Diffuse axonal injury (DAI) is the most severe pathological feature of traumatic brain injury (TBI). However, how primary axonal injury is induced by transient mechanical impacts remains unknown, mainly due to the low temporal and spatial resolution of medical imaging approaches. Here we established an axon-on-a-chip (AoC) model for mimicking DAI and monitoring instant cellular responses. Integrating computational fluid dynamics and microfluidic techniques, DAI was induced by injecting a precisely controlled micro-flux in the transverse direction. The clear correlation between the flow speed of injecting flux and the severity of DAI was elucidated. We next used the AoC to investigate the instant intracellular responses underlying DAI and found that the dynamic formation of focal axonal swellings (FAS) accompanied by Ca²⁺ surge occurs during the flux. Surprisingly, periodic axonal cytoskeleton disruption also occurs rapidly after the flux. These instant injury responses are spatially restricted to the fluxed axon, not affecting the overall viability of the neuron in the acute stage. Compatible with high-resolution live microscopy, the AoC provides a versatile system to identify early mechanisms underlying DAI, offering a platform for screening effective treatments to alleviate TBI.

中文翻译：

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用于模拟创伤性脑损伤潜在的非破坏性弥漫性轴突损伤的片上轴突

弥漫性轴索损伤（DAI）是创伤性脑损伤（TBI）最严重的病理特征。然而，暂时的机械冲击如何引起原发性轴突损伤仍然未知，这主要是由于医学成像方法的时间和空间分辨率较低。在这里，我们建立了一个轴突芯片 (AoC) 模型来模拟 DAI 和监测即时细胞反应。结合计算流体动力学和微流体技术，通过在横向方向注入精确控制的微通量来诱导 DAI。阐明了注入助焊剂的流速与 DAI 严重程度之间的明确相关性。我们接下来使用 AoC 来研究 DAI 下的即时细胞内反应，发现局灶性轴突肿胀 (FAS) 的动态形成伴随着 Ca ²⁺在通量期间发生浪涌。令人惊讶的是，周期性轴突细胞骨架破坏也会在通量后迅速发生。这些即时损伤反应在空间上仅限于变化的轴突，不会影响急性期神经元的整体活力。AoC 与高分辨率活体显微镜兼容，提供了一个多功能系统来识别 DAI 的早期机制，为筛选有效治疗以减轻 TBI 提供了一个平台。