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International Journal of Bioprinting Supramolecular hydrogels as bioinks

5. Supramolecular hydrogels based on complexes. In the context of a 1:1:1 hetero-ternary
different chemistry supramolecular complex, an electron-rich second guest,
such as naphthalene or azobenzene (Azo), interacts with
5.1. Cucurbit[n]uril-based supramolecular hydrogels an electron-deficient first guest, such as methyl viologen
Cucurbit[n]urils (CB[n]s, n = 5–8, 10, and 14) are a (MV) via CB[8]-mediated host-stabilized charge-transfer
group of symmetric barrel-like (pumpkin-shaped) (HSCT) mechanisms. Conversely, a 2:1 homo-ternary
macrocyclic host molecules used in supramolecular supramolecular complex is formed through host-
host–guest chemistry. 57,58 Chemically, they are glycoluril stabilized π–π interactions, with two identical guests (e.g.,
oligomers having two methylene-linked ports with polar naphthalene or anthracene) strongly dimerizing within
ureido-carbonyl groups encircling them. These structures the hydrophobic cavity of CB[8]. Micro/nanostructured
are stable, easily controlled, and versatile in molecular polymer materials based on CB[8] are available in diverse
recognition and self-assembly, having a rigid structure forms, such as networks, vesicles, hydrogels, micelles,
with a tunable binding affinity. 58,59 The molecule maintains colloidal particles, and microcapsules. CB[8] extensively
a constant height of 9.1 angstroms (A), while the size of its participates in the formation of ternary complexes with
inner cavity fluctuates with n, i.e., from CB[5] to CB[10]. both electron-deficient and electron-rich guests through
The inner cavity displays a portal width spanning 2.4–11.0 HSCT interactions, a feature harnessed across these
A and an internal void diameter of 4.4–12.6 A. A guest various forms. Consequently, CB[8] finds application in
molecule confined within this molecular host experiences drug delivery platforms, biomedical engineering, and a
a hydrophobic effect within its internal hydrophobic cavity. spectrum of various biomedical applications.
Furthermore, the guest molecule engages in interactions
including hydrogen bonding and ion-dipole with the In tissue engineering, CB[8]-based hydrogels exhibit
carbonyl portals. CB[n]s exhibit reversible and notably high mechanical strength and advanced self-healing
significant secondary supramolecular interactions, capabilities. A novel microfluidic technique has been
encompassing non-covalent bonds, host-stabilized charge- introduced to create microfibers of supramolecular
transfer (HSCT), and host-enhanced π–π linkages. The hydrogel, effectively mitigating the brittleness inherent in
utilization of CB[n]-oriented host–guest chemistry holds agar hydrogel fibers through the incorporation of CB[8]’s
promise for the creation of supramolecular systems. These reversible molecular recognition. This study holds potential
systems integrate diverse elements, such as nucleic acids, for generating microscale anisotropic supramolecular
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proteins, peptides, amino acids, and therapeutic agents. functional materials.
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Following the initial report on CB[8], subsequent Shim et al. described a 3D printing procedure
investigations revealed CB[5], CB[6], CB[7], and CB[10] for creating a multilayered 3D construct with human
as sequential candidates. Among these, CB[8] stands out MSCs (hMSCs) and a hydrogel made of supramolecular
due to its notable feature of having a substantial internal hyaluronic acid (HA) and atelocollagen (Figure 3A). The
volume, enabling it to concurrently host two guest utilization of a mechanically stable hydrogel based on host–
molecules. This unique characteristic also renders CB[8] guest chemistry was found to be crucial as it facilitated the
particularly effective as a crosslinker within supramolecular easy printing and stacking of two distinct ECM hydrogel
hydrogels. 57,59 Review articles published in 2018 by Zou et types into a single multilayered construct. This process
al. provide a thorough understanding of the non-covalent eliminated the need for hazardous chemical reagents or
combinations found in CB[8]-oriented hydrogels. Many physical stimuli for post-crosslinking. 53
supramolecular polymer hydrogels formed from CB[n] Chen et al. explored the use of the CB[7]-adamantane
host molecules, particularly CB[8], have been extensively (Ad) complementary pair as non-covalent crosslinks,
studied. These polymers encompass a diverse range, showcasing a robust binding affinity. They synthesized
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consisting of both small molecule-based and polymer- two N,N-dimethyl acrylamide-based polymers, each
based systems. Among these, polymer-based hydrogels featuring CB[7] and Ad pendants, respectively. The gelation
emerge as the predominant category, showcasing CB[8] as kinetics of these polymers underwent significant changes
a central component in their design and assembly.
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with pre-saturation of the CB[7] pendant polymer with
Polymer-based CB[8] hydrogels are synthesized different competing guest molecules and concentrations.
using three distinct strategies: three-component The resulting supramolecular hydrogels exhibited unique
systems involving a 1:1:1 hetero-ternary complex, two- mechanical properties, including high elasticity, good
component systems making a 1:1:1 hetero-ternary stability, and shape persistence, due to the strong connection
complex (comprising of CB[8]-incorporated polymer between the CB[7]–AD pairs. Additionally, the hydrogels
and complementary polymer), or 2:1 homo-ternary could be easily adorned with specific groups through host–

Volume 10 Issue 3 (2024) 8 doi: 10.36922/ijb.3223