Photoreconfigurable polymers for biomedical applications: chemistry and macromolecular engineering.

Review pubs.acs.org/Biomac

Photoreconfigurable Polymers for Biomedical Applications: Chemistry and Macromolecular Engineering Congcong Zhu,† Chi Ninh,† and Christopher J. Bettinger*,†,‡,§ †

Department of Materials Science and Engineering and ‡Department of Biomedical Engineering Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States § McGowan Institute of Regenerative Medicine, 450 Technology Drive, Suite 300, Pittsburgh, Pennsylvania 15219, United States ABSTRACT: Stimuli-responsive polymers play an important role in many biomedical technologies. Light responsive polymers are particularly desirable because the parameters of irradiated light and diverse photoactive chemistries produce a large number of combinations between functional materials and associated stimuli. This Review summarizes recent advances in utilizing photoactive chemistries in macromolecules for prospective use in biomedical applications. Special focus is granted to selection criterion when choosing photofunctional groups. Synthetic strategies to incorporate these functionalities into polymers and networks with different topologies are also highlighted herein. Prospective applications of these materials are discussed including programmable matrices for controlled release, dynamic scaffolds for tissue engineering, and functional coatings for medical devices. The article concludes by summarizing the state of the art in photoresponsive polymers for biomedical applications including current challenges and future opportunities.

1. BACKGROUND AND MOTIVATION

microenvironments for elucidating cell-material interactions.32−34 Photoresponsive polymers can be classified into several categories based on the photosensitive functional groups used for macromolecular preparation. There are several types of reported mechanisms applied in light sensitive polymers including photolabile protecting (caging) groups,27,35−38 reversible dimerization,39−45 photoisomerization,46−54 and weak metal−metal bonds55−58 etc. Photoresponsive polymers have been synthesized and engineered to respond to light at wavelengths ranging from ultrashort wavelength lasers to nearinfrared light (Figure 1). Photoresponsive polymers can be processed into diverse formats including self-assembled monolayers,59 nanoscale micelles,60 swollen hydrogels,61 and solid bulk form factors.40 There are many synthetic approaches available for preparing photoreconfigurable polymers for use in biomedical applications such as free radical-mediated photopolymerization. Representative examples of this work include chain growth photopolymerization of alkenes and step growth photopolymerization of thiol−ene systems, both of which have been reviewed extensively elsewhere.62−69 This review primarily focuses on networks that are intrinsically photoactive and can be reconfigured without the need for dedicated photoinitiators. Strategies for engineering light sensitivity will be reviewed and

Research in stimuli-responsive polymers has garnered significant interest in recent years. Polymers can be engineered to respond to a broad range of external stimuli for prospective applications ranging from clean energy to medical devices. Cues include, but are not limited to, temperature changes,1−3 hydrolysis,4 exogenous light,5 shifts in pH,6,7 enzymatic activity,8−10 and electric current.11 Polymeric materials manifest these cues through a diversity of programmable responses including shape change,12−15 altered mechanical properties,16 and on-demand disintegration.17 Molecular-scale reconfiguration of polymeric materials using light is advantageous for several important reasons. Light permits micron-scale and millisecond spatiotemporal resolution thereby enabling tight control over local physical properties.18 The wavelength, intensity and exposure time of irradiated light stimuli can all be tuned to increase the specificity of the applied cue. Welldefined external light cues can be engineered to control polymer solubility,19 degradation,20 and macroscopic form factors of the bulk material.12 Photoresponsive polymers represent an important class of materials that can be used in the design of smart materials for applications including microelectronics fabrication,21 environmentally friendly commodity materials,22 and medical devices.23 The latter category may utilize photoresponsive materials for triggerable matrices for controlled drug release,24−27 templates for three-dimensional biomolecular patterning,28−31 and dynamic model © XXXX American Chemical Society

Received: July 7, 2014 Revised: September 6, 2014

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dx.doi.org/10.1021/bm500990z | Biomacromolecules XXXX, XXX, XXX−XXX

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Figure 1. Typical absorption wavelengths in nanometers for assorted functional groups that are commonly employed in photoreconfigurable polymers.

Scheme 1. Uncaging Process of o-Nitrobenzyl Caged Compounds into the Carboxylic Acid-Bearing Compound and the oNitrosobenzaldehyde/Nitrosoketone By-Product24,79

synthetic biological microenvironments. Many of the chemistries for uncaging of small molecules can be recapitulated in photoresponsive monomers that can be polymerized into more complex structures. 2.1.1. o-Nitrobenzyl Protecting Groups. The mechanism for uncaging in photolabile molecules utilizes selective bond cleavage between caged compounds and protecting groups is triggered by photoinduced intramolecular electron transfer reaction.72 o-Nitrobenzyl derivatives are widely employed as photolabile protecting functional groups.37 The representative uncaging process of o-nitrobenzyl groups is shown in Scheme 1.24,79 A hydrogen free radical is abstracted by an intramolecular excited nitro group, leading to photolysis of onitrobenzyl.80,81 The carboxylic acid group is liberated generating the original molecule and an o-nitrosobenzaldehyde or nitrosoketone byproduct. The product of o-nitrobenzyl photolysis depends on environmental factors such as reaction medium and pH.70 Furthermore, a variety of o-nitrobenzyl derivatives with different substitution groups on the phenyl ring have been synthesized to expand the reaction conditions that permit uncaging. Achievements include increasing the uncaging cross section, red shifting wavelengths for photolysis, and facilitating subsequent synthesis procedure.72 Photodegradable

potential applications will be highlighted. Emerging trends and future prospects for light responsive soft matter will also be addressed.

