Microbubble spectroscopy of ultrasound contrast agents

A new optical characterization of the behavior of single ultrasound contrast bubbles is presented. The method consists of insonifying individual bubbles several times successively sweeping the applied frequency, and to record movies of the bubble response up to 25 million frames/s with an ultrahigh speed camera operated in a segmented mode. The method, termed microbubble spectroscopy, enables to reconstruct a resonance curve in a single run. The data is analyzed through a linearized model for coated bubbles. The results confirm the significant influence of the shell on the bubble dynamics: shell elasticity increases the resonance frequency by about 50%, and shell viscosity is responsible for about 70% of the total damping. The obtained value for shell elasticity is in quantative agreement with previously reported values. The shell viscosity increases significantly with the radius, revealing a new nonlinear behavior of the phospholipid coating.     

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.     

Estimating concentration of ultrasound contrast agents with backscatter coefficients: experimental and theoretical aspects

Ultrasound contrast agents (UCAs) have been explored as a means to enhance therapeutic techniques. Because the effectiveness of these techniques relies on the UCA concentration at a target site, it would be beneficial to estimate UCA concentration noninvasively. In this study, a noninvasive method for estimating UCA concentration was developed in vitro. Backscatter coefficients (BSCs) estimated from measurements of Definity(?) UCAs were fitted to a theoretical scattering model in the 15-25 MHz range using a Levenberg-Marquardt regression technique. The model was defined by the UCA size distribution and concentration, and therefore concentration estimates were extracted directly from the fit. Calculation of the BSC was accomplished using planar reference measurements from the back wall of a Plexiglas(?) chamber and an average of 500 snapshots of ultrasonic backscatter from UCAs flowing through the chamber. In order to verify the ultrasonically derived UCA concentration estimates, a sample of the UCAs was extracted from the flow path and the concentration was estimated with a hemacytometer. UCA concentrations of 1, 2, and 5 times the dose recommended by the manufacturer were used in experiments. All BSC-based estimates were within one standard deviation of hemacytometer based estimates for peak rarefactional pressures of 100-400 kPa.     

Stability analysis of ultrasound thick-shell contrast agents

The stability of thick shell encapsulated bubbles is studied analytically. 3-D small perturbations are introduced to the spherical oscillations of a contrast agent bubble in response to a sinusoidal acoustic field with different amplitudes of excitation. The equations of the perturbation amplitudes are derived using asymptotic expansions and linear stability analysis is then applied to the resulting differential equations. The stability of the encapsulated microbubbles to nonspherical small perturbations is examined by solving an eigenvalue problem. The approach then identifies the fastest growing perturbations which could lead to the breakup of the encapsulated microbubble or contrast agent.     

Evaluation of synthetic phospholipid ultrasound contrast agents

The echogenic properties of synthetic, phospholipid encapsulated, air-filled microbubbles with various carbon-chain length as ultrasound contrast agents are investigated through the use of a flow-through laboratory ultrasound system. Specifically, we investigate the effect of shell carbon-chain length on the ultrasonic signal for a variety of flow rates. Averaged, integrated backscatter power measurements from the lipid encapsulated agents are benchmarked against those of Albunex (Albunex is a registered trademark of Molecular Biosystems, Inc., San Diego, CA), a commercially available, air-filled protein microbubbles contrast agent, approved for clinical use in echocardiography in the United States by the Food and Drug Administration. We find that the lipid encapsulated agents sustain less damage leading to gas dissolution or particle destruction as compared to Albunex in the slow-flow studies performed. The carbon-chain length of the encapsulating lipid molecule is shown not to observably affect the backscattered amplitude of ultrasound at flow velocities exceeding 7 mm/s.     

Acoustic behaviour of current ultrasound contrast agents

A general law gives the approximate change in signal level obtained in a particular imaging mode when a suitable contrast agent is added. It also shows that reduction of background signals is essential to overcome limitations found mainly in conventional (linear) ultrasound contrast imaging. Contrast agents contain stabilized microbubbles with very helpful non-linear properties. Acoustic methods for non-destructive and destructive testing of microbubbles are briefly discussed. In the main part, the linear and non-linear acoustic behaviour of various types of contrast agent are described. The latter is useful for new applications in diagnostic ultrasound.     

