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: 10629368
• 负责人: Ramanathan Kadirvel
• 金额: $ 23.74万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629368
• 关键词: Acceleration; Acute; Address; Affect; Aneurysm; Arteries; Autologous; Biocompatible Materials; Biological; Blood; Blood Platelets; 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; Legal patent; 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; clinical translation; clinically relevant; first-in-human; healing; hemocompatibility; improved; improved outcome; in vivo; innovation; magnetic devices; magnetic field; metallicity; minimally invasive; mortality; multidisciplinary; next generation; novel; response; restoration; safety and feasibility; safety testing; side effect; standard of care; targeted delivery; targeted treatment; thrombogenesis; 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.

项目概要 该应用的重点是推进颅内血流导流领域的发展，该领域目前构成 大约三分之一的未破裂颅内动脉瘤的治疗。仍存在关键限制 阻碍这些转化设备临床应用扩展的技术，迄今为止 范围仅限于沿颈内动脉的未破裂近端动脉瘤。一个主要障碍是 与设备相关的血栓形成，可导致血栓性或栓塞性缺血性中风。这需要管理 双重抗血小板治疗具有严重的出血副作用。另一个主要障碍被推迟 愈合和动脉瘤闭塞，这妨碍了急性破裂动脉瘤的治疗，并且需要 长期抗血小板治疗。我们将通过以下方式打破这些扩大效用的障碍：1）开发一个 铁磁分流器可实现治疗剂的磁性靶向，2) 测试安全性和 通过自体内皮细胞的磁性靶向快速装置愈合的可行性。研究表明 动脉瘤颈部的内皮化对于长期完全动脉瘤闭塞和抗血小板治疗至关重要 可以安全地停止治疗。我们预计，通过我们提出的方法，我们将促进应用 用于治疗破裂动脉瘤和威利斯环远端动脉瘤的新型下一代设备，并将 最大限度地降低血栓栓塞风险。我们之前开发过磁性装置，包括支架、覆膜支架、 和血管移植物，并证明了它们捕获和保留磁性标记内皮细胞的能力。 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 分流器。我们稳健且可重复的统计评估方法将直接评估 1) 设备完整性 和功能，2) 设备生物相容性和血液相容性，3) 设备磁性，4) 磁性 细胞捕获并保留在装置上，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分流器的闭塞。由此得出的发现 假设驱动的、多学科的、临床转化研究将提供对 用于治疗颅内动脉瘤的分流器快速内皮化所带来的好处。目标是 这项研究的目的是减少与装置相关的血栓形成、长期抗血小板治疗相关的并发症发生率 治疗，以及动脉瘤延迟愈合和闭塞。如果成功的话，神经介入医生将能够使用 分流器可安全有效地治疗更广泛的动脉瘤。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。铁磁分流器还可以实现 其他治疗剂靶向递送的未来研究。例如，用于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以及用于局部化影响并减少影响的抗血小板治疗 全身性出血风险。此类研究有可能为颅内疾病的治疗带来变革。 通过显着改善当前的护理标准来治疗动脉瘤。