Cyclodextrin-based supramolecular assemblies and hydrogels: recent advances and future perspectives.

Macromolecular Rapid Communications

Review

Cyclodextrin-Based Supramolecular Assemblies and Hydrogels: Recent Advances and Future Perspectives Shereen Tan, Katharina Ladewig, Qiang Fu, Anton Blencowe,* Greg G. Qiao* The application of cyclodextrin (CD)-based host–guest interactions towards the fabrication of functional supramolecular assemblies and hydrogels is of particular interest in the field of biomedicine. However, as of late they have found new applications as advanced functional materials (e.g., actuators and self-healing materials), which have renewed interest across a wide range of fields. Advanced supramolecular materials synthesized using this noncovalent interaction, exhibit specificity and reversibility, which can be used to impart reversible cross-linking, specific binding sites, and functionality. In this review, various functional CD-based supramolecular assemblies and hydrogels will be outlined with the focus on recent advances. In addition, an outlook will be provided on the direction of this rapidly developing field.

1. Introduction The self-assembly of macromolecular systems into highly ordered nanostructured functional assemblies via supramolecular interactions has received increasing interest in the fields of polymer and materials science. Driven by noncovalent interactions, such as inclusion complexation, sophisticated molecular architectures with high specificity and functionality can be achieved. Inclusion complexation, wherein a “host” reversibly binds to a “guest”

Ms. S. Tan, Dr. K. Ladewig, Dr. Q. Fu, Dr. A. Blencowe, Prof. G. G. Qiao Polymer Science Group, Department of Chemical and Biomolecular Engineering, University of Melbourne, VIC 3010, Australia E-mail: [email protected]; [email protected] Dr. A. Blencowe Mawson Institute, Division of ITEE, The University of South Australia, Mawson Lakes, SA 5095, Australia Macromol. Rapid Commun. 2014, DOI: 10.1002/marc.201400080 © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

encompasses an array of noncovalent interactions that can yield highly complex and ordered structures. As a result of their wide availability and negligible toxicity cyclodextrins (CDs) are one of the most widely used hosts in the field of inclusion chemistry. Usually composed of six to eight D-glucose units, CDs are capable of forming inclusion complexes with various guest moieties and polymeric chains. This capability is attributed to their ether-like oxygen and their hydrocarbon frame creating a hydrophobic cavity wherein appropriately sized molecules and macromolecules can be immobilized via tight, yet reversible associations. Using CD-based inclusion chemistry as a platform, a diverse range of polymeric networks with applications in the life sciences, biotechnology, and materials science can be achieved. This review highlights the versatility of CDbased inclusion chemistry, and how specificity and control can be imparted when designing higher-order structures, such as those found in biological systems. A particularly interesting group of polymeric structures that is achievable via CD-based inclusion chemistry is that of CD-based

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DOI: 10.1002/marc.201400080

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supramolecular hydrogels, which have recently received increased attention as a result of their potential use in a range of biomedical and advanced materials applications, including drug delivery and self-healing materials. After a brief overview of CD-based inclusion chemistry and its use in the assembly and synthesis of supramolecular polymers, this review will discuss the various types of CD-based supramolecular assemblies and hydrogels that have been obtained to date, as well as recent advances in utilizing these materials for a variety of applications. Lastly, we provide an outlook on the direction this rapidly expanding field of research is most likely to follow in the next decade.

2. Cyclodextrin-Based Supramolecular Polymers Some of the most widely used hosts in macromolecular self-assembly are CDs; a class of macrocyclic oligosaccharides commonly consisting of six to eight glucose units arranged in a toroidal structure.[1–3] The primary hydroxyl groups of CD are located at the narrower, primary face, while the secondary hydroxyl groups are situated at the wider, secondary face of the toroid.[1–3] Owing to this restricted 3D conformation, the exterior of CD exhibits high water solubility while the ether-like oxygens and the hydrocarbon frame confer a non-polar interior cavity (Figure 1).[1]

Shereen Tan completed her B. Eng. (Hons) and M.Phil. in Chemical and Biomolecular Engineering from the University of Melbourne (Australia) in 2010 and 2012. Upon graduation, she commenced her Ph.D. studies under the supervision of Prof. Greg Qiao. Her current research focuses on developing sophisticated molecular architectures via cyclodextrin host–guest chemistry for advanced materials. Dr. Katharina Ladewig completed her M.Sc. and Ph.D. degrees in chemistry and biomedical engineering at Chemnitz University of Technology, Germany in 2005 and The University of Queensland, Australia in 2009, respectively. She is interested in chemical and materials science aspects of gene and drug delivery, tissue engineering, and biomaterials research in general and has published a number of research papers in these fields. She is currently appointed at The University of Melbourne where she develops novel hydrogel systems suitable for a variety of tissue engineering applications and currently holds a prestigious Australian Research Council (ARC) Super Science Fellowship. Dr. Qiang Fu obtained his B.Eng. in Chemical Engineering from the Shanghai Jiao Tong University in 2004. He subsequently received his Ph.D in polymer chemistry and physics at Fudan University in 2009. Then, he joined Polymer Science Group, Department of Chemical and Biomolecular Engineering at the University of Melbourne. As a postdoctoral research fellow, he was involved in two research projects within the CRC for Polymers on functional polymer synthesis. Since 2011, he has been an Australia Research Council’s Super Science Fellow under supervision of Prof. Greg Qiao on novel polymeric membranes synthesis. His main research interests are in supramolecular chemistry, polymer chemistry, and polymeric membrane materials. Dr. Anton Blencowe received his Master’s degree in chemistry with honours from the University of Reading in 2002. He completed his Ph.D. under the supervision of Professor Wayne Hayes at the University of Reading in 2006 before working as a Postdoctoral Fellow with Professor Greg Qiao at the University of Melbourne. In 2009, he was awarded an ARC Australian Postdoctoral Fellowship. Currently, he is a Research Leader at the Mawson Institute at the University of South Australia. His research interests span from fundamental studies to applied sciences and encompass the fields of macromolecular engineering and self-assembly, polymer therapeutics, biomaterials, biomimetics, and nanomaterials.

Figure 1. Representations of the structure of various cyclodextrins and their corresponding dimensions.[1]

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Professor Greg G. Qiao received his B. Eng. in Polymer Engineering from the Donghua University in 1982 before completing his Ph.D. in synthetic organic chemistry at the University of Queensland in 1996. Since 2000, he has been the leader of the Polymer Science Group at the University of Melbourne. He is currently a Professor of Macromolecular Chemistry and Engineering at the Department of Chemical and Biomolecular Engineering. Since 2012, he has also been an Australian Research Council's professorial Future Fellow. His main research focuses on novel macromolecular architectures, nanostructured materials, soft tissue engineering, polymeric membranes, biomaterials and functional polymers for industrial applications.

