Dynamic hydrogels mediated by macrocyclic host–guest interactions

Tangxin Xiao *a, Lixiang Xu a, Ling Zhou a, Xiao-Qiang Sun a, Chen Lin *b and Leyong Wang *ab
aSchool of Petrochemical Engineering, Advanced Catalysis and Green Manufacturing Collaborative Innovation Center, Changzhou University, Changzhou, 213164, China. E-mail: xiaotangxin@cczu.edu.cn
bKey Laboratory of Mesoscopic Chemistry of MOE, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China. E-mail: linchen@nju.edu.cn; lywang@nju.edu.cn

Received 5th September 2018 , Accepted 9th October 2018

First published on 9th October 2018


Hydrogels have attracted increasing research interest in recent years due to their dynamic properties and potential applications in biomaterials. Concurrently, macrocycle-based host–guest interactions have played an important role in the development of supramolecular chemistry. Recently, research towards dynamic hydrogels mediated by various macrocyclic host–guest interactions has been gradually disclosed. In this review, we will outline the burgeoning progress in the development of functional hydrogels mediated by various host molecules, such as cyclodextrins, cucurbit[n]urils, calix[n]arenes, pillar[n]arenes, and other macrocycles. Smart hydrogels with outstanding properties, like biocompatibility, toughness, and self-healing, are mainly focused. We believe that this review will highlight the potential of dynamic hydrogels mediated by macrocycle-based host–guest interactions.


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Tangxin Xiao

Tangxin Xiao is a lecturer at the School of Petrochemical Engineering, Changzhou University. He studied chemistry at Nanjing University, where he received his PhD degree under the supervision of Prof. Leyong Wang in 2014. He has been to University of Cambridge as a visiting PhD student supervised by Prof. Oren Scherman in 2013. After postdoctoral research on fine chemicals at Zhejiang University-NHU Company United R&D Center, he joined Changzhou University in 2017. His current research interests concern the supramolecular self-assembly and smart materials.

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Lixiang Xu

Lixiang Xu was born in Jiangsu province, China, in 1994. She obtained her bachelor's degree from Changzhou University in 2017. She is currently pursuing her Master's degree under the supervision of Dr Tangxin Xiao and Prof. Leyong Wang at Changzhou University. Her research interests are focused on the construction of functional supramolecular polymers and hydrogels.

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Ling Zhou

Ling Zhou was born in Anhui, China, in 1993. She received her BS degree from Chuzhou University in 2017. Then she joined the laboratory of Prof. Xiao-Qiang Sun at Changzhou University to pursue her Master's degree in organic chemistry. Her research is focused on AIE gels based on multiple hydrogen bonding.

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Xiao-Qiang Sun

Xiao-Qiang Sun received his PhD from Nanjing University, China, in 1988. Then he went on to pursue his postdoc at the University of Sheffield and University of Birmingham under the supervision of Prof. J. Fraser Stoddart. He became a Professor at Changzhou University in 1997. His current research interests are nano-devices and special chemical functional polymer materials.

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Chen Lin

Chen Lin was born in Jiangsu in China in 1979. He obtained his BS from Nankai University in China in 2001 and PhD from SUNY at Stony Brook in USA in 2005. Afterwards, he joined Nanjing University as an assistant Professor in 2006. Currently he is an associate professor at Nanjing University. His research interests are in the areas of supramolecular chemistry, molecular recognition, and smart materials.

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Leyong Wang

Leyong Wang holds a PhD in Chemistry from Nanjing University in 2000. After research stays at the Institute of Chemistry (CAS), University of Burgundy, and Mainz University from 2000 to 2004, he joined Erlangen-Nürnberg University as AvH Fellow working with Professor John A. Gladysz. Since 2006, he has been specially appointed as the professor of organic and material chemistry at NJU. He has also been a joint professor of Changzhou University since 2017. His current research interests are focused on supramolecular systems ranging from topological molecules to dynamic materials.


1. Introduction

In the past few decades, hydrogels have drawn increasing interest due to their dynamic properties and wide applications in many areas, including materials science and bioscience.1–7 Hydrogels are three-dimensional networks that contain substantial amounts of water, which show special features including soft material properties, solid-like rheology, and swelling–shrinking behaviors. Hydrogels are typically constructed by using chemically crosslinked polymers. In addition, they can also be fabricated by using low molecular weight gelators (LMWG) or physically crosslinked polymers, the so-called supramolecular hydrogels based on LMWG5,8–11 or supramolecular polymeric hydrogels.3,6 Generally, both kinds of hydrogels are called supramolecular hydrogels. It is noteworthy that supramolecular interactions, particularly, macrocyclic host–guest interactions, have played important roles in constructing supramolecular hydrogels or controlling many chemically crosslinked hydrogels. Supramolecular hydrogels are dependent on the formation of transient crosslinks between the linear polymeric chains based on supramolecular interactions. Thus, supramolecular hydrogel formation can be induced in water phase and is driven by supramolecular self-assembly. Supramolecular interactions are dynamic and reversible, usually giving the material the potential for stimuli-responsiveness, which has aroused much study interest.12–17 Stimuli-responsiveness can endow hydrogels with responsive properties to external stimuli, including temperature, pH, light, redox, mechanical force, etc. Notably, some new stimuli such as gas, magnetic field, and near infrared radiation are gradually being used to regulate the properties of hydrogels.18–23 Supramolecular hydrogels usually possess a sol–gel transition process upon external stimuli. By simply using the vial inversion method, the gelating process could be easily detected. The applications of supramolecular hydrogels include injectable drug transporters,24–30 tissue engineering,31–35 biosensors,36,37 and wound healing.38,39 For chemically crosslinked polymeric hydrogels incorporating supramolecular interactions, expansion–contraction behaviors can be controlled depending on the environmental change. Supramolecular interactions usually make such materials not only possess responsive properties but also sometimes adjustable mechanical strength to form double-network hydrogels. For example, chemically crosslinked hydrogels are usually brittle, and supramolecular networks often show pseudoplastic deformation with weak resistance to pressure. This kind of hydrogels have been widely employed in many areas, including actuators,40–42 drug delivery,43,44 and shape memory engineering.45–47

