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

描述（由申请人提供）：缺血性中风可以用化学或机械方法治疗，每种方法都有优缺点。 组织纤溶酶原激活剂（tPA）是一种常见的凝块破坏剂，已用于治疗血栓性凝块，但可能导致过度出血，必须在症状首次出现后立即使用。 机械方法可以快速恢复血流，但具有侵入性，可能在血管壁上留下残留的血栓前物质，增加继发性卒中的风险。 为了解决这些缺点，我们提出了一种通过外部磁场控制的可注射胶体溶液进行靶向递送的方法。 这种非侵入性方法结合了药物和机械方法来清除凝块。 在这里，溶液中的单个颗粒被注射到血液中，并且在施加磁场时，自组装成能够靶向纤维蛋白溶解剂并在没有导管的情况下机械攻击凝块的小型微型装置。 由于微器件组装和驱动力都是由外部场提供的，一旦程序完成，器件就“自分解”成可由身体通过吞噬作用移除的小构建块。 我们注意到，由于该方法本质上是微尺度的，因此可以对其进行调整，以更仔细地清除机械血栓切除术中可能出现的任何血栓前残留凝块。 我们的目标包括：具体目标1：确定胶体器械机械清除凝块的速率。 我们将研究凝块去除率的机械破坏作为一个功能的操作参数，如微流体血管模拟内的微器件尺寸和旋转速率。 具体目标2：确定纤维蛋白溶解修饰的胶体微器械可用于增强凝块清除的有效性。 在这里，我们将合成tPA修饰的磁珠，并证明其作为纤维蛋白溶解剂在微流体血管模拟。 我们预期tPA的直接偶联比单独的机械破坏提高溶解速率。 目的3：证明器械组装和体内环境中的靶向。 我们将通过一个完善的动物中风模型，证明磁性组件的输送、组装和靶向血管闭塞部位。 这些研究将利用现有的小动物MRI设备进行成像，为进一步研究提供必要的原理证明。

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.