Passive Cavitation Detection Research Articles

Prototype of a Coupling Device to Investigate Focused Ultrasound-Induced Inertial Cavitation for Drug Delivery Applications

Abstract Focused ultrasound (FUS) can be used as a drug delivery application for localized chemotherapy to treat cancer. The effect of ultrasound-induced inertial cavitation is promising to trigger drug release from nanocarriers. To investigate this effect, usually, a passive cavitation detection setup is employed. However, applying such a setup is challenging for in vivo experiments, as the test object may need to be fixed inside the water tank. Thus, we present a prototype of a coupling device that could significantly simplify experiments. Since this setup favors undesired sound wave interference and their resulting exceedance of the Mechanical Index, we additionally investigated different signal lengths. The occurrence of standing waves at a signal length of 44 cycles can both be derived from a changing cavitation activity and our calculations. The appearing interference also results in a mean increase of the cavitation activity by ≈ 5.1 %, verified by our experiments as well.

Enhanced thrombolytic effect induced by acoustic cavitation generated from nitrogen-doped annealed nanodiamond particles

In biomedical research, ultrasonic cavitation, especially inertial cavitation (IC) has attracted extensive attentions due to its ability to induce mechanical, chemical and thermal effects. Like ultrasound contrast agent (UCA) microbubbles or droplets, acoustic cavitation can be effectively triggered beyond a certain pressure threshold through the interaction between ultrasound and nucleation particles, leading to an enhanced thrombolytic effect. As a newly developed nanocarbon material, nitrogen-doped annealed nanodiamond (N-AND) has shown promising catalytic performance. To further explore its effects on ultrasonic cavitation, N-AND was synthesized at the temperature of 1000 °C. After systematic material characterization, the potential of N-AND to induce enhanced IC activity was assessed for the first time by using passive cavitation detection (PCD). Based on experiments performed at varied material suspension concentration and cycle number, N-AND demonstrated a strong capability to generate significant cavitation characteristics, indicating the formation of stable bubbles from the surface of the materials. Furthermore, N-AND was applied in the in vitro thrombolysis experiments to verify its contribution to ultrasound thrombolysis. The influence of surface hydrophobicity on the cavitation potentials of ND and N-AND was innovatively discussed in combination with the theory of mote-induced nucleation. It is found that the cavitation stability of N-AND was better than that of the commercial UCA microbubbles. This study would provide better understanding of the potential of novel carbonous nanomaterials as cavitation nuclei and is expected to provide guidance for their future biomedical and industrial applications.

Transcranial focused ultrasound-induced blood‒brain barrier opening in mice without shaving hairs

Acoustic coupling through hairs remains a challenge to performing transcranial-focused ultrasound procedures. Here, we demonstrated that this challenge could be addressed by using oil as the coupling medium, leveraging oil's high affinity to hairs due to their inherent hydrophobicity. We compared focused ultrasound-induced blood–brain barrier opening (FUS-BBBO) outcomes in mice under three coupling conditions: oil with hairs (“oil + hairs”), ultrasound gel with hair shaving (“ultrasound gel + no hair”), and ultrasound gel with hairs (“ultrasound gel + hairs”). The quality of the coupling was evaluated by {mathrm{T}}_{2}-weighted magnetic resonance imaging (MRI) and passive cavitation detection (PCD). The outcome of FUS-BBBO was assessed by MRI contrast agent extravasation using in vivo {mathrm{T}}_{1}-weighted contrast-enhanced MRI. It was also evaluated by ex vivo fluorescence imaging of the mouse brain after intravenous injection of a model drug, Evans blue. The results showed that “oil + hairs” consistently achieved high-quality acoustic coupling without trapping air bubbles. The FUS-BBBO outcome was not significantly different between the “oil + hairs” and the “ultrasound gel + no hair” groups. These two groups had significantly higher levels of BBB opening than the “ultrasound gel + hairs” group. This study demonstrated that oil could be a coupling medium for transcranial FUS procedures without shaving hairs.

