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

Abstract

Physical characterization of an ultrasound contrast agent (UCA) aids in its safe and effective use in diagnostic and therapeutic applications. The goal of this study was to investigate the impact of temperature on the size distribution, shell properties, and stability of Definity, a U.S. Food and Drug Administration-approved UCA used for left ventricular opacification. A Coulter counter was modified to enable particle size measurements at physiologic temperatures. The broadband acoustic attenuation spectrum and size distribution of Definity were measured at room temperature (25 °C) and physiologic temperature (37 °C) and were used to estimate the viscoelastic shell properties of the agent at both temperatures. Attenuation and size distribution was measured over time to assess the effect of temperature on the temporal stability of Definity. The attenuation coefficient of Definity at 37 °C was as much as 5 dB higher than the attenuation coefficient measured at 25 °C. However, the size distributions of Definity at 25 °C and 37 °C were similar. The estimated shell stiffness and viscosity decreased from 1.76 ± 0.18 N/m and 0.21 × 10 ± 0.07 × 10 kg/s at 25 °C to 1.01 ± 0.07 N/m and 0.04 × 10 ± 0.04 × 10 kg/s at 37 °C, respectively. Size-dependent differences in dissolution rates were observed within the UCA population at both 25 °C and 37 °C. Additionally, cooling the diluted UCA suspension from 37 °C to 25 °C accelerated the dissolution rate. These results indicate that although temperature affects the shell properties of Definity and can influence the stability of Definity, the size distribution of this agent is not affected by a temperature increase from 25 °C to 37 °C.

Nonlinear power loss in the oscillations of coated and uncoated bubbles: Role of thermal, radiation and encapsulating shell damping at various excitation pressures

“…The linear thermal model [33,50] is a popular model that has been widely used in studies related to oceanography [4,5] and the modeling and charecterization of coated bubble oscillations [38][39][40][41][42]. In this model through linearization thermal damping is approximated by adding an artificial viscosity term to the liquid viscosity.…”

“…Furthermore, knowledge of the nonlinear attenuation in the medium will help in optimization of applications related to sonochemistry [35][36][37] and medical ultrasound [11-13, 44, 45] by enhancing and controlling the acoustic energy at the target. The majority of the previous studies employed linear approximations [33,[38][39][40][41][42] (limited to very small bubble oscillation amplitudes) to calculate the damping parameters during bubble oscillations. Thus, linear models neglect the dependence of the dissipated energy on the local pressure [33][34][35][36] and are not applicable to conditions under which bubbles are excited in most applications.…”

“…In the 3 models, the first model neglects the thermal effects, the second model includes the thermal effects using linear approximations by introducing an artificial thermal viscosity [50] and the third model includes full thermal effects [49,[51][52][53] (full thermal model). The second model has widely been used in studies related to oceanography [4,5] or ultrasound contrast agent characterization [38][39][40][41][42]). In this paper we call this the linear thermal model.…”

Characterization and Imaging of Lipid-Shelled Microbubbles for Ultrasound-Triggered Release of Xenon

“…The size distributions reported in this study were measured at room temperature. Although the acoustic response of microbubbles varies with temperature [34,67], the size distribution of lipid-shelled contrast agents has been shown to not vary substantially at room and physiological temperatures [37]. Future in vivo studies will be necessary to assess the therapeutic efficacy of Xe delivery using the agents reported in this study.…”

“…The frequency-dependent acoustic attenuation coefficients of Xe-MB, Xe-OFP-MB, and Definity® were measured using through-transmission attenuation spectroscopy as described previously [34,37]. Xe-MB, Xe-OFP-MB, or Definity® was diluted in a 37 ± 0.5°C solution of 0.5% BSA in airsaturated PBS (DO = 99.6 ± 0.5%).…”