2. CHEMISTRY OF PHOTOSENSITIVE FUNCTIONAL GROUPS 2.1. Photolabile Protecting (Caging) Groups. Photolabile protecting groups are a promising strategy to confer photosensitivity in polymers. The concept of integrating photolabile protecting groups into polymer precursors originates from a study that aimed to engineer selective biological activity in signaling molecules. Otherwise bioactive compounds are rendered inactive with the addition of a photosensitive conjugate via covalent bonds.70,71 Light-induced uncaging cleaves photolabile protecting groups to restore the native biological function of the small molecule.72 Lightinduced uncaging is advantageous because the activity of signaling molecules can be controlled in space and time. Photolabile protecting groups can be conjugated to a range of bioactive molecules including calcium,73 peptides,74 proteins,75 neurotransmitters,36,76 and ATP.77,78 This generalizable strategy for light-induced uncaging can produce a broad range of B


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Table 1. Overview of Select o-Nitrobenzyl Caged Compounds

a

Maximum absorption wavelength.

0.065 GM at 750 nm,85 which is below the threshold of 0.1 GM for useful biomedical applications.36,92 2.1.2. Coumarin-4-ylmethyl Protecting Groups. Coumarin4-ylmethyl and its derivatives can also serve as protective groups for selective uncaging.36 The uncaging process of coumarin is shown in Scheme 2.36 Alcohols,93 phenols,93 amino

polymers can be functionalized with o-nitrobenzyl groups at various positions including pendant groups and moieties within the backbone of linear polymers and cross-linked networks. Table 1 summarizes the composition-dependent physicochemical properties of several o-nitrobenzyl derivatives. Substitutions on the aromatic rings of o-nitrobenzyl result in a red shift of maximum absorption wavelengths from less than 300 nm up to approximately 350 nm. Increasing the wavelength of photolysis in compounds is desirable for biomedical applications where short wavelength UV light can potentially cause DNA damage in cells.82 o-Nitrobenzyl derivatives are desirable for photolysis reactions attributed to their fast photolysis kinetics and various synthetic routes.72 o-Nitrosobenzaldehyde byproducts may pose some concerns regarding cytotoxicity in some specific applications.18,83 This concern can be potentially addressed by including substituents on aromatic rings that yield less toxic nitrosoketone byproducts after photolysis compared to aldehydes.84 o-Nitrobenzyl photolabile protecting groups can be cleaved through two-photon absorption. Two-photon absorption is a nonlinear process that requires simultaneous absorption of two photons.87 A two-photon laser can confine the uncaging process within a small volume element (voxel) on the order of 0.5 μm3 (λ3, where λ is the wavelength of laser)88 leaving the surrounding area intact.89 Two-photon absorption provides a very promising path for preparing photoreconfigurable polymers with three-dimensional microstructures for use in regenerative medicine90 and controlled release.91 The twophoton absorption cross sections of o-nitrobenzyl photolabile protecting groups have been reported in the range of 0.015−

Scheme 2. Photodeprotection Procedure of Coumarin-4ylmethyl Caged Compounds36

acids,36,94 and neucleobases95 have been conjugated with coumarin-4-ylmethyl through photolabile bonds. Representative examples of coumarin-4-ylmethyl protected molecules are shown in Table 2. Maximum absorption wavelengths for singlephoton uncaging of coumarin-4-ylmethyl derivatives span into the UVA zone (λmax > 315 nm).36,86,93 Furthermore, certain coumarin-4-ylmethyl molecules can be cleaved upon irradiation with light at near-IR wavelengths through two-photon absorption processes.36 The extinction coefficient of light in tissue is much smaller at near-IR wavelengths compared to visible wavelengths.96 This increases the maximum penetration depth and reduces the risk of damage to cells and tissues.97 Many coumarin-4-ylmethyl derivatives exhibit larger twophoton absorption cross section compared to o-nitrobenzyl photolabile protecting group. For example, 6-bromo-7-hydroxC


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Table 2. Summary of Photolytic Properties of Coumarin-4-ylmethyl Caged Compounds

Maximum absorption wavelength. bExtinction coefficient (M−1 cm−1) at maximum absorption wavelength (λmax). cTwo-photon cross section (GM) at 740 nm. dTwo-photon cross section (GM) at 800 nm. a

trends indicates that a free hydroxyl group on the aromatic ring is necessary for uncaging.86 There are more restrictions on the molecular substitutions of coumarin-4-ylmethyl protecting groups compared to o-nitrobenzyl photolabile groups. The sensitivity is increased when photolabile species are incorporated into polymers.

ycoumarin-4-ylmethyl acetate exhibits an absorption cross section as high as 1.99 GM.36 Substitutions yield a predictable composition-dependent impact on the two-photon cross section. For example, 6-bromo-7-hydroxycoumarin-4-ylmethyl exhibits a higher susceptibility to photolysis during two-photon absorption compared to 7-methoxycoumarin-4-ylmethyl.72 This D


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2.1.3. p-Hydroxyphenacyl Groups. There are fewer examples that utilize p-hydroxyphenacyl as an photolabile protecting group compared to the aforementioned o-nitrobenzyl and coumarin-4-ylmethyl derivatives. p-Hydroxyphenylacetic acids can be uncaged by photosolvolytic rearrangement.101 The photolysis reaction of p-hydroxyphenacyl groups is shown in Scheme 3.102 Uncaging of p-hydroxyphenacyl

Scheme 5. Reversible Photodimerization of Cinnamate and Coumarin Functional Groups43,115

Scheme 3. Photolysis Scheme of p-Hydroxyphenacyl Protecting Groups102

groups is studied primarily in the context of synthesizing caged bioactive molecules with selective activity. This strategy can control the activity of phosphate-based nucleotides102−104 and carboxylate-based peptides.105,106 One remarkable advantage of using p-hydroxyphenacyl as biomolecule photoprotecting group is that its reported uncaging rate at wavelength of 312 nm is several orders of magnitude larger than o-nitrobenzyl analogues.35,105 Therefore, it is a promising protective caging agent for rapid presentation of bioactive compounds. 2.1.4. Acetal and Ketal Protecting Groups. Acetals and ketals have been widely studied used as protecting groups for aldehyde and ketone moieties during nucleophilic substitution reactions.107,108 They can be removed through catalyst-initiated hydrolysis under mild conditions.109,110 Polyketals and polyacetals also exhibit photodegradation properties upon irradiation with low intensity light at wavelengths deep within the UV spectrum.38,111 The proposed photolysis process is shown in Scheme 4.38 When polyketal and polyacetal chains

coumarin groups have been incorporated as functional components into many types of photosensitive macromolecules. They have been used primarily as light-induced reversible cross-linkers for in situ modification of hydrogel cross-link density118−120 or transient stabilization of micelles.121,122 Shape memory elastomers that can switch between temporary and permanent geometries upon exposure to light also utilize reversible photodimerization of cinnamate and coumarin groups.12,117,123 2.3. Photoisomerization. Unlike light-activated uncaging and photodimerization, there is no covalent bond cleavage during a photoisomerization process. Cis−trans and ringopening conversions are two most common classes of isomerization.124 Azobenzene, which contains nitrogen−nitrogen double bond, can switch between trans and cis isomers upon light exposure. The scheme of azobenzene photoisomerization is shown in Scheme 6.125 When the thermody-

