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ABSTRACT: Superheated emulsion droplets are a promising tool for localized drug delivery. The physical mechanisms underlying the ultrasound-triggered vaporization of phase-change emulsions are largely unexplored. Here we study the acoustic vaporization of individual micron-sized perfluoropentane droplets at a nanoseconds timescale. The nucleation and growth of the vapor bubbles was imaged at frame rates up to 20 Mfps. The droplet vaporization dynamics was observed to have three distinct regimes: (1) prior to nucleation, a regime of droplet deformation and oscillatory translations; (2) a rapid growth of a vapor bubble enhanced by ultrasound-driven rectified heat transfer; and (3) a final phase characterized by a relatively slow expansion that is fully dominated by heat transfer. A method to measure the moment of inception of the nucleation event with respect to the phase of the ultrasound wave is proposed. A simple physical model captures quantitatively all of the features of the subsequent vapor bubble growth. In addition, we study the role of gas through a model for a vapor-gas bubble, including thermal diffusion and gas diffusion inside the liquid and we find good agreement with the experimental data. We underline the fundamental role of gas diffusion to prevent total recondensation of the bubble at collapse.
The Journal of the Acoustical Society of America 05/2013; 133(5):3586. · 1.55 Impact Factor
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ABSTRACT: Submicron droplets of liquid perfluorocarbon converted into microbubbles with applied ultrasound have been studied, for a number of years, as potential next generation extravascular ultrasound contrast agents. In this work, we conduct an initial ultra-high-speed optical imaging study to examine the vaporization of submicron droplets and observe the newly created microbubbles in the first microseconds after vaporization. It was estimated that single pulses of ultrasound at 10MHz with pressures within the diagnostic range are able to vaporize on the order of at least 10% of the exposed droplets. However, only part of the newly created microbubbles survives immediately following vaporization - the bubbles may recondense back into the liquid droplet state within microseconds of nucleation. The probability of bubble survival within the first microseconds of vaporization was shown to depend on ultrasound excitation pressure as well as on bubble coalescence during vaporization, a behavior influenced by the presence of coating material on the newly created bubbles. The results of this study show for the first time that although initial vaporization of droplets is necessary to create echogenic bubbles, additional factors, such as coalescence and bubble shell properties, are important and should be carefully considered for the production of microbubbles for use in medical imaging.
Ultrasonics 04/2013; · 1.84 Impact Factor
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ABSTRACT: We demonstrate two methods for vasa vasorum imaging using contrast-enhanced intravascular ultrasound, which can be performed using commercial catheters. Plaque neovascularization was recognized as an independent marker of coronary artery plaque vulnerability. IVUS-based methods to image the microvessels available to date require high bandwidth (-6 dB relative frequency bandwidth >70%), which are not routinely available commercially. We explored the potential of ultraharmonic imaging and chirp reversal imaging for vasa vasorum imaging. In vitro recordings were performed on a tissue-mimicking phantom using a commercial ultrasound contrast agent and a transducer with a center frequency of 34 MHz and a -6 dB relative bandwidth of 56%. Acoustic peak pressures <500 kPa were used. A tissue-mimicking phantom with channels down to 200 μm in diameter was successfully imaged by the two contrast detection sequences while the smallest channel stayed invisible in conventional intravascular ultrasound images. Ultraharmonic imaging provided the best contrast agent detection.
