Liu Nien-Che, Liang Chu-Chun, Li Yi-Chen Ethan, Lee I-Chi
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300044, Taiwan.
Department of Chemical Engineering, Feng Chia University, Taichung 407102, Taiwan.
Pharmaceutics. 2022 May 9;14(5):1022. doi: 10.3390/pharmaceutics14051022.
Stem cell-based in vitro models may provide potential therapeutic strategies and allow drug screening for neurodegenerative diseases, including Alzheimer's disease (AD). Herein, we develop a neural stem cell (NSC) spheroid-based biochip that is characterized by a brain-like structure, well-defined neural differentiation, and neural network formation, representing a brain-on-a-chip. This system consisted of microelectrode arrays with a multichannel platform and allowed the real-time monitoring of network formation and degeneration by impedance analysis. The parameters of this platform for the real-time tracking of network development and organization were established based on our previous study. Subsequently, β-amyloid (Aβ) was added into the brain-on-a-chip system to generate an AD-on-a-chip model, and toxic effects on neurons and the degeneration of synapses were observed. The AD-on-a-chip model may help us to investigate the neurotoxicity of Aβ on neurons and neural networks in real time. Aβ causes neural damage and accumulates around neurites or inside neurospheroids, as observed by immunostaining and scanning electron microscopy (SEM). After incubation with Aβ, reactive oxygen species (ROS) increased, synapse function decreased, and the neurotransmitter-acetylcholine (ACh) concentration decreased were observed. Most importantly, the real-time analysis system monitored the impedance value variation in the system with Aβ incubation, providing consecutive network disconnection data that are consistent with biological data. This platform provides simple, real-time, and convenient sensing to monitor the network microenvironment. The proposed AD-on-a-chip model enhances the understanding of neurological pathology, and the development of this model provides an alternative for the study of drug discovery and cell-protein interactions in the brain.
基于干细胞的体外模型可能提供潜在的治疗策略，并允许对包括阿尔茨海默病（AD）在内的神经退行性疾病进行药物筛选。在此，我们开发了一种基于神经干细胞（NSC）球体的生物芯片，其特征在于具有类脑结构、明确的神经分化和神经网络形成，代表了一种芯片上的大脑。该系统由具有多通道平台的微电极阵列组成，并允许通过阻抗分析实时监测网络的形成和退化。基于我们之前的研究建立了该平台用于实时跟踪网络发育和组织的参数。随后，将β-淀粉样蛋白（Aβ）添加到芯片上的大脑系统中以生成芯片上的AD模型，并观察到对神经元的毒性作用和突触的退化。芯片上的AD模型可能有助于我们实时研究Aβ对神经元和神经网络的神经毒性。通过免疫染色和扫描电子显微镜（SEM）观察到，Aβ会导致神经损伤并在神经突周围或神经球体内积聚。与Aβ孵育后，观察到活性氧（ROS）增加、突触功能下降以及神经递质乙酰胆碱（ACh）浓度降低。最重要的是，实时分析系统监测了Aβ孵育时系统中的阻抗值变化，提供了与生物学数据一致的连续网络断开数据。该平台提供简单、实时且方便的传感以监测网络微环境。所提出的芯片上的AD模型增强了对神经病理学的理解，并且该模型的开发为大脑中药物发现和细胞-蛋白质相互作用的研究提供了一种替代方法。
