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Design and applications of man-made biomimetic fibrillar hydrogels

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Abstract

Many extracellular matrices (ECMs) have a filamentous architecture, which influences cell growth and phenotype and imparts tissues with specific properties. Man-made fibrillar hydrogels can function as biomimetic materials to reproduce the filamentous nature and properties of ECMs and to serve as scaffolds for 3D cell culture and tissue engineering. Different types of synthetic nanofibrillar hydrogels have been developed, with diverse mechanisms of assembly and a variety of physical properties and applications. In this Review, we explore the design and properties of biomimetic man-made nanofibrillar hydrogels. We discuss the assembly of peptides, block copolymer worm-like micelles and filamentous nanoparticles into fibrillar hydrogels and investigate the relationship between structure and physical as well as biochemical properties. Potential applications for 3D cell culture and tissue engineering are examined, and the properties and structure of natural and man-made fibrillar hydrogels are compared. Finally, we critically assess current challenges and future directions of the field.

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Fig. 1: Nanofibrillar extracellular matrices.
Fig. 2: Assembly of man-made nanofibrillar hydrogels.
Fig. 3: Assembly of fibrillar hydrogels from molecular building blocks.
Fig. 4: Assembly of fibrillar hydrogels from colloidal particles.
Fig. 5: Anisotropy of fibrillar hydrogels.
Fig. 6: Structure and properties of fibrillar hydrogels.

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References

  1. Theocharis, A. D., Skandalis, S. S., Gialeli, C. & Karamanos, N. K. Extracellular matrix structure. Adv. Drug Deliv. Rev. 97, 4–27 (2016).

    CAS  Google Scholar 

  2. Bosman, F. T. & Stamenkovic, I. Functional structure and composition of the extracellular matrix. J. Pathol. 200, 423–428 (2003).

    CAS  Google Scholar 

  3. MacKintosh, F. C., Kas, J. & Janmey, P. A. Elasticity of semiflexible biopolymer networks. Phys. Rev. Lett. 75, 4425–4428 (1995). In this study, the authors develop a model for fibrillar gels that explains the elastic properties of these networks, including the concentration dependence of their storage modulus.

    CAS  Google Scholar 

  4. Wozniak, M. A. & Chen, C. S. Mechanotransduction in development: a growing role for contractility. Nat. Rev. Mol. Cell. Biol. 10, 34–43 (2009).

    CAS  Google Scholar 

  5. Dufort, C. C., Paszek, M. J. & Weaver, V. M. Balancing forces: architectural control of mechanotransduction. Nat. Rev. Mol. Cell. Biol. 12, 308–319 (2011).

    CAS  Google Scholar 

  6. Alam, N. et al. The integrin—growth factor receptor duet. J. Cell. Physiol. 213, 649–653 (2007).

    CAS  Google Scholar 

  7. Hynes, R. O. The extracellular matrix: not just pretty fibrils. Science 326, 1216–1219 (2009). This review discusses how extracellular matrix fibres influence growth factor signalling.

    CAS  Google Scholar 

  8. Chau, M., Sriskandha, S. E., Thérien-Aubin, H. & Kumacheva, E. in Advances in Polymer Science Vol. 268 167–199 (Springer, NY, 2015).

  9. Huxley, A. F. Muscular contraction. J. Physiol. 243, 1–43 (1974).

    CAS  Google Scholar 

  10. Madison, K. C. Barrier function of the skin: ‘La Raison d’Être’ of the epidermis. J. Invest. Dermatol. 121, 231–241 (2003).

    CAS  Google Scholar 

  11. Sophia Fox, A. J., Bedi, A. & Rodeo, S. A. The basic science of articular cartilage: structure, composition, and function. Sports Health 1, 461–468 (2009).

    Google Scholar 

  12. Lutolf, M. P. & Hubbell, J. A. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat. Biotechnol. 23, 47–55 (2005).

    CAS  Google Scholar 

  13. Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature 539, 560–564 (2016).

    CAS  Google Scholar 

  14. Morgan, C. E. et al. Tissue-factor targeted peptide amphiphile nanofibers as an injectable therapy to control hemorrhage. ACS Nano 10, 899–909 (2016).

    CAS  Google Scholar 

  15. Ulijn, R. V. & Smith, A. M. Designing peptide based nanomaterials. Chem. Soc. Rev. 37, 664–675 (2008).

    CAS  Google Scholar 

  16. Greenfield, M. A., Hoffman, J. R., Olvera de la Cruz, M. & Stupp, S. I. Tunable mechanics of peptide nanofiber gels. Langmuir 26, 3641–3647 (2010).

    CAS  Google Scholar 

  17. Sur, S., Newcomb, C. J., Webber, M. J. & Stupp, S. I. Tuning supramolecular mechanics to guide neuron development. Biomaterials 34, 4749–4757 (2013).

    CAS  Google Scholar 

  18. Blanazs, A. et al. Sterilizable gels from thermoresponsive block copolymer worms. J. Am. Chem. Soc. 134, 9741–9748 (2012).

    CAS  Google Scholar 

  19. Simon, K. A. et al. Disulfide-based diblock copolymer worm gels: a wholly-synthetic thermoreversible 3D matrix for sheet-based cultures. Biomacromolecules 16, 3952–3958 (2015).

    CAS  Google Scholar 

  20. Warren, N. J., Rosselgong, J., Madsen, J. & Armes, S. P. Disulfide-functionalized diblock copolymer worm gels. Biomacromolecules 16, 2514–2521 (2015).

    CAS  Google Scholar 

  21. Chau, M. et al. Ion-mediated gelation of aqueous suspensions of cellulose nanocrystals. Biomacromolecules 16, 2455–2462 (2015). In this study, the authors report the structure–property relationships of ionically gelled cellulose nanocrystal hydrogels, including how the strength and number of interactions between building blocks influence the stiffness and mesh size of the hydrogels.

    CAS  Google Scholar 

  22. Li, Y. et al. Supramolecular nanofibrillar thermoreversible hydrogel for growth and release of cancer spheroids. Angew. Chemie Int. Ed. 55, 1–6 (2016).

