A Synovium‐on‐Chip Platform to Study Multicellular Interactions in Arthritis

Arthritis progression is modulated by the synovium, yet its cellular crosstalk remains poorly understood, partly due to the limited availability of human-relevant preclinical models. Therefore, we developed a compartmentalized synovium-on-chip (SoC) with a co-culture of primary human fibroblast-like synoviocytes (FLS), THP-1-derived macrophages, and endothelial cells across a 2-µm-thick microporous polydimethylsiloxane membrane. This microscale architecture sustains the co-culture of all cell types for at least ten days, preserving lineage-specific markers (cadherin-11, CD163, VE-cadherin). Without external cues, endothelial lumen remodeling was triggered by FLS migration through the membrane pores. Machine-learning-based image analysis revealed pronounced endothelial phenotypic shifts in response to FLS, highlighting the importance of intercellular communication on the cellular scale. Upon stimulation with TNF-α, synovial inflammation was successfully established, with robust cytokine upregulation. By capturing dynamic, migration-driven interactions between synovium and vasculature in vitro, our SoC platform provides a powerful tool to further study the mechanisms of arthritis progression in the synovium and to identify new targets for therapeutics development.