SBIR Phase I: Optimization of a Microscale Human Liver Tissue for Evaluating Chronic Drug Toxicity

这个小企业技术转移第一阶段项目优化了人体肝组织的体外模型，并评估了其在评估慢性药物暴露后肝脏毒性方面的有效性。虽然从肝脏分离的原代人类肝细胞被制药和生物技术行业用来评估药物的新陈代谢和毒性，但这些细胞在传统培养下迅速失去肝脏特异性功能，这不允许在药物开发的早期测试药物的慢性影响。最近，一种小型化的、多孔的、具有明确的微尺度结构的人类肝组织模型已经被开发出来，它可以保持表型功能数周。该项目将利用微技术工具从功能上优化微尺度的肝组织以延长寿命(几个月)，并使用高内容成像读数和基因表达信号来评估系统在评估临床相关的慢性(周)药物毒性方面的有效性。这项研究的更广泛影响是提供对慢性药物暴露后原代人类肝细胞蛋白质/基因表达变化的更好理解，并开发一种新的用于工业的慢性毒性分析方法。未来，使用微型肝组织进行慢性毒性筛查可能被用于在药物开发管道中更早地消除有毒化合物，以降低每种药物开发成本10亿美元，增加临床成功的可能性，并限制人类接触不安全药物。更广泛地说，微尺度的人体肝组织可能有助于研究毒物的作用机制，允许识别新的生物标志物，并使研究能够评估与接触药物混合物相关的风险。

This Small Business Technology Transfer Phase I project optimizes an in vitro model of human liver tissue and assess its utility for evaluating liver toxicity following chronic drug exposure. While primary human hepatocytes isolated from the liver are utilized by pharmaceutical and biotech industries to evaluate drug metabolism and toxicity, these cells under conventional culture rapidly lose liver-specific functions, which does not allow for chronic effects of drugs to be tested earlier in drug development. Recently, a miniaturized, multiwell human liver tissue model with defined microscale architecture has been developed that maintains phenotypic functions for several weeks. This project will utilize microtechnology tools to functionally optimize the microscale liver tissue for enhanced longevity (months), and assess utility of the system for evaluating clinically-relevant chronic (weeks) drug toxicity using high content imaging readouts and gene expression signatures.The broader impacts of this research are to provide an improved understanding of protein/gene expression changes in primary human hepatocytes following chronic drug exposure, and development of a novel chronic toxicity assay for use in industry. In the future, chronic toxicity screening with microscale liver tissues may be used to eliminate toxic compounds much earlier in the drug development pipeline towards reducing the $1 billion per drug development costs, increasing likelihood of clinical success, and limiting human exposure to unsafe drugs. More broadly, microscale human liver tissues may enable the investigation of mechanisms of toxicant action, allow identification of new biomarkers, and enable studies to assess the risk associated with exposure to mixtures of drugs.