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

项目摘要 下肢外周动脉疾病（PAD），由腿部动脉斑块积聚引起，影响 约占美国人口的10%。在严重的情况下，腿部正常血流的阻塞 会导致威胁肢体的缺血重度PAD通常需要手术干预，包括 血管成形术、血管支架术、动脉内膜切除术或动脉旁路术。最常见的故障模式 PAD的血管内动脉介入治疗是内膜增生，是对血管扩张的肥大反应。 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，外科手术后对抗内膜增生的主要工具是紫杉醇涂层 腔内药物洗脱支架和球囊。然而，紫杉醇涂层器械的使用与 与无涂层器械相比，死亡风险增加，FDA建议停止使用 2019年用于PAD的所有紫杉醇涂层器械。同样，FDA批准的药物西罗莫司已被证明， 安全有效地预防冠状动脉病变的再狭窄;然而，西罗莫司涂层支架 与血管血栓形成风险增加有关。因此，存在对更安全、更安全的设备的未满足的需求。 血管内输送装置，以对抗PAD治疗后的内膜增生。StemPlant LLC是 开发一种新型器械平台，外周血管血管成形术输送器械（PVADD）， 将西罗莫司和可能的其它后续治疗剂递送到外周动脉的内膜下空间。的 PVADD基于标准经皮腔内血管成形术球囊导管， 管状流体路径，其在球囊周围具有远端端口几何形状， 直接进入动脉壁。使用猪模型，我们先前已经证明了 该装置成功地将细胞输送到内膜下区域而不损伤或破坏动脉的功效。 在这一I期SBIR中，StemPlant建议开发一种PVADD，可与西罗莫司配对用于治疗 内膜增生和再狭窄的预防。他们将通过（1）建立一个全面的 符合FDA要求的将液体治疗剂直接输送至外周动脉血管系统的原型 指导，（2）使用猪模型评价液体药物在体内血管内递送的可行性， 作为西罗莫司的替代物，和（3）实现最终装置设计以准备验证构建。 完成拟议的SBIR第一阶段计划将使StemPlant进入统计动力第二阶段 在大型动物内膜增生模型中定量西罗莫司递送和评估西罗莫司疗效的研究 PVADD治疗内膜增生。

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.