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）是一种常见的凝块抑制剂，已被用于治疗血栓性凝块，但可导致过度出血，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液流动，但具有侵入性，并且可能在血管壁上留下残留的血栓原物质，增加继发性中风的风险。为了解决这些缺点，我们提出了一种通过由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去除血栓。在这里，将溶液中的单个颗粒注射到血液中，在磁场的作用下，自组装成能够靶向纤维蛋白溶解剂的小型微型装置，并在没有导管的情况下机械地攻击血块。由于微设备的组装和驱动都是由外部场提供的，一旦这个过程完成，设备就会“自我拆卸”成小的积木，通过吞噬作用被身体移除。我们注意到，由于该方法本质上是微尺度的，它可以更仔细地去除机械血栓切除术中可能出现的任何血栓前残留血栓。我们的目标包括：具体目标1：确定以胶体为基础的装置机械去除血块的速度。我们将研究在微流体血管模拟物中，通过机械破坏来去除凝块的速率，作为操作参数的函数，如微器件尺寸和自旋速率。特定目的2：确定纤溶酶修饰胶体微装置用于增强血块清除的有效性。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。我们期望tPA的直接偶联可以提高溶解速率，而不是单独的机械破坏。目标3：在体内环境中演示设备组装和靶向。通过一个完善的动物中风模型，我们将展示磁性组件的传递、组装和靶向血管闭塞部位。利用现有的小动物核磁共振成像设备进行成像，这些研究将为进一步的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.