Telli Faez

20 years of ultrasound contrast agent modeling

The merits of ultrasound contrast agents (UCAs) were already known in the 1960s. It was, however, not until the 1990s that UCAs were clinically approved and marketed. In these years, it was realized that the UCAs are not just efficient ultrasound scatterers, but that their main constituent, the coated gas microbubble, acts as a nonlinear resonator and, as such, is capable of generating harmonic energy. Subharmonic, ultraharmonic, and higher harmonic frequencies of the transmitted ultrasound frequency have been reported. This opened up new prospects for their use and several detection strategies have been developed to exploit this harmonic energy to discriminate the contrast bubbles from surrounding tissue. This insight created a need for tools to study coated bubble behavior in an ultrasound field and the first models were developed. Since then, 20 years have elapsed, in which a broad range of UCAs and UCA models have been developed. Although the models have helped in understanding the responses of coated bubbles, the influence of the coating has not been fully elucidated to date and UCA models are still being improved. The aim of this review paper is to offer an overview in these developments and indicate future directions for research.

Characterizing the subharmonic response of phospholipid-coated microbubbles for carotid imaging.

The subharmonic vibration of BR14 (Bracco Research S.A., Geneva, Switzerland) contrast agent microbubbles is investigated within the preferable frequency range for carotid ultrasound imaging (8-12 MHz). The response of the bubbles was recorded optically with an ultra-fast recording camera (Brandaris 128) at three acoustic pressures (50, 100 and 120 kPa). The vibration of the microbubbles was measured as a function of the excitation frequency and its frequency content was determined. Among 390 recordings, 40% showed subharmonic oscillations. It was observed that for smaller microbubbles (diameter < 3 μm) the frequency of the maximum subharmonic response increases for increasing pressures (shell hardening) opposite to what has been reported for larger microbubbles (3 μm < diameter < 15 μm). These findings are well predicted by the model proposed by Marmottant et al. (2005) after including the dilatational shell viscosity of the microbubbles measured by Van der Meer et al. (2007), which indicates a marked shear-thinning behavior of the phospholipid shell.

Characterization of Definity™ Ultrasound Contrast Agent at Frequency Range of 5–15 MHz

The status of vasa vasorum, which can be imaged using ultrasound contrast agents, is an indication for the progression of atherosclerosis. The preferred ultrasound frequency for this purpose is between 5 and 15 MHz. Therefore, it is essential to have knowledge about the acoustic properties of microbubbles such as elasticity and viscosity to be able to implement the current models for lipid encapsulated microbubbles developed for frequencies used in precordial imaging. In this study, the shell parameters, stiffness S(p) and friction S(f), of Definity™ microbubbles have been calculated at frequency range of 5-15 MHz by comparing the theoretical modeling of acoustic bubble response and experimental measurements. Derived parameters are in good agreement with previous estimations on SonoVue™ and Sonazoid™ contrast agent. However, the value of S(f) is higher than previously estimated for Definity™ between 12-28 MHz.

Brandaris 128 ultra-high-speed imaging facility: 10 years of operation, updates, and enhanced features

The Brandaris 128 ultra-high-speed imaging facility has been updated over the last 10 years through modifications made to the cameras hardware and software. At its introduction the camera was able to record 6 sequences of 128 images (500 × 292 pixels) at a maximum frame rate of 25 Mfps. The segmented mode of the camera was revised to allow for subdivision of the 128 image sensors into arbitrary segments (1-128) with an inter-segment time of 17 μs. Furthermore, a region of interest can be selected to increase the number of recordings within a single run of the camera from 6 up to 125. By extending the imaging system with a laser-induced fluorescence setup, time-resolved ultra-high-speed fluorescence imaging of microscopic objects has been enabled. Minor updates to the system are also reported here.

Effect of self-demodulation on the subharmonic response of contrast agent microbubbles

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).

Subharmonic spectroscopy of ultrasound contrast agents

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).

Self-demodulation effect on subharmonic response of ultrasound contrast agent

In this work the use of the self-demodulation (S-D) signal as a mean of microbubble excitation at the subharmonic (SH) frequency to enhance the SH emission of ultrasound contrast agent (UCA) is studied. SH emission from the UCA is of interest since it is produced only by the UCA and is free of the artifacts produced in harmonic imaging modes. The S-D wave is a low-frequency signal produced by nonlinear propagation of an ultrasound wave in the medium. Single element transducer experiments and numerical simulations were conducted at 10 MHz to study the effect of the S-D signal on the SH response of the UCA by modifying the envelope of the excitation bursts. For 6 and 20 transmitted cycles, the SH response is increased up to 25 dB and 22 dB because of the S-D stimulation for a burst with a rectangular envelope compared with a Gaussian envelope burst. Such optimized excitations were used in an array-based micro-ultrasound system (Vevo 2100, VisualSonics Inc., Toronto, ON, Canada) at 18 MHz for in vitro validation of SH imaging. This study suggests 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 real-time SH imaging is feasible with shorter transmit burst (6- cycle) and low acoustic pressure (~150 KPa) at high frequencies (>15 MHz).

Optical characterization of inidividual liposome-loaded microbubbles

Newly developed liposome-loaded (LPS) microbubbles are characterized by comparing their oscillating response with standard phospholipid-coated (bare) microbubbles using the ultra-high speed imaging (Brandaris 128) camera. A study of the shell properties indicate nearly the same shell elasticity and a higher shell viscosity for LPS bubbles than for bare bubbles. A frequency and pressure-dependent bubble acoustical behavior study shows a higher threshold for the initiation of bubble vibrations for LPS bubbles. In addition, an “expansion-only” behavior was observed for up to 69% of the investigated LPS bubbles which mostly occurred at lower acoustic pressures (≤30 kPa). Liposome attachment stability were studied using fluorescence imaging. The internal relationship among morphological structure, shell properties and ultrasonic behavior of LPS bubbles by optical characterization facilitate preclinical study and clinical application of LPS bubbles in ultrasound triggered drug delivery system.

Subharmonic imaging for vasa vasorum

It is known that vasa vasorum plays an important role in atherosclerotic plaque pathogenesis and stability. Recent advances in contrast-enhanced ultrasound have shown that this technique can be used to characterize the carotid vasa vasorum and intra-plaque angiogenesis. Ultrasound propagating through tissue is nonlinear and contains higher harmonics of the transmitted wave, but it does not contain energy at the subharmonic frequency, which revives a strong interest in subharmonic emissions (backscattered energy at half the transmit frequency) from contrast agents. Subharmonic imaging (SHI) has potentially a larger contrast to tissue ratio compared to other imaging methods and has already been used in clinical experimental studies. In this study, the subharmonic scattering of phospholipid-coated contrast agents in the frequency range preferred for carotid imaging (5-15 MHz) is investigated optically and acoustically and in vitro and in vivo. The results of the measurements indicate that: -The subharmonic s...