Ultrasound in medicine & biology 02/2013; · 2.02 Impact Factor
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ABSTRACT: In this study, we investigated the effect of secondary Bjerknes forces on targeted microbubbles using high-speed optical imaging. We observed that targeted microbubbles attached to an underlying surface and subject to secondary Bjerknes forces deform in the direction of their neighboring bubble, thereby tending toward a prolate shape. The deformation induces an elastic restoring force, causing the bubbles to recoil back to their equilibrium position; typically within 100 μs after low-intensity ultrasound application. The temporal dynamics of the recoil was modeled as a simple mass-spring system, from which a value for the effective spring constant k of the order 10(-3) Nm(-1) was obtained. Moreover, the translational dynamics of interacting targeted microbubbles was predicted by a hydrodynamic point particle model, including a value of the spring stiffness k of the very same order as derived experimentally from the recoiling curves. For higher acoustic pressures, secondary Bjerknes forces rupture the molecular adhesion of the bubbles to the surface. We used this mutual attraction to quantify the binding force between a single biotinylated microbubble and an avidin-coated surface, which was found to be between 0.9 and 2 nanonewtons (nN). The observation of patches of lipids left at the initial binding site suggests that lipid anchors are pulled out of the microbubble shell, rather than biotin molecules unbinding from avidin. Understanding the effect of ultrasound application on targeted microbubbles is crucial for further advances in the realm of molecular imaging.
Ultrasound in medicine & biology 01/2013; · 2.02 Impact Factor
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ABSTRACT: The merits of ultrasound contrast agents (UCAs) were already known in the 1960s. It was, however, not until the 1990s that UCAs were clinically approved and marketed. In these years, it was realized that the UCAs are not just efficient ultrasound scatterers, but that their main constituent, the coated gas microbubble, acts as a nonlinear resonator and, as such, is capable of generating harmonic energy. Subharmonic, ultraharmonic, and higher harmonic frequencies of the transmitted ultrasound frequency have been reported. This opened up new prospects for their use and several detection strategies have been developed to exploit this harmonic energy to discriminate the contrast bubbles from surrounding tissue. This insight created a need for tools to study coated bubble behavior in an ultrasound field and the first models were developed. Since then, 20 years have elapsed, in which a broad range of UCAs and UCA models have been developed. Although the models have helped in understanding the responses of coated bubbles, the influence of the coating has not been fully elucidated to date and UCA models are still being improved. The aim of this review paper is to offer an overview in these developments and indicate future directions for research.
IEEE transactions on ultrasonics, ferroelectrics, and frequency control 01/2013; 60(1):7-20. · 1.80 Impact Factor
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ABSTRACT: A comparison between phospholipid-coated microbubbles with and without liposomes attached to the microbubble surface was performed using the ultra-high-speed imaging camera (Brandaris 128). We investigated 73 liposome-loaded microbubbles (loaded microbubbles) and 41 microbubbles without liposome loading (unloaded microbubbles) with a diameter ranging from 3-10 μm at frequencies ranging from 0.6-3.8 MHz and acoustic pressures ranging from 5-100 kPa. The experimental data showed nearly the same shell elasticity for the loaded and unloaded bubbles, but the shell viscosity was higher for loaded bubbles compared with unloaded bubbles. For loaded bubbles, a higher pressure threshold for the bubble vibrations was noticed. In addition, an "expansion-only" behavior was observed for up to 69% of the investigated loaded bubbles, which mostly occurred at low acoustic pressures (≤30 kPa). Finally, fluorescence imaging showed heterogeneity of liposome distributions of the loaded bubbles.
Ultrasound in medicine & biology 12/2012; 38(12):2174-85. · 2.02 Impact Factor
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ABSTRACT: Beamforming of plane-wave ultrasound echo signals in the Fourier domain provides fast and accurate image reconstruction. Conventional implementations perform a k-space interpolation from the uniform sampled grid to a nonuniform acoustic dispersion grid. In this paper, we demonstrate that this step can be replaced by a nonuniform Fourier transform. We study the performance of the nonuniform fast Fourier transform (NUFFT) in terms of signal-to-noise ratio and computational cost, and show that the NUFFT offers an advantage in the trade-off between speed and accuracy, compared with other frequency-domain beamforming strategies.
