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.

  • Article
  • Published:

A modular and supramolecular approach to bioactive scaffolds for tissue engineering

Nature Materials volume 4, pages 568–574 (2005)Cite this article

Abstract

Bioactive polymeric scaffolds are a prerequisite for the ultimate formation of functional tissues. Here, we show that supramolecular polymers based on quadruple hydrogen bonding ureido-pyrimidinone (UPy) moieties are eminently suitable for producing such bioactive materials owing to their low-temperature processability, favourable degradation and biocompatible behaviour. Particularly, the reversible nature of the hydrogen bonds allows for a modular approach to gaining control over cellular behaviour and activity both in vitro and in vivo. Bioactive materials are obtained by simply mixing UPy-functionalized polymers with UPy-modified biomolecules. Low-molecular-weight bis-UPy-oligocaprolactones with cell adhesion promoting UPy-Gly-Arg-Gly-Asp-Ser (UPy-GRGDS) and the synergistic UPy-Pro-His-Ser-Arg-Asn (UPy-PHSRN) peptide sequences are synthesized and studied. The in vitro results indicate strong and specific cell binding of fibroblasts to the UPy-functionalized bioactive materials containing both UPy-peptides. An even more striking effect is seen in vivo where the formation of single giant cells at the interface between bioactive material and tissue is triggered.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The modular approach to bioactive supramolecular materials.
Figure 2: Processability of the supramolecular UPy-materials.
Figure 5: In vivo behaviour of the supramolecular bioactive materials.
Figure 3: Cell adhesion and spreading in vitro.
Figure 4: Specific cell binding and reversibility of the spreading mechanism.

Similar content being viewed by others

References

  1. Griffith, L. G. & Naughton, G. Tissue engineering – current challenges and expanding opportunities. Science 295, 1009–1014 (2002).

    Article  CAS  Google Scholar 

  2. Hench, L. L. & Polak, J. M. Third-generation biomedical materials. Science 295, 1014–1017 (2002).

    Article  CAS  Google Scholar 

  3. Hirano, Y. & Mooney, D. J. Peptide and protein presenting materials for tissue engineering. Adv. Mater. 16, 17–25 (2004).

    Article  CAS  Google Scholar 

  4. Clark, E. A. & Brugge, J. S. Integrins and signal transduction pathways: the road taken. Science 268, 233–239 (1995).

    Article  CAS  Google Scholar 

  5. Stupack, D. G. & Cheresh, D. A. Get a ligand, get a life: integrins, signaling and cell survival. J. Cell Sci. 115, 3729–3738 (2002).

    Article  CAS  Google Scholar 

  6. Hersel, U., Dahmen, C. & Kessler, H. RGD modified polymers: biomaterials for stimulated cell adhesion and beyond. Biomaterials 24, 4385–4415 (2003).

    Article  CAS  Google Scholar 

  7. Pierschbacher, M. D. & Ruoslahti, E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature 309, 30–33 (1984).

    Article  CAS  Google Scholar 

  8. Massia, S. P. & Hubbell, J. A. An RGD spacing of 440 nm is sufficient for integrin αvβ3-mediated fibroblast spreading and 140 nm for focal contact and stress fiber formation. J. Cell. Biol. 114, 1089–1100 (1991).

    Article  CAS  Google Scholar 

  9. Ruoslahti, E. RGD and other recognition sequences for integrins. Annu. Rev. Cell Dev. Biol. 12, 697–715 (1996).

    Article  CAS  Google Scholar 

  10. Aota, S. -I., Nomizu, M. & Yamada, K. M. The short amino acid sequence Pro-His-Ser-Arg-Asn in human fibronectin enhances cell-adhesive function. J. Biol. Chem. 269, 24756–24761 (1994).

    CAS  Google Scholar 

  11. Leahy, D. J., Aukhil, I. & Erickson, H. P. 2.0 Å crystal structure of a four-domain segment of human fibronectin encompassing the RGD loop and synergy region. Cell 84, 155–164 (1996).

    Article  CAS  Google Scholar 

  12. Feng, Y. & Mrksich, M. The synergy peptide PHSRN and the adhesion peptide RGD mediate cell adhesion through a common mechanism. Biochemistry 43, 15811–15821 (2004).

    Article  CAS  Google Scholar 

  13. Kokkoli, E., Ochsenhirt, S. E. & Tirrell, M. Collective and single-molecule interactions of α5β1 integrins. Langmuir 20, 2397–2404 (2004).

    Article  CAS  Google Scholar 

  14. Mardilovich, A. & Kokkoli, E. Biomimetic peptide-amphiphiles for functional biomaterials: the role of GRGDSP and PHSRN. Biomacromolecules 5, 950–957 (2004).

    Article  CAS  Google Scholar 

  15. Maynard, H. D., Okada, S. Y. & Grubbs, R. Inhibition of cell adhesion to fibronectin by oligo-peptide-substituted polynorbornenes. J. Am. Chem. Soc. 123, 1275–1279 (2001).

    Article  CAS  Google Scholar 

  16. Aucoin, L., Griffith, C. M., Pleizier, G., Deslandes, Y. & Sheardown, H. Interactions of corneal epithelial cells and surfaces modified with cell adhesion peptide combinations. J. Biomater. Sci. Polym. Edn 13, 447–462 (2002).

