Preclinical testing of a 3D printed external scaffold device to prevent vein graft failure after coronary bypass graft surgery

3D 打印外部支架装置预防冠状动脉搭桥手术后静脉移植失败的临床前测试

• 批准号: 10385132
• 负责人: Alison L Marsden
• 金额: $ 34.51万
• 依托单位: BIOGRAFT, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385132
• 关键词: 3-Dimensional; 3D Print; Address; Animal Model; Animal Testing; Animals; Bilateral; Biocompatible Materials; Biomedical Engineering; Caliber; Cardiac; Chronic; Clinical; Clinical Research; Collaborations; Contralateral; Coronary Arteriosclerosis; Coronary Artery Bypass; Coronary Circulation; Coronary Vessels; Data; Data Analyses; Data Set; Development; Device Designs; Devices; Diffuse; Disease; Doctor of Medicine; Doctor of Philosophy; Engineering; Failure; Follow-Up Studies; Foundations; Funding; Generations; Goals; Gold; Harvest; Heart; Histopathology; Human; Immunohistochemistry; Implant; In Vitro; International; Investments; Lead; Mechanics; Medical Device; Medical Device Designs; Methods; Modeling; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Patients; Performance; Pharmacology; Phase; Positioning Attribute; Postoperative Period; Preclinical Testing; Prevention; Printing; Procedures; Regulatory Pathway; Research; Research Personnel; Safety; Saphenous Vein; Secure; Sheep; Small Business Technology Transfer Research; Stenosis; Stimulus; Stress; Surgeon; Surgical Management; Techniques; Testing; Time; Tissues; Variant; Vein graft; base; biodegradable scaffold; clinical practice; commercialization; design; elastomeric; first-in-human; follow-up; graft failure; hemodynamics; human study; immunogenic; improved; in vivo; in vivo evaluation; mechanical load; mechanical stimulus; mortality; multimodal data; next generation; novel; pre-clinical; preclinical study; preservation; pressure; prevent; professor; prototype; response; scaffold; sheep model; standard care; success

Saphenous vein graft (SVG) failure following coronary artery bypass grafting (CABG) is a critical clinical problem, with recent studies revealing that as many as 25% of vein grafts develop stenosis within 12-18 months after surgery, and up to 50% of grafts occlude within 5-10 years. CABG surgery is the gold standard treatment for patients with severe multi-vessel disease, with over 370,000 procedures performed annually in the U.S. and SVGs are used in 95% of cases. Identification of strategies and devices to prevent SVG failure represents a pressing unmet clinical need. BioGraft will address this unmet need by developing an external biodegradable scaffold device to prevent SVG failure. It is well established that mechanical loading contributes to the cellular and structural changes leading to SVG failure. In current clinical practice, when the SVG is harvested and implanted into the coronary circulation, it is subjected to an abrupt change in mechanical loading (20X change in pressure, 4X change in flow-induced shear), triggering SVG wall remodeling and, often, maladaptation and failure. Our foundational R01-funded research, which laid the scientific foundation for the founding of BioGraft, showed that gradual increases in loading could mitigate or even eliminate graft failure. We demonstrated this concept in vivo, showing more favorable graft adaptation with a first-generation design in an ovine model. Here, to achieve a design that can be manufactured at scale, we propose a next-generation 3D printed biodegradable scaffold, which we will refine and test in this proposal. To achieve our goals, we propose three specific aims. In Aim 1, we will screen 3D-printed design candidates with ex vivo testing and degradation studies. This will allow us to efficiently and inexpensively select designs matching desired targets. In Aim 2, we will perform pre-clinical testing of the scaffold device in an established ovine carotid-jugular interpositional vein graft model of CABG surgery. This will establish preliminary safety and efficacy. In Aim 3, we will characterize device performance using mechanical testing and histopathology. These data will enable follow up fundraising, development of a commercialization plan and initiation of FDA discussions. BioGraft’s founding team leverages a long-standing engineering and clinical collaboration and recent partnerships with renowned investigators at Stanford and Duke who hold IP for unique bioabsorbable materials and bring expertise in rapid 3D printing manufacturing methods. We see a potential annual $1.6B total addressable market for the proposed device.

冠状动脉旁路移植术(CABG)后的大隐静脉移植(SVG)失败是一个严重的临床问题。 最近的研究表明，多达25%的静脉移植物在移植后12-18个月内发生狭窄 手术，高达50%的移植物在5-10年内闭塞。冠脉搭桥术是治疗急性心肌梗塞的金标准 患有严重多支血管疾病的患者，在美国每年进行超过37万例手术， 95%的病例使用了SVG。确定防止SVG故障的策略和设备代表 迫切需要未得到满足的临床需求。BioGraft将通过开发一种外部可生物降解的材料来解决这一未得到满足的需求 脚手架装置，防止SVG故障。众所周知，机械负荷对细胞 以及导致SVG故障的结构变化。在目前的临床实践中，当采集SVG和 植入冠脉循环后，会受到机械负荷的突然变化(变化20倍 在压力方面，流动诱导剪切的4倍变化)，触发SVG室壁重塑，通常是适应不良和 失败了。我们由R01资助的基础性研究为BioGraft的成立奠定了科学基础， 结果表明，逐渐增加负荷可以减轻甚至消除移植物衰竭。我们演示了这一点 概念在体内，表现出更有利的移植物适应与第一代设计在绵羊模型。这里, 为了实现可规模化制造的设计，我们提出了下一代3D打印生物可降解材料 脚手架，我们将在本提案中对其进行完善和测试。为了实现我们的目标，我们提出了三个具体目标。在……里面 目标1，我们将通过体外测试和降解研究来筛选3D打印设计候选者。这将允许 美国以高效和廉价的方式选择与预期目标匹配的设计。在目标2中，我们将进行临床前 支架装置在已建立的绵羊颈-颈静脉间置静脉移植模型中的测试 做手术。这将确立初步的安全性和有效性。在目标3中，我们将描述设备性能 使用机械测试和组织病理学。这些数据将使后续筹款、制定 商业化计划和发起FDA的讨论。BioGraft的创始团队利用长期的 工程和临床合作以及最近与斯坦福大学和杜克大学著名研究人员的合作 他们拥有独特的生物可吸收材料的知识产权，并带来了快速3D打印制造方法的专业知识。 我们预计，拟议中的设备每年的潜在市场总额将达到16亿美元。