WFUMB Safety Symposium on Echo-Contrast Agents: nature and types of ultrasound contrast agents.
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Equipment Design↗
Biomedical subjects
Ayache Bouakaz
Publications and source records attributed to Ayache Bouakaz.
Nitric oxide delivery by ultrasonic cracking: some limitations.
Nitric oxide (NO) has been implicated in smooth muscle relaxation. Its use has been widespread in cardiology. Due to the effective scavenging of NO by hemoglobin, however, the drug has to be applied locally or in large quantities, to have the effect desired. We propose the use of encapsulated microbubbles that act as a vehicle to carry the gas to a region of interest. By applying a burst of high-amplitude ultrasound, the shell encapsulating the gas can be cracked. Consequently, the gas is released upon which its dissolution and diffusion begins. This process is generally referred to as (ultra)sonic cracking. To test if the quantities of released gas are high enough to allow for NO-delivery in small vessels (ø<200 microm), we analyzed high-speed optical recordings of insonified stiff-shelled microbubbles. These microbubbles were subjected to ultrasonic cracking using 0.5 or 1.7 MHz ultrasound with mechanical index MI>0.6. The mean quantity released from a single microbubble is 1.7 fmol. This is already more than the NO production of a 1mm long vessel with a 50 microm diameter during 100 ms. However, we simulated that the dissolution time of typical released NO microbubbles is equal to the half-life time of NO in whole blood due to scavenging by hemoglobin (1.8 ms), but much smaller than the extravascular half-life time of NO (>90 ms). We conclude that ultrasonic cracking can only be a successful means for nitric oxide delivery, if the gas is released in or near the red blood cell-free plasma next to the endothelium. A complicating factor in the in vivo situation is the variation in blood pressure. Although our simulations and acoustic measurements demonstrate that the dissolution speed of free gas increases with the hydrostatic pressure, the in vitro acoustic amplitudes suggest that the number of released microbubbles decreases at higher hydrostatic pressures. This indicates that ultrasonic cracking mostly occurs during the expansion phase.
Capsules↗
Differential diagnosis of focal nodular hyperplasia with quantitative parametric analysis in contrast-enhanced sonography.
OBJECTIVES: We investigated the potential of quantitative parametric analysis in the differential diagnosis of focal nodular hyperplasia (FNH) from other hypervascularized liver focal lesions. MATERIALS AND METHODS: Eighty-five focal liver lesions (in 83 patients) were explored using contrast-enhanced ultrasound (SonoVue and Cadence Contrast Pulse Sequencing) consisting of typical FNH (n=52), hepatocellular carcinoma (n=11), hemangioma with high flow (n=8), hypervascular metastases (n=10), and hepatocellular adenoma (n=4). QontraXt software (AMID, Italy) was used here to estimate the following parameters: maximum peak value, Tr (time corresponding to time for obtaining 63% of the plateau), beta parameter corresponding to the exponential factor, and slope corresponding to the tangent value of the first phase of enhancement. These parameters were obtained from the time-intensity curves derived from the enhancement observed in 2 regions of interest corresponding, respectively, to the whole lesion and the central region only. RESULTS: A significant statistical difference (P<0.05) was found in the values of Tr, beta, and slope between FNH and other hypervascularized lesions on both the whole lesion and central region. Among these parameters, slope appeared as the most valuable whatever the region of interest, ie, central or whole lesion (P<0.01). Central region was more accurate in the differentiation of FNH and concordant with visual characterization. CONCLUSION: Quantitative parametric curve analysis of the different hypervascularized lesions confirms the depiction of the central artery in FNH and thus could help in differentiating this specific focal liver lesion from the others.
Adult↗
Design of a multilayer transducer for acoustic bladder volume assessment.
Catheterization remains the "gold standard" for bladder volume assessment, but it is invasive and introduces the risk of infections and traumas. Therefore, noninvasive bladder volume measurement methods have gained interest. In a preceding study a new technique to measure the bladder volume on the basis of nonlinear ultrasound wave propagation was validated. This paper describes a first prototype of a dedicated multilayer transducer to implement this approach. It is composed of a PZT transducer for transmission and a PVDF layer for reception. Acoustical measurements in a water tank and phantom measurements showed that there is a relation between bladder volume and the harmonic contents of the echo obtained from a region of interest behind the bladder. Simulations with an equivalent transducer model on the basis of KLM-circuit modeling closely matched with the results from the acoustical measurements. The results demonstrated the feasibility of the multilayer transducer design for bladder volume assessment on the basis of nonlinear wave propagation.
