Microbubble-Mediated Sonothrombolysis Improves Outcome After Thrombotic Microembolism-Induced Acute Ischemic Stroke

Abstract

Microbubble-mediated sonothrombolysis is a promising treatment for cerebral microthrombi and is based on ultrasound driven cavitation of microbubbles that accelerate thrombolysis via localized mechanical stress on the thrombi. 17Background and Purpose-Microthrombi originating from disintegrated clots or formed in situ may account for the poor clinical improvement of acute ischemic stroke after recanalization therapy. We attempted to determine whether microbubble-mediated sonothrombolysis could dissolve platelet-rich and erythrocyte-rich microthrombi, thereby reducing their brain injury-causing potential. Methods-Platelet-and erythrocyte-rich microthrombosis were induced by periadventitial application of 5% ferric chloride or thrombin to mesenteric microvessels in 75 Sprague-Dawley rats. Acute ischemic stroke was induced by intracarotid injection of platelet-or erythrocyte-rich microthrombi in another 50 rats. Rats were randomly divided into control (CON), ultrasound (US), ultrasound and microbubble (US+MB), recombinant tissue-type plasminogen activator (r-tPA), and US+MB+r-tPA groups. The post-treatment mesenteric microvessel recanalization rates, cerebral infarct volumes, and neurological scores were determined. Results-The recanalization rates of platelet-and erythrocyte-rich microthrombi in mesenteric microvessels were higher (P<0.05), and the cerebral infarct volumes and neurological scores of rats with either microthrombi were lower in the US+MB group than in the CON group (P<0.01). The infarct volumes and neurological scores were greater in the r-tPA group than in the US+MB and US+MB+r-tPA groups after treatment of rats with platelet-rich microthrombi (P<0.05).In contrast, after treatment of rats with erythrocyte-rich microthrombi, the infarct volumes and neurological scores were similar in the r-tPA and US+MB groups, but smaller in the US+MB+r-tPA group (P<0.05). Conclusions-Microbubble-mediated sonothrombolysis improved the outcomes of microthrombi-induced acute ischemic stroke. Thus, this method may serve as an attractive adjunct to recanalization therapy for acute ischemic stroke.

Advanced Microbubbles as a Multifunctional Platform Combining Imaging and Therapy

“…In comparison, the effect of US + MB + rt-PA groups was the highest in cerebral infarction reduction and neurological deficits improvement. All these studies confirmed that MB-mediated sonothrombolysis has high effectiveness and good outcome in microemboli-induced acute ischemic strokes through dissolution of the microthrombi [85].…”

Sonothrombolysis with Magnetically Targeted Microbubbles

“…Sonothrombolysis, that is, the use of ultrasound (US) for enhanced thrombolysis, is a minimally or non-invasive physical approach that can be used to enhance the action of tPA, thereby reducing the required dose or facilitating clot breakdown in the absence of a drug. Multiple in vitro and in vivo studies have indicated that intravenously administered microbubbles can significantly improve the rate of clot breakdown, with or without concomitant use of a thrombolytic drug (Lu et al 2016;Schleicher et al 2016). Several clinical trials have also reported accelerated recanalisation of occluded vessels (Molina et al 2006;Perren et al 2008).…”

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

“…Another family of FUS therapies utilize biologically inert and preadministrated microbubbles, which reradiate low-intensity, incident ultrasound to further localize and amplify the mechanical effects onto the vasculature. The targeted mechanical effects can result in various beneficial biological effects, including the cellular and/or transcellular permeability enhancement [blood-brain barrier disruption (BBBD) (5-7) and sonoporation (8)], thrombolysis (9), or nonthermal ablation (10). BBBD, the subject of the current study, reversibly opens the blood-brain barrier (BBB) enabling the delivery of even large-molecule therapeutics to the central nervous system and offers great potential for treating multiple neurological disorders.…”