Dual-frequency boiling histotripsy in an ex vivo bovine tendinopathy model.

Histotripsy fractionates most soft tissues; however, healthy tendons have shown resistance to histotripsy fractionation. Prior work has shown that pre-heating tendons increases susceptibility to histotripsy fractionation; combining multiple driving frequencies may also allow successful fractionation of tendons. Here, we evaluate single- and dual-frequency histotripsy in four healthy and eight tendinopathic ex vivo bovine tendons. First, we evaluated single-frequency (1.07, 1.5, and 3.68 MHz) and dual-frequency (1.07 and 1.5 MHz or 1.5 and 3.68 MHz) bubble dynamics with high-speed photography in a tissue-mimicking phantom. Then, tendons were treated with histotripsy. Cavitation activity was monitored with a passive cavitation detector (PCD) and targeted areas were evaluated grossly and histologically. Results in tendinopathic tendons showed 1.5 MHz or 3.68 MHz single-frequency exposure caused focal disruption, whereas 1.5 and 3.68 MHz dual-frequency exposures caused fractionated holes; all treatments caused some thermal denaturation. Exposure to 1.07 MHz alone or combined with 1.5 MHz did not show fractionation in tendinopathic tendons. In healthy tendons, only thermal necrosis was observed for all tested exposures. PCD showed some differences in cavitation activity in tendinopathic tendons but did not predict successful fractionation. These results suggest that full histotripsy fractionation is possible using dual-frequency exposures in tendinopathic tendons.

A Simple and Cost-Effective Benchtop Setup for Assessing Ultrasound-Induced Inertial Cavitation Probability

Passive cavitation detection methods for measuring ultrasound cavitation events have been utilized for many years. They allow clinicians and researchers to measure cavitation device performance and monitor treatment in real-time. Many methods involve complex processing algorithms and/or expensive measurement hardware. Here we describe and provide open-source resources for a simple benchtop apparatus for measuring the acoustic emissions produced by cavitation events, especially in the context of histotripsy device characterization.

Dynamic Behavior of Polymer Microbubbles During Long Ultrasound Tone-Burst Excitation and Its Application for Sonoreperfusion Therapy.

Ultrasound (US)-targeted microbubble (MB) cavitation (UTMC)-mediated therapies have been found to restore perfusion and enhance drug/gene delivery. Because of the potentially longer circulation time and relative ease of storage and reconstitution of polymer-shelled MBs compared with lipid MBs, we investigated the dynamic behavior of polymer microbubbles and their therapeutic potential for sonoreperfusion (SRP) therapy. The fate of polymer MBs during a single long tone-burst exposure (1 MHz, 5 ms) at various acoustic pressures and MB concentrations was recorded via high-speed microscopy and passive cavitation detection (PCD). SRP efficacy of the polymer MBs was investigated in an in vitro flow system and compared with that of lipid MBs. Microscopy videos indicated that polymer MBs formed gas-filled clusters that continued to oscillate, fragment and form new gas-filled clusters during the single US burst. PCD confirmed continued acoustic activity throughout the 5-ms US excitation. SRP efficacy with polymer MBs increased with pulse duration and acoustic pressure similarly to that with lipid MBs but no significant differences were found between polymer and lipid MBs. These data suggest that persistent cavitation activity from polymer MBs during long tone-burst US excitation confers excellent reperfusion efficacy.

