Engineering a Pro-Vasculogenic Capillary Network Regulating Host Responses

再生组织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。 这个过程是必要的，以确保氧气和营养物质的不断供应，以生长的细胞和组织的地区。 PI建议开发一种含有人造血管的可植入支架，以及适当的生物化学品，可以诱导宿主组织血管和工程血管之间的连接。 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这种必要整合提供关键见解，从而加速血管网络严重受损的大型组织的再生。在开展该项目的同时，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一致的活动来整合。该团队将开发1）年级适当的课程组成部分，通过组织工程生物材料植入物中血管生成的模块向高中生介绍工程，2）由PI和CoPI共同教授的新研究生/高级本科课程组织工程。毛细血管彼此相距在~200微米内，以确保氧气、营养物和废物的足够水平的运输。如果没有通过灌注的脉管系统的这种必要的运输过程，细胞将死于缺血，导致坏死区域。 因此，为了设计比该扩散施加的限制更厚的成功的组织构造，需要能够支持灌注的人工血管网络。虽然已经取得了不断的进展，但迄今为止还没有研究表明载有细胞的微流体水凝胶与宿主脉管系统在体内的整合。 这一关键步骤对于充分利用预血管化构建体和使用厚的可植入细胞负载工程组织是必要的。因此，PI提出设计一种可立即灌注的可植入组织构建体，其支持快速血管生成并通过组装含有高密度毛细血管样3D微流体网络的水凝胶显著增强与宿主脉管系统的吻合和宿主向内生长;（ii）干细胞，以促进血管化和通道内皮化;和（iii）短的合成肽，以加速宿主血管生成反应，从而进一步确保及时的血管化，本工作的结果将大大加速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.