Noninvasive Ultrasound Surgery Research Articles

Acoustically Detonated Microbubbles Coupled with Low Frequency Insonation: Multiparameter Evaluation of Low Energy Mechanical Ablation.

Noninvasive ultrasound surgery can be achieved using focused ultrasound to locally affect the targeted site without damaging intervening tissues. Mechanical ablation and histotripsy use short and intense acoustic pulses to destroy the tissue via a purely mechanical effect. Here, we show that coupled with low-frequency excitation, targeted microbubbles can serve as mechanical therapeutic warheads that trigger potent mechanical effects in tumors using focused ultrasound. Upon low frequency excitation (250 kHz and below), high amplitude microbubble oscillations occur at substantially lower pressures as compared to higher MHz ultrasonic frequencies. For example, inertial cavitation was initiated at a pressure of 75 kPa for a center frequency of 80 kHz. Low frequency insonation of targeted microbubbles was then used to achieve low energy tumor cell fractionation at pressures below a mechanical index of 1.9, and in accordance with the Food and Drug Administration guidelines. We demonstrate these capabilities in vitro and in vivo. In cell cultures, cell viability was reduced to 16% at a peak negative pressure of 800 kPa at the 250 kHz frequency (mechanical index of 1.6) and to 10% at a peak negative pressure of 250 kPa at a frequency of 80 kHz (mechanical index of 0.9). Following an intratumoral injection of targeted microbubbles into tumor-bearing mice, and coupled with low frequency ultrasound application, significant tumor debulking and cancer cell death was observed. Our findings suggest that reducing the center frequency enhances microbubble-mediated mechanical ablation; thus, this technology provides a unique theranostic platform for safe low energy tumor fractionation, while reducing off-target effects.

Designing Fully Populated Phased Arrays for Noninvasive Ultrasound Surgery with Controlled Degree of Irregularity in the Arrangement of Elements

When designing phased antenna arrays for use in noninvasive ultrasound surgery, it is desirable to provide the highest possible power for a given array dimensions. At the same time, it is necessary to take into account the limitations on the maximum allowable ultrasound intensity at the array elements and to ensure suppression of spurious diffraction maxima in the spatial structure of the emitted field. The problem can be solved by designing an irregular arrangement combined with the densest filling of the array surface with elements. This paper presents a modification of such a method for creating fully populated arrays with nonperiodic tessellation distribution of elements, based on the restriction of the relaxation mechanism in an iterative array design algorithm. A computer model that allows for controlling the degree of irregularity in distribution of the array elements was developed. The stability of maintaining the low level of acoustic intensity in unwanted grating lobes was tested for various random realizations of the element arrangements by analyzing a statistical ensemble of 500 model arrays. The advantages of the considered arrays in comparison with existing models of fully populated arrays are demonstrated.

Transcranial focused ultrasound with multielement arrays: Decreasing the number of transducers without compromising the focusing quality

Transcranial ultrasonic brain therapy at frequencies higher than 500 kHz requires adaptive focusing to compensate for the aberrations induced by the skull bone. This can be achieved by using multi-element arrays driven by a dedicated electronics. A growing number of elements was used to improve the focusing: 64 elements in 2000 [1], 300 in 2003 [2], 1024 in 2013 [3], and more to come. We will present some of the salient results obtained pre-clinically and clinically with such multi-element transcranial devices. Nevertheless, we will show that comparable transcranial focusing can be achieved with a novel approach in rupture with the current trend. It consists in a single-element transducer covered with a 3D silicone acoustic lens of variable and controlled thickness. Similar lenses have been introduced in the past to perform multiple focusing patterns in homogenous media [4] but recent 3d printing capabilities make 3D lenses a feasible option for transcranial adaptive focusing. We will show that the use of a lenses increases the acoustic intensity by 97 ± 56% on average, on three human skulls. [1] G. Clement et al., “A hemisphere array for non-invasive ultrasound brain therapy and surgery,” Phys. Med. Biol. 2000. [2] M. Pernot et al., “High power transcranial beam steering for ultrasonic brain therapy,” Phys. Med. Biol. 2003. [3] N. Lipsman et al., “MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study,” The Lancet Neurology 2013. [4] T. Fjield et al., “Low-profile lenses for ultrasound surgery,” Phys. Med. Biol. 1999.

