The blood-brain barrier (BBB) regulates molecular trafficking, protects against pathogens, and prevents efficient drug delivery to the brain. Models to date failed to reproduce the human anatomical complexity of brain barriers, contributing to misleading results in clinical trials. To overcome these limitations, a novel 3-dimensional BBB microvascular network model was developed via vasculogenesis to accurately replicate the in vivo neurovascular organization. This microfluidic system includes human induced pluripotent stem cell-derived endothelial cells, brain pericytes, and astrocytes as self-assembled vascular networks in fibrin gel. Gene expression of membrane transporters, tight junction and extracellular matrix proteins, was consistent with computational analysis of geometrical structures and quantitative immunocytochemistry, indicating BBB maturation and microenvironment remodelling. Confocal microscopy validated microvessel-pericyte/astrocyte dynamic contact-interactions. The BBB model exhibited perfusable and selective microvasculature, with permeability lower than conventional in vitro models, and similar to in vivo measurements in rat brain. This robust and physiologically relevant BBB microvascular model offers an innovative and valuable platform for drug discovery to predict neuro-therapeutic transport efficacy in pre-clinical applications as well as recapitulate patient-specific and pathological neurovascular functions in neurodegenerative disease.

中文翻译：

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包含内皮细胞、周细胞和星形胶质细胞的人体血脑屏障 3D 自组织微血管模型。


血脑屏障 (BBB) 调节分子运输、抵御病原体并阻止药物有效输送至大脑。迄今为止的模型未能重现脑屏障的人体解剖复杂性，导致临床试验中出现误导性结果。为了克服这些限制，通过血管发生开发了一种新型的 3 维 BBB 微血管网络模型，以准确复制体内神经血管组织。该微流体系统包括人类诱导的多能干细胞衍生的内皮细胞、脑周细胞和星形胶质细胞，作为纤维蛋白凝胶中自组装的血管网络。膜转运蛋白、紧密连接蛋白和细胞外基质蛋白的基因表达与几何结构和定量免疫细胞化学的计算分析一致，表明血脑屏障成熟和微环境重塑。共聚焦显微镜验证了微血管-周细胞/星形胶质细胞动态接触相互作用。 BBB模型表现出可灌注和选择性的微脉管系统，其渗透性低于传统的体外模型，并且与大鼠脑中的体内测量结果相似。这种稳健且与生理相关的 BBB 微血管模型为药物发现提供了一个创新且有价值的平台，可预测临床前应用中的神经治疗转运功效，并概括神经退行性疾病中患者特异性和病理性神经血管功能。