Rapid restoration of blood flow is critical in treating acute ischemic stroke. Current fibrinolytic therapies using tissue plasminogen activator (tPA) are limited by low recanalization rates and risks of off-target bleeding. Here, we present a strategy using tPA immobilized on micrometer-scale beads to enhance local plasmin generation. We synthesized tPA-functionalized beads of varying sizes (0.1 μm and 1.0 μm) and evaluated their efficacy. assays demonstrated that 1.0 μm tPA-beads generated higher plasmin generation compared to free tPA and 0.1 μm beads, overcoming antiplasmin inhibition and promoting a self-propagating wave of fibrinolysis. In a murine model of acute ischemic stroke, intravenous administration of 1.0 μm tPA-beads at doses nearly two orders of magnitude lower than the standard free tPA dose led to rapid and near-complete thrombus removal within minutes. This approach addresses kinetic and transport limitations of current therapies and may reduce the risk of hemorrhagic complications.
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| http://dx.doi.org/10.1101/2024.11.06.621942 | DOI Listing |
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