Axons-on-a-Chip for Mimicking Non-Disruptive Diffuse Axonal Injury Underlying 2 Traumatic Brain Injury
Axons-on-a-Chip for Mimicking Non-Disruptive Diffuse Axonal Injury Underlying 2 Traumatic Brain Injury
复制标题
用于模拟 2 创伤性脑损伤下的非破坏性弥漫性轴突损伤的芯片上轴突
DOI：
10.1039/d2lc00730d
复制
发表时间：
2022
期刊：
影响因子：
6.1
通讯作者：
Wang Tong
中科院分区：
文献类型：
--
作者：
Pan Xiaorong;Li Jie;Li Wei;Wang Haofei;Durisic Nela;Li Zhenyu;Feng Yu;Liu Yifan;Zhao Chunxia;Wang Tong
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，原发性轴索损伤是如何由瞬时机械冲击引起的仍然是未知的，主要是由于医学成像方法的时间和空间分辨率低。在这里，我们建立了一个轴突芯片（AoC）模型模拟DAI和监测即时细胞反应。结合计算流体力学和微流控技术，通过在横向注入精确控制的微流量来诱导DAI。研究表明，注入焊剂的流速与DAI的严重程度存在明显的相关性。我们接下来使用AOC来研究DAI的瞬时细胞内反应，发现在通量期间发生伴随着Ca 2+浪涌的局灶性轴突鞘（FAS）的动态形成。令人惊讶的是，周期性轴突细胞骨架破坏也迅速发生后流量。这些即时损伤反应在空间上限于流动的轴突，不影响急性阶段神经元的整体活力。与高分辨率活体显微镜兼容，AoC提供了一个多功能系统来识别DAI的早期机制，为筛选有效的治疗方法以缓解TBI提供了一个平台。
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.