A Computational Study on the Use of Phase Shift to Improve Dual-frequency Sonothrombolysis Outcomes

Sonothrombolysis is a technique to remove blood clot from vessels by using ultrasound waves to induce acoustic cavitation (formation of microbubbles). Recent studies have demonstrated improved sonothrombolytic efficacy when using two ultrasound waves of different frequencies (dual-frequency ultrasound). Nevertheless, our recent study suggested that an improper selection of the ultrasound frequency, specifically when one frequency is an integer multiplier of another, can weaken the cavitation intensity and the flow-induced shear stress, leading to poor sonothrombolysis outcomes. This is due to the destructive interference at these frequencies, which reduces the pressure amplitude of the resultant waves that incident on the microbubble. In this study, we investigated the hypothesis that destructive interference due to improper frequency selection can be alleviated by shifting the phase between the two ultrasound waves. To that end, a finite element model of the microbubble undergoing ultrasound-induced oscillation was developed. When an ultrasound of 0.5 MHz was paired with 1 MHz, a phase shift of 270° led to shear stress of 22.5 kPa, which was one order of magnitude higher than the case without phase shift. The results obtained showed that a correctly chosen phase shift can overcome the weakened cavitation of two ultrasound waves with frequencies being an integer multiplier of another. In contrast, non-integer multipliers of frequency pairings did not show significant influence of phase shift on cavitation and shear stress. Findings from this study provide new insights into the mechanics behind sonothrombolysis with dual-frequency ultrasound. This presents an excellent starting point for future advancement and optimisation of this treatment.