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. 2021 Mar 10;12(5):722–729. doi: 10.1039/d1md00019e

Cucurbit[8]uril-based supramolecular hydrogels for biomedical applications

Zeyu Wang 1,†, Mingju Shui 1,†, Ian W Wyman 2, Qing-Wen Zhang 1,✉, Ruibing Wang 1,✉
PMCID: PMC8152811  PMID: 34124671

Abstract

As a member of the cucurbit[n]uril family (where n denotes the number of glycoluril units), cucurbit[8]uril (CB[8]) possesses a large cavity volume and is able to accommodate two guests simultaneously. Therefore, CB[8] has been adapted as a dynamic noncovalent crosslinker to form various supramolecular hydrogels. These CB[8]-based hydrogels have been investigated for various biomedical applications due to their good biocompatibility and dynamic properties afforded by host–guest interactions. In this review, we summarize the hydrogels that have been dynamically fabricated via supramolecular crosslinking of polymers by CB[8] reported during the past decade, and discuss their design principles, innovative applications in biomedical science and their future prospects.

This review summarizes the hydrogels fabricated via cucurbit[8]uril mediated crosslinking of polymers reported during the past decade, and discuss their design principles and various biomedical applications.graphic file with name d1md00019e-ga.jpg

1. Introduction

Hydrogels were introduced in the late 1950s,1 and they consist of crosslinked 3D networks which are able to retain substantial amounts of water through capillary forces and surface tension.2–6 Synthetic polymeric hydrogels are widely utilized in the biomedical sector due to their similarity to soft-tissues7,8 and favourable toxicity profiles.9–11 Hydrogel preparation methods can be classified as covalent and non-covalent approaches. However, the covalently crosslinked hydrogels with permanent non-reversible bonds are generally fragile and they lack the flexibility that would be required for clinical applications.12,13 In recent years, researchers have aimed to address this problem by employing dynamic non-covalent interactions to form the backbone of supramolecular hydrogels.14 In comparison with other non-covalent interactions, host–guest interactions are more stable and easily controlled, and thus supramolecular hydrogels mediated via host–guest interactions have attracted significant attention.

Among all of the suitable supramolecular hosts, cucurbit[8]uril (CB[8]), has great potential as an effective crosslinker for the formation of supramolecular hydrogels.15,16 As a member of cucurbit[n]uril CB[n] family (where n denotes the number of glycoluril units), CB[8] possesses a large cavity volume (479 Å3),17,18 and is thus able to simultaneously accommodate two planar and hydrophobic guests in a π–π-stacked geometry. Consequently, CB[8] complexation can offer reversible crosslinking which can be manipulated by a competitive guest as a stimulus,19,20 thus imparting desirable dynamic properties to a hydrogel network.21 Some examples of these features can include guest responsiveness that would be desirable in drug delivery systems, as well as better mechanical strength and flexible self-healing capabilities. Moreover, with a good biocompatible profile, CB[8] has been widely used as a critical crosslinker for the formation of different types of supramolecular hydrogels in recent years. In this review, we summarize the CB[8]-based hydrogels reported in the past decades, with a particular focus on their applications as drug delivery systems, bioengineering materials and other biomedically relevant materials (Scheme 1).

Scheme 1. Applications of CB[8]-based hydrogels.

Scheme 1

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2. Cucurbit[8]uril-based hydrogels as drug delivery platforms

2.1. Stable drug delivery systems

Thanks to the host–guest responsiveness inherited from the CB[n] family, CB[8] has the potential as an ideal scaffold for drug delivery systems.22–26 Extensive developments have been achieved through this host–guest chemistry, and as a powerful strategy for supramolecular chemistry, dynamic aggregates are also widely formed between CB[8] and polymers that are modified with suitable guests. Therefore, controllable hydrogels can be prepared and utilized as drug delivery platforms. Meanwhile, as hydrogels are three-dimensional networks that consist of hydrophilic polymer chains, they have the ability to store hydrophilic molecules within their porous structures.27–33 This special property of hydrogels also provides them with strong potential as frameworks for stable and controllable drug delivery systems.

