High Intensity Focused Ultrasound (HIFU) Based Thrombolysis Using Multiple Frequency Excitation

High intensity focused ultrasound (HIFU) based thrombolysis has emerged as a promising drug-free approach for ischemic stroke treatment. The large amount of acoustic power required by this approach, however, poses a critical challenge to the future clinical translation because of the potential thermal damages. In this dissertation, multi-frequency acoustic waves at MHz range (near 1.5 MHz) were first introduced as HIFU excitations to reduce the required treatment power as well as the treatment time. It was found that dual-frequency thrombolysis efficiency was statistically better than that of single-frequency, under the same acoustic power and excitation condition. Microbubbles (MBs) combined with dual-frequency focused ultrasound (DFFU) for thrombolysis in vitro was then proposed to further reduce the power required. MBs are widely used in therapeutic ultrasound thrombolysis due to the nonlinear characteristics of their harmonic responses, coalescence and cavitation effects, which could further enhance efficiency. It was shown in this study that MBs, with sufficient concentration, could significantly lower the power threshold for thrombolysis for both DFFU and single-frequency focused ultrasound (SFFU). MBs mediated DFFU thrombolysis were then studied with a flow system that mimicked the blood flow in the artery of the brain. It was found that the cavitation threshold of a DFFU excitation yielded a lower level than that of a SFFU excitation. All the experimental results indicated that multi-frequency ultrasound could improve the thrombolysis efficiency. However, this was not well established numerically. Hence, a numerical investigation on the inertial cavitation threshold of MBs under multifrequency ultrasound irradiation was then investigated to confirm the benefit of using multi-frequency ultrasound for various applications. The main contribution and findings of this dissertation are as follows:;1) For the HIFU along study, when varying the acoustic power while fixing the duty cycle at 5%, it was found that almost 30% of the power can be saved by dual frequency ultrasound to achieve the same thrombolysis efficiency. In the experiment where the duty cycle was increased from 0.5% to 10%, it was shown that dual-frequency ultrasound can achieve the same thrombolysis efficiency with only half of the duty cycle of singlefrequency. Dual-frequency ultrasound could also accelerate the thrombolysis by a factor of 2-4 as demonstrated in this study. The measured cavitation doses of dual-frequency and triple-frequency excitations were at about the same level, both significantly higher than that of single-frequency.;2) For the MBs mediated thrombolysis study, SFFU needed about 96%-156% higher energy to achieve the same thrombolysis efficiency as that of DFFU. The thrombolysis efficiency was also found to increase with the duty cycle. The measured cavitation signals reveal that the enhanced inertial cavitation may contribute to the improved thrombolysis under DFFU and MBs. By adding the flow system, the inertial cavitation was higher than the static model. One reason could be the dissolution of MBs into the flow that lowered the concentration of MBs by a significant amount. In both cases, the inertial cavitation thresh holds of DFFU were lower than SFFU.;3) For the numerical study, we investigated the inertial cavitation threshold of MBs under multi-frequency ultrasound irradiation. The relationships between the cavitation threshold and MB size at various frequencies and in different media were investigated. The results for single, dual and triple frequency sonication showed that inertial cavitation thresholds can be reduced by introducing additional frequencies, which was consistent with previous experimental work. In addition, no significant difference was observed between dual frequency sonication with various frequency differences. This study also provided a possible route for optimizing ultrasound excitations for initiating inertial cavitation.