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ABSTRACT: An acoustical method was developed to study the resonance of single lipid-coated microbubbles. The response of 127 SonoVue microbubbles to a swept sine excitation between 0.5 and 5.5 MHz with a peak acoustic pressure amplitude of 70 kPa was measured by means of a 25 MHz probing wave. The relative amplitude modulation in the signal scattered in response to the probing wave is approximately equal to the radial strain induced by the swept sine excitation. An average damping coefficient of 0.33 and an average resonance frequency of 2.5 MHz were measured. Microbubbles experienced an average peak radial strain of 20%.
The Journal of the Acoustical Society of America 12/2012; 132(6):EL470-5. · 1.55 Impact Factor
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ABSTRACT: Most techniques for contrast-enhanced ultrasound imaging require linear propagation to detect nonlinear scattering of contrast agent microbubbles. Waveform distortion due to nonlinear propagation impairs their ability to distinguish microbubbles from tissue. As a result, tissue can be misclassified as microbubbles, and contrast agent concentration can be overestimated; therefore, these artifacts can significantly impair the quality of medical diagnoses. Contrary to biological tissue, lipid-coated gas microbubbles used as a contrast agent allow the interaction of two acoustic waves propagating in opposite directions (counter-propagation). Based on that principle, we describe a strategy to detect microbubbles that is free from nonlinear propagation artifacts. In vitro images were acquired with an ultrasound scanner in a phantom of tissue-mimicking material with a cavity containing a contrast agent. Unlike the default mode of the scanner using amplitude modulation to detect microbubbles, the pulse sequence exploiting counter-propagating wave interaction creates no pseudoenhancement behind the cavity in the contrast image.
Physics in Medicine and Biology 10/2012; 57(21):L9-L18. · 2.83 Impact Factor
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ABSTRACT: Subharmonic (SH) emission from the ultrasound contrast agent (UCA) is of interest since it is produced only by the UCA and not by tissue, opposite to harmonic imaging modes where both tissue and microbubble show harmonics. In this work, the use of the self-demodulation (S-D) signal as a means of microbubble excitation at the SH frequency to enhance the SH emission of UCA is studied. The S-D wave is a low-frequency signal produced by the weak nonlinear propagation of an ultrasound wave. It is proportional to the second time derivative of the squared envelope of the transmitted signal. A diluted population of BR14 UCA (Bracco Research SA, Geneva, Switzerland) was insonified by a 10 MHz transducer focused at 76 mm firing bursts with different envelopes, durations and peak pressure amplitudes. The center frequency of the S-D signal changes from low frequencies (around 0.5 MHz) toward the transmitted frequency (10 MHz) by modifying the envelope function from gaussian to rectangular. For 6 and 20 transmitted cycles, the SH response is enhanced up to 25 and 22 dB, respectively, when using a rectangular envelope instead of a gaussian one. The experimental results are confirmed by the numerical simulation. The effects of the excitation duration and pressure amplitude are also studied. This study shows that a suitable design of the envelope of the transmit excitation to generate a S-D signal at the SH frequency can enhance the SH emission of UCA, and the SH imaging is feasible at high frequencies with a shorter transmit burst (six-cycle) and low acoustic pressure (∼100 KPa).
Physics in Medicine and Biology 05/2012; 57(12):3675-91. · 2.83 Impact Factor
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L. J. M. Juffermans,
A. van Wamel,
R. H. Henning,
K. Kooiman,
M. Emmer, N. de Jong,
W. H. van Gilst,
R. Musters,
W. J. Paulus,
A. C. van Rossum,
L. E. Deelman,
O. Kamp
[show abstract]
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ABSTRACT: The molecular understanding of diseases has been accelerated in recent years, producing many new potential therapeutic targets.
A noninvasive delivery system that can target specific anatomical sites would be a great boost for many therapies, particularly
those based on manipulation of gene expression. The use of microbubbles controlled by ultrasound as a method for delivery
of drugs or genes to specific tissues is promising. It has been shown by our group and others that ultrasound increases cell
membrane permeability and enhances uptake of drugs and genes. One of the important mechanisms is that microbubbles act to
focus ultrasound energy by lowering the threshold for ultrasound bioeffects. Therefore, clear understanding of the bioeffects
and mechanisms underlying the membrane permeability in the presence of microbubbles and ultrasound is of paramount importance.