IEEE transactions on ultrasonics, ferroelectrics, and frequency control 12/2012; 59(12):2684-2691. · 1.80 Impact Factor
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ABSTRACT: B-mode and Doppler ultrasound are commonly used for the evaluation of atherosclerosis in the carotid arteries. Recently, contrast-enhanced ultrasound (CEUS) has been introduced as a technique to improve the detection of carotid atherosclerosis and evaluate the presence of intraplaque neovascularization, which is considered a marker of plaque vulnerability. The present review focuses on the role of CEUS for the assessment of atherosclerosis and plaque instability. Currently available literature and future developments with CEUS are discussed.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 11/2012; · 3.52 Impact Factor
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ABSTRACT: Intraplaque neovascularization is considered as an important indication for plaque vulnerability. We propose a semiautomatic algorithm for quantification of neovasculature, thus, enabling assessment of plaque vulnerability. The algorithm detects and tracks contrast spots using multidimensional dynamic programming. Classification of contrast tracks into blood vessels and artifacts was performed. The results were compared with manual tracking, visual classification and maximal intensity projection. In 28 plaques, 97% of the contrast spots were detected. In 89% of the objects, the automatic tracking determined the contrast motion with an average distance of less than 0.5 mm from the manual marking. Furthermore, 75% were correctly classified into artifacts and vessels. The automated neovascularization grading agreed within 1 grade with visual analysis in 91% of the cases, which was comparable to the interobserver variability of visual grading. These results show that the method can successfully quantify features that are linked to vulnerability of the carotid plaque.
Ultrasound in medicine & biology 10/2012; · 2.02 Impact Factor
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ABSTRACT: Transesophageal echocardiography (TEE) uses the esophagus as an imaging window to the heart. This enables cardiac imaging without interference from the ribs or lungs and allows for higher frequency ultrasound to be used compared with transthoracic echocardiography (TTE). TEE facilitates the successful imaging of obese or elderly patients, where TTE may be unable to produce images of satisfactory quality. Recently, three-dimensional (3-D) TEE has been introduced, which greatly improves the image quality and diagnostic value of TEE by adding an extra dimension. Further improvement could be achieved by optimizing 3-D TEE for harmonic imaging. This article describes the optimal geometry and element configuration for a matrix probe for 3-D second harmonic TEE. The array concept features separated transmit and receive subarrays. The element geometry was studied using finite element modeling and a transmit subarray prototype was examined both acoustically and with laser interferometry. The transmit subarray is suitable for its role, with a 3 MHz resonance frequency, a 40%-50% -3 dB bandwidth and crosstalk levels <-27 dB. The proposed concept for the receive subarray has a 5.6 MHz center frequency and a 50% -3 dB bandwidth.
Ultrasound in medicine & biology 10/2012; 38(10):1820-32. · 2.02 Impact Factor
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ABSTRACT: The Brandaris 128 ultra-high-speed imaging facility has been updated over the last 10 years through modifications made to the camera's hardware and software. At its introduction the camera was able to record 6 sequences of 128 images (500 × 292 pixels) at a maximum frame rate of 25 Mfps. The segmented mode of the camera was revised to allow for subdivision of the 128 image sensors into arbitrary segments (1-128) with an inter-segment time of 17 μs. Furthermore, a region of interest can be selected to increase the number of recordings within a single run of the camera from 6 up to 125. By extending the imaging system with a laser-induced fluorescence setup, time-resolved ultra-high-speed fluorescence imaging of microscopic objects has been enabled. Minor updates to the system are also reported here.
The Review of scientific instruments 10/2012; 83(10):103706. · 1.52 Impact Factor
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ABSTRACT: The dynamics of coated microbubbles was studied in an in vivo model. Biotinylated lipid-coated microbubbles were prepared in-house and were injected into a chick embryo chorioallantoic membrane (CAM) model on the fifth day of incubation. The microbubbles, ranging between 1.0 and 3.5 μm in diameter, were insonified in the frequency range of 4-7 MHz. Two amplitudes of acoustic pressure were applied: 300 kPa and 400 kPa. The fundamental and subharmonic responses were recorded optically with an ultra-fast camera (Brandaris 128) at 20 million frames per second. A subharmonic response was observed for 44% of the studied bubbles. From the data the frequency of the maximum fundamental and subharmonic response was derived for each individual bubble and resulted in the resonance curves of the microbubbles. All the bubbles showed shell (strain) hardening behavior for a higher acoustic pressure. We conclude that the subharmonic oscillations observed in this study belonged to the transmit at resonance (TR) regime.
