Engineering a Pro-Vasculogenic Capillary Network Regulating Host Responses

非技术摘要再生组织的关键障碍是在受损区域内产生复杂的人工血管网络，以及使宿主组织连接到这些血管网络的能力。这一过程对于确保向该地区生长的细胞和组织持续提供氧气和营养是必要的。PIs建议开发一种可植入的支架，其中包含人造血管以及适当的生物化学物质，可以在宿主组织血管和工程血管之间建立连接。该项目的成功将为如何影响和优化支架植入物和宿主组织之间的这种必要整合提供关键的见解，从而加速血管网络严重受损的大组织的再生。在进行这个项目时，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)适合年级的课程组件，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，以及2)由PI和COPI联合教授的组织工程研究生/高级本科课程。如果没有这一通过灌流的血管系统的必要运输过程，细胞将死于缺血，导致坏死区。因此，为了设计出比这种扩散施加的限制更厚的成功的组织结构，需要能够支持灌流的人工血管网络。虽然已经取得了不断的进展，但到目前为止，还没有研究表明细胞载药的微流体水凝胶与宿主血管系统在体内的整合。这一关键步骤对于充分利用预先血运的结构和使用厚厚的可植入、细胞负载的工程化组织是必要的。因此，PI建议设计一种可立即灌流的可植入组织结构，以支持快速血管生成，并通过组装包含高密度毛细管状3D微流体网络的水凝胶来显著增强与宿主血管的吻合和宿主植入；(Ii)干细胞促进血管形成和通道内皮化；以及(Iii)短合成多肽以加快宿主血管生成反应，进一步确保构建物的及时血管形成/灌流。这项工作的结果将大大加快组织工程在临床上的应用和转化。

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.