Responsive biomimetic networks from polyisocyanopeptide hydrogels

Abstract

Mechanical responsiveness is essential to all biological systems down to the level of tissues and cells1,2. The intra- and extracellular mechanics of such systems are governed by a series of proteins, such as microtubules, actin, intermediate filaments and collagen3,4. As a general design motif, these proteins self-assemble into helical structures and superstructures that differ in diameter and persistence length to cover the full mechanical spectrum1. Gels of cytoskeletal proteins display particular mechanical responses (stress stiffening) that until now have been absent in synthetic polymeric and low-molar-mass gels. Here we present synthetic gels that mimic in nearly all aspects gels prepared from intermediate filaments. They are prepared from polyisocyanopeptides5,6,7 grafted with oligo(ethylene glycol) side chains. These responsive polymers possess a stiff and helical architecture, and show a tunable thermal transition where the chains bundle together to generate transparent gels at extremely low concentrations. Using characterization techniques operating at different length scales (for example, macroscopic rheology, atomic force microscopy and molecular force spectroscopy) combined with an appropriate theoretical network model8,9,10, we establish the hierarchical relationship between the bulk mechanical properties and the single-molecule parameters. Our results show that to develop artificial cytoskeletal or extracellular matrix mimics, the essential design parameters are not only the molecular stiffness, but also the extent of bundling. In contrast to the peptidic materials, our polyisocyanide polymers are readily modified, giving a starting point for functional biomimetic hydrogels with potentially a wide variety of applications11,12,13,14, in particular in the biomedical field.

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Figure 1: Oligo(ethylene glycol)-substituted PICs.
Figure 2: AFM analysis of polymers and gel.
Figure 3: Rheological analysis of PIC gels.
Figure 4: Stiffness of the gel versus stiffness of the constituent polymer.

References

  1. 1

    Kamm, R. D. & Mofrad, M. R. K. in Cytoskeletal Mechanics: Models and Measurements (eds Mofrad, M. R. K. & Kamm, R. D. ) Ch. 1, 1–17 (Cambridge Univ. Press, 2006)

  2. 2

    Fernández, P., Pullarkat, P. A. & Ott, A. A master relation defines the nonlinear viscoelasticity of single fibroblasts. Biophys. J. 90, 3796–3805 (2006)

  3. 3

    Fernandez-Gonzalez, R. & Zallen, J. A. Feeling the squeeze: live-cell extrusion limits cell density in epithelia. Cell 149, 965–967 (2012)

  4. 4

    Storm, C., Pastore, J. J., MacKintosh, F. C., Lubensky, T. C. & Janmey, P. A. Nonlinear elasticity in biological gels. Nature 435, 191–194 (2005)

  5. 5

    Schwartz, E., Le Gac, S., Cornelissen, J. J. L. M., Nolte, R. J. M. & Rowan, A. E. Macromolecular multi-chromophoric scaffolding. Chem. Soc. Rev. 39, 1576–1599 (2010)

  6. 6

    Cornelissen, J. J. L. M. et al. β-helical polymers from isocyanopeptides. Science 293, 676–680 (2001)

  7. 7

    Keereweer, B. et al. in Functional Supramolecular Architectures Vol. 1 (eds Samori, P. & Cacialli, F. ) Ch. 5, 135–152 (VCH, 2011)

  8. 8

    Lin, Y.-C. et al. Origins of elasticity in intermediate filament networks. Phys. Rev. Lett. 104, 058101 (2010)

  9. 9

    MacKintosh, F. C., Kas, J. & Janmey, P. A. Elasticity of semiflexible biopolymer networks. Phys. Rev. Lett. 75, 4425–4428 (1995)

  10. 10

    Gardel, M. L. et al. Elastic behavior of cross-linked and bundled actin networks. Science 304, 1301–1305 (2004)

  11. 11

    Tiller, J. C. Increasing the local concentration of drugs by hydrogel formation. Angew. Chem. Int. Edn 42, 3072–3075 (2003)

  12. 12

    Place, E. S., Evans, N. D. & Stevens, M. M. Complexity in biomaterials for tissue engineering. Nature Mater. 8, 457–470 (2009)

  13. 13

    Peppas, N. A., Hilt, J. Z., Khademhosseini, A. & Langer, R. Hydrogels in biology and medicine: from molecular principles to bionanotechnology. Adv. Mater. 18, 1345–1360 (2006)

  14. 14

    Hirst, A. R., Escuder, B., Miravet, J. F. & Smith, D. K. High-tech applications of self-assembling supramolecular nanostructured gel-phase materials: from regenerative medicine to electronic devices. Angew. Chem. Int. Edn 47, 8002–8018 (2008)

