Microfluidic cellular models, commonly referred to as "organs-on-chips," continue to advance the field of bioengineering via the development of accurate and higher throughput models, captivating the essence of living human organs. This class of models can mimic key in vivo features, including shear stresses and cellular architectures, in ways that cannot be realized by traditional two-dimensional in vitro models. Despite such progress, current organ-on-a-chip models are often overly complex, require highly specialized setups and equipment, and lack the ability to easily ascertain temporal and spatial differences in the transport kinetics of compounds translocating across cellular barriers. To address this challenge, we report the development of a three-dimensional human blood brain barrier (BBB) microfluidic model (μHuB) using human cerebral microvascular endothelial cells (hCMEC/D3) and primary human astrocytes within a commercially available microfluidic platform. Within μHuB, hCMEC/D3 monolayers withstood physiologically relevant shear stresses (2.73 dyn/cm2) over a period of 24 hr and formed a complete inner lumen, resembling in vivo blood capillaries. Monolayers within μHuB expressed phenotypical tight junction markers (Claudin-5 and ZO-1), which increased expression after the presence of hemodynamic-like shear stress. Negligible cell injury was observed when the monolayers were cultured statically, conditioned to shear stress, and subjected to nonfluorescent dextran (70 kDa) transport studies. μHuB experienced size-selective permeability of 10 and 70 kDa dextrans similar to other BBB models. However, with the ability to probe temporal and spatial evolution of solute distribution, μHuBs possess the ability to capture the true variability in permeability across a cellular monolayer over time and allow for evaluation of the full breadth of permeabilities that would otherwise be lost using traditional end-point sampling techniques. Overall, the μHuB platform provides a simplified, easy-to-use model to further investigate the complexities of the human BBB in real-time and can be readily adapted to incorporate additional cell types of the neurovascular unit and beyond.

中文翻译：

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用于评估血脑屏障的人脑微流模型（μHuB）。

通常被称为“芯片上的器官”的微流体细胞模型通过开发精确且更高通量的模型，继续吸引生物人体器官的本质，从而继续推进生物工程领域。此类模型可以模拟传统的二维体外模型无法实现的体内关键特征，包括剪切应力和细胞结构。尽管取得了这些进展，但是当前的单芯片器官模型通常过于复杂，需要高度专业化的设置和设备，并且缺乏轻易确定跨细胞屏障转运的化合物的传输动力学的时空差异的能力。为了应对这一挑战，我们报告了使用人脑微血管内皮细胞（hCMEC / D3）和主要的人类星形胶质细胞在可商购的微流控平台内开发的三维人血脑屏障（BBB）微流模型（μHuB）。在μHuB内，hCMEC / D3单层在24小时内经受了生理相关的切应力（2.73 dyn / cm2），并形成了完整的内腔，类似于体内的血液毛细血管。μHuB中的单层细胞表达表型紧密连接标记（Claudin-5和ZO-1），在出现类似血流动力学的剪切应力后，其表达增加。当单层静态培养，适应剪切应力并进行非荧光葡聚糖（70 kDa）转运研究时，观察到的细胞损伤可忽略不计。μHuB经历了10和70 kDa葡聚糖的大小选择性渗透率，与其他BBB模型相似。但是，μHuBs具有探测溶质分布的时空变化的能力，具有捕获跨细胞单层的渗透率随时间变化的真实变化的能力，并能够评估使用传统方法可能会损失的全部渗透率点采样技术。总体而言，μHuB平台提供了一种简化的，易于使用的模型，可以进一步实时地研究人类BBB的复杂性，并且可以轻松地纳入神经血管单位及其以外的其他细胞类型。μHuB具有捕获整个时间跨细胞单层渗透率的真正变化的能力，并允许评估使用传统终点采样技术可能会丢失的完整渗透率。总体而言，μHuB平台提供了一种简化的，易于使用的模型，可以进一步实时地研究人类BBB的复杂性，并且可以轻松地纳入神经血管单位及其以外的其他细胞类型。μHuB具有捕获整个时间跨细胞单层渗透率的真正变化的能力，并允许评估使用传统终点采样技术可能会丢失的完整渗透率。总体而言，μHuB平台提供了一种简化的，易于使用的模型，可以进一步实时地研究人类BBB的复杂性，并且可以轻松地纳入神经血管单位及其以外的其他细胞类型。