Engineering a Pro-Vasculogenic Capillary Network Regulating Host Responses

设计促血管生成的毛细血管网络调节宿主反应

• 批准号: 1506717
• 负责人: Leon Bellan
• 金额: $ 45万
• 依托单位: Vanderbilt University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1506717&HistoricalAwards=false
• 关键词: Engineering; Pro; Vasculogenic; Capillary; Network

Non-technical AbstractA key hurdle in regenerating tissues is the production of complex network of artificial blood vessels within the damaged areas, and the ability to cause host tissue to connect to these vessel networks. This process is necessary to ensure constant supply of oxygen and nutrient to growing cells and tissues in the areas. The PIs propose to develop an implantable scaffold containing artificial blood vessels, as well as appropriate biochemicals that can induce connections between the host tissue blood vessels and the engineered blood vessels. The success of this project will provide critical insights into how to influence and optimize this necessary integration between scaffold implants and host tissue, thereby accelerating regeneration of large tissues with severely damaged vessel networks. While conducting this project, research and education will be integrated through activities aligned with the efforts of the School for Science and Math at Vanderbilt U. The team will develop 1) grade-appropriate curriculum components that introduce high school students to engineering through a module on angiogenesis in biomaterial implants for tissue engineering and 2) a new graduate/upper level undergraduate course co-taught by the PI and CoPI on Tissue Engineering.Technical AbstractIn most natural tissues, blood capillaries lie within ~200 micrometers from each other to ensure a sufficient level of transport for oxygen, nutrients and waste products. Without this essential transport process through perfused vasculature, cells will die from ischemia, leading to necrotic regions. Thus, to engineer a successful tissue construct thicker than this diffusion-imposed limit, an artificial vascular network capable of supporting perfusion is required. Although continuous progress has been made, to date no research has demonstrated the integration of cell-laden microfluidic hydrogels with host vasculature in vivo. This critical step is necessary to fully exploit prevascularized constructs and enable the use of thick implantable cell-laden engineered tissues. Therefore, the PIs propose to engineer an immediately perfusable, implantable tissue construct that supports rapid angiogenesis and dramatically enhances anastomosis with host vasculature and host ingrowth by assembling hydrogels containing a high density capillary-like 3D microfluidic network; (ii) stem cells to promote vascularization and channel endothelialization; and (iii) short synthetic peptides to expedite host angiogenic response to further ensure timely vascularization/perfusion of the constructsThe results of this work will dramatically accelerate the application and translation of tissue engineering in the clinics.

非技术摘要组织再生的一个关键障碍是在受损区域内产生复杂的人造血管网络，以及使宿主组织连接到这些血管网络的能力。 这个过程对于确保该区域生长的细胞和组织持续供应氧气和营养是必要的。 课题组建议开发一种含有人造血管的可植入支架，以及可以诱导宿主组织血管和工程血管之间连接的适当生化物质。 该项目的成功将为如何影响和优化支架植入物与宿主组织之间的必要整合提供重要见解，从而加速血管网络严重受损的大型组织的再生。在开展该项目时，研究和教育将通过与范德比尔特大学科学与数学学院的努力相结合的活动来整合。该团队将开发 1) 适合年级的课程组成部分，通过组织工程生物材料植入物中的血管生成模块向高中生介绍工程学；2) 由 PI 和 CoPI 共同教授的新的组织工程研究生/高年级本科课程。 摘要在大多数自然组织中，毛细血管彼此之间的距离在约 200 微米以内，以确保氧气、营养物质和废物的充分运输。如果没有这种通过灌注脉管系统的重要运输过程，细胞就会因缺血而死亡，导致坏死区域。 因此，为了设计出比扩散限制更厚的成功组织结构，需要能够支持灌注的人工血管网络。尽管不断取得进展，但迄今为止还没有研究证明载有细胞的微流体水凝胶与宿主体内脉管系统的整合。 这一关键步骤对于充分利用预血管化结构并能够使用厚的可植入的充满细胞的工程组织是必要的。因此，PI建议设计一种可立即灌注、可植入的组织结构，通过组装含有高密度毛细管样3D微流体网络的水凝胶，支持快速血管生成，并显着增强与宿主脉管系统的吻合和宿主向内生长； (ii) 干细胞促进血管化和通道内皮化； (iii)短合成肽可加速宿主血管生成反应，进一步确保构建体的及时血管化/灌注。这项工作的结果将极大地加速组织工程在临床中的应用和转化。