The Shift from 2D to 3D Cell Culture in Neurobiology: Implications for Precision Medicine and Organ-on-Chip Technologies

Background: Traditional two-dimensional (2D) neurobiological models fail to 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 bench to bedside. Main body: This review explores 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. Specific examination is provided regarding the role of mechanotransduction and the blood-brain barrier (BBB) in disease progression. Furthermore, the integration of patient-derived induced pluripotent stem cells (iPSCs) for high-fidelity disease modeling and personalized drug screening are highlighted, which allows for the observation of disease phenotypes—such as amyloid-beta aggregation and phosphorylated tau—that are often absent in 2D or animal models. Conclusion: 3D neurobiological models represent a transformative shift toward precision medicine. They offer more predictive platforms for treating neurodegenerative and neurodevelopmental disorders, ultimately aiming to reduce the economic burden of drug failure and improve patient-specific therapeutic outcomes.