Bead-Based Approach for Combined Mechanical and Pharmacological Treatment of Acut

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DESCRIPTION (provided by applicant): Ischemic strokes can be treated with either chemical or mechanical means, each with advantages and disadvantages. Tissue plasminogen activator (tPA), a common clot buster, has been used to treat thrombotic clots but can lead to excessive bleeding and must be used soon after symptoms first occur. Mechanical methods can restore blood flow quickly but are invasive and can leave residual prothrombotic material on vessel walls, increasing risk for secondary stroke. To address these drawbacks, we propose a targeted delivery approach performed through an injectable colloidal solution controlled by an external magnetic field. This non-invasive approach combines pharmacological and mechanical methods for clot removal. Here, individual particles in solution are injected into the blood and, upon application of a magnetic field, self-assemble into small microdevices capable of targeting fibrinolytic agents and mechanically attacking a clot in the absence of catheters. As both microdevice assembly and driving forces are provided by the external field, once the procedure is finished, devices "self- disassemble" into small building blocks removable by the body via phagocytosis. We note that, as the approach is microscale in nature, it can be tuned to more carefully remove any prothrombotic residual clot that can arise in mechanical thrombectomies. Our aims include: Specific Aim 1: Determine the rate at which colloidal-based devices mechanically remove clots. We will investigate clot removal rate by mechanical disruption as a function of operating parameters such as microdevice size and spin-rate within microfluidic vascular mimics. Specific Aim 2: Determine the effectiveness with which fibrinolytic-modified colloidal microdevices can be used to enhance clot removal. Here, we will synthesize tPA-modified magnetic beads and demonstrate their use as fibrinolytic agents within microfluidic vascular mimics. We expect direct coupling of tPA to enhance dissolution rates over mechanical disruption alone. Aim 3: Demonstrate device assembly and targeting within in vivo environments. With a well-established animal stroke model we will demonstrate the delivery, assembly, and targeting of magnetic assemblies to the site of vascular occlusion. Imaged with available small animal MRI facilities, these studies will provide the necessary proof-of-principle for further investigations.