On the possibility of using multi-element phased arrays for shock-wave action on deep brain structures

A noninvasive ultrasound surgery method that relies on using multi-element focused phased arrays is being successfully used to destroy tumors and perform neurosurgical operations in deep structures of the human brain. However, several drawbacks that limit the possibilities of the existing systems in their clinical use have been revealed: a large size of the hemispherical array, impossibility of its mechanical movement relative to the patient’s head, limited volume of dynamic focusing around the center of curvature of the array, and side effect of overheating skull. Here we evaluate the possibility of using arrays of smaller size and aperture angles to achieve shock-wave formation at the focus for thermal and mechanical ablation (histotripsy) of brain tissue taking into account current intensity limitations at the array elements. The proposed approach has potential advantages to mitigate the existing limitations and expand the possibilities of transcranial ultrasound surgery.

Design and experiment of 256-element ultrasound phased array for noninvasive focused ultrasound surgery

A 256-element phased array high intensity focused ultrasound system has been designed and constructed in our laboratory. The 256-element spherical-section ultrasound phased array made from piezocomposite material operates at 1.1 MHz with 11-cm radius of curvature, 14-cm outer diameter, and 3.4-cm diameter central hole for mounting diagnostic ultrasound imaging probe. First, the explicit sound field calculation approach for the spherical-section phased array and the genetic optimal algorithm are briefly introduced as the optimal focus pattern control methods. Then, the design guidelines of 256-element spherical-section focused ultrasound phased array and 256-channel driver system are given. The results of single on and off axial focus, multiple on and off axial foci, half sub-array focus pattern provide further evidence for the 3D focus steering and sub-array mode for avoiding obstacles in focused ultrasound surgery. The multi-foci pattern can enlarge the treatment volume to 22 times larger than that of a single focus in one sonication. Finally, in vitro and transparent tissue-mimicking phantom experiment results confirm the ability of 256-element spherical-section phased array system to induce thermal lesions for noninvasive ultrasound surgery.

Time reversal for ultrasonic transcranial surgery and echographic imaging

High‐intensity focused ultrasound (HIFU) is able to induce non‐invasively controlled and selective destruction of tissues by focusing ultrasonic beams within organs, analogous to a magnifying glass that concentrates enough sunlight to burn a hole in paper. The brain is an attractive organ in which to perform ultrasonic tissue ablation, but such an application has been hampered by the strong defocusing effect of the skull bone. Our group has been involved in this topic for several years, providing proofs of concept and proposing technological solutions to this problem. Thanks to a high‐power time‐reversal mirror, presented here are in vivo thermal lesions induced through the skull of 12 sheep. Thermal lesions were confirmed by T2‐weighted magnetic resonance post‐treatment images and histological examination. These results provide striking evidence that noninvasive ultrasound brain surgery is feasible. A recent approach for high‐resolution brain ultrasonic imaging will also be discussed with a skull aberration correction technique based on twin arrays technology. The correction of transcranial ultrasonic images is implemented on a new generation of time‐reversal mirrors relying on a fully programmable transmit and receive beamformer.

A noninvasive method for focused ultrasound surgery through the human skull

A technique for focusing ultrasound through the skull bone is described and verified. The approach is based on a layered wave-vector-frequency domain model, which simulates ultrasound propagation through the skull bone using input from CT scans of the head. The algorithm calculates the driving phase of each element in a transducer array in order to maximize the signal at the intended focus. This approach is tested on ten ex vivo human skulls using a 500-element hemispherical array operated at 0.74 MHz. A stereotaxic reference frame is affixed to the skulls in order to provide accurate registration between the CT images and the transducer. The focal quality is assessed with a hydrophone placed inside of the skull. In each trial the phase correction algorithm successfully restored the focus inside the skull in a location within 1 mm from the intended focal point. Focusing at high powers (>800-W electrical input) is demonstrated using a brain phantom placed inside a skull. The results demonstrate the feasibility of using the method for completely noninvasive ultrasound brain surgery and therapy.

A non-invasive method for focusing ultrasound through the human skull

A technique for focusing ultrasound through the human skull is described and verified. The approach is based on a layered wavevector-frequency domain model, which propagates ultrasound from a hemisphere-shaped transducer through the skull using input from CT scans of the head. The algorithm calculates the driving phase of each transducer element in order to maximize the signal at the intended focus. This approach is tested on ten ex vivo human skulls using a 0.74 MHz, 320-element array. A stereotaxic reference frame is affixed to the skulls in order to provide accurate registration between the CT images and the transducer. The focal quality is assessed with a hydrophone placed inside the skull. In each trial the phase correction algorithm successfully restored the focus inside the skull at a location within 1 mm from the intended focal point. The results demonstrate the feasibility of using the method for completely non-invasive ultrasound brain surgery and therapy.