Cellular response to photo-mediated ultrasound therapy

Photo-mediated ultrasound therapy (PUT) is a novel technique that combines relatively low-pressure focused ultrasound and low-fluence laser to enhance cavitation inside blood vessels. Due to the increased shear and circumferential stresses, the enhanced cavitation activity can achieve anti-vascular effect. The role of endothelial cells in the antivascular effect of PUT was explored by quantifying the release of vasodilators-nitric oxide and prostacyclin from endothelial cells after PUT, laser-only, and ultrasound-only therapies in an in vitro vessel mode. PUT was able to suppress both the vasodilators by more than 5% with concurrently applied 0.5MPa ultrasound pressure at 500 kHz and 15 mJ/cm2 laser fluence at 532 nm. Both the laser-only and ultrasound-only therapies at the similar levels resulted only in elevation of these vasodilators with respect to control. The suppression of vasodilators by PUT was justified with cavitation signals observed using passive cavitation detection and apoptosis observed with Annexin V-fluorescein isothiocyante (FITC), at respective levels. The endothelial cellular response to PUT further motivated us to evaluate the effect of PUT on melanoma cells and evaluate cytotoxic effect through MTT assay. PUT was able to destroy cancer cells through the cavitation effect when compared to laser-only and ultrasound-only therapies at the similar energy levels.

Histotripsy of healthy and tendinopathic ex vivo bovine tendons

Histotripsy has successfully fractionated most soft tissues; however, highly collagenous tissues like tendon have been resistant to histotripsy fractionation. Previously, we showed that some histotripsy parameters could create mild mechanical microdamage in healthy ex vivo rat tendons. Our objective here is to evaluate whether complete histotripsy fractionation is possible in tendons. Eight bovine tendons were injected with collagenase to induce tendinopathy; an additional four tendons were unaltered. Tendons were exposed to single- or dual-frequency histotripsy at 1.07-, 1.5-, and/or 3.68-MHz with 10-ms pulses delivered at 1 Hz for 60 s. Treatments were monitored with passive cavitation detection (PCD) and samples were evaluated for damage. Results show that exposure of tendinopathic tendons to 1.5- and 3.68-MHz dual-frequency histotripsy produces a distinct, fractionated hole; 1.5- and 3.68-MHz single-frequency histotripsy produces partial fractionation without a distinct hole. No fractionation was observed in healthy tendons, or in tendinopathic tendons exposed to 1.07 MHz single- or dual-frequency histotripsy. Histologically, all tendons showed evidence of thermal necrosis independent of whether a hole was observed. PCD showsincreases in amplitude and sustainment of cavitation in exposures that successfully fractionated tendon. These results suggest histotripsy fractionation is possible in tendinopathic tendons. [Work supported by NIH R21EB027886 and R01EB032860.]

MRI-guided focused ultrasound drug delivery to DMG tumors in a mouse model

Diffuse midline glioma (DMG) is the most common and unfortunately the most deadly brainstem tumor in childern. Current clincal treatment methods only involve palliative radiotherapy that does not significantly improve survival beyond its poor mean survival of 9 months. These tumors remain difficult to treat with chemotherapy as they maintain an intact blood brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) has been shown to disrupt the BBB, allowing chemotherapeutics to enter the perenchyma. Panobinostat is one of the chemotherapeutics that has difficulty crossing the BBB, although it has promising effects in vitro. In this study, we hypothesized that MB + FUS could disrupt the BBB, allowing a higher concentration of Panobinostat to enter the tumor region and provide a therapeutic effect. Our results demonstrate that MB + FUS can successfully deliver Panobinostat to the pons with DMG tumors over 3-fold, while only slightly increasing the concentration of the forebrain. Passive cavitation detection during treatments showed harmonic cavitation throughout the 3-minute treatment, while not having any significant broadband cavitation. The combination of both Panobinostat and MB + FUS showed major decreases in tumor growth by ∼71% by the end of the treatment weeks when compared to Panobinostat alone. A significant survival benefit was also demonstrated.

