Application of acoustic cavitation for thrombolysis in stroke

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DESCRIPTION (provided by applicant): EKOS Micro-infusion(r) system is an ultrasound-tipped microcatheter well characterized for use in enhancing drug transport into clots. We propose to modify the EKOS microcatheter by incorporating a Cavitation Promoting Surface (CPS). The overall goal of this project is to demonstrate feasibility of incorporating CPS in the microcatheter and obtaining significant enhancement in bioefficacy, in-vitro and in-vivo. The acoustic field emitted from the catheter tip will be used for active induction of cavitation from a CPS on the catheter tip while infusing the drug (t-PA, Activase(r)) directly in the immediate clot volume surrounding the catheter. Our specific aims are: 1. Investigate and incorporate CPS into the microcatheter device: We will identify and characterize the surface of materials that promote cavitation. These materials will then be exposed to ultrasound to learn acoustic parameters that consistently induce cavitation in blood. The CPS will be incorporated in the current microcatheter design and evaluated for thrombogenecity in vivo. 2. Determine bioefficacy in-vitro and in-vivo using CPS-incorporated microcatheter for t-PA delivery: The CPS-incorporated microcatheter will be tested for bioefficacy in-vitro and in-vivo. In-vitro testing will include well-established dynamic clot model that measures thrombolysis. Following demonstration of significant enhancement of thrombolysis by in-vitro tests, in-vivo bioefficacy tests will be conducted. An autologous clot will be formed in a canine basilar artery. t-PA will be delivered into the clot using current and CPS-incorporated microcatheters and exposed to ultrasound. At the end of therapy, time to recanalization determined angiographically will be used to determine bioefficacy. Acute Ischemic Strokes occur due to blockage of an artery in the brain by a blood clot. In ischemic stroke faster restoration of nutrient blood flow greatly improves patient's chances of survival with minimum brain damage and reduced burden of neurologic deficits. Intravenously administered t-PA (tissue plasminogen activator) within 3 hours of symptom onset is the only currently approved stroke therapy. We believe in combination with Intravenous administration, intra-arterial delivery of t-PA at the site of thromboocclusion in presence of ultrasound intensities sufficient to generate intrinsic cavitation can enhance the transport of drug into clots and shorten time to reperfusion of ischemic tissue. This approach holds the potential to improve clinical outcomes in stroke therapy.