Magnetically propelled microwheels for rapid thrombolysis in small arteries

用于小动脉快速溶栓的磁力驱动微轮

• 批准号: 10457816
• 负责人: DAVID WM MARR
• 金额: $ 49.38万
• 依托单位: COLORADO SCHOOL OF MINES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457816
• 关键词: 3-Dimensional; Accounting; Acute; Affect; Alteplase; Arteries; Biochemical; Blood Cells; Blood Platelets; Blood Vessels; Blood flow; Catheters; Cause of Death; Cell Size; Cerebral hemisphere hemorrhage; Cessation of life; Coagulation Process; Complex; Data; Deep Vein Thrombosis; Development; Devices; Diffuse; Diffusion; Drug Delivery Systems; Excision; Fibrin; Fibrinolysis; Geometry; Goals; Grant; Health; Hemorrhage; Hour; Human; Injectable; Intervention; Intravenous; Ischemia; Ischemic Stroke; Larva; Lead; Magnetic Resonance Imaging; Magnetism; Measures; Mechanics; Mediating; Methods; Microfluidics; Mission; Modeling; Motor; Mus; Neurodegenerative Disorders; Neurological outcome; Neurons; Outcome; Pathology; Penetration; Phagocytosis; Public Health; Pulmonary Embolism; Reperfusion Therapy; Research; Resolution; Risk; Safety; Site; Speed; Stroke; Symptoms; System; Testing; Therapeutic; Thrombectomy; Thrombus; Time; United States; United States National Institutes of Health; Work; Zebrafish; artery occlusion; base; cerebral microvasculature; cerebrovascular; improved; improved outcome; in vivo; in vivo imaging; innovation; magnetic beads; magnetic field; mechanical force; microCT; microdevice; mouse model; neurobehavioral; novel; particle; physical model; scale up; stroke model; thrombolysis; thrombotic; thrombotic complications

Project Summary: In small vessel stroke (SVS), which accounts for 20% of ischemic strokes, tissue plasminogen activator (tPA) is ineffective because it can take a prohibitively long time to diffuse to the clot, and catheter-based thrombectomy devices cannot access small vessels. Moreover, treatment associated hemorrhaging limits tPA use to within a few hours of the onset of symptoms for all ischemic strokes. As a result, there is an urgent need for strategies that overcome these limitations, particularly in SVS, while reducing the risks associated with tPA. Building on a successful previous work, a drug delivery strategy is proposed that can selectively target small artery occlusions and deliver mechanical force to accelerate thrombolysis. The objective of this proposal is to investigate and test within realistic models an approach where injected, dispersed magnetic beads are assembled into blood cell sized microwheels (µwheels) capable of targeting occlusive clots located in small vessels and lysing them with a combination of mechanical and biochemical action. The central hypothesis is that µwheels can (i) target occluded small arteries by exploiting the low flow regions at the entrance of these vessels, (ii) achieve reperfusion at rates an order-of-magnitude faster than soluble tPA, and (iii) improve outcomes in murine models of stroke. This hypothesis will be tested with the following specific aims: Aim 1. Identify magnetic field conditions for µwheels targeting of occlusions. µWheels will be assembled in flowing blood and directed to occluded channels or vessels. Microfluidic, zebrafish, and 3D human cerebrovascular models will be used to test the assembly and targeting. Aim 2. Determine rates for thrombolysis of occlusive thrombi using tPA functionalized µwheels. It is postulated that tPA functionalized µwheels can dissolve fibrin- and platelet-rich clots within microfluidic models and achieve reperfusion in zebrafish and 3D human cerebrovascular models, at rates significantly faster than soluble tPA. Aim 3. Measure the functional benefit of µwheel thrombolysis in vivo. In comparison to soluble tPA, µwheel mediated thrombolysis will improve safety, motor, and neurological outcomes in murine stroke models and can be visualized using high-resolution MRI and micro-CT. In Aims 1 and 2 the expected outcomes are identifying the operating conditions for µwheel assembly, targeting, and fibrinolysis that provide faster reperfusion compared to tPA and can be scaled-up to human-size vascular networks. In Aim 3, it will be shown that µwheel thrombolysis is a superior strategy to systemic administration of tPA in terms of neurobehavioral outcomes in a stroke model and can be imaged in vivo. This approach is significant because it could lead to the development of a more rapid and less invasive strategy for alleviating ischemia than methods currently available. This approach is innovative because of the use of external magnetic fields to propel fibrinolytic microdevices to the sites of occlusion and provide mechanical action to accelerate reperfusion time compared to systemic administration of tPA.

