Microbubble Movement Research Articles

A novel gas embolotherapy using microbubbles electrocoalescence for cancer treatment

Background and ObjectiveEmbolotherapy has been increasingly used to disrupt tumor growth. Despite its success in the occlusion of microvessels, it has drawbacks such as limited access to the target location, limited control of the blocker size, and inattention to the tumor characteristics, especially high interstitial fluid pressure. The present work introduces a novel numerical method of gas embolotherapy for cancer treatment through tumor vessel occlusion. MethodsThe gas microbubbles are generated from Levovist bolus injection into the tumor microvessel. The microbubble movement in the blood flow is innovatively controlled by an electric field applied to the tumor-feeding vessel. The interaction between the Levovist microbubbles and the electric field is resolved by developing a fully coupled model using the phase-field model, Carreau model for non-Newtonian blood, Navier-Stokes equations and Maxwell stress tensor. Additionally, the critical effect of high interstitial fluid pressure as a characteristic of solid tumors is included. ResultsThe findings of this study indicate that the rates of microbubble deformation and displacement increase with the applied potential intensity to the microvessel wall. Accordingly, the required time for a microbubble to join the upper microvessel wall reduces from 1.97ms to 22 μs with an increase of the electric potential from 3.5V to 12.5V. Additionally, an electric potential of 12.5V causes the microbubbles coalescence and formation of a gas column against the bloodstream. ConclusionsClinically, our novel embolization procedure can be considered a non-invasive targeted therapy, and under a controlled electric field, the blocker size can be precisely controlled. Also, the proposed method has the potential to be used as a gradual treatment in advanced cancers as tumors develop resistance and relapse.

Recondensation of nano-sized perfluorocarbon droplets after acoustic droplet vaporization for blinking ultrasound localization microscopy

Ultrasound localization microscopy (ULM) is a promising super-resolutionimaging technique based on the build-up of subwavelength localizations of gas-filled ultrasound contrast agents (UCAs) within the microvascular space. Slow flow regions can reduce localization rates and diminish the isolation of microbubble signals from tissue. This work compares the blinking contrast dynamics of nano-sized perfluorocarbon droplets to the slowly changing contrast dynamics of traditional gas-filled UCAs. A 16-MHz linear array connected to a Verasonics research ultrasound system was used to capture high-frame rate acquisitions of contrast agents flowing through an in vitro- flow phantom. Nano-sized droplets produced an on and off contrast signal due to vaporization/recondensation events which enhanced microbubble separation from tissue. This allows for higher localization rates for droplets at slow flow speeds, since a new population of bubbles was localized with each ultrasound pulse and was independent of flow speed. This could improve ULM at slow flow speeds, where UCAs require long acquisition times for adequate microbubble movement via flow to produce sufficient localization rates. Preliminary in-vivo experiments comparing UCAs to nano-sized droplets for contrast-enhanced imaging of a mouse kidney will also be discussed. [This work was supported by NIH grant R21 HD097485.]

Ultrasound Contrast: Gas Microbubbles in the Vasculature.

Gas-filled microbubbles are currently in clinical use as blood pool contrast agents for ultrasound imaging. The goal of this review is to discuss the trends and issues related to these relatively unusual intravascular materials, which are not small molecules per se, not polymers, not even nanoparticles, but larger micrometer size structures, compressible, flexible, elastic, and deformable. The intent is to connect current research and initial studies from 2 to 3 decades ago, tied to gas exchange between the bubbles and surrounding biological medium, in the following areas of focus: (1) parameters of microbubble movement in relation to vasculature specifics; (2) gas uptake and loss from the bubbles in the vasculature; (3) adhesion of microbubbles to target receptors in the vasculature; and (4) microbubble interaction with the surrounding vessels and tissues during insonation.Microbubbles are generally safe and require orders of magnitude lower material doses than x-ray and magnetic resonance imaging contrast agents. Application of microbubbles will soon extend beyond blood pool contrast and tissue perfusion imaging. Microbubbles can probe molecular and cellular biomarkers of disease by targeted contrast ultrasound imaging. This approach is now in clinical trials, for example, with the aim to detect and delineate tumor nodes in prostate, breast, and ovarian cancer. Imaging of inflammation, ischemia-reperfusion injury, and ischemic memory is also feasible. More importantly, intravascular microbubbles can be used for local deposition of focused ultrasound energy to enhance drug and gene delivery to cells and tissues, across endothelial barrier, especially blood-brain barrier.Overall, microbubble behavior, stability and in vivo lifetime, bioeffects upon the action of ultrasound and resulting enhancement of drug and gene delivery, as well as targeted imaging are critically dependent on the events of gas exchange between the bubbles and surrounding media, as outlined in this review.

