Biomaterials for embolization and ablation of arterio-venous malformations

用于动静脉畸形栓塞和消融的生物材料

• 批准号: 10645123
• 负责人: Rahmi Oklu
• 金额: $ 68.28万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645123
• 关键词: Ablation; Acute; Age Years; Angiography; Animals; Anticoagulants; Anticoagulation; Arteries; Arteriovenous fistula; Arteriovenous malformation; Atrial Fibrillation; Biocompatible Materials; Biomedical Engineering; Blood; Blood capillaries; Brain; Bypass; Catheters; Central Nervous System; Circulation; Coagulation Process; Coupled; Data; Dimensions; Ensure; Etiology; Excision; Extravasation; FDA approved; Family suidae; Formulation; Gel; Geometry; Hematology; Hemorrhage; Hemostatic Agents; Histologic; Human; Image; Immune response; Impairment; In Vitro; Injectable; Injections; Label; Left; Liquid substance; Liver; Location; Lung; Mechanics; Medical; Methods; Modeling; Modification; Morbidity - disease rate; Necrosis; Neurofibrillary Tangles; Operative Surgical Procedures; Patients; Pelvis; Performance; Persons; Physicians; Polymers; Positioning Attribute; Prevalence; Property; Rattus; Resected; Risk; Risk Factors; Rodent; Roentgen Rays; Rupture; Safety; Series; Serology; Stress; Stretching; Structure; Symptoms; Testing; Therapeutic Effect; Therapeutic Embolization; Thinness; Time; Veins; Venous; Vertebral column; Visualization; Warfarin; Writing; X-Ray Computed Tomography; age group; biomaterial compatibility; comorbidity; experience; femoral artery; in vitro Model; in vitro testing; in vivo; microCT; minimally invasive; mortality; perfusion imaging; polymerization; pressure; repaired; ultrasound

Abstract Arteriovenous malformation (AVM) is an abnormal connection between an artery and a vein that bypasses the normal capillary circulation, often resulting in a tangle of vessels called a nidus. This abnormal connection causes high-pressure shunting of arterial blood directly to the venous circulation, placing excessive stress on the venous wall. Overstressed veins may enlarge, stretch, and eventually rupture leading to catastrophic bleeding. While AVMs can be congenital or traumatic in etiology, they can occur anywhere in the body (e.g., brain, spine, liver, pelvis and lung); however, they are associated with the highest morbidity and mortality when they occur in the central nervous system (CNS). For treatment, most patients are not surgical candidates for resection either because of comorbidities or it is deemed too risky to resect given the location of the AVM. In these patients, and in patients that present with acute bleeding, endovascular embolization is the preferred method of treatment. However, current FDA approved embolics are of the liquid type and they are only approved for use in the CNS prior to surgical resection to reduce bleeding risk during surgery. As a consequence, physicians are left in a position to use these liquid embolics off-label; they are used for embolization as the definitive treatment in those that cannot receive surgery and in those patients that present with acute bleeding. These liquid embolics (Onyx and Trufill) are far from perfect; they have recanalization rates of up to 36%, they are associated with leakage during injection that can cause non-target embolization, angiotoxicity and the possibility of necrosis. They are also challenging to deliver, they lack the universality to block wide range of vasculature sizes, they require lengthy pre-treatment prior to use (i.e., vortex for 30 min) and they lack intrinsic radiopacity for visualization on X-ray. Its administration requires more experienced operators as unpredictable polymerization may lead to nontarget embolization; even more concerning, the catheter can become entrapped within the polymerized embolic. While liquid embolics offer advantages over open-surgical repair, these drawbacks limit their widespread use. We hypothesize that by using a bioengineered gel embolic material (neuroGEM) that is non-toxic, durable (no recanalization), non- adhesive (avoiding catheter entrapment), and easier to use (hand-held injectable, no pretreatment, visible on X-ray), we would change the standard of medical practice. We aim to make a paradigm shift in the treatment of potentially fatal AVMs using a minimally invasive biomaterial-based platform to fill AVM vasculature using microcatheters with groundbreaking shear-thinning biomaterials. In Aim 1, we will develop neuroGEM compositions for effective AVM embolization. In Aim 2, we will evaluate the therapeutic effect of neuroGEM in rats. Finally in Aim 3, we will evaluate the performance of neuroGEM in vivo in porcine AVM model of embolization.

抽象的 动脉畸形（AVM）是动脉和静脉之间的异常联系 正常的毛细血管循环，通常导致一系列称为Nidus的血管。这种异常连接 导致高压动脉血直接直接向静脉循环造成 静脉墙。压力过高的静脉可能会扩大，伸展并最终破裂，导致灾难性 流血。尽管AVM在病因学上可能是先天性或创伤性的，但它们可以发生在体内的任何地方（例如， 大脑，脊柱，肝脏，骨盆和肺）；但是，它们与当时的发病率和死亡率最高有关 它们发生在中枢神经系统（CNS）中。对于治疗，大多数患者不是手术候选者 切除要么是由于合并症，要么被认为太冒险了，无法在AVM的位置下切除。在 这些患者以及出现急性出血的患者，血管内栓塞是首选 治疗方法。但是，当前FDA批准的栓塞是液体类型，它们仅是 在手术切除之前批准用于中枢神经系统，以降低手术期间出血风险。作为 结果，医生的位置可以在标签外使用这些液体栓塞。他们被用来 在无法接受手术的患者和出现的患者中，栓塞是确定的治疗 急性出血。这些液体栓塞（Onyx和Trufill）远非完美。他们有重新定性 高达36％的速率与注射过程中的泄漏有关，可能导致非目标栓塞， 血管毒性和坏死的可能性。他们也充满挑战，他们缺乏 阻止各种脉管系统尺寸的通用性，它们需要在使用之前进行冗长的预处理（即 涡旋持续30分钟），它们缺乏X射线可视化的固有放射性。它的管理要求 经验丰富的操作员作为不可预测的聚合可能会导致非目标栓塞。更 关于，导管可能被夹在聚合栓塞中。虽然液体栓塞提供 优于开放性维修的优点，这些缺点限制了它们的广泛使用。我们通过 使用无毒，耐用（无重新配置）的生物工程凝胶栓塞材料（神经） 粘合剂（避免导管夹带），并且易于使用（可手持注射，没有预处理，可见 X射线），我们将改变医疗实践的标准。我们的目的是在治疗中改变范式 使用微创生物材料平台填充AVM脉管系统的潜在致命AVM 使用带有开创性剪切稀释生物材料的微心理器。在AIM 1中，我们将发展神经元 有效AVM栓塞的组成。在AIM 2中，我们将评估Neurogem的治疗作用 老鼠。最终，在AIM 3中，我们将评估猪的猪AVM模型中神经元在体内的性能 栓塞。