Sensorization of microfluidic brain-on-a-chip devices: Towards a new generation of integrated drug screening systems

Brain-on-a-chip (BoC) devices show typical characteristics of brain complexity, including the presence of different cell types, separation in different compartments, tissue-like three-dimensioality, and inclusion of the extracellular matrix components. Moreover, the incorporation of a vascular system mimicking the blood-brain barrier (BBB) makes BoC particularly attractive, since they can be exploited to test the brain delivery of different drugs and nanoformulations. In this review, we introduce the main innovations in BoC and BBBonachip models, especially focusing sensorization: electrical, electrochemical, and optical biosensors permit the realtime monitoring of different biological phenomena and markers, such as the release of growth factors, the expression of specific receptors/biomarkers, the activation of immune cells, cell viability, cell-cell interactions, and BBB crossing of drugs and nanoparticles. The recent improvements in signal amplification, miniaturization, and multiplication of the sensors are discussed in an effort to highlight their benefits versus limitations and delineate future challenges in this field.