Brain-on-a-Chip and Blood-Brain Barrier–on-a-Chip Modeling for Neurodegenerative Disorders: Recent Progress

Brain-on-a-chip is a microphysiologic platform that comprises cultured brain cells to understand brain disease pathogenesis and treatment. The blood-brain barrier (BBB) of the neurovascular unit serves as a highly selective molecular transport interface for brain homeostasis. BBB dysfunction promotes neuroinflammation, exacerbates disease progression, and contributes to neurodegenerative diseases. However, the mechanisms of BBB disruption underlying brain disorders remain poorly understood; thus, developing neurotherapeutics that can effectively cross the BBB remains a major challenge. Recent advances in microfluidic brain-on-a-chip platforms now enable the creation of BBB-on-a-chip systems that replicate key structural and functional aspects of the human BBB under dynamic flow conditions. Integration of microelectrode arrays into these microfluidic systems enhances their utility by enabling high-throughput drug screening and targeted delivery, allowing real-time monitoring of neuronal activity and network behavior. Although current brain organoid, brain-on-a-chip, and BBB-on-a-chip platforms remain in developmental stages, significant progress has been made using induced pluripotent stem cell-derived neurons, astrocytes, endothelial cells, pericytes, and microglia from healthy individuals and patients with neurodegenerative diseases. This review highlights recent advances in brain- and BBB-on-a-chip technologies and their potential applications in studying disease pathogenesis and preclinical drug screening for neurodegenerative disorders.