    CAS  Google Scholar 

  23. Liu, M. et al. Chitosan-chitin nanocrystal composite scaffolds for tissue engineering. Carbohydr. Polym. 152, 832–840 (2016).

    CAS  Google Scholar 

  24. Nata, I. F., Wang, S. S.-S., Wu, T.-M. & Lee, C.-K. β-Chitin nanofibrils for self-sustaining hydrogels preparation via hydrothermal treatment. Carbohydr. Polym. 90, 1509–1514 (2012).

    CAS  Google Scholar 

  25. De France, K. J. et al. Injectable anisotropic nanocomposite hydrogels direct in situ growth and alignment of myotubes. Nano Lett. 17, 6487–6495 (2017).

    Google Scholar 

  26. Prabhakaran, M. P., Venugopal, J. & Ramakrishna, S. Electrospun nanostructured scaffolds for bone tissue engineering. Acta Biomater. 5, 2884–2893 (2009).

    CAS  Google Scholar 

  27. Lim, S. H. & Mao, H. Electrospun scaffolds for stem cell engineering. Adv. Drug Deliv. Rev. 61, 1084–1096 (2009).

    CAS  Google Scholar 

  28. Lu, A., Zhu, J., Zhang, G. & Sun, G. Gelatin nanofibers fabricated by extruding immiscible polymer solution blend and their application in tissue engineering. J. Mater. Chem. 21, 18674–18680 (2011).

    CAS  Google Scholar 

  29. Kumbar, S. G., James, R., Nukavarapu, S. P. & Laurencin, C. T. Electrospun nanofiber scaffolds: engineering soft tissues. Biomed. Mater. 3, 034002 (2008).

    CAS  Google Scholar 

  30. Mouw, J. K., Ou, G. & Weaver, V. M. Extracellular matrix assembly: a multiscale deconstruction. Nat. Rev. Mol. Cell. Biol. 15, 771–785 (2014).

    CAS  Google Scholar 

  31. Ushiki, T. Preserving the original architecture of elastin components in the formic acid-digested aorta by an alternative procedure for scanning electron microscopy. J. Electron. Microsc. (Tokyo). 41, 60–63 (1992).

    CAS  Google Scholar 

  32. Baldwin, A. K., Simpson, A., Steer, R., Cain, S. A. & Kielty, C. M. Elastic fibres in health and disease. Expert Rev. Mol. Med. 15, e8 (2013).

    Google Scholar 

  33. Arribas, S. M., Hinek, A. & González, M. C. Elastic fibres and vascular structure in hypertension. Pharmacol. Ther. 111, 771–791 (2006).

    CAS  Google Scholar 

  34. Humphrey, J. D., Dufresne, E. R. & Schwartz, M. A. Mechanotransduction and extracellular matrix homeostasis. Nat. Rev. Mol. Cell. Biol. 15, 802–812 (2014).

    CAS  Google Scholar 

  35. Gelse, K., Pöschl, E. & Aigner, T. Collagens - structure, function, and biosynthesis. Adv. Drug Deliv. Rev. 55, 1531–1546 (2003).

    CAS  Google Scholar 

  36. Zollinger, A. J. & Smith, M. L. Fibronectin, the extracellular glue. Matrix Biol. 60–61, 27–37 (2017).

    Google Scholar 

  37. Pereira, M. et al. The incorporation of fibrinogen into extracellular matrix is dependent on active assembly of a fibronectin matrix. J. Cell Sci. 115, 609–617 (2002).

    CAS  Google Scholar 

  38. Moriya, K. et al. A fibronectin-independent mechanism of collagen fibrillogenesis in adult liver remodeling. Gastroenterology 140, 1653–1663 (2011).

    CAS  Google Scholar 

  39. Singh, P., Carraher, C. & Schwarzbauer, J. E. Assembly of fibronectin extracellular matrix. Annu. Rev. Cell Dev. Biol. 26, 397–419 (2010).

    CAS  Google Scholar 

  40. Bachman, H., Nicosia, J., Dysart, M. & Barker, T. H. Utilizing fibronectin integrin-binding specificity to control cellular responses. Adv. Wound Care 4, 501–511 (2015).

    Google Scholar 

  41. Baneyx, G., Baugh, L. & Vogel, V. Coexisting conformations of fibronectin in cell culture imaged using fluorescence resonance energy transfer. Proc. Natl Acad. Sci. USA 98, 14464–14468 (2001).

    CAS  Google Scholar 

  42. Ohashi, T., Kiehart, D. P. & Erickson, H. P. Dynamics and elasticity of the fibronectin matrix in living cell culture visualized by fibronectin-green fluorescent protein. Proc. Natl Acad. Sci. USA 96, 2153–2158 (1999).

    CAS  Google Scholar 

  43. Fang, M., Yuan, J., Peng, C. & Li, Y. Collagen as a double-edged sword in tumor progression. Tumour Biol. 35, 2871–2882 (2014).

    CAS  Google Scholar 

  44. Cox, T. R. & Erler, J. T. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis. Model. Mech. 4, 165–178 (2011).

    CAS  Google Scholar 

  45. Rybinski, B., Franco-Barraza, J. & Cukierman, E. The wound healing, chronic fibrosis, and cancer progression triad. Physiol. Genom. 46, 223–244 (2014).

    CAS  Google Scholar 

  46. Conklin, M. W. et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011).

    Google Scholar 

  47. Malik, R., Lelkes, P. I. & Cukierman, E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol. 33, 230–236 (2015).

    CAS  Google Scholar 

  48. Klotzsch, E. et al. Fibronectin forms the most extensible biological fibers displaying switchable force-exposed cryptic binding sites. Proc. Natl Acad. Sci. USA 106, 18267–18272 (2009).