(Neth Heart J 2009;17:82-6.)
ultrasound-microbubbles-cell membrane permeability-bioeffects-local therapy
Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 04/2012; 17(2):82-86. · 1.44 Impact Factor
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ABSTRACT: This study investigates the use of an acoustic parametric array as a means for microbubble excitation. The excitation wave is generated during propagation in a nonlinear medium of two high-frequency carrier waves, whereby the frequency of the excitation wave is the difference frequency of the carrier waves. Carrier waves of around 10 and 25 MHz are used to generate low-frequency waves between 0.5 and 3.5 MHz at amplitudes in the range of 25 to 80 kPa in water. We demonstrate with high-speed camera observations that it is possible to induce microbubble oscillations with the low frequency signal arising from the nonlinear propagation process. As an application, we determined the resonance frequency of Definity contrast agent microbubbles with radius ranging from 1.5 to 5 μm by sweeping the difference frequency in the range from 0.5 to 3.5 MHz.
IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control 06/2011; · 1.69 Impact Factor
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ABSTRACT: Real-time three-dimensional (3D) ultrasound imaging has been proposed as an alternative for two-dimensional stress echocardiography for assessing myocardial dysfunction and underlying coronary artery disease. Analysis of 3D stress echocardiography is no simple task and requires considerable expertise. In this paper, we propose methods for automated analysis, which may provide a more objective and accurate diagnosis. Expert knowledge is incorporated via statistical modelling of patient data. Methods for identifying anatomical views, detecting endocardial borders, and classification of wall motion are described and shown to provide favourable results. We also present software developed especially for analysis of 3D stress echocardiography in clinical practice. Interobserver agreement in wall motion scoring is better using the dedicated software (96%) than commercially available software not dedicated for this purpose (79%). The developed tools may provide useful quantitative and objective parameters to assist the clinical expert in the diagnosis of left ventricular function.
Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 06/2011; 19(6):307-10. · 1.44 Impact Factor
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ABSTRACT: Second-harmonic imaging is currently one of the standards in commercial echographic systems for diagnosis, because of its high spatial resolution and low sensitivity to clutter and near-field artifacts. The use of nonlinear phenomena mirrors is a great set of solutions to improve echographic image resolution. To further enhance the resolution and image quality, the combination of the 3rd to 5th harmonics - dubbed the superharmonics - could be used. However, this requires a bandwidth exceeding that of conventional transducers. A promising solution features a phased-array design with interleaved low- and high-frequency elements for transmission and reception, respectively. Because the amplitude of the backscattered higher harmonics at the transducer surface is relatively low, it is highly desirable to increase the sensitivity in reception. Therefore, we investigated the optimization of the number of elements in the receiving aperture as well as their arrangement (topology). A variety of configurations was considered, including one transmit element for each receive element (1/2) up to one transmit for 7 receive elements (1/8). The topologies are assessed based on the ratio of the harmonic peak pressures in the main and grating lobes. Further, the higher harmonic level is maximized by optimization of the center frequency of the transmitted pulse. The achievable SNR for a specific application is a compromise between the frequency-dependent attenuation and nonlinearity at a required penetration depth. To calculate the SNR of the complete imaging chain, we use an approach analogous to the sonar equation used in underwater acoustics. The generated harmonic pressure fields caused by nonlinear wave propagation were modeled with the iterative nonlinear contrast source (INCS) method, the KZK, or the Burger's equation. The optimal topology for superharmonic imaging was an interleaved design with 1 transmit element per 6 receive elements. It improves the SNR by ~5 dB compared wi-
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th the interleaved (1/2) design reported in literature. The optimal transmit frequency for superharmonic echocardiography was found to be 1.0 to 1.2 MHz. For superharmonic abdominal imaging this frequency was found to be 1.7 to 1.9 MHz. For 2nd-harmonic echocardiography, the optimal transmit frequency of 1.8 MHz reported in the literature was corroborated with our simulation results.
IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control 04/2011; · 1.69 Impact Factor
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ABSTRACT: We have investigated the subharmonic vibration of BR14 (Bracco Research S.A., Geneva, Switzerland) contrast agent microbubbles between 8-11 MHz. The response of the bubbles is recorded optically with the ultrafast recording camera (Brandaris 128) at three acoustic pressures 50, 100 and 120 kPa. The vibration of the microbubbles as a function of excitation frequency is measured and frequency content is determined. 40% of studied bubbles show subharmonic oscillations. For bubbles smaller than 3μm in diameter the driving frequency of maximum subharmonic response increases for increasing pressures opposite to what has been reported for larger bubbles (>; 3μm).
