Flow Acceleration for Stroke Thrombolysis (FAST) System

急性缺血性卒中（AIS）是由神经血管系统中的血凝块引起的，是脑卒中的第五大原因。 死亡和神经系统残疾的第一大原因在美国（US）。AIS影响超过70万人 美国人每年有65%的机会死亡或严重残疾。预计到2030年， 仅在美国，经济负担就将超过1800亿美元。 AIS标准治疗包括使用FDA批准的血栓溶解剂阿替普酶（即， 组织纤溶酶原激活剂），并尽早进行血栓切除术， 血管闭塞（超过24小时）。与血栓切除术相反，溶栓不需要确认血栓形成。 血管闭塞。因为只有~10%的AIS患者适合血栓切除术，溶栓仍然是一种治疗方法。 关键的第一线工具，以治疗那些诊断为AIS。当使用时，溶栓与 卒中结局改善约15%，完全恢复约10%。然而，由于约7%的剂量依赖性 阿替普酶的相关出血率，溶栓禁忌用于轻度和唤醒卒中， 占所有AIS事件的约60%。由于安全性问题和有限的可靠性， 在美国，这一比例仍然很低（~10%），90%的AIS患者仅接受姑息治疗。仍存在 迫切需要改善溶栓的一线使用，这可以扩大到所有AIS患者。 UNandUP发明了一种新的溶栓平台，可以安全地加速阿替普酶到达阻塞部位。 血凝块，从而克服已知阻止阿替普酶快速到达 闭塞。所提出的磁性输注平台通过以下方式克服了这一障碍：1）连续输送 阿替普酶到达凝块表面的速度比正常生物扩散快100倍以上（即，分钟对小时）， 和2）在凝块表面机械混合阿替普酶，使得溶解更可靠。因为阿替普酶是 未结合，作用方式纯粹是机械性的，FDA会议确认了CDRH IDE 这一途径适合于支持FDA早期可行性研究，这是一种更短、更便宜的途径。 与CDER IND工艺相比，重要的是，该技术是负担得起的，不需要精确的 聚焦，并且可以被配置为与在医院之间转移的患者一起旅行以进行血栓切除术。一旦 使用目前FDA批准的阿替普酶标签证明安全有效，UNANDUP打算扩大 通过增加较小剂量阿替普酶的溶栓疗效，对轻度和清醒卒中进行溶栓， 以诱发出血。如果成功，溶栓可以安全地扩展到所有70万AIS患者， 第一次，比目前治疗的高10倍。该项目的目标包括：1）建立磁注入 子组件（磁性工作站、二氧化硅涂覆的铁纳米颗粒、纳米颗粒递送系统），以及 进行2）作用机制，3）体内安全性和4）血凝块相互作用研究。所得数据 在FDA早期可行性研究IDE之前，拟议的工作对于解决FDA的问题至关重要。

Acute ischemic stroke (AIS) results from a blood clot in the neurovasculature and is the 5th leading cause of death and 1st leading cause of neurological disability in the United States (US). AIS impacts more than 700,000 Americans annually, with a 65% chance of death or severe disability. By 2030, it is expected that the AIS economic burden will exceed $180B in the US alone. Standard of care AIS therapies include the use of the FDA approved thrombolytic agent alteplase (i.e., tissue plasminogen activator) within 4.5 hours of stroke onset and earliest-possible thrombectomy for large vessel occlusions (out to 24hrs). In contrast to thrombectomy, thrombolysis does not require confirmation of a vessel occlusion. Because only ~10% of AIS victims are eligible for thrombectomy, thrombolysis remains a critical first line tool to treat those diagnosed with AIS. When employed, thrombolysis is associated with a ~15% improvement in stroke outcomes with ~10% fully recovering. However, due to the ~7% dose-dependent associated hemorrhage rate of alteplase, thrombolysis is contraindicated for mild and wake-up strokes which together make up ~60% of all AIS events. Due to safety concerns and limited reliability, usage of thrombolysis in the US remains low (~10%) with 90% of all AIS victims receiving only palliative care. There remains an urgent need to improve first line use of thrombolysis which can be expanded to all AIS victims. UNandUP has invented a novel thrombolysis platform to safely accelerate alteplase to the obstructing blood clot, thereby overcoming the restrictive hemodynamics known to prevent alteplase from quickly reaching the occlusion. The proposed magnetic infusion platform overcomes this barrier by 1) adjunctively conveying alteplase to the clot’s surface more than 100X faster than normal biological diffusion (i.e., minutes vs. hours), and 2) mechanically mixing alteplase at the clot’s surface so that lysis is more reliable. Because alteplase is not conjugated and the mode of action is purely mechanical in nature, FDA meetings confirmed a CDRH IDE pathway is appropriate in support of an FDA Early Feasibility Study, which is a shorter and less expensive pathway compared to a CDER IND process. Importantly, the technology is affordable, does not require precise focusing, and can be configured to travel with patients transferred between hospitals for thrombectomy. Once proven safe and effective using current FDA approved alteplase labeling, UNandUP intends to expand thrombolysis to mild and wake up strokes by increasing the lysis efficacy of smaller alteplase doses known not to induce hemorrhage. If successful, thrombolysis could be safely extended to all 700,000 AIS victims for the first time, which is 10X more than currently treated. The project’s aims include 1) building the magnetic infusion subcomponents (magnetic workstation, silica coated iron nanoparticles, nanoparticle delivery system), and conducting 2) mechanism of action, 3) in vivo safety, and 4) clot interaction studies. Data obtained for the proposed effort will be critical to address FDA concerns in advance of an FDA Early Feasibility Study IDE.