Photoresponsive hydrogels for biomedical applications

Advanced Drug Delivery Reviews 63 (2011) 1257–1266

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Advanced Drug Delivery Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Photoresponsive hydrogels for biomedical applications☆ Itsuro Tomatsu, Ke Peng, Alexander Kros ⁎ Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands

a r t i c l e

i n f o

Article history: Received 11 October 2010 Accepted 20 June 2011 Available online 2 July 2011 Keywords: Hydrogel Photoresponsiveness Drug release Cell-culturing

a b s t r a c t Hydrogels are soft materials composed of a three-dimensional network which contain a high percentage of water similar to body tissue and are therefore regarded as a biocompatible material. Hydrogels have various potential applications in the biomedical field such as drug delivery and as scaffold for tissue engineering. Control over the physical properties of a hydrogel by an external stimulus is highly desirable and is therefore actively studied. Light is a particularly interesting stimulus to manipulate the properties of a hydrogel as it is a remote stimulus that can be controlled spatially and temporally with great ease and convenience. Therefore in recent years photoresponsive hydrogels have been investigated as an emerging biomaterial. Here we will review recent developments and discuss these new materials, and their applications in the biomedical field. © 2011 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photoresponsive groups . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Photoisomerization . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Photocleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Photodimerization . . . . . . . . . . . . . . . . . . . . . . . . . 3. Photoresponsive hydrogels . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Hydrogels modified with photoresponsive groups . . . . . . . . . . 3.2. Polymers crosslinked by a photoresponsive supramolecular assembly. 3.3. Photoresponsive hydrogel formed by low-molecular-weight gelators . 4. Biomedical applications of photoresponsive hydrogels . . . . . . . . . . . 4.1. Drug release from photoresponsive hydrogels . . . . . . . . . . . . 4.2. Photoresponsive hydrogels as a matrix for cell-culturing . . . . . . . 5. Conclusion and outlook. . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Hydrogels are soft materials composed of an extended polymeric 3-D network and containing high percentage of water, which can hold their shapes but still can show deformability. Since a hydrogel has structural similarities to the body tissues, it has been widely used as a biomaterial in a diverse range of applications [1–5]. For example, hydrogel-based drug delivery systems are of great interest since they can be easily modified in order to tune their char☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Hybrid Nanostructures for Diagnostics and Therapeutics”. ⁎ Corresponding author. Fax: + 31 71 527 4397. E-mail address: [email protected] (A. Kros). 0169-409X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2011.06.009

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acteristics and can lead to targeted delivery, extension of circulation time, and reduction of toxicity and side effects. Drug molecules are often physically entrapped in the network and are released from the hydrogel matrix by diffusion, which can be adjusted by changing or can be induced by erosion of the mesh of the network and/or their affinity to the drug [6,7]. Furthermore, hydrogels can be an excellent carrier not only for stable low-molecular-weight drugs but also for fragile bioactive macromolecules including proteins. As hydrogels contain large amounts of water in the polymer network, it allows for the retention of the activity of proteins in the protective polymer network and prevents them from denaturation. Thus hydrogels are regarded as an ideal material to store and deliver proteins [8]. To advance hydrogel-based biomaterials, a wide variety of stimuliresponsive hydrogels have been developed to control their properties