Macromol. Rapid Commun. 2014, DOI: 10.1002/marc.201400080 © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Cyclodextrin-Based Supramolecular Assemblies and Hydrogels: Recent Advances and Future Perspectives

Macromolecular Rapid Communications www.mrc-journal.de

Figure 2. Graphical illustration of a polyrotaxane.

CD using spacer groups containing biologically cleavable linkages. The obtained constructs can potentially be internalized into cells via endocytosis, followed by drug release intracellularly resulting from the presence of suitable biological triggers; e) Core cross-linked star (CCS) polymers with polyrotaxane-based arms whereby α-CDs are threaded onto poly(ε-caprolactone) (PCL) arms and held in place by end-capping via click chemistry.[15] The resultant stars show a rigid core–shell structure attributed to the considerable steric crowding between the CDthreaded arms.[15] Similarly, high-density brush polymers with polyrotaxane grafts have also been prepared;[16] f) Degradable capsules composed of cross-linked α-CD/ PEG polyrotaxanes with alkyne end groups, prepared using sacrificial silica colloidal templates.[17] Utilizing click chemistry, PEG chains were attached onto the periphery of the polyrotaxane capsules to confer biocompatibility, while cystamine was employed to cross-link the polyrotaxanes through their CDs.[17] Covalent incorporation of doxorubicin (DOX) via the hydroxyl groups of the CDs and subsequent release upon contact with the reducing agent glutathione, demonstrated the potential of this system as a therapeutic delivery system.[17]

α-CD-based inclusion complexation with poly(ethylene glycol) (PEG) to yield crystalline complexes was first discovered and elucidated by Harada and co-workers in 1990.[4] The basis of this noncovalent interaction was attributed to three main factors, namely, a dimensional fit between the interior cavity of the CD and the crosssectional area of the polymer, hydrogen bonding between the two and the subsequent hydrogen bonding between adjacent CDs. Through 1H NMR spectroscopy studies it was further determined that this interaction was based on two ethylene glycol units of the PEG main chain complexing with one α-CD moiety.[4] Soon after this discovery, polyrotaxanes (also known as “molecular necklaces”) were obtained by threading numerous CDs onto 2.1. Functional Nanostructures from Cyclodextrin a polymeric backbone and subsequently end-capping the Host–Guest Interactions polymer with bulky end groups (Figure 2).[5,6] This allowed the cyclic rotas (i.e., CDs) to gain both rotational and transAside from polyrotaxane-based architectures, vesicles, lational freedom about the polymeric backbone without micelles, dendrimers, and star polymers can also be complex disassociation occurring.[2] Since these initial reports a variety of sophisticated multi-component, supramolecular assemblies have been fabricated from polyrotaxanes[7] and polyrotaxane-like structures (Figure 3), including: a) Molecular tubes formed from polyrotaxanes where CDs are covalently bound together via short crosslinkers and the polyrotaxane is subsequently disassociated via cleavage of the bulky end groups;[8] b) Polyrotaxanes consisting of alternating α,β-CD derivatives wherein a guest molecule tethered onto α-CD competitively forms a complex with the β-CD derivative and vice versa;[9] c) Poly(catenane)s fabricated via photoirradiation of anthracene-terminated polyrotaxanes, affording a reversible cyclic structure that can undergo transformation back into its linear polyrotaxane counterparts via application of either heat or UV light;[10] d) DrugFigure 3. Illustration of multi-component supramolecular assemblies based on polydelivery vehicles,[11–14] whereby drugs rotaxanes and polyrotaxane-like structures: a) molecular tubes; b) alternating α,β-CD are incorporated into the polyrotaxane suprapolymers; c) poly(catenane)s; d) drug delivery vehicles; e) core cross-linked star structure via the hydroxyl groups of (CCS) polymers, and; f) degradable capsules.




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fabricated through CD host–guest interactions. These constructs have been explored in various applications including controlled drug delivery systems, nanocarriers, catalysis, molecular recognition, and surface modification. As a number of excellent reviews covering these macromolecular structures have been published in recent years,[12,18–22] the following section will only highlight several prominent examples. 2.2.1. Vesicles and Micelles Driven by Host–Guest Interactions The assembly of amphiphilic macromolecules into reversible, higher-order morphologies like vesicles and micelles is a highly controllable process capable of generating promising functional nanomaterials.[23] The amphiphilicity of these assemblies can be easily tailored by variation of several parameters (e.g., block length and inherent hydrophobicity of the polymers used), and various stimuli including light, redox, and pH can be used to initiate reversible conformational changes from higher-order (i.e., supramolecular assemblies) to lower-order assemblies and vice versa.[23] Incorporation of CDs onto polymeric systems containing a guest moiety can result in a change of overall macromolecular amphiphilicity wherein, the part containing the CDs becomes more hydrophilic in nature. The location and distribution of where these noncovalent interactions can be imparted vary and examples are shown in Figure 4.[24–27] For example, block copolymers consisting poly(oligo(ethylene glycol) acrylate) and alkyne-functionalized poly(N-isopropylacrylamide) (PNIPAM)-based blocks were synthesized via reversible addition–fragmentation chain transfer (RAFT) polymerization.[28] The copolymers were conjugated with azido-β-CD via click chemistry and

Figure 4. Illustration of CD-based amphiphilic macromolecules where amphiphilicity can be directed onto a) block copolymers or b) alternating copolymers.

