A stroke occurs every 40 seconds and is a leading cause of long-term disabilities and the 5th leading cause of death for Americans. Although ischemic strokes account for the majority (~87%) of incidents of stroke, hemorrhagic strokes, or strokes as a result of bleeding from a ruptured or weakened blood vessel, account for ~40% of stroke-related deaths1. These statistics are terrifying for those diagnosed with intracranial aneurysms (ICAs) as in most cases the risk of treatment with a mechanical device far outweighs the risk of conservative monitoring. With very little known about the cellular mechanisms that contribute aneurysm growth in the brain and limited means to detect changes in growth, clinicians are left with the complex decision of how to manage patient care. My goal is to probe the mechanisms that govern the progression of ICAs and begin to develop a less invasive therapeutic option using a new in vitro model system. Current animal models either utilize the peripheral vasculature, which lacks anatomical similarities to intracranial vessels, or are implemented in rodents, which limit the testing of clinical grade, catheter-based therapeutics. We are currently validating a canine model of ICA that addresses these issues that will be complete at the start of this fellowship. As animal models are expensive, time intensive and therefore challenging to utilize for parameter optimizations that require large sample sizes, it is also crucial to develop an in vitro model of ICA. This proposal seeks to develop such a model and utilize the model to optimize parameters for delivery of a therapeutic intended to blunt inflammation and stabilize the vessel wall. To this end, we will use biomaterials surface modification, 3D printing and 4D-flow magnetic resonance imaging (MRI) to develop and validate a patient-specific model of ICA that aims to recapitulate the mechanical properties of the blood vessels, to impose patient-specific blood flow profiles (as determined by collaborators) and to incorporate endothelial cells to study mechanisms of endothelial cell activation (Aim 1). This model will allow us to test therapeutics that target the mechanisms of aneurysm progression, mainly therapies designed to quench endothelial cell activation. This leads to Specific Aim 2, which will utilize the in vitro model to optimize and test the potential of mesenchymal stem cells to stabilize endothelial cells within the aneurysmal sac. This research will lay the foundation for more complex in vitro models that are informed by patient data, and will also lead to preclinical and clinical trials of less invasive therapeutics for ICAs. The end goal is to provide clinicians and patients with better options for safely treating those affected with this devastating disease and to provide researchers with a new platform for studying ICA dynamics. The proposed work will be accompanied by a training plan designed specially for me that includes extensive education in neuroscience with a focus on neurovascular pathology via didactic lectures, supplemented with clinical and hands on training with a neurosurgical team, weekly case presentations, and surgical observation.
Here we propose to develop a patient specific in vitro model of intracranial aneurysm to test the consequences of disrupted flow patterns on endothelial cell activation, a suspected contributor to aneurysm development and progression. This will be followed by the delivery and optimization of a stem cell (mesenchymal stem cell) therapy to stop endothelial cell activation within the aneurysm. Completion of these aims will provide us with a novel model system to 1) better understand the development and progression of intracranial aneurysm, so that 2) new, less invasive, avenues of treatment that target the mechanisms of aneurysm formation can be evaluated in terms of safety and efficacy.
