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International Journal of Bioprinting Supramolecular hydrogels as bioinks

enhance the strength of weak gelators and expand their PEG and an aromatic hexapeptide containing Phe and
applicability in tissue engineering. Tyr residues. Due to their amphipathic nature, peptides
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can self-assemble in hydrated conditions at a very low
5.3.2. Short peptide-based supramolecular bioinks concentration (critical aggregation concentration =
Peptide-based supramolecular hydrogels are formed 1.5 × 10 mol/L, 22.8 μg/mL) forming a fibril amyloid-
-5
when peptides self-assemble into 3D networks in a like network. A dry interface is formed by the network
solvent, usually water. The non-covalent interactions of π–π stacking between all the hydrophobic side chains
that bind the peptide molecules in these gels include van of Phe, whereas a wet interface is generated by the
der Waals forces, hydrogen bonding, and electrostatic solvent entangling water in extending hydrogen-bond
interactions. In the context of bioinks for 3D bioprinting, networks that link the Tyr residues. By altering either the
their flexibility and capacity to mimic the ECM render wet interface, the dry interface, or both, three different
them appealing for creating bioprinted structures that peptides, (Nal-Y)3, (F-Dopa)3, and (Nal-Dopa)3, have
closely resemble natural tissues. Peptide-derived hydrogels been reported. However, peptide-based hydrogels can
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within supramolecular assemblies exhibit enhanced also be formed by cleaving the disulfide bonds between
properties, including gel formation in both aqueous the hydrogelator and peptide molecule. In utilizing Phe
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phosphate buffers and aromatic organic solvents. 105,106 dipeptide (FF) as the supramolecular hydrogelator to form
The biocompatible amphiphilic properties of γ-peptide- the hydrogel, the presence of hydrophilic diglutamic acid
injectable hydrogels enable the formation of hydrogels helps maintain a balanced hydrophilicity–hydrophobicity
and organogels (in the form of nanofibrils). The
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subsequently formed gel can load large amounts of drug ratio, facilitating water solubility of the delivered
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with improved solubility, the peptide-based backbone compound. In contrast, non-covalent functionalization
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is relatively flexible, and the resulting gel has higher of peptide occurs when a supramolecular polymer (Fmoc-
hydrophobicity. 106,108 The nanofiber structure of the D/L- RGD) and a covalent polymer (chitosan) are combined to
peptide of NapGDFDFDYGYSV (D-YSV) demonstrated form a biopolymer gel. This is because a hydrogen bond is
superior resistance to proteinase digestion compared to formed between the carboxylic acid group of Fmoc-RGD
its control peptide NapGFFYGYSV (L-YSV). The gel also and the -NH /-OH groups of chitosan and the α-carboxyl
2
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demonstrated enhanced anticancer efficiency in vitro, group of Fmoc-RGD. Similarly, another di-Fmoc-based
attributed to improved cellular uptake, biocompatibility, RGD hydrogel was reported by the same group for efficient
and notable tumor inhibition capacity. 108,109 Non-covalent cell adhesion, where they further incorporated polyaniline
interactions between peptides and fullerenes in peptide- (PAnil) to mimic electrogenic tissue engineering. 114
modulated self-assembled fullerene gels successfully Peptides can self-assemble into a stable hydrogel via
inhibited multi-antibiotic resistant S. aureus and promoted a heating-cooling procedure. Contrastingly, peptides
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wound healing with excellent thermodynamic stability. formed from aliphatic amino acids, such as isoleucine
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Furthermore, peptide-based supramolecular hydrogels (Ile), have a high propensity to form β-sheets in the
possess robustness, pH responsiveness, tunable stiffness, self-assembled hydrogels upon protonation or charge
viscoelastic properties, self-healing properties, shear- recognition/hydrogen bonding. In addition, these amino
thinning behavior, cell media durability, antimicrobial acids can improve water solubility by combining two
activity, and controllable biodegradability. 96,105,111 These aspartic acids (Asp). Falcone et al. utilized an innovative
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properties are highly essential for a bioink to be successfully PA, myristyl-Phe-Phe (C14-FF), to form hydrogels with a
used in 3D bioprinting. β-sheet aggregate-composed nanofiber matrix morphology.
Tert-butoxycarbonyl (Boc)-(S)-β-Phe was developed It was distinguished by a novel solvent-dependent helical
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using Arndt–Eistert homologation of Boc-Phe. Similarly, switching and a record-low gelation concentration.
Boc-(S)-γ-Phe can also be produced from Boc-Phe via Interestingly, Frémy’s salt, an inorganic stable source of
the Wittig reaction, followed by catalytic hydrogenation, free radicals, can modulate the mechanical properties
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saponification, and coupling with N-ethyl-N’-(3- of tyrosine-based self-assembled β-hairpin peptides.
dimethylaminopropyl) carbodiimide hydrochloride In situ gelation can also be utilized for a supramolecular
(EDC) and 1-hydroxybenzotriazole (HOBt). Peptide hydrogel stabilized by electrostatic interactions between
synthesis was performed using conventional solution phase two peptides with opposite charges without the addition
chemistry or solid phase peptide synthesis methods. 106,107,112 of any crosslinkers. Jian et al. developed two 9-Fmoc-
Hydrogen bonding and π–π stacking among peptides dipeptides with opposing charges on their end residues,
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are commonly observed interactions during hydrogel and in situ gelation was accomplished using a layer-wise
formation. 105,106,110,111,113 Similar observations were noted for alternate printing technique (Figure 5A). The resulting
a supramolecular hydrogel consisting of a monodisperse gel exhibited adjustable mechanical characteristics

Volume 10 Issue 3 (2024) 15 doi: 10.36922/ijb.3223