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Enhanced lubrication on tissue and biomaterial surfaces through peptide-mediated binding of hyaluronic acid

Abstract

Lubrication is key for the efficient function of devices and tissues with moving surfaces, such as articulating joints, ocular surfaces and the lungs. Indeed, lubrication dysfunction leads to increased friction and degeneration of these systems. Here, we present a polymer–peptide surface coating platform to non-covalently bind hyaluronic acid (HA), a natural lubricant in the body. Tissue surfaces treated with the HA-binding system exhibited higher lubricity values, and in vivo were able to retain HA in the articular joint and to bind ocular tissue surfaces. Biomaterials-mediated strategies that locally bind and concentrate HA could provide physical and biological benefits when used to treat tissue-lubricating dysfunction and to coat medical devices.

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Figure 1: Tissue-surface modification with a HABpep–polymer system.
Figure 2: Single-step strategy for the application of the HABpep–polymer system to a tissue surface, and functional translation to a joint environment.
Figure 3: Cartilage-surface-bound HA through the HABpep–polymer coating system in the absence of an exogenous lubricant can recapitulate the friction coefficients of high-concentration HA lubricants.
Figure 4: Ocular surface application of the HABpep–polymer system.

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References

  1. Dorinson, A. & Ludema, K. C. Mechanics and Chemistry in Lubrication Ch. 1 (Elsevier, 1985).

    Google Scholar 

  2. Kato, K. Industrial tribology in the past and future. Tribology 6, 1–9 (2011).

    Google Scholar 

  3. Moghani, T., Butler, J. P. & Loring, S. H. Determinants of friction in soft elastohydrodynamic lubrication. J. Biomech. 42, 1069–1074 (2009).

    Google Scholar 

  4. Chawla, K., Ham, H. O., Nguyen, T. & Messersmith, P. B. Molecular resurfacing of cartilage with proteoglycan 4 (PRG4). Acta Biomater. 6, 3388–3394 (2010).

    CAS  Google Scholar 

  5. Flannery, C. R. et al. Prevention of cartilage degeneration in a rat model of osteoarthritis by intracellular treatment with recombinant lubricin. Arthritis Rheum. 60, 840–847 (2009).

    CAS  Google Scholar 

  6. McNary, S. M., Athanasiou, K. A. & Reddi, A. H. Engineering lubrication in articular cartilage. Tissue Eng. Part B Rev. 18, 88–100 (2012).

    CAS  Google Scholar 

  7. Sivan, S. et al. Liposomes act as effective biolubricants for friction reduction in human synovial joints. Langmuir 26, 1107–1116 (2010).

    CAS  Google Scholar 

  8. Hills, B. A. & Butler, B. D. Surfactants identified in synovial fluid and their ability to act as boundary lubricants. Ann. Rheum. Dis. 43, 641–648 (1984).

    CAS  Google Scholar 

  9. Schmidt, T. A., Gastelum, N. S., Nguyen, Q. T., Schumacher, B. L. & Sah, R. L. Boundary lubrication of articular cartilage: Role of synovial fluid constituents. Arthritis Rheum. 56, 882–891 (2007).

    CAS  Google Scholar 

  10. Neu, C. P., Komvopoulos, K. & Reddi, A. H. The interface of functional biotribology and regenerative medicine in synovial joints. Tissue Eng. Part B Rev. 14, 235–247 (2008).

    CAS  Google Scholar 

  11. Chen, M., Briscoe, W. H., Armes, S. P. & Klein, J. Lubrication at physiological pressures by polyzwitterionic brushes. Science 323, 1698–1701 (2009).

    CAS  Google Scholar 

  12. Schmidt, T. A. et al. Transcription, translation, and function of lubricin, a boundary lubricant, at the ocular surface. JAMA Ophthalmol. 131, 766–776 (2013).

    CAS  Google Scholar 

  13. Zmolik, J. M. & Mummert, M. E. Pep-1 as a novel probe for the in situ detection of hyaluronan. J. Histochem. Cytochem. 53, 745–751 (2005).

