 20 Hz; 0.5 J × 40 Hz) and 40 W (1 J × 40 Hz; 0.5 J × 80 Hz) settings (total energy 4.8 kJ) were tested using SP and MD modes. We assessed fragment size distribution and mass lost in fluid (initial mass-final dry mass of all sievable fragments). High-speed video analysis of fragmentation strike rate and vapor bubble characteristics was conducted for 1 J × 20 Hz and 0.5 J × 80 Hz. Laser strike rate (number of strikes divided by frequency) was categorized as: (1) direct-a visual plume of dust ejected from stone while in contact with fiber tip; (2) indirect-a visual plume of dust ejected with distance between stone and fiber tip. RESULTS: For 1 J × 20 Hz (20 W), MD resulted in more mass lost in fluid and a lower distribution of fragments ≥ 2 mm compared to SP (p < 0.05). 0.5 J × 80 Hz (40 W) produced no fragments ≥ 2 mm, and there were no significant differences in fragment distribution between MD and SP (p = 0.34). When using MD at 1 J × 20 Hz, 96% of strikes were indirect vs 61% for SP (p = 0.059). In contrast to the single bubble of SP, with MD, there was forward movement of the collapsing second bubble, away from the fiber-tip. CONCLUSIONS: For lower frequency and power popcorn settings, pulse modulation results in more fragmentation through true non-contact laser lithotripsy.

Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound.

Histotripsy is the first noninvasive, non-ionizing, and non-thermal ablation technology guided by real-time imaging. Using focused ultrasound delivered from outside the body, histotripsy mechanically destroys tissue through cavitation, rendering the target into acellular debris. The material in the histotripsy ablation zone is absorbed by the body within 1-2 months, leaving a minimal remnant scar. Histotripsy has also been shown to stimulate an immune response and induce abscopal effects in animal models, which may have positive implications for future cancer treatment. Histotripsy has been investigated for a wide range of applications in preclinical studies, including the treatment of cancer, neurological diseases, and cardiovascular diseases. Three human clinical trials have been undertaken using histotripsy for the treatment of benign prostatic hyperplasia, liver cancer, and calcified valve stenosis. This review provides a comprehensive overview of histotripsy covering the origin, mechanism, bioeffects, parameters, instruments, and the latest results on preclinical and human studies.

Burnback: the role of pulse duration and energy on fiber-tip degradation during high-power laser lithotripsy.

High-power holmium lasers have become popular for ureteroscopic laser lithotripsy and dusting. Our aim was to investigate the effect of pulse duration and pulse energy on fiber-tip degradation when using high-power settings for popcorn lithotripsy. BegoStones were fragmented in a glass bulb to simulate renal calyx, using a 120 W Ho:YAG laser. A 242 µm fiber was placed via the ureteroscope 2 mm distance from stones (popcorn model). To assess the effect of pulse duration on fiber-tip degradation, long pulse (LP) and short pulse (SP) settings were compared at settings of 1.0Jx20Hz (20 W), 0.5Jx70Hz (35 W), and 1.0Jx40Hz (40 W). To assess the effect of pulse energy on tip degradation, 40 W SP settings (0.5Jx80Hz, 0.8Jx50Hz, and 1.0Jx40Hz) were tested. Pulse duration was measured using a photodetector and peak power was then calculated using the pulse duration and pulse energy. Experiments were conducted for 4 min. Fiber-tip length was measured before and after using a digital caliper. Fiber-tip degradation was least when using LP for all settings tested (p < 0.01). For 40 W settings, tip degradation was significantly lower when using a pulse energy of 0.5 J compared to 0.8 J or 1.0 J (p < 0.004). LP mode results in less fiber burnback for all power settings tested. Total power is more important than frequency in the development of burnback. However, high-power 40 W settings can be utilized with less burnback if lower pulse energies are used. Understanding these parameters can improve the longevity of the laser fiber and improve procedural efficiency.

A cost-effective, multi-flash, "ghost" imaging technique for high temporal and spatial resolution imaging of cavitation using "still-frame" cameras.