    CAS  Google Scholar 

  49. Kouwer, P. H. J. et al. Responsive biomimetic networks from polyisocyanopeptide hydrogels. Nature 493, 651–655 (2013). In this work, polyisocyanopeptide fibrils are used to explore how fibril stiffness and the degree of fibril bundling impact the elastic properties of the resulting hydrogels.

    CAS  Google Scholar 

  50. Vogel, V. Mechanotransducion involving multimodular proteins: converting force into biochemical signals. Annu. Rev. Biophys. Biomol. Struct. 35, 459–488 (2006).

    CAS  Google Scholar 

  51. Notbohm, J., Lesman, A., Rosakis, P., Tirrell, D. A. & Ravichandran, G. Microbuckling of fibrin provides a mechanism for cell mechanosensing. J. R. Soc. Interface 12, 20150320 (2015).

    Google Scholar 

  52. Winer, J. P., Oake, S. & Janmey, P. A. Non-linear elasticity of extracellular matrices enables contractile cells to communicate local position and orientation. PLOS ONE 4, e6382 (2009).

    Google Scholar 

  53. Aghvami, M., Billiar, K. L. & Sander, E. A. Fiber network models predict enhanced cell mechanosensing on fibrous gels. J. Biomech. Eng. 138, 101006 (2016).

    Google Scholar 

  54. Worthington, P. et al. β-hairpin hydrogels as scaffolds for high-throughput drug discovery in three-dimensional cell culture. Anal. Biochem. 535, 25–34 (2017).

    CAS  Google Scholar 

  55. Branco, M. C., Pochan, D. J., Wagner, N. J. & Schneider, J. P. Macromolecular diffusion and release from self-assembled β-hairpin peptide hydrogels. Biomaterials 30, 1339–1347 (2009).

    CAS  Google Scholar 

  56. Altunbas, A., Lee, S. J., Rajasekaran, S. A., Schneider, J. P. & Pochan, D. J. Encapsulation of curcumin in self-assembling peptide hydrogels as injectable drug delivery vehicles. Biomaterials 32, 5906–5914 (2011).

    CAS  Google Scholar 

  57. Zhang, S. et al. A self-assembly pathway to aligned monodomain gels. Nat. Mater. 9, 594–601 (2010). This work demonstrates that the alignment of fibres enables human mesenchymal stem cell alignment and facilitates the formation of action potentials between cardiomyocytes.

    CAS  Google Scholar 

  58. Cheng, T.-Y., Chen, M.-H., Chang, W.-H., Huang, M.-Y. & Wang, T.-W. Neural stem cells encapsulated in a functionalized self-assembling peptide hydrogel for brain tissue engineering. Biomaterials 34, 2005–2016 (2013).

    CAS  Google Scholar 

  59. Yang, Z. & Zhao, X. A. 3D model of ovarian cancer cell lines on peptide nanofiber scaffold to explore the cell–scaffold interaction and chemotherapeutic resistance of anticancer drugs. Int. J. Nanomed. 6, 303–310 (2011).

    CAS  Google Scholar 

  60. Lewis, L., Derakhshandeh, M., Hatzikiriakos, S. G., Hamad, W. Y. & MacLachlan, M. J. Hydrothermal gelation of aqueous cellulose nanocrystal suspensions. Biomacromolecules 17, 2747–2754 (2016).

    CAS  Google Scholar 

  61. Bhattacharya, M. et al. Nanofibrillar cellulose hydrogel promotes three-dimensional liver cell culture. J. Control. Release 164, 291–298 (2012).

    CAS  Google Scholar 

  62. Lou, Y.-R. et al. The use of nanofibrillar cellulose hydrogel as a flexible three-dimensional model to culture human pluripotent stem cells. Stem Cells Dev. 23, 380–392 (2014).

    CAS  Google Scholar 

  63. Raghavan, S. R. & Douglas, J. F. The conundrum of gel formation by molecular nanofibers, wormlike micelles, and filamentous proteins: gelation without cross-links? Soft Matter 8, 8539–8546 (2012).

    CAS  Google Scholar 

  64. Haines-Butterick, L. et al. Controlling hydrogelation kinetics by peptide design for three-dimensional encapsulation and injectable delivery of cells. Proc. Natl Acad. Sci. USA 104, 7791–7796 (2007).

    CAS  Google Scholar 

  65. Thérien-Aubin, H. et al. Temperature-responsive nanofibrillar hydrogels for cell encapsulation. Biomacromolecules 17, 3244–3251 (2016).

    Google Scholar 

  66. Schneider, J. P. et al. Responsive hydrogels from the intramolecular folding and self-assembly of a designed peptide. J. Am. Chem. Soc. 124, 15030–15037 (2002).

    CAS  Google Scholar 

  67. Banwell, E. F. et al. Rational design and application of responsive α-helical peptide hydrogels. Nat. Mater. 8, 596–600 (2009).

    CAS  Google Scholar 

  68. Pashuck, E. T., Cui, H. & Stupp, S. I. Tuning supramolecular rigidity of peptide fibers through molecular structure. J. Am. Chem. Soc. 132, 6041–6046 (2010).

    CAS  Google Scholar 

  69. Stupp, S. I. Self-assembly and biomaterials. Nano Lett. 10, 4783–4786 (2010).

    CAS  Google Scholar 

  70. Knowles, T. P. J. & Buehler, M. J. Nanomechanics of functional and pathological amyloid materials. Nat. Nanotechnol. 6, 469–479 (2011).

    CAS  Google Scholar 

  71. Yokoi, H., Kinoshita, T. & Zhang, S. Dynamic reassembly of peptide RADA16 nanofiber scaffold. Proc. Natl Acad. Sci. USA 102, 8414–8419 (2004).

    Google Scholar 

  72. O’Leary, L. E. R., Fallas, J. A., Bakota, E. L., Kang, M. K. & Hartgerink, J. D. Multi-hierarchical self-assembly of a collagen mimetic peptide from triple helix to nanofibre and hydrogel. Nat. Chem. 3, 821–828 (2011).

