Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Biomimetic cartilage-lubricating polymers regenerate cartilage in rats with early osteoarthritis

Nature Biomedical Engineering volume 5, pages 1189–1201 (2021)Cite this article

Subjects

Abstract

The early stages of progressive degeneration of cartilage in articular joints are a hallmark of osteoarthritis. Healthy cartilage is lubricated by brush-like cartilage-binding nanofibres with a hyaluronan backbone and two key side chains (lubricin and lipid). Here, we show that hyaluronan backbones grafted with lubricin-like sulfonate-rich polymers or with lipid-like phosphocholine-rich polymers together enhance cartilage regeneration in a rat model of early osteoarthritis. These biomimetic brush-like nanofibres show a high affinity for cartilage proteins, form a lubrication layer on the cartilage surface and efficiently lubricate damaged human cartilage, lowering its friction coefficient to the low levels typical of native cartilage. Intra-articular injection of the two types of nanofibre into rats with surgically induced osteoarthritic joints led to cartilage regeneration and to the abrogation of osteoarthritis within 8 weeks. Biocompatible injectable lubricants that facilitate cartilage regeneration may offer a translational strategy for the treatment of early osteoarthritis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Illustration of the overall idea.
Fig. 2: Chemical structures of HA/PA and HA/PM.
Fig. 3: Evaluation of the binding modes between HA/PA and HA/PM.
Fig. 4: Evaluation of the retention of Cy5-labelled biomimetic lubricants (HA/PA and HA/PM) in the OA rat joint environment.
Fig. 5: Confirmation of the recognition between the biomimetic lubricants (HA/PA and HA/PM) and the cartilage proteins in the presence of proteins in synovial fluid and the lubrication of human cartilage using the biomimetic lubricants.
Fig. 6: Tissue compatibility of HA/PA and HA/PM determined using an in vitro 3D cartilage model (LhCG) and healthy rats.
Fig. 7: Evaluation of the chondroprotective effect and ability of HA/PA and HA/PM (alone or in combination) to treat OA in rats.
Fig. 8: Evaluation of the ability of HA/PA and HA/PM (alone or in combination) in promoting cartilage regeneration to treat OA in rats.

Data availability

The main data supporting the results of this study are available within the paper and its supplementary information. The raw and analysed datasets generated during the study are too large to be publicly shared; however, they are available for research purposes from the corresponding authors upon reasonable request.

References

  1. Wieland, H. A., Michaelis, M., Kirschbaum, B. J. & Rudolphi, K. A. Osteoarthritis—an untreatable disease? Nat. Rev. Drug Discov. 4, 331–344 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Li, M. H., Xiao, R., Li, J. B. & Zhu, Q. Regenerative approaches for cartilage repair in the treatment of osteoarthritis. Osteoarthritis Cartilage 25, 1577–1587 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. He, Z., Wang, B., Hu, C. & Zhao, J. An overview of hydrogel-based intra-articular drug delivery for the treatment of osteoarthritis. Colloid Surf. B 154, 33–39 (2017).

    Article  CAS  Google Scholar 

  4. Morgese, G., Benetti, E. M. & Zenobi-Wong, M. Molecularly engineered biolubricants for articular cartilage. Adv. Healthc. Mater. 7, 1701463 (2018).

    Article  CAS  Google Scholar 

  5. Goldring, S. R. & Goldring, M. B. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage–bone crosstalk. Nat. Rev. Rheumatol. 12, 632–644 (2016).

    Article  PubMed  Google Scholar 

  6. Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Morgese, G., Cavalli, E., Muller, M., Zenobi-Wong, M. & Benetti, E. M. Nanoassemblies of tissue-reactive, polyoxazoline graft-copolymers restore the lubrication properties of degraded cartilage. ACS Nano 11, 2794–2804 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Samaroo, K. J., Tan, M., Putnam, D. & Bonassar, L. J. Binding and lubrication of biomimetic boundary lubricants on articular cartilage. J. Orthop. Res. 35, 548–557 (2017).

    Article  CAS  PubMed  Google Scholar 

  9. Morgese, G., Cavalli, E., Rosenboom, J. G., Zenobi-Wong, M. & Benetti, E. M. Cyclic polymer grafts that lubricate and protect damaged cartilage. Angew. Chem. Int. Ed. 57, 1621–1626 (2018).