Ultrasonics Symposium (IUS), 2010 IEEE; 11/2010
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ABSTRACT: It is increasingly recognized that the development of new microvessels (vasa vasorum) within and surrounding atherosclerotic plaques is essential to enable artery lesion growth and plays a central role in rendering it vulnerable to rupture. Currently, there is no established clinical technique capable of imaging the vasa vasorum (VV) in the coronary arteries of humans. It has been shown that contrast-enhanced intravascular ultrasound (CE-IVUS) is capable of imaging VV in vivo. This study aims at reconstructing in three dimensions (3D) a VV model using CE-IVUS with a clinical coronary imaging catheter. A polyvinyl alcohol based VV model was manufactured, exhibiting a VV mimicking branch pattern with a diameter ranging from 200 to 100 μm. After perfusion of the VV model with the ultrasound contrast agent Definity<sup>®</sup>, a manual pullback consisting of 93 cross sectional IVUS images spaced every 200 μm was performed. Perfused areas were segmented in two registered CE-IVUS planes and compared to coregistered 10 μm thick slices of the VV model. The VV mimicking microchannel diameters measured with CE-IVUS agreed within 30% with the slice diameters. As CE-IVUS imaging can be carried out in-vivo, this method could be used during clinical IVUS investigations as an additional diagnostic for plaque vulnerability.
Ultrasonics Symposium (IUS), 2010 IEEE; 11/2010
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ABSTRACT: Since its initial description by Gramiak and Shah in 1968, contrast echocardiography has become an established practice world-wide. Microbubbles have the unique property of being pure intravascular tracers. The basic rationale behind bubble imaging is the characteristic responses to ultrasound power that results in enhanced ultrasound images from the blood pool. Therefore, whenever there is blood pool there is a potential application for contrast ultrasound. Clinical applications of contrast echocardiography have been vastly grown from diagnostic applications such as detection of a persistent foramen ovale to drug delivery. This article reviews the mechanism of action, safety and clinical applications of contrast echocardiography.
Minerva cardioangiologica 06/2010; 58(3):343-55.
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ABSTRACT: A fully automated segmentation for 3D echocardiography (3DE) using 3D Active Appearance Models (AAM) was developed and evaluated on 99 patients. The method used ultrasound specific grey value normalization and two matching algorithms were tested. To our knowledge this is the first report on a fully operational 3D AAM employed in 3DE on a large scale. The 3D AAM detected the endocardial contours accurately, even in the presence of large variations in left ventricular appearance and shape. Matching was successful in 91% of patients and resulted in a median point-to-surface error of 2.69 mm (av±sd: 2.91±1.03mm). Results indicate that fully automated AAM analysis of 3DE is practically feasible in datasets of mixed origin and quality.
Biomedical Imaging: From Nano to Macro, 2010 IEEE International Symposium on; 05/2010
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ABSTRACT: For several years, the standard in ultrasound imaging has been second-harmonic imaging. A new imaging technique dubbed "super-harmonic imaging" (SHI) was recently proposed. It takes advantage of the higher-third to fifth-harmonics arising from nonlinear propagation or ultrasound-contrast-agent (UCA) response. Next to its better suppression of near-field artifacts, tissue SHI is expected to improve axial and lateral resolutions resulting in clearer images than second-harmonic imaging. When SHI is used in combination with UCAs, a better contrast-to-tissue ratio can be obtained. The use of SHI implies a large dynamic range and requires a sufficiently sensitive array over a frequency range from the transmission frequency up to its fifth harmonic (bandwidth > 130%). In this paper, we present the characteristics and performance of a new interleaved dual frequency array built chiefly for SHI. We report the rationale behind the design choice, frequencies, aperture, and piezomaterials used. The array is efficient both in transmission and reception with well-behaved transfer functions and a combined -6-dB bandwidth of 144%. In addition, there is virtually no contamination of the harmonic components by spurious transducer transmission, due to low element-to-element crosstalk (< 30 dB) and a low transmission efficiency of the odd harmonics (< 46 dB). The interleaved array presented in this article possesses ideal characteristics for SHI and is suitable for other methods like second-harmonic, subharmonic, and second-order ultrasound field (SURF) imaging.
IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control 03/2010; · 1.69 Impact Factor
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ABSTRACT: Drug delivery to a diseased tissue will be more efficient if the vascular endothelial permeability is increased. Recent studies have shown that the permeability of single cell membranes is increased by ultrasound in combination with contrast agents. It is not known whether this combination can also increase the permeability of an endothelial layer in the absence of cell damage. To investigate the feasibility of controlled increased endothelial layer permeability, we treated monolayers of human umbilical vein endothelial cells with ultrasound and the contrast agent BR14. Barrier function was assessed by measuring transendothelial electrical resistance (TEER). Ultrasound-activated BR14 significantly decreased TEER by 40.3% ?? 3.7% (p < 0.01). After treatment, no cell detachment or damage was observed. In conclusion, ultrasound-activated BR14 microbubbles increased the endothelial layer permeability. This feature can be used for future ultrasound-guided drug delivery systems.