Numerous drug loading vehicles are based on CB[8]-crosslinked hydrogels.34 Yang et al. utilized viral nanocages and hydroxy propyl cellulose to form hydrogels with CB[8].35 Modified cowpea chlorotic mottle virus (CCMV) particles can hold zinc phthalocyanine within their interiors with a high loading efficiency and these hydrogels can be subsequently crosslinked by CB[8] to yield a controllable drug delivery platform (Fig. 1). The order of drug release can also be regulated, thus avoiding the undesirable burst release of a drug. Moreover, Li et al. also introduced a special double network hydrogel which was interpenetrating with each other.36 The properties of these two hydrogels are complementary to one another, as the DNA Y-scaffold can form a fragile hydrogel with a DNA linker, while CB[8] can recognize the phenylalanine-functionalized carboxymethyl cellulose and thus form a flexible hydrogel to improve the stability of the entire system. This double network hydrogel can also be respectively degraded by related enzymes to enable controllable and responsive drug release.

Fig. 1. Formation of hydrogels based on viral nanocages and CB[8].35.

Fig. 1

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Recently, Xu et al. utilized a microfluidic device to form uniform supramolecular hydrogel beads.37 Here the heteroternary complex formed between CB[8] and functional biopolymers acted as a “handcuff” to restrict the release of a cargo. A more stable release profile was observed as the CB[8] content increased (Fig. 2). Sustained release of fluorescein-tagged dextran (FITC-dextran) from the hydrogel beads can also be realized with 0.5 equiv. of CB[8] in these hydrogel beads. A more stable drug release system was constructed by Wang et al.38 They employed CB[8] as a host and two symmetrical tetrahedron-like macromonomers of the same size as functional 4-arm-PEG guests to decrease the degree of freedom of the micro network structure, thus resulting in a slower release rate of doxorubicin hydrochloride (DOX).

Fig. 2. Use of a microfluidic device to form supramolecular hydrogel beads.37.

Fig. 2

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2.2. Responsive hydrogels

Another important property of CB[8] hydrogels is their responsiveness to various external stimuli such as the solvent composition, temperature, pH, electric potential and light. Moreover, since CB[8] has higher binding affinities with some guests, a competitive release triggered by high-affinity guests is also considered to be a responsive trait of CB[8]-based hydrogels. Lin et al. prepared a pH-responsive gel system via host–guest interactions between CB[8] and N-(4-diethylaminobenzyl)chitosan (EBCS).39 Under acidic conditions, 5-fluorouracil was slowly released from the hydrogel, attributed to the strong host–guest interactions between the diethylamino groups on side chain of EBCS and CB[8]. Under weakly alkaline conditions, the hydrogel dissociated due to the disassembly of CB[8]-based host–guest complexations, resulting in rapid release of payload. Zou et al. accommodated an asymmetric azobenzene within the cavity of CB[8] to form UV-responsive complexes.40 When UV light was applied to the hydrogel, the hydrogel motif was disrupted by the azobenzene photoisomerization, and consequently the hydrogel was converted into a sol. Meanwhile, it could recover back into a hydrogel within several minutes. Such UV-responsive hydrogels can be utilized for the short-term burst release of an encapsulated macromolecular payload and for pulsatile drug delivery (Fig. 3).41

Fig. 3. A light-responsive crosslinked hydrogel.41.