This paper describes a method for acquiring high temporal and spatial resolution images of cavitation events using a multiple-flash-per-camera-exposure imaging technique. A primary challenge associated with imaging cavitation is that the velocity of the bubble wall reaches its maximum (∼1.5×103 m/s) as the bubble size approaches its minimum (≲1 µm). In order to adequately resolve dynamics on these scales, specialized-often prohibitively expensive-cameras with ultra-high frame-rates and resolutions are generally required. This paper describes low-cost, high-speed light emitting diode (LED) flash sources with minimum pulse widths of 20 ns that can be pulsed at rates of up to 17 MHz. The flashes are used to illuminate images of bubbles captured using high-resolution "still-frame" cameras wherein multiple flashes are issued from the LED(s) at known time intervals within a single camera exposure, resulting in overlapping snapshots of the same bubble at multiple unique time-points in a single image. The overlapping snapshots can be uniquely associated with the known time-points of the flashes based on their relative levels brightness. This paper demonstrate effective frame-rates up to 4 Mfps using this technique and the acquisition of snapshots at up to 13 unique time-points per exposure. Hardware descriptions of the flash sources and the programmable device used to control them are provided.

Enhanced shockwave lithotripsy with active cavitation mitigation.

The goal of this study was to examine acoustical mechanisms that manipulate cavitation events in order to improve the efficacy of shockwave lithotripsy (SWL) at higher rates. Previous work has shown that applying low amplitude acoustic pulses immediately after each shockwave (SW) can force cavitation bubbles to coalesce and enhance SWL efficacy. In this study, the effects of applying low amplitude acoustic pulses at different time delays is investigated before and after each SW, which would result in different interactions among residual microbubbles producing forced coalescence and dispersion. Utilizing forced coalescence and dispersion was hypothesized to mitigate the shielding effect of residual bubbles, further improving efficacy particularly for higher SWL rates. A set of in vitro experiments was performed in a water tank so that the behavior of bubbles, coalescence and dispersion, could be observed with a high-speed camera. Model kidney stones were treated by a clinical Dornier lithotripter with firing rates of 30 shocks/min and 120 shocks/min, along with an in-house made transducer to generate low amplitude acoustic pulses fired at different pressures and time delays. The average percentage of untreated stone fragments greater than 2 mm was 15.81% for 120 shocks/min without mitigation and significantly reduced to 0.19% for the optimum mitigation protocol.

MR-based detection of individual histotripsy bubble clouds formed in tissues and phantoms.

PURPOSE: To demonstrate that MR sequences can detect individual histotripsy bubble clouds formed inside intact tissues. METHODS: A line-scan and an EPI sequence were sensitized to histotripsy by inserting a bipolar gradient whose lobes bracketed the lifespan of a histotripsy bubble cloud. Using a 7 Tesla, small-bore scanner, these sequences monitored histotripsy clouds formed in an agar phantom and in vitro porcine liver and brain. The bipolar gradients were adjusted to apply phase with k-space frequencies of 10, 300 or 400 cm-1 . Acoustic pressure amplitude was also varied. Cavitation was simultaneously monitored using a passive cavitation detection system. RESULTS: Each image captured local signal loss specific to an individual bubble cloud. In the agar phantom, this signal loss appeared only when the transducer output exceeded the cavitation threshold pressure. In tissues, bubble clouds were immediately detected when the gradients created phase with k-space frequencies of 300 and 400 cm-1 . When the gradients created phase with a k-space frequency of 10 cm-1 , individual bubble clouds were not detectable until many acoustic pulses had been applied to the tissue. CONCLUSION: Cavitation-sensitive MR-sequences can detect single histotripsy bubble clouds formed in biologic tissue. Detection is influenced by the sensitizing gradients and treatment history. Magn Reson Med 76:1486-1493, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Controlling cavitation-based image contrast in focused ultrasound histotripsy surgery.

PURPOSE: To develop MRI feedback for cavitation-based, focused ultrasound, tissue erosion surgery (histotripsy), we investigate image contrast generated by transient cavitation events. METHODS: Changes in GRE image intensity are observed while balanced pairs of field gradients are varied in the presence of an acoustically driven cavitation event. The amplitude of the acoustic pulse and the timing between a cavitation event and the start of these gradient waveforms are also varied. The magnitudes and phases of the cavitation site are compared with those of control images. An echo-planar sequence is used to evaluate histotripsy lesions in ex vivo tissue. RESULTS: Cavitation events in water cause localized attenuation when acoustic pulses exceed a pressure threshold. Attenuation increases with increasing gradient amplitude and gradient lobe separation times and is isotropic with gradient direction. This attenuation also depends upon the relative timing between the cavitation event and the start of the balanced gradients. These factors can be used to control the appearance of attenuation while imaging ex vivo tissue. CONCLUSION: By controlling the timing between cavitation events and the imaging gradients, MR images can be made alternately sensitive or insensitive to cavitation. During therapy, these images can be used to isolate contrast generated by cavitation.

Histotripsy methods in mechanical disintegration of tissue: towards clinical applications.

