Constant-rate perfused array chip for high-throughput screening of drug permeability through brain endothelium,Lab on a Chip

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Constant-rate perfused array chip for high-throughput screening of drug permeability through brain endothelium
Lab on a Chip ( IF 6.1 ) Pub Date : 2022-10-18 , DOI: 10.1039/d2lc00507g
Rong-Rong Xiao ₁ , Bolin Jing ₂ , Lei Yan ₁ , Jiajia Li ₁ , Pengfei Tu ₂ , Xiaoni Ai ₂

Affiliation

The development of an in vitro model for predicting drug permeability through the human blood–brain barrier (BBB) will greatly accelerate the development of neural therapy. Previously reported platforms for BBB model construction cannot meet the requirements of constant-rate and high-throughput flow, as well as compatibility with the commercial meter for real-time transendothelial electrical resistance (TEER) measurement. Herein, a constant-rate perfused array chip (cPAC) was developed to establish a brain endothelium model for screening drug permeability. The cPAC consisted of 24 units with four layers. Three reservoirs on the top had a 0.5 mm center-to-center spacing, enabling real-time detection of the TEER with the commercial volt–ohm meter. With the optimized chip design, the constant-rate and high-throughput flow by gravity was achieved. Compared with the static culture of the Transwell, the brain endothelium model on the cPAC exhibited superior performance in barrier function, efflux functionality of the transporters, and reversible osmotic opening of the brain endothelium. More importantly, the permeability of model drugs on the cPAC matched the in vivo results with the correlation coefficient reaching 0.994. Finally, the brain endothelium model was cocultured with 3D tumor cells for simultaneous evaluation of drug permeability and brain tumor therapy. The drug efficacy at the target cells on the coculture model was also consistent with clinical findings. These results demonstrated that this platform provides a promising tool for brain endothelium model establishment to predict drug permeability and brain therapy. We anticipate the cPAC to be widely accepted for establishing various barrier models.

中文翻译：

恒速灌注阵列芯片高通量筛选脑内皮药物通透性

体外开发预测药物通过人血脑屏障 (BBB) 渗透性的模型将大大加速神经疗法的发展。以前报道的 BBB 模型构建平台不能满足恒定速率和高通量流量的要求，也不能与用于实时跨内皮电阻 (TEER) 测量的商用仪表兼容。在此，开发了恒速灌注阵列芯片（cPAC）以建立用于筛选药物渗透性的脑内皮模型。cPAC 由四层的 24 个单元组成。顶部的三个储层中心间距为 0.5 毫米，可以使用商用伏特计实时检测 TEER。通过优化的芯片设计，实现了重力恒速高通量流动。与 Transwell 的静态培养相比，cPAC 上的脑内皮模型在屏障功能、转运体的外排功能和脑内皮的可逆渗透开放方面表现出优越的性能。更重要的是，模型药物在 cPAC 上的渗透性与体内结果相关系数达到0.994。最后，将脑内皮模型与 3D 肿瘤细胞共培养，以同时评估药物渗透性和脑肿瘤治疗。共培养模型上靶细胞的药效也与临床发现一致。这些结果表明，该平台为建立脑内皮模型以预测药物渗透性和脑治疗提供了一个有前途的工具。我们预计 cPAC 将被广泛接受以建立各种障碍模型。

更新日期：2022-10-18

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