Animals↗
A simulation study on tissue harmonic imaging with a single-element intravascular ultrasound catheter.
Recently, in vivo feasibility of tissue harmonic imaging with a mechanically rotated intravascular ultrasound (IVUS) catheter was experimentally demonstrated. To isolate the second harmonic signal content, a combination of pulse inversion and analog filtering was used. In this paper the development of a simulation tool to investigate nonlinear IVUS beams is reported, and the influence of transducer rotation and axial catheter-to-tissue motion on the efficiency of PI signal processing is evaluated. Nonlinear beams were simulated in homogeneous tissue-mimicking media at a transmit frequency of 20 MHz, which resulted in second harmonic pressure fields at 40 MHz. The competing effects of averaging and decorrelation between neighboring rf lines on the signal-to-noise ratio (SNR) were studied for a single point scatterer. An optimal SNR was achieved when lines were combined over 3 degrees - 3.75 degrees. When the transducer was rotated with respect to point scatterers, simulating the acoustic response of tissue, the fundamental frequency suppression using PI degraded rapidly with increasing interpulse angles. The effect of axial catheter-to-tissue motion on the efficiency of pulse inversion seemed to be of less influence for realistic motion values. The results of this study will aid in the optimization of harmonic IVUS imaging systems.
Acoustics↗
High-speed optical observations of contrast agent destruction.
Ultrasound contrast agents are now available since a few years and used for diagnostic purposes. Improved diagnostic decisions have been made possible with new imaging methods that are mainly based on the nonlinear properties of gas microbubbles. Since it is well known that contrast agents are destroyed by ultrasound when the acoustic pressure exceeds a threshold, extremely low acoustic pressures were applied to achieve enhanced contrast image quality. However, destruction of contrast microbubbles is not necessarily undesirable, since it is beneficial in, for example, destruction/reperfusion imaging and recently in drug delivery. We investigate in this experimental study the destruction dynamics of a contrast agent consisting of nitrogen bubbles encapsulated in a double polymer/albumin wall shell. This is accomplished using an ultrafast camera Brandaris that operates at a frame rate of 25 MHz and records 128 frames. The measurements were performed with an ultrasound sine burst of 10 cycles at 1.7 MHz. Different acoustic pressures were applied and various microsphere sizes were examined. The results show three different zones depending on the applied pressure and bubble size: these are nondestruction zone, transient zone and destruction zone. The nondestruction zone is reached for either very small microspheres or low mechanical indices (MI) (<0.3). In the destruction zone lie either large microspheres (5 microm or higher) even when irradiated at low MIs or small microspheres (<5 microm) when the MI is above 0.6. The optical observations revealed that the destruction of the microspheres is characterized by shell rupture and gas release. The release of the gas gives rise to new free microbubble that lasts for a few milliseconds and then disappears due to dissolution. In the transient zone, the microspheres are mainly compressed in the first few cycles but no expansion is induced. After intense compressions, the shell fissures and gas escapes in the last cycles of the burst or during a second burst depending on the initial size and MI. These optical recordings are important to investigate contrast bubble destruction and can help in amplifying or minimizing this process. Indeed, bubble disruption remains the basis of most current sensitive methods for detecting perfusion with contrast agents and is an essential component of perfusion quantification with microbubbles, in addition to drug delivery applications and pressure measurements.
Algorithms↗
Multifrequency transducer for microemboli classification and sizing.
The classification of circulating microemboli as gaseous or particulate matter is essential to establish the relevance of the detected embolic signals. Until now, Doppler techniques have failed to determine unambiguously the nature of circulating microemboli. Recently, a new approach based on the analysis of radio frequency (RF) signal and using the nonlinear characteristics of gaseous bubbles to classify emboli was investigated. The main limitation of these studies was the requirement of two separate transducers for transmission and reception. This paper presents a multi-frequency transducer with two independent transmitting elements and a separate receiving part with a wide frequency band. The transmitting elements are positioned in a concentric design and cover a frequency band between 100 and 600 kHz. The receiving part consists of a polyvinylidene fluoride layer. The new transducer has been tested in vitro using gaseous emboli. It could correctly classify and size air emboli with diameters ranging from 10 microm to 105 microm.
Electromagnetic Phenomena↗
Optical observations of acoustical radiation force effects on individual air bubbles.
