Towards a three-dimensional microfluidic liver platform for predicting drug efficacy and toxicity in humans.
Towards a three-dimensional microfluidic liver platform for predicting drug efficacy and toxicity in humans.
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DOI：
10.1186/scrt377
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发表时间：
2013
影响因子：
7.5
通讯作者：
Lansing Taylor D
中科院分区：
文献类型：
--
作者：
Bhushan A;Senutovitch N;Bale SS;McCarty WJ;Hegde M;Jindal R;Golberg I;Berk Usta O;Yarmush ML;Vernetti L;Gough A;Bakan A;Shun TY;DeBiasio R;Lansing Taylor D
虽然药物开发过程需要在人体测试之前在动物中进行功效和毒性测试，但动物模型准确预测人类对外源性物质和其他伤害的反应的能力有限。社会压力也集中在减少并最终取代动物试验上。然而，在过去十年中探索的各种体外模型还不足以取代动物模型。由几个美国联邦机构发起的新倡议试图通过资助在显微芯片上开发生理相关的人体器官模型来解决这个问题。最终目标是通过互连器官模型来模拟芯片上的人类，从而取代药物发现和开发中的动物试验。作为这项计划的一部分，我们的目标是建立一个三维的人类肝脏芯片，模仿腺泡，肝脏的最小功能单位，包括其氧气梯度。我们的肝脏芯片平台将提供一个微流体三维共培养环境，具有稳定的合成和酶功能至少4周。包含荧光生物传感器的哨兵细胞将被集成到芯片中，以提供关键肝功能和病理学的多路复用实时读数。我们还在开发一个数据库来管理实验数据，并利用外部信息来解释多模态数据并创建预测平台。
Although the process of drug development requires efficacy and toxicity testing in animals prior to human testing, animal models have limited ability to accurately predict human responses to xenobiotics and other insults. Societal pressures are also focusing on reduction of and, ultimately, replacement of animal testing. However, a variety of in vitro models, explored over the last decade, have not been powerful enough to replace animal models. New initiatives sponsored by several US federal agencies seek to address this problem by funding the development of physiologically relevant human organ models on microscopic chips. The eventual goal is to simulate a human-on-a-chip, by interconnecting the organ models, thereby replacing animal testing in drug discovery and development. As part of this initiative, we aim to build a three-dimensional human liver chip that mimics the acinus, the smallest functional unit of the liver, including its oxygen gradient. Our liver-on-a-chip platform will deliver a microfluidic three-dimensional co-culture environment with stable synthetic and enzymatic function for at least 4 weeks. Sentinel cells that contain fluorescent biosensors will be integrated into the chip to provide multiplexed, real-time readouts of key liver functions and pathology. We are also developing a database to manage experimental data and harness external information to interpret the multimodal data and create a predictive platform.
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