Engineering Nanofibrillar Hydrogels Mimicking the Nonlinear Mechanical Behavior of Biological Fibrous Networks

Significance 

Biological polymers such as collagen and fibrin exhibit strong stiffening under shear and elongational strains, but soften under compressional strain. This behavior starkly contrasts with the responses seen in networks formed by flexible-strand molecules, setting the stage for innovative biomaterials that can replicate the intricate mechanical properties of natural tissue. Development of a novel engineered hydrogel with properties that mimic the non-linear mechanical behavior characteristic of natural fibrous networks like those found in biological polymers will have wide medical applications. However, inherent mechanical asymmetry of the constituent filaments within these networks, where the modulus of stretching significantly surpasses the bending modulus, attributing to the nonlinear mechanical behavior observed. Traditionally, studies in this domain have been hampered by the limited control over the network architecture when using hydrogels formed by biological polymers. Addressing this challenge, a new study published in Proceedings of the National Academy of Sciences and led by Elisabeth Prince from Waterloo University and Professor Eugenia Kumacheva from the University of Toronto, the researchers developed nanofibrillar hydrogel that mimics the nonlinear mechanical behavior of biological fibrous networks, such as those found in collagen and fibrin. This endeavor was aimed at understanding the complex biomechanical properties of biological tissues and developing biomimetic materials for applications in tissue engineering and regenerative medicine.

The team first synthesized a novel hydrogel, referred to as EKGel, from cellulose nanocrystals (CNCs) and gelatin. The CNCs were chemically modified to introduce aldehyde groups that facilitate covalent cross-linking with the amino groups of gelatin, forming a fibrous network structure. This approach allowed for controlled architecture of the hydrogel, replicating the fibrous nature of biological tissues. The researchers characterized the hierarchical structure of the EKGel using scanning electron microscopy   and confocal microscopy analysis. They quantified the fiber diameters, lengths, and the distribution of gelatin and CNCs within the fibers. This structural characterization confirmed the fibrous architecture and homogeneous distribution of components within the hydrogel. The authors performed rheological tests to assess the mechanical properties of the EKGel, focusing on its response to shear and compressional strains. The experiments demonstrated that the EKGel exhibits shear-stiffening behavior, where the hydrogel becomes significantly stiffer in response to shear strains, and compression-induced softening, where the hydrogel’s stiffness decreases under compressional strain. These findings are in line with the mechanical behavior observed in biological fibrous networks. Moreover, they compared the mechanical properties of EKGel with those of natural fibrous networks, such as fibrin and collagen gels. The EKGel exhibited similar nonlinear mechanical responses, including shear-stiffening and compression-induced softening, validating its biomimetic properties. To provide a theoretical foundation for the observed mechanical behaviors, the researchers utilized an affine model that considers the mechanical asymmetry of the constituent filaments within the hydrogel. The model accurately predicted the shear-stiffening and compression-induced softening behaviors of the EKGel, further corroborating the experimental results.

The authors found that the engineered EKGel successfully replicated the nonlinear mechanical properties of biological fibrous networks, including shear-stiffening and compression-induced softening. The chemical modification of CNCs and the covalent cross-linking with gelatin allowed for precise control over the hydrogel’s fibrous structure, resembling the architecture of biological tissues. Moreover, the authors experimental findings were in agreement with predictions from the affine model, indicating that the nonlinear mechanical properties are attributable to the mechanical asymmetry of the fibrous structure within the hydrogel.  Although not explicitly detailed in the initial overview, the biocompatible materials (cellulose nanocrystals and gelatin) used in EKGel synthesis suggest potential for applications in tissue engineering and regenerative medicine, given its biomimetic mechanical properties. The engineered hydrogel showcases both shear-stiffening and compression-induced softening behaviors, aligning with the predictions of the affine model and thus providing a robust platform to further understand the biomechanical properties of fibrous networks. These findings are not just academic; they hold profound implications for tissue engineering, where mimicking the native mechanical environment of cells is crucial for the successful integration and function of engineered tissues. The variability in the composition of the hydrogel allows for tuning its mechanical properties, offering a versatile tool for researchers to explore the role of mechanical signals in cell behavior, disease progression, and tissue repair and regeneration.