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Figure 5. Synthesis of graft-like complex through cyclodextrin host–guest chemistry and their subsequent self-assembly to afford multicore and core–shell micelles.[29]

subsequently loaded with albendazole (ABZ), a promising anti-cancer agent, through host–guest interactions. Above the lower critical solution temperature (LCST) of PNIPAM, the amphiphilic block copolymers self-assembled into micelles with cores containing CD-ABZ inclusion complexes,[28] which exhibited high toxicity (i.e., up to 90% cell death) towards ovarian cancer cells.[28] In addition, noncovalent host–guest chemistry can be used to introduce amphiphilicity into random copolymers bearing pendent CD moieties. For example, adamantane (Ad) end-functionalized PCL was used to prepare noncovalent graft copolymers through inclusion complexation with pendent β-CD moieties on a poly(vinyl pyrrolidone) (PVP)-based copolymer (Figure 5).[29] It was found that upon application of a selective solvent for the PVP graft backbone, micelles were formed whereby the resulting micelle morphology was dependent on the way in which the non-solvent (i.e., H2O) for the PCL grafts was introduced (i.e., drop-wise addition to or dialysis against water) (Figure 5).[29]






Figure 7. Graphical illustration showing the self-assembly of CD dimer amphiphiles based on noncovalent interactions into micelles in aqueous solutions.[36]

Figure 6. Graphical illustration of the self-assembly of block copolymers in aqueous solutions into core–shell micelles, and their disassembly and release of doxorubicin triggered by the addition of β-CD.[31]

CD-based host–guest interactions do not only provide a mechanism for micelle formation,[30] but can also be applied as an external cue to disassemble micelles via competitive host–guest interactions.[31] For example, Zhang and co-workers synthesized a H-shaped block copolymer composed of a central PEG block and four poly(L-lysine) (PL)-based arms (two at either end of the PEG block) with pendent Ad moieties (Figure 6).[31] In aqueous solutions, the block copolymers self-assembled into core–shell micelles, which could be loaded with the anti-cancer drug DOX. When exposed to β-CD, the micelles underwent triggered disassembly as a result of the formation of inclusion complexes between the CD and pendent Ad groups in the hydrophobic micelle core, simultaneously resulting in the release of DOX.[31] Although, cytotoxicity studies indicated that the unloaded micelles were internalized into HeLa cells with


minimal toxicity, no studies were conducted to assess the possible CD-induced disassembly in cells, which would be conceivably more difficult, particularly given the known toxicity of β-CD resulting from their ability to extract cholesterol.[28,32–35] Site-specific targeted delivery to tumor cells has also been reported using CD-based supramolecular chemistry.[36] Dimers consisting of α-CD and β-CD covalently linked to each other were used to prepare an amphiphilic copolymer, wherein a hydrophilic PNIPAM end functionalized with phenyl groups and a hydrophobic PCL end functionalized with Ad formed inclusion complexes with α-CD and β-CD, respectively (Figure 7).[36] At physiological pH (7.4), the supramolecular amphiphiles formed micelles. Site-specific internalization was incorporated into these systems via conjugation of Arg–Lys– Asp (RGD) sequences onto the PNIPAM, along with PEG chains via Schiff-base linkages.[36] Whereas the grafted PEG chains prevented interaction of the RGD ligands with normal cells, the reduced pH of the tumor tissue results in cleavage of the PEG chains and allowed the deshielded RGD sequences to target cancer cells in the vicinity. The micelles synthesized in the majority of these studies utilize the association between β-CD and Ad



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derivatives as a result of the strong stability (i.e., association constant, K = 35 × 103 L mol−1). This high association combined with the hydrophobicity of the polymers leads to relatively stable micelles for the given applications.[37] 2.2.2. Star Polymers Driven by Host–Guest Interactions Besides micelles and vesicles, star polymer architectures have also been assembled via CD-based host–guest interactions.[38,39] This concept was recently demonstrated by Ritter et al.,[38] who synthesized star polymers utilizing CD-based inclusion complexation. The three-arm star polymers were prepared using a three-pronged β-CD as the core and Ad end-functionalized polyacrylamide as the arms (Figure 8a).[38] Similarly, supramolecular constructs were prepared through the inclusion complexation of Ad midchain-functionalized poly(dimethylacrylamide) (PDMAAm) with β-CD end-functionalized poly(diethylacrylamide), a thermoresponsive polymer. The resulting miktoarm star morphologies were used to prepare micelles in water (Figure 8b)[39] by heating above the LCST (i.e., 44–48 °C) of the PDMAAm. Formation of aggregates with an average Dh of 118 nm were attributed to the hydrophobic block becoming insoluble at elevated temperatures resulting in micelle formation. Heating the constructs further leads to aggregate formation (Dh > 1000 nm).[39]

3. Cyclodextrin-Based Hydrogel Networks Polymeric hydrogel networks are cross-linked hydrophilic structures,[40–43] whose swellability depends on the cross-linking density and the inherent hydrophilicity of the building blocks. As a result of their compositional flexibility, tailorability, and structural similarity to the human body’s extracellular matrix, hydrogels have been employed for a wide range of life science (i.e., tissue engineering, sustained and controlled drug delivery) and biotechnology (i.e., diagnostics and separation technologies) applications.[40–43] Hydrogels containing CD moieties and their derivatives are of great interest as a result of the versatile nature of CD, including its facile functionalization (through the many primary and secondary hydroxyl groups), the inherent biocompatibility of such hydrogels, and their ability to form physical inclusion complexes with guest molecules and polymers.[1–3] As a result of these attributes, CD and its derivatives have been used as building blocks to synthesize hydrogel networks for a wide range of applications. CD-based hydrogels can be classified according to their cross-linking mechanism, including conventional covalent and physical interactions (Figure 9a,b, respectively), and most recently via a new class of cross-linking resulting in networks commonly referred to as sliding-ring (SR) hydrogels, which are topologically interlocked, thus resembling chain-links (Figure 9c). In this section, CD-based hydrogel systems using the aforementioned interactions will be discussed along with their potential applications. 3.1. Covalently Bound Cyclodextrin-Based Networks Covalently bound hydrogel networks based on CD have been prepared via many methods, including the use of di-functional cross-linkers (e.g., diisocyanates[1,44]), covalent linking of CD derivatives with functional polymers, and through the copolymerization of appropriate monomers with vinylic and acryloyl-functionalized CD. By using these approaches, networks have been obtained that can be applied to a wide range of applications, including separation and absorption technologies (i.e., chiral separation and absorption of heavy metal ions for pollutant capture and removal, respectively),[1,45,46] materials science,[47] soft contact lenses,[48,49] and sustained drug delivery systems.[50–56] This section gives a general overview of the progress of the respective fields by focusing primarily on recent examples in the literature. 3.1.1. Cross-Linking of Cyclodextrins via Functional Linkers

Figure 8. Graphical illustration of star polymers driven by host– guest interactions, including a) three-arm star polymers and b) micellar assembly driven by miktoarm star morphology.[38,39]