    CAS  Google Scholar 

  14. Mummert, M. E., Mohamadzadeh, M., Mummert, D. I., Mizumoto, N. & Takashima, A. Development of a peptide inhibitor of hyaluronan-mediated leukocyte trafficking. J. Exp. Med. 192, 769–780 (2000).

    CAS  Google Scholar 

  15. Tolg, C. et al. A RHAMM mimetic peptide blocks hyaluronan signaling and reduces inflammation and fibrogenesis and excisional skin wounds. Am. J. Pathol. 181, 1250–1270 (2012).

    CAS  Google Scholar 

  16. Zaleski, K. J. et al. Hyaluronic acid binding peptides prevent experimental staphylococcal wound infection. Antimicrob. Agents Chemother. 50, 3856–3860 (2006).

    CAS  Google Scholar 

  17. Yang, B., Zhang, L. & Turley, E. A. Identification of two hyaluronan-binding domains in the hyaluronan receptor RHAMM. J. Biol. Chem. 268, 8617–8623 (1993).

    CAS  Google Scholar 

  18. Jay, G. D., Torres, J. R., Warman, M. L., Laderer, M. C. & Breuer, K. S. The role of lubricin in the mechanical behavior of synovial fluid. Proc. Natl Acad. Sci. USA 104, 6194–6199 (2007).

    CAS  Google Scholar 

  19. Zhang, D., Johnson, L. J., Hsu, H. P. & Spector, M. Cartilaginous deposits in subchondral bone in regions of exposed bone in osteoarthritis of the human knee: Histomorphometric study of PRG4 distribution in osteoarthritic cartilage. J. Orthop. Res. 25, 873–883 (2007).

    CAS  Google Scholar 

  20. Presti, D. & Scott, J. E. Hyaluronan-mediated protective effect against cell damage caused by enzymatically produced hydroxyl (OH.) radicals is dependent on hyaluronan molecular mass. Cell Biochem. Funct. 12, 281–288 (1994).

    CAS  Google Scholar 

  21. Julovi, S. M., Yasuda, T., Shimizu, M., Hiramitsu, T. & Nakamura, T. Inhibition of interleukin-1β-stimulated production of matrix metalloproteinases by hyaluronan via CD44 in human articular cartilage. Arthritis Rheum. 50, 516–525 (2004).

    CAS  Google Scholar 

  22. Fraser, J. R. E., Laurent, T. C. & Laurent, U. B. G. Hyaluronan: Its nature, distribution, functions and turnover. J. Intern. Med. 242, 27–33, (1997).

    CAS  Google Scholar 

  23. Buckwalter, J. A. & Mankin, H. J. Articular cartilage. Part II: Degeneration and osteoarthrosis, repair, regeneration, and transplantation. J. Bone Joint Surg. Am. 79, 612–632 (1997).

    Google Scholar 

  24. Morrell, K. C., Hodge, W. A., Krebs, D. E. & Mann, R. W. Corroboration of in vivo cartilage pressures with implications for synovial joint tribology and osteoarthritis causation. Proc. Natl Acad. Sci. USA 102, 14819–14824 (2005).

    CAS  Google Scholar 

  25. Greene, G. W. et al. Adaptive mechanically controlled lubrication mechanism found in articular joints. Proc. Natl Acad. Sci. USA 108, 5255–5259 (2011).

    CAS  Google Scholar 

  26. Das, S. et al. Synergistic interactions between grafted hyaluronic acid and lubricin provide enhanced wear protection and lubrication. Biomacromolecules 14, 1669–1677 (2013).

    CAS  Google Scholar 

  27. Amiel, D. et al. Long-term effect of sodium hyaluronate (Hyalgan®) on osteoarthritis progression in a rabbit model. Osteoarthritis Cartilage 11, 636–643 (2003).

