The Delayed Onset of Subharmonic and Ultraharmonic Emissions from a Phospholipid-Shelled Microbubble Contrast Agent

Abstract

Characterizing the nonlinear response of microbubble contrast agents is important for their efficacious use in imaging and therapy. In this paper, we report that the subharmonic and ultraharmonic response of lipid-shelled microbubble contrast agents exhibits a strong temporal dependence. We characterized nonlinear emissions from Targestar-P® microbubbles (Targeson Inc., San Diego, CA, USA) periodically for 60 minutes, at 10 MHz excitation frequency. The results revealed a considerable increase in the subharmonic and ultraharmonic response (nearly 12–15 and 5–8 dB) after 5–10 minutes of agent preparation. However, the fundamental and the harmonic response remained almost unchanged in this period. During the next 50 minutes, the subharmonic, fundamental, ultraharmonic, and harmonic responses decreased steadily by 2–5 dB. The temporal changes in the nonlinear behavior of the agent appeared to be primarily mediated by gas-exchange through the microbubble shell; temperature and prior acoustic excitation based mechanisms were ruled out. Further, there was no measurable change in the agent size distribution by static diffusion. We envisage that these findings will help obtain reproducible measurements from agent characterization, nonlinear imaging, and fluid-pressure sensing. These findings also suggest the possibility for improving nonlinear imaging by careful design of ultrasound contrast agents.

Chirp-Coded Ultraharmonic Imaging with a Modified Clinical Intravascular Ultrasound System

“…We have previously demonstrated ultraharmonic emissions from Targestar-P® at 10 MHz. 38,39 In addition, our work has shown that chirp-coded excitation enhances the nonlinear response from Targestar-P® at 10 MHz and 20 MHz, frequencies that are relevant for peripheral imaging. 39,40 Targestar-P-HF® is a variant of Targestar-P® that has a smaller size distribution to make it suitable for high-frequency imaging .…”

A new safety index based on intrapulse monitoring of ultra-harmonic cavitation during ultrasound-induced blood-brain barrier opening procedures

“…Shekhar et al observed in vitro an increase in both subharmonic and ultra-harmonic responses 5-10 min after lipid-shelled microbubble preparation 20 . The time evolution of these frequency components is attributed to mechanical changes in microbubble shape and behavior due to gas-exchange through its shell.…”

Contrast-Enhanced Quantitative Intravascular Elastography: The Impact of Microvasculature on Model-Based Elastography

“…We used Targestar-P-HF microbubbles (Targeson Inc. San Diego, CA, USA) as the ultrasound contrast agent. Targestar-P-HF contains decafluorobutane gas and its shell is primarily composed of phospholipid and polyethylene glycol fatty acid (Shekhar, et al 2014). Targestar-P-HF is especially designed for high frequency nonlinear imaging – its size distribution is smaller than conventional Targetsar-P. We measured the size distribution and concentration of Targestar-P-HF with a Coulter counter (Multisizer IV, Beckman Coulter Inc., Fullerton, CA, USA) that used a 50 μ m aperture, with 300 bins between 1-15 μ m ( Fig.…”