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with external stimuli (e.g. cross-link density, hydrophobicity, swelling rate, permeability, degradability and mechanical strength) [9]. These stimuli-responsive hydrogels are potentially beneficial for a diverse range of biotechnology because the properties can be changed by a stimulus at the desired point and time. So far, a large variety of stimuli-responsive hydrogel systems have been developed, which can respond to temperature, pH, light, and other stimuli. Among these stimuli, light is a particularly interesting option as it is a remote stimulus that can be controlled both spatially and temporally with great ease and convenience [10–17]. In fact various light sensitive drug delivery systems have been developed such as photoresponsive prodrugs [18,19] and photoresponsive drug carriers in diverse form including vesicles [20,21], nanoparticles [22–24], nanofibers [25], and polymer materials [26–30]. In this review, we will provide an overview of recent developments on the design of photoresponsive hydrogel systems. In particular, we are going to focus on hydrogel systems that can show gel-to-sol transition by light irradiation, since the control of the erosion of polymeric network is particularly interesting for (bio) technology related applications including development of drug delivering and tissue engineering. We will start with a brief summary of photoresponsive elements, followed by the section on recent developments of photoresponsive hydrogels and their applications as drug compound release systems and cell-culturing matrices as remarkable examples. 2. Photoresponsive groups Photoresponsive hydrogels typically consist of a polymeric network and a photoreactive moiety, usually a photochromic chromophore as the functional part. The optical signal is first captured by the photochromic molecules [31,32]. Next the chromophores in the photoreceptor convert the photoirradiation to a chemical signal through a photoreaction such as isomerization, cleavage and dimerization. The latter signal is transferred to the functional part of hydrogel and controls its properties. The change of the chromophores upon photoirradiation strongly depends on their molecular structures and as a result thereof the required irradiation also varies (Table 1). In this section we will briefly overview photochromic moieties often used in photoresponsive hydrogel systems. Three categories of light-induced reactions can be distinguished; photoisomerization, photocleavage and photodimerization. Some photoreactions are reversible and can be repeated several times, in which the reverse reaction occurs under photoirradiation with a different wavelength or upon other stimuli such as temperature or catalytic reagents (Fig. 1). 2.1. Photoisomerization Photoisomerization processes are often reversible and repeatable. This property makes the photoreactive group attractive and they are used in diverse form to functionalize hydrogel in broad range of applications. In this subsection we summarize the most common moieties. The azobenzene moiety is perhaps the most known compound in this category, which can be isomerized from the E form (so called trans form) to the Z form (so called cis form) by UV irradiation and back to the original form by visible light irradiation or heating [33,34]. When it is in cis configuration, it shows higher polarity than in trans, which can be used to control the hydrophobic interactions [35,36]. This phenomenon was already used to construct a photoresponsive hydrogel system in 1967 [37]. Besides a change in the polarity, a change in conformation of the azobenzene can induce steric hindrance for stacking or complex formation. Thus azobenzene moieties have been used in diverse form to modify hydrogels [38–40], and also supramolecular systems based on peptides [41,42], oligonucleotides [43,44], and complexations with cyclodextrins [45–53] or bovine serum albumin [54].

Table 1 Typical examples of photoreactions. Photoreactive group • Photoisomerization 4-methacryloyloxyazobenzene polymer 4-((4-methacryloyloxy)phenylazo) benzenesulfonic acid polymer 1-(p-(phenylazo)benzyl)pyridinium bromide Poly(4-phenylazomaleinanil-co-4vinylpyridine) 12-aminoundecylamido-4phenylazobenzene amide 2-(4-phenylazophenoxy)ethanol ester Azobenzene-trimethylammonium bromide surfactant Bis(phenylalanine) maleic acid Fumaric amide o-methoxycinnamic acid Acrylated Spirobenzopyran polymer Spironaphthoxazine-methyacryloyl polymer

• Photocleavage o-nitrobenzyl acrylate polymer 4,5-Dimethoxy-2-nitrobenzyl ester 4-(4-(1-chloroethyl)-2-methoxy-5nitrophenoxy)butanate ester

Reaction

Irradiation wavelength

Reference

Trans to cis

366 nm

[117]

Trans to cis

353 nm

[136]

Cis to trans Trans to cis

440 nm 365 nm

[52]


435 nm b 360 nm

[142]


N 440 nm 365 nm

[54]

Cis to trans Trans to cis Cis to trans Trans to cis

436 nm 355 nm 450 nm 320 nm

[116]

Cis to trans Cis to trans Trans to cis Trans to cis Open to closed Closed to open

N 400 nm N 330 nm 266 nm b 400 nm 436 nm 400 - 440 nm 365 nm

[123] [126] [130] [65] [62] [69]

Open to closed

N 510 nm

Cleavage Cleavagea Cleavageb Cleavagea

365 nm 350 nm 750 nm 365, 405, 436 nm 730, 810, 872 nm 365, 405, 436 nm

Cleavageb 4-(4-(1-((2-(methacryloyloxy)ethyl 6-Chloro-7-hydroxycoumarin-3carboxyl)oxy)ethyl)-2-methoxy-5nitrophenoxy)butanate ester

