Abstract Reconstruction of full-thickness skin equivalents with physiologically relevant cellular and matrix architecture is gaining importance as an in vitro tool for basic research, and for the pharmaceutical, toxicological, and cosmetic industries. However, human skin equivalents reconstructed on traditional culture systems are limited by a weak skin barrier function compared to normal human skin. Probable reasons include the lack of mechanical forces and dynamic flow system that provide necessary mechanistic signals and continuous supply and/or drainage of nutrients and metabolites. Here, we combine a fibrin-based dermal matrix with a biomimetic ‘organ-on-chip’ system for the development of human skin equivalents that better recapitulate the structure and functionalities of human skin, compared to conventional static culture systems. We demonstrate that dynamic perfusion and a fine control of the microenvironment enable improved epidermal morphogenesis and differentiation, and enhanced barrier function. It is also shown that integrated 3D culturing and integrity/permeability testing can be conducted directly on the organ-on-chip device owing to the non-contracting properties of the fibrin-based dermal matrix, thus overcoming the limitations of collagen-based skin equivalents used in conventional cell culture inserts and diffusion cells. With this scalable system, it is possible to achieve higher throughput and automation of culture and testing protocols, and deliver low-cost alternatives to animal and clinical studies for drug screening and toxicological applications.

中文翻译：

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具有增强表皮形态发生和屏障功能的全层人体皮肤芯片

摘要 重建具有生理相关细胞和基质结构的全层皮肤等效物作为基础研究以及制药、毒理学和化妆品行业的体外工具越来越重要。然而，与正常人体皮肤相比，在传统培养系统上重建的人体皮肤等效物受到皮肤屏障功能较弱的限制。可能的原因包括缺乏机械力和动态流动系统，这些系统提供必要的机械信号和营养物和代谢物的连续供应和/或排放。在这里，我们将基于纤维蛋白的真皮基质与仿生“器官芯片”系统相结合，用于开发与传统静态培养系统相比更好地概括人类皮肤结构和功能的人体皮肤等效物。我们证明动态灌注和微环境的精细控制能够改善表皮形态发生和分化，并增强屏障功能。还表明，由于基于纤维蛋白的真皮基质的非收缩特性，可以直接在器官芯片装置上进​​行集成的 3D 培养和完整性/渗透性测试，从而克服了基于胶原蛋白的皮肤等效物的局限性用于常规细胞培养插入物和扩散细胞。有了这个可扩展的系统，就可以实现更高的培养和测试协议的吞吐量和自动化，并为药物筛选和毒理学应用的动物和临床研究提供低成本的替代方案。