An Engineered Neurovascular Tissue Model with Perfusable Vascular Network for Disease Modeling and Drug Screening

Authors

• YT Tung
• MJ Song
• M Ferrer

Abstract

The blood-brain-barrier (BBB) remains one of the biggest hurdles for delivering drugs into the brain due to the tight barrier and efflux transporters. There is a need for predictive human BBB in vitro assay platforms for the development of new therapies for brain diseases. Microphysiological systems (MPS) are engineered cellular models that incorporate physiological, and microfluidics features mimicking human tissues and organs, and are being developed as predictive assay platforms for drug discovery and development. Most of the current BBB MPS are limited to low throughput and not amenable to the testing of large number of drugs due to the complexity of microfluidic designs. Thus, there is a need to develop three dimensional (3D) vascularized brain tissue models with perfusion to recapitulate the BBB function in a well-based plate platform to enable high through screening of drug collections. A perfusible 3D neurovascular unit (NVU) model that includes primary human microvascular endothelial cells, pericytes, astrocytes and neuronal progenitor cells, embedded within a fibrin hydrogel had been successful developed in a 384-well format plate, with 128-microfluidic chips connecting 3 wells each (inlet-vasculature-outlet). Perfusion of the NVU vessels was assessed by flowing fluorescently labeled 70kDa or 10kDa dextran dyes solutions from the inlet well and monitoring fluorescence within the vasculature lumens using high content imaging. This NVU platform is perfusible for more than 2 weeks and during this time, neuronal progenitors mature to neuronal and oligodendrocytes. This multi-well MPS NVU model is now used to model drug permeability, glioblastoma growth and neuroinflammatory diseases.

Scientific Focus Area: Biomedical Engineering and Biophysics

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