Real-time transcranial mapping in non-human primates and human subjects during opening of the blood-brain barrier

Opening of the blood-brain barrier (BBB) with focused ultrasound and microbubbles has been shown repeatedly in several preclinical disease models and clinical studies. Transcranial 2D mapping of the cavitation mechanism responsible for BBB opening is however challenging in primate brains due to the skull thickness. A real-time cavitation mapping system will be presented that can transcranially map the cavitation occurrence and dose in real time throughout the BBB opening procedure in Alzheimer’s disease (AD) adult and diffuse intrinsic pontine glioma (DIPG) pediatric patients. Passive acoustic mapping (PAM) with coherence factor (CF) correction is used to passively map the microbubble activity within the brain. Compared to passive cavitation detection (PCD), multi-element CF-PAM allows us to determine the exact location of the BBB opening without the need of contrast-enhanced MRI. An open-architecture ultrasound imager (Vantage, Verasonics, Redmond, WA) with a P4-2 (ATL, Philips) is used to provide the best tradeoff between transcranial propagation, spatial resolution and depth penetration. The system is first optimized in targeting the putamen during BBB opening in non-human primates followed by feasibility in the prefrontal cortex in AD and the pons in DIPG patients, achieving feedback rates of 2 Hz during the clinical procedures.

Cavitation noise characterization and classification using machine-learning techniques

Noise characterization of cavitation has use in biomedicine, sonochemistry, and waste degradation. Typically, spectral features of the cavitation noise signals obtained through Fourier analysis are specific to the experimental set-up and are analyzed to classify the signals in terms of presumed domains of bubble behaviors. The objective of this research was to develop the experimental capabilities and algorithm to monitor and classify cavitation a priori using machine learning (ML) in a precise, repeatable, and translatable fashion among various setups and applications. Initially, simultaneous high-speed videos and passive acoustics maps were acquired for a single oscillating bubble in a simple setup. Machine learning methods such as support vector machine and convolutional neural networks were used to classify the acoustic data and train a classification algorithm. The algorithm was then adapted for a novel sonochemical reactor that induces spontaneous cavitation nucleation and utilizes a passive cavitation detector to monitor cavitation noise. Further research will be done in correlating potassium iodide (KI) degradation with frequency spectra using ML classification in order to optimize the sonochemical efficiency.

Transcranial cavitation mapping of blood–brain barrier opening regions in Alzheimer’s disease patients using a neuronavigation-guided focused ultrasound system

We present real-time cavitation monitoring and mapping in a clinical trial for blood-brain barrier (BBB) opening in Alzheimer’s disease (AD) patients using a neuronavigation-guided focused ultrasound (FUS) system. Six AD patients (N = 6, age = 68.5 ± 9.5) were sonicated at the right prefrontal lobe with a single-element FUS transducer (PNP = 0.2 MPa, fc = 0.25 MHz, pulse length = 10 ms, PRF = 2 Hz, duration = 2 min) with the microbubble administration (Definity). We performed passive cavitation detection (PCD) using a single-element hydrophone (N = 4), and passive acoustic mapping (PAM) with a 64-element phased array transducer (N = 2). Five patients showed successful BBB opening (volume = 654 ± 394 mm3) on day0, and closure on day3, confirmed by contrast-enhanced T1-weighted MRI, while one patient served as a negative BBB opening case due to the insufficient microbubble administration. Ultra-harmonic cavitation dose (CD) correlated with the opening volume (R2 = 0.66, N = 4), but harmonic and broadband CDs showed a relatively poor correlation (R2 = 0.06 and 0.33). Cavitation maps (N = 2) showed a spatial distribution of acoustic energy that roughly coincided with the respective BBB opening location. We thus demonstrated the successful BBB opening and cavitation monitoring with the neuronavigation-guided system that allowed for a cost-effective procedure compared to the MR-guided approaches. The PCD and PAM showed promising results for potentially predicting the BBB opening volume and location found in MRI.

A PVDF Receiver for Acoustic Monitoring of Microbubble-Mediated Ultrasound Brain Therapy.

