A microfluidic chip-based co-culture of fibroblast-like synoviocytes with osteoblasts and osteoclasts to test bone erosion and drug evaluation

Abstract

Targeting fibroblast-like synoviocyte (FLS) migration and invasion-mediated bone erosion is a promising clinical strategy for the treatment of rheumatoid arthritis (RA). Drug sensitivity testing is fundamental to this scheme. We designed a microfluidic chip-based, cell co-cultured platform to mimic RA FLS-mediated bone erosion and perform drug-sensitive assay. Human synovium SW982 cells were cultured in the central channel and migrated to flow through matrigel-coated side channels towards cell culture chamber where RANKL-stimulated osteoclastic RAW264.7 and osteogenic medium (OS)-stimulated bone marrow mesenchymal stem cells (BMSC) were cultured in the microfluidic chip device, mimicking FLS migration and invasion-mediated bone erosion in RA. These SW982 cells showed different migration potentials to osteoclasts and BMSC. The migration of SW982 cells with high expression of cadherin-11 was more potent when SW982 cells were connected with the co-culture of RAW264.7 and BMSC. Simultaneously, in the co-cultured chamber, tartrate-resistant acid phosphatase (TRAP) activity of RANKL-stimulated RAW264.7 cells was enhanced, but alkaline phosphatase (ALP) activity was decreased in comparison with mono-cultured chamber. Furthermore, it was confirmed that celastrol, a positive drug for the treatment of RA, inhibited SW982 cell migration as well as TRAP activity in the cell-cultured microfluidic chips. Thus, the migration and invasion to bone-related cells was reconstituted on the microfluidic model. It may provide an effective anti-RA drug screen model for targeting FLS migration-mediated bone erosion.

Insights Into Leukocyte Trafficking in Inflammatory Arthritis – Imaging the Joint

“…Addition of collagen scaffolds; tuneable chemical gradients ( Wu et al, 2017 ) and stromal cells, to the microfluidic channels are paving the way for the development of personalized “organs-on-a-chip” which present the possibility of precision medicine ( Van Den Berg et al, 2019 ). In the context of inflammatory arthritis, microfluidic systems have been used to track the migration of the cadherin-11 expressing synovial cell line (SW982) toward an activated osteoclast cell line (RAW264.7), where the co-culture construct enhanced SW982 migration and osteoclast activity compared to the monocultures ( Ma et al, 2018 ). Moreover, 3-D “synovium-on-a-chip” with an integrated time-resolved light scatter biosensor has been generated that allows the visualization of TNFα induced fibroblast organization into lining and sublining layers over 2 days ( Rothbauer et al, 2020 ) (e.g., Figure 2G ).…”

Monitoring tissue-level remodelling during inflammatory arthritis using a three-dimensional synovium-on-a-chip with non-invasive light scattering biosensing

“…7 Lining hyperplasia and condensation/aggregation of FLS synoviocytes in the sublining area has been documented both in vitro and in vivo in response to TNF-α 8,9 exposure a wellknown and potent inflammatory cytokine. Although structural changes of the synovial tissue architecture has been previously described, 10 little is known about the dynamics of cellular network degradation, proliferation and cell aggregation that take place during inflammatory arthritis. To assess the ability of our chip-based 3D light scatter biosensing method to detect the onset and progression of tissue-level remodelling processes, 3D synovial organoids were cultivated on chip in the absence and presence of TNF-α.…”

“…Existing in vitro models describing inflammatory arthritis include analysis of (a) acellular synovial fluids, 2,3 (b) different 3D culture models in microtiter plates using hydrogels as extracellular matrix components [4][5][6][7][8][9] and more recently in (c) microfluidic cell culture systems based on two-dimensional (2D) co-cultures of fibroblast-like synoviocytes. 10 To date, in vivo animal models are still considered the gold standard in the study of the pathogenesis of arthritis. Here, arthritic diseases in rodents are commonly induced by injection of collagen or collagen antibody-induced arthritis (CIA/CAIA).…”

Integrating Biosensors in Organs-on-Chip Devices: A Perspective on Current Strategies to Monitor Microphysiological Systems

“…In details, OoCs are not intended to reproduce a whole living organ, but rather to establish the minimal functional unit able to recapitulate certain aspects of human physiology or pathophysiology in a controlled and straightforward manner [ 17 , 19 ]. Various organs and tissues have been modeled, spanning from lung [ 20 , 21 ], heart [ 22 , 23 ], liver [ 24 , 25 ], gut [ 26 , 27 ], kidney [ 28 , 29 ], muscle [ 30 , 31 ], bone [ 32 , 33 ], cartilage [ 34 , 35 ], blood-brain barrier [ 36 , 37 ], as well as nervous systems [ 38 , 39 ]. Many of these systems incorporate biophysical and/or biochemical stimuli (i.e., mechanical [ 22 , 34 ], electrical [ 40 ] and biochemical cues [ 41 ]) to mimic the 3D in vivo physiological environment of the corresponding native organ and to induce the proper cellular phenotypes and tissue maturation.…”