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）后的隐静脉移植（SVG）失败是一个关键的临床问题， 最近的研究表明，多达 25% 的静脉移植物在术后 12-18 个月内出现狭窄 手术，5-10 年内高达 50% 的移植物闭塞，CABG 手术是治疗的金标准。 患有严重多血管疾病的患者，在美国每年进行超过 370,000 例手术 95% 的情况都使用 SVG 识别防止 SVG 故障的策略和设备。 BioGraft 将通过开发外部可生物降解的药物来解决这一未满足的需求。 防止 SVG 失效的支架装置 众所周知，机械负荷有助于细胞的生长。 在当前的临床实践中，当 SVG 被收获和使用时，结构变化会导致 SVG 失效。 植入冠状循环后，它会受到机械负荷的突然变化（20X变化 压力变化，流动引起的剪切力的 4 倍变化），引发 SVG 壁重塑，并且通常会导致适应不良和 我们由 R01 资助的基础研究为 BioGraft 的成立奠定了科学基础， 表明逐渐增加负载可以减轻甚至移植消除失败。 体内概念，在绵羊模型中显示出更有利的移植适应性与第一代设计， 为了实现可大规模制造的设计，我们提出了下一代 3D 打印可生物降解的材料 为了实现我们的目标，我们提出了三个具体目标。 目标 1，我们将通过离体测试和降解研究来筛选 3D 打印设计候选方案。 我们将高效且廉价地选择符合所需目标的设计。在目标 2 中，我们将进行临床前研究。 支架装置在已建立的羊颈动脉-颈间静脉移植冠状动脉搭桥术模型中的测试 这将确定初步的安全性和有效性。在目标 3 中，我们将表征设备的性能。 使用机械测试和组织病理学，这些数据将有助于后续筹款和开发。 BioGraft 的商业化计划和发起的创始团队利用了长期的经验。 工程和临床合作以及最近与斯坦福大学和杜克大学的才华横溢的专家的合作伙伴关系 他们拥有独特生物可吸收材料的知识产权，并带来快速 3D 打印制造方法的专业知识。 我们认为所提议的设备每年潜在的潜在市场总额为 1.6B 美元。