Previous studies dealing with contrast agent microbubbles have demonstrated that ultrasound (US) can significantly influence the movement of microbubbles. In this paper, we investigated the influence of the acoustic radiation force on individual air bubbles using high-speed photography. We emphasize the effects of the US parameters (pulse length, acoustic pressure) on different bubble patterns and their consequences on the translational motion of the bubbles. A stream of uniform air bubbles with diameter ranging from 35 microm to 79 microm was generated and insonified with a single US pulse emitted at a frequency of 130 kHz. The bubble sizes have been chosen to be above, below, and at resonance. The peak acoustic pressures used in these experiments ranged from 40 kPa to 120 kPa. The axial displacements of the bubbles produced by the action of the US pulse were optically recorded using a high-speed camera at 1 kHz frame rate. The experimental results were compared to a simplified force balance theoretical model, including the action of the primary radiation force and the fluid drag force. Although the model is quite simple and does not take into account phenomena like bubble shape oscillations and added mass, the experimental findings agree with the predictions. The measured axial displacement increases quasilinearly with the burst length and the transmitted acoustic pressure. The axial displacement varies with the size and the density of the air bubbles, reaching a maximum at the resonance size of 48 microm. The predicted displacement values differ by 15% from the measured data, except for resonant bubbles for which the displacement was overestimated by about 40%. This study demonstrates that even a single US pulse produces radiation forces that are strong enough to affect the bubble position.
Acoustics↗
Harmonic chirp imaging method for ultrasound contrast agent.
Coded excitation is currently used in medical ultrasound to increase signal-to-noise ratio (SNR) and penetration depth. We propose a chirp excitation method for contrast agents using the second harmonic component of the response. This method is based on a compression filter that selectively compresses and extracts the second harmonic component from the received echo signal. Simulations have shown a clear increase in response for chirp excitation over pulse excitation with the same peak amplitude. This was confirmed by two-dimensional (2-D) optical observations of bubble response with a fast framing camera. To evaluate the harmonic compression method, we applied it to simulated bubble echoes, to measured propagation harmonics, and to B-mode scans of a flow phantom and compared it to regular pulse excitation imaging. An increase of approximately 10 dB in SNR was found for chirp excitation. The compression method was found to perform well in terms of resolution. Axial resolution was in all cases within 10% of the axial resolution from pulse excitation. Range side-lobe levels were 30 dB below the main lobe for the simulated bubble echoes and measured propagation harmonics. However, side-lobes were visible in the B-mode contrast images.
Contrast Media↗
Ultrasound-induced gas release from contrast agent microbubbles.
We investigated gas release from two hardshelled ultrasound contrast agents by subjecting them to high-mechanical index (MI) ultrasound and simultaneously capturing high-speed photographs. At an insonifying frequency of 1.7 MHz, a larger percentage of contrast bubbles is seen to crack than at 0.5 MHz. Most of the released gas bubbles have equilibrium diameters between 1.25 and 1.75 microm. Their disappearance was observed optically. Free gas bubbles have equilibrium diameters smaller than the bubbles from which they have been released. Coalescence may account for the long dissolution times acoustically observed and published in previous studies. After sonic cracking, the cracked bubbles stay acoustically active.
Contrast Media↗
A new ultrasonic transducer for improved contrast nonlinear imaging.
Second harmonic imaging has provided significant improvement in contrast detection over fundamental imaging. This improvement is a result of a higher contrast-to-tissue ratio (CTR) achievable at the second harmonic frequency. Nevertheless, the differentiation between contrast and tissue at the second harmonic frequency is still in many situations cumbersome and contrast detection remains nowadays as one of the main challenges, especially in the capillaries. The reduced CTR is mainly caused by the generation of second harmonic energy from nonlinear propagation effects in tissue, which hence obscures the echoes from contrast bubbles. In a previous study, we demonstrated theoretically that the CTR increases with the harmonic number. Therefore the purpose of our study was to increase the CTR by selectively looking to the higher harmonic frequencies. In order to be able to receive these high frequency components (third up to the fifth harmonic), a new ultrasonic phased array transducer has been constructed. The main advantage of the new design is its wide frequency bandwidth. The new array transducer contains two different types of elements arranged in an interleaved pattern (odd and even elements). This design enables separate transmission and reception modes. The odd elements operate at 2.8 MHz and 80% bandwidth, whereas the even elements have a centre frequency of 900 kHz with a bandwidth of 50%. The probe is connected to a Vivid 5 system (GE-Vingmed) and proper software is developed for driving. The total bandwidth of such a transducer is estimated to be more than 150% which enables higher harmonic imaging at an adequate sensitivity and signal to noise ratio compared to standard medical array transducers. We describe in this paper the design and fabrication of the array transducer. Moreover its acoustic properties are measured and its performances for nonlinear contrast imaging are evaluated in vitro and in vivo. The preliminary results demonstrate the advantages of such a transducer design for improved contrast detection.
