Cold‐induced vasoconstriction is a significant contributor that leads to chilblains and hypothermia in humans. However, current animal models have limitations in replicating cold‐induced acral injury due to their low sensitivity to cold. Moreover, existing in vitro vascular chips composed of endothelial cells and perfusion systems lack temperature responsiveness, failing to simulate the vasoconstriction observed under cold stress. This study presents a novel approach where a microfluidic bioreactor of vessel‐on‐a‐chip was developed by grafting the inner microchannel surface of polydimethylsiloxane with a thermosensitive hydrogel skin composed of N‐isopropyl acrylamide and gelatin methacrylamide. With a lower critical solution temperature set at 30°C, the gel layer exhibited swelling at low temperatures, reducing the flow rate inside the channel by 10% when the temperature dropped from 37°C to 4°C. This well mimicked the blood stasis observed in capillary vessels in vivo. The vessel‐on‐a‐chip was further constructed by culturing endothelial cells on the surface of the thermosensitive hydrogel layer, and a perfused medium was introduced to the cells to provide a physiological shear stress. Notably, cold stimulation of the vessel‐on‐a‐chip led to cell necrosis, mitochondrial membrane potential (ΔΨm) collapse, cytoskeleton disaggregation, and increased levels of reactive oxygen species. In contrast, the static culture of endothelial cells showed limited response to cold exposure. By faithfully replicating cold‐induced endothelial injury, this groundbreaking thermosensitive vessel‐on‐a‐chip technology offers promising advancements in the study of cold‐induced cardiovascular diseases, including pathogenesis and therapeutic drug screening.

中文翻译：

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温度响应水凝胶移植芯片血管：探索寒冷诱导的内皮损伤


寒冷引起的血管收缩是导致人类冻疮和体温过低的重要因素。然而，目前的动物模型由于对寒冷的敏感性较低，在复制寒冷引起的肢端损伤方面存在局限性。此外，现有的由内皮细胞和灌注系统组成的体外血管芯片缺乏温度响应性，无法模拟冷应激下观察到的血管收缩。这项研究提出了一种新方法，通过将聚二甲基硅氧烷的内部微通道表面接枝到由N-异丙基丙烯酰胺和明胶甲基丙烯酰胺组成的热敏水凝胶皮，开发了芯片上容器的微流体生物反应器。当较低的临界溶液温度设置为30°C时，凝胶层在低温下表现出溶胀，当温度从37°C降至4°C时，通道内的流速降低了10%。这很好地模拟了体内毛细血管中观察到的血瘀现象。通过在热敏水凝胶层表面培养内皮细胞进一步构建芯片血管，并向细胞中引入灌注介质以提供生理剪切应力。值得注意的是，对芯片上血管的冷刺激会导致细胞坏死、线粒体膜电位（ΔΨm）崩溃、细胞骨架解聚以及活性氧水平升高。相比之下，内皮细胞的静态培养物对冷暴露的反应有限。通过忠实地复制寒冷引起的内皮损伤，这种突破性的热敏血管芯片技术为寒冷引起的心血管疾病的研究（包括发病机制和治疗药物筛选）提供了有前景的进展。