心血管疾病仍然比所有癌症加在一起夺走更多人的生命，这促使了改进研究模型和治疗选择的需求。尽管从诱导多能干细胞（iPSCs）开始发展成熟的心脏芯片模型在纤维化和心肌病方面取得了显著进展，但缺乏心肌炎的人类细胞模型。在这里，我们通过生物工程创建了一个血管化的心脏芯片系统，并用循环免疫细胞来模拟SARS-CoV-2诱导的急性心肌炎。简而言之，我们观察到 COVID-19 诱导的心肌炎在心脏芯片模型中的标志，免疫细胞的存在增强了促炎因子的表达水平，引发了逐渐恶化的收缩功能障碍和改变的细胞内钙离子转换活动。首先，在体外心脏芯片模型中测量到循环细胞游离线粒体DNA（ccf-mtDNA）的升高，然后在 COVID-19 患者低左室射血分数（LVEF）中得到验证，证明线粒体损伤是炎症诱导心脏功能障碍的重要病理生理标志。在 SARS-CoV-2 诱导的心肌炎背景下，利用这个平台，我们建立了通过TLR-NF-kB信号轴给予人类脐静脉来源的外泌体有效的抢救收缩缺陷、规范细胞内钙处理、提高收缩力和减少ccf-mtDNA和趋化因子释放的方法。

Cardiovascular disease continues to take more human lives than all cancer combined, prompting the need for improved research models and treatment options. Despite a significant progress in development of mature heart-on-a-chip models of fibrosis and cardiomyopathies starting from induced pluripotent stem cells (iPSCs), human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip system with circulating immune cells to model SARS-CoV-2-induced acute myocarditis. Briefly, we observed hallmarks of COVID-19-induced myocardial inflammation in the heart-on-a-chip model, as the presence of immune cells augmented the expression levels of proinflammatory cytokines, triggered progressive impairment of contractile function and altered intracellular calcium transient activities. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the in vitro heart-on-a-chip model and then validated in COVID-19 patients with low left ventricular ejection fraction (LVEF), demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2 induced myocardial inflammation, we established that administration of human umbilical vein-derived EVs effectively rescued the contractile deficit, normalized intracellular calcium handling, elevated the contraction force and reduced the ccf- mtDNA and chemokine release via TLR-NF-kB signaling axis.