and organoid-on-a-chip (OoC) platforms provide microengineered human tissue models that reproduce key physiological features such as perfusion, mechanical cues, and multicellular interfaces while remaining compatible with established gene expression profiling (GEP) techniques. This review examines how conventional transcriptomic methods, including qPCR, microarrays, and bulk and single-cell RNA sequencing, are integrated with OoC systems and how microphysiological control reshapes the interpretation of gene expression data beyond static culture conditions. Representative applications across major organ systems are synthesized to illustrate how chip design parameters (cell source, architecture, flow, mechanical stimulation, and exposure route) influence transcriptional programs associated with disease phenotypes and drug responses. Rather than presenting OoC-derived gene signatures as stand-alone predictors, we emphasize their value as mechanistic endpoints that link controlled environmental perturbations to pathway-level biological responses. The analysis highlights both advantages, such as time-resolved sampling, improved contextual relevance, and reduced reliance on animal models, and persistent challenges, including device-to-device variability, low-input RNA handling, limited interlaboratory reproducibility, and incomplete standardization. Finally, emerging directions are discussed, including multi-organ integration, patient-specific iPSC-derived models, AI-assisted data analysis, and growing regulatory interest in New Approach Methodologies (NAMs) for safety and efficacy decision support. Together, these developments position OoC-coupled GEP as a promising but still maturing approach for translational research and personalized medicine. • Organ and Organoids-on-Chip Based In Vitro Models for the evaluation of gene expression profiling • Gene expression analysis research using Organ and Organoids-on-Chip Based In Vitro Models is in its infancy stage. • Comparative summary of 2D Cell Cultures, Organoids, Animal Models, and Organ-on-a-Chip Systems. • Comparative summary of Organ-on-Chip Platforms Integrated with High-Throughput Sequencing Techniques.
Alwadi et al. (Sun,) studied this question.