Engineered tissues can be used to model human pathophysiology and test the efficacy and safety of drugs. Yet, to model whole-body physiology and systemic diseases, engineered tissues with preserved phenotypes need to physiologically communicate. Here we report the development and applicability of a tissue-chip system in which matured human heart, liver, bone and skin tissue niches are linked by recirculating vascular flow to allow for the recapitulation of interdependent organ functions. Each tissue is cultured in its own optimized environment and is separated from the common vascular flow by a selectively permeable endothelial barrier. The interlinked tissues maintained their molecular, structural and functional phenotypes over 4 weeks of culture, recapitulated the pharmacokinetic and pharmacodynamic profiles of doxorubicin in humans, allowed for the identification of early miRNA biomarkers of cardiotoxicity, and increased the predictive values of clinically observed miRNA responses relative to tissues cultured in isolation and to fluidically interlinked tissues in the absence of endothelial barriers. Vascularly linked and phenotypically stable matured human tissues may facilitate the clinical applicability of tissue chips.

工程组织可用于模拟人类病理生理学并测试药物的功效和安全性。然而，为了模拟全身生理学和全身疾病，具有保留表型的工程组织需要进行生理通讯。在这里，我们报告了组织芯片系统的开发和适用性，其中成熟的人类心脏、肝脏、骨骼和皮肤组织生态位通过再循环血管流连接起来，以允许重现相互依赖的器官功能。每个组织都在其自己的优化环境中培养，并通过选择性渗透的内皮屏障与常见的血管流分开。相互关联的组织在培养 4 周后保持了其分子、结构和功能表型，概括了多柔比星在人体中的药代动力学和药效学特征，允许识别心脏毒性的早期 miRNA 生物标志物，并提高了临床观察到的 miRNA 反应相对的预测值。隔离培养的组织和在没有内皮屏障的情况下流体互连的组织。血管相连且表型稳定的成熟人体组织可能有助于组织芯片的临床应用。