Ultrasound in medicine & biology 07/2012; 38(9):1608-17. · 2.02 Impact Factor
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Stijn C H van den Oord,
Gerrit L Ten Kate,
Zeynettin Akkus,
Guillaume Renaud,
Eric J G Sijbrands,
Folkert J Ten Cate,
Aad van der Lugt,
Johan G Bosch, Nico de Jong,
Antonius F W van der Steen,
Arend F L Schinkel
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ABSTRACT: AIMS: The sensitivity of standard carotid ultrasound and colour Doppler for the detection of subclinical atherosclerotic plaques is suboptimal. The aim of this study is to assess whether contrast-enhanced ultrasound (CEUS) added to standard carotid ultrasound improves the detection of subclinical atherosclerosis. METHODS AND RESULTS: Carotid intima-media thickness (CIMT) measurement, standard carotid ultrasound including colour Doppler imaging, and CEUS were performed in 100 asymptomatic patients with one or more risk factors for atherosclerosis. CEUS was performed using intravenous administration of SonoVue™ contrast agent (Bracco S.p.A., Milan, Italy). CIMT, standard ultrasound, colour Doppler, and CEUS were reviewed by two independent observers. Standard ultrasound, colour Doppler, and CEUS were scored for the presence of atherosclerotic plaques. Subclinical atherosclerosis was diagnosed if patients had a CIMT above their age-corrected threshold value or if atherosclerotic plaques were present on standard carotid ultrasound clips or CEUS clips. McNemar's test was performed to compare between groups. Twenty-one patients (21%) had a thickened CIMT value and were considered to have subclinical atherosclerosis. Standard carotid ultrasound including colour Doppler demonstrated atherosclerotic plaques in 77 patients (77%). The addition of CEUS to the standard ultrasound protocol demonstrated atherosclerotic plaques in 88 patients (88%). The incorporation of CEUS into the standard carotid ultrasound protocol resulted in a significantly improved detection of patients with subclinical atherosclerosis (P < 0.01). CONCLUSION: CEUS has an incremental value for the detection of subclinical atherosclerosis in the carotid arteries. Atherosclerotic plaques which were only detected with CEUS and not with standard carotid ultrasound and colour Doppler imaging were predominantly hypoechoic.
European heart journal cardiovascular Imaging. 05/2012;
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ABSTRACT: We report microscopic observations of the primary flow oscillation of an acoustically driven bubble in contact with a wall, captured with the ultra high-speed camera Brandaris 128 (Chin etal. 2003). The driving frequency is up to 200kHz, and the imaging frequency is up to 25MHz. The details of the bubble motion during an ultrasound cycle are thus resolved, showing a combination of two modes of oscillations: a radius oscillation and a translation oscillation, perpendicular to the wall. This motion is interpreted using the theory of acoustic images to account for the presence of the wall. We conclude that the bubble is subjected to a periodic succession of attractive and repulsive forces, exerted by its own image. Fast-framing recordings of a tracer particle embedded in the liquid around the particle are performed. They fully resolve the acoustic streaming flow induced by the bubble oscillations. This non-linear secondary flow appears as a tiny drift of the particle position cycle after cycle, on top of the primary back and forth oscillation. The high oscillation frequency accounts for a fast average particle velocity, with characteristic timescales in the millisecond range at the lengthscale of the bubble. The features of the bubble motion being resolved, we can apply the acoustic streaming theory near a wall, which provides predictions in agreement with the observed streaming velocity.
