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International Journal of Bioprinting Supramolecular hydrogels as bioinks

gene delivery. In a study reported in 2012, a hydrogel amino acids and dipeptides, have emerged as alternatives
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incorporated with plasmid DNA (pDNA) polyplexes to peptide assemblies in recent years. Specifically,
and active cationic copolymers successfully delivered N-fluorenylmethoxycarbonyl phenylalanine (Fmoc-
genes. Biodegradable triblock methoxy-PEG (MPEG)- Phe) constituents are a notable group of molecules
PCL-poly[2-(dimethylamino)ethyl methacrylate] that possess self-assembling properties and exhibit the
(PDMAEMA) copolymers were developed and effectively necessary characteristics for drug delivery applications.
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condensed pDNA into polyplexes, with hydrophilic A study conducted by Jagrosse et al. introduced proteins
MPEG forming the outer corona. These polyplexes were being encapsulated in and released from supramolecular
then encapsulated in α-CD-based supramolecular PpRX hydrogels made of perfluorinated Fmoc-modified
hydrogels, demonstrating the sustained release of pDNA phenylalanine (Fmoc-F5-Phe-DAP). They demonstrated
as polyplex NPs for up to 6 days. The released pDNA the release of four model proteins, namely RNase A, TI,
polyplexes exhibited high bioactivity comparable to the BSA, and IgG, from these hydrogels, emphasizing the
protein expression levels of freshly prepared poly(ethylene active and time-sensitive characteristics of protein release.
imine) (PEI) polyplexes, highlighting the potential of this Depending on the molecular weight and isoelectric point
thixotropic and in situ gelling system without solvent of the protein, the release profile can be optimized. These
as an injectable vehicle for long-term gene delivery. findings substantiate the possibility of this supramolecular
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PpRX-based supramolecular hydrogels have been studied LMW hydrogel as a viable approach for sustained and
as durable scaffolds for delivering recombinant adeno- localized therapeutic protein release. 14,100,101 In an effort to
associated virus (rAAV) vectors in cartilage regeneration. enhance mechanical rigidity and comprehend the effects of
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Gels containing polysaccharides (HA or chondroitin hydrophobicity and conformational freedom, researchers
sulfate) with α-CD demonstrated reinforced viscoelasticity designed modified aromatic amino acid-based building
and resistance to autoclaving. The specific gels exhibited blocks, Fmoc-γ-Phe and Fmoc-(3-hydroxy)-γ-Phe. Fmoc-
higher transgene expression levels and sustained release of
rAAV vectors compared to free vectors, with the specific gel γ-Phe formed a stable hydrogel possessing remarkable
compositions influencing release kinetics and interactions mechanical and thermal characteristics, while Fmoc-
with viral vectors. These results demonstrate the possibility (3-hydroxy)-γ-Phe exhibited transient fibrillar hydrogel
of PpRX gels as promising tools for tissue engineering and formation, followed by microcrystalline aggregation,
regenerative medicine strategies by acting as a sustained shedding light on the structure–assembly relationship
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delivery vehicle. A study successfully developed injectable of amino acid-based hydrogels. A novel approach was
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supramolecular gels based on PpRXs, combining α-CD employed by Li and his team to overcome the fragility of
with temperature-responsive copolymers. These gels hydroxyapatite (HAP) by integrating it with supramolecular
exhibited gelling in situ at physiological temperature and hydrogels. The resulting hybrid supramolecular N-(9-
demonstrated the ability to accommodate large amounts of Fmoc)-L-Phe/nano-HAP (Fmoc-L-Phe/nHAP) hydrogels
microspheres. Furthermore, the gels served as 3D scaffolds exhibited enhanced mechanical strength due to the
for MSCs, promoting osteogenic differentiation and intermolecular interaction between Fmoc-L-Phe and
displaying resilience to lyophilization and reconstitution nHAP. Furthermore, these hybrid hydrogels demonstrated
with minimal changes in rheological and structural inherent antibacterial properties, cytocompatibility, and
properties. Ohshita et al. reported a PpRX gel composed promising potential as drug delivery carriers, as indicated
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of CDs and PEG-PPG-PEG triple block copolymers by the successful release of chlorogenic acid with significant
(Pluronics F108, F87, F68, and L44) and reported inhibition effects on S. aureus. The tuning of viscoelastic
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noteworthy benefits of stabilizing human immunoglobulin properties of supramolecular hydrogels for tissue
G (IgG), surpassing CD/PEG and generic gels. Based on engineering has gained relevance due to their influence on
these results, CD/Pluronic gels have great potential as cell fate. To enhance stability and mechanical properties,
medicinal materials for antibody compositions. 95 polysaccharide dextran derivatives were incorporated into
a C2-phenylalanine gelator (LPF) through π–π stacking and
5.3. Peptide-based supramolecular hydrogels
hydrogen bonding. The resulting hybrid hydrogels, LPF-
5.3.1. Amino acid-based supramolecular hydrogels ADx and LPF-CMDHx, [C2-phenylalanine gelator (LPF),
To overcome the cytotoxicity and non-biocompatibility carboxymethyl dextran (CMDH), aminodextran (AD),
issues associated with polymer-based hydrogels, x represents the amount of AD and CMDH] exhibited
supramolecular hydrogels assembled from oligonucleotides, dense highly-branched fibers and improved mechanical
carbohydrates, proteins, and peptides have been utilized properties, with LPF-CMDH3 displaying the best elastic
as cell-friendly alternatives. Supramolecular hydrogels modulus at 11,654 Pa. The incorporation of biodegradable
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composed of LMW ingredients, like functionalized additives into these hydrogels offers opportunities to

Volume 10 Issue 3 (2024) 14 doi: 10.36922/ijb.3223