Khetani Salman R, Berger Dustin R, Ballinger Kimberly R, Davidson Matthew D, Lin Christine, Ware Brenton R
Department of Mechanical Engineering, Colorado State University, Fort Collins, CO, USA School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA
School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA.
J Lab Autom. 2015 Jun;20(3):216-50. doi: 10.1177/2211068214566939. Epub 2015 Jan 23.
Drug-induced liver injury (DILI) is a leading cause of drug attrition. Significant and well-documented differences between animals and humans in liver pathways now necessitate the use of human-relevant in vitro liver models for testing new chemical entities during preclinical drug development. Consequently, several human liver models with various levels of in vivo-like complexity have been developed for assessment of drug metabolism, toxicity, and efficacy on liver diseases. Recent trends leverage engineering tools, such as those adapted from the semiconductor industry, to enable precise control over the microenvironment of liver cells and to allow for miniaturization into formats amenable for higher throughput drug screening. Integration of liver models into organs-on-a-chip devices, permitting crosstalk between tissue types, is actively being pursued to obtain a systems-level understanding of drug effects. Here, we review the major trends, challenges, and opportunities associated with development and implementation of engineered liver models created from primary cells, cell lines, and stem cell-derived hepatocyte-like cells. We also present key applications where such models are currently making an impact and highlight areas for improvement. In the future, engineered liver models will prove useful for selecting drugs that are efficacious, safer, and, in some cases, personalized for specific patient populations.
药物性肝损伤（DILI）是药物研发失败的主要原因。目前，动物和人类肝脏代谢途径存在显著且有充分文献记载的差异，这使得在临床前药物研发过程中，有必要使用与人类相关的体外肝脏模型来测试新的化学实体。因此，已经开发出了几种具有不同程度体内相似复杂性的人类肝脏模型，用于评估药物代谢、毒性以及对肝脏疾病的疗效。最近的趋势是利用工程工具，例如借鉴半导体行业的工具，来精确控制肝细胞的微环境，并实现小型化，以适应更高通量的药物筛选。将肝脏模型整合到芯片上器官装置中，使不同组织类型之间能够相互作用，正在积极探索以获得对药物作用的系统层面理解。在此，我们综述了与由原代细胞、细胞系和干细胞衍生的类肝细胞构建的工程化肝脏模型的开发和应用相关的主要趋势、挑战和机遇。我们还介绍了这些模型目前产生影响的关键应用领域，并强调了有待改进的方面。未来，工程化肝脏模型将被证明有助于选择有效、更安全且在某些情况下针对特定患者群体个性化的药物。