Cleavagea

Cleavageb bis(4-(dimethylamino)phenyl)(4vinylphenyl)methylelu cocyanide polymer diphenyliodonium-2-carboxylate monohydrate • Photodimerizarion 4-methyl-(7-(methacryloyl)oxyethyloxy)coumarin polymer poly(N-( (7-coumaryloxy)acetyl)ethylenimine) Cinnamylidene acetate ester Nitrocinnamate ester Poly(3,4-dihydroxycinnamic acid-co-4-hydroxycinnamic acid) 2-Anthracenecarbonyl ester 9-Anthracenecarbonyl ester

• Photothermal effect Copper chlorophyllin Malachite green isothiocyanate Gold nanorods Singlewalled nanocarbons a b

Via single-photon process. Via two-photon process.

[53]

[76] [70] [78]

[78]

Cleavage

730, 810, 872 nm b 254 nm

[82]

Cleavage

280 - 400 nm

[86]

Dimerization

N 310 nm

[90]

Cleavage Dimerization

b 260 nm N 300 nm

[88]

Cleavage Dimerization Cleavage Dimerization Cleavage Dimerization

253 nm 300–400 nm 254 nm 365 nm 254 nm N 280 nm

Dimerization Dimerization Cleavage

N 300 nm 365 nm 254 nm

[99] [97]

488 nm 632.8 nm 810 nm 1064 nm 1064 nm

[102] [104] [105] [107] [113]

[93] [95] [98]


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improve the efficiency for two-photon degradation, coumarin fluorophore has been coupled with o-nitrobenzylether moiety [78]. Since the two-photon process can be achieved with near-infrared (NIR) radiation which is less absorbed by the living tissues than UV radiations, it is beneficial for in vivo applications. Triphenylmethane derivatives dissociate into ion pairs under irradiation, producing intensely colored triphenylmethyl cations which can be thermally recombined with the counter anions [79]. Thus triphenylmethane derivatives act as reversibly ionizable groups by photoirradiation [80], and have been used to control the swelling property of hydrogels [81–84]. Photolysis of azosulfonate [85], diphenyliodonium-2-carboxylate [86], and pyrenylmethyl ester [87] have also been used in the related fields. Thus these moieties can also be applicable for photoresponsive hydrogel systems. 2.3. Photodimerization The coumarin group has been used as a reversible crosslinking point; Chujo et al. used the photodimerization of coumarin groups to induce gelation, and the reverse reaction photocleavage to control the crosslink density [88]. In this way, swelling properties of hydrogels can be regulated [89–91]. Other photodimerization processes based on cinnamylidene acetate [92–94], nitrocinnamate [95,96], anthracene [97], and poly(cinnamic acid) [98] have also been used for hydrogel formation as photoreversible crosslinking points. Photodimerization of anthracene moieties have also been used to induce gel-to-sol transition of a dendron based low-molecular-weight hydrogelator upon UV irradiation as the resulting dimers prevents interaction between the gelators [99]. Fig. 1. Representative photoactive groups used for construction of photoresponsive hydrogel system.

Stilbene moieties have a similar chemical structure to azobenzene and also trans-cis photoisomerise [55], and are therefore also used as a photo switching moiety in supramolecular systems [56–59]. The required wavelength for photo isomerisation from cis to trans is shorter and the thermal stability of the cis form is higher than those for azobenzene. Other molecules that can undergo photoinduced cistrans isomerisation and are thus potentially useful to modify hydrogel systems are reviewed by Dugave and Demange [60]. The spiropyran group is also widely used to control the structure and function of biomaterials by light, which isomerise from the hydrophilic (zwitterionic) merocyanine state (so called open form) to the hydrophobic (neutral) spiropyrane state (so called closed form) under blue light irradiation. By using the change in property of spiropyrane moiety, photoresponsive hydrogels have been prepared [61–65] and the association properties of peptides [66], polymers [67], and lowmolecular-weight gelators [68] have been controlled by light to construct a photoresponsive hydrogel system. Similarly spironaphthoxazine group has also been used for functionalization of hydrogel [69]. 2.2. Photocleavage The o-nitrobenzyl group is one of the most useful photolabile compounds for photoresponsive hydrogel systems for biomedical applications because biocompatibility of the o-nitrobenzyl moiety has been shown; both the residues before and after photodegradation and the degradation process are inert for fragile biomacromolecules including proteins, DNAs and RNAs. This photo cleavage reaction has been used to break a polymer network [70–74] and to control supramolecular interactions by changing the chemical properties of interacting molecules [75,76]. Furthermore photochemical properties including the quantum yield, absorbance maxima, and extinction coefficient can be adjusted by substitutions [77]. In particular, to

