Modifying the size distribution of microbubble contrast agents for high-frequency subharmonic imaging

Purpose: Subharmonic imaging is of interest for high frequency (>10 MHz) nonlinear imaging, because it can specifically detect the response of ultrasound contrast agents (UCA). However, conventional UCA produce a weak subharmonic response at high frequencies, which limits the sensitivity of subharmonic imaging. We hypothesized that modifying the size distribution of the agent can enhance its high-frequency subharmonic response. The overall goal of this study was to investigate size-manipulated populations of the agent to determine the range of sizes that produce the strongest subharmonic response at high frequencies (in this case, 20 MHz). A secondary goal was to assess whether the number or the volume-weighted size distribution better represents the efficacy of the agent for high-frequency subharmonic imaging. Methods: The authors created six distinct agent size distributions from the native distribution of a commercially available UCA (Targestar-P (R)). The median (number-weighted) diameter of the native agent was 1.63 mu m, while the median diameters of the size-manipulated populations ranged from 1.35 to 2.99 mu m. The authors conducted acoustic measurements with native and size-manipulated agent populations to assess their subharmonic response to 20 MHz excitation (pulse duration 1.5 mu s, pressure amplitudes 100-398 kPa). Results: The results showed a considerable difference between the subharmonic response of the agent populations that were investigated. The subharmonic response peaked for the agent population with a median diameter of 2.15 mu m, which demonstrated a subharmonic signal that was 8 dB higher than the native agent. Comparing the subharmonic response of different UCA populations indicated that microbubbles with diameters between 1.3 and 3 mu m are the dominant contributors to the subharmonic response at 20 MHz. Additionally, a better correlation was observed between the subharmonic response of the agent and the number-weighted size-distribution (R-2 = 0.98) than with the volume-weighted size distribution (R-2 = 0.53). Conclusions: Modifying the size distribution of the agent appears to be a viable strategy to improve the sensitivity of high-frequency subharmonic imaging. In addition, when the size distribution of the UCA has not been suitably modified, the number-weighted size distribution is a useful parameter to accurately describe the efficacy of the agent for high-frequency subharmonic imaging. (C) 2013 American Association of Physicists in Medicine.