Macrocyclic host–guest interactions have played a pivotal role in supramolecular materials owing to their excellent dynamic nature.48–52 The reversible complexation process between host and guest molecules has become one of the most important driving forces in supramolecular chemistry. Consequently, the combination of dynamic properties of host–guest interactions with hydrogels provides a promising way to create novel soft materials with outstanding chemical and physical properties, such as self-healing, stimuli-responsiveness, and adaptability.6,53 Water soluble macrocyclic hosts or their derivatives, including cyclodextrins (CD), cucurbit[n]urils (CB[n]), calix[n]arenes, and pillar[n]arenes (PA[n]s), are the most commonly used building blocks for constructing hydrogels. Notably, CD and CB[n] are intrinsic water soluble hosts and are capable of operating in aqueous media, while CA[n]s and PA[n]s could be easily modified with hydrophilic substituents to make them soluble in H2O. By introducing complementary guest molecules in aqueous media, these water soluble hosts display selective and stimuli-responsive host–guest binding behaviors. These highly specific binding motifs possess different binding strengths and dynamic properties, offering scientists with various opportunities to design and tailor the properties of hydrogels. The general idea to design a smart or functional hydrogel based on macrocyclic molecules includes three approaches: (a) linking the macrocyclic host to the polymer chain, (b) linking the guest group to the polymer chain, or (c) connecting the host and the guest to the polymer chain. The exciting applications of such materials include macroscopic recognition, drug delivery, and stimuli-responsive materials, such as smart windows and actuators.

In this review, we aim to summarize the recent developments in the investigation of dynamic hydrogels mediated by macrocyclic host–guest molecular recognition motifs, with an emphasis on their applications in the fields of biomedical materials, self-healing materials, and smart materials. Specifically, we classify the resulting dynamic hydrogels depending on the type of macrocyclic hosts. Therefore, the content of this review is organized as follows: (a) dynamic hydrogels mediated by CDs, (b) dynamic hydrogels mediated by CB[n]s, (c) dynamic hydrogels mediated by CA[n]s, (d) dynamic hydrogels mediated by PA[n]s, and (e) dynamic hydrogels mediated by other macrocyclic hosts. Moreover, we mainly focus on polymer-based hydrogels, including both physically and chemically cross-linked hydrogels. In the present review, we discuss the variety of supramolecular hosts that were incorporated in hydrogels, covering their fabrication, properties, and applications. And then, current challenges and future perspectives of dynamic hydrogels mediated by host–guest interactions are also illustrated.

2. Dynamic hydrogels mediated by cyclodextrins (CDs)

Cyclodextrins (CDs) are cyclic oligosaccharides made up of D-glucose repeating units coupled through α-1,4-glucosidic bonds.54–56 CDs could be hydrolyzed from starch by enzymatic degradation. According to the number of the repeating unit, the most common CDs refer to α-, β-, and γ-CD, corresponding to 6, 7, and 8 D-glucose units, respectively. The shape of CDs is like a truncated cone with a hydrophobic inner cavity and a hydrophilic outer surface. Hydrophobic and van der Waals interactions between CD and guest molecules with an appropriate molecular size are responsible for host–guest complexes of CDs.57 Hydrogels mediated by CDs have been extensively studied since the 1990s and the number of corresponding reports are more than for any other macrocycles. This might be due to their commercial availability with low price, water solubility, biocompatibility, and the capability of forming various inclusion complexes with many different guests. Since CD-based host–guest supramolecular hydrogels have already been reviewed in detail recently,58 the cases in this section will only cover a few selected reports on chemically cross-linked hydrogels mediated by CD.59 This kind of hydrogels are usually constructed from polymeric networks modified by guest molecules, or CD, or both of them in the same system.

In order to develop real-world functional materials from host–guest interactions, macroscopic self-assembly based on molecular recognition should realize unique macroscopic architectures and functions. One of the research targets from the Harada group was to realize “macroscopic molecular recognition” by employing host–guest systems. They chose a polyacrylamide hydrogel as a scaffold because such gel does not have interaction with DNA, proteins, and CD. They prepared host gels based on CDs and guest gels by copolymerization of acrylamide, the functional monomer, and N,N′-methylenebis(acrylamide) (cross-linkers).60 The guest gels were based on polymeric networks modified with guest moieties on the side chain, such as adamantyl (Ad), n-butyl (n-Bu) and t-butyl (t-Bu) groups. The β-CD-gel (red) and Ad-gel (light green) were stained by dyes for visualization. β-CD gel strongly adhered to an Ad guest gel through molecular recognition, which led to difficulty in separation (Fig. 1). Although they tried to separate the gels using a creep meter, it did not work well. Furthermore, a mixture of pieces of α-CD-gel, β-CD-gel, n-Bu-gel, and t-Bu-gel showed very good fidelity just by mixing and shaking in water. α-CD-gel only adhered to n-Bu-gel, and β-CD-gel selectively adhered to t-Bu-gel to realize macroscopic self-assemblies. Therefore, the CD gels can discriminate guest gels at the macroscopic level by molecular recognition. In this example, the host and the guest are linked to independent polymer chains to realize macroscopic recognition. Such materials have potential in medical applications. For instance, biological molecules like antigens and biotin could become the guest in hydrogels, and the corresponding antibodies and avidin could become the hosts, owing to their specific recognition ability.


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Fig. 1 (a) Chemical structures of host and guest gels, (b) macroscopic self-assembly between CD host gels and guest gels. Reproduced with permission from ref. 60. Copyright 2011, Nature Publishing Group.

