BIOMATERIALS FOR CARDIOVASCULAR TISSUE ENGINEERING

用于心血管组织工程的生物材料

• 批准号: 8359621
• 负责人: Robert E Akins
• 金额: $ 11.71万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359621
• 关键词: Address; Adult; Area; Autologous; Biocompatible Materials; Biological; Biopolymers; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Communication; Cell Line; Cell physiology; Cells; Cellular biology; Childhood; Clinical; Complex; Defect; Delaware; Development; Devices; Disease; Engineering; Environment; Functional disorder; Funding; Goals; Grant; Growth; Home environment; Human; Hyperplasia; Implant; Interdisciplinary Study; Left; Liquid substance; Mechanics; Medial; Molecular; Muscle; National Center for Research Resources; Pathway interactions; Pediatric Hospitals; Physiological; Physiology; Polymers; Preparation; Principal Investigator; Production; Property; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Resources; Seeds; Smooth Muscle Myocytes; Source; Structure; Supervision; System; Systems Biology; Technology; Testing; Time; Tissue Engineering; Tissues; Training; Translational Research; Tube; United States National Institutes of Health; Universities; Work; base; cellular engineering; cost; design; graduate student; implantation; in vivo; nanofiber; programs; repaired; scaffold; self-renewal

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The engineering of cardiovascular (CV) grafts that mimic the properties of native tissue remains a formidable research and clinical challenge and a principal area for translational research emphasis. In particular, controlling the organization of cells in engineered tissues is a critical issue, and there is a important and well-recognized need to identify physical and molecular pathways that can be manipulated to direct the formation of desirable constructs. Unfortunately, little is known about (i) the types of physical substrates that might be most effective in guiding multi-cellular assembly, (ii) the cellular mechanisms that drive the formation of integrated structures ex vivo, and (iii) the effects of organizational strategies on the component cells of engineered tissues. With this application, we seek initial funds for a new interdisciplinary research program to address these areas within the context of developing critically-needed implants to treat congenital and acquired CV disease. Mammalian CV systems are essentially closed, fluid-filled networks of conduits that contain varying degrees of muscle to control luminal volume and restrict or generate flow. Implantable biosynthetic conduits that reproduce essential CV functions would be valuable for the treatment of adult disease but are also uniquely suited for the repair of pediatric defects. Indeed, CV tissue engineering will offer opportunities for the growth and remodeling of implants while minimizing thrombogenesis and intimal hyperplasia and providing for appropriate physiologic responsiveness and graft self-renewal over the lifetime of the implant recipient. Our long-term goal is the development of composite ves-sels (see Figure 1) with bio-synthetic components that act initially as scaffolds to provide mechanical support while recruiting the appropriate cellular/biological components but that later degrade leaving a completely biologic vessel. The development of such implants will require advances in multiple areas including, 3D fabrication technologies, molecular and physical mechanisms to control cell distribution and function, and evaluating interactions between scaffold materials, cells, and the host physiology. Once fully developed, envisioned applications would involve (i) production of synthetic composite tubes comprising nonoriented and oriented nanofibrous scaffolding, (ii) seeding with autologous cells to populate the layers and establish a biosynthetic device that responds to the in vivo mechanical and humoral environment, and (iii) implantation into a host where conversion to a completely biological conduit would proceed by interaction with the host physiology. Thus, there are substantial areas of research needed in the field and clear opportunities for interdisciplinary research programs. Accordingly, we have assembled a research team composed of investigators with expertise in polymer and biopolymer design, polymer characterization, CV cell biology and physiology, human CV pathophysiology, and system biology so that the properties of engineered CV grafts can ulti-mately be engineered from the molecular through the macroscopic, optimized, tested and prepared for eventual transfer into the clinical setting. The proposed research is interdisciplinary and cross institutional involving investigators from the Alfred I duPont Hospital for Children, the DuPont Expe-rimental Station, and the University of Delaware. Together, the team will develop an interdisciplinary research program in CV engineering using funds from INBRE to seed key areas of research and sponsor two graduate students, who will be under the direct supervision of Drs. Akins and Rabolt. Undergraduates will be encouraged to participate in the research program by working in the lab for course credit or in preparation for senior honors theses in their home department, and a course focusing on cardiovascular dynamics and the associated engineering challenges will be developed for advanced undergraduates and graduate students. The investigators will continue to submit conventional and MPI-based R01 applications to further the development of the scientific goals of the program and to continue the development of graduate and undergraduate training initiatives in CV tissue engineering beyond the time-frame of the INBRE mechanism. The present application centers on two focused aims that address areas critical to the development of the interdisciplinary program. Both aims center on the muscular component (i.e. medial layer) of biosynthetic conduits (see Figure 1). The first aim investigates the preparation of a complex composite conduit evaluated with a simple cell system  human smooth muscle cell line, and the second aim investigates the effects of a relatively simple biomaterial on the complex cell:cell interactions found in primary cardiac cells. This design takes full advantage of the expertise of the research team, leverages available INBRE Core Resources, and fits within the budgetary requirements of the INBRE me-chanism.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 模拟天然组织特性的心血管(CV)移植物工程仍然是一项艰巨的研究和临床挑战，也是翻译研究重点的主要领域。特别是，控制工程组织中细胞的组织是一个关键问题，有一个重要的和公认的需要确定可以操纵的物理和分子途径，以指导理想结构的形成。不幸的是，对于(I)在引导多细胞组装方面可能最有效的物理底物的类型，(Ii)驱动体外整合结构形成的细胞机制，以及(Iii)组织策略对工程组织组成细胞的影响，人们知之甚少。通过这项申请，我们为一个新的跨学科研究计划寻求初始资金，以在开发急需的植入物治疗先天性和获得性心血管疾病的背景下解决这些领域。哺乳动物的CV系统本质上是封闭的、充满液体的管道网络，其中包含不同程度的肌肉来控制管腔容量并限制或产生血流。可植入的生物合成导管可以复制基本的心血管功能，对成人疾病的治疗很有价值，但也是唯一适合修复儿童缺陷的管道。事实上，CV组织工程将为植入物的生长和重塑提供机会，同时将血栓形成和内膜增生降至最低，并在植入物接受者的一生中提供适当的生理反应和移植物自我更新。我们的长期目标是开发具有生物合成成分的复合VES-SEL(见图1)，这些成分最初充当支架，提供机械支持，同时招募适当的细胞/生物成分，但后来降解，留下一个完全生物的血管。这类植入物的发展需要在多个领域取得进展，包括3D制造技术，控制细胞分布和功能的分子和物理机制，以及评估支架材料、细胞和宿主生理之间的相互作用。一旦完全开发出来，设想的应用将包括(I)生产包含无取向和取向纳米纤维支架的合成复合管，(Ii)种植自体细胞来填充这些层并建立响应体内机械和体液环境的生物合成装置，以及(Iii)植入宿主，其中通过与宿主生理相互作用来转换为完全生物的管道。因此，在该领域需要大量的研究领域，并为跨学科研究计划提供明确的机会。 因此，我们组建了一个研究团队，由具有聚合物和生物聚合物设计、聚合物表征、CV细胞生物学和生理学、人类CV病理生理学和系统生物学专业知识的研究人员组成，以便能够从分子到宏观、优化、测试和准备最终转移到临床环境中的工程CV移植物的特性。这项拟议的研究是跨学科和跨机构的，涉及来自阿尔弗雷德·I·杜邦儿童医院、杜邦实验站和特拉华大学的研究人员。该团队将共同开发简历工程的跨学科研究计划，利用INBRE的资金为关键研究领域提供种子，并资助两名研究生，他们将在Akins博士和拉博尔特博士的直接指导下。本科生将被鼓励通过在实验室工作以获得课程学分或准备本国系的高级荣誉论文来参与研究计划，并将为高级本科生和研究生开发一门专注于心血管动力学和相关工程挑战的课程。研究人员将继续提交常规的和基于MPI的R01申请，以进一步发展该计划的科学目标，并在INBRE机制的时间框架之外继续发展心血管组织工程的研究生和本科生培训计划。目前的申请集中在两个重点目标上，这两个目标涉及对跨学科计划发展至关重要的领域。这两个目标都集中在生物合成管道的肌肉部分(即内侧层)(见图1)。第一个目的是研究一种复杂的复合导管的制备，用一个简单的细胞系统的人类平滑肌细胞系进行评估，第二个目的是研究一种相对简单的生物材料对复杂细胞的影响：在原代心肌细胞中发现的细胞相互作用。这一设计充分利用了研究团队的专业知识，利用了INBRE现有的核心资源，并符合INBRE机制的预算要求。