  15. 15

    Rowan, A. E. et al. Method for the preparation of high molecular weight oligo(alkylene glycol) functionalized polyisocyanopeptides. European Patent 2,287,221. (2011)

  16. 16

    Grason, G. M. & Bruinsma, R. F. Chirality and equilibrium biopolymer bundles. Phys. Rev. Lett. 99, 098101 (2007)

  17. 17

    Pollard, T. D. & Cooper, J. A. Actin and actin-binding proteins — a critical evaluation of mechanisms and functions. Annu. Rev. Biochem. 55, 987–1035 (1986)

  18. 18

    Leterrier, J. F., Kas, J., Hartwig, J., Vegners, R. & Janmey, P. A. Mechanical effects of neurofilament cross-bridges — modulation by phosphorylation, lipids, and interactions with F-actin. J. Biochem. 271, 15687–15694 (1996)

  19. 19

    Han, S., Hagiwara, M. & Ishizone, T. Synthesis of thermally sensitive water-soluble polymethacrylates by living anionic polymerizations of oligo(ethylene glycol) methyl ether methacrylates. Macromolecules 36, 8312–8319 (2003)

  20. 20

    Lutz, J. F. & Hoth, A. Preparation of ideal PEG analogues with a tunable thermosensitivity by controlled radical copolymerization of 2-(2-methoxyethoxy)ethyl methacrylate and oligo(ethylene glycol) methacrylate. Macromolecules 39, 893–896 (2006)

  21. 21

    Wang, H. et al. A structure-gelation ability study in a short peptide-based ‘Super Hydrogelator’ system. Soft Matter 7, 3897–3905 (2011)

  22. 22

    Mason, T. G., Dhople, A. & Wirtz, D. Linear viscoelastic moduli of concentrated DNA solutions. Macromolecules 31, 3600–3603 (1998)

  23. 23

    Onck, P. R., Koeman, T., van Dillen, T. & van der Giessen, E. Alternative explanation of stiffening in cross-linked semiflexible networks. Phys. Rev. Lett. 95, 178102 (2005)

  24. 24

    Huisman, E. M., van Dillen, T., Onck, P. R. & Van der Giessen, E. Three-dimensional cross-linked F-actin networks: relation between network architecture and mechanical behavior. Phys. Rev. Lett. 99, 208103 (2007)

  25. 25

    Broedersz, C. P. & MacKintosh, F. C. Molecular motors stiffen non-affine semiflexible polymer networks. Soft Matter 7, 3186–3191 (2011)

  26. 26

    Bustamante, C., Marko, J. F., Siggia, E. D. & Smith, S. Entropic elasticity of λ-phage DNA. Science 265, 1599–1600 (1994)

  27. 27

    Van Buul, A. M. et al. Stiffness versus architecture of single helical polyisocyanopeptides. Chem. Sci (submitted)

  28. 28

    Bathe, M., Heussinger, C., Claaessens, M. M. A. E., Bausch, A. R. & Frey, E. Cytoskeletal bundle mechanics. Biophys. J. 94, 2955–2964 (2008)

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Acknowledgements

We thank B. Norder for assistance with rheological experiments, C. Broersz for support with nonlinear rheology, F. MacKintosh for discussions on the interpretation of the semi-flexible polymer network theory and E. Cator for work on the statistical analysis of the AFM images. We acknowledge financial support from Technology Foundation STW, the Council for the Chemical Sciences of the Netherlands Organisation for Scientific Research (NWO-CW-7005644), NRSCC, the Royal Academy for Arts and Sciences and EU projects Hierarchy (PITN-CT-2007-215851) and Superior (PITN-CT-2009-238177).

Author information

P.H.J.K. and A.E.R. wrote the manuscript and developed the model. M.K, Z.H.E.-A., T.W., E.S., H.J.K. and R.H. were involved in the design, synthesis and characterization of the materials. M.J. and A.M.v.B. conducted the SMFS measurements. V.A.A.L.S., P.H.J.K., E.M. and S.J.P. designed, conducted and interpreted the rheological experiment. P.H.J.K., R.J.M.N. and A.E.R. supervised the project.

Correspondence to Paul H. J. Kouwer or Alan E. Rowan.

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The authors declare no competing financial interests.

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Kouwer, P., Koepf, M., Le Sage, V. et al. Responsive biomimetic networks from polyisocyanopeptide hydrogels. Nature 493, 651–655 (2013) doi:10.1038/nature11839

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