As mentioned above, the development of stimuli-responsive materials is very important, especially for the creation of remotely manipulated materials with an actuator. In a follow-up study, Harada and co-workers reported a photo-responsive supramolecular actuator by incorporating host–guest recognition interactions and photo-switching ability in a hydrogel.42 They selected azobenzene (Azo) as guest molecules as the binding constant of α-cyclodextrin (α-CD) for trans-azobenzene (trans-Azo) is much bigger than that for cis-azobenzene (cis-Azo) (trans-Azo: Ka = 12[thin space (1/6-em)]000 M−1; cis-Azo: Ka = 4.1 M−1). Then they prepared a reversible expansion–contraction hydrogel, which showed an actuator-like artificial molecular muscle system. The hydrogel consisted of a poly(acrylamide) network cross-linked by N,N′-methylene bis(acrylamide) and a complex of α-CD and Azo, a photo-responsive host–guest pair. They fabricated a plate from the hydrogel. Irradiating the plate with UV light (λ = 365 nm) from the left side made the gel bend to the right. Then, irradiating the bent plate with visible light (λ = 430 nm) from the same side for an hour recovered the initial state. Different from the last example, the host and the guest herein are linked to the same polymer chain. Moreover, this is an excellent example where photo-responsiveness is used to create simple, reversible stimuli-responsive materials.

The expansion and contraction of muscles have inspired scientists to design and develop actuators capable of responding to external stimuli. The construction of actuators that reversibly alter their shapes and sizes in response to external stimuli will have wide applications in areas such as medical treatment and micromachine. In 2013, Harada and co-workers further developed a redox-driven hydrogel actuator mediated by β-CD and ferrocene (Fc) based host–guest recognition interactions.41 The structure of this hydrogel actuator was similar to that in the above example. In this case, the host–guest complex was changed to β-CD and Fc, a redox-responsive pair (Fig. 2). They regulated the size of the β-CD-Fc gels by employing redox reagents. β-CD exhibited a high affinity for the Fc group due to its hydrophobicity. However, for the oxidized state of the Fc group, Fc+ showed a low affinity for β-CD owing to its cationic nature, leading to the dissociation of β-CD/Fc. The authors designed the following experiments to estimate the mechanical work done by the hydrogel actuator via the redox-responsive expansion–contraction process. A weight (291 mg) was attached to the bottom of a rectangular hydrogel. Oxidation made the hydrogel expand and the position of the weight dropped down. Reduction caused the gel to contract and the weight was recovered to the original position. Finally, the authors calculated the mechanical work that was about 2.0 mJ. Again, this is an excellent example where CD-based host–guest interactions are employed to build reversible actuator materials.


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Fig. 2 (a) Chemical structure and illustration of the β-CD-Fc hydrogel. (b) Illustration of the hydrogel actuator. (c) Photographs of a β-CD-Fc hydrogel actuator in response to redox stimuli. After immersion into the buffer with an oxidant (CAN), the length of the hydrogel increased and the attached weight was lowered. Subsequent immersion into the buffer restored the weight to the original position. Scale bar: 1 cm. Reproduced with permission from ref. 41. Copyright 2013, Wiley Publishers.

Bioinspired artificial soft materials have drawn increasing interest due to their medical applications. The chemically cross-linked polyacrylic acids are the widely used superabsorbent materials for water. The degree of swelling is related to different parameters, like pH, temperature or light. Controlling the swelling degree of soft materials on the centimeter scale by using CD is challenging. Ritter and co-workers prepared a kind of smart hydrogels that are triggered by CD-based host–guest interactions.61 This hydrogel possesses an intriguing swelling behavior and a shape-memory effect in the centimeter region. They used 2-(N′-(adamantane-1-yl)ureido)ethyl methacrylate (AdMA) as a hydrophobic co-monomer to prepare water-swelled polymer networks, in which the adamantane group also served as the guest moiety of β-CD. The cross-linker ethylene glycol dimethacrylate was kept at 0.5 mol%. The disc-shaped sample with a diameter of 12 mm was changed to 15 mm when it was immersed in pure water. However, the diameter was changed to 26 mm when the sample was immersed in aqueous β-CD solution. This result can be ascribed to the introduction of the hydrophobic adamantane group into the network which can be switched to hydrophilic after binding a β-CD host. Moreover, the soft material exhibited a shape-memory effect in aqueous β-CD solution rather than in pure water. In this case, only the guest was attached to polymer chains, while the host β-CD served as an independent building block that was dissolved in water. This strategy greatly reduces the complexity of material synthesis. These interesting results implied potential applications of this smart material in the field of biomedicine.

As described above, chemically crosslinked hydrogels are generally brittle, while supramolecular hydrogels often show pseudoplastic deformation with weak resistance to pressure. In 2016, Burdick and co-workers reported novel double-network (DN) hydrogels through supramolecular and chemical crosslinking.25 Such material displayed interesting properties, such as injectability and cytocompatibility. 1-Adamantane (Ad) acetic acid and aminated β-CD (CD) were attached to hyaluronic acid (HA) to produce polymers Ad-HA and CD-HA. Upon mixing Ad-HA and CD-HA solutions (5.0 wt% overall), a guest–host hydrogel (GH) was formed (Fig. 3a). The hydrogel showed expected frequency dependent moduli on account of the dynamic bond and yielded at high strain (>75% reduction in G′) and recovered (>95%) within 6 s after removing the high-strain conditions. The GH complexation was successfully created in the fabrication of a primary network. Dithiothreitol (DTT) was reacted with methacrylated HA to form a covalently crosslinked hydrogel (MeHA), which constructed the secondary network (Fig. 3b). The combination of non-covalent and covalent crosslinks enabled the engineering of DN hydrogels with tailored properties (Fig. 3c), including injectability, tunability and self-healing properties. Simply mixing the polymer solutions generated the GH DN hydrogel. Incorporating methacrylates into the GH network enabled the coupling of the two interpenetrating networks, leading to MethGH DN hydrogels. According to compressive loading experiments, MethGH DN hydrogels showed the best recovery ability with only minor defects observed. The encapsulation and delivery of cells are often necessary for biomedical applications. Confocal microscopy showed that all hydrogels exhibited homogeneous cell distributions and enabled maintenance of high cell viability. Furthermore, upon injection into aqueous media, GH DN and MethGH DN hydrogels demonstrated almost immediate supramolecular re-assembly. These double networks took the advantages of both covalent and non-covalent interactions. Due to the above described properties, orthogonal supramolecular-covalent DN hydrogels are promising materials for biomedical applications.


