Publication date: Jul 16, 2025

The development of microphysiological systems for preclinical research is often hindered by the limited availability of reliable cell sources, especially when multiple organs or tissues from a single patient are needed for comparative studies of the host innate immune response. In this study, we develop human airway-on-chip and alveolus-on-chip models using lung progenitor cells derived from isogenic induced pluripotent stem cells. Our results using SARS-CoV-2 and influenza reveal distinct initial innate immune responses in the airway- and alveolus-on-chip models. SARS-CoV-2-infected airway chips show a robust early interferon-dependent innate immune response, while alveolus chips show dysregulated and delayed interferon activation alongside a significantly upregulated chemokine pathway. In contrast, influenza infection induces a more pronounced innate immune response and greater cellular damage in both chips compared with SARS-CoV-2. Consequently, airway- and alveolus-on-chip models derived from induced pluripotent stem cells offer a viral pathology platform with screening potential for future therapeutic agents.

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