Osmond Matthew J, Dabertrand Fabrice, Quillinan Nidia, Su Enming J, Lawrence Daniel A, Marr David W M, Neeves Keith B
Department of Bioengineering, University of Colorado Denver | Anschutz Medical Campus.
Department of Anesthesiology, University of Colorado Anschutz Medical Campus.
bioRxiv. 2024 Nov 8:2024.11.06.621942. doi: 10.1101/2024.11.06.621942.
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.
快速恢复血流在急性缺血性中风治疗中至关重要。目前使用组织型纤溶酶原激活剂（tPA）的纤维蛋白溶解疗法受限于低再通率和非靶向出血风险。在此，我们提出一种策略，即使用固定在微米级珠子上的tPA来增强局部纤溶酶生成。我们合成了不同尺寸（0.1μm和1.0μm）的tPA功能化珠子并评估其疗效。实验表明，与游离tPA和0.1μm珠子相比，1.0μm的tPA珠子产生更高的纤溶酶生成，克服了抗纤溶酶抑制并促进了纤维蛋白溶解的自传播波。在急性缺血性中风的小鼠模型中，静脉注射剂量比标准游离tPA剂量低近两个数量级的1.0μm tPA珠子，在数分钟内导致血栓快速且几乎完全清除。这种方法解决了当前疗法的动力学和转运限制，并可能降低出血并发症的风险。