The real-time monitoring of spectral characteristics of microbubble (MB) acoustic emissions permits the prediction of increases in blood-brain barrier (BBB) permeability and of tissue damage in MB-mediated focused ultrasound (FUS) brain therapy. Single-element passive cavitation detectors provide limited spatial information regarding MB activity, greatly affecting the performance of acoustic control. However, an array of receivers can be used to spatially map cavitation events and thus improve treatment control. The spectral content of the acoustic emissions provides additional information that can be correlated with the bio-effects, and wideband receivers can thus provide the most complete spectral information. Here, we develop a miniature polyvinylidene fluoride (PVDF thickness = 110 μm, active area = 1.2 mm2) broadband receiver for the acoustic monitoring of MBs. The receiver has superior sensitivity (2.36-3.87 V/MPa) to those of a commercial fibre-optic hydrophone in the low megahertz frequency range (0.51-5.4 MHz). The receiver also has a wide -6 dB acceptance angle (54 degrees at 1.1 MHz and 13 degrees at 5.4 MHz) and the ability to detect subharmonic and higher harmonic MB emissions in phantoms. The overall acoustic performance of this low-cost receiver indicates its suitability for the eventual use within an array for MB monitoring and mapping in preclinical studies.

Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety.

Background: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is a noninvasive, safe and reversible technique for targeted drug delivery to the brain. Most preclinical systems developed to perform and monitor BBB opening are comprised of a separate geometrically focused transducer and passive cavitation detector (PCD) or imaging array. This study builds upon previous work from our group developing a single imaging phased array configuration for simultaneous BBB opening and monitoring called theranostic ultrasound (ThUS), leveraging ultra-short pulse lengths (USPLs) and a novel rapid alternating steering angles (RASTA) pulse sequence design for simultaneous bilateral sonications with target-specific USPL. The RASTA sequence was further employed to evaluate the impact of USPL on BBB opening volume, power cavitation imaging (PCI) pixel intensity, BBB closing timeline, drug delivery efficiency, and safety. Methods: A P4-1 phased array transducer driven by a Verasonics Vantage ultrasound system was operated using a custom script to run the RASTA sequence which consisted of interleaved steered, focused transmits and passive imaging. Contrast-enhanced magnetic resonance imaging (MRI) confirmed initial opening volume and closure of the BBB by longitudinal imaging through 72 hours post-BBB opening. For drug delivery experiments, mice were systemically administered a 70 kDa fluorescent dextran or adeno-associated virus serotype 9 (AAV9) for fluorescence microscopy or enzyme-linked immunosorbent assay (ELISA) to evaluate ThUS-mediated molecular therapeutic delivery. Additional brain sections were also H&E-stained to evaluate histological damage, and IBA1- and GFAP-stained to elucidate the effects of ThUS-mediated BBB opening on stimulation of key cell types involved in the neuro-immune response, microglia and astrocytes. Results: The ThUS RASTA sequence induced distinct BBB openings simultaneously in the same mouse where volume, PCI pixel intensity, level of dextran delivery, and AAV reporter transgene expression were correlated with brain hemisphere-specific USPL, consistent with statistically significant differences between 1.5, 5, and 10-cycle USPL groups. BBB closure after ThUS required 2-48 hours depending on USPL. The potential for acute damage and neuro-immune activation increased with USPL, but such observable damage was nearly reversed 96 hours post-ThUS. Conclusion: ThUS is a versatile single-array technique which exhibits the potential for investigating a variety of non-invasive therapeutic delivery applications in the brain.

Stable Cavitation-Mediated Delivery of miR-126 to Endothelial Cells.

In endothelial cells, microRNA-126 (miR-126) promotes angiogenesis, and modulating the intracellular levels of this gene could suggest a method to treat cardiovascular diseases such as ischemia. Novel ultrasound-stimulated microbubbles offer a means to deliver therapeutic payloads to target cells and sites of disease. The purpose of this study was to investigate the feasibility of gene delivery by stimulating miR-126-decorated microbubbles using gentle acoustic conditions (stable cavitation). A cationic DSTAP microbubble was formulated and characterized to carry 6 µg of a miR-126 payload per 109 microbubbles. Human umbilical vein endothelial cells (HUVECs) were treated at 20-40% duty cycle with miR-126-conjugated microbubbles in a custom ultrasound setup coupled with a passive cavitation detection system. Transfection efficiency was assessed by RT-qPCR, Western blotting, and endothelial tube formation assay, while HUVEC viability was monitored by MTT assay. With increasing duty cycle, the trend observed was an increase in intracellular miR-126 levels, up to a 2.3-fold increase, as well as a decrease in SPRED1 (by 33%) and PIK3R2 (by 46%) expression, two salient miR-126 targets. Under these ultrasound parameters, HUVECs maintained >95% viability after 96 h. The present work describes the delivery of a proangiogenic miR-126 using an ultrasound-responsive cationic microbubble with potential to stimulate therapeutic angiogenesis while minimizing endothelial damage.

