Unfocused ultrasound waves for manipulating and imaging microbubbles

With unfocused plane/diverging ultrasound waves, the capability of simultaneous sampling on each element of an array transducer has spawned a branch known as high-frame-rate (HFR) ultrasound imaging, whose frame rate can be two orders of magnitude faster than traditional imaging systems. Microbubbles are micron-sized spheres with a heavy gas core that is stabilized by a shell made of lipids, polymers, proteins, or surfactants. They are excellent ultrasound scatters and have been used as ultrasound contrast agents, and more recently researched as a mechanism for targeted drug delivery. With the Ultrasound Array Research Platform II (UARP II), the objective of this thesis was to develop and advance several techniques for manipulating and imaging microbubbles using unfocused ultrasound waves. These techniques were achieved by combining custom transmit/receiving sequencing and advanced signal processing algorithms, holding promise for enhanced diagnostic and therapeutic applications of microbubbles. A method for locally accumulating microbubbles with fast image guidance was first presented. A linear array transducer performed trapping of microbubble populations interleaved with plane wave imaging, through the use of a composite ultrasound pulse sequence. This technique could enhance image-guided targeted drug delivery using microbubbles. A key component of targeted drug delivery using liposome-loaded microbubbles and ultrasound is the ability to track these drug vehicles to guide payload release locally. As a uniquely identifiable emission from microbubbles, the subharmonic signal is of interest for this purpose. The feasibility of subharmonic plane wave imaging of liposome-loaded microbubbles was then proved. The improved subharmonic sensitivity especially at depth compared to their counterpart of bare (unloaded) microbubbles was confirmed. Following plane wave imaging, the combination of diverging ultrasound waves and microbubbles was investigated. The image formation techniques using coherent summation of diverging waves are susceptible to tissue and microbubble motion artefacts, resulting in poor image quality. A correlation-based 2-D motion estimation algorithm was then proposed to perform motion compensation for HFR contrast-enhanced echocardiography (CEE). A triplex cardiac imaging technique, consisting of B mode, contrast mode and 2-D vector flow imaging with a frame rate of 250 Hz was presented. It was shown that the efficacy of coherent diverging wave imaging of the heart is reliant on carefully designed motion compensation algorithms capable of correcting for incoherence between steered diverging-wave transmissions. Finally, comparisons were made between the correlation-based method and one established image registration method for motion compensation. Results show that the proposed correlation-based method outperformed the image registration model for motion compensation in HFR CEE, with the improved image contrast ratio and visibility of geometrical borders both in vitro and in vivo

Combining Acoustic Trapping with Plane Wave Imaging for Localized Microbubble Accumulation in Large Vessels

The capability of accumulating microbubbles using ultrasound, could be beneficial for enhancing targeted drug delivery. When microbubbles are used to deliver a therapeutic payload, there is a need to track them, for a localized release of the payload. In this study, a method for localizing microbubble accumulation with fast image guidance is presented. A linear array transducer performed trapping of microbubble populations interleaved with plane wave imaging, through the use of a composite pulse sequence. The acoustic trap in the pressure field was created parallel with the direction of flow in a model of a vessel section. The acoustic trapping force resultant from the large gradients in the acoustic field was engendered to directly oppose the flowing microbubbles. This was demonstrated numerically with field simulations, and experimentally using an Ultrasound Array Research Platform II (UARP II). SonoVue microbubbles at clinically relevant concentrations were pumped through a tissue-mimicking flow phantom and exposed to either the acoustic trap or a control ultrasonic field composed of a single-peak acoustic radiation force beam. Under the flow condition at a shear rate of 433 s-1, the use of the acoustic trap led to lower speed estimations (p< 0.05) in the center of the acoustic field, and an enhancement of 71 ± 28% (p< 0.05) in microbubble image brightness

Trapped air metamaterial concept for ultrasonic sub-wavelength imaging in water

Funding for this work was provided through the UK Engineering and Physical Sciences Research Council (EPSRC), Grant Numbers EP/N034163/1, EP/N034201/1 and EP/N034813/1.Acoustic metamaterials constructed from conventional base materials can exhibit exotic phenomena not commonly found in nature, achieved by combining geometrical and resonance effects. However, the use of polymer-based metamaterials that could operate in water is difficult, due to the low acoustic impedance mismatch between water and polymers. Here we introduce the concept of “trapped air” metamaterial, fabricated via vat photopolymerization, which makes ultrasonic sub-wavelength imaging in water using polymeric metamaterials highly effective. This concept is demonstrated for a holey-structured acoustic metamaterial in water at 200–300 kHz, via both finite element modelling and experimental measurements, but it can be extended to other types of metamaterials. The new approach, which outperforms the usual designs of these structures, indicates a way forward for exploiting additive-manufacturing for realising polymer-based acoustic metamaterials in water at ultrasonic frequencies.Publisher PDFPeer reviewe

A metallic additively manufactured metamaterial for enhanced monitoring of acoustic cavitation‐based therapeutic ultrasound

