Mark T. Burgess

Passive imaging with pulsed ultrasound insonations

Previously, passive cavitation imaging has been described in the context of continuous-wave high-intensity focused ultrasound thermal ablation. However, the technique has potential use as a feedback mechanism for pulsed-wave therapies, such as ultrasound-mediated drug delivery. In this paper, results of experiments and simulations are reported to demonstrate the feasibility of passive cavitation imaging using pulsed ultrasound insonations and how the images depend on pulsed ultrasound parameters. The passive cavitation images were formed from channel data that was beamformed in the frequency domain. Experiments were performed in an invitro flow phantom with an experimental echo contrast agent, echogenic liposomes, as cavitation nuclei. It was found that the pulse duration and envelope have minimal impact on the image resolution achieved. The passive cavitation image amplitude scales linearly with the cavitation emission energy. Cavitation images for both stable and inertial cavitation can be obtained from the same received data set.

The potential applications of high-intensity focused ultrasound (HIFU) in vascular neurosurgery.

This review assesses the feasibilty of high-intensity focused ultrasound (HIFU) in neurosurgical applications, specifically occlusion of intact blood vessels. Fourteen articles were examined. In summary, MRI was effective for HIFU guidance whereas MR angiography assessed vessel occlusion. Several studies noted immediate occlusion of blood vessels with HIFU. Long-term data, though scarce, indicated a trend of vessel recanalization and return to pre-treatment diameters. Effective parameters for extracranial vascular occlusion included intensity ranges of 1,690-8,800 W/cm(2), duration <15 seconds, and 0.68-3.3 MHz frequency. A threshold frequency-intensity product of 8,250 MHzW/cm(2) was needed for vascular occlusion with a sensitivity of 70% and a specificity of 86%. Complications include skin burns, hemorrhage, and damage to surrounding structures. With evidence that HIFU can successfully occlude extracranial blood vessels, refinement in applications and demonstrable intracranial occlusion are needed.

Treatment of Rabbit Liver Cancer In Vivo Using Miniaturized Image-Ablate Ultrasound Arrays

In the preclinical studies reported here, VX2 cancer within rabbit liver has been treated by bulk ultrasound ablation employing miniaturized image-ablate arrays. Array probes were constructed with 32 elements in a 2.3 × 20 mm(2) aperture, packaged within a 3.1 mm stainless steel tube with a cooling and coupling balloon for in vivo use. The probes were measured capable of 50% fractional bandwidth for pulse-echo imaging (center frequency 4.4 MHz) with >110 W/cm(2) surface intensity available at sonication frequencies 3.5 and 4.8 MHz. B-scan imaging performance of the arrays was measured to be comparable to larger diagnostic linear arrays, although nearfield image quality was reduced by ringdown artifacts. A series of in vivo ablation procedures was performed using an unfocused 32-element aperture firing at 4.8 MHz with exposure durations 20-70.5 s and in situ spatial average, temporal average intensities 22.4-38.5 W/cm(2). Ablation of a complete tumor cross-section was confirmed by vital staining in seven of 12 exposures, with four exposures ablating an additional margin >1 mm beyond the tumor in all directions. Analysis suggests a threshold ablation effect, with complete ablation of tumor cross-sections for exposures with delivery of >838 J acoustic energy. The results show feasibility for in vivo liver cancer ablation using miniaturized image-ablate arrays suitable for interstitial deployment.

Synthesis of phase-shift nanoemulsions with narrow size distributions for acoustic droplet vaporization and bubble-enhanced ultrasound-mediated ablation.

High-intensity focused ultrasound (HIFU) is used clinically to thermally ablate tumors. To enhance localized heating and improve thermal ablation in tumors, lipid-coated perfluorocarbon droplets have been developed which can be vaporized by HIFU. The vasculature in many tumors is abnormally leaky due to their rapid growth, and nanoparticles are able to penetrate the fenestrations and passively accumulate within tumors. Thus, controlling the size of the droplets can result in better accumulation within tumors. In this report, the preparation of stable droplets in a phase-shift nanoemulsion (PSNE) with a narrow size distribution is described. PSNE were synthesized by sonicating a lipid solution in the presence of liquid perfluorocarbon. A narrow size distribution was obtained by extruding the PSNE multiple times using filters with pore sizes of 100 or 200 nm. The size distribution was measured over a 7-day period using dynamic light scattering. Polyacrylamide hydrogels containing PSNE were prepared for in vitro experiments. PSNE droplets in the hydrogels were vaporized with ultrasound and the resulting bubbles enhanced localized heating. Vaporized PSNE enables more rapid heating and also reduces the ultrasound intensity needed for thermal ablation. Thus, PSNE is expected to enhance thermal ablation in tumors, potentially improving therapeutic outcomes of HIFU-mediated thermal ablation treatments.

