hiPSC-derived Organoids and Organ-on-chip Systems: New Frontiers in Neural Tube Defect Research.

Neural tube defects (NTDs) result from failure of neural tube closure and remain a major cause of neonatal morbidity worldwide. Genetic, epidemiological, and animal studies have identified multiple NTD‑associated factors, but the mechanisms underlying human NTDs remain incompletely understood. Direct investigation of human NTD pathogenesis is limited by restricted access to embryonic tissues and by species differences in animal models. Conventional two‑dimensional cultures also fail to capture dynamic developmental processes such as neuroepithelial folding, tissue morphogenesis, and spatial patterning. This review synthesizes current evidence on the genetic, environmental, and morphogenetic mechanisms associated with NTDs and evaluates the applications and limitations of human organoid and organoid-on-chip models in this field. NTD‑associated genetic and environmental perturbations can produce measurable cellular and morphological phenotypes in organoid systems. These phenotypes support functional assessment of candidate pathogenic factors and mechanistic investigation. Microfluidic and bioengineering approaches further improve control over geometric boundaries, mechanical cues, and morphogen gradients, while enhancing model reproducibility. Overall, human organoid and organoid‑on‑chip platforms expand the experimental toolkit for NTD research and show potential for developmental toxicity assessment, risk‑factor screening, and patient‑specific disease modeling.