Microphysiological Neurovascular Barriers to Model the Inner Retinal Microvasculature

Abstract

Blood-neural barriers regulate nutrient supply to neuronal tissues and prevent neurotoxicity. In particular, the inner blood-retinal barrier (iBRB) and blood-brain barrier (BBB) share common origins in development, and similar morphology and function in adult tissue, while barrier breakdown and leakage of neurotoxic molecules can be accompanied by neurodegeneration. Therefore, pre-clinical research requires human in vitro models that elucidate pathophysiological mechanisms and support drug discovery, to add to animal in vivo modeling that poorly predict patient responses. Advanced cellular models such as microphysiological systems (MPS) recapitulate tissue organization and function in many organ-specific contexts, providing physiological relevance, potential for customization to different population groups, and scalability for drug screening purposes. While human-based MPS have been developed for tissues such as lung, gut, brain and tumors, few comprehensive models exist for ocular tissues and iBRB modeling. Recent BBB in vitro models using human cells of the neurovascular unit (NVU) showed physiological morphology and permeability values, and reproduced brain neurological disorder phenotypes that could be applicable to modeling the iBRB. Here, we describe similarities between iBRB and BBB properties, compare existing neurovascular barrier models, propose leverage of MPS-based strategies to develop new iBRB models, and explore potentials to personalize cellular inputs and improve pre-clinical testing.

Keywords: 3D models; blood-neural barriers; disease modeling; inner blood-retinal barrier; microphysiological systems; neurovascular unit; organ-on-a-chip.

Figure 1

Healthy and diseased NVU. (a) Vascularization in brain development originates from the PNVP with sprouting vessels extending along neural stem and progenitor cells and oligodendrocyte precursors that give rise to differentiated neuronal cell types; (b) In retinal development, an astrocyte network forms radially from the optic nerve to the periphery followed by sprouting vessels that vascularize the neuroretina following the astrocyte network, as shown in the retinal flat mounts and cross section of the retinal layers; (c) Neurovascular unit composed of endothelial cells, pericytes and astrocytes with structural features in healthy conditions (left), and during barrier breakdown (right). Adapted from [73,83].

Figure 2

Personalized approaches for neurovascular barrier models. Patient or donor tissue is a source for cellular and genetic manipulation with the aim of treating patients through regenerative medicine or disease modeling approaches. Self-organization of relevant cell types in MPS models provide valuable tools to test targets in a personalized manner and develop drugs that are pre-validated in vitro on autologous cells. Created with BioRender.com.