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

Abstract

Retinal cells within neurovascular units generate the blood-retinal barrier (BRB) to regulate the local retinal microenvironment and to limit access to inflammatory cells. Breakdown of the endothelial junctional complexes in the BRB negatively affects neuronal signaling and ultimately causes vision loss. As new therapeutics are being developed either to prevent barrier disruption or to restore barrier function, access to physiologically relevant human in vitro tissue models that recapitulate important features of barrier biology is essential for disease modeling, target validation, and toxicity assessment. Here, a tunable organ-on-a-chip model of the retinal microvasculature using human retinal microvascular endothelial cells with integrated flow is described. Automated imaging and image analysis methods are employed for facile screening of leakage mediators and cytokine inhibitors on barrier properties. The developed retinal microvasculature-on-a-chip will enable improved understanding of BRB biology and provide an additional tool for drug discovery.

A Microfluidic Eye Facsimile System to Examine the Migration of Stem-like Cells

“…Microfluidic technologies are well-suited for the study of retinal degenerative diseases, as well as the development of novel therapies, by developing models that mimic the physiological environment at the retinal microscale. Organ-on-a-chip platforms (reviewed in [ 61 , 62 ]) have been recently developed by multiple groups using retinal stem and progenitor cells (SCs) [ 63 , 64 , 65 , 66 ] or organoids [ 67 , 68 , 69 , 70 ] to recapitulate the retinal cellular niche in both healthy and disease states. Some existing systems use 3D, organotypic systems that integrate explanted retina to measure tissue viability and cytotoxicity [ 71 ], while others examine the delivery of therapeutic compounds [ 41 , 42 ].…”

Microphysiological Neurovascular Barriers to Model the Inner Retinal Microvasculature

“…For modeling the BBB, astrocytes and neuronal cells are embedded in adjacent gels to establish a BBB-like organization that can have various applications such as disease modeling [126][127][128]. For the iBRB, an endothelial barrier was used to probe permeability in response to disease triggers [129]. Similar models were achieved using the viscous fingering method or by casting the gel around needles or wires that can subsequently be removed leaving hollow tubular channels, all within a petri dish or microfluidic device, which can subsequently be seeded with cells of interest [130][131][132].…”

“…Barrier permeability can be assessed by TEER or fluorescently labeled molecules such as dextrans in combination with time-lapse imaging, depending on the model and platform. Permeability readouts can be used to assess whether barrier integrity is affected by disease triggers (e.g., VEGFA-induced permeability [129]) and test compound efficacy to prevent and/or restore barrier dysfunction. As previously discussed, crossing of molecules at the BBB can be quantified by adding a fluorescent tag to the compound of interest and measuring the accumulation of signal in the perivascular compartment (or the organoid core in case of iBRB/BBB spheroids [119,123]).…”

Adoption of organ-on-chip platforms by the pharmaceutical industry

“…OoC models have also been applied by industry researchers in disease modelling, compound screening and target identification. For example, scientists from Roche reported a human retinal microvascular tubule-on-a-chip designed to mimic the blood-retina barrier 7 , which can be disrupted in diabetic retinopathy and age-related macular degeneration. the Supplementary information have been in business for more than half a decade.…”