Interaction effects on acoustic emissions of submicron ultrasound contrast agents at subharmonic resonances

Submicron ultrasound contrast agents hold great potential to extend the bubble-mediated theranostics beyond the vasculature, but their acoustic response and the interaction effects between them remain poorly understood. This study set out to numerically examine the interaction effects on the subharmonic oscillations of nanobubbles and the resultant acoustic emissions under subharmonic resonance conditions. Results showed that a negative correlation between bubble size and subharmonic resonance frequency is readily obtained from the radius response curves. Moreover, it was also found that the larger nanobubble in a two-nanobubble system generally acts as the primary determinant for the subharmonic oscillations of the smaller one. Specifically, a larger nanobubble excited at its subharmonic resonance conditions can force a smaller nanobubble to undergo subharmonic oscillations, resulting in the generation of subharmonic acoustic emissions. Conversely, under specific resonance conditions, a smaller nanobubble undergoing subharmonic oscillations can also be restrained by a larger nanobubble that is off-resonance and consequently its subharmonic component disappears. Furthermore, it also clearly demonstrated that the generation of subharmonic resonance is pressure threshold dependent and the subharmonic resonant radius is distinctly reduced as the acoustic pressure increases. By contrast, a larger nanobubble has a lower pressure threshold than that of a smaller one, when subjected to their subharmonic resonance conditions respectively. More importantly, the higher pressure threshold of a smaller nanobubble can be prominently decreased by the interaction effects from a nearby larger nanobubble. For two interacting nanobubbles, the interaction effects strongly depend on the inter-bubble distance, and the farther the two nanobubbles is, the weaker the interaction effects become and even can be ignored. Additionally, the impacts of the lipid shell properties indicated that increasing shell viscoelasticity can increase the subharmonic resonant radius but dampen the subharmonic oscillations and the resultant acoustic emissions, which is more sensitive to the shell viscosity. This study can contribute to a better understanding of the complex interaction effects between submicron ultrasound contrast agents on the resultant acoustic emissions, potentially advancing nanobubble-specific ultrasound applications.