    Article  CAS  Google Scholar 

  10. Singh, A. et al. Enhanced lubrication on tissue and biomaterial surfaces through peptide-mediated binding of hyaluronic acid. Nat. Mater. 13, 988–995 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lawrence, A. et al. Synthesis and characterization of a lubricin mimic (mLub) to reduce friction and adhesion on the articular cartilage surface. Biomaterials 73, 42–50 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Prudnikova, K. et al. Biomimetic proteoglycans mimic macromolecular architecture and water uptake of natural proteoglycans. Biomacromolecules 18, 1713–1723 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Banquy, X., Burdynska, J., Lee, D. W., Matyjaszewski, K. & Israelachvili, J. Bioinspired bottle-brush polymer exhibits low friction and Amontons-like behavior. J. Am. Chem. Soc. 136, 6199–6202 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Faivre, J. et al. Intermolecular interactions between bottlebrush polymers boost the protection of surfaces against frictional. Wear. Chem. Mat. 30, 4140–4149 (2018).

    Article  CAS  Google Scholar 

  15. Klein, J. Molecular mechanisms of synovial joint lubrication. Proc. Inst. Mech. Eng. Part J J. Eng. Tribol. 220, 691–710 (2006).

    Article  CAS  Google Scholar 

  16. Banquy, X., Lee, D. W., Das, S., Hogan, J. & Israelachvili, J. N. Shear-induced aggregation of mammalian synovial fluid components under boundary lubrication conditions. Adv. Funct. Mater. 24, 3152–3161 (2014).

    Article  CAS  Google Scholar 

  17. Seror, J. et al. Normal and shear interactions between hyaluronan–aggrecan complexes mimicking possible boundary lubricants in articular cartilage in synovial joints. Biomacromolecules 13, 3823–3832 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Seror, J. et al. Articular cartilage proteoglycans as boundary lubricants: structure and frictional interaction of surface-attached hyaluronan and hyaluronan–aggrecan complexes. Biomacromolecules 12, 3432–3443 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Maeda, S., Hara, Y., Sakai, T., Yoshida, R. & Hashimoto, S. Self-walking gel. Adv. Mater. 19, 3480–3484 (2007).

    Article  CAS  Google Scholar 

  20. Means, A. K., Shrode, C. S., Whitney, L. V., Ehrhardt, D. A. & Grunlan, M. A. Double network hydrogels that mimic the modulus, strength, and lubricity of cartilage. Biomacromolecules 20, 2034–2042 (2019).

    Article  CAS  PubMed  Google Scholar 

  21. Ishihara, K. Highly lubricated polymer interfaces for advanced artificial hip joints through biomimetic design. Polym. J. 47, 585–597 (2015).

    Article  CAS  Google Scholar 

  22. Laterra, J., Silbert, J. E. & Culp, L. A. Cell surface heparan sulfate mediates some adhesive responses to glycosaminoglycan-binding matrices, including fibronectin. J. Cell Biol. 96, 112–123 (1983).

    Article  CAS  PubMed  Google Scholar 

  23. Rossi, J. D., & Wallace, B. A. Binding of fibronectin to phospholipid vesicles. J. Biol. Chem. 258, 3327–3331 (1983).

    Article  CAS  PubMed  Google Scholar 

  24. Heremans, A., de Cock, B, Cassiman, J. J., Van den Berghe, H. & David, G. The core protein of the matrix-associated heparan sulfate proteoglycan binds to fibronectin. J. Biol. Chem. 285, 8716–8724 (1990).

    Article  Google Scholar 

  25. Oh, E. J. et al. Control of the molecular degradation of hyaluronic acid hydrogels for tissue augmentation. J. Biomed. Mater. Res. Part A 86, 685–693 (2008).

    Article  CAS  Google Scholar 

  26. Jahn, S., Seror, J. & Klein, J. Lubrication of articular cartilage. Annu. Rev. Biomed. Eng. 18, 235–258 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Klein, J. Hydration lubrication. Friction 1, 1–23 (2013).

    Article  CAS  Google Scholar 

  28. Silbert, G., Kampf, N. & Klein, J. Normal and shear forces between charged solid surfaces immersed in cationic surfactant solution: the role of the alkyl chain length. Langmuir 30, 5097–5104 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Su, K., Lau, T. T., Leong, W., Gong, Y. & Wang, D.-A. Creating a living hyaline cartilage graft free from non-cartilaginous constituents: an intermediate role of a biomaterial scaffold. Adv. Funct. Mater. 22, 972–978 (2012).

