Bioengineering approaches for modelling retinal pathologies of the outer blood-retinal barrier

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.