    Google Scholar 

  73. Sarkar, B., O’Leary, L. E. R. & Hartgerink, J. D. Self-assembly of fiber-forming collagen mimetic peptides controlled by triple-helical nucleation. J. Am. Chem. Soc. 136, 14417–14424 (2014).

    CAS  Google Scholar 

  74. Smith, A. M. et al. Fmoc-diphenylalanine self assembles to a hydrogel via a novel architecture based on π–π interlocked β-sheets. Adv. Mater. 20, 37–41 (2008).

    CAS  Google Scholar 

  75. Jayawarna, V. et al. Introducing chemical functionality in Fmoc-peptide gels for cell culture. Acta Biomater. 5, 934–943 (2009).

    CAS  Google Scholar 

  76. Hartgerink, J. D., Beniash, E. & Stupp, S. I. Self-assembly and mineralization of peptide amphophile nanofibers. Science 294, 1684–1688 (2001). This article is the first to report the self-assembly of peptide amphiphiles into nanofibres, demonstrating their potential use as a scaffold for bone mineralization.

    CAS  Google Scholar 

  77. Rajangam, K. et al. Heparin binding nanostructures to promote growth of blood vessels. Nano Lett. 6, 2086–2090 (2006).

    CAS  Google Scholar 

  78. Stendahl, J. C., Rao, M. S., Guler, M. O. & Stupp, S. I. Intermolecular forces in the self-assembly of peptide amphiphile nanofibers. Adv. Funct. Mater. 16, 499–508 (2006).

    CAS  Google Scholar 

  79. Paramonov, S. E., Jun, H.-W. & Hartgerink, J. D. Self-assembly of peptide−amphiphile nanofibers: the roles of hydrogen bonding and amphiphilic packing. J. Am. Chem. Soc. 128, 7291–7298 (2006).

    CAS  Google Scholar 

  80. Newcomb, C. J. et al. Supramolecular nanofibers enhance growth factor signaling by increasing lipid raft mobility. Nano Lett. 16, 3042–3050 (2016).

    CAS  Google Scholar 

  81. Shah, R. N. et al. Supramolecular design of self-assembling nanofibers for cartilage regeneration. Proc. Natl Acad. Sci. USA 107, 3293–3298 (2010).

    CAS  Google Scholar 

  82. Mata, A. et al. Biomaterials Bone regeneration mediated by biomimetic mineralization of a nanofiber matrix. Biomaterials 31, 6004–6012 (2010).

    CAS  Google Scholar 

  83. Webber, M. J. et al. Capturing the stem cell paracrine effect using heparin-presenting nanofibres to treat cardiovascular diseases. J. Tissue Eng. Regen. Med. 4, 600–610 (2010).

    CAS  Google Scholar 

  84. Bates, C. M. & Bates, F. S. 50th anniversary perspective: block polymers-pure potential. Macromolecules 50, 3–22 (2017).

    CAS  Google Scholar 

  85. Won, Y.-Y., Davis, H. T. & Bates, F. S. Giant wormlike rubber micelles. Science 283, 960–963 (1999).

    CAS  Google Scholar 

  86. Warren, N. J., Mykhaylyk, O. O., Mahmood, D., Ryan, A. J. & Armes, S. P. RAFT aqueous dispersion polymerization yields poly(ethylene glycol)-based diblock copolymer nano-objects with predictable single phase morphologies. J. Am. Chem. Soc. 136, 1023–1033 (2014).

    CAS  Google Scholar 

  87. Won, Y.-Y., Paso, K., Davis, H. T. & Bates, F. S. Comparison of original and cross-linked wormlike micelles of poly(ethylene oxide- b -butadiene) in water: rheological properties and effects of poly(ethylene oxide) addition. J. Phys. Chem. B 105, 8302–8311 (2001).

    CAS  Google Scholar 

  88. Nagarajan, R. Molecular packing parameter and surfactant self-assembly: the neglected role of the surfactant tail. Langmuir 18, 31–38 (2002).

    CAS  Google Scholar 

  89. Israelachvili, J. N., Mitchell, D. J. & Ninham, B. W. Theory of self-assembly of hydrocarbon amphiphiles into micelles and bilayers. J. Chem. Soc. Faraday Trans. 2 72, 1525–1568 (1975).

    Google Scholar 

  90. Lovett, J. R. et al. Can percolation theory explain the gelation behavior of diblock copolymer worms? Chem. Sci. 9, 7138–7144 (2018).

    CAS  Google Scholar 

  91. Penfold, N. J. W. et al. pH-Responsive non-ionic diblock copolymers: protonation of a morpholine end-group induces an order–order transition. Polym. Chem. 7, 79–88 (2016).

    CAS  Google Scholar 

  92. Lovett, J. R., Warren, N. J., Ratcliffe, L. P. D., Kocik, M. K. & Armes, S. P. pH-responsive non-ionic diblock copolymers: ionization of carboxylic acid end-groups induces an order-order morphological transition. Angew. Chemie Int. Ed. 54, 1279–1283 (2015).

    CAS  Google Scholar 

  93. Araki, J., Yamanaka, Y. & Ohkawa, K. Chitin-chitosan nanocomposite gels: reinforcement of chitosan hydrogels with rod-like chitin nanowhiskers. Polym. J. 44, 713–717 (2012).

    CAS  Google Scholar 

  94. Zhang, X. et al. Structure and properties of polysaccharide nanocrystal-doped supramolecular hydrogels based on cyclodextrin inclusion. Polymer (Guildf) 51, 4398–4407 (2010).

    CAS  Google Scholar 

  95. De France, K. J., Hoare, T. & Cranston, E. D. Review of hydrogels and aerogels containing nanocellulose. Chem. Mater. 29, 4609–4631 (2017).

    Google Scholar 

  96. Way, A. E., Hsu, L., Shanmuganathan, K., Weder, C. & Rowan, S. J. pH-responsive cellulose nanocrystal gels and nanocomposites. ACS Macro Lett. 1, 1001–1006 (2012).