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Fig. 3 (a) Schematic of adamantane (Ad-HA, blue) and β-CD (CD-HA, yellow) modified hyaluronic acid crosslinked through guest–host (GH) complexation. (b) Schematic of Michael addition crosslinking of methacrylated hyaluronic acid (MeHA) by DTT (red), where crosslink density was controlled through the thiol:methacrylate ratio (XDTT). (c) Network architectures examined included a guest–host (GH) hydrogel, covalently crosslinked (MeHA) hydrogel, GH DN, and MethGH DN. Local stress under loading (red) dissipated through reversible GH complex rupture (i) within the primary GH network; increased stress led to covalent bond rupture (ii) within the secondary covalent network, whereas energy dissipation from the GH network reversibly protected the secondary MeHA network from bond rupture within the double networks (iii), a mechanism which was enhanced through network tethering to enable stress transference (iv). Reproduced with permission from ref. 25. Copyright 2016, Wiley Publishers.

3. Dynamic hydrogels mediated by cucurbit[n]urils (CB[n]s)

Cucurbit[n]urils (CB[n]) are pumpkin-shaped macrocyclic molecules with prominent host–guest chemistry in water.62–68 They are synthesized from a condensation reaction of formaldehyde and glycoluril. These pumpkin-shaped containers possess a rigid hydrophobic cavity and two identical hydrophilic portals rimmed with polar carbonyl groups. Generally, the solubility of CB[n]s in various organic solvents is less than 10−5 M. Therefore, the investigation of CB[n]s chemistry has primarily been done in water.6 Moreover, the CB[n] family has been proved to be non-toxic and generally compatible with various cell cultures, endowing them with potential applications in biomedical fields.69 Due to the strong charge–dipole, hydrogen bonding, and hydrophobic/hydrophilic interactions derived from the rigid inner cavities and the negative portals of CB[n]s, almost all studies on CB[n]s have been focused on constructing supramolecular assemblies like other macrocyclic receptors, such as crown ethers and CDs. Different types of CBs have distinct host–guest behavior. Therefore, in this section, we will discuss dynamic hydrogels mediated by various types of CBs, from CB[6] to CB[10].

Similar to CDs, both CB[6] and CB[7] display remarkable binding affinities towards different positively charged guests and usually form stable 1[thin space (1/6-em)]:[thin space (1/6-em)]1 binary host–guest complexes. The extracellular matrix (ECM) plays an important role in cells. Hyaluronic acid (HA) is a natural linear polysaccharide and one of the main constituents of ECM. Hydrogels have been excellent candidates for mimicking ECM. Kim and co-workers reported a facile in situ modular modification of biocompatible hydrogels for cellular engineering applications.70 These hydrogels were constructed from CB[6]-conjugated HA (CB[6]-HA), diaminohexane-conjugated HA (DAH-HA), and tags-CB[6]. CB[6] can tightly bind polyamines (PA), such as DAH or spermine, to form stable 1[thin space (1/6-em)]:[thin space (1/6-em)]1 complexes with an association constant up to 1010 or 1012 M−1. As shown in Fig. 4, simple mixing of CB[6]-HA with PA-HA produced a hydrogel in the presence of cells without other reagents. The hydrogels can be further modified by introducing various “tags”-attached CB[6] (tags-CB[6]), which could be fixed on the residual DAH units on the hydrogel by host–guest interactions. Cytocompatibility experiments showed that the in situ formation of hydrogels in the presence of NIH3T3 cells displayed high cell viability, enzymatic degradability, and negligible cytotoxicity. The authors also investigated the in vivo applications of the CB[6]/DAH-HA hydrogels. The formation of hydrogel under the skin of nude mice was realized by sequential injections of CB[6]-HA and DAH-HA solutions. The CB[6]/DAH-HA hydrogel under the skin could be kept for more than 2 weeks. By simple injection of fluorescein isothiocyanate (FITC)-CB[6] into the hydrogel under the mice skin, the hydrogel could be modified in situ and the fluorescence was kept for up to 11 days. This work suggested the feasibility of CB[6]-based hydrogels as an artificial ECM for many biomedical applications, including cell therapy and tissue engineering. Herein, both the host CB[6] and guest moieties were linked to polymers. In another research work, the authors again employed the same system for the controlled chondrogenesis of human mesenchymal stem cells.71


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Fig. 4 (a) Schematic representations of in situ formation of supramolecular biocompatible hydrogel and its modular modification using highly selective and strong host–guest interactions. The simple mixing of CB[6]-HA and polyamine-conjugated HA (PA-HA) resulted in the formation of CB[6]/PA-HA hydrogel, which was further modularly modified with various tags-CB[6]. The chemical structures of (b) CB[6] and (c) PAs of diaminohexane (DAH) and spermine (SPM). Reproduced with permission from ref. 70. Copyright 2012, American Chemical Society.

The development of gelation process under control is one of the main goals of hydrogel technology. However, the control of gelation kinetics is still a challenge. In 2016, Tan and co-workers developed an approach to control the gelation kinetics of CB[7]-adamantane (CB[7]-AD) cross-linked hydrogels by employing competing guests.72 They prepared two N,N-dimethyl acrylamide type polymers with AD and CB[7] as pendant groups, respectively. Hydrogels could be fabricated by mixing AD-based polymer and CB[7]-based polymer solutions. Through pre-saturation of the CB[7]-based polymer with various competing guests, the gelation kinetics change dramatically and the gelation time varies from seconds to hours. The strong interaction of the CB[7]-AD host–guest complex endows the non-covalent hydrogels unique mechanical properties like good stability, high elasticity, and shape persistence. Such hydrogels displayed potential applications for both injection and printing with tailored properties.

Another interesting research work appeared in 2000 when Kim and co-workers reported the first 1[thin space (1/6-em)]:[thin space (1/6-em)]2 ternary complex between CB[8] and two doubly charged guest molecules.73 Later, they successfully prepared the ternary complexes composed of CB[8] and a hetero-guest pair which were methylviologen and 2,6-dihydroxynaphthalene.73 Since then, CB[8] has become one of the most attractive hosts in the CB family and has been employed to create different kinds of functional materials. Different from other CBs in hydrogels, CB[8] is usually not linked to polymer chains due to synthetic complexity and its ability to bind two guests which usually acted as pendant groups on the polymer chain. The following section is mainly focused on functional hydrogel materials fabricated from CB[8] based host–guest interactions.