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CD-based covalent networks and polymers were originally investigated as column material for chromatographic






extended to high-performance capillary electrophoresis,[57] whereby β-CD was covalently embedded into dextran polymer gel networks and consequently applied to the chiral separation of peptides and small ions.[58] This ideology was further extrapolated for use within the pharmaceutical industry as drug deposits, whereby networks were fabricated through the cross-linking of CDs with epichlorohydrin.[1,59–61] Aside from epichlorohydrin, other functional linkers that have been used include diisocyanates,[1,44] anhydrides,[62,63] and functional polymers.[44,47,64] Recently, covalent CD-based polymeric networks synthesized via the cross-linking of diisocyanate-terminated PEG with β-CDs were shown to entrap metal ions for the fabrication of hybrid organic/inorganic materials displaying both soft and hard characteristics.[47] Reduction of the metal ions resulted in the formation of soft hydrogels studded with inorganic nanoparticles. Importantly, pre-encapsulation of the metal ions followed by reduction was shown to result in higher loadings and more uniform distributions of nanoparticles as compared to diffusion techniques used on preformed networks.[47] This facile fabrication technique provides a potential route towards hybrid soft/hard nanoparticle composites for future use in catalysis, sensing and electronics.[47] 3.1.2. Covalently Bound Networks Combining Cyclodextrin Derivatives and Polymers

Figure 9. Illustration of CD-based hydrogel networks synthesized via a) covalent interactions where the CDs act as cross-linkers, b) physical interactions via hydrogen bonding between neighboring CDs (upper) or via host–guest chemistry (lower), and c) via the topological interlocking of the gel components.

separations[1,45,46] and it was shown that aromatic amino acids could be simply separated from non-aromatic amino acids on the basis that the former forms inclusion complexes with CD.[46] The use of these systems was further


Facile chemical modification of both the primary and secondary hydroxyl groups of CDs provides access to multifunctional CDs. Using this as a platform, covalently bound hydrogel networks have been formed through the cross-linking of functionalized CD derivatives with suitably functionalized polymers. The resulting networks have been extensively studied for potential application to sustained drug release systems,[44,54,55,64,65] wherein the CDs moieties act as drug deposit sites. For example, β-CD/ PEG-based covalent hydrogels were obtained through the cross-linking of β-CD with diisocyanates and aminofunctionalized PEG.[54] Lysozyme, β-estradiol, and quinine were loaded into the hydrogels by swell embedding and release studies showed that lysozyme displayed faster release kinetics than the two hydrophobic drugs.[54] This difference in release kinetics was attributed to the nonspecific entrapment of lysozyme into the network, while β-estradiol and quinine formed inclusion complexes with the embedded CDs, leading to slower release rates.[54] This study demonstrates the potential of hydrogel networks conjugated with CD moieties to act as multifunctional drug delivery systems, in which both hydrophilic and hydrophobic molecules can be incorporated.[54] Furthermore, the rate of hydrophobic drug release was shown to be somewhat controllable, wherein higher CD/PEG molar ratios correlated to a slower rate of drug release.[54]



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of CD motives. This concept was shown where nanogels with high β-CD content were fabricated using a sixarm poly(propylene glycol)-block-poly(ethylene glycol) (PPG-b-PEG) star with terminal isocyanate groups via direct polyaddition in aqueous surfactant-free solutions (Figure 11),[66] noting that the PPG units of the star formed aggregates prior. The hydroxyl groups of β-CD were found to undergo preferential nucleophilic addition with the isocyanate groups on the star. Increasing the CD content within the system led to more stable nanogels with narrower size distributions as evaluated by dynamic light scattering measurements and scanning electron

Figure 10. Inclusion of ondansetron via cyclodextrin host–guest interactions within alginate-based hydrogel networks. Transfer of mechanical stress along the CDs confers release of the drug.[56]

Recently, the release of ondansetron, an anti-emetic drug used in cancer chemotherapy, from CD bound covalent networks was elegantly achieved through the simple application of a small external stress (e.g., mild compression by a patient’s hand). The alginate-based hydrogel networks were synthesized by the simple cross-linking of alginate chains with amino-functionalized β-CDs (Figure 10),[56] and used to form host–guest complexes with ondansetron.[56] Drug release upon application of stress was attributed to the external stress being transferred along the network, thereby causing distortion and/ or conformational restriction of the CD moieties, and in turn reducing the ability of the CD to form stable inclusion complexes with the drug.[56] Drug release systems using CDs have also been fabricated as nanogels, where their high surface area leads to higher drug encapsulation. Specific binding activity can also be introduced into these systems by incorporation

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Figure 11. One-pot synthesis of CD-based nanogels using CD and isocyanate-functionalized stars in aqueous media, and the subsequent inclusion of hydrophobic molecules.[66]






microscopy.[66] Owing to the high surface area, the nanogels swelled to four times their dry weight. Quantitative calculation of active CDs (i.e., available CDs for complexation) was achieved using a dye absorption method with phenolphthalein, which revealed that 60% were accessible.[66] 3.1.3. Covalently Bound Networks by Polymerization of Cyclodextrin Derivatives and Monomers Covalent networks containing CD derivatives have also been fabricated via conventional free radical polymeri zation[44,48–50,52,55,67,68] using suitably functionalized CD derivatives. Although mono-functionalization of CDs can be challenging as a result of the abundance of hydroxyl groups present on the exterior faces, when achieved, copolymerization of such mono-functional CD derivatives with acryloyl or vinyl monomers yields materials suitable as soft contact lenses that offer sustained release of various drugs. For example, eye drops doped with drugs are currently used to topically treat many ophthalmic diseases such as glaucoma. However, less than 1% of the applied drug is considered to be effective as the majority of the drug is almost immediately eliminated due to lacrimation, tear turnover, and drainage.[48] By covalently incorporating molecules like CD into hydrogel networks, the cavity of CD can act as a drug deposit, which allows for sustained drug release while the hydrogel itself acts as a protective layer against tear turnover.[48–50] For example, copolymerization of mono-functionalized β-CD methacrylate with 2-hydroxylethyl methacrylate and the tri-functional cross-linker, trimethylolpropane trimethacrylate, under conventional UV-initiated radical polymerization in concave molds provided facile access to hydrogels with appropriate shapes for use as contact lenses (Figure 12).[48] It was found that both the tensile strength and oxygen permeance of the hydrogel constructs increased with increasing β-CD content, which was attributed to the rigidity and large volume of the CD molecule reducing the flexibility of the polymer chains by forming interchain junctions. Puerarin, a drug commonly used in commercial eye drops was loaded into the hydrogel networks with loading efficiencies ranging from 7% to 23% (relative to the total amount of CD within the hydrogels).[48] Drug release from the preloaded contact lens was then tested in vivo in rabbits and compared to conventional eye drops, which revealed that the drug-loaded CD-based hydrogels provided a higher pre-corneal retention time and a higher drug bioavailability than the eye drops without eliciting any observable eye irritation.[48] Additionally, as a result of their good mechanical strength, it was suggested that the hydrogel constructs may be recyclable and suitable for daily wear.[48]