    CAS  Google Scholar 

  97. Abe, K. & Yano, H. Formation of hydrogels from cellulose nanofibers. Carbohydr. Polym. 85, 733–737 (2011).

    CAS  Google Scholar 

  98. Dufresne, A. Nanocellulose: a new ageless bionanomaterial. Mater. Today 16, 220–227 (2013).

    CAS  Google Scholar 

  99. Saito, T., Kimura, S., Nishiyama, Y. & Isogai, A. Cellulose nanofibers prepared by TEMPO-mediated oxidation of native cellulose. Biomacromolecules 8, 2485–2491 (2007).

    CAS  Google Scholar 

  100. Wada, M., Okano, T. & Sugiyama, J. Synchrotron-radiated X-ray and neutron diffraction study of native cellulose. Cellulose 4, 221–232 (1997).

    CAS  Google Scholar 

  101. Sugiyama, J., Vuong, R. & Chanzy, H. Electron diffraction study on the two crystalline phases occurring in native cellulose from an algal cell wall. Macromolecules 24, 4168–4175 (1991).

  102. Saxena, I. M. & Brown, R. M. Cellulose biosynthesis: current views and evolving concepts. Ann. Bot. 96, 9–21 (2005).

    CAS  Google Scholar 

  103. Baker, A. A., Helbert, W., Sugiyama, J. & Miles, M. J. High-resolution atomic force microscopy of native valonia cellulose I microcrystals. J. Struct. Biol. 119, 129–138 (1997).

    CAS  Google Scholar 

  104. Jakob, H. F., Tschegg, S. E. & Fratzl, P. Hydration dependence of the wood-cell wall structure in picea abies. A small-angle X-ray scattering study. Macromolecules 29, 8435–8440 (1996).

    CAS  Google Scholar 

  105. Sehaqui, H., Zhou, Q. & Berglund, L. A. Nanostructured biocomposites of high toughness — a wood cellulose nanofiber network in ductile hydroxyethylcellulose matrix. Soft Matter 7, 7342–7350 (2011).

    CAS  Google Scholar 

  106. Habibi, Y., Lucia, L. A. & Rojas, O. J. Cellulose nanocrystals: chemistry, self-assembly, and applications. Chem. Rev. 110, 3479–3500 (2010).

    CAS  Google Scholar 

  107. Sanna, R. et al. Poly(N-vinylcaprolactam) nanocomposites containing nanocrystalline cellulose: a green approach to thermoresponsive hydrogels. Cellulose 20, 2393–2402 (2013).

    CAS  Google Scholar 

  108. Dong, X. M. & Gray, D. G. Effect of counterions on ordered phase formation in suspensions of charged rodlike cellulose crystallites. Langmuir 13, 2404–2409 (1997).

    CAS  Google Scholar 

  109. Lin, N. & Dufresne, A. Surface chemistry, morphological analysis and properties of cellulose nanocrystals with gradiented sulfation degrees. Nanoscale 6, 5384–5393 (2014).

    CAS  Google Scholar 

  110. De France, K. J., Chan, K. J. W., Cranston, E. D. & Hoare, T. Enhanced mechanical properties in cellulose nanocrystal–poly(oligoethylene glycol methacrylate) injectable nanocomposite hydrogels through control of physical and chemical cross-linking. Biomacromolecules 17, 649–660 (2016).

    Google Scholar 

  111. Prince, E. et al. Patterning of structurally anisotropic composite hydrogel sheets. Biomacromolecules 19, 1276–1284 (2018).

    CAS  Google Scholar 

  112. Fernández-Colino, A., Arias, F. J., Alonso, M. & Rodríguez-Cabello, J. C. Self-organized ECM-mimetic model based on an amphiphilic multiblock silk-elastin-like corecombinamer with a concomitant dual physical gelation process. Biomacromolecules 15, 3781–3793 (2014).

    Google Scholar 

  113. Marelli, B., Ghezzi, C. E., James-Bhasin, M. & Nazhat, S. N. Fabrication of injectable, cellular, anisotropic collagen tissue equivalents with modular fibrillar densities. Biomaterials 37, 183–193 (2015).

    CAS  Google Scholar 

  114. Gladman, A. S., Matsumoto, E. A., Nuzzo, R. G., Mahadevan, L. & Lewis, J. A. Biomimetic 4D printing. Nat. Mater. 15, 413–418 (2016).

    Google Scholar 

  115. Sano, K., Ishida, Y. & Aida, T. Synthesis of anisotropic hydrogels and their applications. Angew. Chem. Int. Ed. Engl. 57, 2–14 (2018).

    Google Scholar 

  116. Chau, M. et al. Composite hydrogels with tunable anisotropic morphologies and mechanical properties. Chem. Mater. 28, 3406–3415 (2016).

    CAS  Google Scholar 

  117. Lin, P., Zhang, T., Wang, X., Yu, B. & Zhou, F. Freezing molecular orientation under stretch for high mechanical strength but anisotropic hydrogels. Small 12, 4386–4392 (2016).

    CAS  Google Scholar 

  118. Prang, P. et al. The promotion of oriented axonal regrowth in the injured spinal cord by alginate-based anisotropic capillary hydrogels. Biomaterials 27, 3560–3569 (2006).

    CAS  Google Scholar 

  119. Sleep, E. et al. Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation. Proc. Natl Acad. Sci. USA 114, E7919–E7928 (2017).

    CAS  Google Scholar 

  120. Håkansson, K. M. O. Online determination of anisotropy during cellulose nanofibril assembly in a flow focusing device. RSC Adv. 5, 18601–18608 (2015).

    Google Scholar 

  121. Mawer, P. J. et al. Small-angle neutron scattering from peptide nematic fluids and hydrogels under shear. Langmuir 19, 4940–4949 (2003).

    CAS  Google Scholar 

  122. Jaalouk, D. E. & Lammerding, J. Mechanotransduction gone awry. Nat. Rev. Mol. Cell. Biol. 10, 63–73 (2009).

    CAS  Google Scholar 

  123. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    CAS  Google Scholar 

  124. Ng, M. R. & Brugge, J. S. A. Stiff blow from the stroma: collagen crosslinking drives tumor progression. Cancer Cell 16, 455–457 (2009).

