Thrombolysis using multi-frequency high intensity focused ultrasound at MHz range: anin vitrostudy

Abstract

High intensity focused ultrasound (HIFU) based thrombolysis has emerged as a promising drug-free treatment approach for ischemic stroke. The large amount of acoustic power required by this approach, however, poses a critical challenge to the future clinical translation. In this study, multi-frequency acoustic waves at MHz range (near 1.5 MHz) were introduced as HIFU excitations to reduce the required power for treatment as well as the treatment time. In vitro bovine blood clots weighing around 150 mg were treated by single-frequency and multi-frequency HIFU. The pulse length was 2 ms for all experiments except the ones where the duty cycle was changed. It was found that dual-frequency thrombolysis efficiency was statistically better than single-frequency under the same acoustic power and excitation condition. When varying the acoustic power but fixing the duty cycle at 5%, it was found that dual-frequency ultrasound can save almost 30% power in order 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 single-frequency. Dual-frequency ultrasound could also accelerate the thrombolysis by a factor of 2-4 as demonstrated in this study. No significant differences were found between dual-frequencies with different frequency differences (0.025, 0.05, and 0.1 MHz) and between dual-frequency and triple-frequency. The measured cavitation doses of dual-frequency and triple-frequency excitations were at about the same level but both were significantly higher than that of single-frequency.

Intravascular forward-looking ultrasound transducers for microbubble-mediated sonothrombolysis

“…Bovine blood clot samples were prepared in a similar protocol as described in previous work 50 . Bovine blood was obtained from Densco Marketing, Inc. (Woodstock, IL, USA).…”

High-intensity focused ultrasound: past, present, and future in neurosurgery

“…9,17,57,67,76,85 FUS causes microbubble oscillation, leading to mechanical disruption of the ischemic clot and improving rates of recanalization. 20 Low-intensity ultrasound combined with systemic delivery of microbubble contrast agents has been shown to improve thrombolysis in the presence or absence of tissue plasminogen activator (tPA) in the past.…”

“…1,18 HIFU as a stand-alone method for thrombolysis seems to be more advantageous, as it reduces the risk of hemorrhage by eliminating the side effects of thrombolytic drugs as well as adequately causing thrombolysis without damage to the targeted vessels. 9,57,85 Also, HIFU reduces the treatment time from hours to minutes, which may cause significant reductions in the size of infarct and lead to better clinical outcomes in stroke patients, 9,17,57,67,76,85 and therefore has the potential to revolutionize current treatment paradigms. Further investigations and clinical trials are warranted.…”

Magnetic resonance–guided, high-intensity focused ultrasound sonolysis: potential applications for stroke

“…However, low-frequency waves can be difficult to focus, resulting in thermal and mechanical damage to adjacent tissues. 6,23,58,68,72 Several techniques have been developed to improve the safety and efficiency of MRg-HIFU thrombolysis. The presence of intracranial standing waves secondary to resonance from acoustic reflections within the cranial vault can have unpredictable and detrimental effects, including the formation of unexpected hot spots and an elevated risk of ICH.…”

“…4,19,20,28,37,49,56 Furthermore, given its negligible thermal effects and the stagnancy of the clot, lowintensity sonothrombolysis is not applicable to ICH. 1,2,9,68 In contrast, MRg-HIFU thrombolysis is an emerging stand-alone therapy for rapid transcranial clot disintegration in patients with ELVO and ICH and, according to in vitro and in vivo models, can potentially achieve recanalization and liquefaction rates of 63%-93% and > 95%, respectively. 10,25,30,45,50,51,73,75 Herein, we review the technological development, preclinical results, and future applications of MRg-HIFU thrombolysis.…”