The shift from 2D to 3D cell culture in neurobiology: implications for precision medicine and organ-on-chip technologies

Traditional two-dimensional (2D) neurobiological models do not capture the complex spatial, mechanical, and biochemical microenvironment of the human brain. This limitation has contributed to a high failure rate in translating neuroprotective drugs from the bench to the bedside. Of this review is to explore the technological evolution toward three-dimensional (3D) systems, including neural organoids, scaffold-based hydrogels, and microfluidic Organ-on-Chip (OoC) platforms. This review discusses how these systems facilitate realistic synaptic connectivity and neurovascular unit modeling. By mimicking the native extracellular matrix (ECM) and introducing dynamic fluid flow, these models provide a more accurate representation of human CNS pathophysiology. A specific examination of the role of mechanotransduction and the blood-brain barrier (BBB) in disease progression is provided. Furthermore, the integration of patient-derived induced pluripotent stem cells (iPSCs) for high-fidelity disease modeling and personalized drug screening is highlighted, allowing for the observation of disease phenotypes—such as amyloid-beta (A β ) aggregation and phosphorylated tau—that are often absent in 2D or animal models. 3D neurobiological models represent an evolving approach toward precision medicine, providing platforms that better replicate the physiological complexities of neurodegenerative and neurodevelopmental disorders.