Organ-On-A-Chip Technologies for Advanced Blood–Retinal Barrier Models

Abstract

The blood-retinal barrier (BRB) protects the retina by maintaining an adequate microenvironment for neuronal function. Alterations of the junctional complex of the BRB and consequent BRB breakdown in disease contribute to a loss of neuronal signaling and vision loss. As new therapeutics are being developed to prevent or restore barrier function, it is critical to implement physiologically relevant in vitro models that recapitulate the important features of barrier biology to improve disease modeling, target validation, and toxicity assessment. New directions in organ-on-a-chip technology are enabling more sophisticated 3-dimensional models with flow, multicellularity, and control over microenvironmental properties. By capturing additional biological complexity, organs-on-chip can help approach actual tissue organization and function and offer additional tools to model and study disease compared with traditional 2-dimensional cell culture. This review describes the current state of barrier biology and barrier function in ocular diseases, describes recent advances in organ-on-a-chip design for modeling the BRB, and discusses the potential of such models for ophthalmic drug discovery and development.

Human Retinal Microvasculature‐on‐a‐Chip for Drug Discovery

“…[24] While several organ-on-a-chip models of the oBRB have been developed, there are currently no such models for the iBRB. [24][25][26] In this manuscript, we describe a humanized organon-a-chip model of the retinal microvasculature that integrates 3D architecture of human retinal microvascular endothelial cells (hRMVECs), perfusion, and an ECM to mimic the vascular microenvironment and model iBRB barrier properties. We show that the retinal microvasculature-on-a-chip recapitulates important features of barrier biology including low permeability, formation of junctional complexes, and pro-inflammatory cytokineinduced permeability.…”

Degenerative disease‐on‐a‐chip: Developing microfluidic models for rapid availability of newer therapies

“…It also controls the efflux transporters that participate in the entry and exit of drugs, based on their physicochemical properties, structure and sizes. [ 81 ] BRB is composed of two distinct barriers, the inner BRB (iBRB) consisting of retinal endothelial cells with highly organized tight junctions and the vesicles responsible for transcellular transport, restricting the non‐specific passage of circulating toxins and pathogens from the vascular circulation. The outer BRB (oBRB) consists of retinal pigment epithelial cells (RPE) that govern the choriocapillaris flux.…”

“…The VEGF acts as a stimulating factor for caveolae‐mediated transcytosis, in a nitric oxide synthase‐dependent manner. [ 81,83 ] Hyperglycemia has been studied for its by‐product formation; the glycation end‐product responsible for increase in caveolar mediated transport and leading to a compromised role of BRB. [ 84 ] Also, some of the pro‐inflammatory cytokines alter the tight junction complexes and thereby affect the paracellular permeability.…”

Coculture techniques for modeling retinal development and disease, and enabling regenerative medicine

“…These cells are attached to their basement membrane which forms the innermost layer of Bruch's membrane, and whose outermost membrane is formed by the basement membrane of the choroidal endothelium. 32 The degree to which these three layers are interdependent is critical to accurate modeling of disease and regener- 38,80,99,100 Here, we will aim to answer the above questions, which are of relevance to the development of in vitro systems for testing regenerative therapies.…”

“…Other recent reviews have looked broadly at the current state of oBRB modelling. 38,80,99,100 Here, we will aim to answer the above questions, which are of relevance to the development of in vitro systems for testing regenerative therapies.…”