Ultrasound contrast agents: from imaging to therapy

International audienceContrast agents, consisting of tiny gas microbubbles are currently approved for ultrasound imaging in cardiology and in radiology. The microbubbles have a mean size of about 3 microns and are encapsulated by a thin biocompatible layer. Multiple clinical studies have established the utility of ultrasound contrast agents (UCA) in improving accuracy of echography for the diagnosis of many diseases and in reducing health care costs by eliminating the need for additional testing. Future clinical applications of UCA extend beyond imaging and diagnostic, offering to ultrasound technology a new therapeutic dimension. Since a few years, novel therapeutic strategies are explored using microbubbles and ultrasound. Our current data demonstrate that in the presence of microbubbles, ultrasound waves destabilize transiently the cell membrane allowing the incorporation of drugs, including genes into the cells. Moreover, the microbubbles might be used as a drug vehicle to achieve a spatially and temporally controlled local release. Besides, microbubbles are able to identify diseased targets through specific targeting

Bias voltage modulation methods and its optimization for nonlinear contrast imaging

Congrès sous l’égide de la Société Française de Génie Biologique et Médical (SFGBM).National audienceThe main difficulty in applying ultrasound contrast imaging techniques with cMUT probe comes from the intrinsic nonlinearity of the transducer itself. An approach has been developed in order to adapt the amplitude modulation techniques (AM) to cMUTs. Bias Voltage Modulation (BVM)[1] allows a complete cancellation of the echoes from linear reflectors and thus an enhancement of the contrast agent detection. The main limit is that it can only be applied with low bias voltage, far from the maximum of the probe sensitivity (i.e. at the collapse). Here is proposed an optimization of the BVM sequence allowing a good compensation of cMUT intrinsic nonlinearity even at high bias voltages

Effect of an elastic wall on the behavior of encapsulated microbubbles

International audienceThe aim of this work is to study how boundaries with different mechanical properties affect the acoustic response of contrast agent microbubbles. To this end, numerical simulations are performed for two types of walls: a polystyrene (OptiCell) wall and a biological tissue. For each wall, the behavior of contrast microbubbles of three sizes is investigated. The spectral characteristics of the scattered pressure produced by the microbubbles are compared for two cases: the bubble oscillates far away from the wall and the same bubble oscillates in the immediate vicinity of the wall. The results of the simulations allow one to draw the following main conclusions. The effect of the OptiCell wall on the acoustic bubble response is stronger than that of the tissue wall. Changes in the bubble response near the wall are stronger when bubbles are excited above their fundamental resonance frequency. Changes are stronger for smaller bubbles and changes in the 2nd harmonic are stronger than those in the fundamental. The results obtained allow one to gain an insight into conditions under which the effect of an elastic wall on the acoustic response of a contrast agent microbubble is easier to be detected

Nonlinear tissue mimicking phantoms characterization using the Nakagami statistical model: simulations and measurements

International audienceIn order to improve the tissue characterization, the probability density function of ultrasonic backscattered echoes which may be treated as random signals, is modeled by using Nakagami statistical distribution. Recently, it has been found that Nakagami statistical model constitutes a quite good model in tissue characterization due to its simplicity and general character. In the present study, computer simulations and experiments on phantoms have been carried out to test the validity of Nakagami distribution in order to model the backscattered envelope of ultrasonic signals in the nonlinear regime. Experiments were performed using a 5MHz linear array connected to an open research platform. A commercially available phantom was used to mimick tissue backscatter. For different sizes and positions of the sampling window, the RF signals have been acquired at different frequencies and bandwidths, then filtered around the center frequency and around twice the center frequency. The signals obtained have been analyzed in order to evaluate the Nakagami parameter (m), the scaling parameter (Ω) and the probability density function. These results have been compared to those obtained by using Field II software

Effect of contact with an elastic wall on the spectral characteristics of the scattered echo of a contrast microbubble

