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

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Abstract

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 dissolution via the 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 10–20 µm 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 infused via a 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.

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Acknowledgments

Partial support for this research is provided by the National Institutes of Health under NIH Grants S10 RR025594 and R01 HL141752 to JAH and by a NSF GRFP fellowship to AJD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or NSF.

Author Contributions

AJD, JAH, ZZ conceived of study. AJD wrote main manuscript text. AJD, JMRR, JL conducted experiments and analyzed data. JAH, ALK, and ZZ supervised the study and all authors reviewed the manuscript.

Conflict of Interest

Authors AJD and JAH are inventors listed on an issued patent (US Patent No. 9895,158) that relates to some aspects of the content of this study.18

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA

    Adam J. Dixon, John-Marschner Robert Rickel, Alexander L. Klibanov & John A. Hossack

  2. Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, VA, USA

    Jun Li & Zhiyi Zuo

  3. Cardiovascular Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA

    Alexander L. Klibanov

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  1. Adam J. Dixon
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  2. Jun Li
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Correspondence to John A. Hossack.

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Associate Editor Agata A. Exner oversaw the review of this article.

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Dixon, A.J., Li, J., Rickel, JM.R. et al. Efficacy of Sonothrombolysis Using Microbubbles Produced by a Catheter-Based Microfluidic Device in a Rat Model of Ischemic Stroke. Ann Biomed Eng 47, 1012–1022 (2019). https://doi.org/10.1007/s10439-019-02209-0

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