Fig. 3

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However, non-specific stimuli-responsive behaviors are not desirable, as they may cause premature drug leakage. In order to improve targeting responsiveness, Ding et al. encapsulated two phenylalanine (Phe) units of Phe-grafted chitosan (CS-Phe) into one cavity of CB[8] to form hydrogel with a mean diameter of 85 nm (±5.1 nm) which was defined as nanogel. DOX was employed as a model drug loaded into the nanogel for targeted tumor treatment.42 Competitive payload release was triggered by spermine which is overexpressed in tumor cells, and can be leveraged to induce the release of DOX from CB[8]-based nanogels at tumor sites.43,44 Meanwhile, amantadine has a high binding affinity toward CB[8] and can also be used to liberate DOX from this nanogel, thus demonstrating that CB[8]-derived hydrogels can provide a precise stimuli-responsive anti-tumor drug delivery system. In a recent work by Ding et al., they successfully developed another stimuli-responsive oral colon-targeted hydrogel, which was able to retain its structural integrity in acidic gastric environments and was finally responsive to the enzymes that exist in the colon, thus enabling the targeted delivery of berberine (BBR) to inflammatory sites.45 Konjac glucomannan was used as the main responsive module, which was covalently modified with phenylalanine (Phe).46,47 This module was readily crosslinked into hydrogel by CB[8] via CB[8]–Phe 1 : 2 ternary complexation, where a model drug was encapsulated during the hydrogel formation. A selective, enzyme-responsive drug release was achieved in the colon with this oral drug delivery system, which also exhibited a decent safety profile and a high in vivo treatment efficacy (Fig. 4).

Fig. 4. Preparation and oral administration of a konjac glucomannan hydrogel that targets the colon.45.

Fig. 4

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2.3. Hydrogel for sustained payload release

One of the developments that has been achieved with hydrogel-based drug delivery systems is the ability to release drugs over a prolonged period, which is a critical requirement for many clinical treatments. Appel et al. developed a CB[8]-crosslinked hydrogel which can provide sustained protein release.48 With a high water content existing in this self-assembled hydrogel, the sustained release of protein after injection will be prolonged and thus reduce the number of required injections. Therefore this hydrogel can provide a much more compliant option for patients who need a prolonged treatment against a related immune disease.

Meanwhile, Rowland et al.49 have reported that the in situ injection of a special hydrogel can provide further tumor suppression after glioma excision. Naturally-occurring amino acids can undergo complexation with hyaluronic acid backbones to produce HA-CF/CB[8] hydrogels. As a more flexible material than traditional chips, this hydrogel was able to reduce the extra harm to the operation area, while providing the excision area with sustained release of an anti-cancer drug (Fig. 5). By using such a functional hydrogel as a soft material, the overall rate of drug diffusion and distance reached by that drug can be improved, thus providing more convenient options for clinical therapy.

Fig. 5. Hydrogel implanted in a tumour resection sustaining release drug.49.

Fig. 5

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3. CB[8]-based hydrogel for biomedical engineering

3.1. Enhanced mechanical strength and self-healing capabilities

With their high water content, softness, biocompatibility, and easily controlled mass transfer properties, hydrogels have been widely utilized as bioengineering agents.50–56 These properties enable hydrogels to mimic the cells and tissue in living organisms, and thus they can act as analogues of the natural extracellular matrix (ECM).57 In addition, the noncovalent interactions of CB[8]-based hydrogels provide enhanced flexibility as well as structural stability, so that these systems can be widely used in various bioengineering applications.58–64

One of the most impressive properties of hydrogels that is improved by CB[8] is the self-healing capability, which is an essential requirement for a bioengineering material.65 Traditional covalent interactions based hydrogels are stable but are not easily recovered once they are broken. However, the unique complexation capabilities of CB[8] enable it to continuously form and cleave crosslinking junctions within polymer networks.66–69 This dynamic behavior provides more possibilities for the development of supramolecular hydrogels. Cao et al. successfully utilized reversible CB[8]-enhanced π–π interactions to construct a self-healing hydrogel.70 They employed naphthalene groups to form a 1 : 2 ternary complex with CB[8] and the self-healing performance was further improved by means of dipole–dipole interactions between the polar carbonyl groups of CB[8] and quaternary ammonium cations. Employing another hydrogel to form a dual-cross-linked hydrogel is also an effective strategy to optimize the hydrogel network. Zhang et al. chose phenylalanine-functionalized ε-polylysine (Phe-EPL) as the polymer backbone to achieve dual-crosslinking.71 The imine on the backbone formed linkages with slow dynamics to support the mechanical strength, and the linkage between the phenylalanine moiety and CB[8] supplied self-healing properties by forming covalent linkages with a fast dynamics. By such a complementary design, the performance of dynamic hydrogels was enhanced, while the responsiveness to stimuli was also retained. In order to stabilize the dynamic noncovalent crosslinking, Zhang et al. synthesized chitosan microspheres as both cross-linking centers and a polyfunctional initiator of a hydrogel system.72 This hybrid microsphere-based supramolecular hydrogel showed better mechanical strength and was also able to recover quickly from damage at room temperature.

