Nanotechnology in tissue engineering for autologous cardiac valve development

项目摘要/摘要 这项拟议的研究的目标是开发具有功能性的自体三层心脏瓣膜叶 使用三层纳米纤维衬底的本地小叶的胶原纤维取向以及扩展这一点 开发具有天然心脏瓣膜功能的完全自体心脏瓣膜的方法。拟议中的工作 将开发一种技术，用FDA批准的聚合物制造三层纳米纤维基板 模拟天然心脏瓣膜叶的胶原纤维的三层结构和取向。建议数 然后，Work将应用叶状三层纳米纤维衬底来开发非收缩自体 通过体内组织工程模拟本地叶的结构的瓣叶。宣传单的构造将 在体外进行测试，以验证其形态、结构和功能特性以及收缩性能。这个 拟议的工作将开发心脏瓣膜形状的纳米纤维衬底，其中包含小叶形状 工程用三层纳米纤维基板和周向取向管状纳米纤维基板 体内具有与天然心脏瓣膜性质相当的自体非收缩心脏瓣膜 组织工程学。工程设计的阀门将进行形态、结构、机械和 体外功能特性。工程设计的自体瓣膜也将进行临床相关测试 在绵羊植入模型中，结果包括功能、血栓形成和钙化。这些 瓣膜有望成为临床翻译发展的重要一步。 拟议的研究将候选人的研究集中在一个新的方向，以提供关于新的 开始向独立过渡所需的技能。应聘者拥有材料科学博士学位和 他来自华盛顿大学工程系，目前是梅奥诊所的助理研究员。他的博士学位。 论文工作涉及组织工程和再生医学生物材料的开发。这导致了 他的博士后工作涉及设计和开发用于生物心脏的纳米纤维生物材料 阀门开发。他的博士后工作还包括开发脱细胞心脏瓣膜、心包 基于组织的心脏瓣膜和支架移植物及其在绵羊/猪植入模型中的功能测试。 候选人的直接职业目标是通过以下方式从指导过渡到独立研究 完成博士后培训，开始在一家主要研究机构担任终身教职 上大学。这将需要将他目前的项目集中在一个新的研究方向上，同时也需要 成功完成心血管组织当前和未来项目所需的额外培训 工程部作为独立的调查员。K99/R00机制是实现这一目标的理想手段 进球。候选人的长期职业目标是建立一个独立的和外部资助的 心血管组织工程领域的转化性研究计划将具有重要意义 改善患者护理，培养下一代科学家、医生和工程师。 获奖期间的研究职业发展将包括与跨学科指导团队合作 临床医生、科学家和工程师。候选人的主要导师，医学博士阿米尔·勒曼博士是 梅奥诊所心血管研究，提供心血管生物学和临床专业知识 是李·格里菲斯博士，他是心血管病教授 梅奥诊所的疾病，并提供生物材料和体内受体炎症、免疫和 心血管领域的再生反应，医学博士约翰·斯图拉克是心血管外科教授 在梅奥诊所工作，提供晚期心力衰竭手术治疗方面的专业知识， 心脏科。候选人的共同导师 还有罗伯特医生 明尼苏达大学生物医学工程系主任特兰奎罗博士提供 在生物医学工程和心血管组织工程方面的专业知识。与他的导师一起工作， 应聘者将在 支架和模具设计，心血管生理学，细胞生物学和病理学，所有 绵羊体内组织工程模型、组织工程瓣膜和绵羊的功能试验 新型心脏瓣膜的模型分析。 候选人还将接受其他基本技能方面的培训，包括 研究成果的交流、指导和项目管理。最后，教育机会 这样的研究生课程工作在 分子细胞生物学 、心血管生理学以及各种研究和 临床系列研讨会，将完善培训经验。梅奥诊所提供各种教育和 通过研究生院、医学院、研究教育办公室和中心提供的支持服务 对于临床和翻译科学，这将促进必要的培训。 梅奥诊所致力于支持翻译研究，最近成立了 将再生医学作为一项战略举措。我们有多个领域的世界专家提供服务 以改善患者护理为共同目标的协作。梅奥还提供各种研究资源。 以及包括核心设施的设施，如显微镜和细胞分析核心、生物统计核心、 组织学核心，材料和结构测试核心。工程部有一个完整的 机械车间、电器车间和玻璃吹制车间，以支持工程设计和研究要求 发展。梅奥还有几个动物设施，包括心血管创新实验室， 它的特点是有一个专门用于动物研究的完整的心导管实验室。

Project Summary/Abstract The goals of the proposed research are to develop functional autologous trilayered heart valve leaflets with collagen fibril orientations of a native leaflet using trilayered nanofibrous substrates and to extend this approach in developing fully autologous heart valves with native heart valve functionality. The proposed work will develop a technology to fabricate trilayered nanofibrous substrates from a FDA approved polymer mimicking trilayered structure and orientations of collagen fibrils of native heart valve leaflets. The proposed work will then apply leaflet-shaped trilayered nanofibrous substrates to develop non-contractile autologous valve leaflets mimicking the structure of native leaflets by in-body tissue engineering. The leaflet constructs will be tested in-vitro to verify their morphological, structural, and functional properties and contractility. The proposed work will then develop heart valve-shaped nanofibrous substrates containing leaflet-shaped trilayered nanofibrous substrates and circumferentially oriented tubular nanofibrous substrates to engineer autologous non-contractile heart valves with comparable properties of native heart valves through in-body tissue engineering. The engineered valves will be tested for their morphological, structural, mechanical and functional properties in-vitro. The engineered autologous valves will also be tested for clinically-relevant outcomes including function, thrombus formation, and calcification in an ovine implantation model. These valves are expected to be an important step in the development toward clinical translation. The proposed research focuses the candidate's research in a novel direction to provide training on new skills required to begin the transition to independence. The candidate holds a Ph.D. in Materials Science and Engineering from the University of Washington and is currently a research associate at Mayo Clinic. His Ph.D. thesis work involved development of biomaterials for tissue engineering and regenerative medicine. This led to his postdoctoral work that involves design