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: 10502874
• 负责人: Rahmi Oklu
• 金额: $ 69.93万
• 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/10502874
• 关键词: Ablation; Acute; Age-Years; Angiography; Animals; Anticoagulants; Anticoagulation; Arteries; Arteriovenous fistula; Arteriovenous malformation; Atrial Fibrillation; Biocompatible Materials; Biomedical Engineering; Blood; Blood Circulation; Blood capillaries; Brain; Bypass; Catheters; Coagulation Process; Coupled; Data; Dimensions; Ensure; Etiology; Excision; Extravasation; FDA approved; Family suidae; Formulation; Gel; Geometry; Hand functions; Hematology; Hemorrhage; Hemostatic Agents; Histologic; Human; Image; Immune response; Impairment; In Vitro; Injectable; Injections; Label; Lead; Left; Liquid substance; Liver; Location; Lung; Mechanics; Medical; Methods; Modeling; Modification; Morbidity - disease rate; Necrosis; Neuraxis; Neurofibrillary Tangles; Operative Surgical Procedures; Patients; Pelvis; Performance; Persons; Physicians; Polymers; Positioning Attribute; Prevalence; Property; Rattus; 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; X-Ray Computed Tomography; age group; base; 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 动静脉畸形 (AVM) 是动脉和静脉之间绕过动脉的异常连接 正常的毛细血管循环，通常会导致血管缠结，称为病灶。这种连接异常 导致动脉血直接高压分流至静脉循环，对身体造成过度压力 静脉壁。压力过大的静脉可能会扩大、拉伸并最终破裂，导致灾难性的后果 流血。虽然动静脉畸形的病因可能是先天性或外伤性，但它们也可能发生在身体的任何部位（例如， 脑、脊柱、肝脏、骨盆和肺）；然而，当发生以下情况时，它们与最高的发病率和死亡率相关： 它们发生在中枢神经系统（CNS）中。对于治疗而言，大多数患者不适合手术治疗 由于合并症而需要切除，或者考虑到 AVM 的位置，切除风险太大。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。然而，目前 FDA 批准的栓塞剂是液体类型，并且它们仅 批准用于手术切除前的中枢神经系统，以减少手术期间的出血风险。作为一个 结果，医生只能在标签外使用这些液体栓塞药物；它们用于 栓塞作为无法接受手术的患者和存在症状的患者的最终治疗方法 伴有急性出血。这些液体栓塞剂（Onyx 和 Trufill）远非完美；他们有再通 发生率高达 36%，它们与注射期间的渗漏有关，可能导致非目标栓塞， 血管毒性和坏死的可能性。他们的交付也具有挑战性，他们缺乏 由于具有阻断各种脉管系统尺寸的通用性，因此它们在使用前需要长时间的预处理（即， 涡旋 30 分钟），并且它们缺乏 X 射线可视化的内在射线不透性。其管理要求 经验丰富的操作员，因为不可预测的聚合可能会导致非目标栓塞；更 值得注意的是，导管可能会陷入聚合栓塞中。虽然液体栓塞提供 尽管与开放手术修复相比具有优势，但这些缺点限制了其广泛使用。我们假设通过 使用无毒、耐用（无再通）、非生物工程凝胶栓塞材料 (neuroGEM) 粘合剂（避免导管卡住），更易于使用（手持式注射，无需预处理，可见于 X 射线），我们将改变医疗实践的标准。我们的目标是改变治疗模式 使用基于微创生物材料的平台填充 AVM 脉管系统可能致命的 AVM 使用具有突破性剪切稀化生物材料的微导管。在目标1中，我们将开发neuroGEM 用于有效AVM栓塞的组合物。在目标 2 中，我们将评估 NeuroGEM 在以下方面的治疗效果： 老鼠。最后，在目标 3 中，我们将评估 NeuroGEM 在猪 AVM 模型中的体内性能 栓塞。