3. Photoresponsive hydrogels Photoresponsive hydrogels that can show changes upon photoirradiation in their physical and/or chemical properties such as elasticity, viscosity, shape, and degree of swelling are of interest for various biomedical applications. To construct a photoresponsive system, the choice of the photoreactive group and the fundamental structure of the gels are crucial. Both physically (non-covalently) crosslinked and chemically (covalently) crosslinked hydrogel have been used and many strategies have been developed to incorporate the photoactive group into the hydrogel network over the years. In this section we focus on the methods to introduce photoresponsiveness to hydrogel systems which can be roughly divided into three categories; (1) modification of hydrogels with photoresponsive groups, (2) modification of polymer with supramolecularly interacting groups that can respond to photoirradiation, and (3) supramolecular hydrogel formation of photoresponsive low-molecularweight-gelators (Fig. 2). 3.1. Hydrogels modified with photoresponsive groups Chemical modification of a hydrogel with photoresponsive moieties is the most straightforward method to obtain a photoresponsive hydrogel. Depending on the applications, hydrogels are not necessary to be decomposed into a fluidic solution; some change in the properties of hydrogels maybe provides sufficient effect [100]. For example, Ishihara et al. [35] obtained a hydrogel composed of poly(2-hydroxyethyl methacrylate) functionalized with pendant azobenzene groups. Upon irradiation with ultraviolet light these gels deswelled, while the reversal process could be induced with visible light [36]. These photoresponsive swelling-deswelling hydrogels have been engineered to fabricate photoactive microcantilevers [101]. Functionalization of polymeric networks with photoreactive groups that can undergo photocleavage is another way to obtain a

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Fig. 2. Schematic representations of typical photoresponsive hydrogels. (a) Hydrogel modified with photoresponsive group shows deswelling upon irradiation. (b) Hydrogel crosslinked by photoresponsive supramolecular assemblies shows dissociation after irradiation resulting in a gel-to-sol transition. (c) Hydrogel composed of a photoresponsive supramolecular polymer that was formed by low-molecular-weight gelators also shows a gel-to-sol transition because of the dissociation of the polymeric structure.

photoresponsive hydrogel. Reversibly photodimerizable groups have been used to control crosslinking density in the gel matrices [88–91,93– 95,97,98]. And photodegradable o-nitrobenzyl group has also introduced in the gel matrix for one time use [73,74]. Suzuki and Tanaka [102] constructed a photoresponsive hydrogel with a combination of a thermosensitive hydrogel and a chromophore. The light absorbed by the chromophores is dissipated as heat and increase the local temperature, which affects thermosensitive hydrogel network to induce phase transition resulting in a photoresponsive hydrogel system [103,104]. As gold nanorods [105–109], gold nanoparticles [110–112], and single-walled nanocarbons [113] can effectively convert near-infrared radiation to heat, these materials have also been used with thermosensitive hydrogels to develop photoresponsive hydrogel systems.