Abstract 15305: The Dynamic Behavior of Polymer Microbubbles During Long Ultrasound Tone-Burst Excitation and Its Application for Sonoreperfusion Therapy

Objective: Ultrasound (US)-targeted microbubble (MB) cavitation (UTMC) mediated therapies have been shown to restore perfusion and enhance drug/gene delivery. Due to the potentially longer circulation time and relative ease of storage and reconstitution of polymer shelled MBs compared with lipid MBs, we investigated the dynamic behavior of polymer MBs and its therapeutic potential for sonoreperfusion (SRP) therapy. Methods: We explored the fate of polymer MBs during a single long tone-burst exposure (1 MHz, 5 ms) at various acoustic pressures (0.25-1.5 MPa) and MB concentrations (2х10 6 -2х10 8 MB/mL) via direct high-speed microscopy observation and passive cavitation detection (PCD) and compared with lipid MBs. SRP efficacy of these MBs was investigated in an in vitro constant flow system at various pulse durations (1 MHz, 1-5 ms every 3 sec for 20 min) and acoustic pressures (0.6-1.5 MPa). The pressure differential across a porous mesh partially occluded with microthrombi was recorded as a function of time during treatment and used as a measure of thrombus burden. The terminal pressure drop and the initial rate of pressure drop were derived and compared. Results: Both polymer and lipid MBs first underwent stable or inertial cavitation depending on the acoustic pressure, and then formed gas-filled clusters that continued to oscillate, fragment, and form new gas-filled clusters during the single US burst. PCD confirmed continued acoustic activity throughout the 5-ms US excitation. SRP efficacy with polymer MBs increased with the pulse duration and acoustic pressure ( p <0.05, ANOVA), similarly to that of lipid MBs, but no significant differences were found between polymer and lipid MBs ( Figure 1 ). Conclusion: Under the acoustic conditions tested, both polymer and lipid MBs demonstrate similar thrombolytic effects in vitro suggesting that persistent cavitation activity from polymer MBs during long tone-burst US confers excellent reperfusion efficacy.

Passive and active Doppler methods and metrics to quantify inertial cavitation induced by pulsed focused ultrasound

Inertial cavitation induced by pulses of nonlinearly distorted focused ultrasound (FUS) at moderate intensity can result in mild mechanical disruption of tissue, short of its complete mechanical disintegration—histotripsy. This effect can be used to enhance diffusion of subsequently systemically administered drugs or biologics. Previously, single-element passive cavitation detection (PCD) of broadband noise emissions was successfully used to quantify tissue disruption and enhancement in drug concentration. This metric, however, has limitations: minimal spatial resolution and challenges with calibration when used at large depths in acoustically variable tissue. To address this, we developed a combination of passive and active Doppler-based methods that relied on relative, rather than absolute signal metrics. Specifically, destructive cavitation behaviors were previously linked to substantial motion of the bubbles during the FUS pulse due to acoustic radiation force and shock scattering. This was reflected in the backscattered FUS harmonics as Doppler shift and measurable from PCD. The bubbles were observed to dissolve within milliseconds following each FUS pulse, thus their distribution could be visualized as an area of rapid change via fast plane wave Doppler ensemble following the FUS pulse. The Doppler power distribution was spatially correlated with the area of tissue disruption in the in vivo experiments. [Work supported by NIH R01CA154451, R01EB025187, and R01EB23910.]

