Self-Organized Tissue Microvasculature

描述(由申请人提供)：器官衰竭导致的死亡是一个重大的医学挑战，在美国每年仅肝功能衰竭就导致超过35,000人死亡。目前，唯一能显著改善预后的治疗方法是器官置换，但由于可移植器官的供不应求，只有病情最严重的病例才会被转介进行移植。虽然工程组织提供了减轻器官衰竭带来的痛苦的希望，但它们仍然缺乏使其成为可行的治疗选择的关键功能。特别是，组织需要发达的血管网络来输送营养和氧气，并清除代谢废物。这一点在肝脏等高度新陈代谢和复杂的组织中尤为重要。血管化组织结构的问题已经通过各种方法解决，但到目前为止，这些方法的成功有限，主要是因为缺乏可扩展性。自组织，即基本的构建块自主地构建到更大的结构中，已经成功地应用于各种工程应用中。我们认为，控制河流支流发展的相同的自组织物理原理可以用来在粘性颗粒悬浮液中构建有效的微血管网络。我们建议使用细胞水凝胶模块作为基本的组织构建块，构建一个灌流系统，其中宏观系统参数可以进行调整，以创建一个血管网络，有效地将营养物质输送到整个组织的细胞，以维持组织的长期功能和生存能力。该项目的总体目标是开发一种体外肝组织血管化的方法，在这种方法中，组织可以预先设计并使用基本的组织构建块从头开始构建。我们假设侵蚀的物理模型可以应用于细胞水凝胶的悬浮液，这些模型将使我们能够优化能够维持细胞功能和活力的血管网络的组织。为了实现这一目标，我们建议：(1)研究微尺度水凝胶在流动条件下粘附性悬浮液中的自组织；(2)优化微尺度水凝胶的自组织，以建立表型功能的体外肝脏模型。其结果将是一种完全可扩展的技术，用于从头开始设计复杂的组织结构。

DESCRIPTION (provided by applicant): Mortality due to organ failure presents a significant medical challenge with liver failure alone responsible for over 35,000 deaths per year in the United States. Currently, the only therapy that offers any significantly improved prognosis is organ replacement, but because the demand for transplantable organs far exceeds supply, only the most severe cases are referred for transplant. While engineered tissues offer the promise to alleviate the suffering imposed by organ failure, they continue to lack key features that would make them a viable treatment option. In particular tissues require a developed vascular network to deliver nutrients and oxygen and to remove metabolic waste products. This is particularly important in highly metabolic and complex tissues like the liver. The problem of vascularizing tissue constructs has been addressed using a variety of approaches, but to date those approaches have seen limited success due primarily to lack of scalability. Self-organization, where basic building blocks are built autonomously into larger structures, has been successfully employed in a variety of engineering applications. We propose that the same physical principles of self-organization that govern the development of river tributaries can be utilized to construct an efficient microvascular network in an adhesive particle suspension. Using cell-laden hydrogel modules as the basic tissue building blocks, we propose to construct a perfusion system in which the macroscopic system parameters can be tuned to create a vascular network that efficiently delivers nutrients to cells throughout the tissue to maintain long-term tissue function and viability. The overall goal of this project is to develop an approach to vascularizing liver tissue in vitro, where the tissue can be designed a priori and built from the ground up using basic tissue building blocks. We hypothesize that physical models of erosion can be applied to suspensions of cell-laden hydrogels and that these models will allow us to optimize the organization of a vascular network that is capable of maintaining cell function and viability. In order to achieve this goal, we propose: (1) to study self-organization in an adhesive suspension of microscale hydrogels under flow and (2) to optimize self-organization of microscale hydrogels for developing a phenotypically functional in vitro liver model. The result will be a fully scalable technique for designing complex tissue architecture from the ground up.