Computational and Biological Approach to Flow Diversion

项目摘要 该竞争性更新申请的重点是推进颅内血流导向（FD）领域， 目前约占未破裂颅内动脉瘤治疗的三分之一。那里 仍然是知识的关键差距，阻碍了这些转化的临床应用的扩展。 迄今为止，这些器械的范围仅限于沿颈内动脉沿着的未破裂的近端动脉瘤。 我们设想，通过我们提出的发现系统，我们将促进新的下一代 器械用于破裂动脉瘤和Willis环远端动脉瘤，并允许定制 最大限度地降低个体患者血栓栓塞风险的方法。我们将打破这些障碍， 通过1）了解动脉瘤闭塞的关键方面，例如急性和 穿过动脉瘤颈的适当纤维蛋白沉积，2）解开侧分支下方的机制 闭塞（即血液动力学的影响，或侧分支的新生内膜生长和内皮化 口，或两者），以及3）识别导致血栓栓塞风险升高的潜在风险因素 并发症，如血流动力学变量、器械贴壁不良、血小板功能和不良纤维蛋白 沉积在动脉瘤瘤颈之外，等等。我们建议采用创新方法， 体内血管内纤维蛋白分子成像、计算流体动力学建模和改进的动物模型 建模，最后在临床研究中发现生物标志物。这些方法可以改善 不仅是FD，而且通过更好地理解两者的机制， 动脉瘤愈合和并发症。我们强大的和可重复的统计评估方法将 直接评估1）动脉瘤颈部器械中纤维蛋白沉积速度的作用有助于稳健 2）肠系膜上上级动脉分支模拟动脉瘤通畅的适宜性和有效性 FD覆盖的小穿支血管，以及3）将生物学和成像数据与延迟 FD治疗后的缺血性事件。从这个假设驱动的，多学科的， 多模态，临床转化研究将提供一个强大的理解，不仅机制， FD在动脉瘤愈合中的作用，以及器械相关并发症的发生。这些 这些发现可以为临床医生使用当前技术提供指导，以优化结果并最大限度地减少 并发症，以及研究人员和工程师开发改进的设备。最终，这些信息 将允许神经介入医生在器械选择方面做出更明智的决定，从而改善 病人护理

PROJECT SUMMARY This competitive renewal application focuses on advancing the field of intracranial flow diversion (FDs), that currently constitutes approximately one-third of the treatment of unruptured intracranial aneurysms. There remain key gaps in the knowledge 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. We envision that, with our proposed discovery system, we will facilitate application of novel, next-generation devices in ruptured aneurysms and in aneurysms distal to the Circle of Willis, and will allow customization of approaches to minimize thromboembolic risk in individual patients. We will break down these barriers to expanded utility by 1) understanding of key aspects of aneurysm occlusion, such as the role of acute and appropriate fibrin deposition across the aneurysm neck, 2) unraveling the mechanisms underlying side branch occlusion (i.e. the impact of hemodynamic, or neointimal growth and endothelizalization across the side branch ostia, or both), and 3) identifying the potential risk factors that cause elevated risk of thromboembolic complications, such as hemodynamical variable, device malapposition, platelet function, and untoward fibrin deposition beyond the neck of the aneurysm, among others. We propose to employ innovative approaches in in vivo intravascular fibrin molecular imaging, computational fluid dynamics modeling, and improved animal modeling, and finally biomarker discovery in clinical studies. These approaches can improve the outcome of not only FD, but other devices in treating aneurysms by better understanding of the mechanisms of both aneurysm healing and complications. Our robust and reproducible methods of statistical evaluations will directly assess 1) the role of fibrin deposition rapidity in the device at the neck of the aneurysm aids robust aneurysm, 2) the suitability and validity of the superior mesenteric artery branches to simulate the patency of the small perforating vessels covered by FDs, and 3) correlate biological and imaging data with delayed ischemic events following FD therapy.The discoveries from this hypothesis-driven, multidisciplinary, multimodality, clinical-translational research will provide a robust understanding of not only the mechanism of action of FDs in aneurysm healing, but also the development of device-related complications. These discoveries can provide guidance to clinicians using current technologies to optimize outcomes and minimize complications, as well as investigators and engineers to develop improved devices. Ultimately, this information will allow neurointerventionalists to make better informed decisions on device choice, leading to improved patient care.