Experiments in Fluids 04/2012; 41(2):147-153. · 1.74 Impact Factor
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Gerrit L ten Kate,
Guillaume G J Renaud,
Zeynettin Akkus,
Stijn C H van den Oord,
Folkert J ten Cate,
Vijay Shamdasani,
Rob R Entrekin,
Eric J G Sijbrands, Nico de Jong,
Johan G Bosch,
Arend F L Schinkel,
Antonius F W van der Steen
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ABSTRACT: The present study describes the presence of pseudoenhancement during contrast-enhanced ultrasound (CEUS) imaging of human carotid arteries and the reproduction of this pseudoenhancement in vitro. Seventy patients underwent bilateral CEUS examination of the carotid arteries using a Philips iU22 ultrasound system equipped with a L9-3 ultrasound probe and SonoVue microbubble contrast. During CEUS of the carotid arteries, we identified enhancement in close proximity to the far wall, parallel to the main lumen. The location of this enhancement does not correlate to the anatomical location of a parallel vessel. To corroborate the hypothesis that this is a pseudoenhancement artifact, the enhancement was recreated in a tissue-mimicking material phantom, using the same ultrasound system, settings and contrast agent as the patient study. The phantom study showed that pseudoenhancement may be present during vascular CEUS and that the degree of pseudoenhancement is influenced by the size and concentration of the microbubbles. During vascular CEUS, identification of the artifact is important to prevent misinterpretation of enhancement in and near the far wall.
Ultrasound in medicine & biology 04/2012; 38(4):593-600. · 2.02 Impact Factor
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ABSTRACT: Newly developed liposome-loaded (LPS) microbubbles [1] were characterized by comparing their oscillating response with standard phospholipid-shelled (BARE) microbubbles using the ultra-high speed imaging camera (Brandaris 128). 73 LPS bubbles and 41 BARE bubbles of diameters ranging from 3 μm to 10 μm were insonified by narrow band pulses with a driving frequency ranging from 0.5 MHz to 4 MHz and an acoustic pressure from 5 kPa to 100 kPa. Shell elasticity of LPS bubbles (0.17±0.1 N/m) was nearly the same as that of BARE bubbles (0.19±0.1 N/m) for all investigated bubble sizes. Clear difference of shell viscosity was found for bubbles larger than 6 μm. Averaged viscosity of LPS bubbles (2.5×10(-8) kg/s) was almost twice of that of BARE bubbles (1.4×10(-8) kg/s). A second finding for LPS bubbles was the dominant "expansion-only" behavior (70% of LPS bubbles), while this was only 13% for BARE bubbles. Results from this study will facilitate future preclinical studies and clinical applications of LPS bubbles for ultrasound triggered drug delivery system. Reference 1. Geers, B., et al., J Control Release, 2011. 152(2): p. 249-56.
The Journal of the Acoustical Society of America 04/2012; 131(4):3248. · 1.55 Impact Factor
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ABSTRACT: It is known that vasa vasorum plays an important role in atherosclerotic plaque pathogenesis and stability. Recent advances in contrast-enhanced ultrasound have shown that this technique can be used to characterize the carotid vasa vasorum and intra-plaque angiogenesis. Ultrasound propagating through tissue is nonlinear and contains higher harmonics of the transmitted wave, but it does not contain energy at the subharmonic frequency, which revives a strong interest in subharmonic emissions (backscattered energy at half the transmit frequency) from contrast agents. Subharmonic imaging (SHI) has potentially a larger contrast to tissue ratio compared to other imaging methods and has already been used in clinical experimental studies. In this study, the subharmonic scattering of phospholipid-coated contrast agents in the frequency range preferred for carotid imaging (5-15 MHz) is investigated optically and acoustically and in vitro and in vivo. The results of the measurements indicate that: -The subharmonic scattering of the microbubbles is sufficiently detectable (-10 dB below the fundamental) at 10 MHz at low acoustic pressures of 100 kPa. -The subharmonic response of microbubbles can be dynamically manipulated using a 2.5 kHz pressure wave. In conclusion, SHI has a great potential to be exploited for carotid imaging.