    CAS  Google Scholar 

  28. Yoshimi, T. et al. Effects of high-molecular-weight sodium hyaluronate on experimental osteoarthrosis induced by the resection of rabbit anterior cruciate ligament. Clin. Orthop. Relat. Res. 298, 296–304 (1994).

    Google Scholar 

  29. Elmory, S. et al. Chondroprotective effects of high-molecular-weight cross-linked hyaluronic acid in a rabbit knee osteoarthritis model. Osteoarthritis Cartilage 22, 121–127 (2014).

    Google Scholar 

  30. Yu, C-J. et al. Proteomic analysis of osteoarthritic chondrocyte reveals the hyaluronic acid regulated proteins involved in chondroprotective effect under oxidative stress. J. Proteomics 99, 40–53 (2014).

    CAS  Google Scholar 

  31. Moreland, L. W. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: Mechanisms of action. Arthritis Res. Ther. 5, 54–67 (2003).

    CAS  Google Scholar 

  32. Sharma, B., Williams, C. G., Khan, M., Manson, P. & Elisseeff, J .H. In vivo chondrogenesis of mesenchymal stem cells in photopolymerized hydrogel. Plast. Reconstr. Surg. 119, 112–120 (2007).

    CAS  Google Scholar 

  33. Jackson, D. W. & Simon, T. M. Intra-articular distribution and residence time of Hylan A and B: A study in the goat knee. Osteoarthritis Cartilage 14, 1248–1257 (2006).

    CAS  Google Scholar 

  34. Zhang, W. et al. OARSI recommendations for the management of hip and knee osteoarthritis: Part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage 18, 476–499 (2010).

    CAS  Google Scholar 

  35. Strauss, E. J., Hart, J. A., Miller, M. D., Altman, R. D. & Rosen, J. E. Hyaluronic acid viscosupplementation and osteoarthritis: Current uses and future directions. Am. J. Sports Med. 37, 1636–1644 (2009).

    Google Scholar 

  36. Brandt, K. D., Smith, G. N. & Simon, L. S. Intraarticular injection of hyaluronan as treatment for knee osteoarthritis: What is the evidence. Arthritis Rheum. 43, 1192–1203 (2000).

    CAS  Google Scholar 

  37. Sharma, B. et al. Human cartilage repair with a photoreactive adhesive-hydrogel composite. Sci. Transl. Med. 5, 167ra6 (2013).

    Google Scholar 

  38. Wang, D. A. et al. Multifunctional chondroitin sulphate for cartilage tissue-biomaterial integration. Nature Mater. 6, 385–392 (2007).

    CAS  Google Scholar 

  39. Messman, J. M., Lokitz, B. S., Pickel, J. M. & Kilbey, S. M. Highly tailorable materials based on 2-vinyl-4,4-dimethyl azlactone: (co)polymerization, synthetic manipulation and characterization. Macromolecules 42, 3933–3941 (2009).

    CAS  Google Scholar 

  40. Brown, T. J., Laurent, U. B. G. & Fraser, J. R. E. Turnover of hyaluronan in synovial joints: Elimination of labeled hyaluronan from the knee joint of the rabbit. Exp. Physiol. 76, 125–134 (1991).

    CAS  Google Scholar 

  41. Smith, G. N., Mickler, E. A., Myers, S. L. & Brandt, K. D. Effect of intraarticular hyaluronan injection on synovial fluid hyaluronan in the early stage of canine post-traumatic osteoarthritis. J. Rheum. 28, 1341–1346 (2001).

    CAS  Google Scholar 

  42. Caligaris, M., Canal, C. E., Ahmad, C. S., Gardner, T. R. & Ateshian, G. A. Investigation of the frictional response of osteoarthritic human tibiofemoral joints and the potential beneficial tribological effect of healthy synovial fluid. Osteoarthritis Cartilage 17, 1327–1332 (2009).

    CAS  Google Scholar 

  43. Lee, S. S. et al. Frictional response of normal and osteoarthritic articular cartilage in human femoral head. Proc. Inst. Mech. Eng. H. 227, 129–137 (2013).

