Approaches for recapitulating the extracellular matrix in organs-on-chip.

Recent initiatives to reduce animal use in preclinical research have accelerated the development of organs-on-chip (OoC) for modeling human physiology. While OoCs have advanced structural and cellular complexity beyond 2D culture, strategies to reproduce the extracellular matrix (ECM) remain limited. This review synthesizes emerging strategies to recapitulate native ECM within OoCs, emphasizing both solid and fluid phases of the microenvironment. We define key mechanical parameters governing cell-matrix interactions and outline how these properties are engineered in biomimetic hydrogels. Natural polymers, their modified derivatives, and synthetic polymers are discussed alongside top-down methods using ECM from xenogeneic and human tissues, highlighting tradeoffs among biochemical and biomechanical fidelity, reproducibility, and compatibility with OoC fabrication. By comparing these strategies across tissues and disease models, we identify design principles for engineering ECM that balance physiological relevance with manufacturability, guiding the next generation of OoC platforms toward improved physiological relevance and translational utility.