Advancing microfluidic nerve-on-a-chip systems: From physiological simulation to disease modeling.

The nervous system stands as the most intricate regulatory system network in living organisms, characterized by its multilayered structural organization and functional diversity, from fine-scale synaptic interactions among neurons to the overarching coordination of large-scale neural circuits. This complexity underpins the diversity of neurological diseases. The emergence of microfluidic chip technologies, featuring micron-scale channel architectures and highly precise fluid manipulation, has revolutionized experimental platforms for studying neural systems. These microfluidic devices allow for the integration of multiple cell types within three-dimensional (3D) cultures, enabling the investigation of complex physiological behaviors and pathological mechanisms in vitro. This review provides an overview of physiological models developed using Nerve-on-a-Chip (NoC) systems to study neural functions, and summarizes advances in disease modeling for conditions such as neurovascular, neurodegenerative, and neuroimmune disorders. We conclude with a discussion on the strengths and limitations of NoC platforms in nervous system research and outline their potential applications and future directions in personalized medicine.