Self-Organized Tissue Microvasculature

描述（由申请人提供）：器官衰竭导致的死亡率是一个重大的医学挑战，仅肝功能衰竭就导致美国每年超过35，000例死亡。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需求远远超过供应，只有最严重的病例才能接受移植。虽然工程组织提供了减轻器官衰竭所带来的痛苦的希望，但它们仍然缺乏使其成为可行的治疗选择的关键特征。特别地，组织需要发达的血管网络来输送营养物和氧气并去除代谢废物。这在高度代谢和复杂的组织如肝脏中特别重要。血管化组织构建体的问题已经使用多种方法来解决，但迄今为止，这些方法主要由于缺乏可扩展性而取得了有限的成功。自组织，其中基本的构建块自主地构建成更大的结构，已成功地应用于各种工程应用。我们建议，可以利用相同的物理原理，管理河流支流的发展，自组织构建一个有效的微血管网络中的粘性颗粒悬浮液。使用细胞负载的水凝胶模块作为基本的组织构建块，我们建议构建一个灌注系统，其中宏观系统参数可以被调整，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，以保持长期的组织功能和活力。该项目的总体目标是开发一种体外血管化肝组织的方法，其中组织可以先验设计并使用基本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载有细胞的水凝胶的悬浮液，并且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，我们提出：（1）研究流动下的微尺度水凝胶的粘附悬浮液中的自组织和（2）优化微尺度水凝胶的自组织以开发表型功能性体外肝脏模型。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.