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。通过皮肤吸收的化学物质可能在肝脏代谢，而受影响的肝脏也可能影响皮肤。由于技术上的挑战，集中于研究这种串扰的研究是有限的，并且产生了误导性和相互矛盾的结果。由于真皮的副作用，有必要建立一种新的体外仿生多器官模型来研究皮肤与相关器官的相互作用。 大多数商业上可用的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、免疫反应或阻止化学扩散的屏障层。此外，在以前的模型中使用的皮肤活检受到捐赠者特有的变异的影响。主要的挑战是开发一种综合平台，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向所有细胞层提供长期的功能器官，同时保持最上层的气液界面。对于肝脏模型，目前的芯片上肝脏模型仍然缺乏必要的细胞类型和生理相关的结构。此外，由于血管与器官系统有密切的相互作用，血管化可以改善它们的性能。目前还没有通过血管系统将两个仿生功能器官(特别是皮肤和肝脏模型)整合在一起的系统。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。 在这里，我们建议开发一种仿生皮肤模型，利用微流体方法集成微型化的肝脏和血管系统。这种多器官模型可以用来描述皮肤和相关器官的相互作用，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寿命和性能的影响；2)表征每个器官不同生物标记物的消耗和释放，以确定合适的生物标记物；以及3)开发多个器官长期共培养的共同介质。拟议的芯片上的皮肤血管系统肝脏模型(SVLOC)将有可能满足预测新的和现有的化学品和药物对皮肤、血管系统或肝脏的致敏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 skin­vasculature­liver 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.