Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip

Thomas L. Maurissen, Alena J. Spielmann, Gabriella Schellenberg, Marc Bickle, Jose Ricardo Vieira, Si Ying Lai, Georgios Pavlou, Sascha Fauser, Peter D. Westenskow, Roger D. Kamm () and Héloïse Ragelle ()
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Thomas L. Maurissen: F. Hoffmann-La Roche Ltd
Alena J. Spielmann: F. Hoffmann-La Roche Ltd
Gabriella Schellenberg: F. Hoffmann-La Roche Ltd
Marc Bickle: F. Hoffmann-La Roche Ltd
Jose Ricardo Vieira: F. Hoffmann-La Roche Ltd
Si Ying Lai: F. Hoffmann-La Roche Ltd
Georgios Pavlou: Massachusetts Institute of Technology
Sascha Fauser: F. Hoffmann-La Roche Ltd
Peter D. Westenskow: F. Hoffmann-La Roche Ltd
Roger D. Kamm: Massachusetts Institute of Technology
Héloïse Ragelle: F. Hoffmann-La Roche Ltd

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Diabetic retinopathy (DR) is a microvascular disorder characterized by inner blood-retinal barrier (iBRB) breakdown and irreversible vision loss. While the symptoms of DR are known, disease mechanisms including basement membrane thickening, pericyte dropout and capillary damage remain poorly understood and interventions to repair diseased iBRB microvascular networks have not been developed. In addition, current approaches using animal models and in vitro systems lack translatability and predictivity to finding new target pathways. Here, we develop a diabetic iBRB-on-a-chip that produces pathophysiological phenotypes and disease pathways in vitro that are representative of clinical diagnoses. We show that diabetic stimulation of the iBRB-on-a-chip mirrors DR features, including pericyte loss, vascular regression, ghost vessels, and production of pro-inflammatory factors. We also report transcriptomic data from diabetic iBRB microvascular networks that may reveal drug targets, and examine pericyte-endothelial cell stabilizing strategies. In summary, our model recapitulates key features of disease, and may inform future therapies for DR.

Date: 2024
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DOI: 10.1038/s41467-024-45456-z

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