Scheme 4. Photolysis Process of Acetal and Ketal Protecting Groups38

Scheme 6. Reversible trans−cis Photoisomerization of Azobenzene125

absorb high-energy photons (λ < 254 nm), carbon−oxygen bonds are likely cleaved to form zwitterion intermediates followed by the cleaved product of a carbonyl and hydroxyl. Photolysis induces degradation of the polymer by reducing the molecular weight via chain scission.112,113 Pulsed lasers can confine degradation within focused spots in order to eliminate light-induced heating and damage to cells and tissue.38 2.2. Reversible Dimerization. Light-induced reversible dimerization is another strategy to confer photosensitivity to polymeric structures. Dimerization describes the process in which two previously unbound molecules are covalently coupled to each other. Several small molecule compounds have been reported having such reversible dimerization properties upon exposure of light including cinnamon44 and coumarin.114 The proposed photodimerization reaction is shown in Scheme 5.43,115 Photodimerization of cinnamate and coumarin moieties proceeds through the excitation of π electrons to antibonding molecular oribitals that ultimately form a cyclobutane ring between two adjacent molecules.43,116 This process is initiated by irradiation at wavelengths λ > 260 nm. Photocleavage of the cyclobutane ring is possible by irradiation at wavelengths λ < 260 nm.41,117 Cinnamate and

namically stable trans isomer is exposed to UV light of wavelength λ = 365 nm, the newly formed π−π* transitions bias the formation of the cis isomer. The cis isomer, which is a metastable state, can return to its trans isomer through n−π* transition when irradiated with visible light at a wavelength of approximately λ = 445 nm.47 Spiropyran groups are photochromic compounds with isomer-dependent optical absorption spectra that undergo ring-opening conversion reactions.54 The scheme of spiropyran photoisomerization is shown in Scheme 7.50 Colorless spiropyran is converted into the ring-open merocyanine isomer (λmax = 560 nm) upon irradiation with UV light.126 Retro-conversion reactions can be catalyzed by exposure to visible light exposure or elevated temperature.52 Incorporating compounds capable of photoisomerization produces a class of photoresponsive materials that can be reversibly reconfigured in response to light. 2.4. Photocleavable Metal−Metal Bond. Photoresponsive polymers that contain metal−metal bonds can undergo E


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are converted into hydrophilic poly(methacrylic acid) segments upon photolysis by single- and two-photon absorption. Destabilized micelles release the model small molecule payload on-demand (Figure 2). Photoresponsive micelles with small molecule payloads are susceptible to leakage in the absence of light cues due to diffusion of the compounds through the hydrophobic phase. Premature leakage of the payload from block copolymer micelles can be reduced by incorporating additional countermeasures to reduce free diffusion of the drug. Strategies to increase the structural stability of drug-loaded micelles include covalent cross-linking within the core−shell matrices or conjugation of the free drug to micellar structures via photocleavable bonds. Tang et al.127 introduced a chemically cross-linked micelle core using ATRP to increase the thermal stability of micelles. Liu et al.128 describes a method for covalent conjugation of o-nitrobenzyl to camptothecin in micelles with cross-linked hydrophilic shells. These additional features restrict free diffusion and ultimately reduce the rate of premature drug release. External light stimulus therefore dominates temporal control of drug release within these materials. Macromolecular chains bearing pendant o-nitrobenzyl functional groups can be used as photoresists for selective surface modification. Azzaroni et al.129,130 grafted polymer brushes of 4,5-dimethoxy-2-nitrobenzyl methacrylate on glass/silicon wafer through surface-initiated ATRP. The hydrophilicity of polymer-coated surfaces is increased by photolysis of onitrobenzyl upon UV exposure (Figure 3). Irradiated polymer surfaces are also pH-response due to the presence of newly formed methacrylic acid polyanions. Released poly(methacrylic acid) dissolves into surrounding medium at a pH above 6.6 while remaining stable on the surface at a lower pH. Irvine et al.28 used selective dissolution to create two-component micropatterns of proteins on surfaces by adapting multistep light exposure process followed by developing in phosphate buffered saline. Light-induced deprotection is therefore a suitable method for biomolecular micropatterning using mild aqueous conditions that can preserve the bioactivity and viability of intact proteins and cells.29 Shoichet et al. reported an alternative strategy of applying onitrobenzyl as pendant functional groups in hydrogels. Hydrogels have garnered recent interest as a material platform for neural tissue engineering owing to the tunable physical properties, swollen hydrated environment that mimics the natural extracellular matrix, and high mechanical compliance that is comparable to that of brain matter.68,153 Shoichet et al.131 modified agarose hydrogels with photosensitive S-2nitrobenzyl-cysteine, which can be selectively removed by exposing the desired region to high intensity light from a UV laser that releases reactive sulphydryl groups. Maleimidoterminated biomolecules are then patterned within the functionalized agarose gels channels by reacting with free sulphydryl groups. GRGDS peptides were immobilized within the exposed region as demonstrated by selective spreading and migration of dorsal root ganglia cells. This strategy enables the formation of spatially selective peptide-modified microstructures within hydrogel matrices. Biomolecular micropatterning of hydrogels is a potentially valuable tool to study interactions