    Article  CAS  Google Scholar 

  30. Lee, H. P., Gu, L., Mooney, D. J., Levenston, M. E. & Chaudhuri, O. Mechanical confinement regulates cartilage matrix formation by chondrocytes. Nat. Mater. 16, 1243–1251 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lorenz, H., Wenz, W., Ivancic, M., Steck, E. & Richter, W. Early and stable upregulation of collagen type II, collagen type I and YKL40 expression levels in cartilage during early experimental osteoarthritis occurs independent of joint location and histological grading. Arthritis Res. Ther. 7, 156–165 (2005).

    Article  Google Scholar 

  32. Inada, M. et al. Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc. Natl Acad. Sci. USA 101, 17192–17197 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Desando, G. et al. Short-term homing of hyaluronan-primed cells: therapeutic implications for osteoarthritis treatment. Tissue Eng. Part C 24, 121–133 (2018).

    Article  CAS  Google Scholar 

  34. Ishikawa, M. et al. Biocompatibility of cross-linked hyaluronate (Gel-200) for the treatment of knee osteoarthritis. Osteoarthr. Cartil. 22, 1902–1909 (2014).

    Article  CAS  Google Scholar 

  35. Yoshioka, K. et al. Biocompatibility study of different hyaluronan products for intra-articular treatment of knee osteoarthritis. BMC Musculoskel. Dis. 20, 424 (2019).

    Article  CAS  Google Scholar 

  36. Vincent, T. L. Targeting mechanotransduction pathways in osteoarthritis: a focus on the pericellular matrix. Curr. Opin. Pharmacol. 13, 449–454 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Meinert, C. et al. Tailoring hydrogel surface properties to modulate cellular response to shear loading. Acta Biomater. 52, 105–117 (2017).

    Article  CAS  PubMed  Google Scholar 

  38. Bonnevie, E. D. et al. Microscale frictional strains determine chondrocyte fate in loaded cartilage. J. Biomech. 74, 72–78 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Jin, M., Frank, E. H., Quinn, T. M., Hunziker, E. B. & Grodzinsky, A. J. Tissue shear deformation stimulates proteoglycan and protein biosynthesis in bovine cartilage explants. Arch. Biochem. Biophys. 395, 41–48 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Kellum, M. G., Harris, C. A., Mccormick, C. L. & Morgan, S. E. Stimuli-responsive micelles of amphiphilic AMPS-b-AAL copolymers in layer-by-layer films. J. Polym. Sci. Pol. Chem. 49, 1104–1111 (2011).

    Article  CAS  Google Scholar 

  41. Kellum, M. G., Smith, A. E., York, S. K. & McCormick, C. L. Reversible interpolyelectrolyte shell cross-linked micelles from pH/salt-responsive diblock copolymers synthesized via RAFT in aqueous solution. Macromolecules 43, 7033–7040 (2010).

    Article  CAS  Google Scholar 

  42. Bhuchar, N., Deng, Z., Ishihara, K. & Narain, R. Detailed study of the reversible addition–fragmentation chain transfer polymerization and co-polymerization of 2-methacryloyloxyethyl phosphorylcholine. Polym. Chem. 2, 632–639 (2011).

    Article  CAS  Google Scholar 

  43. Chan, J. W., Yu, B., Hoyle, C. E. & Lowe, A. B. Convergent synthesis of 3-arm star polymers from RAFT-prepared poly(N,N-diethylacrylamide) via a thiol-ene click reaction. Chem. Commun. 40, 4959–4961 (2008).

    Article  CAS  Google Scholar 

  44. Korogiannaki, M., Zhang, J. & Sheardown, H. Surface modification of model hydrogel contact lenses with hyaluronic acid via thiol-ene “click” chemistry for enhancing surface characteristics. J. Biomater. Appl. 32, 446–462 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Maier, J. A. et al. ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J. Chem. Theory Comput. 11, 3696–3713 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Case, D. A. et al. The amber biomolecular simulation programs. J. Comput. Chem. 26, 1668–1688 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang, J., Wang, W., Kollman, P. A. & Case, D. A. Automatic atom type and bond type perception in molecular mechanical calculations. J. Mol. Graph. 25, 247–260 (2006).