Figure 12. Synthesis of contact lenses with sustained drug release properties through the covalent incorporation of CD via conventional radical polymerization.[48]

Aside from drug delivery systems, CD-based hydrogels fabricated using conventional polymerization techniques have also been utilized as adsorbents for heavy metal ions. CDs are good candidates for these systems as a result of the presence of many hydroxyl groups that facilitate strong interactions with metal ions and their inherent biodegradability.[68] For example, Huang et al. fabricated CD-based hydrogels from β-CD, acrylic acid, and MBAAm via microwave irradiation.[68] The uptake and removal of heavy metal ions (i.e., Cd2+, Pb2+, and Cu2+) of the hydrogels was shown to be driven by an ion exchange process, whereby water and the metal ion are in competition for adsorption sites. The adsorption rate for the metal ions was shown to be fast, reaching equilibrium within 60–90 min. Furthermore, at pH 5 a higher loading of metal ions was observed relative to lower solution pH values (e.g., pH = 2), which was attributed to the higher proportion of negative charges at the surface of the hydrogel. Biodegradability tests were also conducted by incubating the hydrogels with various strains of algae at 30 °C. Results showed that G. trabeum was able to degrade up to 79.4% of the hydrogel after 21 d.[68] A series of CD-based hydrogel actuators has recently been developed by Harada et al., which display reversible contraction and expansion characteristics upon application of various stimuli, including alternating ultraviolet (UV) and visible (vis) irradiation, and the oxidation and reduction of metal complexes.[37,69] In both cases, the



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In comparison, when Fc and β–CD were incorporated, the expansion and retraction of the hydrogel could be controlled by a change in the oxidation state of the Fc leading to decomplexation and complexation of the supramolecular cross-links. For example, oxidation of the hydrogels with ceric ammonium results in formation Fc+ cations, leading to decomplexation and an increase in the size of the hydrogel (Figure 13b). Upon reduction, the hydrogels reverted to their original size.[37] Interestingly, the mechanical work done by hydrogel actuators upon expansion and reduction was also measured and found to increase as the amount of supramolecular cross-links within the networks increased.[37] 3.2. Physically Bound Hydrogel Networks Based on Cyclodextrin

Figure 13. a) Synthesis of hydrogel actuators based on cyclodextrin-based host–guest interactions. b) Reversible contraction and expansion controlled by alternating visible and ultraviolet light or reduction and oxidation.[37,69]

hydrogel networks were synthesized via conventional radical copolymerization protocols using acrylamide, an acrylamide CD monomer, an acrylamide-functionalized guest monomer, and an di-functional cross-linker, MBAAm (Figure 13a).[37,69] As a result of host–guest interactions between the CD monomers and guest monomers prior to cross-linking the hydrogel networks consist of both covalent and noncovalent supramolecular crosslinks (Figure 13b). The noncovalent nature of the supramolecular cross-links allowed for reversible macroscopic contraction and expansion of the hydrogels in response to certain stimuli (Figure 13b).[37,69] When azobenzene (AB) derivatives and α-CD were incorporated, the resulting hydrogels responded to light owing to the trans- to cisisomerization of the AB, which causes decomplexation of the supramolecular cross-links and allows the hydrogels to expand. Therefore, UV irradiation of the hydrogels leads to an increase in weight (124% relative to the initial weight), whereas continuous visible irradiation leads to reversion to the initial volume and weight (Figure 13b).[69]

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In addition to covalently cross-linked CD-based hydrogels, physically assembled networks based upon the supramolecular interaction of CDs with various molecules and polymers have been studied. As a result of the physical nature of the cross-linking points, the resulting functional materials generally possess responsive and reversible properties, which differ from their covalently cross-linked counterparts. Owing to these characteristics, physical hydrogels bound by CD host–guest interactions have found wide application, particularly in the field of biotechnology and materials science. Based upon the nature of crosslinking, CD-based physical hydrogels can be classified into two main categories. The first class involves the aggregation of polypseudorotaxanes (PPRXS) as a result of intermolecular hydrogen bonding between CDs on different polymer chains (Figure 14a).[70,71] The second class is mediated via host–guest interactions between CD-containing polymers and polymers that are functionalized with appropriate hydrophobic guests (Figure 14b–d). 3.2.1. Cyclodextrin-Based Physical Hydrogels Assembled via Microcrystalline Formation Physical hydrogel systems based upon the aggregation of PPRXs have attracted great interest as a result of their thermo-reversible thixotropic nature and biocompatibility, which allows them to serve as potential injectable drug delivery systems.[70–72] For this class of hydrogels network formation results from the microcrystalline formation of PPRXs (i.e., many CDs threaded onto a polymeric chain). This phenomenon was first reported in 1994 using high-molecular-weight PEG.[71,73] The formation of these hydrogels is based on a hierarchical self-assembly process beginning with the formation of PPRXS, whereby multiple CDs are threaded onto a polymeric chain.[70,71] The subsequent aggregation of the PPRXS (resulting from both inter and intramolecular hydrogen bonding between the CDs)






Figure 14. Illustration of physically bound hydrogel networks utilizing a) intermolecular hydrogen bonding between CDs or host– guest interactions where CDs are used as b) dimers, c) attached as pendent groups on polymers, or d) on the periphery of star polymers.

results in microcrystalline domains that hold the supramolecular hydrogel networks together (Figure 15).[70,71] In addition to the weak mechanical properties and rapid hydrogel dissociation, the use of high-molecularweight PEG (Mn = 10 kDa) within these systems may lead to difficulties in tissue engineering applications as a result of the size restriction of renal filtration.[71] Therefore, much effort has been devoted to address these deficiencies before any real world applications can proceed. In overcoming the issue of poor mechanical strength, various groups have incorporated hydrophobic segments onto the backbone,[74] side chain, or via the use of amphiphilic block copolymers.[75–78] Hydrophobic domains with integrated biodegradability can also be also incorporated via the use of polyesters, such as poly[(R)-3-hydroxybutyrate][79,80] and PCL.[77,81–83] Aside from using α-CD and its interaction with PEG (or its derivatives) physical hydrogel systems have also been fabricated using α-CD with cationic (e.g., poly(ethylene imine) and poly(lysine)),[84,85] α-CD with viologen-based polymers,[86] β-CD (and its derivatives) with poly(propylene glycol),[87] and γ-CD with PEG.[88,89] Through these approaches the resulting supramolecular systems were shown to possess sustained drug-release capabilities while maintaining their reversible sol–gel nature. The hydrophobic interactions

