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）后大隐静脉移植物（SVG）失效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。冠状动脉旁路移植术是金标准治疗， 严重多支血管疾病患者，美国每年进行超过370，000例手术， SVG在95%的情况下使用。识别防止SVG故障的策略和设备代表了 未满足的临床需求。BioGraft将通过开发一种外部可生物降解的 脚手架装置，以防止SVG故障。众所周知，机械负荷有助于细胞的生长。 以及导致SVG故障的结构变化。在当前的临床实践中，当SVG被采集并且 植入冠状动脉循环后，它会受到机械负荷的突然变化（20倍变化 在压力，4倍的变化，在流动引起的剪切），触发SVG壁重塑，往往是适应不良， 失败我们的基础R 01资助的研究，为BioGraft的成立奠定了科学基础， 表明逐渐增加负荷可以减轻甚至消除移植失败。我们证明了这一点 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。在这里， 为了实现可以大规模制造的设计，我们提出了下一代3D打印可生物降解的 scaffold，我们将在本提案中对其进行改进和测试。为了实现我们的目标，我们提出了三个具体目标。在 目标1，我们将通过体外测试和降解研究筛选3D打印的候选设计。这将允许 我们可以有效地和廉价地选择设计匹配所需的目标。在目标2中，我们将进行临床前 支架装置在建立的羊颈动脉-颈静脉间置静脉移植物CABG模型中的测试 手术这将确定初步的安全性和有效性。在目标3中，我们将描述器械性能 使用机械测试和组织病理学。这些数据将使后续筹款，发展 商业化计划和启动FDA讨论。BioGraft的创始团队充分利用了 工程和临床合作，以及最近与斯坦福大学和杜克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，并在快速3D打印制造方法方面拥有专业知识。 我们看到拟议设备的潜在年度可寻址市场总额为16亿美元。