Efficacy of Sonothrombolysis Using Microbubbles Produced by a Catheter-Based Microfluidic Device in a Rat Model of Ischemic Stroke

Limitations of existing thrombolytic therapies for acute ischemic stroke have motivated the development of catheter-based approaches that utilize no or low doses of thrombolytic drugscombined with a mechanical action to either dissolve or extract the thrombus. Sonothrombolysis accelerates thrombusdissolution via the application of ultrasound combined with microbubblecontrast agents and low doses of thrombolytics to mechanically disrupt the fibrin mesh. In this work, we studied the efficacy of catheter-directed sonothrombolysis in a rat model of ischemic stroke. Microbubblesof 10–20 µm diameter with a nitrogen gas core and a non-crosslinked albumin shell were produced by a flow-focusingmicrofluidic device in real time. The microbubbleswere dispensed from a catheter located in the internal carotid artery for direct delivery to the thrombus-occluded middle cerebral artery, while ultrasound was administered through the skull and recombinant tissue plasminogen activator(rtPA) was infused via a tail vein catheter. The results of this study demonstrate that flow focusingmicrofluidic devices can be miniaturized to dimensions compatible with human catheterization and that large-diameter microbubblescomprised of high solubility gases can be safely administered intraarterially to deliver a sonothrombolytic therapy. Further, sonothrombolysis using intraarterial delivery of large microbubblesreduced cerebral infarct volumes by approximately 50% vs. no therapy, significantly improved functional neurological outcomes at 24 h, and permitted rtPA dose reduction of 3.3 (95% CI 1.8–3.8) fold when compared to therapy with intravenous rtPA alone.