Michel Versluis

Microbubble surface modes [ultrasound contrast agents]

We have investigated surface vibrations generated by ultrasound excitation of individual unencapsulated micron-sized bubbles. In addition, we present surface modes (n=2 and 3) observed for phospholipid-coated ultrasound contrast agents excited through excitation of radial modes at frequencies between 1 and 4 MHz. Even higher modes of vibration (up to mode 5) are observed for coated microbubbles at insonation frequencies of 10 and 19 MHz. The potential relevance of surface modes for medical ultrasound is discussed, including the possible implications for current theoretical models of ultrasound contrast agents.

1B-5 Surface Modes of Ultrasound Contrast Agent Microbubbles

We study non-spherical oscillations (surface modes) of the coated microbubbles used in ultrasound contrast agents. We show that an acoustic pressure of 100 kPa, at a frequency of 1.7 MHz, is sufficient to excite surface modes for radii between 2 and 4 mum. Surface modes develop as a parametric instability. We derive their evolution equation accounting for the effect of the shell viscoelasticity. We identify a critical radius (1 to 3 mum, depending on the mode number) below which no surface mode can occur

9B-1 Coupled Dynamics of an Isolated UCA Microbubble Pair

We present time-resolved optical measurements of the coupled dynamics of two UCA microbubbles in ultrasound. We isolate microbubble pairs using optical tweezers to move them away from confining walls and study purely the bubble-bubble interaction. The dynamics in ultrasound is recorded optically using the ultra-high speed camera Brandaris 128. Our measurements indicate that the viscous drag on a translating and oscillating microbubble is not accounted for with enough accuracy by existing models using the elementary form of Stokes drag.

Segmented high speed imaging of vibrating microbubbles during long ultrasound pulses

Detailed information about the response of microbubbles to long ultrasound pulses (>100 cycles) is hampered by the limited time span ultra fast-framing cameras (> 10 MHz) cover. We therefore developed a new imaging mode for the Brandaris 128 camera [1], facilitating high speed imaging during small time windows (segments), equally distributed over a relatively large time span.

1F-2 Optical Trapping of Ultrasound Contrast Agent Microbubbles: Study of the Bubble-Wall and Bubble-Bubble Interaction in Ultrasound

Here we present optical tweezers as a micromanipulation tool for the study of ultrasound contrast agent (UCA) microbubbles. Optical trapping and the resulting manipulation of individual and multiple microbubbles enables the study of their dynamics with controlled boundary conditions. The bubble response to ultrasound is recorded optically using the ultra high-speed Brandaris 128 camera. In our experiments, the amplitude of bubble oscillations was found to be strongly influenced by the vicinity of the sample chamber wall. Experiments with two trapped bubbles also showed a considerable influence of the neighboring bubble on the amplitude of oscillations of the other one

Probing microbubble adhesion using secondary acoustic radiation force

In this study we investigated the translational dynamics of mutually attracting targeted microbubbles during and after ultrasound (US) insonification in more detail and show this mutual attraction can be used to determine the binding force. In general, similar sized microbubbles are known to attract each other during US application as a result of an acoustic radiation force leading to clustering and coalescence. Targeted microbubbles, however, move back to their initial position after US is turned off, implying the presence of an elastic restoring force, which in turn opposes the net pulling force. From the recoiling curves, a value for the effective spring constant k could be obtained, which was of the order of 2.4 mN/m. For higher acoustic pressures the pulling force exceeded the binding force and the bubbles detached. A threshold force for detachment was calculated with the obtained value of the spring constant. For biotinylated microbubbles (R=2-2.5 μm) targeted to a NeutrAvidin coated surface, the threshold force was between 0.9 nN and 2.0 nN. We also show that the translational dynamics of targeted microbubbles during US application can be modelled accurately using a hydrodynamic model [1], including a value for the spring constant k of the very same order as derived experimentally.