Prediction and suppression of HIFU-induced vessel rupture using passive cavitation detection in an ex vivo model

BackgroundOcclusion of blood vessels using high-intensity focused ultrasound (HIFU) is a potential treatment for arteriovenous malformations and other neurovascular disorders. However, attempting HIFU-induced vessel occlusion can also cause vessel rupture, resulting in hemorrhage. Possible rupture mechanisms include mechanical effects of acoustic cavitation and heating of the vessel wall.MethodsHIFU exposures were performed on 18 ex vivo porcine femoral arteries with simultaneous passive cavitation detection. Vessels were insonified by a 3.3-MHz focused source with spatial-peak, temporal-peak focal intensity of 15,690–24,430 W/cm2 (peak negative-pressure range 10.92–12.52 MPa) and a 50% duty cycle for durations up to 5 min. Time-dependent acoustic emissions were recorded by an unfocused passive cavitation detector and quantified within low-frequency (10–30 kHz), broadband (0.3–1.1 MHz), and subharmonic (1.65 MHz) bands. Vessel rupture was detected by inline metering of saline flow, recorded throughout each treatment. Recorded emissions were grouped into ‘pre-rupture’ (0–10 s prior to measured point of vessel rupture) and ‘intact-vessel’ (>10 s prior to measured point of vessel rupture) emissions. Receiver operating characteristic curve analysis was used to assess the ability of emissions within each frequency band to predict vessel rupture.Based on these measurements associating acoustic emissions with vessel rupture, a real-time feedback control module was implemented to monitor acoustic emissions during HIFU treatment and adjust the ultrasound intensity, with the goal of maximizing acoustic power delivered to the vessel while avoiding rupture. This feedback control approach was tested on 10 paired HIFU exposures of porcine femoral and subclavian arteries, in which the focal intensity was stepwise increased from 9,117 W/cm2 spatial-peak temporal-peak (SPTP) to a maximum of 21,980 W/cm2, with power modulated based on the measured subharmonic emission amplitude. Time to rupture was compared between these feedback-controlled trials and paired controller-inactive trials using a paired Wilcoxon signed-rank test.ResultsSubharmonic emissions were found to be the most predictive of vessel rupture (areas under the receiver operating characteristic curve (AUROC) = 0.757, p < 10-16) compared to low-frequency (AUROC = 0.657, p < 10-11) and broadband (AUROC = 0.729, p < 10-16) emissions. An independent-sample t test comparing pre-rupture to intact-vessel emissions revealed a statistically significant difference between the two groups for broadband and subharmonic emissions (p < 10-3), but not for low-frequency emissions (p = 0.058).In a one-sided paired Wilcoxon signed-rank test, activation of the control module was shown to increase the time to vessel rupture (T- = 8, p = 0.0244, N = 10). In one-sided paired t tests, activation of the control module was shown to cause no significant difference in time-averaged focal intensity (t = 0.362, p = 0.363, N = 10), but was shown to cause delivery of significantly greater total acoustic energy (t = 2.037, p = 0.0361, N = 10).ConclusionsThese results suggest that acoustic cavitation plays an important role in HIFU-induced vessel rupture. In HIFU treatments for vessel occlusion, passive monitoring of acoustic emissions may be useful in avoiding hemorrhage due to vessel rupture, as shown in the rupture suppression experiments.

Power cavitation-guided blood-brain barrier opening with focused ultrasound and microbubbles

Image-guided monitoring of microbubble-based focused ultrasound (FUS) therapies relies on the accurate localization of FUS-stimulated microbubble activity (i.e. acoustic cavitation). Passive cavitation imaging with ultrasound arrays can achieve this, but with insufficient spatial resolution. In this study, we address this limitation and perform high-resolution monitoring of acoustic cavitation-mediated blood-brain barrier (BBB) opening with a new technique called power cavitation imaging. By synchronizing the FUS transmit and passive receive acquisition, high-resolution passive cavitation imaging was achieved by using delay and sum beamforming with absolute time delays. Since the axial image resolution is now dependent on the duration of the received acoustic cavitation emission, short pulses of FUS were used to limit its duration. Image sets were acquired at high-frame rates for calculation of power cavitation images analogous to power Doppler imaging. Power cavitation imaging displays the mean intensity of acoustic cavitation over time and was correlated with areas of acoustic cavitation-induced BBB opening. Power cavitation-guided BBB opening with FUS could constitute a standalone system that may not require MRI guidance during the procedure. The same technique can be used for other acoustic cavitation-based FUS therapies, for both safety and guidance.

