Advancing immunity research with immune-integrated organ-on-a-chip technologies

Organ-on-a-chip (OoC) platforms are a key subclass of microphysiological systems (MPS), designed to mimic the dynamic and physiological properties of native human tissue and organs. These systems have attracted significant attention, particularly following the Food and Drug Administration (FDA) approval of their use in the pharmaceutical and biomedical industries as alternatives to traditional models. However, their physiological relevance is often limited due to the lack of functional immune compartments, which are responsible for maintaining homeostasis and to modulate disease progression in the human body. In this review, we present a critical overview of immune-integrated OoC platforms, highlighting their capacity to emulate complex immunological processes such as immune cell trafficking, extravasation, and cytokine-mediated inflammation. We further explore recent advances in microfluidic design and on-chip biosensor integrations to perform real-time monitoring of immune dynamics. Despite their immense potential for drug development and personalized medicine, we highlight that their clinical translation remains challenged by biological and microarchitectural limitations, the lack of systemic multi-organ networks, hurdles in on-chip biosensor integration, and operational drawbacks. Overall, we outline a strategic roadmap for the standardization of immunocompetent OoC platforms to generate the robust and reproducible datasets required for artificial intelligence (AI) models and subsequent FDA qualification.