Principles and recent developments in ultrasound contrast agents

The behaviour of gas bubbles and gas encapsulated spheres as echographic contrast agents is reviewed. Compared with rigid spheres, gas bubbles are superior scattering agents and they offer a number of useful properties which can be exploited in a variety of ways. The analysis of their velocity of sound, back-scatter intensity, second harmonic emission and resonant frequency opens up new perspectives in the development of contrast agents for echocardiographic research with potential clinical applications.     

Superhydrophobic silica nanoparticles as ultrasound contrast agents

Microbubbles have been widely studied as ultrasound contrast agents for diagnosis and as drug/gene carriers for therapy. However, their size and stability (lifetime of 5–12 min) limited their applications. The development of stable nanoscale ultrasound contrast agents would therefore benefit both. Generating bubbles persistently in situ would be one of the promising solutions to the problem of short lifetime. We hypothesized that bubbles could be generated in situ by providing stable air nuclei since it has been found that the interfacial nanobubbles on a hydrophobic surface have a much longer lifetime (orders of days). Mesoporous silica nanoparticles (MSNs) with large surface areas and different levels of hydrophobicity were prepared to test our hypothesis. It is clear that the superhydrophobic and porous nanoparticles exhibited a significant and strong contrast intensity compared with other nanoparticles. The bubbles generated from superhydrophobic nanoparticles sustained for at least 30 min at a MI of 1.0, while lipid microbubble lasted for about 5 min at the same settings. In summary MSNs have been transformed into reliable bubble precursors by making simple superhydrophobic modification, and made into a promising contrast agent with the potentials to serve as theranostic agents that are sensitive to ultrasound stimulation.     

Excitation of polymer-shelled contrast agents with high-frequency ultrasound

Few experimental and complementary theoretical studies have investigated high-frequency (>20 MHz) nonlinear responses from polymer-shelled ultrasound contrast agents. Three polymer agents with different shell properties were examined for their single-bubble backscatter when excited with a 40 MHz tone burst. Higher-order harmonic responses were observed for the three agents; however, their occurrence was at least partly due to nonlinear propagation. Only one of the agents (1.1 microm mean diameter) showed a subharmonic response for longer excitations (approximately 10-15 cycles) and midlevel pressure excitations ( 2.5 MPa). Theoretical calculations of the backscattered spectrum revealed behavior similar to the experimental results in specific parameter regimes.     

超声造影剂研究进展

本文综述超声造影剂的现状及新进展，在简要介绍造影剂物理原理的基础上，对超声造影剂在医学超声领域尤其是低速血流测量与组织灌注成像中的应用进行了总结与讨论，并介绍了用于实验研究和第二期临床试验的国际上最新的超声造影剂的特点，制备技术与评价方法。     

Physical phenomena affecting quantitative imaging of ultrasound contrast agents

Microbubbles stabilized by a surfactant or polymer coating are the most effective form of contrast agent available for ultrasound imaging. They have shown great potential as a means of quantifying tissue perfusion, in particular determining physiologically significant parameters such as relative vascular volume and flow velocity. Clinical implementation of quantitative imaging procedures, however, has been hindered by poor characterisation of the complex relationship between microbubble concentration, scattering and image intensity. The aim of this paper is to describe theoretical and experimental investigations of the physical phenomena underlying these effects, such as the time, pressure and frequency dependence of microbubble behaviour, the influence of the bubble coating, size distribution and concentration; and to discuss the challenges involved in developing accurate quantitative imaging protocols.     

A theoretical investigation of chirp insonification of ultrasound contrast agents

A theoretical investigation of second harmonic imaging of an Ultrasound Contrast Agent (UCA) under chirp insonification is considered. By solving the UCA’s dynamical equation analytically, the effect that the chirp signal parameters and the UCA shell parameters have on the amplitude of the second harmonic frequency are examined. This allows optimal parameter values to be identified which maximise the UCA’s second harmonic response. A relationship is found for the chirp parameters which ensures that a signal can be designed to resonate a UCA for a given set of shell parameters. It is also shown that the shell thickness, shell viscosity and shell elasticity parameter should be as small as realistically possible in order to maximise the second harmonic amplitude. Keller-Herring, Second Harmonic, Chirp, Ultrasound Contrast Agent.     

