Recapitulating monocyte extravasation to the synovium in an organotypic microfluidic model of the articular joint.

The synovium of osteoarthritis (OA) patients can be characterized by an abnormal accumulation of macrophages originating from extravasated monocytes. Since targeting monocyte extravasation may represent a promising therapeutic strategy, our aim was to develop an organotypic microfluidic model recapitulating this process. Synovium and cartilage were modeled by hydrogel-embedded OA synovial fibroblasts and articular chondrocytes separated by a synovial fluid channel. The synovium compartment included a perfusable endothelialized channel dedicated to monocyte injection. Monocyte extravasation in response to chemokines and OA synovial fluid was quantified. The efficacy of chemokine receptor antagonists, RS-504393 (CCR2 antagonist) and Cenicriviroc (CCR2/CCR5 antagonist) in inhibiting extravasation was tested pre-incubating monocytes with the antagonists before injection. After designing and fabricating the chip, culture conditions were optimized to achieve an organotypic model including synovial fibroblasts, articular chondrocytes, and a continuous endothelial monolayer expressing intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. A significantly higher number of monocytes extravasated in response to the chemokine mix (

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