The Journal of the Acoustical Society of America 04/2012; 131(4):3323. · 1.55 Impact Factor
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ABSTRACT: Liquid emulsion nanodroplets composed of perfluorocarbon (PFC) and a drug (Doxorubicin) are currently being studied as a potential highly efficient system for tumor imaging and for local drug delivery. The nanodroplets have the ability to extravasate through hyperpermeable tumor blood vessel walls, and to accumulate in interstitial tissue. The extravasated droplets can be triggered and vaporized with focused ultrasound, converting them into gas bubbles while the encapsulated drugs are released during the explosive evaporation of the droplet. Single and double emulsions of PFC-in-water and oil-in-PFC-in-water upscaled to 5-10 um size were prepared and the nucleation and growth of the vapor bubbles (f=3.5 MHz, P_=4.5 MPa) was imaged at frame rates of up to 20 Mfps with the Brandaris ultra high-speed imaging facility. The recorded images provide new and detailed insight in the physical mechanisms associated with the vaporization dynamics. This include droplet deformation and oscillatory motion along with surrounding fluid with an amplitude of 200-400 nm, rapid growth of a vapor nucleus with a speed of 40 m/s and consecutive oscillations and collapse of several bubbles.
The Journal of the Acoustical Society of America 04/2012; 131(4):3247. · 1.55 Impact Factor
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ABSTRACT: In medical ultrasound, fundamental imaging (FI) uses the reflected echoes from the same spectral band as that of the emitted pulse. The transmission frequency determines the trade-off between penetration depth and spatial resolution. Tissue harmonic imaging (THI) employs the second harmonic of the emitted frequency band to construct images. Recently, superharmonic imaging (SHI) has been introduced, which uses the third to the fifth (super) harmonics. The harmonic level is determined by two competing phenomena: nonlinear propagation and frequency dependent attenuation. Thus, the transmission frequency yielding the optimal trade-off between the spatial resolution and the penetration depth differs for THI and SHI. This paper quantitatively compares the concepts of fundamental, second harmonic, and superharmonic echocardiography at their optimal transmission frequencies. Forward propagation is modeled using a 3D-KZK implementation and the iterative nonlinear contrast source (INCS) method. Backpropagation is assumed to be linear. Results show that the fundamental lateral beamwidth is the narrowest at focus, while the superharmonic one is narrower outside the focus. The lateral superharmonic roll-off exceeds the fundamental and second harmonic roll-off. Also, the axial resolution of SHI exceeds that of FI and THI. The far-field pulse-echo superharmonic pressure is lower than that of the fundamental and second harmonic. SHI appears suited for echocardiography and is expected to improve its image quality at the cost of a slight reduction in depth-of-field.
The Journal of the Acoustical Society of America 11/2011; 130(5):3148-57. · 1.55 Impact Factor
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ABSTRACT: A detailed understanding of the response of single microbubbles subjected to ultrasound is fundamental to a full understanding of the contrast-enhancing abilities of microbubbles in medical ultrasound imaging, in targeted molecular imaging with ultrasound, and in ultrasound-mediated drug delivery with microbubbles. Here, single microbubbles are isolated and their ultrasound-induced radial dynamics recorded with an ultra-high-speed camera at up to 25 million frames per second. The sound emission is recorded simultaneously with a calibrated single element transducer. It is shown that the sound emission can be predicted directly from the optically recorded radial dynamics, and vice versa, that the nanometer-scale radial dynamics can be predicted from the acoustic response recorded in the far field.
The Journal of the Acoustical Society of America 11/2011; 130(5):3271-81. · 1.55 Impact Factor
