Rapidly healing flow diverters using magnetic cell targeting for intracranial aneurysm treatment

项目摘要 这项应用侧重于推进颅内血流分流领域，目前构成 约三分之一的未破裂颅内动脉瘤的治疗。仍然存在关键限制 到目前为止，阻碍这些变革性设备临床应用扩展的技术 范围仅限于沿颈内动脉的未破裂的近端动脉瘤。一个主要障碍是 设备相关血栓形成，可导致血栓形成或栓塞性缺血性中风。这需要管理 双重抗血小板治疗，有严重的出血副作用。另一个主要障碍被推迟了 愈合和动脉瘤闭塞，这排除了对急性破裂的动脉瘤的治疗，并需要 延长抗血小板治疗时间。我们将通过1)开发一种 铁磁流量分流器，以实现治疗剂的磁靶向和2)测试安全性和 自体内皮细胞磁靶向快速装置愈合的可行性。研究表明， 动脉瘤颈内皮化是长期完全闭塞动脉瘤和抗血小板治疗的关键 治疗可以安全地停止。我们设想，通过我们提出的方法，我们将促进应用 在破裂的动脉瘤和威利斯环远端的动脉瘤中使用新的下一代设备，并将 最大限度地减少血栓栓子的风险。我们之前已经开发了磁性设备，包括支架、支架移植物、 和血管移植物，并展示了它们捕获和保留磁性标记的内皮细胞的能力。 我们将把我们的磁性细胞靶向技术扩展到血流快速内皮化的应用 导流者。我们强大且可重现的统计评估方法将直接评估1)设备的完整性 和功能性，2)设备生物兼容性和血液兼容性，3)设备磁性，4)磁性 5)快速内皮化和动脉瘤形成的安全性和可行性 在活体动脉瘤模型中闭塞磁化内皮化血流分流装置。从这里得到的发现 假说驱动、多学科、临床-翻译研究将提供对 用于治疗颅内动脉瘤的分流装置的快速内皮化带来的好处。的目标是 这项研究是为了减少与设备相关的血栓形成、延长抗血小板药物的并发症发生率 治疗，以及延迟动脉瘤愈合和闭塞。如果成功，神经干预者将能够使用 流量分流装置可安全有效地治疗范围更广的动脉瘤。优化结果和最小化 并发症将显著改善患者的护理并拯救生命。铁磁分流装置也将使 未来对其他治疗剂的靶向递送的研究。例如，治疗快速动脉瘤的纤维蛋白 闭塞、用于快速愈合的间充质干细胞和抗血小板治疗以定位影响和减少 系统性出血风险。这样的研究有可能在治疗颅内疾病方面产生变革。 在目前护理标准的基础上有了显著改进，从而减少了动脉瘤的风险。

Project Summary This application focuses on advancing the field of intracranial flow diversion, that currently constitutes approximately one-third of the treatment of unruptured intracranial aneurysms. There remain key limitations to the technology that hinder expansion of the clinical application of these transformational devices, which to date are limited in scope to unruptured, proximal aneurysms along the internal carotid artery. One major barrier is device-related thrombosis, which can lead to thrombotic or embolic ischemic stroke. This requires administration of dual anti-platelet therapy, which has the serious side effect of bleeding. Another major barrier is delayed healing and aneurysm occlusion, which precludes treatment of acutely ruptured aneurysms and necessitates prolonged anti-platelet therapy. We will break down these barriers to expanded utility by 1) developing a ferromagnetic flow diverter to enable magnetic targeting of therapeutic agents and 2) testing the safety and feasibility of rapid device healing by magnetic targeting of autologous endothelial cells. Studies have shown that endothelialization of the aneurysm neck is critical for long term complete aneurysm occlusion and anti-platelet therapy can be safely discontinued. We envision that, with our proposed approach, we will facilitate application of novel, next-generation devices in ruptured aneurysms and in aneurysms distal to the Circle of Willis, and will minimize thromboembolic risk. We have previously developed magnetic devices including stents, stent-grafts, and vascular grafts and demonstrated their ability to capture and retain magnetically-labeled endothelial cells. We will extend our magnetic cell targeting technologies to the application of rapid endothelialization of flow diverters. Our robust and reproducible methods of statistical evaluation will directly assess 1) device integrity and functionality, 2) device biocompatibility and hemocompatibility, 3) device magnetic properties, 4) magnetic cell capture and retention to the devices, and 5) safety and feasibility of rapid endotheliazation and aneurysm occlusion of magnetically endothelialized flow diverters in an in vivo aneurysm model. The discoveries from this hypothesis-driven, multidisciplinary, clinical-translational research will provide a robust understanding of the benefits conferred by rapid endothelization of flow diverters used to treat intracranial aneurysms. The goal of this research is to reduce the complication rate associated with device-related thrombosis, prolonged anti-platelet therapy, and delayed aneurysm healing and occlusion. If successful, neurointerventionalists will be able to use flow diverters to treat a broader range of aneurysms safely and effectively. Optimizing outcomes and minimizing complications will significantly improve patient care and save lives. A ferromagnetic flow diverter will also enable future investigations of targeted delivery of other therapeutic agents. For example, fibrin for rapid aneurysm occlusion, mesenchymal stem cells for rapid healing, and anti-platelet therapy to localize the effects and reduce systemic bleeding risk. Such investigations have the potential to be transformative in the treatment of intracranial aneurysms by significantly improving upon the current standard of care.