Qualitative comparison between numerical and experimental results of unsteady flow in a radial diffuser pump

Comparison between numerical simulation and experimental results for unsteady flow field in a radial diffuser pump is presented for the design operating point. The numerical result is obtained by solving three-dimensional, unsteady Reynolds-averaged Navier-Stokes equations by the commercial CFD code CFX-10 withk-ω based shear stress transport turbulence model. Two-dimensional PIV measurements are conducted to acquire the experiment result. The phase-averaged velocity and turbulent kinetic energy fields are compared in detail between the results by the two methods in the impeller, diffuser and return channel regions. The qualitative comparison between CFD and PIV results is quite good in the phase-averaged velocity field. Although the turbulence level by PIV is higher than that by CFD generally, the main turbulence features are nearly the same. Furthermore, the blade orientation effect and other associated unsteady phenomena are also examined, in order to enhance the understanding on impeller-diffuser interaction in a radial diffuser pump.     

Study on the multiple scattering effects of ultrasound contrast agents

In this paper, the multiple scattering of interacting encapsulated microbubbles in suspensions is calculated using two novel approaches--Kargl's effective medium approach and Ye and Ding's approach of 2nd-order correction. Two types of contrast agents with bubbles of different sizes and concentrations are chosen for our numerical simulations. One is Albunex, which is depicted by Church and has a size range of several microns, and the other is sodium laureate solution (before fractionation) described by Soetanto and Chan and has an average size of 35.5 microm. The numerical results from these two approaches are compared with that from the linear approximation. It is found that the multiple scattering effects on attenuation and dispersion of sound in suspensions are evident in the cases of high bubble volume fractions, basically greater than the order of 1 x 10(-4), and much more obvious for larger bubbles with average size of tens of microns.     

准高斯声束对超声造影剂的声辐射力研究*

超声造影剂的定向输运在超声医学成像领域有着极为重要的意义,而声辐射力作用是实现该过程的关键,相比于高斯声束,准高斯声束是无源亥姆霍兹方程的精确解,可以使用标准波分解法简化计算。因此,本文研究了准高斯声束对超声造影剂的声辐射力作用。文章首先分析了准高斯声束与高斯声束之间的相关性;随后通过数值计算求得了准高斯声束对超声造影剂模型的声辐射力函数与无量纲频率之间的关系;最后,本文研究了不同造影剂气泡情况下的声辐射力。研究结果表明:声辐射力函数随无量纲频率变化将在不同位置出现共振峰,不同的波束宽度值将改变辐射力强度,但不改变共振峰的位置。相关结果可为利用声辐射力定向输运超声造影剂至靶向位置提供理论参考。     

Sonochemiluminescence observation of lipid- and polymer-shelled ultrasound contrast agents in 1.2 MHz focused ultrasound field

Ultrasound contrast agents (UCAs) are frequently added into the focused ultrasound field as cavitation nuclei to enhance the therapeutic efficiency. Since their presence will distort the pressure field and make the process unpredictable, comprehension of their behaviors especially the active zone spatial distribution is an important part of better monitoring and using of UCAs. As shell materials can strongly alter the acoustic behavior of UCAs, two different shells coated UCAs, lipid-shelled and polymer-shelled UCAs, in a 1.2 MHz focused ultrasound field were studied by the Sonochemiluminescence (SCL) method and compared.The SCL spatial distribution of lipid-shelled group differed from that of polymer-shelled group. The shell material and the character of focused ultrasound field work together to the SCL distribution, causing the lipid-shelled group to have a maximum SCL intensity in pre-focal region at lower input power than that of polymer-shelled group, and a brighter SCL intensity in post-focal region at high input power. The SCL inactive area of these two groups both increased with the input power. The general behavior of the UCAs can be studied by both the average SCL intensity and the backscatter signals. As polymer-shelled UCAs are more resistant to acoustic pressure, they had a higher destruction power and showed less reactivation than lipid-shelled ones.     

锯齿波信号激励增强超声造影剂的次谐波信号

提出了一种利用锯齿波激励以增强超声造影剂微气泡激发的次谐波信噪比的方法。基于修正的Church方程,采用数值计算分析了锯齿波激励下微气泡产生的次谐波的声压阈值及变化特性,并与正弦波激励进行了比较。实验中采用声压相等的基频为2 MHz的锯齿波及正弦波激发一种自制的包膜微气泡造影剂,测量了产生次谐波的激励声压阈值及与激励声压的关系。结果表明,锯齿波信号激励可以增强次谐波信号的强度,相对于正弦波激励增强约13 dB,并且激发声压阈值较低。实验结果与数值计算结果相符。     

Experimental investigation of the pulse inversion technique for imaging ultrasound contrast agents