The implications of the new study is significant in the development of biomimetic materials that can closely replicate the complex mechanical properties of biological tissues. This is particularly crucial in the field of regenerative medicine, where there is a persistent need for materials that can support the growth, differentiation, and function of cells in a manner that mimics their natural environment.  In a nutshell, the work by Professors Elisabeth Prince and Eugenia Kumacheva successfully developed engineered hydrogels that closely mimic the nonlinear mechanical behavior of natural fibrous networks, offering new insights into the structural and mechanical complexities of fibrous networks.  This should be valuable tool for researchers to investigate the fundamental principles of biomechanics and their implications for health and disease. Moreover, these innovative materials are set to play a central role in the development of therapeutic strategies that harness the body’s own regenerative capabilities, marking a new era in regenerative medicine and tissue engineering.

Engineering Nanofibrillar Hydrogels Mimicking the Nonlinear Mechanical Behavior of Biological Fibrous Networks - Advances in Engineering
Biomimetic architecture of the Nanocolloidal hydrogel. Image Credit: Advances in Engineering Graphics Team.

About the author

Professor Eugenia Kumacheva
University of Toronto

Eugenia Kumacheva serves or served on Advisory Boards of the Brookhaven National Laboratory (USA), and the Triangle Materials Science and Engineering Center (USA), RIKEN Institute (Japan), Leibnitz Institute for Interactive Materials (Germany), Freiburg Institute for Advanced Studies (Germany), and Max Planck Institute for Polymer Research (Germany). She serves on the European Research Council Chemistry comittee and is a member of the New Fellows Committee of the Royal Society (U.K.). She is an Associate Editor of Science Advances. Since 2018 professor Kumacheva has been a member of the international jury for L’Oreal-UNESCO “Women in Science” award and has been serving as a Nature research awad ambassador. Professor Kumacheva became a member of the Order of Canada, one of the highest civilian honour in Canada, for her contributions to chemistry, notably through microfluidics and polymer research, and for her efforts as an advocate for women in science. In 2021, Professor Eugenia Kumacheva has been honoured with one of this year’s prestigious Guggenheim Fellowships.

Research Interests:

  1. Polymers at surfaces and interfaces. One current project involves studies of equilibrium and dynamic properties of macromolecules with essential rigidity. We are interested in self-assembly of rigid-rod polymers in solutions and on various substrates, surface modification, surface-induced liquid crystallinity, interaction between rigid macromolecules attached to the surface in a controlled fashion, and shear in confined liquid crystalline phases. Secondly, we are engaged in studies of interaction between surface-attached layers of water-soluble polymers bearing hydrophobic groups. These polymers are used as viscosity modifiers in the coatings industry. Particularly, we are interested in how chemical architecture of macromolecules affects surface-induced micellization, self-assembly on various surfaces, hydrophobic interaction between molecules, compressibility and shear properties of adsorbed polymer layers.
  2. Development of advanced polymer materials. We are particularly interested in polymer composites for 3D memory storage, optical application, and electronics. By employing colloid-chemical methods we produce polymeric materials with periodic modulations in composition. This project includes synthesis of latexes tailoring desired properties, fabrication of 2D and 3D highly ordered nanocomposites, and studies of their optical and electric properties.
  3. Convection in polymeric liquids. By inducing temperature gradients in thin layers of polymeric fluids we generate in them non-equilibrium patterns with a high degree of order and symmetry. We propose to use UV-crosslinking of polymeric fluids to preserve these patterns in a solid state. This is a novel approach to producing large scale ordered mesostructures in polymeric composites.

About the author

Assistant Professor Elisabeth Prince

Department of Chemical Engineering
Waterloo University

At the University of Waterloo, Elisabeth’s group will build on her polymer and materials science expertise to design the molecular architecture of polymer networks, including hydrogels, elastomers, and thermosets. They will develop biomimetic hydrogels for applications in tissue engineering and in-vitro modeling of disease. They will also develop new tools for addressing the global plastic waste crisis.

Reference

Elisabeth Prince, Sofia Morozova, Zhengkun Chen, Vahid Adibnia, Ilya Yakavets, Sergey Panyukov, Michael Rubinstein, Eugenia Kumacheva. Nanocolloidal hydrogel mimics the structure and nonlinear mechanical properties of biological fibrous networks. Proceedings of the National Academy of Sciences, 2023; 120 (51) DOI: 10.1073/pnas.2220755120

Go to Proceedings of the National Academy of Sciences

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