美国乔治亚理工学院Wilbur A. Lam课题组宣布他们研究出通过芯片上的血栓炎症解决临床相关的血栓。相关论文于2025年4月2日发表在《自然》杂志上。

在这里，课题组人员介绍了一种基于水凝胶的血栓炎症芯片模型，该模型具有长期培养能力，可以模拟微血管血栓炎症，并在临床和生理相关的时间尺度（长达数月）内监测血栓溶解。使用该系统，研究团队绘制了微血管血栓炎症中血块溶解的不同时间阶段。使用多路复用RNA荧光原位杂交结合他们的血栓炎症芯片模型，小组观察到炎症改变内皮纤维蛋白溶解平衡，有利于血栓形成，并确定中性粒细胞弹性蛋白酶是一把双刃剑，诱导血栓溶解，但也导致组织损伤。

然后该研究团队研究了预防微血管血栓形成或加速血栓溶解的潜在治疗药物的机制。具体来说，研究人员观察到，在血栓炎症中，(1)早期组织纤溶酶原激活剂在3H直接改善内皮屏障功能；(2)预防性去纤维肽和依诺肝素通过内皮介导的机制抑制微血管血栓炎症；(3)依诺肝素联合克里赞单抗降低镰状细胞病微血管闭塞，保护内皮功能。这些数据介绍了一种范式，用于研究血栓炎性凝块溶解的潜在机制并进行药物发现。

据悉，血栓炎症发生在多种疾病中，可导致危及生命的微血管闭塞并导致终末器官衰竭。重要的是，由于微血管的规模小，这个过程持续时间长（几周到几个月），微血管血栓炎症如何解决仍然知之甚少。

附：英文原文

Title: Clinically relevant clot resolution via a thromboinflammation-on-a-chip

Author: Qiu, Yongzhi, Lin, Jessica, Wang, Audrey, Fang, Zhou, Sakurai, Yumiko, Choi, Hyoann, Williams, Evelyn K., Hardy, Elaissa T., Maher, Kristin, Coskun, Ahmet F., Woods, Gary, Lam, Wilbur A.

Issue&Volume: 2025-04-02

Abstract: Thromboinflammation occurs in various diseases, leading to life-threatening microvascular occlusion with resulting end-organ failure1,2,3,4. Importantly, how microvascular thromboinflammation resolves remains poorly understood due to the small size-scale of microvasculature and the long duration (weeks to months) of this process. Here we introduce a hydrogel-based thromboinflammation-on-a-chip model with long-term culture capabilities to model microvascular thromboinflammation and monitor clot resolution over clinically and physiologically relevant timescales (up to months). Using this system, we mapped out the distinct temporal phases of clot resolution in microvascular thromboinflammation. Using multiplexed RNA fluorescence in situ hybridization in combination with our thromboinflammation-on-a-chip model, we observed that inflammation shifts the endothelium fibrinolytic balance to favour thrombosis and pinpointed neutrophil elastase as a double-edged sword that induces clot resolution but also tissue damage. We then investigated the mechanisms of potential therapeutic agents that either prevent microvascular thrombosis or accelerate clot resolution. Specifically, we observed that, in thromboinflammation, (1) early tissue plasminogen activator administration within 3h directly improves endothelial barrier function; (2) prophylactic defibrotide and enoxaparin suppress microvascular thromboinflammation through endothelium-mediated mechanisms; and (3) combining enoxaparin with crizanlizumab reduces microvascular occlusion and protects endothelial function in sickle cell disease. These data introduce a paradigm in investigating the underlying mechanisms of thromboinflammatory clot resolution and conducting drug discovery thereof.

DOI: 10.1038/s41586-025-08804-7

Source: https://www.nature.com/articles/s41586-025-08804-7