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Molecular transport in articular cartilage — what have we learned from the past 50 years?

  • Review Article
  • Published:

From Nature Reviews Rheumatology

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Abstract

Developing therapeutic molecules that target chondrocytes and locally produced inflammatory factors within arthritic cartilage is an active area of investigation. The extensive studies that have been conducted over the past 50 years have enabled the accurate prediction and reliable optimization of the transport of a wide variety of molecules into cartilage. In this Review, the factors that can be used to tune the transport kinetics of therapeutics are summarized. Overall, the most crucial factor when designing new therapeutic molecules is solute size. The diffusivity and partition coefficient of a solute both decrease with increasing solute size as indicated by molecular mass or by hydrodynamic radius. Surprisingly, despite having an effective pore size of ~6 nm, molecules of ~16 nm radius can diffuse through the cartilage matrix. Alteration of the shape or charge of a solute and the application of physiological loading to cartilage can be used to predictably improve solute transport kinetics, and this knowledge can be used to improve the development of therapeutic agents for osteoarthritis that target the cartilage.

Key points

  • Therapeutic agents for arthritis treatment vary widely in their capacity to diffuse through cartilage.

  • Solute size and molecular mass strongly influence the diffusivity of a molecule in cartilage.

  • Linear, flexible solutes (such as dextrans) exhibit fundamentally different transport kinetics compared with those of spherical solutes (such as antibodies).

  • Altering the solute shape or charge and applying physiological loading to cartilage can be used to predictably increase the transport of therapeutics into cartilage.

  • Even molecules that are larger than the effective pore size of cartilage (~6 nm) can diffuse through the entire depth of healthy cartilage.

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Fig. 1: Relative sizes of cartilage-targeted therapeutics and relation to cartilage matrix structure.
Fig. 2: Experimental techniques used to identify the solute diffusivity and partition coefficient.
Fig. 3: Cartilage matrix changes in osteoarthritis affect molecular transport.

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Acknowledgements

The work of the authors was supported by the National Science Foundation (grant NSF-1536463; awarded to L.J.B. and I. Cohen). The authors also thank I. Cohen, L. Bartell, L. Fortier and M. Delco for their help in refining the message of the manuscript.

Referee accreditation statement

Nature Reviews Rheumatology thanks M. Bottini, N. E. Lane and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Review criteria

PubMed served as the primary database to identify all relevant articles using the search terms “articular cartilage” and “solute transport”. All articles that reported solute transport metrics in articular cartilage were included unless the data were collected using diseased or degraded tissue. For all other aspects of this manuscript, the most representative papers were chosen, with a bias towards articles that are recent and clinical.

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Authors and Affiliations

  1. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA

    Chris D. DiDomenico, Marianne Lintz & Lawrence J. Bonassar

  2. Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, USA

    Lawrence J. Bonassar

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  1. Chris D. DiDomenico
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  3. Lawrence J. Bonassar
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C.D.D. and L.J.B. wrote the article. All authors researched the data for the article, provided substantial contributions to discussions of its content, and reviewed or edited the manuscript before submission.

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Correspondence to Lawrence J. Bonassar.

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Glossary

Hydrodynamic radius

A molecular characteristic that quantifies the size of the solute; this characteristic assumes that the solute can be approximated as a sphere, so it might not be appropriate to use for all solutes.

Anisotropic

The state of having properties that depend on direction (for example, parallel versus perpendicular to the articular surface).

Fixed charge density

The concentration of charge that results from the constituent parts of the cartilage matrix, primarily determined by the presence of sulfated glycosaminoglycans.

Poroelastic mechanical response

The time-dependent behaviour of cartilage, which arises from fluid movement through the porous matrix.

Diffusion coefficient

A solute transport metric that quantifies how quickly diffusive transport occurs in a medium; this metric decreases rapidly with increasing solute size and also depends on other factors.

Partition coefficient

A solute transport metric that quantifies the equilibrium concentration of a solute in cartilage compared with the concentration of the solute in synovial fluid; this metric often decreases with increasing solute size.

Cyclical mechanical loading

The mechanical loading of cartilage tissue within the joint, which occurs over a wide range of frequencies and amplitudes, depending on the type of physical activity involved.

Convective transport

Transport of solutes caused by induced fluid flow within cartilage; this type of transport can be caused by mechanical loading of the joint during walking or jumping.

Donnan equilibrium

The unequal distribution of solutes across the cartilage–synovial fluid interface as a result of the high fixed charge density of the tissue, which produces high concentrations of cationic solutes and low concentrations of anionic solutes in cartilage.

Isoelectric point

A molecular characteristic that quantifies the charge of a solute by calculating the pH at which the solute is neutrally charged. Values above 7 denote a positive charge, whereas values below 7 denote a negative charge.

Linear solutes

Solutes with a flexible, chain-like molecular structure that can change shape from an extended linear geometry to a more compact geometry (random coil).

Spherical solutes

Solutes with a generally spherical molecular structure that cannot substantially change their shape.

Peclet number

A solute transport metric that quantifies the relative contributions of convective transport and diffusive transport. Values above 1 indicate that convection is more important than diffusion, whereas values below 1 indicate that diffusion is more important than convection.

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DiDomenico, C.D., Lintz, M. & Bonassar, L.J. Molecular transport in articular cartilage — what have we learned from the past 50 years?. Nat Rev Rheumatol 14, 393–403 (2018). https://doi.org/10.1038/s41584-018-0033-5

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