Oil-filled polymeric ultrasound contrast agent as local drug delivery system for lipophilic drugs

Novel polymeric microcapsules, filled with a mixture of gas and oil, were produced and their potential as ultrasound contrast agent-based drug delivery system for lipophilic drugs was investigated. Microcapsules were synthesized that contained either no oil, were almost half-filled with oil, or were almost completely filled with oil. Mean number weighted diameters were between 1.22 and 1.31 mum. At a low MI (1 MHz, P_ of 0.24 MPa), microcapsules typically compressed without cracking. At a high MI (1 MHz, P_ of 0.51 MPa), microcapsules cracked, thereby releasing their content. Guidance and monitoring of therapy will be possible because the microcapsules were echogenic and stable at low MI. These microcapsules therefore have great potential as local drug delivery system for lipophilic drugs.

Highly non-linear contrast agent oscillations: the compression-only behavior

Here we report the observation of a highly non-linear bubble response of phospholipid coated contrast agents, termed compression-only behavior where the microbubbles only compress, yet hardly expand. The occurrence of this phenomenon has been studied retrospectively and it was found that 33% of the examined cases show this behavior. The compression-only behavior is described by a newly developed shell model for phospholipid coated bubbles. The model extends previous elastic models with shell compressibility, a buckling radius and a break-up tension. It also predicts large amplitude oscillations, and bubble break-up.

P5B-4 Optimization of Chirp Reversal for Ultrasound Contrast Imaging

Chirp reversal consists of transmitting first a chirp with upsweep frequencies (UPF) then a second chirp with downsweep frequencies (DNF). We have shown that contrast bubbles react differently to these chirps allowing the use of chirp reversal for ultrasound contrast imaging. The aim of the current study is to explore how chirp reversal can be optimized in terms of transmit frequency, bubble size, acoustic pressure and frequency bandwidth. Simulations were carried out to determine ultrasound parameters that provide largest differences in bubbles response to UPF and DNF chirps. Scattered pressures were calculated using a modified Rayleigh-Plesset equation. To evaluate the performance of chirp reversal for bubble detection, the echo from an UPF chirp was correlated to the time reversed echo from a DNF chirp for each scanning parameter. Simulations and optical measurements allow for an optimization of chirp reversal and demonstrate a potential application for contrast imaging when appropriate scanning parameters are selected.

2C-4 Chirp Reversal Ultrasound Contrast Imaging

We present a new contrast imaging approach based on chirps named chirp reversal contrast imaging. The technique consists of transmitting a first excitation signal being a chirp of increasing frequency with time (the so-called upsweep) and a second excitation signal, the downsweep, being a replica of the first signal, but time reversed with a sweep of decreasing frequency with time. Simulations and optical observations were carried out to explore the potential of the chirp reversal approach in detecting microbubbles. Simulations using a Rayleigh-Plesset equation were performed considering various microbubbles excited with chirps at 1.7 MHz center frequency and 50% bandwidth. Optical observations with the Brandaris camera were carried out using BR14 bubbles of radii from 1 mum to 5 mum. Chirps with center frequencies of 1.7 MHz and 50% bandwidth were transmitted with peak negative pressures ranging from 70 kPa to 200 kPa. Simulations showed that for larger bubbles (>2 mum), significant differences occur between upsweep chirp response and down sweep response at 1.7 MHz transmit frequency. Optical observations confirmed these results. From the optical radius-time curves, the larger bubbles showed different dynamics when upsweep or downsweep frequencies were used in transmission. Upsweep excitation chirps produce highly damped responses with large amplitude excursions whereas the response to downsweep chirps showed a pronounced resonance behavior with smaller amplitudes. Smaller bubbles (<2 mum) appear to be less sensitive to frequency sweep at 1.7 MHz transmit frequency. However, driven at a higher center frequency, smaller bubbles tend to be more sensitive. Experimental and theoretical data confirm that chirp reversal is feasible and can be used to detect contrast microbubbles and to improve the contrast to tissue ratio