Development of miniaturized multi-organ human skin-vasculature-liver model on chip (SVLOC) for biological investigation of cross-talk of multiple organs

了解皮肤与其他器官，如呼吸道、胃肠道，特别是肝脏的相互作用，是至关重要的。经皮肤吸收的化学物质可在肝脏代谢，而受影响的肝脏也可影响皮肤。针对这种串音的研究是有限的，并且由于技术上的挑战而产生了误导和矛盾的结果。由于真皮的副作用，迫切需要建立一种新型的体外仿生多器官模型来研究皮肤与相关器官的串扰。***大多数市售或现有的体外皮肤模型不包括重要的细胞类型、细胞外基质（ECM）蛋白、免疫反应或防止化学扩散的屏障层。此外，以前模型中使用的皮肤活检存在供体特异性差异。主要的挑战是开发一个集成平台，可以使皮肤内不同细胞类型的生理相关层在适当的营养供应下为所有细胞层提供长期功能器官，同时在顶层保持气液界面。对于肝脏模型，目前的肝脏芯片模型仍然缺乏必要的细胞类型和生理相关结构。此外，由于血管与器官系统有密切的相互作用，血管化可以提高它们的性能。目前还没有将两个仿生功能器官（特别是皮肤和肝脏模型）通过脉管系统连接起来的系统。主要的挑战是如何设计血管系统与器官的整合，以及如何调整不同器官和血管系统的寿命。***在此，我们建议采用微流体的方法开发一个集成了微型肝脏和血管系统的仿生皮肤模型。该多器官模型可用于表征皮肤和相关器官的串扰，并针对几个主要的生物学问题，例如：1)确定血管系统对多器官模型的寿命和性能的影响；2)表征每个器官中不同生物标志物的消耗和释放，以确定合适的生物标志物；3)开发用于多器官长期共培养的通用培养基。提出的皮肤血管-肝脏芯片模型（SVLOC）将有可能解决预测新的和现有的化学物质和药物对皮肤，血管或肝脏的致敏性或毒性潜力的迫切需求

Understanding the cross-talk of skin with other organs such as the respiratory, gastro-intestinal tract and particularly the liver, is of paramount importance. The chemical absorbed through skin may be metabolized at liver, while the affected liver may also influence the skin. The studies focused on investigating this cross-talk are limited and have produced misleading and contradictory results due to technical challenges. Due to the side effect of dermal There is an essential need to establish a novel biomimetic in vitro multi-organ model to investigate the cross-talk of skin with relevant organs.***The majority of commercially available or existing in vitro skin models do not include important cell types, extracellular matrix (ECM) proteins, immune response or the barrier layer against chemical diffusion. In addition, skin biopsies used in previous models suffer from donor-specific variations. The main challenge is to develop an integrated platform that can make physiologically relevant layers of different cell types within the skin to provide a long-term functional organ under appropriate nutrient supply to all cell layers, while maintaining an air-liquid interface at the top layer. For the liver model, the current liver on chip models still lack the essential cell types and physiologically relevant structure. Additionally, since blood vessels have a close interaction with the organ systems, vascularization can improve their performance. There is still no system integrating two biomimetic functional organs (in particular skin and liver models) interconnected through vasculature. The major challenge is how to engineer the integration of vasculature to organs and how to adjust the lifetimes of different organs and vasculature. ***Here, we propose to develop a biomimetic skin model integrated with miniaturized liver and vasculature using microfluidic approaches. This multi-organ model can be useful to characterize cross-talk of skin and associated organs and to target several principle biological questions, such as: 1) determining the impact of the vasculature system on the lifetime and performance of multi-organs models; 2) characterizing the consumption and release of different biomarkers at each organ to identify appropriate biomarkers, and 3) developing common media for long-term co-culture of multiple organs. The proposed skin-vasculature-liver model on chip (SVLOC) will have a potential to address a pressing need for predicting the allergenic or toxic potential of novel and existing chemicals and drugs on skin, vasculature or liver.**