    CAS  Google Scholar 

  125. Truong, D. et al. Breast cancer cell invasion into a three dimensional tumor-stroma microenvironment. Sci. Rep. 6, 34094 (2016).

    CAS  Google Scholar 

  126. Anseth, K. S., Bowman, C. N. & Brannon-Peppas, L. Mechanical properties of hydrogels and their experimental determination. Biomaterials 17, 1647–1657 (1996).

    CAS  Google Scholar 

  127. Almdal, K., Dyre, J., Hvidt, S. & Kramer, O. Towards a phenomenological definition of the term ‘gel’. Polym. Gels Networks 1, 5–17 (1993).

    CAS  Google Scholar 

  128. De Rosa, M. E. & Winter, H. H. The effect of entanglements on the rheological behavior of polybutadiene critical gels. Rheol. Acta 33, 220–237 (1994).

    Google Scholar 

  129. Münstera, S. et al. Strain history dependence of the nonlinear stress response of fibrin and collagen networks. Proc. Natl Acad. Sci. USA 110, 12197–12202 (2013).

    Google Scholar 

  130. Brown, A. E. X., Litvinov, R. I., Discher, D. E., Purohit, P. K. & Weisel, J. W. Multiscale mechanics of fibrin polymer: gel stretching with protein unfolding and loss of water. Science 325, 741–744 (2009).

    CAS  Google Scholar 

  131. Janmey, P. A. et al. Negative normal stress in semiflexible biopolymer gels. Nat. Mater. 6, 48–51 (2007).

    CAS  Google Scholar 

  132. Gennes, P.-G. Scaling Concepts in Polymer Physics (Cornell Univ. Press, 1979).

  133. Ozbas, B., Rajagopal, K., Schneider, J. P. & Pochan, D. J. Semiflexible chain networks formed via self-assembly of β-hairpin molecules. Phys. Rev. Lett. 93, 268106 (2004).

    Google Scholar 

  134. Verber, R., Blanazs, A. & Armes, S. P. Rheological studies of thermo-responsive diblock copolymer worm gels. Soft Matter 8, 9923–9932 (2012).

    Google Scholar 

  135. Lovett, J. R. et al. A robust cross-linking strategy for block copolymer worms prepared via polymerization-induced self-assembly. Macromolecules 49, 2928–2941 (2016).

    CAS  Google Scholar 

  136. Guvendiren, M., Lu, H. D. & Burdick, J. A. Shear-thinning hydrogels for biomedical applications. Soft Matter 8, 260–272 (2012).

    CAS  Google Scholar 

  137. White, J. A. & Deen, W. M. Agarose-dextran gels as synthetic analogs of glomerular basement membrane: water permeability. Biophys. J. 82, 2081–2089 (2002).

    CAS  Google Scholar 

  138. Wallace, D. G. & Rosenblatt, J. Collagen gel systems for sustained delivery and tissue engineering. Adv. Drug Deliv. Rev. 55, 1631–1649 (2003).

    CAS  Google Scholar 

  139. Johnson, E. M. & Deen, W. M. Hydraulic permeability of agarose gels. AIChE J. 42, 1220–1224 (1996).

    CAS  Google Scholar 

  140. Yang, Y., Motte, S. & Kaufman, L. J. Pore size variable type I collagen gels and their interaction with glioma cells. Biomaterials 31, 5678–5688 (2010).

    CAS  Google Scholar 

  141. Serpooshan, V., Quinn, T. M., Muja, N. & Nazhat, S. N. Hydraulic permeability of multilayered collagen gel scaffolds under plastic compression-induced unidirectional fluid flow. Acta Biomater. 9, 4673–4680 (2013).

    CAS  Google Scholar 

  142. Amsden, B. An obstruction-scaling model for diffusion in homogeneous hydrogels. Macromolecules 32, 874–879 (1999).

    CAS  Google Scholar 

  143. Whitaker, S. Flow in porous media I: a theoretical derivation of Darcy’s law. Transp. Porous Media 1, 3–25 (1986).

    Google Scholar 

  144. Erikson, A., Anderson, N. H., Naess, S. N., Sikorski, P. & de Lange Davies, C. Physical and chemical modification of collagen gels: impact on diffusion. Biopolymers 89, 135–143 (2007).

    Google Scholar 

  145. Ramanujan, S. et al. Diffusion and convection in collagen gels: implications for transport in the tumor interstitium. Biophys. J. 83, 1650–1660 (2002).

    CAS  Google Scholar 

  146. Boekhoven, J. & Stupp, S. I. 25th anniversary article: supramolecular materials for regenerative medicine. Adv. Mater. 26, 1642–1659 (2014).

    CAS  Google Scholar 

  147. Maheshwari, G., Brown, G., Lauffenburger, D. A., Wells, A. & Griffith, L. G. Cell adhesion and motility depend on nanoscale RGD clustering. J. Cell Sci. 113, 1677–1686 (2000).

    CAS  Google Scholar 

  148. Mata, A. et al. Micropatterning of bioactive self-assembling gels. Soft Matter 5, 1228–1236 (2009).

    CAS  Google Scholar 

  149. Taraballi, F. et al. Glycine-spacers influence functional motifs exposure and self-assembling propensity of functionalized substrates tailored for neural stem cell cultures. Front. Neuroeng. 3, 1 (2010).

    CAS  Google Scholar 

  150. Zupancich, J. A., Bates, F. S. & Hillmyer, M. A. Synthesis and self-assembly of RGD-functionalized PEO-PB amphiphiles. Biomacromolecules 10, 1554–1563 (2009).

    CAS  Google Scholar 

  151. Cheng, G., Castelletto, V., Jones, R. R., Connon, C. J. & Hamley, I. W. Hydrogelation of self-assembling RGD-based peptides. Soft Matter 7, 1326–1333 (2010).