IEEE Transactions on Biomedical Engineering 02/2010; · 2.28 Impact Factor
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ABSTRACT: Second harmonic imaging is currently the standard in commercial echographic systems. A new modality, super harmonic imaging (SHI), is based on combining the 3rd to 5th harmonic generated during sound propagation in tissue. This emerging modality could further enhance resolution and quality of echographic images. To meet the bandwidth requirement for SHI an interleaved phased array was developed. Array elements used in transmission generally have bandwidths of ~ 80% leading to gaps between harmonics in the spectral domain. This causes ripple artifacts in the echo image. Last year we introduced a new dual pulse frequency compounding method to reduce these artifacts and showed initial single element results [1]. In this work we implement and optimize the dual pulse method for an interleaved array on an ultrasound system and research its imaging characteristics, i.e. point spread functions (PSF). In the dual pulse SHI method each trace is constructed by the summing of two firings, the second slightly frequency shifted compared to the first. To study the dual pulse method's performance an interleaved array (44 1 MHz and 44 3.7 MHz elements, optimized for echocardiography) was used in combination with a fully programmable ultrasound system. Initial estimates for the frequencies of the first and second pulses as well as the pulse duration were optimized experimentally. Our findings confirm that the transfer functions of both transducer and system have to be taken into account to determine the optimal transmission frequencies for the dual pulse SHI method. Moreover, a trade off exists between dual pulse signal length and peak intensity. The optimal results with the dual pulse technique were achieved using a transmission length of 2.5 cycles and transmission frequencies of 0.87 MHz and 1.12 MHz. The lateral beam widths of the optimal dual pulse signal are 1.2 times smaller at the -6 dB level and equal at the -20 dB level compared to the third harmonic. The axial beam widths-
of the optimal dual pulse signal are 3.1 times smaller at the -6 dB level and 1.6 times smaller at the -20 dB level compared to the third harmonic. Not only does dual pulse method solve the ripple artifacts associated with imaging using multiple harmonic bands, dual pulse SHI has markedly improved axial and lateral resolutions compared to the third harmonic at higher than second harmonic intensities.
Ultrasonics Symposium (IUS), 2009 IEEE International; 10/2009
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ABSTRACT: This paper describes the design of a transesophageal probe using a matrix (2D array) ultrasonic transducer for 3D echocardiography. To obtain images with sufficient resolution, several thousand elements are required. To reduce the channel count from the transducer to the imaging system, it is necessary to include electronics close to the transducer and use smart signal processing for data reduction. A micro-beamforming method called pre-steering is proposed. All the groups have the same delay configuration, which will simplify the required electronics. For a correct design, delay steps and the maximum delay are of importance. Furthermore, the delay should be programmable for each direction. Simulations are performed to investigate the effect of pre-steering on the received field. The delay and sum operations are realized by an integrated circuit. Simulations show that, for the micro-beamformer of a matrix transducer, the pre-steering approach is an effective method to reduce the complexity of the electronics and the channel count, while maintaining an adequate receive field.
Ultrasonics Symposium (IUS), 2009 IEEE International; 10/2009
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ABSTRACT: Detection of contrast agent in perfused tissues has been an important research topic for many years. Currently available methods are mostly based on the strong nonlinear scattering of contrast agent microbubbles. These methods selectively extract those parts of the spectrum that show the largest difference in nonlinearity between contrast agent and tissue. The method introduced in this paper expands this extraction approach in that it additionally exploits differences in system behavior between tissue and contrast bubbles. The resonant nature of contrast bubbles implies that the response of a contrast bubble is stateful, i.e., the response not only depends on the current input, but also on all previous inputs. Tissue does not show this dependence on previous inputs. Our method is based on a 3 pulse design in which the echoes from 2 nonoverlapping pulses are subtracted from a third pulse. With this method we aim to separate and suppress those parts in an echo signal that originate from tissue while leaving the part originating from contrast bubbles relatively undisturbed. Simulation results show increases up to 30 dB in contrast-to-tissue ratio (CTR) with this method relative to single pulse echoes. This was confirmed in an in vitro experiment that showed an increase of approximately 12 dB in CTR.
IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control 07/2009; · 1.69 Impact Factor
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L J M Juffermans,
D B M Meijering,
A van Wamel,
R H Henning,
K Kooiman,
M Emmer, N de Jong,
W H van Gilst,
R Musters,
W J Paulus,
A C van Rossum,
L E Deelman,
O Kamp
[show abstract]
[hide abstract]
ABSTRACT: The molecular understanding of diseases has been accelerated in recent years, producing many new potential therapeutic targets. A noninvasive delivery system that can target specific anatomical sites would be a great boost for many therapies, particularly those based on manipulation of gene expression. The use of microbubbles controlled by ultrasound as a method for delivery of drugs or genes to specific tissues is promising. It has been shown by our group and others that ultrasound increases cell membrane permeability and enhances uptake of drugs and genes. One of the important mechanisms is that microbubbles act to focus ultrasound energy by lowering the threshold for ultrasound bioeffects. Therefore, clear understanding of the bioeffects and mechanisms underlying the membrane permeability in the presence of microbubbles and ultrasound is of paramount importance. (Neth Heart J 2009;17:82-6.).
Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 03/2009; 17(2):82-6. · 1.44 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Detection of contrast agent in perfused tissues has been an important research topic for many years. Currently available methods are mostly based on the strong nonlinear scattering of contrast agent microbubbles. These methods selectively extract those parts of the spectrum that show the largest difference in nonlinearity between contrast agent and tissue. The method introduced in this paper expands this extraction approach in that it additionally exploits differences in system behavior between tissue and contrast bubbles. The resonant nature of contrast bubbles implies that the response of a contrast bubble is stateful, i.e., the response not only depends on the current input, but also on all previous inputs. Tissue does not show this dependence on previous inputs. Our method is based on a 3 pulse design in which the echoes from 2 nonoverlapping pulses are subtracted from a third pulse. With this method we aim to separate and suppress those parts in an echo signal that originate from tissue while leaving the part originating from contrast bubbles relatively undisturbed. Simulation results show increases up to 30 dB in contrast-to-tissue ratio (CTR) with this method relative to single pulse echoes. This was confirmed in an in vitro experiment that showed an increase of approximately 12 dB in CTR.
IEEE transactions on ultrasonics, ferroelectrics, and frequency control 02/2009; 56(6):1151-8. · 1.80 Impact Factor
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ABSTRACT: Active response of a microbubble is characterized by its resonance behavior where the microbubble might oscillate after the excitation waveform has been turned off. We investigate in this paper an excitation approach based on this resonance phenomenon using chirps. The technique, called chirp reversal, consists in transmitting a first excitation signal, the up-sweep chirp (UPF) of increasing frequency with time, and a second excitation signal, the down-sweep (DNF) that is a replica of the first signal, but time reversed with a sweep of decreasing frequency with time. Simulations using a modified Rayleigh-Plesset equation were carried out to determine bubble response to chirp reversal. In addition, optical observations and acoustical measurements were carried out to corroborate the theoretical findings. Results of simulations show differences between bubbles' oscillations in response to up-sweep and down-sweep chirps mainly for transmitted center frequencies above the bubble's resonance frequency. Bubbles that are at resonance or far away from resonance engender identical responses. From the optical data, the larger bubbles showed different dynamics when up-sweep or down-sweep chirps were transmitted. Smaller bubbles (< 2 microm diameter) appear to be less sensitive to frequency sweep at 1.7 MHz center frequency. However, driven at a higher center frequency, smaller bubbles tend to be more sensitive. These results were confirmed through the acoustical measurements. We concluded that simulations and experimental data show that significant differences might be observed between bubbles' responses to UPF and DNF chirps. We demonstrate in this study that, for an optimal use of chirp reversal, the transmit frequency should be higher than the resonance frequency of the contrast microbubbles.
IEEE transactions on ultrasonics, ferroelectrics, and frequency control 02/2009; 56(6):1199-206. · 1.80 Impact Factor
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ABSTRACT: Catheterization remains the gold standard for bladder volume assessment, but it is invasive, uncomfortable to the patient, and introduces the risk of infections and trauma. To reduce the need for a urinary catheter, a new method has recently been introduced that non-invasively and instantaneously measures the bladder volume on the basis of nonlinear wave propagation and using a single diverging acoustic beam. The performance of the original computational method to quantitatively measure volume was compared with an alternative algorithm using simulations on nonlinear wave propagation and in-vivo measurements. Measurements were performed with an experimental setup including a custom designed multilayer transducer.
Ultrasonics Symposium, 2008. IUS 2008. IEEE; 12/2008
