Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip model

Abstract

Owing to population aging, the social impact of osteoarthritis (OA)—the most common musculoskeletal disease—is expected to increase dramatically. Yet, therapy is still limited to palliative treatments or surgical intervention, and disease-modifying OA (DMOA) drugs are scarce, mainly because of the absence of relevant preclinical OA models. Therefore, in vitro models that can reliably predict the efficacy of DMOA drugs are needed. Here, we show, using a newly developed microphysiological cartilage-on-a-chip model that enables the application of strain-controlled compression to three-dimensional articular cartilage microtissue, that a 30% confined compression recapitulates the mechanical factors involved in OA pathogenesis and is sufficient to induce OA traits. Such hyperphysiological compression triggers a shift in cartilage homeostasis towards catabolism and inflammation, hypertrophy, and the acquisition of a gene expression profile akin to those seen in clinical osteoarthritic tissue. The cartilage on-a-chip model may enable the screening of DMOA candidates.

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Fig. 1: Microscale system for mechanical confined compression of 3D cell microconstructs.
Fig. 2: Construct deformation field: computations and experimental validation.
Fig. 3: Establishment of a human model of healthy COC.
Fig. 4: Effect of mechanical compression on COC anabolic traits.
Fig. 5: Effect of mechanical compression on COC catabolic enzymes, inflammation, hAC phenotypic switching and the OA-correlating gene profile.
Fig. 6: Drug screening using the OA COC model.

Data availability

The main data supporting the findings of this study are available within the paper and its Supplementary Information. All data generated for this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful to G. Pagenstert for provision of the articular cartilage biopsies. We also thank Fidia Farmaceutici (Italy) for provision of the HYADD 4 and LMW-HA compounds—in particular, D. Galesso, R. Beninatto and C. Guarise for feedback on the results. Device manufacturing was partially performed at PoliFAB—the micro- and nanofabrication facility of Politecnico di Milano. This work was partially funded by the Swiss National Science Foundation (numbers 310030_149614/1 and 310030_175660/1).

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M.R., A.B. and P.O. conceived the project. M.R. and A.M. conceived the device. E.V. and A.M. implemented the finite element model and performed the simulations. A.M. performed the mechanical characterization of the device. A.M. and P.O. produced the devices. P.O. and A.M. performed and analysed the biological experiments. Q.V.-M. and M.E. produced the PEG gel. P.O., A.M., M.R., A.B. and I.M. wrote the manuscript. All authors discussed the results, commented on the manuscript and contributed to its final version.

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Correspondence to Andrea Barbero.

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Supplementary Information

Supplementary methods, figures, tables, references and video captions.

Reporting Summary

Supplementary Video 1

PEG hydrogel strain field on 30% compression.

Supplementary Video 2

3D reconstruction of the COC in static culture or after HPC.

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Occhetta, P., Mainardi, A., Votta, E. et al. Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip model. Nat Biomed Eng 3, 545–557 (2019). https://doi.org/10.1038/s41551-019-0406-3

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