cally modified poly(acrylic acid). When the azobenzene moiety was in the trans form, it formed a micelle together with the hydrophobes attached to the polymers and the resulting micelle acted as a crosslinking point. After photoisomerization, the cis azobenzene surfactants did not form a micelle due to the change in critical aggregation concentration, thus micellar crosslinking points were no longer formed. In this way, the photoresponsive system composed of polymer and photoresponsive surfactant was obtained [116]. Not only low-molecular-weight surfactants, copolymers having photoresponsive groups can also be used in a similar way. Alvarez-Lorenzo et al. demonstrated that hydrophobicity changes in azobenzene groups of poly(N,N-dimethylacrylamide-co-methacryloyloxyazobenzene) can be used to control the hydrogel formation based on the micelle formation of Pluronic F128, consisting of hydrophilic poly(ethylene oxide) and hydrophobic poly(propylene oxide) blocks [117]. Hydrophobic interaction of amphiphilic polymers can also be controlled by adding cyclodextrins, which can form inclusion complex with hydrophobes on the polymer and shield the hydrophobic interaction. If photoresponsive competitive guest molecules were added, which can form inclusion complexes with the cyclodextrin only when it was in certain form, hydrophobic interaction among the polymers can be governed by these photoresponsive additives, thus a photoresponsive hydrogel system can be obtained. For example, physical gel formation of dodecyl modified poly(sodium acrylate) was controlled by the presence of α-cyclodextrin and azobenzene diacid. In this system, trans azobenzenes form inclusion complexes with cyclodextrins, results in gelation of dodecyl modified poly(sodium acrylate). Upon photoisomerization, cis azobenzenes are expelled from the cyclodextrins, thus the latter forms complexes with the dodecyl groups on the polymer resulting in dissociation of the hydrogel [51]. Complexation of cyclodextrins on poly(ethylene glycol) chains results in a physical hydrogels [118]. Jiang et al. introduced photoresponsiveness in this system by using the addition of azobenzene as a photoresponsive competitive guest molecule [52]. Stoddart et al. have also obtained a photoresponsive hydrogel from two components photoresponsive azobenzene carrying polymer and hydrophobic deoxycholic acid-modified β-cyclodextrin [53]. When the pendant azobenzene groups are in trans form, cyclodextrin bind them and hydrophobic deoxycholates aggregate, resulting in a gelation. And upon photoisomerization, cis azobenzenes are expelled from the cyclodextrins, thus cyclodextrin forms complexes with the deoxycholates resulting in dissociation of the hydrogel.

3.2. Polymers crosslinked by a photoresponsive supramolecular assembly Photoresponsive supramolecular assemblies have also been used as a photoresponsive crosslinker. Thus polymers modified with these interacting groups form photoresponsive hydrogel through temporal complex formations. For example, non-covalent azobenzene– cyclodextrin complex has been used as a reversible crosslinking. When azobenzene is in the trans form, it binds in the cavity of cyclodextrins firmly, while the cis azobenzene does not. Thus azobenzene functionalized polymers and cyclodextrin functionalized polymers can form multiple photoresponsive crosslinking points by forming inclusion complexes of trans azobenzene and cyclodextrin. Upon photoisomerization of the azobenzene groups, the crosslinking will decrease resulting in photoresponsive hydrogels [45–50]. Instead of cyclodextrin polymers, bovine serum albumin, which can bind several trans azobenzene groups in one molecule, has also been used as a complex forming macromolecule with azobenzene carrying polymers [54]. Utilizing change in properties of photoactive additives, polymer– polymer interactions have been controlled. This principle has also been used to construct a photoresponsive hydrogel system [37,114]. For example, photoresponsive surfactants have been developed and used for controlling the association behavior of amphiphilic polymers governed by hydrophobic interaction [115]. Azobenzene carrying surfactants were used to control the micelle formation of hydrophobi-

3.3. Photoresponsive hydrogel formed by low-molecular-weight gelators Low-molecular-weight gelators (LMWGs) have been developed based on a diverse range of compounds [119–122]. Most of the LMWGs form fibril structure through various interactions such as hydrogen bonding, and entanglements of the resulting fibers lead to a high viscosity and elasticity. By introducing photoresponsive moieties, interaction between the molecules can be controlled by light. Oligopeptides have been studied as a LMWG which form fibril structures due to a combination of interactions such as van der Waals interaction, ionic interaction, π–π stacking and hydrogen bonding. Bis (phenylalanine) connected by photoresponsive maleic–fumaric acid amides in the middle can show sol-to-gel transition upon UV irradiation [123]. This is because of the formation of unfavoured structures for stacking of bis(phenylalanine)s resulting in dissociation of the fibril structure. Zhang et al. have reported a reversible gel-to-sol and sol-togel transitions system using spiropyran functionalized dialanine. In this system non-planar spiropyran moieties prevent interactions among dipeptide LMWGs while the isomerized merocyanine moieties have a strong tendency to form π–π stacking that can support dipeptide interactions. The isomerization can be controlled by photoirradiation and pH adjustment [68]. Xu et al. showed an enzymatic formation of a


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Fig. 3. Schematic representation of photoresponsive protein release from the hydrogel composed of trans azobenzene modified dextran and cyclodextrin modified dextran. Upon the UV light irradiation azobenzene moieties isomerise from trans to cis configurations, resulting in the dissociation of crosslinking points, and allow the entrapped protein to migrate into the media. Pictures show the gel and sol states. (Reference [49] – Reproduced by permission of The Royal Society of Chemistry.)

photoresponsive supramolecular hydrogel with an azobenzene modified oligopeptide [124]. Hamachi et al. developed glycolipid-based photoresponsive LMWGs composed of hydrophilic sugar groups connected to a photoresponsive module and lipid tails, in which a fumaric moiety can be photoisomerized to a maleic moiety upon UV irradiation [125,126] (see later section). Long flexible thread- or worm-like micelles are known to show a characteristic viscoelastic behavior, which can be obtained from a combination of ionic surfactants and aromatic counter ions [127–129]. Using photoisomerizable o-methoxycinnamic acid (OMCA), Raghavan et al. have developed a photoresponsive system based on a cationic surfactant CTAB micelles [130,131]. When OMCA is in its trans form, it associates strongly with CTAB, leading to the formation of long, wormlike micelles. These micelles entangle into a transient network and thereby give a highly viscoelastic fluid. Upon UV irradiation, trans-OMCA is isomerized to cis configuration. The cis isomer has a less favorable geometry to bind at the micellar interface and more hydrophilic property than trans isomer. Thus, the cis isomer tends to form shorter micelles. As a result, the sample is converted into a low-viscosity solution. 4. Biomedical applications of photoresponsive hydrogels In this section recent progress on biomedical applications of the photoresponsive hydrogel are discussed. As photoresponsive hydro-

gels are a particularly interesting option to advance drug delivery systems and tissue engineering, here we highlight their applications for photocontrolled compound releasing and cell-culturing. 4.1. Drug release from photoresponsive hydrogels Use of the erosion of the hydrogel network is a long-standing method to regulate compound release. Since the release of compounds from the hydrogel matrix can be controlled by the change of mesh size of the network, photoresponsive hydrogel systems are potentially useful for drug delivery systems with a controlled release. The network structure of the hydrogel matrices can be used to encapsulate macromolecules including proteins. Andreopoulos et al. have investigated relationship among the sizes of proteins (myoglobin, hemoglobin, and lactate dehydrogenase-L) and their diffusion coefficients in the photoresponsive hydrogel whose mesh size can be adjusted by light [92]. Kros and coworkers used cyclodextrinmodified dextran hydrogels for the in vivo release of hydrophobic drugs [132,133]. In a recent example, a photoresponsive hydrogel composed of cyclodextrin or azobenzene modified dextrans was studied as a controlled release system of proteins [49] (Fig. 3). In a related project, a photodegradable, covalently crosslinked hydrogel system was constructed from dextran and poly(ethylene glycol) using the acrylate–thiol Michael addition as the crosslinking method [134]. Light sensitivity of this hydrogel was introduced by

Fig. 4. (a) Scheme of trans to cis photoisomerization of the LMWG and a schematic illustration of the pseudo-reversible gel–sol transition of the hydrogel induced by UV/Vis irradiation. (b) Photocontrolled release of vitamin B12 from the hydrogel. Time courses of release ratio [%] of vitamin B12 from gel to bulk solution without or with UV irradiation (c) Release ratio [%] of vitamin B12, FITC-ConA, and 100 and 250 nm fluorescent beads from the hydrogel without or with UV irradiation. (Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission from reference [125].)