Figure 15. Synthesis of cyclodextrin-based supramolecular hydrogels using a) high-molecular-weight PEG, followed by b) the addition of a saturated aqueous solution of α-cyclodextrin resulting in polypseudorotaxane (PPRX) formation. c) Through hydrogen bonding microcrystalline domains are formed resulting in network formation.[71]


within the networks confer long-term sustained release of various drug molecules,[79,81,83,90] proteins,[74,88,91] and amino acids where loading of the payload could be implemented under mild conditions (i.e., physiological pH and room temperature) and prior to gelation, which is particularly advantageous in the field of tissue engineering. In addition to thermo-responsiveness,[76,84,85] pH-,[84,85,89,92] photo-,[93] and redox-responsiveness[91] have also been incorporated into these systems by careful selection of the polymers. Although these systems may serve as scaffolds for sustained release systems, their true potential is yet to be realized, with many reports still in the in vitro stage using (model) drugs and proteins.[72,74,78,79,90–92] Information regarding the implementation of these systems in vivo is limited with only preliminary results regarding cytotoxicity, cell viability, and basic release studies being reported.[81,88] For example, the in vivo release of insulinloaded γ-CD-PEG-based PPRX hydrogels subcutaneously injected into rats revealed that an increase in the amount of CD resulted in prolonged levels of insulin within the body.[88] Recently, supramolecular hydrogel systems have also been employed as injectable gene transfection agents, wherein sustained release of plasmid DNA (pDNA) was achieved.[82] Incorporation of such agents into hydrogel networks is appealing as the network itself can act as a localized depot allowing sustained systemic release, thereby circumventing repetitive single-dose administration. In addition, the hydrogel may also protect the DNA from degradation. Initially, a series of well-defined biodegradable triblock copolymers (i.e., poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly[2-(dimethylamino) ethylmethacrylate] (MEG-PCL-PDMAEMA)) was synthesized and subsequently shown to complex pDNA into polyplexes via electrostatic interactions with the cationic block (Figure 16).[82] The polyplexes were then incorporated into α-CD/PEG PPRX supramolecular hydrogels using a simple vial-titling method. Compared to a control prepared in the absence of the polyplex, the supramolecular polyplex hydrogel gelled significantly faster (i.e., up to 10 times faster) and possessed a higher mechanical strength (i.e., up to 12.4 times tougher). This behavior was attributed to the polyplexes acting as extra crosslink points, whereby the PEG arms at the periphery of the polyplexs also participated in inclusion complexation with α-CD. The DNA release kinetics of the hydrogels were studied in vitro via a hydrogel dissolution study. Whereas sustained release of DNA occurred for 5–6 d with the polyplex hydrogels, the control (free pDNA entrapped within α-CD/PEG hydrogel), only showed sustained release for up to 3 d. The prolonged release was attributed to the polyplexes acting as multi-arm cross-linking sites and providing better stability against dissolution.



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Figure 16. Synthesis of polyplex supramolecular hydrogels via the addition of PEG and α-CD.[82]

3.2.2. Cyclodextrin-Based Physical Hydrogels Assembled via Host–Guest Interactions Aside from utilizing the aggregation of CDs on polymer chains to yield microcrystalline domains, CD-based supramolecular physical hydrogels can also be obtained via host–guest interactions. A plethora of hydrogels have been synthesized through this mechanism using varying methods (Figure 14), including: b) the mixing of linear (or star shaped) polymers with guest moieties attached either on their side chain or ends with CD (derivatives) or CD dimers (or their higher order constructs);[94–98] c) the

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mixing of two linear polymeric chains having CDs and the appropriate guest attached onto their side chains, respectively,[99–101] and; d) through host–guest interactions whereby the periphery of star-shaped polymers are functionalized with CDs and their appropriate guests.[102–104] Stimuli-responsiveness has also been included into these systems by the employment of thermo-,[94,98,105] light-,[101,105–108] redox-[107,109,110] and pH-responsive[111] polymers and molecules, including PNIPAM,[94,98] AB derivatives,[101,105,106,108,112] Fc,[109,110] and diethylenetriamine,[111] respectively. The field of CD-based supramolecular hydrogels driven by host–guest chemistry is still in its infancy with many instances of sophisticated architectures being reported. Most proposed applications are focused on drug[113] and protein[101,103] release from the obtained constructs, although more recently self-healing[109,114] and elastomeric materials[115] were reported. Self-healing materials have attracted much attention over the past decade as a result of the vast improvement in their potential life-span. One approach to impart selfhealing properties to materials is to assemble them via noncovalent bonding. For example, Harada et al. fabricated a series of self-healing hydrogels based on CD host– guest interactions.[109,114] The supramolecular hydrogels were based upon poly(acrylic acid) (PAA) modified with β-CD (4–5 mol% of the acrylic acid repeat units) as the host polymer (PAA-CD) and PAA modified with Fc (2.7 mol% of the acrylic acid repeat units) was used as the guest polymer (PAA–Fc) (Figure 17a). Upon mixing an aqueous solution of the guest polymer with the host polymer (1:1 molar ratio) at a total of 2 wt%, an increase in solution viscosity followed by hydrogelation was observed. To clarify that gelation resulted from host–guest interactions between polymer bound β-CD and Fc, competitive binding species (i.e., an Ad derivative or free β-CD) were added to the hydrogels, which resulted in a transition from the gel state to a solution state. In addition, as variation in the redox potential of Fc affects inclusion complexation between Fc and β-CD, the authors investigated the effect of redox reagents on the sol–gel switching. As expected, the addition of an oxidant (i.e., NaCIO) led to a transition from the gel state to the sol state, whereas the continuous addition of a reducing agent (i.e., glutathione) led to reversion to the gel state (Figure 17b). Significantly, the hydrogels could be cut in half with a razor and then rejoined without defects, highlighting the large binding constants between CD and Fc (Figure 17c). This same concept was further extended in later papers by the same group whereby CD acrylamide monomers were copolymerized with either n-butyl acrylate (nBuAc) or Ad acrylamide monomers via conventional radical techniques to afford noncovalent hydrogels.[114] The mechanical strength of the supramolecular hydrogels before and after re-adhesion was shown to be dependent






shape-memory characteristics. Through a creep meter test, it was shown that the breaking strain of the hydrogels is related to the number of inclusion complexes, with more host–guest complexes resulting in greater elastic properties. In addition, the hydrogels were shown to possess shape-memory behavior, reverting back to their initial strain when stretched to 180% repeated over several cycles.[115] In order to prepare composite materials with novel properties, various groups have fabricated CD-based supramolecular hydrogels that incorporate inorganic components (i.e., including quantum dots,[116–119] graphene sheets,[120] carbon nanotubes,[121] and silica particles)[122,123] into their networks. For example, Jiang and Chen incorporated CdS quantum dots (QDs) into supramolecular hydrogels via coating the QDs with β-CDs.[116] Thermogravimetric analysis revealed that the organic (CD) content of the obtained QDs was 48% by mass. Subsequently, amphiphilic di-block copolymers where synthesized using an azo-functionalized chain transfer agent that initiated the polymerization of dimethylacrylamide followed by N-isopropylacrylamide (NIPAM) (Figure 18).[116] Upon complexation with the functionalized QDs via the inclusion of the azo end groups with CD, supramolecular constructs were obtained wherein the inorganic core was noncovalently attached to the organic