The application of ultrasound contrast agents aims to detect low velocity blood flow in the microcirculation. To enhance discrimination between tissue and blood containing the contrast agent, harmonic imaging is used. Harmonic imaging requires the application of narrow-band signals and is obscured by high levels of native harmonics generated in an intervening medium. To improve discrimination between contrast agent and native harmonics, a pulse inversion technique has been proposed. Pulse inversion allows wide-band signals, thus preserving the axial resolution. The present study examines the interference of native harmonics and discusses the practical difficulties of wide-band pulse inversion measurements of harmonics by a single transducer. Native harmonics are not eliminated by pulse inversion. Furthermore, only even harmonics remain and are amplified by 6 dB, alleviating the requirement for selective filtering. Finally, it is shown that the contaminating third harmonic contained in the square wave activation signal leaks through in the emitted signal. The spectral location of the contaminating third harmonic is governed by the transducer spectral characteristics while the location of the native and contrast agent second harmonics is not. Thus the contaminating third harmonic and the native and contrast agent second harmonics may overlap and interfere. Optimal discrimination requires a balance between maximal sensitivity for the second harmonic at reception and minimal interference from the contaminating third harmonic.     

Generation of ultraharmonics in surfactant based ultrasound contrast agents: use and advantages.

A unique distinction between surfactant stabilized ultrasound contrast agent ST68 and water (or tissue), is the enhanced ability of the agent to generate non-linear frequencies such as sub-harmonics (f0/2), higher harmonics (2fo, 3fo, 4fo,...), and ultraharmonics (3f0/2, Sf0/2, 7f0/2,...), when insonated with fundamental frequency f0. Currently, second harmonics (2f0) have been predominantly researched, to exploit the diagnostic benefits of the contrast-specific non-linear imaging. However, we found that at normal imaging pressures (100 kPa-1 MPa), ST68 agent-generated second harmonic enhancements dropped to approximately 8 dB at 100 kPa and approximately 2 dB at 1 MPa. Moreover, at these pressures water (or tissue) produced strong second harmonics due to non-linear propagation. Ultraharmonics and sub-harmonics on the other hand, were generated only by the agent, and were not produced due to the non-linear propagation of ultrasound in either water or tissue. Additionally, ultraharmonic (3f0/2) enhancements of approximately 23 dB at 100 kPa, approximately 35 dB at 0.5 MPa and approximately 41dB at 1.1 MPa for ST68-PFC, offer much greater signal to noise ratio than higher harmonics.     

Asymmetric radial expansion and contraction of rat carotid artery observed using a high-resolution ultrasound imaging system

The geometry of carotid artery bifurcation is of high clinical interest because it determines the characteristics of blood flow that is closely related to the formation and development of atherosclerotic plaque. However, information on the dynamic changes in the vessel wall of carotid artery bifurcation during a pulsatile cycle is limited. This pilot study investigated the cyclic changes in carotid artery geometry caused by blood flow pulsation in rats. A high-resolution ultrasound imaging system with a broadband scanhead centered at 40 MHz was used to obtain longitudinal images of the rat carotid artery. A high frame rate retrospective B-scan imaging technique based on the use of electrocardiogram to trigger signal acquisition was used to examine precisely the fast arterial wall motion. Two-dimensional geometry data obtained from nine rats showed that the rat carotid artery asymmetrically contracts and dilates during each cardiac cycle. Systolic/diastolic vessel diameters near the upstream and downstream regions from the bifurcation were 0.976 ± 0.011/0.825 ± 0.015 mm and 0.766 ± 0.015/0.650 ± 0.016 mm, respectively. Their posterior/anterior wall displacement ratios in the radial direction were 41.0 ± 14.9% and 2.9 ± 1.6%, respectively. These results indicate that in the vicinity of bifurcation, the carotid artery favorably expands to the anterior side during the systolic phase. This phenomenon was observed to be more prominent in the downstream region near the bifurcation. The cyclic variation pattern in wall movement varies depending on the measurement site, which shows different patterns at far upstream and downstream of the bifurcation. The asymmetric radial expansion and contraction of the rat carotid artery observed in this study may be useful in studying the hemodynamic etiology of cardiovascular diseases because the pulsatile changes in vessel geometry may affect the local hemodynamics that determines the spatial distribution of wall shear stress, one of important cardiovascular risk factors. Further systematic study is needed to clarify the effects of wall elasticity, branch angle and vessel diameter ratio on the asymmetric wall motion of carotid artery bifurcation.