The neurovascular unit, which consists of vascular cells surrounded by astrocytic end-feet and neurons, controls cerebral blood flow and the permeability of the blood–brain barrier (BBB) to maintain homeostasis in the neuronal milieu. Studying how some pathogens and drugs can penetrate the human BBB and disrupt neuronal homeostasis requires in vitro microphysiological models of the neurovascular unit. Here we show that the neurotropism of Cryptococcus neoformans—the most common pathogen causing fungal meningitis—and its ability to penetrate the BBB can be modelled by the co-culture of human neural stem cells, brain microvascular endothelial cells and brain vascular pericytes in a human-neurovascular-unit-on-a-chip maintained by a stepwise gravity-driven unidirectional flow and recapitulating the structural and functional features of the BBB. We found that the pathogen forms clusters of cells that penetrate the BBB without altering tight junctions, suggesting a transcytosis-mediated mechanism. The neurovascular-unit-on-a-chip may facilitate the study of the mechanisms of brain infection by pathogens, and the development of drugs for a range of brain diseases.

神经血管单元由被星形胶质细胞末端足和神经元包围的血管细胞组成，控制脑血流和血脑屏障 (BBB) 的通透性以维持神经元环境中的体内平衡。研究一些病原体和药物如何穿透人类血脑屏障并破坏神经元稳态需要神经血管单元的体外微生理模型。在这里，我们表明新型隐球菌的神经嗜性- 引起真菌性脑膜炎的最常见病原体 - 及其穿透 BBB 的能力可以通过人类神经血管单元上的人类神经干细胞、脑微血管内皮细胞和脑血管周细胞的共培养来建模。芯片由逐步重力驱动的单向流维护，并概括了 BBB 的结构和功能特征。我们发现病原体形成了细胞簇，这些细胞可以穿透 BBB 而不会改变紧密连接，这表明存在转胞吞作用介导的机制。神经血管芯片单元可能有助于研究病原体感染大脑的机制，以及开发治疗一系列脑部疾病的药物。