Sonothrombolysis is a technique that utilises ultrasound waves to excite microbubbles surrounding a clot. Clot lysis is achieved through mechanical damage induced by acoustic cavitation and through local clot displacement induced by acoustic radiation force (ARF). Despite the potential of microbubble-mediated sonothrombolysis, the selection of the optimal ultrasound and microbubble parameters remains a challenge. Existing experimental studies are not able to provide a complete picture of how ultrasound and microbubble characteristics influence the outcome of sonothrombolysis. Likewise, computational studies have not been applied in detail in the context of sonothrombolysis. Hence, the effect of interaction between the bubble dynamics and acoustic propagation on the acoustic streaming and clot deformation remains unclear. In the present study, we report for the first time the computational framework that couples the bubble dynamic phenomena with the acoustic propagation in a bubbly medium to simulate microbubble-mediated sonothrombolysis using a forward-viewing transducer. The computational framework was used to investigate the effects of ultrasound properties (pressure and frequency) and microbubble characteristics (radius and concentration) on the outcome of sonothrombolysis. Four major findings were obtained from the simulation results: (i) ultrasound pressure plays the most dominant role over all the other parameters in affecting the bubble dynamics, acoustic attenuation, ARF, acoustic streaming, and clot displacement, (ii) smaller microbubbles could contribute to a more violent oscillation and improve the ARF simultaneously when they are stimulated at higher ultrasound pressure, (iii) higher microbubbles concentration increases the ARF, and (iv) the effect of ultrasound frequency on acoustic attenuation is dependent on the ultrasound pressure. These results may provide fundamental insight that is crucial in bringing sonothrombolysis closer to clinical implementation.
Sonothrombolysis is a technique that employs the ultrasound waves to break down the clot. Recent studies have demonstrated significant improvement in the treatment efficacy when combining two ultrasound waves of different frequencies. Nevertheless, the findings remain conflicted on the ideal frequency pairing that leads to an optimal treatment outcome. Existing experimental studies are constrained by the limited range of frequencies that can be investigated, while numerical studies are typically confined to spherical microbubble dynamics, thereby restricting the scope of the analysis. To overcome this, the present study investigated the microbubble dynamics caused by the different combinations of ultrasound frequencies. This was carried out using computational modelling as it enables the visualisation of the microbubble behaviour, which is difficult in experimental studies due to the opacity of blood. The results showed that the pairings of two ultrasound waves with low frequencies generally produced stronger cavitation and higher flow-induced shear stress on the clot surface. However, one should avoid the frequency pairings that are integer multipliers of each other, i.e., frequency ratio of 1/3, 1/2 and 2, as they led to resultant wave with low pressure amplitude that weakened the cavitation. At 0.5 + 0.85 MHz, the microbubble caused the highest shear stress of 60.5 kPa, due to its large translational distance towards the clot. Although the pressure threshold for inertial cavitation was reduced using dual-frequency ultrasound, the impact of the high-speed jet can only be realised when the microbubble travelled close to the clot. The results obtained from the present study provide groundwork for deeper understanding on the microbubble dynamics during dual-frequency sonothrombolysis, which is of paramount importance for its optimisations and the subsequent clinical translation.