Scheme 7. Reversible Ring Close−Open Photoisomerization of Spiropyran50

light-induced homolysis of metal−metal bonds followed by the capture of radical traps. (Scheme 8)56 Radical traps include, but are not limited to, oxygen or other electrophilic groups within the structure.57 Photodegradation can be initiated by irradiation with visible light.55 The typical procedure of synthesizing metal−metal bonds containing polymers is to use step polymerization of difunctional, cyclopentadienyl-substituted metal dimers. However, efficient polymerization is challenging because it is difficult to prevent cleavage of weak metal−metal bonds during aggressive reaction conditions.23 New synthetic strategies to produce metal containing polymers have been explored, such as ADMET polymerization (acyclic diene metathesis polymerization) that can reduce scission of metal−metal bonds by utilizing mild reaction conditions.58

3. STRATEGIES TO INCORPORATE PHOTOSENSITIVE FUNCTIONAL GROUPS IN POLYMERS Photosensitive functional groups can be incorporated into macromolecules in various topological configurations. Photoresponsive polymers can incorporate light-sensitive moieties as pendant groups of linear polymers, as cross-linkers within branched networks, or within the backbone of linear macromolecules. A brief summary of the topographic categories is shown in Table 3. The selection criterion for the specific photosensitive chemistry to be integrated into the polymer is context-dependent. This section will compare and contrast recent examples in which light-sensitive polymers contain photoresponsive groups across a wide rage of topologies. 3.1. Pendant Functional Groups That Bear Photosensitive Moieties. Photolabile protecting groups have been incorporated in block copolymers as pendant side moieties to render photosensitive segments. Amphiphilic block copolymers can self-assemble into micelles in selective solvents with photolabile and hydrophobic cores.25,150 The design and synthesis of this class of materials has been motivated by potential applications as a photoresponsive matrix for programmable on-demand controlled release. In the envisioned scenario, the micelle cores are loaded with a payload and selfassemble in aqueous environments due to hydrophobic interactions.151 Light-induced bond cleavage between photosensitive groups and polymer backbone increases the hydrophilicity of the block, destabilizes micelle structures and ultimately releases the payload. Photolysis of pendant groups converts amphiphilic block copolymers into uniformly hydrophilic water-soluble polymer chains, which disintegrates the micelles.152 The Zhao group synthesized light-sensitive micelles composed of poly(o-nitrobenzyl methacrylate)−poly(ethylene oxide) (PNBM−PEO) block copolymer using atom transfer radical polymerization (ATRP).24 Hydrophobic PNBM blocks Scheme 8. Photolysis Process of Metal−Metal Bond56−58

F


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Table 3. Representative Examples of Incorporating Photoresponsive Groups within Polymers Using Different Topological Arrangements

Figure 2. (a) Photodeprotection procedure of PEG-poly(o-nitrobenzyl methacrylate) diblock copolymer during single- and two-photon absorption processes. (b) Schematic illustration of photoinduced dissociation of polymer micelles and the subsequent release of the entrapped Nile Red dye payload. Adapted with permission from ref 24. Copyright 2006 American Chemical Society.

micelles and releases a small molecule payload. This capability may be used for use as responsive carrier for controlled release. The Almutairi group synthesized polymers that can be degraded using near-IR light. The synthetic strategy polymerizes self-immolative quinone-methide moieties that bear 4bromo7-hydroxycoumarin as pendant triggering groups.18,154 The disassembly of the polymer was demonstrated by a decreased molecular weight after irradiation with light at nearIR wavelengths and intensities that are benign to surrounding tissues. Macromolecules that contain coumarin-4-ylmethyl have an advantage over o-nitrobenzyl-containing compounds because the former exhibit a higher two-photon uncaging

between cells and biomimetic extracellular matrices by systematically varying the spatial presentation of adhesive ligands. Coumarin-4-ylmethyl protecting groups exhibit a large twophoton absorption cross section.36 They can be integrated into polymer chains as pendant functional groups. Both micelles and polysaccharide gels have been successfully prepared from coumarin-4-ylmethyl contained polymers.60,132 The Zhao group prepared two-photon sensitive micelles with amphiphilic diblock copolymers that are composed of [7-(diethylamino)coumarin-4-yl]methyl and poly(ethylene glycol) (PEG) blocks.60 Irradiation with light at near-IR wavelengths ruptures G


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Figure 3. Photofunctional groups can be used to modulate the properties of interfaces upon exposure to light. The surface can be selectively altered from hydrophobic to hydrophilic states by photolysis of covalently coated poly(4,5-dimethoxy-2-nitrobenzyl methacrylate) brushes. The resulting poly(methacrylic acid) exists as a hydrophilic ionomer in aqueous environments. Adapted with permission from ref 129. Copyright 2009 American Chemical Society.

Figure 4. (a) Schematic illustration of 3D immobilization of FGF2 protein on coumarin-4-ylmethyl modified agarose hydrogels via two-photon absorption processes. (b) Thiol groups are deprotected by light-induced photolysis of 6-bromo-7-hydroxymethylcoumarin. FGF2 is bound to agarose hydrogels by forming disulfides bonds between thiol groups and free cysteines on FGF2-ABD. (c) FGF2 protein is patterned within hydrogels through physical interactions between ABD and maleimide modified HSA. Adapted with permission from ref 132. Copyright 2011 American Chemical Society.