Figure 17. Synthesis of redox-responsive self-healing hydrogels through CD-based host–guest inclusion complexes prepared from a) CD and ferrocene-functionalized PAA derivatives. Illustrations showing b) the reversibility of the system and structures obtained after oxidation and reduction and c) the ability of the system to undergo self-healing after fracture.[109]

on the association contents (Ka) between the hosts and guests. Through dynamic mechanical testing it was shown that elastic modulus of the β-CD/Ad hydrogels were 100–1000 times larger than that of the α-CD nBuAc gel. This was attributed to a larger Ka value of 1500 M−1 for the β-CD/Ad interaction in comparison to α-CD with nBu group (Ka = 57 M−1). Following scission of the hydrogels, the adhesive strength at the rupture point upon rejoining, after 24 h of standing, was measured. Whereas the β-CD/Ad hydrogels could reach 99% of the initial strength, the α-CD/nBuAc gel could only reach 74% of its initial strength, reconfirming the importance of Ka values. Harada et al. have also introduced highly elastomeric hydrogels prepared via CD host–guest interactions.[115] Polymerization of inclusion complexes (i.e., β-CD and Ad monomers) in aqueous media yielded supramolecular hydrogels possessing both highly elastic and


Figure 18. Graphical illustration showing hydrogel formation driven by cyclodextrin host–guest chemistry and thermally induced aggregation. Decomplexation of the host–guest interaction allows for the disassociation of the hydrogel.[116]



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polymeric shell. When the temperature was increased to above the LCST of PNIPAM, hydrogels were obtained as a result of the aggregation of the PNIPAM blocks. The hydrogels possessed independent dual responsiveness wherein gel-to-sol transitions could be triggered by decreasing the temperature below the LCST of PNIPAM or through the addition of a competitive guest for CD, namely Ad (Figure 18).[116] Using the same platform, the group further showed redox-responsive hydrogels could also be obtained using the interaction between Fc and β-CD.[117] Hybrid hydrogels with inorganic and organic components not only show enhanced mechanical stability[122] in comparison to their pure organic counterparts, but also more importantly, may lead to new avenues of research in fluorescence sensing for imaging,[124] photovoltaic systems, and nanocarriers. To date, only a few studies have demonstrated application of hybrid hydrogel systems.[118,123] For example, Kim et al. fabricated novel CD-covered nanocontainer hydrogels that can release guest molecules upon photoirradiation as a result of the presence of a photocleavable linker.[123] The system consists of mesoporous silica particles (Si-MP) that acts as a reservoir for the molecule, calcein. Initially, carboxylic groups were introduced onto the Si-MPs surface via silanization with 3-aminopropyltriethoxysilane followed by reaction with succinic anhydride. The photocleavable linker, an o-nitrobenzyl ester derivative, was then attached via coupling chemistry. Calcein was then loaded into the pores of the nanocontainers prior to the attachment of mono-azido β-CD onto the photocleavable group via click chemistry (Figure 19).[123] The entrapment and subsequent release of calcein was monitored by fluorescence measurements. Whereas very weak fluorescence intensity was observed in the dark as a result of the pore entrance being blocked by CD, UV irradiation resulted in photolysis of the photocleavable group and a significant increase in the fluorescence intensity resulting from the release of calcein. Using the photoresponsive nanocarriers, the authors subsequently fabricated photoresponsive hydrogels via host–guest interactions between the silica surface anchored β-CDs and a six-arm PEG star with dodecyl end groups, which acts as a cross-linker, joining multiple silica particles together (Figure 19). The addition of a competitive host (i.e., α-CD) and UV irradiation resulted in disassembly of the hydrogel and an increase in fluorescence intensity, indicative of calcein release. This system displays promising potential for sustained and localized on-demand release applications.

Figure 19. Illustration of photo-induced release of calcein from silica-based nanocarriers, and hydrogel formation upon the addition of a six-arm poly(ethylene glycol). Hydrogel disassembly can be achieved upon the addition of free α-CD.[123]

differ from conventional methods such as physical and chemical cross-links. Specifically, CDs can be incorporated into networks to fabricate unique materials referred to as SR networks. SR networks were first postulated by De Gennes in 1999,[125] who hypothesized that networks with enhanced flexibility and swellability (upon application of low stresses) could be fabricated if the slip-link model was applied. It was suggested that this phenomenon could be conceptually achieved if negatively charged chains were mixed with multi-functional cationic metal (M) crosslinkers to generate networks (Figure 20), and upon application of stress the anionic chains could simply slide along the cationic charges without energy expense, so long

3.3. Sliding-Ring Hydrogel Systems Based on Cyclodextrin Recently, CDs have been used to synthesize hydrogel networks using innovative cross-linking mechanisms that

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Figure 20. Conceptual illustration of the sliding-ring networks based upon the slip-link model postulated by De Gennes using multi-functional cationic cross-linkers and anionic chains.[125]






as the number of interactions between the components remains constant.[125] This concept was experimentally demonstrated by Okumura and Ito using CD-based polyrotaxanes.[126,127] Pure SR networks were obtained via the chemical crosslinking of polyrotaxanes consisting of many α-CDs threaded onto a high-molecular-weight PEG chain, which was end-capped using bulky end-groups. By chemically cross-linking the CDs on different polyrotaxanes network formation was achieved. The resultant networks are not based upon chemical cross-links, nor do they resemble physical networks. Instead, they are topologically interlocked by “figure-of-eight” CD cross-links.[126,127] For SR networks, the cross-link points possess translational freedom about the polymer chain, but are prevented from disassociation via bulky end groups.[126,127] Therefore, when tension is imparted on these networks, the force is distributed homogeneously across the whole network by movement of the CDs (Figure 21a).[127] This differs from conventional chemical networks, whereby any tension that is imparted onto the network cannot be equalized as a result of the static nature of the cross-link points (Figure 21b).[127] Furthermore, it was shown that the elasticity of the SR hydrogels can be tuned by controlling the extent of cross-linking between the CDs and the inclusion ratio (i.e., number of CDs per PEG chain).[128] Owing to their enhanced elasticity, SR networks have great

