Flow Responsive Embolic Agent for the Complete Devascularization of Meningiomas

项目摘要 意义：脑膜瘤的术前栓塞（POE）是一种成熟的神经血管内手术 进行手术以减少肿瘤切除术期间发生的大量失血。目前的做法 由于目前用于非适应症的栓塞剂的有效性和安全性缺陷， 此指示（其中没有一个是专门为POE设计的）。聚乙烯醇颗粒使用最多 栓塞剂，但疗效数据提出了他们的临床效益的关注。Trufill和Onyx是液基栓塞剂 替代方案，但充满了自己的局限性。例如，Onyx含有有毒溶剂， 患者疼痛和不适，而Trufill相关的技术风险否定了其广泛采用 在美国因此，需要一种易于使用的、按标签使用的栓塞剂，该栓塞剂专门为POE设计 提供安全和完全的断流术。这样的栓塞会导致更快， 更安全的手术切除，代表脑膜瘤患者治疗的重大进展。 方法：在这个直接进入第二阶段SBIR的过程中，阿森纳医疗将推进其剪切稀化生物材料技术， 一种血流反应性栓塞剂（FRE），用于治疗脑膜瘤的POE。为了使POE有效、完整 脑膜瘤的血运阻断是需要的，这是通过完全闭塞所有远端血管来实现的， 肿瘤我们的I期研究结果表明，FRE的远端穿透力上级 商业液体栓塞剂，是生物相容的，并且可以通过神经血管手动注射， 微导管。该提案的目标是将概念验证公式推向产品 通过早期可行性研究（EFS）准备进行临床测试的配置， 商业化在目标1中，我们将最终确定输送系统，并与临床医生确认产品的可用性。 目标2将包括选择商业上可行的灭菌方法，然后确认产品 保质期将通过临床前研究确认FRE的生物相容性，以确定神经血管 响应和安全性（目标3）以及通过生物和化学进行的ISO 10993生物相容性试验 表征测定（目的4）。拟议的工作提供了一个基础数据集， 第二阶段后的活动，以推进商业化。 创新：FRE生物材料具有自适应特性，使其能够在高温下成为低粘度流体。 穿透并填充脑膜瘤远端血管的剪切。随着栓塞的进展， 剪切力将不断降低;作为响应，FRE的粘度逐渐增加，成为粘稠的糊状物 控制注射。结果是整个脉管系统的完全铸造和闭塞。相比其他 液体栓塞剂，FRE不太容易发生不完全闭塞，因为它的固化机制发生 独立于微环境。例如，玛瑙通过沉淀作用固化，形成坚硬的外层 可阻塞血管分支通路的壳体，防止其发生深血管栓塞。

PROJECT SUMMARY Significance: Pre-operative embolization (POE) of meningiomas is an established neuroendovascular procedure performed to reduce the extensive amount of blood loss that occurs during tumor resection. The current practice is significantly hampered because of efficacy and safety deficiencies of current embolic agents used off-label for this indication (none of which are designed specifically for POE). Polyvinyl alcohol particles are the most used embolic agent, but efficacy data raise concerns of their clinical benefit. Trufill and Onyx are liquid-based embolic alternatives but are fraught with limitations of their own. For example, Onyx contains toxic solvent that causes patient pain and discomfort while the technical risks associated with Trufill have negated its wide-spread adoption in the United States. Thus, there is a need for an easy-to-use, on-label embolic agent designed specifically for POE of meningiomas that provides safe and complete devascularization. Such an embolic would result in faster and safer surgical resection, representing a significant evolution in the treatment of meningioma patients. Approach: In this Direct to Phase II SBIR, Arsenal Medical will advance its shear-thinning biomaterial technology, a flow responsive embolic (FRE) agent, as a therapy for the POE of meningiomas. For POE to be effective, complete devascularization of the meningioma is desired, which is achieved by total occlusion of all distal vessels that supply the tumor. Our Phase I results have demonstrated that the FRE exhibits superior distal penetration compared to commercial liquid embolics, is biocompatible, and can be manually injected through a neurovascular microcatheter. The goal of this proposal is to advance the proof-of-concept formulation towards a product configuration that is ready for clinical testing via an early feasibility study (EFS), enabling an efficient path to commercialization. In Aim 1, we will finalize the delivery system and affirm the product’s usability with clinicians. Aim 2 will consist of selection of a commercially viable sterilization method, followed by confirmation of product shelf-life. Biocompatibility of the FRE will be confirmed via a pre-clinical study to determine the neurovascular response and safety (Aim 3) and ISO10993 biocompatibility testing through biological and chemical characterization assays (Aim 4). The proposed work provides a foundational data set that will be complemented with post-Phase II activities to advance towards commercialization. Innovation: The FRE biomaterial has adaptive properties enabling it to become a low viscosity fluid under high shear that penetrates and fills the distal vessels supplying the meningioma. As embolization progresses, flow and shear will continually decrease; in response, the FRE progressively increases in viscosity becoming a viscous paste for controlled injection. The result is complete casting and occlusion of the entire vasculature. Compared to other liquid embolics, the FRE is less susceptible to incomplete occlusion because its solidification mechanism occurs independent of its microenvironment. Onyx, for example, solidifies via a precipitation effect, forming a hard outer shell that can block vessel branch pathways preventing them from deep vessel embolization.