Smart liquid embolic agent for dynamic adjustments to brain aneurysm embolization and healing

Brain aneurysms are pathological dilations that mostly form at branch points of the cerebral vasculature. More than 60% of aneurysms are currently treated with minimally invasive endovascular methods including endovascular flow diversion or the permanent implantation of metallic intrasaccular coils. However, current devices show unfavorable primary outcomes in 20-30% of cases and success rates are substantially lower depending on aneurysm type and location. In this project, we discuss the development of an injectable, multi-functional, reverse thermo-responsive, in situ cross-linkable, shape-conforming, intrasaccular porous scaffold that harnesses the unique behavior of a family of reverse thermo-responsive (RTR) polymers resulting in enhanced clinical performance. The aqueous solutions of these polymers display low viscosity at infa-physiological temperatures and are gels at 37 degrees. The device is an easily syringable, low viscosity multi-component aqueous solution comprising: [a] a cross-linkable RTR component that forms a robust and homogeneously porous scaffold for controlled intrasaccular thrombosis, [b] a leachable RTR-displaying component acting as the porogen, [c] an iodine-rich radiopaque agent, [d] a polymerizable (RGD)-containing oligopeptide that will in situ co-polymerize with the other components, aimed at accelerating the generation of an endothelial cell layer at the aneurysm neck, [e] inclusion of basic Fibroblast Growth Factor (bFGF) in the cross-linked component to promote thrombus organization and intrasaccular fibrosis/remodeling, and [f] a cross-linkable oligopeptide containing the matrix metalloprotease (MMP)- degradable leucine-glycine motif that will be in situ co-crosslinked with the RTR components, to impart to the polymer device to degrade in a personalized, patient-specific manner, as a function of the healing process. This process, representing a major step in aneurysm treatment, shortens treatment time, requires no chronic anti-platelet medications, promotes endothelialization of the parent-vessel interface, enhances aneurysm ‘sac’ fibrosis, and degrades in a patient-specific manner to leave no trace of the pathology or the treatment, with lower costs.