    Google Scholar 

  152. Zhou, M. et al. Self-assembled peptide-based hydrogels as scaffolds for anchorage-dependent cells. Biomaterials 30, 2523–2530 (2009).

    CAS  Google Scholar 

  153. Storrie, H. et al. Supramolecular crafting of cell adhesion. Biomaterials 28, 4608–4618 (2007).

    CAS  Google Scholar 

  154. Webber, M. J. et al. Development of bioactive peptide amphiphiles for therapeutic cell delivery. Acta Biomater. 6, 3–11 (2010).

    CAS  Google Scholar 

  155. Lee, S. S. et al. Gel scaffolds of BMP-2-binding peptide amphiphile nanofibers for spinal arthrodesis. Adv. Healthc. Mater. 4, 131–141 (2015).

    CAS  Google Scholar 

  156. Griffith, L. G. & Swartz, M. A. Capturing complex 3D tissue physiology in vitro. Nat. Rev. Mol. Cell Biol. 7, 211–224 (2006).

    CAS  Google Scholar 

  157. Li, Y. & Kumacheva, E. Hydrogel microenvironments for cancer spheroid growth and drug screening. Sci. Adv. 4, eaas8998 (2018).

    Google Scholar 

  158. Ranga, A., Gjorevski, N. & Lutolf, M. P. Drug discovery through stem cell-based organoid models. Adv. Drug Deliv. Rev. 69–70, 19–28 (2014).

    Google Scholar 

  159. Canton, I. et al. Mucin-inspired thermoresponsive synthetic hydrogels induce stasis in human pluripotent stem cells and human embryos. ACS Cent. Sci. 2, 65–74 (2016).

    CAS  Google Scholar 

  160. Kambe, Y., Murakoshi, A., Urakawa, H., Kimura, Y. & Yamaoka, T. Vascular induction and cell infiltration into peptide-modified bioactive silk fibroin hydrogels. J. Mater. Chem. B 5, 7557–7571 (2017).

    CAS  Google Scholar 

  161. Dvir, T., Timko, B. P., Kohane, D. S. & Langer, R. Nanotechnological strategies for engineering complex tissues. Nat. Nanotechnol. 6, 13–22 (2011).

    CAS  Google Scholar 

  162. Pääkko, M. et al. Enzymatic hydrolysis combined with mechanical shearing and high-pressure homogenization for nanoscale cellulose fibrils and strong gels. Biomacromolecules 8, 1934–1941 (2007).

    Google Scholar 

  163. Ushiki, T. Collagen fibers, reticular fibers and elastic fibers. A comprehensive understanding from a morphological viewpoint. Arch. Histol. Cytol. 65, 109–126 (2002).

    Google Scholar 

  164. Sill, T. J. & von Recum, H. A. Electrospinning: applications in drug delivery and tissue engineering. Biomaterials 29, 1989–2006 (2008).

    CAS  Google Scholar 

  165. Oberpenning, F., Meng, J., Yoo, J. J. & Atala, A. De novo reconstitution of a functional mammalian urinary bladder by tissue engineering. Nat. Biotechnol. 17, 149–155 (1999).

    CAS  Google Scholar 

  166. Yan, C. et al. Injectable solid hydrogel: mechanism of shear-thinning and immediate recovery of injectable β-hairpin peptide hydrogels. Soft Matter 6, 5143–5156 (2010).

    CAS  Google Scholar 

  167. Zhang, M. et al. Self-healing supramolecular gels formed by crown ether based host – guest interactions. Angew. Chem. Int. Ed. Engl. 124, 7117–7121 (2012).

    Google Scholar 

  168. Acerbi, I. et al. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr. Biol. 7, 1120–1134 (2015).

    CAS  Google Scholar 

  169. Engler, A. J., Richert, L., Wong, J. Y., Picart, C. & Discher, D. E. Surface probe measurements of the elasticity of sectioned tissue, thin gels and polyelectrolyte multilayer films: correlations between substrate stiffness and cell adhesion. Surf. Sci. 570, 142–154 (2004).

    CAS  Google Scholar 

  170. Chaudhuri, O. et al. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat. Mater. 15, 326–334 (2016).

    CAS  Google Scholar 

  171. Gautieri, A., Vesentini, S., Redaelli, A. & Buehler, M. J. Viscoelastic properties of model segments of collagen molecules. Matrix Biol. 31, 141–149 (2012).

    CAS  Google Scholar 

  172. Buehler, M. J. Nature designs tough collagen: explaining the nanostructure of collagen fibrils. Proc. Natl Acad. Sci. USA 103, 12285–12290 (2006).

    CAS  Google Scholar 

  173. Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S. & Buehler, M. J. Molecular model of human tropoelastin and implications of associated mutations. Proc. Natl Acad. Sci. USA 115, 201801205 (2018).

    Google Scholar 

  174. Stylianopoulos, T., Diop-frimpong, B., Munn, L. L. & Jain, R. K. Diffusion anisotropy in collagen gels and tumors: the effect of fiber network orientation. Biophys. J. 99, 3119–3128 (2010).

    CAS  Google Scholar 

  175. Shi, C., Wright, G. J., Ex-Lubeskie, C. L., Bradshaw, A. D. & Yao, H. Relationship between anisotropic diffusion properties and tissue morphology in porcine TMJ disc. Osteoarthr. Cartil. 21, 625–633 (2013).

    CAS  Google Scholar 

  176. Murphy, S. V. & Atala, A. 3D bioprinting of tissues and organs. Nat. Biotechnol. 32, 773–785 (2014).

    CAS  Google Scholar 

  177. Lee, J. et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9, 391–403 (2006).

    CAS  Google Scholar 

  178. Birgersdotter, A., Sandberg, R. & Ernberg, I. Gene expression perturbation in vitro — a growing case for three-dimensional (3D) culture systems. Semin. Cancer Biol. 15, 405–412 (2005).

    Google Scholar 

  179. Moreno-Arotzena, O., Meier, J., del Amo, C. & García-Aznar, J. Characterization of fibrin and collagen gels for engineering wound healing models. Materials (Basel). 8, (1636–1651 (2015).