    Article  CAS  Google Scholar 

  48. Ryckaert, J.P., Ciccotti, G. & Berendsen, H. J. C. Numerical integration of the cartesian equations of motion of a system with constraints molecular dynamics of n-alkanes. J. Comput. Phys. 23, 327–341 (1977).

    Article  CAS  Google Scholar 

  49. Miller, B. R. III et al. MMPBSA.py: an efficient program for end-state free energy calculations. J. Chem. Theory Comput. 8, 3314–3321 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Schmidt, T. A. & Sah, R. L. Effect of synovial fluid on boundary lubrication of articular cartilage. Osteoarthr. Cartil. 15, 35–47 (2007).

    Article  CAS  Google Scholar 

  51. Ko, J. Y., Choi, Y. J., Jeong, G. J. & Im, G. I. Sulforaphane-PLGA microspheres for the intra-articular treatment of osteoarthritis. Biomaterials 34, 5359–5368 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Kang, M. L., Ko, J. Y., Kim, J. E. & Im, G. I. Intra-articular delivery of kartogenin-conjugated chitosan nano/microparticles for cartilage regeneration. Biomaterials 35, 9984–9994 (2014).

    Article  CAS  PubMed  Google Scholar 

  53. Feng, Q. et al. Sulfated hyaluronic acid hydrogels with retarded degradation and enhanced growth factor retention promote hMSC chondrogenesis and articular cartilage integrity with reduced hypertrophy. Acta Biomater. 53, 329–342 (2017).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We sincerely thank X. Miao from South China University of Technology for her contributions to the AFM characterizations. We also sincerely appreciate the help and guidance of F. Zhang and S. Jiang from Sun Yat-Sen University for the anterior-cruciate-ligament-transection-induced OA surgery. S.L. and L.R. are thankful for financial support from the National Natural Science Foundation of China (51673071), the Natural Science Foundation of Guangdong Province (2016A030313509), the Guangdong Scientific and Technological Project (2014B090907004), and the National Key Research and Development Program of China (2017YFC1105004). Y.Z. and C.M. would like to acknowledge support from the Institute for Biomedical Engineering, Science and Technology of the University of Oklahoma.

Author information

Author notes

  1. These authors contributed equally: Renjian Xie, Hang Yao and Angelina S. Mao.

Authors and Affiliations

  1. School of Materials Science and Engineering, South China University of Technology, Guangzhou, China

    Renjian Xie, Hang Yao, Dawei Qi, Yongguang Jia, Meng Gao, Yunhua Chen, Lin Wang, Sa Liu & Li Ren

  2. National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, China

    Renjian Xie, Hang Yao, Dawei Qi, Yongguang Jia, Meng Gao, Yunhua Chen, Lin Wang, Sa Liu & Li Ren

  3. Guangdong Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou, China

    Renjian Xie, Sa Liu & Li Ren

  4. School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, China

    Hang Yao

  5. Norman North High School, Norman, OK, USA

    Angelina S. Mao

  6. Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA

    Ye Zhu & Chuanbin Mao

  7. Department of Biomedical Engineering, City University of Hong Kong, Hong Kong SAR, China

    Dong-An Wang

  8. Department of Joint Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China

    Kun Wang

  9. School of Materials Science and Engineering, Zhejiang University, Hangzhou, China

    Chuanbin Mao

Authors
  1. Renjian Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hang Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angelina S. Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ye Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dawei Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yongguang Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Meng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yunhua Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dong-An Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sa Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Li Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Chuanbin Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.X., S.L., L.R. and C.M. supervised the project. H.Y. carried out the synovial stem cell experiments under the supervision of D.-A.W. R.X., H.Y., A.S.M., Y.Z., Y.J., M.G., Y.C. and L.W. carried out the rest of the experiments and characterization. D.Q. assisted in analysing the confocal results, and K.W. provided fruitful discussion in the results of the animal experiments. A.S.M. designed the illustrations and edited the writing. All the authors contributed to the discussions and writing of the manuscript.

Corresponding authors

Correspondence to Sa Liu, Li Ren or Chuanbin Mao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Biomedical Engineering thanks the anonymous reviewers for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary methods and figures.

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xie, R., Yao, H., Mao, A.S. et al. Biomimetic cartilage-lubricating polymers regenerate cartilage in rats with early osteoarthritis. Nat Biomed Eng 5, 1189–1201 (2021). https://doi.org/10.1038/s41551-021-00785-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-021-00785-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing