CAREER: Origami-inspired design for a tissue engineered heart valve

出生时心脏瓣膜形状不正确的儿童将面临一生的手术和困难。其中许多儿童将接受人工心脏瓣膜替代品。目前的人工心脏瓣膜存在许多问题，包括它们不能随着孩子的成长而生长。一种由能够自我修复和生长的活体生物组织制成的心脏瓣膜替代物将提供一种优越得多的治疗选择。这个教师早期职业发展（Career）项目的总体研究目标是利用克服当前障碍的新方法开发一种活体心脏瓣膜替代品。例如，一种受折纸启发的新设计有望实现一种更容易制造、使用寿命更长的阀门。此外，瓣膜将以一种类似于心脏瓣膜自然形成的方式填充活细胞。这将使细胞产生具有适当行为和功能的更自然的瓣膜。该CAREER项目还包括教育和推广活动，旨在通过招募不同群体的成员从事研究，扩大STEM的参与，并通过在图书馆和中学提供教育社区推广和课堂活动，提高公众的科学素养和公众对科学技术的参与。活动包括在当地公共图书馆举办的“科学新闻”系列研讨会，以及面向当地中学生的“折纸工程设计挑战赛”外展活动。迫切需要开发一种功能持久且生理准确的组织工程心脏瓣膜，为先天性心脏病患儿提供更好的治疗选择。该项目的总体研究目标是开发一种具有细胞活性的生物阀，以维持流体动力功能。核心假设是，一个具有组织样特性的支架，巧妙地折叠成瓣膜结构，并植入与发育相适应的细胞，可以产生一个具有前所未有的功能和耐久性的生物瓣膜。目的1是合成一种模拟关键组织特性的多孔弹性支架。这将通过将氯化钠（NaCl）孔隙剂掺入聚甘油癸二酸酯（PGS）中来实现，以创建具有组织样孔隙度和弹性的生物相容性支架。目的二是研制一种具有流体动力功能和耐久性的人工心脏瓣膜。这将使用一种新颖的折纸启发的折叠方法来制造一个不包含传统失效点的功能性人工心脏瓣膜。目的3是产生具有适当生物活性的常驻瓣膜细胞类型。这将通过使用患者来源的脐带血来产生内皮祖细胞来实现，内皮祖细胞可以通过模拟胚胎发育来产生原生样瓣膜细胞群。目的4是成熟的组织工程心脏瓣膜，以实现天然结构和持久功能。这将通过使用具有生物力学合理设计的组织工程心脏瓣膜和具有适当生物来源的驻留细胞来产生瓣膜新组织来实现。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Children born with improperly formed heart valves face a lifetime of surgeries and hardship. Many of these children will receive artificial heart valve substitutes. Current artificial heart valves have many problems including that they cannot grow as the child grows. A heart valve substitute made from living biological tissue that can self-repair and grow would provide a far superior treatment option. The overall research goal of this Faculty Early Career Development (CAREER) project is to develop a living heart valve substitute using new approaches that will overcome current barriers. For example, a new origami-inspired design is expected to achieve a valve that is easier to make and that lasts longer. Additionally, the valve will be populated with living cells in a way that is similar to how heart valves naturally form. This will allow the cells to produce a more natural valve with appropriate behavior and functionality. This CAREER project also includes education and outreach activities designed to broaden STEM participation by recruiting members from diverse groups to work on the research and to increase public scientific literacy and public engagement with science and technology by offering educational community outreach and classroom activities in libraries and middle schools. Activities include a “Science in the News” seminar series open to the public and hosted at local public libraries and an “Origami-based Engineering Design Challenge” outreach activity targeted towards students in local middle schools.There is an urgent need to develop a tissue engineered heart valve that is both functionally durable and physiologically accurate to provide better treatment options for children born with congenital heart disease. The overall research objective of this project is to develop a biological valve with cellular activity that sustains hydrodynamic functionality. The central hypothesis is that a scaffold with tissue-like properties, cleverly folded into a valve configuration, and seeded with developmentally appropriate cells, can produce a biological valve with unprecedented functionality and durability. Objective 1 is to synthesize a porous and elastic scaffold that mimics critical tissue properties. This will be accomplished by incorporating a sodium chloride (NaCl) porogen into poly(glycerol sebacate) (PGS) to create a biocompatible scaffold with tissue-like porosity and elasticity. Objective 2 is to develop a prosthetic heart valve with hydrodynamic functionality and durability. This will be accomplished using a novel origami-inspired folding approach to fabricate a functional prosthetic heart valve that does not contain traditional failure points. Objective 3 is to generate resident valve cell types with appropriate biological activity. This will be accomplished by using patient-derived umbilical cord blood to generate endothelial progenitor cells which can give rise to native-like valve cell populations by mimicking embryonic development. Objective 4 is to mature a tissue engineered heart valve to achieve native structure and durable functionality. This will be accomplished by using a tissue engineered heart valve with a biomechanically sound design and resident cells with appropriate biological origins to generate valve neotissue.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.