Development of a balloon angioplasty catheter capable of simultaneous endovascular delivery of liquid therapeutic agents into the vascular wall

项目总结 下肢外周动脉疾病(PAD)，由腿部动脉斑块积聚引起，影响 大约占美国人口的10%。在严重的情况下，这种对腿部正常血液流动的阻碍 会导致危及肢体的缺血。严重的PAD通常需要手术干预，包括 血管成形术、血管支架置入术、动脉内膜切除术或动脉搭桥术。最常见的故障模式是 血管内介入治疗PAD是一种血管肥大反应，即内膜增生。 导致再狭窄和血管功能不全症状复发的重建手术。直到 最近，紫杉醇涂层是治疗外科干预后内膜增生的主要工具。 腔内药物洗脱支架和球囊。然而，紫杉醇涂层装置的使用与 与没有涂层的设备相比，死亡风险增加，FDA发布了一项建议，停止使用这种设备 在2019年用于PAD的所有紫杉醇涂层设备中。同样，FDA批准的药物西罗莫司已被证明 在预防冠状动脉病变再狭窄方面是安全有效的；然而，西罗莫司涂层支架是 与血管血栓形成的风险增加有关。因此，对更安全的需求尚未得到满足 血管内给药装置，用于对抗PAD治疗后的内膜增生。StemPlants LLC是 开发一种新型设备平台--外周血管成形术输送装置(PVADD)，以直接 将西罗莫司和可能的其他后续治疗药物输送到外周动脉的内膜下间隙。这个 PVADD基于标准的经皮腔内血管成形术球囊导管，结合了独特的 球囊周围的管状流体通道具有设计用于输送液体治疗的远端端口几何形状 在气球充气时直接进入动脉壁。使用猪模型，我们之前已经演示了 这种装置在不损伤或破坏动脉的情况下成功地将细胞输送到内膜下区域的效果。 在这个第一阶段的SBIR中，StemPlant公司建议开发一种PVADD，它可以与西罗莫司配对治疗高血压 血管内膜增生与预防再狭窄。他们将通过(1)建立一个完全整合的 符合FDA的将液体治疗直接输送到外周动脉血管系统的原型 指南，(2)使用猪模型和评价体内液体药物血管内给药的可行性 作为西罗莫司的替代品，以及(3)完成最终的设备设计，为验证构建做准备。 拟议的SBIR第一阶段计划的完成将使StemPLANT在统计上获得动力的第二阶段 西罗莫司定量给药及评价西罗莫司疗效的大型动物血管内膜增生模型研究 PVADD用于治疗内膜增生症。

PROJECT SUMMARY Lower extremity peripheral artery disease (PAD), caused by the buildup of plaque in the leg arteries, affects approximately 10% of the American population. In severe cases, this obstruction of normal blood flow in the legs can cause limb-threatening ischemia. Severe PAD typically requires surgical intervention consisting of angioplasty, vascular stenting, endarterectomy, or arterial bypass. The most common failure mode of endovascular arterial interventions for PAD is intimal hyperplasia, a hypertrophic response to vascular reconstructive procedures that leads to restenosis and the return of vascular insufficiency symptoms. Until recently, the primary tools for combating intimal hyperplasia following surgical intervention were paclitaxel-coated intraluminal drug-eluting stents and balloons. However, the use of paclitaxel-coated devices was associated with an increased risk of death compared to uncoated devices, and the FDA issued a recommendation to halt the use of all paclitaxel-coated devices for PAD in 2019. Similarly, the FDA-approved drug sirolimus has been shown to be safe and effective in preventing restenosis in coronary artery lesions; however, sirolimus-coated stents are associated with an increased risk of vascular thrombosis. As a result, there is an unmet need for safer endovascular delivery devices to combat intimal hyperplasia following PAD treatment. StemPlant LLC is developing a novel device platform, the Peripheral Vascular Angioplasty Delivery Device (PVADD), to directly deliver sirolimus, and possibly other follow-on therapeutics, into the subintimal space of peripheral arteries. The PVADD, based on the standard Percutaneous Transluminal Angioplasty balloon catheter, incorporates unique tubular fluid paths peripherally around the balloon with distal port geometry designed to deliver liquid therapeutics directly into the arterial wall during balloon inflation. Using a swine model, we have previously demonstrated the efficacy of this device in successfully delivering cells to the subintimal area without injuring or destroying the artery. In this Phase I SBIR, StemPlant proposes to develop a PVADD that can be paired with sirolimus for treatment of intimal hyperplasia and prevention of restenosis. They will accomplish this by (1) establishing a fully integrated prototype for delivering liquid therapeutic directly to the peripheral artery vasculature in compliance with FDA guidance, (2) evaluating the feasibility of endovascular delivery of a liquid drug in vivo using a swine model and Fluorescite® as a proxy for sirolimus, and (3) achieving a final device design in preparation for validation builds. Completion of the proposed SBIR Phase I program will position StemPlant for a statistically powered Phase II study in a large animal intimal hyperplasia model to quantify sirolimus delivery and assess efficacy of the sirolimus PVADD to treat intimal hyperplasia.