Passive and Doppler-based assessment of cavitation activity induced by pulsed focused ultrasound

Pulsed focused ultrasound (pFUS) exposures utilizing short, nonlinearly distorted pulses at low duty cycle have been shown to enhance drug and gene delivery to targeted tissue through inertial cavitation activity. Passive cavitation detection (PCD) and mapping of broadband emissions are current conventional methods to monitor and quantify cavitation but provide limited spatial resolution. Here, plane-wave Doppler imaging was used with PCD to quantify pFUS-induced cavitation in ex vivo bovine tissues and in vivo surgically exposed porcine liver, kidney, and pancreas. A 1.5 MHz FUS transducer (aperture 75 mm, F-number 0.75) was used to deliver 60 pulses (duration 1 ms, 0.1% duty cycle, focal pressure p+ = 70i–110 MPa, p− = 13–20 MPa). A coaxially mounted ATL P7-4 ultrasound imaging probe was used for PCD during the FUS pulse, and Doppler and B-mode sequences. Disrupted tissue areas were collected for histology and compared to Doppler power images. Maximum Doppler power was found to correlate to broadband noise level for each FUS pulse. The Doppler power map integrated over the exposure was observed to correlate spatially with tissue disruption area from histology, which thus represents a promising real-time metric for quantifying cavitation activity induced by pFUS exposures. [Work supported by NIH R01CA154451, R01EB025187, and R01EB23910.]

Characterization and monitoring of cavitation behavior induced by a dual-mode pulsed high-intensity focused ultrasound array

Pulsed high-intensity focused ultrasound (pHIFU) is capable of inducing cavitation in tissue without the need for contrast agents, thereby enhancing permeability and passive drug penetration in tissue with poor perfusion. We have developed and characterized the performance of a 64-element linear ultrasound array for image-guided therapy, capable of generating sufficient levels of inertial cavitation at 1 MHz, along with B-mode and Doppler imaging for targeting and cavitation assessment, respectively. Cavitation behaviors induced by different pHIFU exposures were investigated using high-speed imaging in agarose and polyacrylamide phantoms in conjunction with passive cavitation detection (PCD) and plane wave Doppler imaging. Image quality assessment was performed on in vivo porcine models, and cavitation monitoring was demonstrated on ex vivo tissues. High-speed images of the induced cavitation behavior while steering the beam focus both axially and laterally (within ±1.2 cm) were in agreement with Doppler power distributions and broadband noise emissions from PCD. Destructive cavitation behaviors in both gels and tissue were induced at relatively low peak-negative pressures (3–4 MPa), provided that the pHIFU focal waveform was nonlinearly distorted. B-mode image quality is sufficient for recognizing the relative position of anatomic landmarks and targeting cm-sized regions. [Work supported by NIH grants R01EB023910 and R01EB025187.]

Sub-megahertz cavitation detection and characterization in mouse brains

A key consideration in ultrasound medical device safety is the potential for cavitation related bioeffects. Device testing should address possible cavitation pathways, such as bubble formation, either in the focal region or at the device-tissue interface along with possible consequences regarding both safety and effectiveness. This has been particularly important in a number of emerging transcranial therapies including ablation, neuromodulation, and targeted opening of the blood-brain barrier (BBB) in conjunction with microbubbles. Subharmonic, and ultraharmonic emissions have been identified as indicators of treatment outcome and are a basis for safety and feedback control in BBB disruption. However, there remains a scarcity of baseline cavitation threshold data in the living mammalian brain, particularly at lower ultrasound frequencies. In our ongoing study, we are measuring and evaluating in vivo cavitation response in mice using a passive cavitation detector (PCD) for ultrasound frequencies as low as 40 kHz. Additional measurements are being carried out using a hydrophone imbedded in the brain tissue of mouse cadavers to characterize absolute pressure values as well as evaluate the sensitivity and reliability of the PCD measurements. Analyzed data will be presented along with detailed methodology and potential implications in future product evaluation will be discussed.