Acoustics↗
Radionuclide tumour therapy with ultrasound contrast microbubbles.
Radionuclides have shown to be effective in tumour therapy. However, the side effects determine the maximum deliverable dose. Recently, it has been demonstrated that cells can be permeabilised through sonoporation using ultrasound and contrast microbubbles. The use of sonoporation in treatment of tumours may increase the anti-tumour efficacy of radionuclide treatment. The mechanisms as well as the effects sonoporation in tumour treatment strategies are still not understood. The purpose of this study is to determine the effects of ultrasound and contrast microbubbles on the internalisation of the radionuclide (111)In-DOTA-Tyr(3)-octreotate in tumour cells. To optimize ultrasound settings for ultrasound adjunctive tumour therapy we incubated rat pancreatic CA20948 tumour cells with two dyes (MW 40 and 70 kDa). The uptake levels were compared with cells treated with ultrasound and contrast microbubbles for different ultrasound settings. The highest molecular uptake was found with addition of contrast microbubbles (ratio of 10 bubbles to 1 cell) and with the ultrasound setting: duty cycle 0.013%, mechanical index (MI) 0.42, and treatment times of 30 and 60 min. These settings were used to enhance the internalisation of (111)In-DOTA-Tyr(3)-octreotate. We found a 160% higher internalisation of (111)In-DOTA-Tyr(3)-octreotate by tumour cells adjunctively treated with ultrasound and contrast microbubbles compared to untreated cells. These results show that adjunctive tumour treatment with the radionuclide (111)In-DOTA-Tyr(3)-octreotate and ultrasound contrast microbubbles may be feasible. When using adjunctive ultrasound contrast microbubble treatment, a lower radionuclide doses are required to reach the same anti-tumour effect.
Animals↗
Noninvasive microbubble-based pressure measurements: a simulation study.
This paper describes a noninvasive method to measure local hydrostatic pressures in fluid filled cavities. The method is based on the disappearance time of a gas bubble, as the disappearance time is related to the hydrostatic pressure. When a bubble shrinks, its response to ultrasound changes. From this response, the disappearance time, and with it the hydrostatic pressure, can be determined. We investigated the applicability of the gases Ar, C(3)F(8), Kr, N(2), Ne, and SF(6), based on their diffusive properties. For pressure measurements with a limited duration, e.g. 150 ms, Kr and Ar bubbles are most suitable, since they are most sensitive to pressure change. If there is also a limitation to bubble size, e.g. a maximum diameter of 6 microm, SF(6) is most suitable. We present improvements of a method that correlates the duration of the decay of the fundamental ultrasound response to the hydrostatic overpressure. We propose to correlate the duration until subharmonic occurrence in combination with its decay, to hydrostatic overpressure, since the subharmonic decays more rapidly than the fundamental response. For a dissolving Ar gas bubble with an initial diameter of 14 microm, the overpressure can be determined 4 times as precise from the decay of the subharmonic response as from the decay of the fundamental response. Overpressures as small as 11 mmHg may be discriminated with this method.
Contrast Media↗
Noninvasive bladder volume measurements based on nonlinear wave distortion.
The purpose of this study is to suggest a new approach to measure noninvasively the fluid content of a human cavity; in particular, the bladder volume. Determination of bladder volume is important clinically for patients suffering from bladder dysfunction. Several ultrasonic methods were proposed in the past for such a purpose. Most of these methods are based on multiple cross-sectional images and detection of echoes from the bladder wall. We propose here, in a first step, a simple approach that is able to provide an indication of whether or not the bladder volume has exceeded a certain threshold volume. Second, the possibility of accurate volume assessment will be discussed. The approach takes advantage of the difference in harmonic generation of liquids (urine) and tissues. We know that nonlinear effects occur most strongly when ultrasound (US) propagates through liquids with relatively low acoustic attenuation, such as water or urine. However, within soft tissues, the tendency for wave distortion to occur is limited as a result of different acoustic characteristics, most notably the attenuation. Our method is based on measuring the presence of harmonics in an echo from a region-of-interest (ROI) at fixed depth beyond the bladder. The harmonic content in the echo will increase with increase of fluid in the echo path. Phantom measurements were carried out with a single-element transducer and a phased-array transducer. Phantoms containing different volumes were used. Furthermore, measurements on volunteers were performed. The results confirmed that the harmonic content of an echo measured at a deep ROI increases for a full bladder and decays strongly after the volunteer has voided. These preliminary results demonstrate the feasibility of the approach.
Biophysical Phenomena↗
Contrast harmonic transesophageal echocardiography: a feasibility study.