项目摘要：在小血管中风（SVS）中，占缺血性，组织的20％ 纤溶酶原激活剂（TPA）无效，因为可能需要长时间的时间才能扩散到凝块，并且 基于传统的血栓切除术设备无法进入小容器。而且，相关的治疗 出血限制TPA在所有缺血性中风的症状发作后的几个小时内使用。 结果，迫切需要策略克服这些限制，尤其是在SV中，同时还要减少 与TPA相关的风险。在成功的先前工作的基础上，提出了一种药物输送策略 可以选择性地靶向小动脉闭塞并传递机械力以加速溶栓。这 该建议的目的是在现实模型中调查和测试一种注射的方法， 分散的磁珠组装成能够靶向的血细胞大小的微角度（µWHEEL） 位于小容器中的闭合凝块，并与机械和生化的组合将它们裂开 行动。中心假设是µWheels可以（i）通过利用低流量来阻塞小动脉 这些船只入口处的区域，（ii）以比率的速度达到速度的速度快于 可溶性TPA和（iii）改善了中风模型的结果。该假设将通过 以下特定目的：目标1。识别瞄准遮挡的磁场条件。 µWHEELS 将在流动的血液中组装，并针对堵塞的通道或容器。微流体，斑马鱼和 3D人脑血管模型将用于测试组件和靶向。目标2。确定费率 使用TPA功能化µWheels对闭塞血栓的溶栓。假设TPA功能化 µWheels可以在微流体模型中溶解纤维蛋白和富含血小板的凝块，并在 斑马鱼和3D人脑血管模型的速度明显比实心TPA快得多。目标3。测量 µ轮溶栓在体内的功能益处。与实心TPA相比，µ轮介导 溶栓将改善鼠卒中模型中的安全性，运动和神经系统结果，可以是 使用高分辨率MRI和Micro-CT可视化。在目标1和2中，预期的结果正在确定 µ轮组件，靶向和纤维蛋白溶解的工作条件可提供更快的再灌注 到TPA，可以扩展到人类大小的血管网络。在AIM 3中，将显示µWHEEL 溶栓是根据神经行为预后的TPA进行全身管理TPA的超级策略 中风模型，可以在体内成像。这种方法很重要，因为它可能导致发展 比目前可用的方法，一种减轻缺血的更快，侵入性更少的策略。这 方法是创新的，因为使用外部磁场将纤维蛋白水解的微论述推向 与全身性相比 TPA的管理。

项目成果

Reconfigurable microbots folded from simple colloidal chains

• DOI: 10.1073/pnas.2007255117
• 发表时间: 2020-07
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Tao Yang;Brennan Sprinkle;Yang Guo;Jun Qian;D. Hua;A. Donev;D. Marr;Ning Wu

Breaking the fibrinolytic speed limit with microwheel co-delivery of tissue plasminogen activator and plasminogen.

• DOI: 10.1111/jth.15617
• 发表时间: 2022-03
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Disharoon D;Trewyn BG;Herson PS;Marr DWM;Neeves KB
• 通讯作者: Neeves KB

Multimodal microwheel swarms for targeting in three-dimensional networks.

• DOI: 10.1038/s41598-022-09177-x
• 发表时间: 2022-03-24
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Zimmermann CJ;Herson PS;Neeves KB;Marr DWM
• 通讯作者: Marr DWM

Paddlebots: Translation of Rotating Colloidal Assemblies near an Air/Water Interface

Paddlebots：空气/水界面附近旋转胶体组件的平移

• DOI: 10.1021/acs.langmuir.3c00701
• 发表时间: 2023
• 期刊: Langmuir
• 影响因子: 3.9
• 作者: Wolvington, E.;Yeager, L.;Gao, Y.;Zimmermann, C.J.;Marr, D.W.M.
• 通讯作者: Marr, D.W.M.

Magnetically Powered Chitosan Milliwheels for Rapid Translation, Barrier Function Rescue, and Delivery of Therapeutic Proteins to the Inflamed Gut Epithelium.

• DOI: 10.1021/acsomega.3c00886
• 发表时间: 2023-03-28
• 期刊: ACS OMEGA
• 影响因子: 4.1
• 作者: Osmond, Matthew J.;Korthals, Elizabeth;Zimmermann, Coy J.;Roth, Eric J.;Marr, David W. M.;Neeves, Keith B.
• 通讯作者: Neeves, Keith B.