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

使用磁性细胞靶向治疗颅内动脉瘤的快速愈合分流器

• 批准号: 10508348
• 负责人: Ramanathan Kadirvel
• 金额: $ 21万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10508348
• 关键词: Acute; Address; Affect; Aneurysm; Arteries; Autologous; Biocompatible Materials; Biological; Blood; Blood flow; Catheters; Cells; Circle of Willis; Clinical; Clinical Research; Clinical Treatment; Complication; Coronary; Data; Devices; Distal; Elastases; Embolism; Endothelial Cells; Endothelium; Evaluation; Fibrin; Future; Goals; Hemorrhage; Impaired healing; Internal carotid artery structure; Intracranial Aneurysm; Investigation; Ischemic Stroke; Label; Lead; Life; Magnetic nanoparticles; Magnetism; Measures; Mechanics; Mesenchymal Stem Cells; Modeling; Morbidity - disease rate; Neck; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Parents; Patient Care; Persons; Preclinical Testing; Principal Investigator; Property; Reproducibility; Research; Research Proposals; Risk; Rupture; Ruptured Aneurysm; Safety; Side; Site; Stainless Steel; Statistical Methods; Stents; Surface; Techniques; Technology; Testing; Therapeutic Agents; Therapeutic Embolization; Thromboembolism; Thrombosis; Translational Research; Tubular formation; United States; Vascular Graft; Work; biomaterial compatibility; clinical application; clinically relevant; ferrite; first-in-human; healing; hemocompatibility; improved; improved outcome; in vivo; innovation; magnetic field; metallicity; minimally invasive; mortality; multidisciplinary; nanoparticle delivery; next generation; novel; response; restoration; safety and feasibility; safety testing; side effect; standard of care; targeted delivery; targeted treatment; thrombotic; translational approach

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.

项目摘要 该应用的重点是推进目前构成的颅内流动转移领域 大约三分之一的颅内动脉瘤治疗。仍然存在关键的局限 阻碍这些转型设备的临床应用扩展的技术，迄今为止 沿颈内动脉的近端，近端动脉瘤受到限制。一个主要障碍是 与装置相关的血栓形成，可能导致血栓形成或栓塞性缺血性中风。这需要管理 双重抗血小板疗法的出血严重副作用。另一个主要障碍是延迟 愈合和动脉瘤阻塞，这排除了急性破裂的动脉瘤的治疗 长时间的抗血小板治疗。我们将在1）开发一个扩展公用事业的障碍中分解这些障碍 铁磁流量分流器能够实现治疗剂的磁靶向和2）测试安全性和 自体内皮细胞的磁靶向快速装置愈合的可行性。研究表明 动脉瘤颈的内皮化对于长期完整动脉瘤闭塞和抗平台至关重要 可以安全地停止治疗。我们设想，通过我们提出的方法，我们将促进应用 新颖的下一代设备在破裂的动脉瘤和威利斯圆圈远端的动脉瘤中 最小化血栓栓塞风险。我们以前已经开发了包括支架，支架移植物，包括支架，支架， 和血管移植物，并证明了它们捕获和保留磁性标记的内皮细胞的能力。 我们将将磁性电池靶向技术扩展到流量快速内皮化的应用 分机。我们稳健和可重复的统计评估方法将直接评估1）设备完整性 2）设备生物相容性和血流相容性，3）设备磁性特性，4）磁性 细胞捕获和对设备的保留，以及5）快速内皮化和动脉瘤的安全性和可行性 体内动脉瘤模型中磁性内皮化流动器的闭塞。从中发现 假设驱动的，多学科的临床翻译研究将提供对 通过用于治疗颅内动脉瘤的流动分化器的快速内皮化所赋予的益处。目标 这项研究是为了降低与设备相关血栓形成相关的并发症率，较长的抗血域 治疗，并延迟动脉瘤愈合和闭塞。如果成功，神经干预主义者将能够使用 流动分流器可以安全有效地处理更广泛的动脉瘤。优化结果并最小化 并发症将显着改善患者护理并挽救生命。铁磁流量分流器也将启用 对其他治疗剂的有针对性递送的未来研究。例如，用于快速动脉瘤的纤维蛋白 闭塞，间质干细胞可快速愈合和抗血小板治疗，以定位影响并降低 系统性出血风险。这样的研究有可能在颅内治疗方面具有变革性 动脉瘤通过显着改善当前护理标准。