Biological and medical applications of a brain-on-a-chip.
Biological and medical applications of a brain-on-a-chip.
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DOI：
10.1177/1535370214537738
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Hogberg HT
中科院分区：
文献类型：
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作者：
Pamies D;Hartung T;Hogberg HT
开发和评估药物作为应对生物和化学威胁的潜在对策的愿望，要求测试系统也可以取代通常对药物开发至关重要的临床试验。目前的动物模型对人类药物疗效的预测性有限，因为大多数药物在临床试验中都失败了。我们对中枢神经系统的功能和大脑的复杂性，特别是在发育和神经元可塑性方面的了解有限。简单的体外系统并不能代表大脑的生理和功能。此外，研究人类遗传和环境因素之间的相互作用的困难导致对导致神经疾病的事件缺乏了解。微生理系统(MPS)有望产生更复杂的体外人体模型，更好地模拟器官的生物学和功能。MPS将不同类型的细胞组合在特定的三维(3D)配置中，以模拟具有具体功能的器官。这些MPS的最终目标是将不同的“有机化合物”结合起来，产生一个芯片上的人，这一方法将允许研究复杂的生理器官相互作用。最近发现的诱导多能干细胞(IPSCs)提供了一系列可能性，使具有不同遗传背景的个体(例如，人类疾病模型)的细胞研究成为可能。来自不同供体的IPSCs在MPS中的应用为更好地了解MPS的发病机制提供了机会，并可能成为药物开发、毒理学和医学的一种新工具。为了生成芯片上的脑，我们根据我们使用3D大鼠初级聚集脑模型的经验，从人类IPSCs建立了3D模型。分化四周后，人3D集合体对不同神经元标志物呈阳性染色，并显示与2D培养相比，各种神经元分化标志物的基因表达更高。在这里，我们介绍了这项新兴技术的应用和挑战。
The desire to develop and evaluate drugs as potential countermeasures for biological and chemical threats requires test systems that can also substitute for the clinical trials normally crucial for drug development. Current animal models have limited predictivity for drug efficacy in humans as the large majority of drugs fails in clinical trials. We have limited understanding of the function of the central nervous system and the complexity of the brain, especially during development and neuronal plasticity. Simple in vitro systems do not represent physiology and function of the brain. Moreover, the difficulty of studying interactions between human genetics and environmental factors leads to lack of knowledge about the events that induce neurological diseases. Microphysiological systems (MPS) promise to generate more complex in vitro human models that better simulate the organ’s biology and function. MPS combine different cell types in a specific three-dimensional (3D) configuration to simulate organs with a concrete function. The final aim of these MPS is to combine different “organoids” to generate a human-on-a-chip, an approach that would allow studies of complex physiological organ interactions. The recent discovery of induced pluripotent stem cells (iPSCs) gives a range of possibilities allowing cellular studies of individuals with different genetic backgrounds (e.g., human disease models). Application of iPSCs from different donors in MPS gives the opportunity to better understand mechanisms of the disease and can be a novel tool in drug development, toxicology, and medicine. In order to generate a brain-on-a-chip, we have established a 3D model from human iPSCs based on our experience with a 3D rat primary aggregating brain model. After four weeks of differentiation, human 3D aggregates stain positive for different neuronal markers and show higher gene expression of various neuronal differentiation markers compared to 2D cultures. Here we present the applications and challenges of this emerging technology.