H


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Figure 5. (a) Synthesis and photodeprotection schemes of ABA triblock copolymers bearing pendant coumarin-4-ylmethyl functional groups. (b) Schematic illustration of single- and two-photon-induced phase inversion and disintegration of physically cross-linked hydrogels. Reproduced from ref 134 with permission of The Royal Society of Chemistry. Copyright 2014 The Royal Society of Chemistry. http://dx.doi.org/10.1039/ c3tb21689f.

efficiency. Three-dimensional biomolecular patterning within hydrogels can also provide a biomimetic environment for in vitro cell culture. Shoichet et al. created three-dimensional amine patterns within an agarose hydrogel by chemically bonding the gel with 6-bromo-7-hydroxymethylcoumarin protected amine which is subsequently uncaged using twophoton laser.61 Proteins have also been patterned within gels using similar method (Figure 4).132 Immobilization of fibroblast growth factor-2 (FGF2) was achieved using two synthetic schemes. One approach is to form disulfides bonds between FGF2 and agarose gels directly through uncaging of coumarin-4-ylmethyl protected thiol groups. An alternative strategy is to use a two-step binding procedure in which maleimide modified human serum albumin (HSA) is immobilized and reacted with FGF2-ABD (albumin binding domain) fusion protein. Zhu et al. reported on the synthesis of ABA triblock copolymers bearing pendant photolabile o-nitrobenzyl and coumarin-4-ylmethyl functional groups, respectively, for the formation of photodegradable hydrogels (Figure 5).133,134 Poly(ethylene glycol) was chosen as the flexible B block because it has a low glass transition temperature and is hygroscopic. Phase segregation occurs upon hydration due to

the differential hydrophilicity of the A and B segments, leading to the spontaneous formation of physically cross-linked hydrogel networks. Physical cross-links are composed of phases that are enriched in photolabile A blocks. Photolabile phases are susceptible to photolysis reactions that occur by either single- and two-photon absorption processes. Photolysis reactions convert physically cross-linked hydrogels into watersoluble poly(methacrylic acid) segments. Light is therefore a potent cue for spatially selective disintegration of self-assembled polymer networks. Physically cross-linked photolabile hydrogels exhibit robust mechanical properties that can be modulated in real-time by exogenous light. Furthermore, three-dimensional structures with arbitrary geometries can be fabricated within the coumarin-based gels by two-photon near-IR laser beam. This material has potential applications as a functional surface that can be selectively expunged of adherent species, either abiotic or living. For example, this polymer could be used as a functional surface for spatiotemporal-controlled release of specific cell populations using light. The ring-opening photoisomerization of spiropyran has been employed in the synthesis of photosensitive polymers. One of the essential properties of spiropyran isomerization is that the merocyanine isomer is more hydrophobic than its ring-closed I


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Figure 6. (a) The reversible ring-opening photoisomerization of spiropyran as pendant groups in linear poly(L-glutamic acid)-PEG block copolymer. (b) The disruption and recovery of polypeptide diblock copolymer micelles can be achieved by reversible ring-opening photoisomerization of spiropyran. Adapted with permission from ref 135. Copyright 2011 American Chemical Society.

isomer due to a change in dipole moment.51 Spiropyran can be used as photoswitches to modify surface wettability or dissociate nanostructures for controlled drug release.50,135 Spiropyran-containing alkene can be grafted on silicon substrates using ATRP.49 Water-in-air contact angle measurements show a 44° decrease in the contact angle on silicon substrates after 5 min of irradiation at UV wavelengths. The hydrophobic state can be recovered by irradiating the surface with visible light for 20 min. Reversible wettability is very promising for applications such as self-cleaning surfaces,155 microfluidic channel fabrication53 and study of cell-material interactions.52,136 Spiropyran has also been incorporated into block copolymers as pendant functional groups for the formation of photoresponsive micelles that can become dissociated by light-induced hydrophilicity transition from ring-closed spiropyran to ring-opening merocyanine.137 Kotharangannagari et al. synthesized poly(L-glutamic acid)−PEG block copolymers bearing spiropyran as pendant groups (Figure 6).135 Flower-shaped micellar aggregations are formed in an aqueous environment due to the differential hydrophilicity of the spiropyran-containing block and PEG segments,

respectively. Micellar disruption occurs upon irradiation with UV light to switch hydrophobic spiropyran to its hydrophilic ring-opening isomer merocyanine. Micelles are recovered upon illumination with visible light. 3.2. 3D Polymer Networks with Photoresponsive Groups as Cross-Linkers. o-Nitrobenzyl groups can be used as a cross-linker in three-dimensional polymer networks. These moieties have substitution groups at the meta or para positions of the phenyl rings to enable bridging between polymer chains. Anseth et al.20 synthesized a photodegradable cross-linker using PEG-diamine and acrylated nitrophenol acid. The cross-linker produces PEG-based hydrogels via redox polymerization in aqueous environments. The key feature of this photoresponsive hydrogel is that the cross-link density can be tuned dynamically through photolysis of o-nitrobenzyl groups. Hydrogels prepared using this strategy can be remotely controlled with light to alter the intrinsic physical properties, create microstructures, or release bioactive peptides. Kasko et al.138 used a similar synthesis scheme to prepare amide bearing o-nitrobenzyl-containing PEG hydrogels with increased stability compared to hydrolytically labile ester bonds. Polymeric J


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structures with submicron-scale features are fabricated within the swollen gel. Coumarin moieties can also be covalently integrated into the gel to confer reactivity for two-photon adsorption processes. Photodegradable hydrogels were also explored as material platforms for selective encapsulation and release of mammalian cells.139 Human mesenchymal stem cells were first incorporated into hydrogels during copolymerization stage and gradually released on-demand using light. Both light intensity and exposure time were minimized to reduce the risk of cell damage. These hydrogels provide a complex threedimensional microenvironment to study dynamic cell-material interactions. Furthermore, specific cell populations can be harvested through selective removal from synthetic matrices. Cinnamate functional groups have been conjugated with linear or branched polyethylene glycol to form hydrogels using light exposure with initiator-free systems.118−120 Multibranched PEG chains exhibit an advantage over linear PEG chains because branched PEG precursors can form hydrogel networks with lower light intensities and shorter irradiation time. The swelling ratio was studied as a function of the irradiation time. The swelling ratio drops from >20 to 13 as the irradiation time increases from 1 to 4 h. This indicates a positive correlation between hydrogel cross-link density and irradiation time. Hydrogel disintegration can be initiated by irradiating networks with UV light at λ = 254 nm. The topography of hydrogels changes from a smooth surface to rough amorphous after 10 min of exposure as assessed by environmental scanning electron microscopy. These data can be used to infer the precise time for the onset of disintegration of the photoresponsive networks. Cinnamic acid can be incorporated into polymer networks via covalent conjugation to confer shape-memory properties to polymers with macroscopic form factors.12 Irradiating prestrained bulk polymers creates a temporary network of covalent cross-links composed of cinnamic acid dimers. The permanent geometry can be recovered via retro-dimerization of truxillic acid by exposing the networks to light at wavelengths of λ < 254 nm (Figure 7). Thermoresponsive shape memory polymers shift between temporary and permanent geometries via thermomechanical transitions between glassy and rubbery phases. Light-induced recovery of permanent geometries in shape-memory polymers using reversible network formation/ cleavage via cinnamate-based cross-links represents an orthogonal actuation cue compared to temperature changes, which are more commonly used. The Zhao group copolymerized a coumarin-containing random copolymer that can be cross-linked into a single chain nanoparticles using intramolecular photodimerization of coumarin moieties.41 A dilute polymer solution was used during the dimerization process to reduce the likelihood of intermolecular reactions. Reversible photodimerization of coumarin can stabilize micelles to achieve complex programmable drug release profiles that are controlled by exogenous light.121 Other strategies have employed coumarin-based photodimerization as a strategy to create cross-linked networks from linear polymers such as poly(ε-caprolactone),140 poly(vinyl acetate),42 and polyacrylate.141 Although photodimerization can cross-link and cleave polymer chains using light, practical biomedical applications remain elusive because light-catalyzed reactions require long irradiation times using light with high intensities and short wavelengths.114 Retro-cycloaddition reaction requires short wavelength UVC, which can cause cell damage.156 Harsh

