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  • Review Article
  • Published:

Joint-on-chip platforms: entering a new era of in vitro models for arthritis

Nature Reviews Rheumatology volume 18, pages 217–231 (2022)Cite this article

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Abstract

Arthritis affects millions of people worldwide. With only a few disease-modifying drugs available for treatment of rheumatoid arthritis and none for osteoarthritis, a clear need exists for new treatment options. Current disease models used for drug screening and development suffer from several disadvantages and, most importantly, do not accurately emulate all facets of human joint diseases. A humanized joint-on-chip (JoC) model or platform could revolutionize research and drug development in rheumatic diseases. A JoC model is a multi-organ-on-chip platform that incorporates a range of engineered features to emulate essential aspects and functions of the human joint and faithfully recapitulates the joint’s physiological responses. In this Review, we propose an architecture for such a JoC platform, discuss the status of the engineering of individual joint tissues and the efforts to combine them in a functional JoC model and identify unresolved issues and challenges in constructing an accurate, physiologically relevant system. The goal is to ultimately obtain a reliable and ready-to-use humanized model of the joint for studying the pathophysiology of rheumatic diseases and screening drugs for treatment of these conditions.

Key points

  • Current in vitro and in vivo models only partly recapitulate the complexity of human arthritic diseases and consequently lack translational power in the development of new disease-modifying treatments.

  • Engineering a miniaturized version of the human joint as a joint-on-chip platform that faithfully emulates key aspects of a healthy joint and in which disease-specific triggers can be introduced could substantially advance research into arthritic diseases.

  • The minimal functional joint-on-chip requires an osteochondral unit and a synovial membrane unit that emulate the composition of the extracellular matrix and appropriate cell types in the respective tissues and that are connected to each other using microfluidic coupling.

  • The minimal joint-on-chip can be extended with additional tissue units, such as those emulating the meniscus, ligaments and Hoffa’s fat pad; inter-organ communication could be achieved by connecting the different tissue units to a motherboard with integrated sensors to enable real-time measurements.

  • Although promising and potentially revolutionary, multiple challenges must still be overcome to produce a reliable joint-on-chip model that could be used in arthritis research and drug development programmes.

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Fig. 1: Tissue units for establishing a joint-on-chip system.
Fig. 2: Preparation and organization of osteochondral and synovial membrane units of the joint-on-chip platform.
Fig. 3: Using organ-on-chip models to mimic pathogenetic features of rheumatoid arthritis.
Fig. 4: Architecture of a proposed joint-on-chip platform.

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Acknowledgements

The authors acknowledge financial support from the Dutch Arthritis Association (ReumaNetherlands grant LLP-25).

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Authors and Affiliations

  1. Applied Microfluidics for BioEngineering Research, MESA+Institute for Nanotechnology & TechMed Centre, University of Twente, Enschede, Netherlands

    Carlo Alberto Paggi & Séverine Le Gac

  2. Department of Developmental BioEngineering, TechMed Centre, University of Twente, Enschede, Netherlands

    Carlo Alberto Paggi, Liliana Moreira Teixeira & Marcel Karperien

  3. Organ-on-Chip Center Twente, MESA+Institute for Nanotechnology & TechMed Centre, University of Twente, Enschede, Netherlands

    Carlo Alberto Paggi, Liliana Moreira Teixeira, Séverine Le Gac & Marcel Karperien

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Contributions

C.A.P., S.L.G. and M.K. researched data for the article and contributed substantially to discussion of the content. All authors wrote the article, reviewed and/or edited the manuscript before submission and agree on the content of the submitted article.

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Correspondence to Séverine Le Gac or Marcel Karperien.

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Nature Reviews Rheumatology thanks M. Goldring, A. Mainardi, who co-reviewed with I. Martin, and P. Ertl, for their contribution to the peer review of this work.

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Glossary

Mechanical actuation module

The part of a microfluidic device that enables repeated (cyclic) application of mechanical loading on the cell-laden 3D hydrogel.

Microfluidic device

Module or system used to precisely control and manipulate fluids in micrometre-sized structures. Microfluidics is at the crossroad of different fields such as engineering, physics, chemistry, nano- and micro-biotechnology.

Uniaxial loading

Mechanical stimulation of the joint in one direction only (for example, compression or stretching). Referred to as uniaxial mechanical actuation when a tissue (cell-laden hydrogel or 3D cell construct) is stimulated in vitro.

Microfluidic chamber

Chamber of a microfluidic device of miniaturized dimensions in the micrometre range that is typically filled with a fluid (liquid or air) or a hydrogel material supplemented with cells.

Microfluidic motherboard

Module for controlling nutrient supply to single-tissue units, which can include analytical modalities, to characterize tissue communication and integrated sensors for real-time monitoring. Individual tissue units could be connected to the motherboard, which thereby provides a standardized connection between units.

Pumping module

In organ-on-chip, a module for pressure or flow control that allows application of constant or cyclic pressure for regulating fluid flow in the nutrient compartment and mechanical actuation.

Plug-and-play solution

System that allows easy addition or removal of a single organ-on-chip unit from the overall joint-on-chip device.

Sensing units

Devices and/or modules for detecting events or changes in the physical environment, such as pressure, temperature, oxygen or biomolecules.

Microfluidic circuitry

Micrometre-sized tubing or channels connecting a series of microfluidic and/or organ-on-chip platforms with each other, and possibly incorporating devices for molecular analysis and biochemical sensing.

Peltier element

A thermoelectric component capable of a temperature shift from one side of the system to the other using electrical energy.

Electrochemical microsensors

Micromachined, micrometer-sized (10−3–10−5 m) sensing structures for detecting and quantifying specific chemical and biochemical substances in fluids, through application of a potential to induce an oxidation or reduction reaction, and recording of a current. Typically fabricated from metal materials.

Non-fouling coatings

Chemical coatings that stop the interactions of molecules in solution with surfaces to notably prevent their non-desired adsorption on the surface.

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Paggi, C.A., Teixeira, L.M., Le Gac, S. et al. Joint-on-chip platforms: entering a new era of in vitro models for arthritis. Nat Rev Rheumatol 18, 217–231 (2022). https://doi.org/10.1038/s41584-021-00736-6

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