    Google Scholar 

  44. Desrochers, J., Amrein, M. W. & Matyas, J. R. Microscale surface friction of articular cartilage in early osteoarthritis. J. Mech. Behav. Biomed. Mater. 25, 11–22 (2013).

    CAS  Google Scholar 

  45. Rah, M. J. A review of hyaluronan and its ophthalmic applications. Optometry 82, 38–43 (2011).

    Google Scholar 

  46. Fonn, D. Targeting contact lens induced dryness and discomfort: What properties will make lenses more comfortable. Optom. Vis. Sci. 84, 279–285 (2007).

    Google Scholar 

  47. Hargittai, I. & Hargittai, M. Molecular structure of hyaluronan: An introduction. Struct. Chem. 19, 697–717 (2008).

    CAS  Google Scholar 

  48. Inoue, M. & Katakami, C. The effect of hyaluronic acid on corneal epithelial cell proliferation. Invest. Opthalmol. Vis. Sci. 34, 2313–2315 (1993).

    CAS  Google Scholar 

  49. Pauloin, T., Dutot, M., Joly, F., Warnet, J. M. & Rat, P. High molecular weight hyaluronan decreases UVB-induced apoptosis and inflammation in human epithelial corneal cells. Mol. Vis. 15, 577–583 (2009).

    CAS  Google Scholar 

  50. Rothenfluh, D. A., Bermudez, H., O’Neil, C. P. & Hubbell, J. A. Biofunctional polymer nanoparticles for intra-articular targeting and retention in cartilage. Nature Mater. 7, 248–254 (2008).

    CAS  Google Scholar 

  51. Löster, K., Zeilinger, K., Schuppan, D. & Reutter, W. The cysteine-rich region of dipeptidyl peptidase IV (CD26) is the collagen-binding site. Biochem. Biophys. Res. Commun. 217, 341–348 (1995).

    Google Scholar 

  52. Sistiabudi, R. & Ivanisevic, A. Collagen-binding peptide interaction with retinal tissue surfaces. Langmuir 24, 1591–1594 (2008).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  54. Jones, A. R. et al. Binding and localization of recombinant lubricin to articular cartilage surfaces. J. Orthop. Res. 25, 283–292 (2007).

    CAS  Google Scholar 

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Acknowledgements

We thank F. Guilak (Duke University) for helpful discussions on the friction testing. A.S. was supported by the Arthritis Research Foundation Award 5885 and S.A.U. was supported in part by the National Institutes of Health (NIH) under the Ruth L. Kirschstein National Research Service Award AG328232. Funding sources gratefully acknowledged are NIH R01AR054005, DoD-PRORP grant, the Wallace H. Coulter Foundation, the Ort Philanthropic Fund for supporting the rheometer and the Jules Stein Professorship from the Research to Prevent Blindness Foundation. We gratefully acknowledge the Johns Hopkins A.B. Mass Spectrometry/Proteomic Facility for providing access to the matrix-assisted laser-desorption ionization time-of-flight spectrometer, the Johns Hopkins Department of Chemistry Instrumentation Facility for providing access to the peptide synthesizer, and the Johns Hopkins Department of Materials Science and the Fairbrother research group for use of the surface analysis laboratory.

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The experiments were designed by A.S., M.C., S.A.U., P.M. and J.H.E., and carried out by A.S., M.C., S.A.U. and K.A.W. Data analyses were performed by A.S., M.C. and J.H.E. The manuscript was written by A.S. and J.H.E.

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Correspondence to Jennifer H. Elisseeff.

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The authors declare no competing financial interests.

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Singh, A., Corvelli, M., Unterman, S. et al. Enhanced lubrication on tissue and biomaterial surfaces through peptide-mediated binding of hyaluronic acid. Nature Mater 13, 988–995 (2014). https://doi.org/10.1038/nmat4048

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