International audienceA modified Rayleigh-Plesset equation is proposed to model the oscillation of a contrast microbubble attached to an elastic wall. The equation shows that contact with the wall affects the bubble oscillation as if the bubble oscillated in a liquid with a changed (effective) density. As a result, depending on the wall properties, the natural frequency of the attached bubble can be either lower or higher than the natural frequency of the same bubble in an unbounded liquid. Numerical simulations were made to study the spectral characteristics of the scattered pressure of an attached contrast microbubble. It was assumed that the bubble shell properties are described by the Marmottant model and the properties of the wall correspond to walls of OptiCell chambers commonly used in experiments. It has been found that, depending on the value of the driving frequency, the contact with the wall can noticeably increase or decrease the magnitudes of the fundamental component, the second harmonic, and the subharmonic relatively to their values in an unbounded liquid. These findings can be used to distinguish the scattered echoes produced by contrast agents attached to a wall from echoes produced by agents being at a distance from a wall

Ultrasound-induced Gas Release from Contrast Agent Microbubbles

We investigated gas release from two hard-shelled 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 /spl mu/m. 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

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\ud patterns and their consequences on the translational motion of the bubbles. A stream of uniform air bubbles with diameter ranging from 35 um to 79 um 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 um. 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

Air bubble in an ultrasound field:theoretical and optical results

The radial motion of a gas bubble has been widely investigated in various studies using different theoretical models. The aim of this study is to compare, qualitatively and quantitatively, the results obtained by optical recording with those of a theoretical model. Bubble oscillations were optically recorded using an ultrafast digital camera, Brandaris. The radius-time, R(t), curves are directly computed from 128 video frames. The resting diameters of the air bubbles were 26-100 /spl mu/m. The ultrasound field was defined as an 8 cycle pulse at a frequency of 130 kHz generating an acoustic pressure of 10-150 kPa. The time and the frequency response of the bubble radial motion were compared to the Keller model. From the results, it is concluded that the Keller model can be used to accurately predict the fundamental and harmonic behavior of gas bubbles

Improvement of the power response in contrast imaging with transmit frequency optimization

© 2009 IEEE. Reprinted, with permission, from Sébastien Ménigot, Anthony Novell, Ayache Bouakaz and Jean-Marc Girault, Improvement of the power response in contrast imaging with transmit frequency optimization, 2009 IEEE International Ultrasonics Symposium (IUS), 20---23 Sept. 2009. This material is posted here with permission of the IEEE. Such permission of the IEEE does not in any way imply IEEE endorsement of any of the Université François Rabelais de Tours' products or services. Internal or personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution must be obtained from the IEEE by writing to [email protected] audienceConventionnal ultrasound contrast imaging systems use a fixed transmit frequency. However it is known that the insonified medium (microbubbles) is time-varying and therefore an adapted time-varying excitation is expected. We suggest an adaptive imaging technique which selects the optimal transmit frequency that maximizes the contrast tissue ratio (CTR). Two algorithms have been proposed to find an US excitation for which the frequency has been optimal with microbubbles. Simulations were carried out for encapsulated microbubbles of 2µm-radius by considering the modified Rayleigh-Plesset equation for a 2.25MHz transmitted frequency and for various pressure levels (20 kPa up to 420kPa). In vitro experiments have been carried out using a 2.25 MHz transducer and using a programmable waveform generator. Responses of a 1/2000 blood mimicking fluid-diluted solution of Sonovue(TM) were measured by a 3.5 MHz transducer. We show through simulations that our adaptive imaging technique allows to reduce the transmit maximal pressure. As for in vitro experiments the CTR can reach 10 dB. By proposing a close loop system whose frequency adapts itself with the perfused media, throughout the examination, the optimization system adapt itself to the remaining bubbles population thus allowing an increase of the 30\% examination duration

Caractérisations théoriques et expérimentales d'agents de contraste ultrasonore ciblés