Histologic analysis of rabbit liver cancer treated by bulk ultrasound ablation

VX2 rabbit liver cancer, treated in vivo using bulk ultrasound ablation by miniaturized image-ablate arrays, was histologically analyzed using TTC vital stain and DAPI nucleic acid stain. VX2 cells were implanted into rabbit liver lobes and allowed to grow for 11-21 days. Liver lobes containing solid VX2 tumors were then treated with 4.8 MHz, 22.5-38.5 W/cm2 in situ intensity, unfocused ultrasound for exposure times of 20-120 s. After animal sacrifice, thermal lesions were bisected along the imaging/treatment plane, one face stained with TTC, and the other with DAPI. Levels of TTC uptake (no uptake, partial uptake, and complete uptake) in liver parenchyma corresponded to three discrete regions of tan, pink and red color. By processing images of DAPI-stained parenchymal tissue from these three regions, cellular damage was quantified. A viability index parameter incorporating the size and shape of DAPI-stained nuclei correlated significantly with levels of TTC uptake, and thus with local tissue viability. F...

Role of Cavitation in Bulk Ultrasound Ablation: A Histologic Study

The role of cavitation in bulk ultrasound ablation has been evaluated in a series of in vitro experiments. Fresh bovine liver tissue was ablated with a 3.1 MHz ultrasound image‐ablate probe at 31 W/cm2 for 20 minutes under normal and elevated ambient pressures. A 1 MHz passive cavitation detector recorded acoustic emission signals which were quantified by computation of average subharmonic, broadband, and low‐frequency emission levels. After ablation, tissue was sliced and stained with 2% TTC to evaluate thermal damage. Emission levels were quantified and correlated with tissue ablation histology. The results indicate that bubble activity significantly affects heat deposition in ultrasound bulk ablation, in a manner different from high‐intensity focused ultrasound (HIFU) ablation.

Transcranial acoustic cavitation localization with ultrafast power cavitation imaging in non-human primates

Acoustic cavitation-guided blood-brain barrier (BBB) opening with focused ultrasound (FUS) and microbubbles is a promising technique for safe and controlled opening of the BBB. Passive cavitation imaging has the ability to monitor the spatial intensity of acoustic cavitation for targeting verification and treatment monitoring. However, isolating acoustic cavitation emissions from tissue and skull reflections is a major challenge. In this study, we perform transcranial passive cavitation imaging with a 1.5D imaging array (M5Sc-D, bandwidth: 1.5–4 MHz, GE Medical Systems) placed in the central opening of a 0.5 MHz FUS transducer (H204, Sonic Concepts) in non-human primates. Broadband FUS pulses were used along with synchronous transmit and receive sequences to perform delay and sum beamforming with absolute time delays. Image sets were acquired at ultrafast frame rates (>1000 frames per second) for calculation of mean intensity images, i.e., power cavitation images. Spatiotemporal clutter filtering of image...

Pulse inversion enhances the passive mapping of microbubble-based ultrasound therapy

Therapeutic ultrasound combined with preformed circulating microbubbles has enabled non-invasive and targeted drug delivery into the brain, tumors, and blood clots. Monitoring the microbubble activity is essential for the success of such therapies; however, skull and tissues limit our ability to detect low acoustic signals. Here, we show that by emitting consecutive therapeutic pulses of inverse polarity, the sensitivity in the detection of weak bubble acoustic signals during blood-brain barrier opening is enhanced compared to therapeutic pulses of the same polarity. Synchronous passive mapping of the cavitation activity was conducted using delay-and-sum beamforming with absolute time delays, which offers superior spatial resolution compared to the existing asynchronous passive imaging techniques. Sonication with pulse inversion allowed filter-free suppression of the tissue signals by up to 8 dB in a tissue-mimicking phantom and by 7 dB in vivo, compared to exposure without pulse inversion, enabling enhanced passive mapping of microbubble activity. Both therapeutic schemes resulted in similar free-field microbubble activation in vitro and efficient blood-brain barrier opening in vivo.