Biomaterials for embolization and ablation of arterio-venous malformations

摘要 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，常导致血管缠结，称为坏死灶。这种不正常的连接 导致动脉血液的高压分流直接进入静脉循环，对 静脉壁。压力过大的静脉可能会扩张、拉伸，最终破裂，导致灾难性的后果 在流血。虽然动静脉畸形在病因上可能是先天性的或创伤性的，但它们可以发生在身体的任何地方(例如， 脑、脊柱、肝脏、骨盆和肺)；然而，在以下情况下，它们的发病率和死亡率最高 它们发生在中枢神经系统(CNS)。对于治疗，大多数患者不是外科手术的候选对象 切除要么是因为合并疾病，要么是考虑到动静脉畸形的位置，认为切除风险太大。在……里面 这些患者以及出现急性出血的患者首选血管内栓塞术。 治疗方法。然而，目前FDA批准的栓塞剂是液体类型的，它们只是 在手术切除前被批准用于中枢神经系统，以降低手术中出血的风险。作为一名 结果，医生可以在标签外使用这些液体栓塞剂；它们用于 栓塞术作为不能接受手术的患者和存在的患者的最终治疗 并伴有急性出血。这些液体栓塞剂(玛瑙和特鲁菲尔)远非完美；它们有再通的作用。 高达36%的发生率，它们与注射过程中的渗漏有关，这可能导致非靶点栓塞， 血管毒性和坏死的可能性。他们也很难交付，他们缺乏 广泛性以阻断广泛的血管大小，它们在使用之前需要长时间的预处理(即， 涡流30分钟)，在X射线上显示时缺乏固有的射线不透明度。它的管理部门要求 更有经验的操作员，因为不可预测的聚合可能会导致非靶点栓塞；甚至更多 值得注意的是，导管可能会卡在聚合的栓塞物中。而液体栓塞剂提供了 与开放手术修复相比，这些缺点限制了它们的广泛使用。我们假设，通过 使用无毒、耐用(无再通)、无血管再通的生物工程凝胶栓塞剂(NeuGEM) 粘合剂(避免导管卡住)，更易于使用(手持注射，无需预处理，可见 X光)，我们会改变医疗实践的标准。我们的目标是实现治疗模式的转变 使用基于生物材料的微创平台填充动静脉畸形血管的潜在致命动静脉畸形 使用具有突破性剪切变稀生物材料的微导管。在目标1中，我们将开发神经GEM 有效的动静脉畸形栓塞术组合物。在目标2中，我们将评估神经GEM对小鼠的治疗效果。 老鼠。最后，在目标3中，我们将评估神经GEM在猪AVM模型中的体内表现。 栓塞术。

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.