    Google Scholar 

  180. Cukierman, E. Taking cell-matrix adhesions to the third dimension. Science 294, 1708–1712 (2001).

    CAS  Google Scholar 

  181. Yamamoto, K., Yokoi, H. & Otani, A. Hierarchical structure of the fibrillar hydrogel network of a self-assembled synthetic peptide revealed by x-ray scattering and atmospheric scanning electron microscopy. Macromol. Symp. 358, 85–94 (2015).

    CAS  Google Scholar 

  182. Oldberg, A. et al. Collagen-binding proteoglycan fibromodulin can determine stroma matrix structure and fluid balance in experimental carcinoma. Proc. Natl Acad. Sci. USA 104, 13966–13971 (2007).

    CAS  Google Scholar 

  183. Yamamoto, S. et al. Atomic force microscopic studies of isolated collagen fibrils of the bovine cornea and sclera. Arch. Histol. Cytol. 60, 371–378 (1997).

    CAS  Google Scholar 

  184. Komai, Y. & Ushiki, T. The three-dimensional organization of collagen fibrils in the human cornea and sclera. Invest. Ophthalmol. Vis. Sci. 32, 2244–2258 (1991).

    CAS  Google Scholar 

  185. Barton, S. P. & Marks, R. Measurement of collagen-fibre diameter in human skin. J. Cutan. Pathol. 11, 18–26 (1984).

    CAS  Google Scholar 

  186. Silver, F. H., Kato, Y. P., Ohno, M. & Wasserman, A. J. Analysis of mammalian connective tissue: relationship between hierarchical structures and mechanical properties. J. Long. Term. Eff. Med. Implants 2, 165–198 (1992).

    CAS  Google Scholar 

  187. Ushiki, T. & Murakumo, M. Scanning electron microscopic studies of tissue elastin components exposed by a KOH-collagenase or simple KOH digestion method. Arch. Histol. Cytol. 54, 427–436 (1991).

    CAS  Google Scholar 

  188. Singer, I. I. The fibronexus: a transmembrane association of fibronectin-containing fibers and bundles of 5 nm microfilaments in hamster and human fibroblasts. Cell 16, 675–685 (1979).

    CAS  Google Scholar 

  189. Chen, L. B., Murray, A., Segal, R. A., Bushnell, A. & Walsh, M. L. Studies on intercellular LETS glycoprotein matrices. Cell 14, 377–391 (1978).

    CAS  Google Scholar 

  190. He, S., Cao, H., Antovic, A. & Blombäck, M. Modifications of flow measurement to determine fibrin gel permeability and the preliminary use in research and clinical materials. Blood Coagul. Fibrinolysis 16, 61–67 (2005).

    CAS  Google Scholar 

  191. Gersh, K. C., Nagaswami, C. & Weisel, J. W. Fibrin network structure and clot mechanical properties are altered by incorporation of erythrocytes. Thromb. Haemost. 102, 1169–1175 (2010).

    Google Scholar 

  192. Ryan, E. A., Mockros, L. F., Weisel, J. W. & Lorand, L. Structural origins of fibrin clot rheology. Biophys. J. 77, 2813–2826 (1999).

    CAS  Google Scholar 

  193. Piechocka, I. K., Bacabac, R. G., Potters, M., Mackintosh, F. C. & Koenderink, G. H. Structural hierarchy governs fibrin gel mechanics. Biophys. J. 98, 2281–2289 (2010).

    CAS  Google Scholar 

  194. Allen, P., Melero-Martin, J. & Bischoff, J. Type I collagen, fibrin and PuraMatrixmatrices provide permissive environments for human endothelial and mesenchymal progenitor cells to form neovascular networks. J. Tissue Eng. Regen. Med. 5, e74–e86 (2011).

    CAS  Google Scholar 

  195. Jansen, K. A. et al. The role of network architecture in collagen mechanics. Biophys. J. 114, 2665–2678 (2018).

    CAS  Google Scholar 

  196. Chen, W. et al. Revealing the structures of cellulose nanofiber bundles obtained by mechanical nanofibrillation via TEM observation. Carbohydr. Polym. 117, 950–956 (2015).

    CAS  Google Scholar 

  197. Rabionet, M., Yeste, M., Puig, T. & Ciurana, J. Electrospinning PCL scaffolds manufacture for three-dimensional breast cancer cell culture. Polymers (Basel) 9, (328 (2017).

    Google Scholar 

  198. Vaquette, C. & Cooper-White, J. A simple method for fabricating 3D multilayered composite scaffolds. Acta Biomater. 9, 4599–4608 (2013).

    CAS  Google Scholar 

  199. Vaquette, C. & Cooper-White, J. J. Increasing electrospun scaffold pore size with tailored collectors for improved cell penetration. Acta Biomater. 7, 2544–2557 (2011).

    CAS  Google Scholar 

  200. Haj, J., Haj Khalil, T., Falah, M., Zussman, E. & Srouji, S. An ECM-mimicking, mesenchymal stem cell-embedded hybrid scaffold for bone regeneration. Biomed Res. Int. 2017, 8591073 (2017).

    Google Scholar 

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Acknowledgements

The authors are grateful to the Natural Sciences and Engineering Research Council (NSERC) of Canada (Discovery Grant) for their financial support. E.K. thanks the Canada Research Chairs Program. E.P. is grateful to the NSERC of Canada Graduate Scholarship-Doctoral Program.

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  1. Department of Chemistry, University of Toronto, Toronto, ON, Canada

    Elisabeth Prince & Eugenia Kumacheva

  2. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada

    Eugenia Kumacheva

  3. Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada

    Eugenia Kumacheva

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E.P. and E.K. wrote and edited the manuscript. E.P. researched data for the article.

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Prince, E., Kumacheva, E. Design and applications of man-made biomimetic fibrillar hydrogels. Nat Rev Mater 4, 99–115 (2019). https://doi.org/10.1038/s41578-018-0077-9

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