Bale Shyam Sundhar, Vernetti Lawrence, Senutovitch Nina, Jindal Rohit, Hegde Manjunath, Gough Albert, McCarty William J, Bakan Ahmet, Bhushan Abhinav, Shun Tong Ying, Golberg Inna, DeBiasio Richard, Usta Berk Osman, Taylor D Lansing, Yarmush Martin L
Center for Engineering in Medicine (CEM) at Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston MA 02114.
University of Pittsburgh Drug Discovery Institute, Pittsburgh PA 15260.
Exp Biol Med (Maywood). 2014 Sep;239(9):1180-1191. doi: 10.1177/1535370214531872. Epub 2014 Apr 24.
The liver is a heterogeneous organ with many vital functions, including metabolism of pharmaceutical drugs and is highly susceptible to injury from these substances. The etiology of drug-induced liver disease is still debated although generally regarded as a continuum between an activated immune response and hepatocyte metabolic dysfunction, most often resulting from an intermediate reactive metabolite. This debate stems from the fact that current animal and in vitro models provide limited physiologically relevant information, and their shortcomings have resulted in "silent" hepatotoxic drugs being introduced into clinical trials, garnering huge financial losses for drug companies through withdrawals and late stage clinical failures. As we advance our understanding into the molecular processes leading to liver injury, it is increasingly clear that (a) the pathologic lesion is not only due to liver parenchyma but is also due to the interactions between the hepatocytes and the resident liver immune cells, stellate cells, and endothelial cells; and (b) animal models do not reflect the human cell interactions. Therefore, a predictive human, in vitro model must address the interactions between the major human liver cell types and measure key determinants of injury such as the dosage and metabolism of the drug, the stress response, cholestatic effect, and the immune and fibrotic response. In this mini-review, we first discuss the current state of macro-scale in vitro liver culture systems with examples that have been commercialized. We then introduce the paradigm of microfluidic culture systems that aim to mimic the liver with physiologically relevant dimensions, cellular structure, perfusion, and mass transport by taking advantage of micro and nanofabrication technologies. We review the most prominent liver-on-a-chip platforms in terms of their physiological relevance and drug response. We conclude with a commentary on other critical advances such as the deployment of fluorescence-based biosensors to identify relevant toxicity pathways, as well as computational models to create a predictive tool.
肝脏是一个具有多种重要功能的异质性器官，包括药物代谢，并且极易受到这些物质的损伤。药物性肝病的病因仍存在争议，尽管通常被认为是激活的免疫反应与肝细胞代谢功能障碍之间的连续过程，最常见的原因是中间活性代谢产物。这场争论源于当前动物和体外模型提供的生理相关信息有限，其缺点导致“沉默”的肝毒性药物进入临床试验，通过撤市和后期临床失败给制药公司造成巨大经济损失。随着我们对导致肝损伤的分子过程的理解不断深入，越来越清楚的是：（a）病理损伤不仅归因于肝实质，还归因于肝细胞与驻留肝免疫细胞、星状细胞和内皮细胞之间的相互作用；（b）动物模型不能反映人类细胞间的相互作用。因此，一个具有预测性的人体体外模型必须考虑主要人类肝细胞类型之间的相互作用，并测量损伤的关键决定因素，如药物的剂量和代谢、应激反应、胆汁淤积效应以及免疫和纤维化反应。在本综述中，我们首先通过已商业化的实例讨论宏观体外肝脏培养系统的现状。然后我们介绍微流控培养系统的范例，该系统旨在利用微纳制造技术，通过模拟具有生理相关尺寸、细胞结构、灌注和物质运输的肝脏。我们根据其生理相关性和药物反应对最突出的芯片肝平台进行综述。我们最后对其他关键进展进行评论，如部署基于荧光的生物传感器以识别相关毒性途径，以及构建计算模型以创建预测工具。
