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

描述(申请人提供)：缺血性中风可以用化学或机械方法治疗，每种方法各有优缺点。组织纤溶酶原激活剂(TPA)是一种常见的血栓灭活剂，已被用于治疗血栓形成，但可能会导致大量出血，必须在症状出现后立即使用。机械方法可以快速恢复血流，但具有侵入性，可能会在血管壁上留下残余的血栓前物质，增加二次中风的风险。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。这种非侵入性的方法结合了药理和机械方法来清除血栓。在这里，溶液中的单个颗粒被注入血液中，在施加磁场后，自我组装成能够靶向纤溶剂的小型微型设备，并在没有导管的情况下机械地攻击血栓。由于微设备的组装和驱动力都是由外场提供的，一旦完成这一过程，设备就会“自我分解”成可由身体通过吞噬作用移除的小积木。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取栓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：确定胶体设备机械清除凝块的速度。我们将研究机械破碎的血块清除率与操作参数的函数关系，例如微流体血管模拟器中的微设备尺寸和自旋率。具体目标2：确定纤溶修饰的胶体微设备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，并展示它们在微流控血管模拟物中作为纤溶剂的用途。我们预计tPA的直接偶联将比单独的机械破坏更能提高溶解速度。目标3：演示体内环境中的设备组装和靶向。通过一个成熟的动物卒中模型，我们将演示磁性组件在血管闭塞部位的传递、组装和靶向。利用现有的小动物核磁共振成像设备，这些研究将为进一步研究提供必要的原则证据。

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.