Developing Therapeutic Gel Embolic Agents for Arteriovenous Malformation Embolization

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.