ADVANCING HUMAN SYNOVIAL JOINTS-ON-CHIPS

Karina Wright, Martin Knight (QMUL), Timothy Hopkins, Sally Roberts, Charlotte Hulme and Clare Thompson (QMUL)

Funded by the Orthopaedic Institute

There is an unmet need for novel, physiologically relevant models of the human synovial joint for the appraisal of existing treatments, and the screening of new disease-modifying pharmaceuticals, for the treatment of osteoarthritis (OA). Organ-on-a-chip technology can be utilised to generate new in vitro models with a greater capacity to replicate human physiology in health and disease. Over the course of this proof-of-concept (PoC) study we carried out the initial development and validation of two organ-on-a-chip models of the human synovial joint: ‘Vascularised synovium-on-a[1]chip’, and ‘Cartilage-synovium on-a-chip’. Both models were developed using the Emulate human emulation system, a commercially available, two-channel, microfluidic chip (see picture insert).

In the vascularised synovium-on-a-chip, healthy human fibroblast-like synoviocytes (hFLS) were cultured in the top channel (to mimic the synovium) and human umbilical vein endothelial cells (HUVECs) in the bottom channel (to mimic a blood vessel), with the two cell populations separated by a flexible, porous membrane. Biomechanical stimulation, in the form of fluid shear and periodic cyclic tensile strain, was applied. The hFLS exhibited characteristic morphology and organisation and deposited characteristic matrix proteins. The addition of an inflammatory stimulus (interleukin-1 ) into the synovium channel was used to mimic synovial inflammation and resulted in the increased secretion of inflammatory and catabolic mediators, as well as the synovial fluid constituent protein, hyaluronan (HA). Enhanced expression of the inflammatory marker, intercellular adhesion molecule-1 (ICAM[1]1), was observed in the vascular channel, accompanied by increased attachment of circulating monocytes, which were added to the bottom channel under flow.

This vascularised human synovium-on-a-chip model recapitulates a number of the functional characteristics of both healthy and inflamed human synovium and can be used to examine human synovial biology and inflammation, identify novel druggable targets and test new therapeutics.