On the relationship between microbubble fragmentation, deflation and broadband superharmonic signal production

Acoustic angiography imaging of microbubble contrast agents uses the superharmonic energy produced from excited microbubbles and enables high-contrast, high-resolution imaging. However, the exact mechanism by which broadband harmonic energy is produced is not fully understood. To elucidate the role of microbubble shell fragmentation in superharmonic signal production, simultaneous optical and acoustic measurements were performed on individual microbubbles at transmit frequencies from 1.75 to 3.75 MHz and pressures near the shell fragmentation threshold for microbubbles of varying diameter. High-amplitude, broadband superharmonic signals were produced with shell fragmentation, whereas weaker signals (approximately 25% of peak amplitude) were observed in the presence of shrinking bubbles. Furthermore, when populations of stationary microbubbles were imaged with a dual-frequency ultrasound imaging system, a sharper decline in image intensity with respect to frame number was observed for 1-μm bubbles than for 4-μm bubbles. Finally, in a study of two rodents, increasing frame rate from 4 to 7 Hz resulted in decreases in mean steady-state image intensity of 27% at 1000 kPa and 29% at 1300 kPa. Although the existence of superharmonic signals when bubbles shrink has the potential to prolong the imaging efficacy of microbubbles, parameters such as frame rate and peak pressure must be balanced with expected re-perfusion rate to maintain adequate contrast during in vivo imaging.