Bioengineered human brain organoids and organ-on-chip platforms for exposure-aware assessment of developmental neurotoxicity induced by general anesthetics and sedatives.

General anesthetic agents and sedative-hypnotic drugs are essential for fetal, neonatal, pediatric, and intensive care procedures, but their administration can overlap with vulnerable stages of human brain development. Available evidence indicates that developmental responses vary with exposure duration, repetition, developmental timing, and host susceptibility. The objective of this review is to critically evaluate bioengineered human brain organoids, brain microphysiological systems, and organ-on-chip platforms as human-relevant tools for exposure-aware assessment of anesthetic developmental neurotoxicity. We first discuss cerebral, cortical, region-specific, and patient-derived brain organoids, together with BBB- and immune-integrated chip systems, as human-relevant models for exposure-aware testing. Particular attention is given to exposure delivery, measured concentration, gas- or liquid-phase stability, microfluidic flow, matrix properties, maturation stage, recovery interval, and assay scalability. We then organize anesthetic-associated changes into platform-detectable developmental stress modules, including progenitor-zone disruption, altered lineage progression, mitochondrial and oxidative stress, ferroptotic or apoptotic injury, synaptic dysregulation, glial and neuroimmune remodeling, and network dysfunction. We further examine how divergent responses are shaped by drug class, dose, duration, brain-region identity, cellular composition, BBB or immune integration, and model architecture. Finally, we propose susceptibility-informed preclinical risk modeling based on patient-derived or isogenic organoids, multimodal readouts, biomarker anchoring, model benchmarking, and reporting standards. These platforms may support mechanism discovery, biomarker prioritization, protective-strategy screening, and translational qualification within an exposure-aware preclinical framework.