Development of 3D Micro-scale Engineered Tissue Model Systems for Drug Discovery

描述(由申请人提供)：用于药物发现和开发的3D微尺度工程组织模型系统的开发是一个漫长而昂贵的过程。最近的调查表明，在美国上市的新药平均需要10到15年的研究和3亿美元的投资。药物的发现和开发得益于新技术，例如用于识别先导化合物的高通量筛选方法。然而，使用动物模型进行药物测试导致了预测人类反应、安全性和有效性的不准确和高昂的成本。解决这一问题的一种方法是开发3D工程化组织模型系统，该系统可以紧密模拟复杂的环境和人体器官系统的相互作用。尽管它们在药物发现和开发中很有用，但目前可用的微尺度工程化组织模型设备都是硅基的，具有微孔和腔状结构。在培养过程中，细胞倾向于排列在这些结构的壁上形成2D或2=D聚集体，这些聚集体可能没有正常的3D组织结构来执行组织特定的功能。这项拟议研究的目标是开发一种创新的制造方法，以创建用于药物发现的3D微尺度工程化组织模型系统。该方法将选择性发泡和微细研磨相结合，制备出具有局部多孔微结构的聚合物生物芯片，这些微结构与微流控通道相连，以模拟人体组织和器官的生物环境。多孔微结构允许细胞的3D培养，从而可以保持组织特有的结构和功能。利用所制作的组织模型系统，还将对肿瘤化疗药物的耐药性、间质-上皮细胞相互作用以及肝脏代谢的影响进行生物学研究。这项拟议的研究将填补微流控设备和3D组织工程支架制造能力的最先进水平之间的差距。本研究提出的工程化组织模型系统将在药物发现和开发以及基础和临床研究中有广泛的应用。

DESCRIPTION (provided by applicant): Development of 3D Micro-scale Engineered Tissue Model Systems for Drug Discovery and development is a lengthy and expensive process. Recent surveys indicate that the average new drug taken to market in the United States requires 10 to 15 years of research and $300 million of investment. Drug discovery and development has benefited from new technology such as high- throughput screening methods for identifying lead compounds. However, the use of animal models for drug tests has caused inaccuracies and high cost to predict human responses, safety, and efficacy. A solution to this problem is the development of 3D engineered tissue model systems that closely mimic the complex environment and interaction of human organ systems. Despite their usefulness in drug discovery and development, currently available micro-scale engineered tissue model devices are all silicon based, with micro well and chamber like structures. During culture, cells tend to line on the walls of these structures to form 2D or 2=D aggregates, which may not have normal 3D tissue architecture to perform tissue specific functions. The goal of the proposed research is to develop an innovative fabrication method to create 3D micro- scale engineered tissue model systems for drug discovery. The proposed method combines selective foaming and micro milling to produce polymeric biochips with localized porous microstructures that are connected with microfluidic channels to emulate the biological environment of human tissue and organs. The porous microstructures allow 3D culture of cells such that tissue specific architecture and function can be maintained. With the fabricated tissue model systems, biological studies are also proposed on drug resistance, stromal-epithelial cell interaction, and liver metabolism effect on cancer chemotherapy drugs. The proposed research will bridge the gap in the state-of-the-art fabrication capabilities for microfluidic devices and 3D tissue engineering scaffolds. The engineered tissue model systems proposed in this research will have wide applications in drug discovery and development, as well as in basic and clinical research.