Human Brain Organoids-on-Chip: Advances, Challenges, and Perspectives for Preclinical Applications

There is an urgent need for predictive in vitro models to improve disease modeling and drug target identification and validation, especially for neurological disorders. Cerebral organoids, as alternative methods to in vivo studies, are powerful tools to decipher complex biological processes thanks to their ability to recapitulate many features of the human brain. Combining these models with microfluidic technologies (brain organoids-on-chips) allows modeling the microenvironment of several neuronal cell types in 3D, opening avenues for relevant in vitro approaches for preclinical applications in neuroscience. Transfer to pharmaceutical drug discovery and adoption by the scientific community require innovative microphysiological systems that generate reproducible, high-quality cerebral organoids with structural and functional maturation, compatible with automation and high-throughput screening. This review focuses on the advantages of cerebral organoids for disease modeling and how their combination with microfluidic systems can enhance reproducibility and quality. It concludes by explaining why brain organoids-on-chips are promising platforms for pharmacological applications.