In vitro platforms for evaluating liver toxicity.
In vitro platforms for evaluating liver toxicity.
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DOI：
10.1177/1535370214531872
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Yarmush ML
中科院分区：
文献类型：
--
作者：
Bale SS;Vernetti L;Senutovitch N;Jindal R;Hegde M;Gough A;McCarty WJ;Bakan A;Bhushan A;Shun TY;Golberg I;DeBiasio R;Usta BO;Taylor DL;Yarmush ML
肝脏是具有许多重要功能的异质器官，包括药物的代谢，并且非常容易受到这些物质的损伤。药物性肝病的病因仍有争议，尽管通常被认为是激活的免疫应答和肝细胞代谢功能障碍之间的连续体，最常见的是由中间反应性代谢物引起的。这场争论源于这样一个事实，即目前的动物和体外模型提供有限的生理相关信息，它们的缺点导致“沉默”的肝毒性药物被引入临床试验，通过撤回和后期临床失败为制药公司带来巨大的经济损失。随着我们深入了解导致肝损伤的分子过程，越来越清楚的是：a）病理性病变不仅是由于肝实质，而且还由于肝细胞与驻留的肝免疫细胞、星状细胞和内皮细胞之间的相互作用;和，B）动物模型不反映人类细胞相互作用。因此，预测性人类体外模型必须解决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。在这篇小型综述中，我们首先讨论了宏观规模的体外肝培养系统的现状，并列举了已商业化的例子。然后，我们介绍了微流控培养系统的范例，其目的是通过利用微和纳米纤维技术来模拟具有生理相关尺寸、细胞结构、灌注和质量传输的肝脏。我们回顾了最突出的肝脏芯片平台的生理相关性和药物反应。最后，我们对其他关键进展进行了评论，例如部署基于荧光的生物传感器来识别相关的毒性途径，以及创建预测工具的计算模型。
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.
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