Alterations of the junctional complex of the outer blood-retinal barrier (oBRB), which is integrated by the close interaction of the retinal pigment epithelium, the Bruch's membrane, and the choriocapillaris, contribute to the loss of neuronal signalling and subsequent vision impairment in several retinal inflammatory disorders such as age-related macular degeneration and diabetic retinopathy. Reductionist approaches into the mechanisms that underlie such diseases have been hindered by the absence of adequate in vitro models using human cells to provide the 3D dynamic architecture that enables expression of the in vivo phenotype of the oBRB. Conventional in vitro cell models are based on 2D monolayer cellular cultures, unable to properly recapitulate the complexity of living systems. The main drawbacks of conventional oBRB models also emerge from the cell sourcing, the lack of an appropriate Bruch's membrane analogue, and the lack of choroidal microvasculature with flow. In the last years, the advent of organ-on-a-chip, bioengineering, and stem cell technologies is providing more advanced 3D models with flow, multicellularity, and external control over microenvironmental properties. By incorporating additional biological complexity, organ-on-a-chip devices can mirror physiologically relevant properties of the native tissue while offering additional set ups to model and study disease. In this review we first examine the current understanding of oBRB biology as a functional unit, highlighting the coordinated contribution of the different components to barrier function in health and disease. Then we describe recent advances in the use of pluripotent stem cells-derived retinal cells, Bruch's membrane analogues, and co-culture techniques to recapitulate the oBRB. We finally discuss current advances and challenges of oBRB-on-a-chip technologies for disease modelling.

由视网膜色素上皮、布鲁赫膜和脉络膜毛细血管的紧密相互作用整合而成的外血-视网膜屏障 (oBRB) 连接复合体的改变导致神经元信号传导的丧失和随后的视力损害。视网膜炎症性疾病，如年龄相关性黄斑变性和糖尿病视网膜病变。由于缺乏足够的体外模型，使用人体细胞来提供能够表达 oBRB 体内表型的 3D 动态结构，这阻碍了对这些疾病背后机制的还原论方法。传统的体外细胞模型基于二维单层细胞培养，无法正确概括生命系统的复杂性。传统 oBRB 模型的主要缺点也来自细胞来源、缺乏适当的布鲁赫膜类似物以及缺乏流动的脉络膜微血管。在过去几年中，器官芯片、生物工程和干细胞技术的出现提供了更先进的 3D 模型，这些模型具有流动性、多细胞性和对微环境特性的外部控制。通过结合额外的生物复杂性，芯片上的器官设备可以反映天然组织的生理相关特性，同时提供额外的设置来建模和研究疾病。在这篇综述中，我们首先检查了当前对 oBRB 生物学作为一个功能单元的理解，强调了不同成分对健康和疾病屏障功能的协调贡献。然后我们描述了使用多能干细胞衍生的视网膜细胞、布鲁赫膜类似物和共培养技术来概括 oBRB 的最新进展。最后，我们讨论了用于疾病建模的 oBRB-on-a-chip 技术的当前进展和挑战。