In 2010, Scherman and co-workers reported the first example of a supramolecular hydrogel cross-linked by CB[8] host–guest interactions.74 By employing two kinds of side-chain polymers with different pendant guest moieties (viologen and naphthoxy), the formation of hydrogel in the presence of CB[8] was proved. These materials showed intermediate mechanical properties at 5 wt% in water (plateau modulus = 350–600 Pa and zero-shear viscosity = 555 Pa s), providing a complement to traditional supramolecular hydrogels and implying their potential use in the industrial field. The results obtained from these dynamic hydrogels will contribute to progress in the field of smart materials. In the next study, they prepared ultrahigh water-content (up to 99.75% water) supramolecular polymeric hydrogels based on renewable cellulosic resources (Fig. 5).75 The dynamics of the CB[8] ternary complex endowed such hydrogels with self-healing and shear-thinning properties. Moreover, the hydrogels had good tunable mechanical properties which could be simply controlled by the ratios of the three ingredients. In addition, they showed responsiveness to multiple external stimuli, such as temperature, competing guests, and chemical potential. Controlled release of drugs from soft hydrogels is an important objective for the development of innovative therapies. Later, they used this high water-content hydrogel to realize the sustained release of proteins (Fig. 5).76 They showed the release of bovine serum albumin (BSA) and lysozyme from the hydrogels containing only 1.5 wt% polymeric constituents. Notably, the release of BSA was observed over the course of 160 days. These materials showed important potential for prolonged therapeutic applications. In 2014, they further prepared a series of physically crosslinked hydrogels mediated by CB[8]-based host–guest interactions.77 The authors studied the release characteristics of the molecular cargo from these hydrogels. The experimental results showed that the release rate constant was directly related with the dynamics of the supramolecular interactions for crosslinking. This investigation showed an example to study the impact of crosslink dynamics on cargo release, for example, the effect on diffusion through the ECM of various biological tissues.


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Fig. 5 (a) Two-step, three-component binding of CB[8] in water. (b) Schematic representation of the release of proteins from extremely high water content hydrogels through strong host–guest interactions of CB[8]. Reproduced with permission from ref. 76. Copyright 2012, Elsevier Publishers.

Since their first report on hydrogels mediated by CB[8],74 the Scherman group has developed a series of CB[8]-based functional hydrogels, covering supramolecular hydrogel beads,78 supramolecular hydrogel microcapsules,79 biomimetic supramolecular polymer networks,80 and bioinspired supramolecular fibers.81,82 Very recently, they have developed CB[8] supramolecular hydrogel networks which served as tough and healable adhesives to dynamically bond various substrates.83 In this system, the CB[8] acted as the promoter (cohesive domains) to keep the network integrity, while the polymer chains were adsorbed onto the substrates through van der Waals interactions (adhesive domains, Fig. 6). The testing experiments showed that two bonded glass slides with an overlap area of ca. 375 mm2 could readily sustain a mass as high as 1.65 kg, about 1000 times of the mass of the adhesive used. The shear stress reached a value of 1.1 MPa for the glued glass slides. Herein, excellent adhesion strength and efficient energy dissipation from the bulk hydrogel are critical factors that lead to strong conjunction. This simple strategy for bonding indicated various applications including stretchable hydrogel electronics, biomedical implants and tissue/bone regeneration.


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Fig. 6 (a) The CB[8] supramolecular ternary complexes serve as dynamic cross-links, forming a network structure which behaves as an adhesive for two substrates. The CB[8] host–guest interactions also act as sacrificial bonds that dynamically rupture under deformation to dissipate energy, which can further re-form, resulting in tough interfacial adhesion. (b) Stepwise formation of 2[thin space (1/6-em)]:[thin space (1/6-em)]1 ternary host–guest complexation between CB[8] and guest molecules. Reproduced with permission from ref. 83. Copyright 2018, Wiley Publishers.

As described for CD-based hydrogels, double network hydrogels exhibit intriguing properties. Based on this strategy, Liu and co-workers prepared an entirely supramolecular double network hydrogel.84 This hydrogel was fabricated by the combination of two different hydrogel systems: one through host–guest interactions of CB[8] and the other by DNA hybridization. Unlike the synthetic complexity of the chemically crosslinked double network, this hydrogel can be prepared by a simple “one-pot” mixing method due to the specific recognition units (Fig. 7). The DNA linker and the DNA Y-scaffold can bind each other owing to the precise hybridization of complementary DNA sequences, resulting in the formation of the first supramolecular crosslinked hydrogel network (DNA hydrogel). Alternatively, phenylalanine-functionalized carboxymethyl cellulose (CMCphe) and CB[8] can also recognize each other due to the host–guest interaction between phenylalanine and CB[8] to form the second supramolecular crosslinked hydrogel network (CB[8] hydrogel). By mixing these components in phosphate-buffered saline (PBS) buffer (0.1 M, pH 7.4), a double network hydrogel was formed. The two interpenetrating networks displayed outstanding properties superior to the CB[8] hydrogel and the DNA hydrogel. For example, upon concurrent addition of CMC-phe and CB[8] to the DNA hydrogel, G′ increased from 80 ± 1.6 to 281 ± 2.4 Pa, which is greater than the sum of values for the two single hydrogels. Moreover, the double network hydrogel showed a higher gel–sol transition point (62 ± 1.2 °C) compared to the CB[8] hydrogel (46 ± 0.8 °C) and the DNA hydrogel (51 ± 0.5 °C), once again proving that the interpenetrating networks strengthened the thermal stability of the material. Based on the dynamic nature, this material possesses thixotropic and shear-thinning properties, which imply potential as an injectable material for in vivo biomedical applications.


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Fig. 7 The formation process of double network hydrogels through supramolecular interactions. 2[thin space (1/6-em)]:[thin space (1/6-em)]1 homoternary complexation of Phe units pendant from carboxymethyl cellulose to CB[8] affords one macroscopic network. A second network is crosslinked by hybridization of DNA “sticky ends”. The resulting double network hydrogel possesses combined properties of each single network hydrogel, such as greater mechanical strength and stimuli responsiveness. Reproduced with permission from ref. 84. Copyright 2015, Wiley Publishers.