In high intensity focused ultrasound (HIFU) therapy, an ultrasound beam is focused within the body to locally affect the targeted site without damaging intervening tissues. The most common HIFU regime is thermal ablation. Recently there has been increasing interest in generating purely mechanical lesions in tissue (histotripsy). This paper provides an overview of several studies on the development of histotripsy methods toward clinical applications. Two histotripsy approaches and examples of their applications are presented. In one approach, sequences of high-amplitude, short (microsecond-long), focused ultrasound pulses periodically produce dense, energetic bubble clouds that mechanically disintegrate tissue. In an alternative approach, longer (millisecond-long) pulses with shock fronts generate boiling bubbles and the interaction of shock fronts with the resulting vapour cavity causes tissue disintegration. Recent preclinical studies on histotripsy are reviewed for treating benign prostatic hyperplasia (BPH), liver and kidney tumours, kidney stone fragmentation, enhancing anti-tumour immune response, and tissue decellularisation for regenerative medicine applications. Potential clinical advantages of the histotripsy methods are discussed. Histotripsy methods can be used to mechanically ablate a wide variety of tissues, whilst selectivity sparing structures such as large vessels. Both ultrasound and MR imaging can be used for targeting and monitoring the treatment in real time. Although the two approaches utilise different mechanisms for tissue disintegration, both have many of the same advantages and offer a promising alternative method of non-invasive surgery.

Prostate histotripsy: evaluation of prostatic urethral treatment parameters in a canine model.

OBJECTIVE: To assess the impact of histotripsy treatment parameters (pulse number and pulse-repetition frequency [PRF]) on the efficiency of histotripsy induced homogenisation of the prostatic urethra. MATERIALS AND METHODS: In all, 34 transabdominal prostate histotripsy treatments were applied along a perpendicular plane traversing the prostatic urethra of 21 dogs. Prostate histotripsy was applied with (i) escalating pulse number with fixed PRF or (ii) at fixed pulse number with varying PRFs. The development of urethral homognisation ≤14 days of histotripsy was evaluated endoscopically and confirmed histologically. RESULTS: Within 14 days of histotripsy 50%, 83%, 83%, and 100% of dogs receiving 12 500, 25 000, 50 000, and 100 000 pulses/mm of treatment path (delivered at 500 Hz PRF), respectively developed prostatic urethral disintegration. Delivery of 100 000 pulses/mm was required to achieve urethral disintegration in all dogs within 24 h of histotripsy treatment. Increasing histotripsy PRF from 50 to 500 to 2000 Hz while applying a constant dose of 25 000 pulses/mm treatment was associated with increased rate of urethral disintegration (50% vs 75% vs 100% at 14 days, respectively). CONCLUSIONS: Increasing the number of histotripsy pulses and/or increasing the PRF of histotripsy treatment applied to the urethra may improve the rate and efficiency of prostatic urethral disintegration in the canine model. This understanding will aid in the development of treatment strategies for prostate histotripsy for benign prostatic hyperplasia in human trials.

In Vivo Cavitation-based Aberration Correction of Histotripsy in Porcine Liver.

Histotripsy is a non-invasive ablation technique that focuses ultrasound pulses into the body to destroy tissues via cavitation. Heterogeneous acoustic paths through tissue introduce phase errors that distort and weaken the focus, requiring additional power output from the histotripsy transducer to perform therapy. This effect, termed phase aberration, limits the safety and efficacy of histotripsy ablation. It has been shown in vitro that the phase errors from aberration can be corrected by receiving the acoustic signals emitted by cavitation. For transabdominal histotripsy in vivo, however, cavitation-based aberration correction is complicated by acoustic signal clutter and respiratory motion. This study develops a method that enables robust, effective cavitation-based aberration correction in vivo and evaluates its efficacy in the swine liver. The method begins with a high-speed pulsing procedure to minimize the effects of respiratory motion. Then, an optimal phase correction is obtained in the presence of acoustic clutter by filtering with the singular value decomposition. This aberration correction method reduced the power required to generate cavitation in the liver by 26% on average (range: 0% to 52%) and required ~2 s for signal acquisition and processing per focus location. These results suggest that the cavitation-based method could enable fast and effective aberration correction for transabdominal histotripsy.

Nanoparticle-Mediated Histotripsy Using Dual-Frequency Pulsing Methods.

