PROJECT SUMMARY This competitive renewal application focuses on advancing the rapidly-evolving field of intracranial flow diversion, which, over the span of less than 5 years, has grown to encompass up to one-third of intracranial aneurysm treatments in the US. We will address clinically-relevant, ongoing gaps in knowledge, including 1) what constitutes the primary mechanism of action of flow diverter efficacy, 2) what underlies the unusual, but devastating complications, including ipsilateral, intraparenchymal hemorrhage and spontaneous aneurysm rupture, and 3) what design features of these devices can be enhanced to optimize outcomes? Our translational, hypothesis-driven methodology traverses from computational/in vitro work (computational fluid dynamics and in vitro bioreactor studies) to in vivo experiments in a rabbit model and, finally, to clinical studies. Our statistically robust evaluations will directly address 1) the role of wall apposition in aneurysm healing and risk for complication, 2) downstream hemodynamic derangements caused by flow diverter implantation vis-à- vis risk for spontaneous hemorrhage, and 3) the relative impact of diversion of flow versus other factors, including thrombus formation and endothelialization, in healing. The discoveries from this competitive renewal will be directly applicable to clinicians treating patients with currently-approved devices and managing patients following flow diversion treatment in order to optimize outcomes and minimize complications, as well as to engineers and scientists focused on developing idealized, future devices, even those with patient-specific, individualized features.