Isaacs and co-workers reported the preparation and purification of nor-seco-cucurbit[10]uril (ns-CB[10]), which displays a different size and shape from CB[n] (n = 6, 7 and 8).85 Interestingly, ns-CB[10] can also bind two guest molecules simultaneously, like adamantylamine (AdA) or MV in the cavity. In 2017, Kim and co-workers reported a self-healing hydrogel formed by supramolecular crosslinking between ns-CB[10] and AdA-terminated 4-armed polyethylene glycol (AdA-4-arm-PEG).86 Simple mixing of ns-CB[10] and AdA-4-arm-PEG solutions produced a shape-persistent and freestanding hydrogel. The dynamic nature endowed the non-covalent hydrogel with the ability to rapidly regain its physical properties, even undergoing multiple self-healing cycles.

4. Dynamic hydrogels mediated by calix[n]arenes (CA[n]s)

Calix[n]arenes (CA[n]s) are cup-like macrocyclic molecules composed of multiple phenolic units linked by methylene groups at the 2- and 6-positions.87 They can be obtained from the condensation of p-alkylphenols with formaldehyde under alkaline conditions. CA[n]s are among the most widely investigated supramolecular hosts and have wide application in many fields. CA[n]s represent the third generation of macrocyclic hosts, which appeared after CDs and crown ethers, and before CB[n]. Although CA[n] molecules are generally hydrophobic, they can be easily changed to be hydrophilic by chemical modification. For example, p-sulfonatocalix[n]arenes (SCA[n]s) are outstanding water-soluble CA derivatives with the ability to bind guest molecules in water.88,89 As discussed above, macrocyclic hosts like CD and CB[n] were widely used as prominent building blocks for hydrogels due to their intrinsic water solubility. By contrast, hydrogels mediated by water-soluble CA[n] have been reported relatively infrequently. Therefore, several cases of CA-based hydrogels were selected to discuss in this section.

In 2015, Liu and co-workers reported the fabrication of a novel supramolecular hydrogel from poly(vinyl alcohol) randomly modified with viologen (PVA-MV) and SCA[4] decorated with dodecyl groups on the lower rim (SC4AD).90SC4AD is cone-shaped and prone to form spherical micelles in water where the dodecyl tails are directed inwards. Subsequently, the anionic calixarene cavities which are located on the outer surface of micelles can further associate with guests (Fig. 8). For example, polycations in this system can induce the formation of secondary assemblies as a 3D network. The obtained hydrogel exhibited responsiveness to multiple stimuli, such as temperature, redox, and ionic strength. Photo-luminescent hydrogels with multicolor emissions have drawn much attention on account of their potential applications in light-emitting materials. In a follow-up investigation, Liu and co-workers developed a tunable white-light emission supramolecular hydrogel this year.91 This hydrogel was mediated by CA[4] and CD simultaneously in an orthogonal way.


image file: c8tb02339e-f8.tif
Fig. 8 (a) Structure of SC4AD and PVA-MV. (b) Schematic representation of a supramolecular hydrogel prepared through secondary assembly of SC4AD with PVA-MV.

In some examples, CA[n] only plays the role of a scaffold instead of showing host–guest interactions in the construction of soft materials.92,93 Sometimes, these systems also exhibited fascinating properties. Therefore, we also discuss one of the examples in this section. Different from conventional covalent bonds, dynamic covalent (DC) bonds are not only stable but also reversible. Soft materials like gels constructed by dynamic covalent bonds also show interesting properties. In 2017, Fang and co-workers designed and prepared DC gels through acylhydrazone reaction between a p-tert-butylcalix[4]arene derivative (CTH) and benzaldehyde-terminated PEG derivatives (Fig. 9).92 The DC gels displayed excellent self-healing, pH and temperature responsiveness, and mechanical properties. Because of the poor solubility of CTH in pure water, a mixed solvent of water and ethanol was employed in the preparation process to obtain gel G-0. However, dry gel G-0 was obtained naturally at room temperature and was then swollen in pure water, resulting in a hydrogel (HG-0). Rheological measurements showed that the storage modulus (G′) of the material is always higher than the loss modulus (G′′), indicating that the system always existed in gel state during the tests. All the gel samples displayed strong mechanical strength and exhibited fracture stress higher than 6 MPa, and the Young's modulus was higher than 0.8 KPa. Moreover, the reversible nature of the dynamic acylhydrazone bond also endowed the gels with self-healing properties. Compared to CB[n] and CD, CA[n]s are easier to functionalize. Therefore, the strategy to exploit the scaffold of CA is an alternative way for constructing hydrogels by using macrocycles.


image file: c8tb02339e-f9.tif
Fig. 9 (a) Schematic representation of the formation of calixarene-derived gel networks based on a dynamic acylhydrazone bond. Images of (b) a mixed solvent gel sample of G-0, (c) corresponding dried-gel, and (d) swollen hydrogel of HG-0. (e) SEM image of the freeze-dried xerogel of G-0. Reproduced with permission from ref. 92. Copyright 2018, Wiley Publishers.

5. Dynamic hydrogels mediated by pillar[n]arenes (PA[n]s)

Pillar[n]arenes (PA[n]s) are a relatively new family of macrocyclic hosts in supramolecular chemistry and have drawn much attention in fabricating supramolecular materials.94–103 In contrast to the above mentioned various hosts, PA[n]s combine many of their helpful features. The repeating moieties of PA[n]s are similar to CA[n]s, making them easy to modify. The symmetrical pillar-shaped structures are similar to pumpkin-shaped CB[n]s. Furthermore, PA[n]s have multiple phenolic units on both lower and upper rims, making them very similar to the highly functionalized CDs. Additionally, PA[n]s are easy to prepare and have unique shape, versatile solubility, and functionality, which make them good candidates for host–guest chemistry. Notably, the symmetrical pillar structure and easy modification endow PA[n]s with a good ability to bind various types of guest molecules, including neutral guests, cationic guests, anionic guests, rigid guests, flexible chain guests, and hydrophilic and hydrophobic guests.104 In recent years, PA[n]s have been utilized to create soft materials, such as organogels and hydrogels.53 In this section, we mainly focus on supramolecular hydrogels mediated by PA-based host–guest interactions.