Figure 7. (a) Schematic illustration of light-activated shape-memory polymer mechanism. Reversible photodimerization of cinnamate functional groups (denoted by triangles in the schematic) serves as a secondary cross-linked network that stabilizes a permanent primary covalent network. Dimerization fixes the temporary shape of the strained network, while retro-dimerization abolishes the secondary network and recovers the permanent geometry. (b) Molecular scale reconfigurability can induce macroscopic shape change. The (i) permanent geometry is strained and fixed through cinnamate crosslinking to form the (ii) temporary shape. (iii) The secondary network is abolished to recover the permanent geometry. Adapted by permission from Macmillan Publishers Ltd.: Nature, ref 12. Copyright 2005 Nature Publishing Group. http://www.nature.com/nature/ journal/v434/n7035/full/nature03496.html.

conditions could potentially limit the scope of biomedical applications that utilize this class of photoreponsive polymers. Cinnamate- and coumarin-bearing polymers could have more promise when used as photoresists for microelectronic fabrication or as environmentally benign materials that can be rendered compostable upon light exposure after the expected lifecycle of the material. Utilizing azobenzene photoisomerization in photosensitive polymers relies on the host−guest interaction between azobenzene and cyclodextrin. Tamesue et al.48 used azobenzene photoisomerization to produce photoswitchable sol−gel systems. Polysaccharides were modified with cyclodextrin. These precursors form supramolecular hydrogels when combined with azobenzene modified poly(acrylic acid). Sol− gel transformations are controlled by tuning the relative association and dissociation between azobenzene and cyclodextrin groups.157 Reversible gel formation proceeds under K


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Figure 8. (a) Chemical structure of (blue) o-nitrobenzyl functional groups used as photolabile linkers between (green) maleimide-terminated PEG chains and (red) oleyl groups. (b) Schematic illustration of cell pattern formation by selectively removal of oleyl groups through light-induced scission of o-nitrobenzyl linkers to release cells that were previously anchored using lipid insertion into the cell membrane. Adapted with permission from ref 144. Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

solvent exposure.159 Nanoporous materials can be obtained after one block is selectively removed. Aggressive chemical treatments and complex synthetic routes are typically used to fabricate nanoporous materials using block copolymers. Kang et al.142 invented a process that may overcome these processing limitations. Block copolymers that contain photolabile linkers between segments were synthesized. This feature permits selective facile removal of specific domains under mild conditions. Specifically, Kang et al.142 synthesized PEG-NB as a macroinitiator and used ATRP method to create the photosensitive PEG-NB-polystyrene diblock copolymer. The covalent couple between the polystyrene and PEG blocks can be cleaved upon irradiation with longwave UV light after just 2 h. PEG blocks are then removed by developing the structure in a mixture of methanol and H2O. The remaining polystyrene contained nanopores that are formed by the vacated PEG phase. Facile preparation of nanoporous materials will accelerate the prospective use of photoresponsive polymers in many applications including nanofabrication,160 gas storage,161

mild irradiation conditions, which is a distinct advantage over networks that use other chemistries such as o-nitrobenzyl, cinnamate, and coumarin functionalities. 3.3. Photosensitive Groups Integrated into Polymer Backbones. Incorporating photosensitive moieties in polymer backbones can confer photodegradability of polymers. Main chain scission achieved by bond cleavage of photosensitive functional groups in the backbone can dissociate polymer chains into fragments with lower molecular weights compared to the initial macromolecule. This strategy can be used to impart dynamic physicochemical properties of polymers and networks. Photosensitive moieties can be placed in various positions on polymer backbones, such as at the midpoint of a homopolymer chain, between different segments of a block copolymer, or even as part of the repeat units.158 3.3.1. Photoresponsive Linkers in Block Copolymers. oNitrobenzyl groups have been incorporated as connectors between segments in block copolymers to achieve selective removal of one block domain. Block copolymers self-assemble into ordered nanostructures via annealing by temperature or L


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Figure 9. (a) Schematic illustration of the formation and dissociation of polymeric nanotubes based on the host−guest interactions of azobenzene and cyclodextrin end-capped linear homopolymers. (b) TEM images showing the reversible assembly and disassembly of nanotubes controlled by UV/visible light irradiation. Adapted from ref 148 with permission of The Royal Society of Chemistry. Copyright 2011 The Royal Society of Chemistry. http://dx.doi.org/10.1039/c1cc12644j.

water purification,162 electrochemical energy storage,163 and biosensors.164 Surface modification is another promising application for onitrobenzyl-based photocleavable linkers. In this embodiment, o-nitrobenzyl groups can connect functional polymer chains to substrates. Hydrophobicity,59 protein immobilization, and cell adhesion143 to substrates can be controlled by using photosensitive materials that can be cleaved using external light. Nagamune et al.144 synthesized photocleavable PEG-lipid by adding a photolabile o-nitrobenzyl linker between PEG chains and oleyl groups (Figure 8). Oleyl moieties bind to nonadherent cells via insertion into the cell membranes. Therefore, selective removal of oleyl groups from PEG chains prevents cell adhesion and promotes detachment from photoresponsive substrates. Micropatterned cell populations are created by selectively exposing the PEG-lipid-coated surfaces to light using a photomask. Cells aggregate in masked regions and detach in exposed regions. Yang et al.147 prepared the amphiphilic diblock copolymer poly(ethylene glycol)-b-poly(acrylate) with truxillic acid as linkers between the two blocks. Block copolymers self-assemble in aqueous environments to form photolabile nanoparticles.

