Abstract
Supramolecular nanostructures formed through peptide self-assembly can have a wide range of applications in the biomedical landscape. However, they often lose biomechanical properties at low mechanical stress due to the non-covalent interactions working in the self-assembling process. Herein, we report the design of cross-linked self-assembling peptide hydrogels using a one-pot in situ gelation system, based on 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide/N-hydroxysulfosuccinimide (EDC/sulfo–NHS) coupling, to tune its biomechanics. EDC/sulfo–NHS coupling led to limited changes in storage modulus (from 0.9 to 2 kPa), but it significantly increased both the strain (from 6% to 60%) and failure stress (from 19 to 35 Pa) of peptide hydrogel without impairing the spontaneous formation of β-sheet-containing nano-filaments. Furthermore, EDC/sulfo–NHS cross-linking bestowed self-healing and thixotropic properties to the peptide hydrogel. Lastly, we demonstrated that this strategy can be used to incorporate bioactive functional motifs after self-assembly on pre-formed nanostructures by functionalizing an Ac-LDLKLDLKLDLK-CONH2 (LDLK12) self-assembling peptide with the phage display-derived KLPGWSG peptide involved in the modulation of neural stem cell proliferation and differentiation. The incorporation of a functional motif did not alter the peptide’s secondary structure and its mechanical properties. The work reported here offers new tools to both fine tune the mechanical properties of and tailor the biomimetic properties of self-assembling peptide hydrogels while retaining their nanostructures, which is useful for tissue engineering and regenerative medicine applications.
Highlights
Mechanobiology is drawing widespread attention for its potential value in the field of biomaterial design for tissue engineering and regenerative medicine [1,2].Cells are sensitive to the mechanical properties of the extracellular matrix (ECM) in both physiological and pathological conditions [3,4,5]; it is becoming increasingly clear that the mechanical properties of the ECM are critical in directing cell fate, homeostasis, and survival [6,7,8].synthetic but bio-inspired nanomaterials designed to mimic the ECM should aim to recapitulate most of the features of the native ECM
By using a one-pot and in situ gelation system, we demonstrated, for the first time, that EDC/sulfo–NHS reacts with LDLK12-assembled nanostructures, enhancing their mechanical properties without altering the spontaneous formation of β-sheet-containing nanofilaments
We reported the design of cross-linked self-assembling peptides (SAPs) via a one-pot and in situ gelation system based on EDC/sulfo–NHS coupling, yielding self-healing and functionalized hydrogels
Summary
Mechanobiology is drawing widespread attention for its potential value in the field of biomaterial design for tissue engineering and regenerative medicine [1,2]. We investigated the use of a post-assembly modification of LDLK12 nanostructures using EDC/sulfo–NHS as an alternative approach to add bioactive functional motifs after self-assembling took place, i.e., for all jellified SAP hydrogels. We carried out such a post-assembly functionalization of nanofibers by using a KLPGWSG [22] phage display-derived epitope as a bioactive cue. Coupling yield was minimal when EDC/sulfo–NHS was added to SAPs immediately after their solubilization in water, while, after the chosen overnight stay, cross-linking showed a rapid peptide coupling after EDC/sulfo–NHS addition This suggests an interesting correlation between the degree of coupling and the physico-chemical conditions of peptide molecules. Since this reaction takes place in situ, at physiological conditions (pH 7.4), relatively fast, and without the need of external stimuli (such as temperature or ionic strength), it could be useful as filler in traumatic brain injury (TBI) [42,43], acute spinal cord injury (SCI) [41,44,45,46], or as sprayable hemostatic solution in combination with common clotting bandages during uncontrolled bleeding in surgeries [47]
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