Ultrasound contrast agents for ultrasound molecular imaging.

Ultrasound is a real-time imaging technique which is widely used in many clinical applications for its capacity to provide anatomic information with high spatial and temporal resolution. The advent of ultrasound contrast agents in combination with contrast-specific imaging modes has given access to perfusion assessments at an organ level, leading to an improved diagnostic accuracy. More recently, the development of biologically-targeted ultrasound contrast agents has expanded the role of ultrasound even further into molecular imaging applications. Ultrasound molecular imaging can be used to visualize the expression of intravascular markers, and to assess their local presence over time and/or during therapeutic treatment. Major applications are in the field of inflammation and neoangiogenesis due to the strictly intravascular presence of microbubbles. Various technologies have been investigated for attaching the targeting moiety to the shell from simple biotin-avidin constructs to more elaborated insertion within the shell through attachment to PEG residues. This important improvement has allowed a clinical translation of initial pre-clinical investigations, opening the way for an early detection and an accurate characterization of lesions in patients. The combination of anatomic, functional and molecular information/data provided by contrast ultrasound is a powerful tool which is still in its infancy due to the lack of agents suitable for clinical use. The advantages of ultrasound techniques combined with the molecular signature of lesions will represent a significant advance in imaging in the field of personalized medicine.

Perfusion quantification in contrast-enhanced ultrasound (CEUS)--ready for research projects and routine clinical use.

With contrast-enhanced ultrasound (CEUS) now established as a valuable imaging modality for many applications, a more specific demand has recently emerged for quantifying perfusion and using measured parameters as objective indicators for various disease states. However, CEUS perfusion quantification remains challenging and is not well integrated in daily clinical practice. The development of VueBox™ alleviates existing limitations and enables quantification in a standardized way. VueBox™ operates as an off-line software application, after dynamic contrast-enhanced ultrasound (DCE-US) is performed. It enables linearization of DICOM clips, assessment of perfusion using patented curve-fitting models, and generation of parametric images by synthesizing perfusion information at the pixel level using color coding. VueBox™ is compatible with most of the available ultrasound platforms (nonlinear contrast-enabled), has the ability to process both bolus and disruption-replenishment kinetics loops, allows analysis results and their context to be saved, and generates analysis reports automatically. Specific features have been added to VueBox™, such as fully automatic in-plane motion compensation and an easy-to-use clip editor. Processing time has been reduced as a result of parallel programming optimized for multi-core processors. A long list of perfusion parameters is available for each of the two administration modes to address all possible demands currently reported in the literature for diagnosis or treatment monitoring. In conclusion, VueBox™ is a valid and robust quantification tool to be used for standardizing perfusion quantification and to improve the reproducibility of results across centers.

Nonlinear contrast imaging with an array-based micro-ultrasound system.

The main goal of this study was to determine the optimal strategy for a real-time nonlinear contrast mode for small-animal imaging at high frequencies, on a new array-based micro-ultrasound system. Previously reported contrast imaging at frequencies above 15 MHz has primarily relied on subtraction schemes involving B-mode image data. These approaches provide insufficient contrast to tissue ratios under many imaging conditions. In this work, pulse inversion, amplitude modulation and combinations of these were systematically investigated for the detection of nonlinear fundamental and subharmonic signal components to maximize contrast-to-tissue ratio (CTR) in the 18-24 MHz range. From in vitro and in vivo measurements, nonlinear fundamental detection with amplitude modulation provided optimal results, allowing an improvement in CTR of 13 dB compared with fundamental imaging. Based on this detection scheme, in vivo parametric images of murine kidneys were generated using sequences of nonlinear contrast images after intravenous bolus injections of microbubble suspensions. Initial parametric images of peak enhancement (PE), wash-in rate (WiR) and rise time (RT) are presented. The parametric images are indicative of blood perfusion kinetics, which, in the context of preclinical imaging with small animals, are anticipated to provide valuable insights into the progression of human disease models, where blood perfusion plays a critical role in either the diagnosis or treatment of the disease.

Three-stage approach to ultrasound contrast detection.

A new method for detecting ultrasound contrast agents using a three-stage pulsing sequence is proposed. The method is based on observations showing that the scattering properties of contrast agents are modified by ultrasonic insonation at high power, but remain unchanged at low power. The objective of the first stage of the pulsing sequence is to use low power pulses to obtain a high resolution reference image without altering the agent. Higher power pulses in the second stage modify the contrast agent. The third stage detects the changes imposed to the contrast agent using low power pulses. A temporal filter is proposed to discriminate contrast response from clutter signal. The method is similar to power Doppler methods in that it uses several pulses to survey the target while destroying the agent. The new idea is to separate detection and destruction to circumvent a trade-off between sensitivity and resolution. Results from in vitro experiments with three different contrast agents are presented. The results are compared with harmonic power Doppler processed from the same data and show that an improvement in sensitivity is achievable by including the high power burst in the pulsing sequence. The results also show that the proposed filter reduces clutter artifacts from moving tissue.

A new ultrasound contrast imaging approach based on the combination of multiple imaging pulses and a separate release burst.

A new ultrasound contrast imaging technique is described that optimally employs the rupture of the contrast agent. It is based on a combination of multiple high frequency, broadband, imaging pulses and a separate release burst. The imaging pulses are used to survey the target before and after the rupture and release of free gas bubbles. In this way, both processes (imaging and release) can be optimized separately. The presence of the contrast agent is simply detected by correlating or subtracting the signal responses of the imaging pulses. Because the time delay between the imaging pulses can be very short, the subtraction is less affected by tissue motion and can be done in real time. In vitro measurements showed that by using a release burst, the detection sensitivity increased 12 to 43 dB for different types of contrast agents. In the presence of a moving phantom, the increase in sensitivity was 22 dB. This new method is very sensitive for contrast agent detection in fundamental imaging mode and, therefore, non-linear propagation effects do not limit the maximum obtainable agent-to-tissue ratio. However, because of the inherent destruction of the contrast agent, it has to operate in an intermittent way. Through experiments, we have demonstrated the potential of the method to achieve simultaneous high sensitivity for contrast detection, i.e., high agent-to-tissue ratio, and high spatial resolution performance for different types of contrast agents.