Recently, Meng et al.73 reported a microfluidic method to fabricate supramolecular hydrogel microfibers. By combination with the reversible molecular recognition offered by CB[8], the brittleness of agar hydrogel fibers was reversed. This microfluidic platform also offered an efficient method to produce anisotropic supramolecular functional materials at the microscale.

3.2. Construction of adhesives based on CB[8] hydrogels

Supramolecular hydrogels also have excellent potential as adhesives due to their noncovalent interactions. The biomedical applications of traditional adhesives have often been restricted by their poor adhesion strength during their contact with wet surfaces. Liu et al. overcame this problem by using CB[8] supramolecular hydrogel networks.74 The high water content in this hydrogel makes it possible to employ such an adhesion strategy in systems containing significant amounts of water without requiring any additional curing reagents. The polymer chains are able to become physically adsorbed onto the substrates via van der Waals interactions, while the host–guest interactions will retain the integrity of the overall network. With a combination of a desirable soft characteristic and a tough bonding capability between two substrates, these hydrogels could serve as hybrid systems for biomedical implants, even for applications such as tissue/bone regeneration. In another work of Liu et al., they formed a hydrogel that was suitable for wet surfaces by CB[8]-threaded highly branched polyrotaxanes (HBP-CB[8]).75 The large cavity of CB[8] was able to incorporate a second guest into the system to stabilize this hydrogel-based adhesive, adding versatility and more functionality. Such a flexible soft hydrogel has promising potential for wound dressings, as well as repairs of tissue without the need for suturing.

Strong adhesion is an essential property for wound dressings. However, frequently replacing a high-adhesion wound dressing may cause additional trauma to the damaged tissue.76 Xu et al. developed an easily removable wound dressing material, which was able to efficiently alleviate pain and shorten healing time during the treatment.77 The dynamic nature of the supramonomer (as a guest species of CB[8] for formation of ternary complexation) ensures that the hydrogel can dissolve in the presence of memantine, as a strong guest molecule of CB[8], within two minutes, while this hydrogel also can deliver ofloxacin to improve the healing efficiency (Fig. 6). These discoveries may lead to a new generation of highly effective and minimally invasive wound dressings.

Fig. 6. Illustration depicting the facile removal of a hydrogel-based wound dressing.77.

Fig. 6

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3.3. Cell encapsulation by CB[8]-based hydrogels

The excellent 3D structures of hydrogels provide these materials with another advantage for applications such as cell entrapment.78 Once the host–guest interactions based on CB[8] are introduced to a hydrogel, the hydrogel system will be able to undergo dynamic crosslinking, which can enhance its responsiveness to cellular forces by breaking and reforming crosslinking junctions. Zou et al. composed a hydrogel with a thermoresponsive micelle which was appended at two ends with CB[8]-related guests.79 As the temperature increases, the micelle emerges with a high density of guests at its periphery (Fig. 7). These guests are able to undergo crosslinking with CB[8] to form percolated hydrogel networks. The system can quickly wrap around NIH-3T3 fibroblasts and thus encapsulate them within the hydrogel and they can be injected into a patient without destroying the integrity of cells. For example, most of the cells still remained viable thirty minutes post-injection. Recently, Madl et al. prolonged the encapsulation time to seven days with a novel supramolecular hydrogel, which was rapidly formed via crosslinking by CB[8] from the cell-adhesive biopolymer gelatin.80 This system was able to encapsulate human fetal lung fibroblasts (MRC-5s) which were homogeneously distributed throughout this hydrogel and remained alive for seven days (Fig. 8).