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introducing a non-toxic photolabile o-nitrobenzyl moiety in between dextran backbone and acrylate group. Hydrogels were prepared under physiological conditions without the need of any additional reagents by mixing solutions of dextran functionalized with acrylate-modified o-nitrobenzyl moieties (Dex-AN) and dithiolated poly(ethylene glycol) (DSPEG). The degradation of the hydrogel due to UV irradiation resulted in the release of the model protein green fluorescent protein (GFP). Furthermore, photodegradation of the hydrogel via two photon excitation was also examined using focused pulsed near infrared (NIR) laser beam as a light source. The photocontrolled release of vitamin B12, concanavalin A, and nanobeads with diameters of 100 or 250 nm from photoresponsive hydrogel composed of a glycolipid-based photoresponsive LMWG have been shown by Hamachi et al. [125] (Fig. 4). Furthermore, the same photoresponsive hydrogel system was used to control bacterial movement and rotation of F1-ATPase motor. Using photolithographic techniques, gel/sol photopatterning was also successfully conducted. A phosphate carrying photoresponsive hydrogelator has also been developed by the same group, which was used to create a molecular logic gate to control the release of bioactive compounds [135]. Park et al. obtained a hydrogel system composed of mesoporous silica nanoparticles and six-arm poly(ethylene glycol) as shown in Fig. 5. Fig. 5. Schematic illustration of the photoresponsive release of guest molecules from the pores of mesoporous silica particle functionalized with β-cyclodextrins through a photolabile group (Si-MP-4) and sol–gel transitions induced by the complex formation of β-cyclodextrin and dodecyl groups on six-arm poly(ethylene glycol) (6-PEG-C12). (Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission from reference [72]).

Fig. 6. (a) Schematic illustration of reversible photoregulated substrate release and uptake with molecularly imprinted photoresponsive hydrogel. (b) Photoregulated release and uptake of substrates (paracetamol, phenacetin, and antifebrin) in an aqueous solution by the paracetamol imprinted poly(acrylamide) hydrogel containing azobenzene moieties. Reprinted with permission from reference [136]. Copyright 2008 American Chemical Society.

Fig. 7. Schematic illustration of the in vivo test (top); the nanogels were systemically injected into mice and the right kidney was immediately irradiated using the NIR laser. White (a) and light-gray (b) bars indicate distributions of PNIPAM-coated gold nanorods without irradiation after 10 and 30 min from injection, respectively. Black bars (c) indicate distributions after injection of PNIPAM-coated gold nanorods followed by laser irradiation on the right kidney. Dark-gray bars (d) indicate distributions after injection of non-responsive PEG-modified gold nanorods with irradiation. Significant accumulation of gold in the irradiated right kidney was observed after irradiation of the right kidney, while accumulation was not observed in the left kidney (c). Reprinted with permission from reference [109]. Copyright 2009 American Chemical Society.


Upon mixing, the cyclodextrin modified silica particles are crosslinked with dodecyl modified poly(ethylene glycol) through the complexation of cyclodextrin and dodecyl groups. In this system the silica particles can be used as a container since it has a porous structure and the opening of the pores are covered by bulky cyclodextrins. Furthermore as cyclodextrins are bound to the silica particles through a photocleavable o-nitrobenzyl ester moiety, a photocontrolled compound release from the hydrogel can be expected [72]. Recently a photoresponsive molecular imprinted hydrogel matrix has been developed by Lam et al. [136]. In the matrix, azobenzene based molecular recognition sites for a target molecule paracetamol were formed during the preparation of the hydrogel in the presence of paracetamol. Since photoisomerization of the azobenzene moieties induces structural change of the recognition sites, the release and

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uptake of paracetamol were controlled by light (Fig. 6). As the recognition sites were prepared for paracetamol, phenacetin and antifebrin were less efficiently uptaken and released. In general the size of hydrogels can be tailored from a macroscopic to the nanometer scale, depending on the potential applications. Nanometer sized hydrogels, nanogels, are of particular interest as drug delivery systems as these can provide a way for targeted delivery of drugs via blood circulation [137–140]. Various type of photoresponsive nanogel particles have been developed [48,63,91,98,104– 106,112,126,141,142] and the compound releases from the particles have also been shown [90,143,144]. However examples of in vivo use of nanogels are still limited partially because of light transmittance of tissues. Niidome et al. injected nanogels composed of gold nanorods coated with thermosensitive poly(N-isopropylacrylamide) (PNIPAM)