In 2015, Yao and co-workers reported a Cu2+ specific metallohydrogel, which was fabricated from a terpyridine based low molecular weight ligand (Fig. 10).105 Such a ligand formed a hydrogel under slightly acidic conditions only in the presence of Cu2+ and other metal ions could not lead to gelation. It may have potential applications in biological fields due to the important role of copper ions in physiological processes. The hydrogel showed multiple stimuli-responsiveness towards gel–sol transitions, such as thixotropy, temperature, and the addition of alkali or sodium L-ascorbate. Interestingly, the metallogel was collapsed to sol upon addition of equal equiv. of water-soluble PA[5] derivative (WP5). Simultaneously, the morphology of the material was changed to vesicles with a diameter of 300 nm. This might be due to the fact that the introduction of rigid PA[5] formed a host–guest complex with the ligand, which caused the gelation to stop. In this example, such supramolecular hydrogel was constructed from low molecular weight building blocks, indicating the diversity of hydrogels based on PA[n]s.


image file: c8tb02339e-f10.tif
Fig. 10 Chemical structures of ligand and water-soluble pillar[5]arene and representations of the gelation process and WP5-induced morphology transformation.

Some hydrogels showed expansion–contraction behaviors upon external stimuli. The swelling–shrinking transition of hydrogels is critical for their applications including shape-memory materials, actuators, and drug delivery. Realization of a large degree of swelling–shrinking transition of hydrogels at a macroscopic scale with multiple stimuli-responsiveness by host–guest interactions is still a big challenge. Based on our previously study on the host–guest chemistry between PA[6] and ferrocene in water to construct supramolecular vesicles,106,107 we have recently successfully developed a smart hydrogel whose swelling ratio could be dramatically promoted by such host–guest interactions (Fig. 11).108 In this work, we synthesized a covalently crosslinked polymer network G1c with pendant ferrocene groups, and while G1c was immersed in WP6 aqueous solution, a dramatically well-swollen G1c·WP6 hydrogel was achieved. When a dried disc of G1c was immersed in pure water until the swelling equilibrium was reached, the disc diameter only increased 37% from 8 mm to 11 mm. However, when dried G1c was immersed in WP6 aqueous solution (10 mM), the diameter of the disc dramatically increased and finally reached 31 mm with a 287% increment. The G1c·WP6 hydrogel showed responsiveness to multiple stimuli, such as temperature, pH, redox, and competitive guests, by tuning the reversible dissociation/association of WP6–ferrocene inclusion complexes. In addition, this system was successfully employed to control drug release through the pH-tuned dissociation of WP6–ferrocene which led to the shrinking of the hydrogel. Employing independent PA to mediate chemically cross-linked hydrogels is a very attractive approach on account of the synthetic simplicity and easy regulation. The strategy reported herein is similar to that of CD-based hydrogels studied by Ritter and co-workers.61


image file: c8tb02339e-f11.tif
Fig. 11 Illustration of the dramatically promoted swelling of G1c by WP6–ferrocene host–guest interactions, and subsequently pH-responsive swelling–shrinking transition and application in controlled drug (DOX·HCl) release.

The non-covalent interactions play a vital role in nature, because they are the basic driving force for the fabrication of biomolecules such as DNA and protein. In recent years, supramolecular hydrogels have been well known for the characteristics of adhesion, shape-memory, self-healing, and swelling. However, little investigation has been done on the shrinking ability of hydrogels mediated by host–guest interactions. Inspired by the above example of the well-swollen hydrogel, we further fabricated a polyacrylamide-based polymer network, which showed a shrinking property upon addition of water-soluble PA[5] (WP5) with the synergetic effect of electrostatic interactions and host–guest recognition (Fig. 12).109 When the prepared hydrogels were immersed in WP5 aqueous solution, the diameters of the disc-shaped samples greatly decreased in 36 h from 45 mm to about 22 mm. The shrinking behavior in WP5 solution should be ascribed to host–guest interactions between WP5 and ammonium groups attached to the polymer backbone and electrostatic interactions between them too. The encapsulation of two drug models was obtained by immersing the hydrogels in aqueous solution of calcein or rhodamine B. For rhodamine B, the samples displayed a similar and almost complete release after being immersed in WP5, MP, and NaCl aqueous solution after 12 h. Interestingly, the calcein-loaded hydrogels showed the same experimental result only after being immersed in WP5 aqueous solution, which exhibited the remarkable selective release of calcein-loaded hydrogels only with the addition of WP5. This work and the last example suggest that PA-based dynamic hydrogels have great potential in the area of controlled release.


image file: c8tb02339e-f12.tif
Fig. 12 Structures of trimethylammonium-containing polymer networks, WP5, MP, calcein, and rhodamine B; illustration of the dramatically shrinking behavior of the samples and controlled release of the calcein-loaded hydrogel and rhodamine B-loaded hydrogel by different triggers.

PA[n]s with multiple triethylene oxide (TEO) groups exhibit lower critical solution temperature (LCST) behavior.110 At temperatures above the LCST, the materials display decreased solubility, leading to a fall in transmittance. In a follow-up study, due to the thermo-responsive property of TEO-modified PA[6] (EGP6) and the redox-induced reversible color switching of ferrocene/ferrocenium groups, our group has further developed a hydrogel based smart window (Fig. 13).111 Based on the above research, we synthesized a well-swollen hydrogel (Fc-gel·EGP6) which was obtained by immersing dry Fc-gel in the aqueous solution of EGP6. As a result, the water absorption capacity of the Fc-gel·EGP6 hydrogel is dramatically improved, leading to a dramatically improved swelling behavior and an enhanced transparency. Upon increasing the temperatures above its cloud point, EGP6 aggregated and microseparated from water inside the hydrogel and finally resulted in the generation of an opaque hydrogel. When decreasing the temperature from 40 to 25 °C, the opaque hydrogel returned to its original transparency due to the re-dissolution of EGP6. Because of this thermo-responsiveness of EGP6 and the reversible transformation between orange and green colors of ferrocene/ferrocenium groups under redox-response, we have orthogonally integrated the functional properties to prepare a warm/cool tone-switchable thermochromic material. We believed that such a material is highly suitable for the construction of smart windows with dual functionality, regulating the input of solar energy and improving the feelings and emotions of inhabitants.


image file: c8tb02339e-f13.tif
Fig. 13 Chemical structures and schematic illustration of the warm/cool tone switchable thermochromic material for smart windows.

