Developing Therapeutic Gel Embolic Agents for Arteriovenous Malformation Embolization

开发用于动静脉畸形栓塞治疗的凝胶栓塞剂

• 批准号: 10667726
• 负责人: Jingjie Hu
• 金额: $ 7.2万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667726
• 关键词: Acute; Address; Adhesives; Alcohols; Alginates; Aneurysm; Animal Model; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Arteries; Arteriovenous malformation; Biocompatible Materials; Biological; Biomedical Engineering; Blood; Blood Vessels; Blood capillaries; Brain; Brain hemorrhage; Bypass; Cardiovascular system; Catheters; Cell Line; Cerebral hemisphere hemorrhage; Characteristics; Circulation; Clinical; Coagulation Process; Contrast Media; Crosslinker; Cyanoacrylates; Defect; Development; Dimethyl Sulfoxide; Distal; Drug Carriers; Drug Delivery Systems; Engineering; Ensure; Ethylenes; Evaluation; Exhibits; FDA approved; Failure; Family suidae; Fibrinolysis; Fluoroscopy; Formulation; Gel; Geometry; Growth; Headache; Hemorrhage; Hemostatic Agents; Hypertension; In Vitro; Inflammation; Inflammatory Response; Injectable; Injections; Intracranial Hemorrhages; Iohexol; Liquid substance; Magnetic Resonance Imaging; Mechanics; Medical; Microsurgery; Modeling; Morbidity - disease rate; Nature; Neurofibrillary Tangles; Neurologic Deficit; Organic solvent product; Penetration; Performance; Pharmacotherapy; Pilot Projects; Plasma; Polymers; Property; Radiosurgery; Recurrence; Research Support; Resistance; Risk Reduction; Roentgen Rays; Rupture; Safety; Seizures; Shunt Device; Site; Solid; Solvents; Stress; Survivors; System; Testing; Therapeutic; Therapeutic Embolization; Thinness; Thrombus; Time; Tissues; Toxic effect; Travel; Veins; Venous; Venous Pressure level; Visualization; Work; X ray visualization; angiogenesis; biomaterial compatibility; brain arteriovenous malformations; clinically relevant; cost; curative treatments; design; disability; experience; feeding; flexibility; genipin; imaging agent; imaging modality; in vivo evaluation; malformation; mechanical properties; microCT; migration; minimally invasive; mortality; polymerization; prevent; regenerative; stem; thrombogenesis; tumor

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.

项目总结 动静脉畸形(AVM)是动脉和静脉之间的异常连接，绕过 正常的毛细血管循环，导致血管缠绕，称为病灶。畸形导致过度 对静脉壁施加压力，并可导致压力过大的静脉破裂。脑动静脉畸形特别是 由于脑出血有最严重的并发症，包括癫痫发作和神经学 赤字。脑动静脉畸形破裂后的死亡率为12%-66.7%，23%-40%的幸存者有 严重残疾。此外，局部炎症被发现是脑AVM进展的原因。 和破裂。因此，抗炎药物治疗可能是稳定脑动静脉畸形的一种可能性。当前 脑动静脉畸形的治疗包括显微手术、栓塞术和放射外科手术。在栓塞方面，这是 这项工作的重点是通过导管输送液体栓塞剂，以在动静脉畸形上游或内部进行栓塞。 分流，旨在使静脉压恢复正常。动静脉畸形栓塞术的主要挑战来自于 难以充分穿透致密、曲折、低阻的病灶。近端咬合 导致侧支血管发育，促进血管生成。因此，病灶和结节的堵塞 供血动脉对于成功的栓塞术是必不可少的。目前FDA批准的脑部栓塞剂 动静脉畸形栓塞术包括玛瑙和氰基丙烯酸正丁酯。两者都是液体栓塞剂，都会经历液体- 一旦与血液接触，就会发生固态转变。它们的目的是从释放地点向远方行进以穿透 细小的血管结构。尽管临床上可以使用，但这两种液体都有明显的缺点，不能起到治愈的作用。 动静脉畸形的治疗。限制因素包括有机溶剂的毒性、运送困难、洗涤危险。 远离，缺乏通用性来阻挡广泛的血管大小，在X线上没有内在的射线不透明。 雷，以及缺乏治疗方法。在这项提案中，我们将开发凝胶栓塞剂作为微创平台 这是生物相容的，可成像，耐用，止血和消炎，以栓塞和稳定动静脉动静脉畸形。我们 假设含有天然交联剂京尼平的凝胶栓塞剂将1)提供弹性以穿透不同的 动静脉动静脉畸形的几何形状/大小，2)增强血栓-凝胶系统在栓塞动静脉畸形中的机械稳健性，以防止 迁移，以及3)作为动静脉畸形稳定的抗炎疗法。在目标1中，我们将制定不同的 有效栓塞剂的凝胶组合物。在目标2中，我们将评估凝胶的机械性能、可注射性 以及体外封闭能力，以优化封闭能力。最后，在目标3中，我们将研究其生物学特性 利用相关细胞系对凝胶进行体外生物安全性评价和疗效表征。成功 这项研究的完成将表明，治疗性凝胶栓塞剂可以安全有效地闭塞。 具有治疗特征的。这项初步研究将为进一步在大型动物研究中进行活体试验奠定基础。 使用临床相关的AVM模型。我们设想，这种栓塞剂平台可以广泛传播到 其他应用，如静脉高压、动脉瘤和肿瘤栓塞术。