and development of nanofibrous biomaterials for biological cardiac valve development. His postdoctoral work also includes development of decellularized heart valve, pericardium tissue-based heart valve and stent graft, and their functionality testing in an ovine/porcine implantation model. The candidate's immediate career goal is to transition from mentored to independent research by completing his postdoctoral training and beginning a tenure track faculty position at a major research university. This will require focusing his current projects into a novel research direction while also receiving additional training needed to successfully complete the current and future projects in cardiovascular tissue engineering as an independent investigator. The K99/R00 mechanism is the ideal means of achieving this goal. The candidate's long-term career objective is to establish an independent and extramurally funded translational research program within the field of cardiovascular tissue engineering that will meaningfully improve patient care and train the next generation of scientists, physicians, and engineers. Research career development during the award will include working with an interdisciplinary mentoring team of clinicians, scientists, and engineers. The candidate's primary mentor, Dr. Amir Lerman, M.D., is the chair of Cardiovascular Research at Mayo Clinic and provides expertise in cardiovascular biology and clinical are Dr. Leigh Griffith, Ph.D., who is a professor of cardiovascular diseases at Mayo Clinic and provides expertise in biomaterials and in-vivo recipient inflammatory, immune and regenerative responses in cardiovascular area, Dr. John Stulak, M.D., is a professor of cardiovascular surgery at Mayo Clinic and provides expertise in surgical treatment of advanced heart failure, cardiology. The candidate's co-mentors and Dr. Robert Tranquillo, Ph.D., chair of the Department of Biomedical Engineering at the University of Minnesota, provides expertise in biomedical engineering and cardiovascular tissue engineering. Working with his mentors, the candidate will train in scaffold and mold design, cardiovascular physiology, cell biology and pathology, all aspects of in-body tissue engineering in ovine model, functionality tests of tissue-engineered valves and ovine model analysis of novel cardiac valves. The candidate will also train in other essential skills including communication of research findings, mentoring, and project management. Finally, educational opportunities such graduate coursework in molecular cell biology , cardiovascular physiology as well as various research and clinical seminar series, will round out the training experience. Mayo Clinic offers a variety of educational and support services through the Graduate School, College of Medicine, Office of Research Education, and Center for Clinical and Translation Science that will facilitate the necessary training. Mayo Clinic is committed to supporting translational research and recently established the Center for Regenerative Medicine as a strategic initiative. World experts in a variety of fields are available for collaboration with the common goal to improve patient care. Mayo also offers a variety of research resources and facilities including core facilities such as the Microscopy and Cell Analysis Core, the Biostatistics Core, the Histology Core, and the Materials and Structural Testing Core. The Division of Engineering features a full machine shop, electrical shop, and glassblowing shop to support research requests for engineering design and development. Mayo also has several animal facilities including the Cardiovascular Innovation Laboratory, which features a full cardiac catheterization laboratory dedicated to animal studies.