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， 正常的毛细血管循环，经常导致血管缠结，称为病灶。这种不正常的联系 导致动脉血直接向静脉循环的高压分流， 静脉壁静脉受压过度可能会扩大，拉伸，并最终破裂，导致灾难性的 流血了虽然AVM的病因可能是先天性或创伤性的，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，当 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人， 由于合并症或考虑到AVM的位置，认为切除风险太大而切除。在 这些患者以及存在急性出血的患者，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的，并且它们仅 批准在手术切除前用于CNS，以降低手术期间的出血风险。作为 因此，医生可以在标签外使用这些液体栓塞剂;它们用于 栓塞作为不能接受手术的患者和存在以下情况的患者的最终治疗： 急性出血这些液体栓塞剂（Onyx和Trufill）远非完美;它们可以再通 发生率高达36%，它们与注射过程中的泄漏相关，可能导致非靶向栓塞， 血管毒性和坏死的可能性。他们也是具有挑战性的交付，他们缺乏 通用性以阻断大范围的脉管系统尺寸，它们在使用前需要长时间的预处理（即， 涡旋30分钟），并且它们缺乏内在的射线不透性以在X射线上可视化。其管理要求 更有经验的操作者，因为不可预测的聚合可能导致非靶向栓塞;甚至更多 因此导管可能被截留在聚合的栓塞物内。虽然液体栓塞提供了 尽管开放手术修复具有许多优点，但这些缺点限制了它们的广泛使用。我们假设 使用生物工程凝胶栓塞材料（neuroGEM），该材料无毒、耐用（无再通）、 粘性（避免导管截留），更易于使用（手持式注射剂，无预处理， X光），我们将改变医疗实践的标准。我们的目标是在治疗上做出一个范式的转变 使用微创生物材料平台填充AVM血管系统的潜在致命性AVM 使用微导管和突破性的剪切变稀生物材料。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： 大鼠最后，在目标3中，我们将评价neuroGEM在猪AVM模型中的体内性能， 栓塞

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.