High-Intensity Focused Ultrasound (HIFU) for Dissolution of Clots in a Rabbit Model of Embolic Stroke

Abstract

It is estimated that only 2–6% of patients receive thrombolytic therapy for acute ischemic stroke suggesting that alternative therapies are necessary. In this study, we investigate the potential for high intensity focused ultrasound (HIFU) to initiate thrombolysis in an embolic model of stroke. Iron-loaded blood clots were injected into the middle cerebral artery (MCA) of New Zealand White rabbits, through the internal carotid artery and blockages were confirmed by angiography. MRI was used to localize the iron-loaded clot and target the HIFU beam for treatment. HIFU pulses (1.5 MHz, 1 ms bursts, 1 Hz pulse repetition frequency, 20 s duration) were applied to initiate thrombolysis. Repeat angiograms and histology were used to assess reperfusion and vessel damage. Using 275 W of acoustic power, there was no evidence of reperfusion in post-treatment angiograms of 3 rabbits tested. In a separate group of animals, 415 W of acoustic power was applied and reperfusion was observed in 2 of the 4 (50%) animals treated. In the last group of animals, acoustic power was further increased to 550 W, which led to the reperfusion in 5 of 7 (∼70%) animals tested. Histological analysis confirmed thatthe sonicated vessels remained intact after HIFU treatment. Hemorrhage was detected outside of the sonication site, likely due to the proximity of the target vessel with the base of the rabbit skull. These results demonstrate the feasibility of using HIFU, as a stand-alone method, to cause effective thrombolysis without immediate damage to the targeted vessels. HIFU, combined with imaging modalities used to identify and assess stroke patients, could dramatically reduce the time to achieve flow restoration in patients thereby significantly increasing the number of patients which benefit from thrombolysis treatments.

Experimental demonstration of passive acoustic imaging in the human skull cavity using CT‐based aberration corrections

“…Images of bubble activity were obtained starting at pressure levels below the threshold for BBB opening, which is consistent with our previous results obtained without the presence of a human skull. 66 Although the technique was applied during FUS-induced BBB opening in the present work, the method is directly applicable to other cavitation-mediated brain therapies, such as ultrasoundassisted clot lysis, 24,25 tissue fractionation, 26,27 or cavitationenhanced ablation. [101][102][103] Furthermore, the proposed technology could be used to confirm the absence of inertial cavitation during thermal ablation therapies in the brain, in order to avoid hemorrhagic events.…”

“…Apart from thermal-based applications of FUS in the brain, a number of promising nonthermal, cavitation-mediated brain therapies are currently undergoing preclinical investigations, such as blood-brain barrier (BBB) opening for targeted drug delivery, [17][18][19][20][21] sonothrombolysis, [22][23][24][25] and ultrasound-induced tissue fractionation. 26,27 In contrast with the thermal-based therapies described above, these treatments rely on mechanical interactions, namely, those of the incident ultrasound field with gas-or vapor-filled microspheres that are either formed via nucleation using high amplitude pulsed ultrasound exposures 28 or injected intravenously in the form of encapsulated microbubbles, long used as contrast agents in diagnostic imaging.…”

Registration of human skull computed tomography data to an ultrasound treatment space using a sparse high frequency ultrasound hemispherical array

“…However, there are nonthermal, cavitation-mediated applications of FUS that are being investigated preclinically, such as transient opening of the blood-brain barrier (BBB) for targeted drug delivery 9,10 or sonothrombolysis for the treatment of ischemic stroke. 11,12 For these interventions MRI may be useful for assessing treatment outcome, but is not well suited for realtime monitoring of cavitation processes. Additionally, MRI is not widely accessible and could be prohibitively expensive if frequent treatments are required.…”

The use of transcranial focused ultrasound in CNS diseases

“…[80] на животной модели продемон-стрировали возможность быстрого лизиса тромбов в цере-бральных артериях с помощью ФУЗ низкой частоты при одновременном введении специальных микропузырьков с повышенным сродством к тромбоцитам. В другой моде-ли зафиксирована деградация тромбов в интракраниаль-ных сосудах после воздействия ФУЗ высокой интенсив-ности без введения дополнительных агентов [81].…”