These nanostructures disassemble via truxillic acid junction cleavage upon irradiation with light in the deep UV spectrum. Irradiation of the material for 24 h introduces micron-sized precipitates that are composed of hydrophobic polyacrylate chains, which have limited solubility in water. Incorporating truxillic acid as a photocleavable junction in copolymers is advantageous because the nanostructures can undergo reversible coupling and the polymers are benign with limited intrinsic toxicity.165 Compared to o-nitrobenzyl functional groups, truxillic acid requires longer irradiation time and UV light with a shorter wavelength, which may potentially limit broad utility in biomedical applications. Host−guest interactions between azobenzene and cyclodextrin have been used as end-cap functionalities in linear homopolymers. These precursors utilize exogenous light to initiate assembly and dissociation of multiple polymer chains.148,149 Diblock or triblock copolymers can be prepared in a facile manner using homopolymer segments with different end-caps. Homopolymers containing either trans-azobenzenecapped guest chains or cyclodextrin-capped host chains can be combined to form block copolymers. Block copolymers can be disassembled by UV light exposure to activate the trans−cis M


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exposure. Irradiating polycarbonate films on silicon substrates for 30 min reduces the film thickness by 120 nm. Light-induced surface erosion has potential applications as compostable materials or bulk materials for 3D fabrication. However, the biggest challenge of this strategy and class of materials is the slow disintegration kinetics in the solid state. There are many open questions that must be answered to address this issue: Is it possible to create photodegradable polymers with robust mechanical properties and rapid photodegradation kinetics? In the context of biomedical applications, is it possible to achieve light-induced surface erosion of mechanically stable bulk materials while obviating tissue damage? Addressing these challenges in synthesis and processing may yield new polymeric materials with broad-reaching applications.

isomerization of azobenzene moieties.157 Higher order nanoscale macromolecular networks formed by block copolymers are consequently dissociated, making it a promising carrier for light controlled drug release. Yan et al.148 prepared lightcontrolled polymeric nanotubes based on terminal host−guest interactions of two linear homopolymers (Figure 9). Reversible assembly and dissociation of poly(ε-caprolactone) (PCL)cyclodextrin/poly(acrylic acid) (PAA)-trans-azobenzene nanotubes is achieved by alternating irradiation between UV and visible light. This study reports near 100% release of an encapsulated model payload composed of Rhodamine B. 3.3.2. Utilizing Photolabile Monomers in Photoresponsive Macromolecules. Polymer backbones with high densities of photosensitive functional groups provide an efficient method for photodegradable polymer preparation. Irradiation can degrade high molecular weight polymers into freely diffusible oligomers. Zhao et al.145 synthesized model compounds composed of amphiphilic ABA triblock copolymers where B blocks contain o-nitrobenzyl modified polyurethane in each repeat unit. Photosensitive amphiphiles form micelles spontaneously that can be rapidly dissociated after brief periods of illumination with light in the UV spectrum. The disintegration rate of micelles prepared using this mechanism is more rapid compared to light-induced phase inversion of diblock copolymers with o-nitrobenzyl pendant functional groups. Metal−metal bonds containing photodegradable polymers along their backbones further expand the spectrum of light sensitivity beyond UV wavelengths to include visible light.23 Polymer synthesis strategies have employed metal dimer complexes composed of many elements including molybdenum,166 tungsten,167 and iron.58 Polyurethane thin films bearing functional metal−metal bonds degrade completely in two months by showing decreased absorbance peak at 508 nm upon exposure to ambient sunlight in the presence of oxygen. Polymers either not exposed to light or kept in an oxygen-free environment exhibit limited disintegration.56 These results demonstrate that light and oxygen are both necessary and sufficient for scission of metal−metal bonds. The synthesis strategy of step polymerization is universal for preparing commodity polymers such as polyurethanes, polyureas, polyamides, and polyvinyls.56 Argitis et al.38 prepared photodegradable substrates from polyketals and polyacetals which are susceptible to backbone scission into carbonyl and hydroxyl products by illumination with lasers in the deep UV (λmax = 248 and 193 nm). Low molecular weight polymer fragments were produced and removed by aqueous medium, leading to layer-by-layer materials loss upon laser ablation. These materials are employed as a sacrificial substrate for selective cell detachment and patterning study. The viability of detached cells is preserved during photoablation in aqueous conditions. Furthermore, the number of detached cells is found to be proportional to the ablation area. The extent of cell detachment is controlled by the amount of exposed light. This cell harvesting strategy is therefore advantageous because the specific subpopulations and quantities of cells can be recovered. Sun et al.146 synthesized alkoxyphenacyl-based polycarbonates, which are susceptible to disintegration using light exposure with wavelength between 250 to 320 nm. GPC traces show an elongated elution time after UV irradiation, demonstrating a reduction of the molecular weight distribution. UV−vis absorption spectra of polymer solutions indicate a rapid decrease of absorption peak at λabs = 280 nm after 10 min of