OBJECTIVE: Nanoparticle-mediated histotripsy (NMH) is a novel ablation method that combines nanoparticles as artificial cavitation nuclei with focused ultrasound pulsing to achieve targeted, non-invasive, and cell-selective tumor ablation. The study described here examined the effect of dual-frequency histotripsy pulsing on the cavitation threshold, bubble cloud characteristics, and ablative efficiency in NMH. High-speed optical imaging was used to analyze bubble cloud characteristics and to measure ablation efficiency for NMH inside agarose tissue phantoms containing perfluorohexane-filled nanocone clusters, which were previously developed to reduce the histotripsy cavitation threshold for NMH. METHODS: Dual-frequency histotripsy pulsing was applied at a 1:1 pressure ratio using a modular 500 kHz and 3 MHz dual-frequency array transducer. Optical imaging results revealed predictable, well-defined bubble clouds generated for all tested cases with similar reductions in the cavitation thresholds observed for single-frequency and dual-frequency pulsing. RESULTS: Dual-frequency pulsing was seen to nucleate small, dense clouds in agarose phantoms, intermediate in size of their component frequencies but closer in area to that of the higher component frequency. Red blood cell experiments revealed complete ablations were generated by dual-frequency NMH in all phantoms in <1500 pulses. This result was a significant increase in ablation efficiency compared with the ∼4000 pulses required in prior single-frequency NMH studies. CONCLUSION: Overall, this study indicates the potential for using dual-frequency histotripsy methods to increase the ablation efficacy of NMH.

An Ultrasound Array of Emitter-Receiver Stacks for Microbubble-Based Therapy.

Most therapeutic ultrasound devices place emitters and receivers in separate locations, so that the long therapeutic pulses (>1 ms) can be emitted while receivers monitor the procedure. However, with such placement, emitters and receivers are competing for the same space, producing a trade-off between emission efficiency and reception sensitivity. Taking advantage of recent studies demonstrating that short-pulse ultrasound can be used therapeutically, we aimed to develop a device that overcomes such trade-offs. The array was composed of emitter-receiver stacks, which enabled both emission and reception from the same location. Each element was made of a lead zirconate titanate (PZT)-polyvinylidene fluoride (PVDF) stack. The PZT (frequency: 500 kHz, diameter: 16 mm) was used for emission and the PVDF (thickness: 28 µm, diameter: 16 mm) for broadband reception. 32 elements were assembled in a 3D-printed dome-shaped frame (focal length: 150 mm; [Formula: see text]-number: 1) and was tested in free-field and through an ex-vivo human skull. In free-field, the array had a 4.5 × 4.5 × 32 mm focus and produced a peak-negative pressure (PNP) of 2.12 MPa at its geometric center. The electronic steering range was ±15 mm laterally and larger than ±15 mm axially. Through the skull, the array produced a PNP of 0.63 MPa. The PVDF elements were able to localize broadband microbubble emissions across the skull. We built the first multi-element array for short-pulse and microbubble-based therapeutic applications. Stacked arrays overcome traditional trade-offs between the transmission and reception quality and have the potential to create a step change in treatment safety and efficacy.

Neuronavigation-Guided Transcranial Histotripsy (NaviTH) System.

OBJECTIVE: The goal of the work described here was to develop the first neuronavigation-guided transcranial histotripsy (NaviTH) system and associated workflow for transcranial ablation. METHODS: The NaviTH system consists of a 360-element, 700 kHz transmitter-receiver-capable transcranial histotripsy array, a clinical neuronavigation system and associated equipment for patient-to-array co-registration and therapy planning and targeting software systems. A workflow for NaviTH treatments, including pre-treatment aberration correction, was developed. Targeting errors stemming from target registration errors (TREs) during the patient-to-array co-registration process, as well as focal shifts caused by skull-induced aberrations, were investigated and characterized. The NaviTH system was used in treatments of two <96 h post-mortem human cadavers and in experiments in two excised human skullcaps. RESULTS: The NaviTH was successfully used to create ablations in the cadaver brains as confirmed in post-treatment magnetic resonance imaging A total of three ablations were created in the cadaver brains, and targeting errors of 9, 3.4 and 4.4 mm were observed in corpus callosum, septum and thalamus targets, respectively. Errors were found to be caused primarily by TREs resulting from transducer tracking instrument design flaws and imperfections in the treatment workflow. Transducer tracking instrument design and workflow improvements reduced TREs to <2 mm, and skull-induced focal shifts, following pre-treatment aberration correction, were 0.3 mm. Total targeting errors of the NaviTH system following the noted improvements were 2.5 mm. CONCLUSIONS: The feasibility of using the first NaviTH system in a human cadaver model has been determined. Although accuracy still needs to be improved, the proposed system has the potential to allow for transcranial histotripsy therapies without requiring active magnetic resonance treatment guidance.