Rethinking Organ on a Chip through the Lens of Sex Differences

Biological sex profoundly influences human physiology, disease susceptibility, and drug response, yet traditional preclinical models rarely capture these differences.Organ on a chip (OoC) technology offers a human relevant platform capable of integrating sex defined cell sources, controlled hormonal environments, and physiologically realistic microenvironments.These capabilities make OoCs uniquely suited for dissecting the genetic, endocrine, and immunological factors that underlie sexual dimorphism.This review summarizes key biological drivers of sex differences and outlines engineering principles necessary for building sex-specific OoCs, including donor matched XX or XY cells, precise hormone dosing, and microenvironmental tuning.Emerging applications across cardiovascular, hepatic, neurological, renal, and musculoskeletal systems demonstrate sex dependent responses in electrophysiology, metabolism, inflammation, and barrier function.Ultimately, integrating sex as a core design variable will enable OoC platforms to improve drug safety prediction and support more inclusive precision medicine.