Ultrasound contrast imaging: current and new potential methods.

For 10 years, it was thought that ultrasound (US) contrast agents could be sufficiently detected and imaged with the conventional imaging techniques, now referred to as fundamental imaging. However, it turned out that fundamental imaging was not sensitive enough to detect the contrast agents in the presence of tissue. New imaging techniques that are based on specific properties of the contrast agents, such as nonlinear and transient scattering, proved to be more sensitive. US contrast imaging modalities used today are fundamental, second harmonic, harmonic power Doppler, and pulse inversion; new modalities, such as release burst and subharmonic imaging are emerging. Second harmonic imaging is still not optimal for perfusion imaging applications. However, in combination with Doppler techniques such as power Doppler, it is one of the most sensitive techniques currently available. A complete understanding of the US-contrast agent interaction is essential for further improvements of current detection methods, and the development of new imaging techniques.

Detection procedures of ultrasound contrast agents.

In the early days, it was believed that ultrasound contrast agents (UCA) could be sufficiently detected and imaged with the conventional imaging methods nowadays referred to as fundamental imaging. Newer imaging techniques proved to be more sensitive and are based on specific properties of the UCA. In general, these new characteristics involve non-linear and transient characteristics of contrast agents that appear at the high end of the diagnostic acoustic intensity. Imaging modalities used today for UCA are, besides fundamental imaging, second harmonic imaging, power Doppler, harmonic power Doppler, pulse inversion and pulse inversion Doppler, multi-pulse imaging and subharmonic imaging. Although the results of conventional second harmonic imaging are still not optimal for perfusion imaging applications, in combination with Doppler techniques (colour Doppler, power Doppler) it is one of the most sensitive techniques currently available in terms of agent-to-tissue ratio. Further improvements in current and future detection methods demand a complete understanding of the ultrasound-UCA interaction.

Optical imaging of contrast agent microbubbles in an ultrasound field with a 100-MHz camera.

Ultrasound (US) contrast agents, used in the field of medical diagnosis, contain small microbubbles of a mean diameter of about 3 microm. The acoustic behavior of these bubbles in US field has been subject to many investigations. In this study, we propose a method to visualize the behavior of the bubbles in a 0.5-MHz US field under a microscope with a frame rate of 4 MHz. For low acoustic pressures (peak negative pressure of 0.12 MPa), the radius-time curve as measured from the optical images is in agreement with the theory. For higher acoustic pressures (peak negative pressure of 0.6 MPa), the recorded radius is significantly larger than predicted by theory and sudden change in the bubbles shapes has been noticed. The proposed method enables the study and characterization of individual bubbles and their encapsulation. It is expected that this will open new areas for quality control, US contrast imaging and US-guided drug delivery.

Noninvasive measurement of the hydrostatic pressure in a fluid-filled cavity based on the disappearance time of micrometer-sized free gas bubbles.

A new method for noninvasive pressure measurement, based on the disappearance time of micrometer-sized free gas bubbles, is described in this article. An ultrasound (US) contrast agent, consisting of encapsulated gas bubbles, is used as a vehicle to transport the free gas bubbles to the desired region where the pressure is to be measured. The small free gas bubbles are generated at the region of interest (e.g., heart chambers), from the encapsulated gas bubbles, which rupture when they are exposed to a single low-frequency (e.g., 0.5 MHz), high acoustic amplitude US burst. The released gas bubbles persist for only a few ms and dissolve in the liquid, depending on their size, the gas, the liquid characteristics and ambient parameters such as temperature, gas concentration and pressure. A pressure-disappearance time relationship is determined using a sequence of high-frequency (e.g., 10 MHz), low acoustic amplitude US pulses. From in vitro experiments, reproducible results show a significant difference between the disappearance time of the bubbles as function of the local pressure, resulting in a quicker disappearance of the bubble for higher values of the pressure. The sensitivity of the method to small pressure changes (50 mmHg) is demonstrated.

Acoustic modeling of shell-encapsulated gas bubbles.

Existing theoretical models do not adequately describe the scatter and attenuation properties of the ultrasound contrast agents Quantison and Myomap. An adapted version of the Rayleigh-Plesset equation, in which the shell is described by a viscoelastic solid, is proposed and validated for these agents and Albunex. The acoustic transmission and scattering are measured in the frequency band from 1-10 MHz. The measured transmission is used to estimate two parameters, the effective bulk modulus, Keff, describing the elasticity, and the friction parameter, SF, describing the viscosity of the shell. For the scattering, the difference between measurements and calculations is < 3 dB. For Quantison, the effective bulk modulus is independent of the bubble diameter. For Albunex, it increases for decreasing bubble diameter. The nonlinear response of Quantison is minimal for acoustic pressures up to 200 kPa. For acoustic pressures above 200 kPa, the measured scattering abruptly increases. This increase reaches a level of 20 dB for an acoustic pressure of 1.8 MPa. This response cannot be predicted by the theoretical model developed in this article.

Effect of ultrasound on the release of micro-encapsulated drugs.

Although ultrasound is used extensively in medical therapies and diagnostics, it has been recognized only recently as a method for external controlled diversity of drugs. In this paper, firstly, a literature review on drug delivery and the combination with ultrasound is given. Then an experiment is described on measuring the release of a model drug (hexabrix) under ultrasound irradiation, from a polymer carrier.