Similar to CA[n], in some cases only the scaffold of PA[n] instead of their host–guest chemistry was utilized to construct hydrogels. For example, Huang and co-workers have recently developed an easy way to produce gels with tunable mechanical characteristics via Schiff's base formation to form acylhydrazone bonds.112 They utilized a PA[5] with ten hydrazide moieties to react with the bis(p-formylphenyl)sebecate compound, resulting in an organogel in DMSO. After changing the solvent, mechanically robust hydrogels were obtained. Interestingly, the hydrogels showed high strength and stiffness. The breaking stress in tension and Young's modulus of such hydrogels were 1.2–2.7 and 20–60 MPa, respectively, 20 and 100 times larger than those of the corresponding organogels. Another example from Liu's group is that they reported enzyme-regulated rapid self-healing of a PA[5] hydrogel.113 They prepared a PEG4000 derivative functionalized with benzaldehydes at terminals, which could react with a hydrazide-functionalized PA[5] derivative, resulting in dynamic covalently bonded hydrogels. The hydrogels displayed outstanding mechanical and self-healing properties. Notably, the mediation of dual-enzyme played an important role in accelerating the self-healing rate. It took about 5 minutes to achieve full recovery under enzyme catalysis, while it took more than 24 h if enzymes were absent.

6. Dynamic hydrogels mediated by other macrocyclic hosts

Macrocyclic molecules with host–guest properties are one of the important driving forces in the development of supramolecular chemistry. During the past decade, various new macrocyclic hosts have emerged besides classical macrocycles, such as helic[n]arene,114 “Texas-sized” box,115 ExBox,116 biphen[n]arene,117etc. Concurrently, an increasing number of stimuli-responsive functional materials have been constructed from these emerging macrocyclic molecules. Therefore, some interesting examples of hydrogels mediated by these non-classical macrocyclic hosts have also been reported in recent years.

In 2018, Sessler and co-workers reported some functional hydrogel materials mediated by tetracationic macrocyclic anion receptors.118,119 For example, they prepared a series of fluorescent hydrogels that consist of a poly(acrylamide) (pAAm) network cross-linked by N,N′-methylenebis(acrylamide) (MBAAm), tethered tetracationic macrocyclic anion receptors and a pendant alkyl sulfonate subunit, as well as pendant fluorescent moieties.119 The blue (G1), green (G2), and red (G3-1, G3-2) fluorescent hydrogels were realized by incorporating coumarin, BODIPY, and rhodamine B moieties, respectively (Fig. 14). These hydrogels could be physically fabricated into different integrated multicolor fluorescent patterns when pushed together on a black nitrile substrate. Interestingly, these patterns were used as fluorescent 3D codes that could be read out by a smartphone. The information could be erased, transformed, or rehealed. Furthermore, the encoded information provided by patterns of these hydrogels could be transformed through either a physical approach or a chemical stimulus. This work provided new tunable hydrogels for information readout, modification, and storage. Moreover, this example represents dynamic hydrogels constructed by using other macrocycles besides the typical hosts described in this review, indicating that more and more functional hydrogels based on new macrocyclic hosts will be created.


image file: c8tb02339e-f14.tif
Fig. 14 Chemical structures and cartoon representations of the nonfluorescent hydrogel G0, blue-fluorescent hydrogel G1, green-fluorescent hydrogel G2, nonresponsive red-fluorescent hydrogel G3-1, and ammonia-responsive red-fluorescent hydrogel G3-2. Reproduced with permission from ref. 119. Copyright 2018, Wiley Publishers.

7. Conclusions and perspectives

Macrocyclic molecules are considered as versatile building blocks to fabricate various kinds of supramolecular architectures, from simple pseudorotaxane structures to complex molecular machines. For the formation of macrocyclic host-based physically cross-linked hydrogels, host–guest interactions between macrocycles and complementary guests are the main driving forces for the 3D networks of supramolecular hydrogels. For macrocycle-based chemically cross-linked hydrogels, host–guest interactions play a crucial role in controlling the structures and functions of the resulting hydrogels. The good reversibility and stimuli-responsiveness of host–guest interactions endow these hydrogels with fascinating stimuli-responsive properties.

There are different and diverse dynamic hydrogels mediated by different macrocyclic host-based molecular recognition. Cyclodextrins and cucurbit[n]urils are intrinsic water soluble macrocyclic hosts, which are suitable for construction of dynamic hydrogels directly. By contrast, calix[n]arenes and pillar[n]arenes are synthetic organic molecules, which need further modification to make them soluble in aqueous solutions. However, calix[n]arenes and pillar[n]arenes have an advantage over other hosts due to the fact that the way of functionalization of their structures is diverse and easy to carry out.

Although a great number of macrocycle-based dynamic hydrogels have been created, some basic challenges remain to be resolved before the reported applications can be brought into practical use. The perspectives are listed as follows: (a) further studies on the mechanism of dynamic hydrogel formation, and deeper insights into the thermodynamics and kinetics of hydrogels are still necessary. Much more attention should be paid to the structure–property relationships as well as the improvement of the physical, chemical, and mechanical properties of the resulting dynamic hydrogels. (b) The application of dynamic hydrogels in the fields of biomedicine and biomaterials is a hot trend. However, biocompatibility and cytotoxicity experiments are very scarce, and further research is needed to take action in these areas. (c) With the development of macrocyclic chemistry, the use of emerging macrocycles remains challenging. Nevertheless, the hydrogel mediated by macrocyclic hosts is still a burgeoning research area. We believe that these challenges will be gradually studied and resolved to achieve more practical applications.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge the financial support of the National Natural Science Foundation of China (No. 21702020, 21672102). This work is also supported by the Fundamental Research Funds for the Central Universities (No. 020514380131).

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