Doppler Passive Acoustic Mapping.

In therapeutic ultrasound using microbubbles, it is essential to drive the microbubbles into the correct type of activity and the correct location to produce the desired biological response. Although passive acoustic mapping (PAM) is capable of locating where microbubble activities are generated, it is well known that microbubbles rapidly move within the ultrasound beam. We propose a technique that can image microbubble movement by estimating their velocities within the focal volume. Microbubbles embedded within a wall-less channel of a tissue-mimicking material were sonicated using 1-MHz focused ultrasound. The acoustic emissions generated by the microbubbles were captured with a linear array (L7-4). PAM with robust Capon beamforming was used to localize the microbubble acoustic emissions. We spectrally analyzed the time trace of each position and isolated the higher harmonics. Microbubble velocity maps were constructed from the position-dependent Doppler shifts at different time points during sonication. Microbubbles moved primarily away from the transducer at velocities on the order of 1 m/s due to primary acoustic radiation forces, producing a time-dependent velocity distribution. We detected microbubble motion both away and toward the receiving array, revealing the influence of acoustic radiation forces and fluid motion due to the ultrasound exposure. High-speed optical images confirmed the acoustically measured microbubble velocities. Doppler PAM enables passive estimation of microbubble motion and may be useful in therapeutic applications, such as drug delivery across the blood-brain barrier, sonoporation, sonothrombolysis, and drug release.

Control of microbubble movement with magnetic field

Control of microbubble movement with magnetic field

Improved Super-Resolution Ultrasound Microvessel Imaging With Spatiotemporal Nonlocal Means Filtering and Bipartite Graph-Based Microbubble Tracking

Super-resolution ultrasound microvessel imaging with contrast microbubbles has recently been proposed by multiple studies, demonstrating outstanding resolution with high potential for clinical applications. This paper aims at addressing the potential noise issue in in vivo human super-resolution imaging with ultrafast plane-wave imaging. The rich spatiotemporal information provided by ultrafast imaging presents features that allow microbubble signals to be separated from background noise. In addition, the high-frame-rate recording of microbubble data enables the implementation of robust tracking algorithms commonly used in particle tracking velocimetry. In this paper, we applied the nonlocal means (NLM) denoising filter on the spatiotemporal domain of the microbubble data to preserve the microbubble tracks caused by microbubble movement and suppress random background noise. We then implemented a bipartite graph-based pairing method with the use of persistence control to further improve the microbubble signal quality and microbubble tracking fidelity. In an in vivo rabbit kidney perfusion study, the NLM filter showed effective noise rejection and substantially improved microbubble localization. The bipartite graph pairing and persistence control demonstrated further noise reduction, improved microvessel delineation, and a more consistent microvessel blood flow speed measurement. With the proposed methods and freehand scanning on a free-breathing rabbit, a single microvessel cross-sectional profile with full-width at half-maximum of could be imaged at approximately 2-cm depth (ultrasound transmit center frequency = 8 MHz, theoretical spatial resolution ). Cortical microvessels that are apart can also be clearly separated. These results suggest that the proposed methods have good potential in facilitating robust in vivo clinical super-resolution microvessel imaging.