Focusing of therapeutic ultrasound through a human skull: A numerical study

A numerical model was developed which can use digitized layer interfaces to calculate ultrasound wave absorption, diffraction, reflection, and refraction. This model was used to evaluate the feasibility of ultrasound therapy and surgery through a human skull. A digitized human skull profile was obtained from magnetic resonance (MR) images and used to calculate the ultrasound field in the brain of a volunteer from a spherically curved phased array. With no phase correction, the focus of the array was shifted and defocused. The phased array technique was used to correct focal shift, reduce side lobes, and enhance focal amplitude. The optimum source element width was estimated for each frequency to obtain a near optimium focus, and an appropriate frequency range for transskull ultrasound therapy and surgery was determined. Acoustic pressure amplitude on the skull surfaces was examined, and it was shown that the skull heating problem could be overcome. Despite high attenuation, complex interface shape, and nonuniform thickness of a human skull, a sharply focused transskull ultrasound field can be generated for noninvasive ultrasound therapy and surgery in the brain.

A study of various parameters of spherically curved phased arrays for noninvasive ultrasound surgery

The spherically curved square element phased array design for ultrasound surgery was studied in several of its important aspects. A method for determining the spatial limitations of the multiple-foci region was developed for spherically curved phased arrays. The effects on the ultrasound fields of varying the phases and the amplitudes at control points were investigated. It was found that the phases and the magnitudes of control points have an impact on the ultrasound field distributions. The effects of multiple-foci spacing, pulse duration, and maximum temperature on the size and shape of necrosed tissue were investigated. For a spherically curved phased array with an 8 cm radius of curvature, an projected area, and a 1.5 MHz operating frequency, the minimum number of phased array elements that could produce the largest acceptable necrosed tissue volume was 256. The tissue volume necrosed during the sonication could be increased to approximately with this array.

New developments in therapeutic ultrasound

The main purpose of this article is to review selective research and developments during the last decade in the field. There has been tremendous progress in engineering and science coupled with ultrasound transducer technology and imaging modalities during the last 10 years. These new R and D efforts have enhanced the capabilities of ultrasound therapy, and it now appears that the ultrasound therapy base will be expanded for clinical applications, particularly as noninvasive surgery becomes a more acceptable method of treatment. This article limits its review to novel developments in ultrasound hyperthermia and noninvasive ultrasound surgery. Along with descriptions of ultrasound devices and new accompanying techniques such as magnetic resonance image (MRI) guided noninvasive surgery, some relevant clinical results are summarized as a measure of progress.

The Usefulness of a Contrast Agent and Gradient-Recalled Acquisition in a Steady-State Imaging Sequence for Magnetic Resonance Imaging-Guided Noninvasive Ultrasound Surgery

The ability of magnetic resonance imaging to detect small temperature elevations from focused ultrasound surgery beams was studied. In addition, the value of a contrast agent in delineating the necrosed tissue volume was investigated. Gradient-recalled acquisition in a steady state (GRASS) T1-weighted images were used to follow the temperature elevation and tissue changes during 2-minute sonications in the thigh muscles of 10 rabbits. The effects of the treatment on the vascular network was investigated by injecting a contrast agent bolus before or after the sonication. The signal intensity decreased during the sonication, and the reduction was directly proportional to the applied power and increase in temperature. The signal intensity returned gradually back to baseline after the ultrasound was turned off. Injection of the contrast agent increased the signal intensity in muscle, but not in the necrosed tissue. The dimensions of the delineated tissue volume were the same as measured from the T2-weighted fast-spin-echo images and postmortem tissue examination. These results indicate that magnetic resonance imaging can be used to detect temperature elevations that do not cause tissue damage and that contrast agent can be used to delineate the necrosed tissue volume.

MRI-guided noninvasive ultrasound surgery.

In this study, the feasibility of using magnetic resonance imaging (MRI) to detect tissue necrosis induced by focussed ultrasound beams was investigated. It was shown that lesions produced in dog's thigh muscle in vivo were clearly visible in T2-weighted images and that the lesion dimensions measured from the images correlated with the postmortem measurements of the visible tissue damage. It was also shown that the sonications can be done in the magnet and that the lesions are visible immediately after the sonications with increasing image contrast as a function of time. These results showed that MRI can be used to direct and monitor on-line noninvasive ultrasound surgery. This may have a major impact in future patient treatments.