Developing Therapeutic Gel Embolic Agents for Arteriovenous Malformation Embolization

项目摘要 动静脉畸形（AVM）是一种动脉和静脉之间的异常连接， 正常的毛细血管循环，导致血管缠结，称为病灶。畸形导致过度的 静脉壁受到应力，并可能导致静脉应力过大而破裂。脑AVM尤其是 由于脑出血有最严重的并发症，包括癫痫发作和神经系统疾病， 赤字脑AVM破裂后的死亡率为12%-66.7%，23%-40%的存活者 严重残疾。此外，发现局部炎症是脑AVM进展的原因 和破裂因此，抗炎药物治疗可能是稳定脑AVM的一种可能。电流 脑AVM的治疗包括显微外科手术、栓塞和放射外科手术。在栓塞中， 这项工作的重点是，通过导管输送液体栓塞剂，以栓塞上游或AVM内 分流，旨在使静脉压恢复正常。栓塞AVM的主要挑战来自于 难以充分穿透致密、迂曲和低阻力病灶。近端闭塞 导致侧支血管的发展，促进血管生成。因此，阻塞病灶和 供血动脉是成功栓塞的关键。目前FDA批准的脑栓塞系统 AVM栓塞包括Onyx和氰基丙烯酸正丁酯。两者都是液体栓塞剂，经过液体- 一旦与血液接触，固体转变。它们预期从释放部位向远端行进，以穿透 良好的脉管系统尽管临床上可用，但这两种液体都有明显的缺点，不能作为治疗剂。 AVM的治疗。局限性包括有机溶剂的毒性、输送困难、被冲洗的危险 远离，缺乏广泛的血管尺寸阻断的通用性，没有内在的不透射线性，无法在X线上可视化， 射线和缺乏治疗方法。在本提案中，我们将开发凝胶栓塞剂作为微创平台 其具有生物相容性、可成像性、耐久性、止血性和抗炎性，以栓塞和稳定AVM。我们 认为含有天然交联剂京尼平的凝胶栓塞剂将1）提供穿透不同血管的灵活性， AVM几何形状/尺寸，2）增强栓塞AVM中凝块-凝胶系统的机械稳健性，以防止 迁移，和3）作为AVM稳定的抗炎治疗。在目标1中，我们将开发不同的 用于有效栓塞的凝胶组合物。在目标2中，我们将评估凝胶的机械性能、可注射性 和体外闭塞能力，以优化闭塞能力。最后，在目标3中，我们将研究生物学特性 使用相关细胞系进行生物安全性评价和治疗表征。成功 这项研究的完成将表明治疗性凝胶栓塞剂可以安全使用并有效闭塞 具有治疗特性。这项初步研究将为进一步在大型动物研究中进行体内试验奠定基础 使用临床相关的AVM模型。我们设想这种栓塞平台可以广泛传播， 其他应用，如静脉高压、动脉瘤和肿瘤栓塞。

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.