The combination of ultrasound and microbubbles allows treatment of indications that would be impossible or too risk adverse with conventional surgery. During treatment, subharmonic and ultraharmonic components that can only be generated from microbubbles are of great interest for intraoperative monitoring. However, the microbubble emissions are several orders of magnitude lower in power compared to that of the fundamental frequency component from the ultrasound applicator, resulting in a low signal‐to‐noise ratio (SNR) for monitoring. A 3D acoustic metamaterial (AMM) immersed in water is proposed for suppressing unwanted ultrasound waves, which allows the improved sensitivity for detecting weak microbubble emissions. Numerically, the importance of shear waves on the AMM transfer properties is highlighted, though only longitudinal ultrasound waves are transmitted through water. Experimentally, the design is implemented in titanium using additive manufacturing, with an attenuation level of 40 dB at the fundamental frequency. Consequently, the application of the AMM efficiently improves the SNR for subharmonic and ultraharmonic microbubble emissions by 11.8 and 11.9 dB, respectively. The subharmonic components originally overwhelmed by noise are recovered. This is the first time that AMMs have been applied to passive acoustic monitoring and this work stands to improve treatment outcomes from cavitation‐mediated focused ultrasound therapy

High-Frame-Rate Contrast-Enhanced Echocardiography Using Diverging Waves: 2-D Motion Estimation and Compensation

Combining diverging ultrasound waves and microbubbles could improve contrast-enhanced echocardiography (CEE), by providing enhanced temporal resolution for cardiac function assessment over a large imaging field of view. However, current image formation techniques using coherent summation of echoes from multiple steered diverging waves (DWs), are susceptible to tissue and microbubble motion artifacts, resulting in poor image quality. In this study, we used correlation-based 2-D motion estimation to perform motion compensation for CEE using DWs. The accuracy of this motion estimation method was evaluated with Field II simulations. The root-mean-square velocity errors were 5.9% ± 0.2% and 19.5% ± 0.4% in the axial and lateral directions, when normalized to the maximum value of 62.8 cm/s which is comparable to the highest speed of blood flow in the left ventricle (LV). The effects of this method on image contrast ratio (CR) and contrast-to-noise ratio (CNR) were tested in vitro using a tissue mimicking rotating disk with a diameter of 10 cm. Compared against the control without motion compensation, a mean increase of 12 dB in CR and 7 dB in CNR were demonstrated when using this motion compensation method. The motion correction algorithm was tested in vivo on a CEE dataset acquired with the Ultrasound Array Research Platform II performing coherent DW imaging. Improvement of the B-mode and contrast-mode image quality with cardiac motion and blood flow induced microbubble motion was achieved. The results of motion estimation were further processed to interpret blood flow in the LV. This allowed for a triplex cardiac imaging technique, consisting of B mode, contrast mode and 2-D vector flow imaging with a high frame rate of 250 Hz

Optimised polymer trapped-air lenses for ultrasound focusing in water exploiting Fabry-Pérot resonance

The concept of employing air volumes trapped inside polymer shells to make a lens for ultrasound focusing in water is investigated. The proposed lenses use evenly-spaced concentric rings, each having an air-filled polymer shell construction, defining concentric water-filled channels. Numerical simulations and experiments have shown that a plane wave can be focused, and that the amplification can be boosted by Fabry-Pérot resonances within the water channels with an appropriate choice of the lens thickness. The effect of the polymer shell thickness and the depth of the channels is discussed, as these factors can affect the geometry and hence the frequency of operation. The result was a lens with a Full Width at Half Maximum value of 0.65 of a wavelength at the focus. Results obtained on a metal-based counterpart are also shown for comparison. An advantage of this polymeric design is that it is easily constructed via additive manufacturing. This study shows that trapped-air lenses made of polymer are suitable for ultrasound focusing in water near 500 kHz. [Abstract copyright: Copyright © 2022. Published by Elsevier B.V.

Contrast-Enhanced High-Frame-Rate Ultrasound Imaging of Flow Patterns in Cardiac Chambers and Deep Vessels

Cardiac function and vascular function are closely related to the flow of blood within. The flow velocities in these larger cavities easily reach 1 m/s, and generally complex spatiotemporal flow patterns are involved, especially in a non-physiologic state. Visualization of such flow patterns using ultrasound can be greatly enhanced by administration of contrast agents. Tracking the high-velocity complex flows is challenging with current clinical echographic tools, mostly because of limitations in signal-to-noise ratio; estimation of lateral velocities; and/or frame rate of the contrast-enhanced imaging mode. This review addresses the state of the art in 2-D high-frame-rate contrast-enhanced echography of ventricular and deep-vessel flow, from both technological and clinical perspectives. It concludes that current advanced ultrasound equipment is technologically ready for use in human contrast-enhanced studies, thus potentially leading to identification of the most clinically relevant flow parameters for quantifying cardiac and vascular function.ImPhys/Medical Imagin