Fig. 8. (Up) The general strategy used to create adhesive biochemical 3-D channels in agarose hydrogel matrices. (Down) Primary rat dorsal root ganglia cells were plated on 3-D patterned GRGDS oligopeptide-modified agarose gels. Three days after plating, cells grew within GRGDS-oligopeptide-modified agarose channels only, and not in surrounding volumes as viewed by (a) optical microscopy; (b) confocal fluorescent microscopy, where the channel is green (due to a fluorescein-labeled oligopeptide) and the cells are red (due to the cytoskeletal F-actin rhodamine–phalloidin stain); and (c) fluorescent microscopy, where a nuclear DAPI stain (blue) confirms cell migration into the oligopeptide-modified channel.(Scale bars:100 μm). Reprinted by permission from Macmillan Publishers Ltd: Nature Materials [156], copyright (2004).

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gel into mice, which can deswell under the near-infrared irradiation resulting in the formation of a hydrophobic surface of the nanogels. And it was demonstrated that the nanogels were significantly accumulated in the irradiated kidney due to the photothermal phase transition at the irradiated site [109] (Fig. 7). 4.2. Photoresponsive hydrogels as a matrix for cell-culturing Hydrogel matrices have been used as a growth media for cell cultures since it has a structure similar to hydrated living tissues [145]. Serious efforts have been made recently to create smart matrices to support, guide and stimulate the development of cells [146–148]. Three dimensional micropatterns can be formed inside of photoresponsive hydrogels using photolithographic technique including two-photon excitations [149–152]. Moreover the dynamic nature of photoresponsive hydrogels is beneficial to induce local property change such as adhesive activity and mechanical strength, which can allow for the dynamic manipulation of the environment surrounding the cells [153,154]. o-Nitrobenzyl moieties have been used for the selective functionalization and release of oligopeptides such as RGDS in hydrogel matrices to guide cell growth including 3 T3 fibroblasts, primary rat dorsal root ganglia cells and DRG neurons via integrin-mediated cell adhesion [155–157]. Recently, Anseth et al. [73,74] presented hydrogel materials which possessed both chemical and mechanical patterns through photodegradation. As a result it was possible to control the migration of stem cells within the hydrogel network via photodegradation. And these materials show great promise as tissue engineering scaffolds with control over the cell behavior (Fig. 8). 5. Conclusion and outlook In this review we highlighted recent developments of photoresponsive hydrogel systems and their applications. The combination of hydrogel and light makes these systems beneficial for biomedical applications as hydrated structure of hydrogel makes them attractive as a bio-friendly material and use of light allows to control their properties in a dynamic way. For the future applications, following technologies are currently under investigation and in parallel, evaluation of the materials from the aspect of biocompatibility or toxicity becomes more important for actual use in biotechnological applications. For future drug delivery systems, since nanometer scale particles can provide a way for targeted delivery via blood circulation and the living tissue has less absorption in nearinfrared (NIR) region, the combination of nanogel technology and NIR radiation becomes more attractive. To use NIR as the light source to trigger the release, engineering on the two photon process will be more important. The current penetration depth of light used with the current chromophores (Table 1) is rather small. Therefore future in-vivo applications would greatly benefit if a new generation of reactive chromophores that adsorb light of higher wavelengths would be designed. These new reactive molecules would, in combination with the two-photon technology, open up a myriad of applications of these photoresponsive hydrogels to be used for the controlled delivery of drugs deeply under the skin. In order to advance the progress in the field of tissue-engineering, in situ forming hydrogel systems in a physiological condition will play important role, as in this way a threedimensional environment can be easily created for the cells or microorganisms. And micropatterning of the cell growth media using photolithography techniques will be used more commonly to control microenvironments of cells as similar as their native environments. Acknowledgements The authors (A. K. and I. T.) acknowledge the support of the Smart Mix Programme of the Netherlands Ministry of Economic Affairs and the Netherlands Ministry of Education, Culture and Science.

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