A Next-Generation 3D Tissue-Engineered Model of the Human Brain Microvasculature to Study the Blood-Brain Barrier

Abstract

More than a billion people are affected by neurological disorders, and few have effective therapeutic options. A key challenge that has prevented promising preclinically proven strategies is the translation gap to the clinic. Humanized tissue engineering models that recreate the brain environment may aid in bridging this translational gap. Here, we showcase the methodology that allows for the practical fabrication of a comprehensive microphysicological system (MPS) of the blood-brain barrier (BBB). Compared to other existing 2D and 3D models of the BBB, this model features relevant cytoarchitecture and multicellular arrangement, with branching and network topologies of the vascular bed. This process utilizes 3D bioprinting with digital light processing to generate a vasculature lumen network surrounded by embedded human astrocytes. The lumens are then cellularized with primary human brain microvascular endothelial cells and pericytes. To initiate mechanotransduction pathways and complete maturation, vascular structures are continuously perfused for 7 days. Constructs are validated for complete endothelialization with viability dyes prior to functional assessments that include barrier integrity (permeability) and immune-endothelial interactions. This MPS has applications for the study of novel therapeutics, toxins, and elucidating mechanisms of pathophysiology.

Involvement of Astrocytes in the Formation, Maintenance, and Function of the Blood–Brain Barrier

“…In vitro testing platforms, named microphysiological systems (MPSs), have been, in particular, used for the analysis of the ability of drugs to cross the BBB [170,171]. A microfluidic in vitro BBB model (BBB-on-a-chip) has been used to evaluate the possibility to study, in a human in vitro system, the permeability of nanoparticles loaded with therapeutic agents [158,172].…”

Fabrication Method for Shape-Controlled 3D Tissue Using High-Porosity Porous Structure

“…The biological function of 3D tissues more closely resembles that of natural living tissues than that of 2D cell layers [1][2][3][4][5]. These 3D tissues are used in various types of research, such as regenerative medicine [6,7], drug discovery [8][9][10], and biological robotics [11][12][13].…”