Depuis leur introduction, les agents de contraste ont révolutionné l'imagerie échographique. Ils sont composés de microbulles gazeuses, qui injectés par voie intraveineuse dans le sang, ils améliorent l'image échographique. Une autre application pour laquelle les caractéristiques physiques des agents de contraste sont exploitées est l'imagerie ciblée. Une approche basée sur l'utilisation de ligands intégrés à la paroi des microbulles, celles-ci adhérent aux facteurs de surfaces moléculaires surexprimés par les cellules endothéliales qui tapissent la paroi interne des vaisseaux sanguins. Pour pouvoir distinguer ces microbulles de celles qui circulent librement, elles doivent réfléchir un signal acoustique suffisamment intense. Cependant, le faible taux d'adhérence des microbulles engendre une réduction du signal acoustique. Pour résoudre ce problème, il est important de déterminer l'effet des parois sur leurs dynamiques acoustiques. Dans cette thèse, nous avons étudié l effet des parois élastiques sur le comportement dynamique des microbulles constituant les agents de contraste. Dans un premier temps, un modèle théorique représentant une paroi avec une épaisseur finie a été développé. Il a été démontré que l amplitude de l écho rétrodiffusé par une microbulle proche d une paroi avec une épaisseur finie est inférieure à celui d une microbulle se trouvant dans un fluide infini. D'autres parts, pour représenter la paroi d un vaisseau sanguin, les propriétés mécaniques de la paroi élastique ont été intégrées au modèle. Il a été observé que la fréquence de résonance d une microbulle proche d une paroi est supérieure à celle dans un fluide infini. Par la suite, nous avons étudié l effet de trois types de parois sur le comportement d une microbulle parmi lesquelles la paroi d'OptiCell communément utilisée en expérimentations ultrasonores. Les résultats ont montré que la microbulle proche de la paroi d OptiCell diffuse un écho supérieur à celui de la microbulle éloignée de la paroi, lorsque la fréquence d excitation est au-dessus de sa fréquence de résonance. Nous avons constaté aussi que les petites bulles sont plus sensibles à la proximité de la paroi. Par la suite, nous avons développé un modèle décrivant une microbulle attachée à une paroi élastique. Nous avons montré que le contact direct de la bulle avec la paroi induit une diminution de l'écho par rapport à la même bulle dans un liquide infini. Le contact direct de la bulle avec la paroi engendre une augmentation de la fréquence de résonance part rapport à une bulle sans contact direct. Enfin, une étude expérimentale a montré l'avantage de l'imagerie sous-harmonique pour différencier les microbulles attachées des microbulles libres.Since they were introducted, contrast agents have revolutionized the ultrasound imaging. They are composed of tiny gaseous microbubbles and when injected intravenously into the blood, they improve the ultrasound image. Targeted imaging is another application based on the physical characteristics of contrast agents. This approach is based on the ligands incorporation into the microbubbles shell. The microbubble attach to the molecular factors overexpressed by endothelial cells, covering the inner wall of blood vessels. To distinguish these microbubbles from those freely circulating, attached microbubble have to produce an acoustic signal that is sufficiently strong. However, the low microbubbles adhesion induces a decrease of the acoustic signal. To make it possible, it is important to determine the effect of the elastic wall on their acoustic response. This thesis aimed to study the effect of elastic walls on the ultrasonic behavior of targeted microbubbles. First, a theoretical model describing a wall with finite thickness was developed. It has been shown that the scattered echo amplitude by a microbubble near a wall with finite thickness is small in comparison to the echo from a microbubble located in an infinite fluid. Furthermore, and in order to account for the effect of blood vessel wall, the mechanical properties of the wall have been incorporated into the model. The results showed that the resonane frequency of a microbubble near the wall is higher than the resonanace of the same microbubble in an infinite medium. Subsequently, we studied the effect of three types of walls on the microbubble behavior including the wall of OptiCell chamber which is commonly used in ultrasonic experiments. We have shown that microbubbles near the OptiCell wall diffuses a higher echo than those far from the wall when the excitation frequency is above the microbubble resonance frequency. On the other side, we observed that small microbubbles to the presence of the wall. Afterward, we developed a model describing a microbubble attached to the wall. We have shown that the microbubble in direct contact with the wall induces a decrease of the echo amplitude compared to the same bubble in infinite liquid. Moreover, the direct contact of the bubble with the wall generates an increase of the resonance frequency relative to a bubble without direct contact. Finally, an experimental study has shown the advantage of the subharmonic imaging to differentiate attached microbubbles from the free ones.TOURS-Bibl.électronique (372610011) / SudocSudocFranceF