Figure 21. Illustration showing a) sliding-ring and b) conventional chemical networks before and during tensile deformation.[126]


potential for various biomedical applications including soft contact lenses, and artificial blood vessels and skin.[127,129,130] Since the inception of SR networks, several groups have reported the functionalization of these constructs through modification of the CD moieties,[131–134] by changing the components of the polyrotaxanes,[135,136] or by using templates.[137] For example, photoresponsive SR networks were obtained by conjugating azobenzene derivatives onto CDs via their hydroxyl groups. Owing to the conjugated photoisomerizable moieties, the networks exhibited reversible expansion and contraction upon application of alternating UV–vis as a result of the cis-to-trans isomerism of the azobenzene moieties. This phenomena were attributed to the conformational size differences between the cis- and trans-isomer, with the cis-conformation being sterically larger.[131] Similarly, SR films displaying highly elastomeric characteristics have been prepared from PCL grafted polyrotaxanes (Figure 22). The PCL grafted polyrotaxanes where prepared via ringopening polymerization of ε-caprolactone initiated by the hydroxyl groups of the CD moieties of the polyrotaxanes, and subsequently cross-linked using hexamethylene diisocyanate.[134] Supramolecular polypseudorotaxane-based organogels were fabricated in a one-pot approach via copper-catalyzed azide–alkyne cycloaddition (CuAAC) click chemistry using propargyl-functionalized PCL and mono azido β-CD.[138] Network formation was achieved through the simultaneous formation of PPRXS and cross-linking. As a result of the one-pot nature of the reaction, it is expected that the networks contain both SR cross-links and branching points were CDs are attached onto the PCL side chains (resulting from the reversible nature of inclusion complexation).[138] As the major network component PCL is not water soluble, the organogels were only swellable in organic solvents such as dimethyl sulfoxide and dimethylformamide.[138] Although many studies have introduced functionality into SR hydrogels, very few novel approaches towards their synthesis have been reported since their introduction. Traditionally the synthesis of SR networks involves numerous isolation and purification steps and requires the use of excessive amounts of CD.[126–128] The general procedure for the synthesis of SR networks involves firstly polypseudorotaxane formation via the threading of many α-CDs onto a PEG backbone, which then precipitates from solution as a result of extensive hydrogen-bonding between the CDs (Figure 23). Following isolation of this precipitate from excess CD, the PPRXS are end-capped by redissolving the assembly in a suitable solvent and attaching bulky end groups to prevent dissociation of the CDs, thereby affording polyrotaxanes. After further purification and isolation, intermolecular cross-linking of the



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Figure 23. Synthesis of sliding-ring hydrogel networks via the cross-linking of preformed polyrotaxanes.

our group has synthesized hybrid SR hydrogel networks (Figure 24)[139] in a one-pot, two-step CuAAC click-mediated approach using α,ω-dialkyne PEG and azido-functionalized α-CD (in a 1:1 mole ratio), wherein the CD acts as both the cross-link point and the end-capping agent, with the aim of simultaneously forming polyrotaxanes and SR cross-links. As a result of the one-pot approach used, the resultant networks composed of a combination of both covalent and SR cross-link points. The extent

Figure 22. Illustration showing the synthesis of PCL graft polyrotaxanes and the resulting networks after cross-linking.[134]

hydroxyl groups of CDs on different polyrotaxanes results in the formation of figure-of-eight cross-links and hence network formation. To date, only a couple of one-pot methods for the synthesis of SR hydrogels have been reported, which highlights the difficulty of in situ polyrotaxane formation and cross-linking as a result of polyrotaxane solubility and excess free CD. In an attempt to simplify the methodology used to synthesize SR hydrogel networks with high elasticity,

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Figure 24. Graphical illustration of the synthesis of hybrid sliding-ring and covalent hydrogels in a one-pot approach.[139] Reproduced with permission. Copyright 2013, The Royal Society of Chemistry.






of inclusion complexation and the ratio of SR to covalent cross-links within the networks was shown to be dependent on the concentration of the precursors and also the curing temperature.[139] The resultant hydrogel networks are potentially capable of supporting post-functionalization with various (bio)molecules or therapeutics through utilization of any remaining azide groups on the CD moieties. Furthermore, cytotoxicity studies revealed that the hydrogels did not impede cell growth and demonstrated negligible toxicity.

4. Future Perspective As a result of the reversible inclusion of CDs with guest molecules and polymers, CD-based interactions offer a route towards the synthesis of highly complex and sophisticated supramolecular structures and hydrogels with great potential for a wide range of applications. Thus far, the breadth of the study in this field has mainly focused on preparing hydrogel networks for sustained drug release. Furthermore, as a result of the reversibility of CD-based host–guest interactions, it is also well documented that their resulting hydrogel networks can be rendered injectable and therefore, potentially applied as in situ hydrogel systems. Although many studies have focused on preparing CD-based hydrogels (and supramolecular structures), the implementation of these constructs towards tackling specific real world issues is still in its infancy, with much research simply citing basic in vitro studies. It is expected that as the field matures various complications will become apparent (e.g., unforseen and detrimental interactions, dilution within the body, and other environmental factors), and need to be addressed to drive advances in CD-based systems. Aside from drug delivery applications, supramolecular hydrogels based on CD have recently been applied for the synthesis of intelligent systems including self-healing, actuator, elastomeric, and hybrid organic/inorganic materials. The incorporation of stimuli-responsive molecules into these networks allows for advanced systems that can react upon application of certain stimuli. As a result of the wide range of methods and approaches available for the synthesis of CD-based networks and strong reversible binding ability of CD, it is expected that these networks will play a major role in the development of the next generation of advanced materials. It is anticipated that the high level of academic research in this area will lead to significant advances in the areas of tissue engineering, waste water treatment, remotely controlled actuators, molecular machines, and (bio)sensors. Received: February 5, 2014; Revised: March Published online: ; DOI: 10.1002/marc.201400080


7,

2014;

Keywords: cyclodextrin; host–guest supramolecular chemistry

chemistry;

hydrogels;

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