The effects of temperature on the nonlinear oscillations of contrast enhancing microbubbles

Abstract

Micron-sized, gas encapsulated bubbles are used as ultrasound contrast agents to improve diagnostic image quality. These microbubbles, which are vascular agents, undergo linear and non-linear oscillations when excited. It is the non-linear response of microbubbles that facilitates the ability to distinguish between signals from the tissue -mostly linear-, and signals from the bubbles, which represents vasculature. This opens up numerous clinical applications such as echocardiography, focal lesion identification, perfusion imaging, etc… Characterization studies of microbubbles gained importance as the possible clinical applications increased. One aspect that these studies focused on is the temperature dependence of the microbubble dynamics. However, these studies were mostly comparing bubble dynamics at room temperature to their dynamics at the physiological temperatures. This study is focused on the changes in the characteristic bubble dynamics as a function of temperature. More specifically microbubble attenuation and scattering is measured as a function of temperature and time. Subharmonic emissions from bubbles were found to be sensitive to changes in the temperature of the medium such that 15°C of temperature change increased the subharmonic to harmonic signal ratio by 15 dB. IntroductionContrast enhanced ultrasound imaging (CEUS) with microbubble contrast agents is a wellestablished imaging modality for clinical use. Injection of agents into the blood stream for increasing ultrasound echogenicity was first introduced in 1968 1 . The first CEUS applications date back to the early 1970's for cardiac imaging 2-4 . These studies speculated that the increased echoes were due to the formation of air bubbles, which were larger in size than today's contrast agents. These bubbles were unstable and had a limited circulation time. A second generation of contrast enhancing microbubbles was developed with a more stable shell and a low-solubility gas to resolve the issues faced in the earlier studies 5,6 .

Effect of Temperature on the Size Distribution, Shell Properties, and Stability of Definity®

“…Previous studies have shown that the stability of Definity ® may reduce once the phase transition has been reached. These results should be considered if Definity ® is used for hyperthermia or UCA-enhanced heating studies (Guiot 2004; Guiot 2006; Meral 2014).…”

“…Mulvana et al (2011) performed high-speed imaging of SonoVue ® exposed to ultrasound, and observed stronger radial excursion, shell fragmentation, and jet formation at body temperature than at room temperature. Meral et al (2014) investigated the impact of temperature on the stable cavitation activity of a lipid-shelled UCA. Increasing the temperature from 25 °C to 40 °C was reported to increase subharmonic scattering relative to harmonic scattering by 10 dB.…”

“…Several studies have documented an increase in the acoustic attenuation of UCAs at physiological versus room temperature, both at conventional diagnostic and intravascular ultrasound frequencies (Meral 2014; Mulvana et al 2010; Raymond et al 2014; Sun et al 2016). Our group has previously reported broadband (2 MHz – 25 MHz) attenuation measurements of phospholipid shelled UCAs such as Definity ® , Micromarker ® (Bracco, Geneva, Switzerland and VisualSonics, Toronto, Canada), and echogenic liposomes (Raymond et al 2014).…”