Advancements in modelling human blood brain-barrier on a chip.

The human Blood Brain Barrier (hBBB) is a complex cellular architecture separating the blood from the brain parenchyma. Its integrity and perfect functionality are essential for preventing that neurotoxic plasma components and pathogens enter the brain. Although vital for preserving the correct brain activity, the low permeability of hBBB represents a huge impediment to treat mental and neurological disorders or to adress brain tumors. Indeed, the vast majority of potential drug treatments are unable to reach the brain crossing the hBBB. On the other hand, hBBB integrity can be damaged or its permeability increas as result of infections or in presence of neurodegenerative diseases. Current in vitro systems and in vivo animal models used to study the molecular/drug transport mechanism through the hBBB have several intrinsic limitations that are difficult to be overcome. In this scenario, Organ-on-Chip (OoC) models based on microfluidic technologies are considered promising innovative platforms that combine the handiness of an in vitro model with the complexity of a living organ, while reducing time and costs. In this review, we focus on recent advances in OoCs for developing hBBB models, with the aim of providing the reader a critical overview of the main guidelines to design and manufacture a hBBB-on-chip, featuring chip areas able to mimick the "blood side" and "brain side", to choose the cells types that are both representative and convenient, and to adequatly evaluate the barrier integrity, stability, and functionality.