Successful Microbubble Sonothrombolysis Without Tissue-Type Plasminogen Activator in a Rabbit Model of Acute Ischemic Stroke

Abstract

Background Microbubbles (MB) combined with ultrasound (US) have been shown to lyse clots without tissue plasminogen activator (tPA) both in vitro and in vivo. We evaluated sonothrombolysis with three types of MB using a rabbit embolic stroke model. Methods New Zealand White rabbits (n=74) received internal carotid angiographic embolization of single 3 day-old cylindrical clots (0.6×4.0-mm). Groups included: 1) control (n=11) embolized without treatment, 2) tPA (n=20), 3) tPA+US (n=10), 4) Perflutren Lipid MB+US (n=16), 5) albumin 3µm MB+US (n=8), and 6) tagged albumin 3µm MB+US (n=9). Treatment began 1 hour post-embolization. Ultrasound was pulsed-wave (1 MHz; 0.8 W/cm2) for 1 hour; rabbits with tPA received intravenous tPA (0.9 mg/kg) over 1 hour. Lipid MB dose was intravenous (0.16 mg/kg) over 30 minutes. Dosage of 3µm MB was 5×109 MB intravenously alone or tagged with eptifibatide and fibrin antibody over 30 minutes. Rabbits were euthanized at 24 hours. Infarct volume was determined using vital stains on brain sections. Hemorrhage was evaluated on H&E sections. Results Infarct volume percent was lower for rabbits treated with Lipid MB+US (1.0%±0.6%; P=0.013), 3µm MB+US (0.7%±0.9%; P=0.018), and tagged 3µm MB+US (0.8%±0.8%; P=0.019) compared with controls (3.5%±0.8%). The three MB types collectively had lower infarct volumes (P=0.0043) than controls. Infarct volume averaged 2.2%±0.6% and 1.7%±0.8% for rabbits treated with tPA alone and tPA+US, respectively (P=NS). Conclusions Sonothrombolysis without tPA using these MB is effective in decreasing infarct volumes. Study of human application and further MB technique development are justified.

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.…”

Sonothrombolysis in acute stroke and myocardial infarction: A systematic review

“…They also showed effective sonolysis using microbubbles and ultrasound without TPA in a rabbit stroke model. Less intracranial hemorrhage was observed in animals treated with microbubbles and ultrasound alone compared to animals also treated with TPA [30]. This reduction was significant compared to earlier human trials with TPA [26,27,31].…”

“…Almost all studies thus far have used a sonothrombolysis treatment combined with a full dose (recombinant) tPA therapy. Low and no dose tPA experiments are successful in animal models, showing a decrease in systemic side-effects, especially bleeding, while maintaining a local sonothrombolytic effect [10,30]. Studies treating patients with low dose fibrinolytic regimens combined with ultrasound and microbubbles should be designed next to achieve a balance between efficacy and bleeding risk.…”

Progress in Sonothrombolysis for the Treatment of Stroke

“…18,20 -23 Recently, treatment with microbubbles and US in a rabbit model of embolic stroke was shown to decrease the incidence of intracerebral hemorrhage 24 as compared with tPA and also to result in similar reduction of infarct volume as tPA. 25 …”