    Article  CAS  Google Scholar 

  17. Hojo, K. et al. Amino acids and peptides. Part 39: a bivalent poly(ethylene glycol) hybrid containing an active site (RGD) and its synergistic site (PHSRN) of fibronectin. Bioorg. Med. Chem. Lett. 11, 1429–1432 (2001).

    Article  CAS  Google Scholar 

  18. Susuki, Y. et al. Preparation and biological activities of a bivalent poly(ethylene glycol) hybrid containing an active site and its synergistic site of fibronectin. Chem. Pharm. Bull. 50, 1229–1232 (2002).

    Article  CAS  Google Scholar 

  19. Kim, T. -I. et al. Design and biological activity of synthetic oligopeptides with Pro-His-Ser-Arg-Asn (PHSRN) and Arg-Gly-Asp (RGD) motifs for human osteoblast-like cell (MG-63) adhesion. Biotech. Lett. 24, 2029–2033 (2002).

    Article  CAS  Google Scholar 

  20. Kao, W. J., Lee, D., Schense, J. C. & Hubbell, J. A. Fibronectin modulates macrophage adhesion and FBGC formation: The role of RGD, PHSRN, and PRRARV domains. J. Biomed. Mater. Res. 55, 79–88 (2001).

    Article  CAS  Google Scholar 

  21. Kao, W. J. & Lee, D. In vivo modulation of host response and macrophage behavior by polymer networks grafted with fibronectin-derived biomimetic oligopeptides: the role of RGD and PHSRN domains. Biomaterials 22, 2901–2909 (2001).

    Article  CAS  Google Scholar 

  22. Fittkau, M. H. et al. The selective modulation of endothelial cell mobility on RGD peptide containing surfaces by YIGSR peptides. Biomaterials 26, 167–174 (2005).

    Article  CAS  Google Scholar 

  23. Sijbesma, R. P. et al. Reversible polymers formed from self-complementary monomers using quadruple hydrogen bonding. Science 278, 1601–1604 (1997).

    Article  CAS  Google Scholar 

  24. Beijer, F. H., Sijbesma, R. P., Kooijman, H., Spek, A. L. & Meijer, E. W. Strong dimerization of ureidopyrimidinones via quadruple hydrogen bonding. J. Am. Chem. Soc. 120, 6761–6789 (1998).

    Article  CAS  Google Scholar 

  25. Söntjens, S. H. M., Sijbesma, R. P., van Genderen, M. H. P. & Meijer, E. W. Stability and lifetime of quadruply hydrogen bonded 2-ureido-4[1H]-pyrimidinone dimers. J. Am. Chem. Soc. 122, 7487–7493 (2002).

    Article  Google Scholar 

  26. Folmer, B. J. B., Sijbesma, R. P., Versteegen, R. M., van der Rijt, J. A. J. & Meijer, E. W. Supramolecular polymer materials: chain extension of telechelic polymers using a reactive hydrogen-bonding synthon. Adv. Mater. 12, 874–878 (2000).

    Article  CAS  Google Scholar 

  27. Keizer, H. M., Sijbesma, R. P. & Meijer, E. W. The convenient synthesis of hydrogen-bonded ureidopyrimidinones. Eur. J. Org. Chem. 2004, 2553–2555 (2004).

    Article  Google Scholar 

  28. Hutmacher, D. W. et al. Mechanical properties and cell cultural response of polycaprolactone scaffolds designed and fabricated via fused deposition modeling. J. Biomed. Mater. Res. 55, 203–216 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Jolanda Spiering for the synthesis of the functionalized polymer in large quantities, Hans Adams for the help with the peptide synthesis, Gaby van Gemert and Henk Janssen for synthesizing the water-soluble UPy-molecules, Rob Hermans for the help with the toxicity tests, Ralf Bovee for the help with the preparative RPLC, Nico Kamperman and Maarten de Graauw for producing the FDM scaffolds, Cláudia Vaz for making the electrospun scaffold, Linda van Beek for spinning the fibres, Sagitta Peters for the degradability studies and Guido Krenning for the great help with the PCR and FACS study. Finally, we like to thank the many fruitful discussions with Rint Sijbesma, Nico Sommerdijk, Carlijn Bouten and Frank Baaijens. This work is supported by the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (CW-NWO).

Author information

Authors and Affiliations

  1. Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, PO Box 513, Eindhoven, NL-5600 MB, The Netherlands

    Patricia Y. W. Dankers & E. W. Meijer

  2. Department of Pathology and Laboratory Medicine, Medical Biology Section, University Medical Center Groningen, Hanzeplein 1, Groningen, NL-9713 GZ, The Netherlands

    Martin C. Harmsen, Linda A. Brouwer & Marja J. A. Van Luyn

Authors
  1. Patricia Y. W. Dankers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin C. Harmsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linda A. Brouwer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marja J. A. Van Luyn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. W. Meijer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. W. Meijer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figures and methods (PDF 729 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dankers, P., Harmsen, M., Brouwer, L. et al. A modular and supramolecular approach to bioactive scaffolds for tissue engineering. Nature Mater 4, 568–574 (2005). https://doi.org/10.1038/nmat1418

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nmat1418

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