Developing Therapeutic Gel Embolic Agents for Arteriovenous Malformation Embolization

项目总结

PROJECT SUMMARY Arteriovenous malformation (AVM) is an abnormal connection between an artery and vein that bypasses the normal capillary circulation, resulting in a tangle of vessels called a nidus. The malformation results in excessive stress on the venous wall, and can cause the rupturing of overstressed veins. Brain AVMs are particularly concerning since brain hemorrhage has the most severe complications, including seizures and neurologic deficits. The mortality rate after brain AVM rupture ranges from 12%-66.7%, and 23%-40% of survivors have significant disability. Furthermore, localized inflammation is found to be responsible for brain AVM progression and rupture. Anti-inflammatory drug therapy may, therefore, be a possibility to stabilize brain AVMs. Current treatment for brain AVMs includes microsurgery, embolization and radiosurgery. In embolization, which is the focus of this work, liquid embolic agents are delivered through catheters to embolize upstream or within the AVM shunt, aiming to return venous pressure to normal. The main challenge in embolizing AVMs stems from the difficulty involved with adequately penetrating the dense, tortuous and low resistance nidus. Proximal occlusion leads to the development of collateral vessels, promoting angiogenesis. Therefore, blockage of both nidus and the feeding arteries is essential for successful embolization. Current FDA approved embolic systems for brain AVM embolization include Onyx and n-butyl cyanoacrylate. Both are liquid embolic agents that undergo liquid- solid transition once in contact of blood. They are intended to travel distally from the site of release to penetrate fine vasculature. Despite clinical availability, both liquids have significant drawbacks and cannot serve as curative treatment of AVM. Limitations include toxicity from organic solvents, difficulty in delivery, danger of being washed away, lack of universality to block wide range of vasculature sizes, no intrinsic radiopacity for visualization on X- ray, and lack of therapeutics. In this proposal, we will develop gel embolic agent as a minimally invasive platform that is biocompatible, imageable, durable, hemostatic and anti-inflammatory to embolize and stabilize AVMs. We posit that gel embolic agents containing natural crosslinker, genipin, will 1) offer flexibility to penetrate different AVM geometries/sizes, 2) enhance mechanical robustness of the clot-gel system in embolized AVMs to prevent migration, and 3) serve as an anti-inflammatory therapy for AVM stabilization. In Aim 1, we will develop different gel compositions for effective embolization. In Aim 2, we will evaluate the gel’s mechanical properties, injectability and in vitro occlusion ability to optimize occlusion capability. Lastly in Aim 3, we will study the biological properties of the gels in vitro using relevant cell lines for biosafety evaluation and therapeutic characterization. Successful completion of this study will show that therapeutic gel embolic agents can be used safely and occlude effectively with therapeutic characteristics. This pilot study will set the stage for further in vivo testing in large animal studies using clinically relevant AVM models. We envision that this embolization platform can be widely disseminated to other applications, such as venous hypertension, aneurysms, and tumor embolization.