Advanced manufacturing of a bioprosthetic collagen heart valve

心血管疾病是美国、欧洲和日本的主要死亡原因， 一系列的病理。最常见的手术之一是心脏瓣膜置换术，并且在以下情况下需要 瓣膜因返流而失效或在心动周期内无法完全打开。原因包括先天性 缺陷、钙化和脱垂，但无论起源如何，修复瓣膜和手术的选择有限。 治疗主要集中在替换。据估计，每年有超过15万名患者 接受心脏瓣膜置换术，每次手术的平均成本约为20万美元，相当于 医疗保健系统。心脏瓣膜市场在过去十年中持续增长，这是由于以下方面的进步： 与心脏瓣膜放置相关的外科手术和微创技术。然而，目前的阀门 在适合性、生物学性能、耐久性和外科手术方面存在一些折衷， 与当前机械和生物假体心脏瓣膜相关的优点和缺点。在这 我们的目标是使用先进的制造方法开发一种新的生物人工心脏瓣膜 具有机械瓣膜的耐久性，生物瓣膜的非血栓形成性， 微创经导管输送，以及定制适合任何患者解剖结构的能力。这么做 FluidForm，Inc与卡内基梅隆大学合作将开发一种新的自由形式可逆嵌入 悬浮水凝胶（FRESH）3D打印心脏瓣膜，使用I型胶原蛋白重建层流和 各向异性细胞外基质（ECM）结构在天然瓣膜。我们的初步数据显示， 印刷可用于完全由胶原制造功能性三叶心脏瓣膜， 生理流速和压力。在这里，我们将通过以下方式提高阀门性能： 通过两项研究重建天然瓣叶中的胶原纤维排列和机械性能， 目标。首先，我们将证明I型胶原蛋白的FRESH 3D打印可以重建胶原纤维， 自体主动脉瓣叶不同层的结构，平均取向差异<10% 角度其次，我们将证明FRESH 3D打印的胶原蛋白瓣膜小叶可以被工程化， 周向弹性模量、非线性应力-应变响应、蠕变和疲劳寿命均在本征值的75%以内 主动脉瓣叶第一阶段概念验证的成功将为第二阶段SBIR项目奠定坚实的基础 这将在体外流动系统中验证完整的FRESH打印生物假体主动脉瓣， 在临床前绵羊模型中评估血液相容性和生物相容性 反应

Cardiovascular disease is a leading cause of death in the US, Europe and Japan and is comprised of a wide range of pathologies. One of the most common procedures is heart valve replacement and is required when the valve fails due to regurgitation or is unable to open fully during the cardiac cycle. Causes include congenital defects, calcification and prolapse, but regardless of origin there are limited options to repair valves and surgical treatments are focused primarily on replacement. It is estimated that each year more than 150,000 patients receive heart valve replacements at a mean cost of ~$200,000 per procedure, corresponding to >$30B cost to the healthcare system. The heart valve market has continued to grow over the past decade due to advances in surgical and minimally-invasive technologies associated with heart valve placement. However, current valves represent some compromise in fit, biological performance, durability and surgical procedure, with unique advantages and disadvantages associated with current mechanical and bioprosthetic heart valves. In this proposal our objective is to develop a new bioprosthetic heart valve using advanced manufacturing approaches that has the durability of mechanical valves, the non-thrombogenicity of biologic valves, the soft deformability for minimally-invasive transcatheter delivery, and the ability to custom fit the anatomy of any patient. To do this FluidForm, Inc in collaboration with Carnegie Mellon University will develop a new freeform reversible embedding of suspended hydrogels (FRESH) 3D printed heart valve using collagen type I that recreates the laminar and anisotropic extracellular matrix (ECM) architecture in native valves. Our preliminary data shows that FRESH 3D printing can be used to manufacture functional tri-leaflet heart valves entirely from collagen and can support physiologic flow rates and pressure for short periods of time. Here we will improve valve performance by recreating the collagen fiber arrangement and mechanical properties in native valve leaflets via two research aims. First, we will demonstrate that FRESH 3D printing of collagen type I can recreate the collagen fiber architecture in the different layers of the native aortic valve leaflets with <10% difference in mean orientation angle. Second, we will prove that FRESH 3D printed collagen valve leaflets can be engineered to have radial and circumferential elastic modulus, non-linear stress-strain response, creep, and fatigue life within 75% of native aortic valve leaflets. Phase I proof-of-concept success will provide a strong foundation for a Phase II SBIR project that will validate the complete FRESH printed, bioprosthetic aortic valve in an in vitro flow system that simulates human pressure and flow rate and in a pre-clinical ovine model to assess hemocompatibility and biological response.