Ultrasound (US) contrast agents serve as tracers for the noninvasive quantification of blood flow, and many of them are now approved for left ventricular opacification and for enhanced endocardial border delineation. The availability of more stable contrast bubbles has stimulated many new classes of imaging methods, such as harmonic imaging, which is already employed in commercial systems for transthoracic imaging. However, transesophageal echocardiography (TEE) still lacks appropriate technology, mainly transducer technology, to be able to take advantage of contrast harmonic benefits. We investigate, in this study, a new TEE transducer that has a frequency bandwidth wide enough to be able transmit at a lower fundamental frequency and to receive the second harmonic frequency. The transducer characteristics are measured, as well as the optimal transmit settings that allow the achievement of a high contrast-to-tissue ratio. The transducer has a center frequency of 3.5 MHz with a bandwidth ranging from 2.3 MHz to 3.9 MHz. For optimal harmonic imaging, transmit settings consisted of a transmit pulse at 2.5 MHz containing two periods. The transducer, using these settings, was then evaluated in patients to investigate myocardial contrast perfusion imaging using TEE in the operating theater.
Cardiomyopathies↗
Micromanipulation of endothelial cells: ultrasound-microbubble-cell interaction.
Ultrasound (US) in combination with contrast microbubbles has been shown to alter the permeability of cell membranes without affecting cell viability. This permeabilisation feature is used to design new drug delivery systems using US and contrast agents. The underlying mechanisms are still unknown. One hypothesis is that oscillating microbubbles cause cell deformation resulting in enhanced cell membrane permeability. This technical note reveals the interaction between oscillating microbubbles and endothelial cells under a microscope recorded with a fast framing camera at 10 million frames per second. A microbubble expansion of 100% resulted a 2.3-mum displacement of the cell membrane. During the insonification, changes of approximately 15% in the cross-sectional distance of the endothelial cells were observed due to microbubble vibrations. In conclusion, the use of such a camera makes it possible to reveal the mechanisms of interactions between ultrasound, microbubbles and cells.
Animals↗
Contrast superharmonic imaging: a feasibility study.
Harmonic imaging provided significant improvement in image quality by taking advantage of the scattered second harmonic (2H) component from contrast bubbles. However, differentiation between contrast and tissue (usually termed contrast-to-tissue ratio, CTR) is sometimes cumbersome and this is mainly due to tissue contamination. We have previously demonstrated, using simulations and in vitro measurements, that CTR increases as a function of the order of the harmonic number. A new contrast imaging method based on the detection of the higher harmonics was developed and termed superharmonic (SH). This technique has been shown to be more sensitive to contrast by increasing the signal from contrast and suppressing that from tissue (high CTR). The purpose of this study was to determine the clinical feasibility and usefulness of SH in patients using a commercially available contrast agent (SonoVue(R)) for quantification of myocardial perfusion. A total of 10 patients with various cardiac diseases were assessed. Apical four-chamber views were acquired using SH in triggered mode before and after contrast injection. The superharmonic was performed with a newly developed probe transmitting at 0.8 MHz with a mechanical index of 0.2. Myocardial perfusion was determined visually and analyzed quantitatively using radiofrequency (RF) processing from different regions of interest. The results showed that, before contrast injection, SH was totally blinded to tissue and no superharmonic components were generated in the image view. After administration of SonoVue(R), myocardial opacification was visualized by SH after contrast entered the myocardium. An increase of more than 15 dB in the myocardial bubbles echo compared to tissue echo was measured. In addition, the technique was used to visualize myocardial perfusion after myocardial septal ablation for hypertrophic cardiomyopathy. The clinical results showed the ability of contrast SH imaging in differentiating low and normal perfusion areas, demonstrating the high sensitivity and specificity of the technique.
Adult↗
Visualization of myocardial perfusion after percutaneous myocardial septal ablation for hypertrophic cardiomyopathy using superharmonic imaging.
Harmonic imaging is used for detection of ultrasound contrast agents in myocardial perfusion studies. However, harmonic imaging has limitations because of the presence of tissue harmonics, which results in less specificity and sensitivity, thus, lower contrast-to-tissue ratio. We describe a clinical example using superharmonic imaging. This technique detects the third, fourth, and fifth harmonics. These harmonics are not created in tissue, resulting, hence, in a high contrast-to-tissue ratio. After myocardial alcohol ablation for hypertrophic cardiomyopathy areas of nontreated and treated myocardium, normal and low flow could be visualized with superharmonic imaging.
Cardiomyopathy, Hypertrophic↗