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

ABSTRACT 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.