Fig. 7. Hydrogel with micelle appended at two ends with CB[8]-related guests.79.

Fig. 7

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Fig. 8. The use of dynamic crosslinking with a hydrogel to retain cell viability.80.

Fig. 8

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4. CB[8]-based hydrogels for other biomedical applications

Besides the applications mentioned above, CB[8]-based hydrogel still has some unique applications in other biomedically related fields. CB[8] is able to form complexes with two guests, and when room-temperature phosphorescence (RTP) emission compounds are encapsulated within CB[8] as one of the guest species, the hydrogel with CB[8] in its matrix may be imparted with unique photophysical properties. Wang et al. utilized a heavy-atom-modified molecule (triazine derivative, TBP) together with CB[8] to achieve hydrogel of RTP emission in an aqueous solution.81 Adjusting the ratio of CB[8] in the hydrogel can also change the colour of the photoluminescence, which can have applications in areas such as cellular imaging and biological sensing.

Dynamic crosslinking can also be used to transform the morphology and physical properties of CB[8]-based hydrogels. Recently, tunable polymeric nanostructures have gained much attention from researchers.82,83 With the ability to transform in response to different controlled conditions, supramolecular hydrogels may be utilized in biomedical fields.84 Zou et al. transitioned hydrogel crosslinking from physical to chemical networks by using CB[8] to catalyze the reversible photodimerization of polymer-appended guests.85 This switching resulted in the formation of a hydrogel exhibiting varying degrees of hardness in response to different light irradiation treatments, thus providing the ability to pattern the hydrogel and even to utilize this material in biological 3D printing (Fig. 9). A similar “smart” polymeric nanostructure was also developed by Wang et al.86 They assembled a special nanofiber based on an achiral monomer and CB[8], which was also able to undergo a reversible gel–sol transition due to the host–guest combination and hydrophobic forces. These developments provide a promising strategy for the construction of tunable supramolecular hydrogels.

Fig. 9. Light-induced hardness switching of hydrogels.85.

Fig. 9

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Conclusions

In summary, CB[8] can be used as a highly dynamic crosslinker for the fabrication of various supramolecular hydrogels with wide-ranging applications in pharmaceutical science and bioengineering. The host–guest interactions provide promising responsiveness and controllability to the hydrogels and also lead to improvements in the mechanical strength and self-healing capabilities. In addition, CB[8] can enhance the florescence intensity of an encapsulated guest, so that light-switchable hydrogels can also be prepared for cellular imaging. Dynamic switching provides a convenient strategy for the smart transformation of supramolecular hydrogel networks. Meanwhile, although various bioengineering applications have been discussed in this review, there are still some unexplored areas for CB[8]-based supramolecular hydrogels, particularly with regards to antithrombotic hydrogels, which is one of the major application areas of hydrogels in general.87–89 Additionally, although CB[8] is a highly biocompatible supramolecular host,90 toxicity and metabolism studies of the hydrogel networks, especially in vivo, should also be conducted in greater depth to enhance the possibility of clinical application. By narrowing these gaps, we believe that emerging supramolecular hydrogels provide more versatile capabilities and they can fulfil diverse requirements of biomedical applications.

Conflicts of interest

There are no conflicts to declare.

Acknowledgments

The Science and Technology Development Fund (FDCT), Macau SAR (grant no. 0121/2018/A3 and SKL-QRCM(UM)-2020-2022) and the National Natural Science Foundation of China (grant no.: 21871301 and 22071275) are gratefully acknowledged for providing financial support to this work.

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