Flow Acceleration for Stroke Thrombolysis (FAST) System

急性缺血性中风(AIS)是由神经血管中的血块引起的，是导致 在美国，死亡是神经性残疾的第一大原因。AIS影响超过70万人 美国人每年死亡或严重残疾的几率为65%。到2030年，预计AIS 仅在美国，经济负担就将超过1800亿美元。 标准护理AIS疗法包括使用FDA批准的溶栓剂阿替普酶(即， 组织纤溶酶原激活剂)在卒中发病4.5小时内，最早-可能的大血栓切除术 血管闭塞(24小时结束)。与血栓切除术不同，溶栓治疗不需要确认 血管闭塞。因为只有大约10%的AIS患者有资格接受血栓切除术，溶栓治疗仍然是一种 关键的第一线工具，治疗那些被诊断为AIS的人。当采用溶栓治疗时，溶栓治疗与 中风预后改善约15%，完全恢复约10%。然而，由于~7%的剂量依赖性 阿尔替普酶、溶栓治疗的相关出血率对于轻度和觉醒的中风是禁忌的， 加在一起约占所有AIS活动的60%。由于安全问题和有限的可靠性，溶栓的使用 在美国，这一比例仍然很低(约10%)，90%的AIS患者只接受姑息治疗。那里仍然有一个 迫切需要改善溶栓治疗的第一线使用，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Alteplase到达阻塞 血凝块，从而克服已知的限制血流动力学，阻止阿尔替普酶快速到达 遮挡。所提出的磁性输液平台通过1)辅助输送克服了这一障碍 阿尔替普酶到达血栓表面的速度比正常生物扩散快100倍以上(即几分钟比几小时)， 2)在凝块表面机械混合阿尔替普酶，使溶解更可靠。因为阿尔替普酶是 不是共轭的，作用模式本质上是纯机械的，FDA会议确认了CDRH IDE 路径适合支持FDA的早期可行性研究，这是一种更短、更便宜的研究 与CDER IND过程相比，这是一条新的途径。重要的是，该技术是负担得起的，不需要精确 调焦，可以配置为与在医院之间转院进行血栓切除术的患者一起旅行。一次 使用目前FDA批准的Alteplase标签被证明是安全有效的，UNANUP打算扩大 通过增加小剂量阿尔替普酶的溶栓效果来溶栓治疗轻度和清醒的中风 以引起出血。如果成功，溶栓治疗可以安全地扩大到所有70万AIS患者 第一次，这是目前治疗的10倍。该项目的目标包括1)建立磁力输液器 子部件(磁性工作站、二氧化硅包覆铁纳米颗粒、纳米颗粒输送系统)和 进行2)作用机制，3)体内安全性，以及4)凝块相互作用研究。所获得的数据 提议的努力对于在FDA早期可行性研究集成开发环境之前解决FDA的担忧至关重要。

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.