Efficacy of Sonothrombolysis Using Microbubbles Produced by a Catheter-Based Microfluidic Device in a Rat Model of Ischemic Stroke.
Efficacy of Sonothrombolysis Using Microbubbles Produced by a Catheter-Based Microfluidic Device in a Rat Model of Ischemic Stroke.
复制标题
在缺血性中风大鼠模型中使用基于导管的微流体装置产生的微泡进行声溶栓的功效。
DOI：
10.1007/s10439-019-02209-0
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发表时间：
2019
影响因子：
3.8
通讯作者：
Hossack,JohnA
中科院分区：
文献类型：
--
作者：
Dixon,AdamJ;Li,Jun;Rickel,John-MarschnerRobert;Klibanov,AlexanderL;Zuo,Zhiyi;Hossack,JohnA
现有的急性缺血性卒中溶栓治疗的局限性促使开发了基于导管的方法，该方法不使用或使用低剂量的溶栓药物结合机械作用来溶解或提取血栓。超声溶栓可加速血栓溶解，即超声联合微泡造影剂和低剂量溶栓剂机械性破坏纤维蛋白网。在这项工作中，我们研究了导管导向超声溶栓在大鼠缺血性中风模型中的疗效。通过流动聚焦微流控装置在真实的时间中产生具有氮气核和非交联白蛋白壳的直径为10-20μm的微泡。微泡从位于颈内动脉的导管分配，直接输送到血栓闭塞的大脑中动脉，而超声通过颅骨给药，重组组织纤溶酶原激活剂（rtPA）通过尾静脉导管输注。本研究的结果表明，流动聚焦微流体装置可以小型化到与人体导管插入术兼容的尺寸，并且由高溶解度气体组成的大直径微泡可以安全地动脉内施用以提供超声溶栓治疗。此外，与无治疗相比，使用动脉内递送大微泡的超声溶栓使脑梗死体积减少约50%，显著改善24小时的功能性神经结局，并且与单独静脉rtPA治疗相比，允许rtPA剂量减少3.3倍（95%CI 1.8-3.8）。
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 drugs combined with a mechanical action to either dissolve or extract the thrombus. Sonothrombolysis accelerates thrombus dissolutionviathe application of ultrasound combined with microbubble contrast 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. Microbubbles of 10–20µm diameter with a nitrogen gas core and a non-crosslinked albumin shell were produced by a flow-focusing microfluidic device in real time. The microbubbles were 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 infusedviaa tail vein catheter. The results of this study demonstrate that flow focusing microfluidic devices can be miniaturized to dimensions compatible with human catheterization and that large-diameter microbubbles comprised of high solubility gases can be safely administered intraarterially to deliver a sonothrombolytic therapy. Further, sonothrombolysis using intraarterial delivery of large microbubbles reduced 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.