Control of microbubble movement with magnetic particles

Control of microbubble movement with magnetic particles

Exploiting flow to control the in vitro spatiotemporal distribution of microbubble-seeded acoustic cavitation activity in ultrasound therapy

Focused ultrasound and microbubbles have been extensively used to generate therapeutic bioeffects. Despite encouraging in vivo results, there remains poor control of the magnitude and spatial distribution of these bioeffects due to the limited ability of conventional pulse shapes and sequences to control cavitation dynamics. Thus current techniques are restricted by an efficacy-safety trade-off. The primary aim of the present study was to incorporate the presence of flow in the design of new short pulse sequences, which can more uniformly distribute the cavitation activity. Microbubbles flowing (fluid velocity: 10 mm s−1) through a 300 μm tube were sonicated with a focused 0.5 MHz transducer while acoustic emissions were captured with an inserted focused 7.5 MHz passive cavitation detector. The two foci were co-axially aligned and their focal points were overlapped. Whereas conventional sequences are composed of a long burst (>10 000 cycles) emitted at a low burst repetition frequency (<10 Hz), we decomposed this burst into short pulses by adding intervals to facilitate inter-pulse microbubble movement. To evaluate how this sequence influenced cavitation distribution, we emitted short pulses (peak-rarefactional pressure (PRP): 40–366 kPa, pulse length (PL): 5–25 cycles) at high pulse repetition frequencies (PRF: 0.625–10 kHz) for a burst length of 100 ms. Increased cavitation persistence, implied by the duration of the microbubble acoustic emissions, was a measure of improved distribution due to the presence of flow. Sonication at lower acoustic pressures, longer pulse intervals and lower PLs improved the spatial distribution of cavitation. Furthermore, spectral analysis of the microbubble emissions revealed that the improvement at low pressures is due to persisting stable cavitation. In conclusion, new short-pulse sequences were shown to improve spatiotemporal control of acoustic cavitation dynamics during physiologically relevant flow. This could lead to adjustable distribution of the generated in vivo bioeffect and therefore efficient and safe treatment of a wide range of pathologies.

Ultrasound Imaging of Focal Liver Lesions with a Second-Generation Contrast Agent

For several years, the major diagnostic objective in using US contrast agents has been to detect flow in the circulation at a lower level than that otherwise possible in Doppler techniques. However, it turned out that enhanced color and power Doppler could provide fine details on small and deep vessels, but were not sensitive enough to detect contrast agents in the microcirculation. As a result, the usefulness of contrast agents in the field of liver imaging was limited to the evaluation of the vascular architecture of focal lesions. Recently, the development of new US techniques that produce images based on nonlinear acoustic effects of US interaction with microbubble contrast agents has opened new prospects for US imaging of the liver. These contrast-specific imaging techniques, in fact, can display microbubble enhancement in gray-scale, thus maximizing contrast and spatial resolution and enabling the analysis of the microcirculation. These techniques offer high sensitivity either to microbubble movement or to microbubble collapse independent of the level of the applied acoustic peak pressure. At low acoustic peak pressure levels grossly reflected by a low mechanical index (MI) the microbubble destruction can be reasonably neglected and the microbubble movement effect due to blood circulation is predominant. In contrast, when increasing the acoustic peak pressure levels (high MI), the destruction phenomena become the most important: the signal, in fact, is produced by microbubble collapse, and is related to microbubble concentration and not to blood flow velocity (1–3). We performed a pilot clinical study aimed at investigating the usefulness of both destructive (high MI) and non-destructive (low MI) gray-scale US techniques, in combination with a second-generation contrast agent, for the detection and characterization of focal liver lesions.

Tissue harmonic and contrast-specific imaging: back to gray scale in ultrasound.

The development of new US techniques that produce images based on nonlinear acoustic effects of US interaction with matter or microbubble contrast agents has opened new prospects for gray-scale US in native tissue and contrast imaging. Tissue harmonic imaging uses higher frequencies generated on propagation of the US beam through matter to improve image quality and resolve small anatomic structures and details, and is becoming a routine approach in US examination of many abdominal districts. Contrast-specific imaging techniques display enhancement of US agents in gray-scale with optimal contrast and spatial resolution, and offer high sensitivity either to microbubble movement or to microbubble destruction in dependence of the level of the applied acoustic peak pressure. Owing to the ability to exploit the microcirculation, contrast-specific techniques have enabled the evolution of contrast US from vascular imaging to the imaging of perfused tissues. Several studies have shown that these methods can substantially improve US detection and characterization of focal liver lesions, and promising results have been reported in other areas of investigation. This article reviews physical principles, technical issues, and clinical applications of tissue harmonic and contrast-specific imaging. It is foreseen that the new gray-scale US techniques will rapidly become a tool in numerous clinical scenarios.