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

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.

Modeling inherited retinal diseases using human induced pluripotent stem cell derived photoreceptor cells and retinal pigment epithelial cells

“…Organ-on-a-chip approaches have been leveraged to capture the anatomical architecture and cellular diversity of the human retina. Maurissen et al ( 122 ) developed an inner blood-retinal barrier-on-a-chip model by culturing primary human retinal microvascular cells into perfusable microvascular networks. The chip demonstrated both organization and expression of cellular markers that were similar to native tissue affected by diabetic retinopathy.…”

Complex In Vitro Model Characterization for Context of Use in Toxicologic Pathology: Use Cases by Collaborative Teams of Biologists, Bioengineers, and Pathologists

“…Owing to their special construction, MPS models often require an adaptation by direct fixation and embedding in the device in a lithographic manner 63 to preserve the morphology of the cellular network in the chamber (Figure 4E). As exemplified by the human inner blood-retinal barrier-on-a-chip 42 (Figure 4J), the fixed and embedded cell networks and layers can usually only be extracted when removing the chip material surrounding them.…”

“…(I) Intestinal organoids grown on Matrigel™ were subjected to droplet embedding to decrease the manual handling. (J) The cellular channel of a microvascular-on-a-chip 42 was embedded in agarose from inside and outside to preserve the morphology (lithography). Scale bar = 50 µm.…”