The influence of inter-bubble spacing on the resonance response of ultrasound contrast agent microbubbles.

Ultrasound-driven microbubbles, typically between 1 and 8 µm in diameter, are resonant scatterers that are employed as diagnostic contrast agents and emerging as potentiators of targeted therapies. Microbubbles are administered in populations whereby their radial dynamics - key to their effectiveness - are greatly affected by intrinsic (e.g. bubble size) and extrinsic (e.g. boundaries) factors. In this work, we aim to understand how two neighbouring microbubbles influence each other. We developed a finite element model of a system of two individual phospholipid-encapsulated microbubbles vibrating in proximity to each other to study the effect of inter-bubble distance on microbubble radial resonance response. For the case of two equal-sized and identical bubbles, each bubble exhibits a decrease between 7 and 10% in the frequency of maximum response (f) and an increase in amplitude of maximum response (A) by 9-11% as compared to its isolated response in free-space, depending on the bubble size examined. For a system of two unequal-sized microbubbles, the large bubble shows no significant change, however the smaller microbubble shows an increase in f by 7-11% and a significant decrease in A by 38-52%. Furthermore, in very close proximity the small bubble shows a secondary off-resonance peak at the corresponding f of its larger companion microbubble. Our work suggests that frequency-dependent microbubble response is greatly affected by the presence of another bubble, which has implications in both imaging and therapy applications. Furthermore, our work suggests a mechanism by which nanobubbles show significant off-resonance vibrations in the clinical frequency range, a behaviour that has been observed experimentally but heretofore unexplained.