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 该应用程序的重点是推进颅内血流导向领域，目前构成 约占未破裂颅内动脉瘤治疗的三分之一。仍然存在关键限制， 阻碍这些转换装置临床应用扩展的技术， 局限于沿着颈内动脉沿着的未破裂的近端动脉瘤。一个主要障碍是 器械相关血栓形成，可能导致血栓性或栓塞性缺血性卒中。这需要行政管理 双重抗血小板治疗，有严重的出血副作用。另一个主要障碍是延迟 愈合和动脉瘤闭塞，这妨碍了急性破裂动脉瘤的治疗， 长期抗血小板治疗。我们将打破这些障碍，以扩大效用1）开发一个 铁磁分流器，以实现治疗剂的磁性靶向，以及2）测试安全性， 通过磁靶向自体内皮细胞实现快速器械愈合的可行性。研究表明 动脉瘤颈的内皮化对于长期完全动脉瘤闭塞和抗血小板至关重要 可以安全地停止治疗。我们设想，通过我们提出的方法， 新一代器械用于破裂动脉瘤和Willis环远端动脉瘤， 最大程度降低血栓栓塞风险。我们之前已经开发了磁性装置，包括支架，支架移植物， 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。 我们将把我们的磁性细胞靶向技术扩展到血流的快速内皮化应用中， 转移者我们稳健且可重复的统计评价方法将直接评估1）器械完整性 2）器械生物相容性和血液相容性，3）器械磁性，4）磁性 细胞捕获和保留到装置，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血流导向装置的闭塞。从中得到的发现 假设驱动，多学科，临床转化研究将提供一个强大的理解， 用于治疗颅内动脉瘤的血流导向装置的快速内皮化带来的益处。的目标 本研究旨在降低与器械相关血栓形成相关的并发症发生率， 治疗和延迟动脉瘤愈合和闭塞。如果成功，神经介入医生将能够使用 血流导向装置可安全有效地治疗更广泛的动脉瘤。优化成果， 并发症将显著改善患者护理并挽救生命。铁磁分流器还将使 其他治疗剂的靶向递送的未来研究。例如，纤维蛋白用于快速动脉瘤 闭塞，用于快速愈合的间充质干细胞，以及抗血小板治疗，以定位效应并减少 全身出血风险。这些研究有可能在颅内肿瘤的治疗中起到革命性的作用。 通过显著改善当前的护理标准来治疗动脉瘤。