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

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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.