4. PHOTOTHERMAL RECONFIGURABLE NETWORKS Many examples of light-sensitive materials examined previously in this review utilize mechanisms that require π-bonded systems to harvest the light and generate reactive substituents. These transient species can then participate in subsequent reactions such as photolysis, cycloadditions, or isomerization. One tremendous advantage of using photochemical conversion in network modulation is that exotic chemistries can be coupled with specific wavelengths to produce well-defined reactions. Polymer networks can also utilize irradiation through other photoconversion mechanism. For example, the intrinsic energy from irradiated light can be converted into heat through materials with high photon-phonon conversion efficiency. Localized heating can be leveraged to control the properties of dynamic networks that are sensitive to thermal stimuli. Photothermal mechanisms are advantageous because there is a broad range of materials that are capable of harvesting light to induce thermally actuated phase transitions. Furthermore, there is a potentially broader range of wavelengths that can be used to initiate these responses. Somewhat obvious disadvantages are that the spatiotemporal control is less precise because these transitions are essentially localized thermal transitions that can be impacted by the ambient temperature and thermal diffusion. Thermal responsive polymers serve as a suitable foundation for the design of photothermal materials. For example, sol−gel phase transitions in thermally responsive hydrogels have been used extensively in various biomedical applications including dynamic matrices in controlled release systems.168,169 However, temperature stimulus alone has limitations in clinical applications and cannot allow for local control of the material. In order to transform temperature sensitive networks into lightsensitive material, a common strategy is through incorporation of photothermal sensitizers. Photothermal sensitizers such as metal nanoparticles have unique optical properties due to greater absorbance cross sections associated with surface plasmons.170−172 Irradiated light is absorbed by the photothermal sensitizers and converted to heat, leading to local heating of the surrounding matrix. When coupled with a temperature sensitive polymer matrix, the local heat generation can increase the temperature and induce the desired phase transformations. This structural change provides local actuation and modulation of the material for a wide range of potential biomedical applications such as modulated drug delivery.170,173−181 Strategies to form photothermal networks from thermally sensitive polymer doped with photothermal sensitizers are described here. 4.1. Metallic Nanostructures as Photothermal Sensitizers. Nanoparticles featuring gold cores have been extensively N


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Figure 10. Schematic of phase transitions of photoresponsive hydrogel networks from PLGA−PEG−PLGA triblock copolymers doped with melanin nanoparticles (MelNP). PLGA−PEG−PLGA solutions incubated with MelNP (SOL) form physically cross-linked hydrogels (GEL) as the temperature is increased above the SOL−GEL transition. (a) In the SOL phase, micelles are formed from triblock PLGA−PEG−PLGA. (b) Adsorption process of some micelles on MelNP is hypothesized. UV irradiation of the hydrogel network increases the temperature rapidly through local heating of MelNP, leading to network disintegration via precipitate formation (SOL-precipitate). Adapted from ref 176 with permission of The Royal Society of Chemistry. Copyright 2014 Royal Society of Chemistry. http://dx.doi.org/10.1039/c3bm60321k.

studied for decades.170 Colloidal gold has been used in cancer theragnostics including a material that can be used for thermal ablation of cancer tumors.182,183 Gold nanostructures are attractive because gold is bioinert, does not oxidize, is bioexcretable, can be prepared using facile methods, and can be functionalized through bioorthogonal conjugation chemistries.170 Various nanostructures with gold cores have been synthesized and studied to tailor the desired optical properties.174,177,181,184−188 Sershen et al. reported a photothermally modulated drug delivery system based on a hydrogel composite of copolymers of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm) with embedded gold nanoshells.177 NearIR light at wavelengths between 800 and 1200 nm can pass through tissue189,190 and be absorbed by the nanoshells, heating the whole network above its lower critical solution temperature (LCST). The hydrogel’s structure is then collapsed, resulting in a rapid on-demand release of any soluble material held within the matrix. Thermo-reversible phase transition of NIPAAm-coAAm hydrogel coupled with photothermal effect of gold nanoshells affords controlled release profiles through laser irradiation.177 Other gold nanostructures such as gold nanocages,181 gold nanorods,185,186 silica-gold nanoshells,174 and so forth have also been synthesized and modified to tune the desired optical properties. The majority of these research activities utilize PNIPAAm and its derivatives.174,186,191 Oishi et al. recently reported PEGylated nanogels containing gold nanoparticles for multistimuli-triggered drug release. 188 Although bulk gold is generally recognized as a benign and bioinert material with widespread applications in dentistry, the potential toxicity of gold nanostructures is still under investigation.170 The effect of local thermal gradients on the surrounding tissues is also an active area of investigation.192 4.2. Carbon-Based Nanomaterials as Photothermal Sensitizers. Carbon-based materials such as carbon nanotubes and reduced graphene oxide absorb light across a broad spectrum from UV to near-IR wavelengths. Carbon-based nanostructures convert light into heat through nonradiative decay.193−199 Fujigaya et al. incorporated single-walled carbon nanotubes in PNIPAAm composite hydrogel to induce lightirradiated reversible volume phase transition.193 Hydrogel composites composed of PNIPAAm doped with graphene

oxide can yield light-triggered scaffolds for tissue regeneration.195 Sahu et al. reported the formation of a self-assembled hydrogel of graphene oxide nanosheets by physically crosslinking within solutions of Pluronic block copolymers.198 The material can be used as an injectable hydrogel due to the sol− gel temperature close to body temperature.198 Recently, Wang et al. combined reduced graphene oxide nanosheets with biomimetic elastin-based polypeptides (ELPs) to produce hydrogel actuators.200 The use of ELPs has distinct advantages compared to chemically synthesized polymers for biomedical applications because it is a biopolymer composed of natural amino acid monomers.178 ELP hydrogels undergo large changes in swelling and elastic deformations.201 Furthermore, the mechanical properties can also be tuned precisely by genetic manipulation.200 The potential toxicity of carbon-based nanostructures including C60, carbon nanotubes, and graphene is still being investigated for prospective use in clinical applications.197,202 The potential toxicity of these materials is context-dependent and is a function of the form factor and the specific location within the body. 4.3. Metal-Free Photothermally Responsive Hydrogel Composites. Next-generation strategies for photoreconfigurable networks will benefit from simpler mechanisms that minimize the use of exotic chemistries and eliminate the need for high-powered irradiation. This trend is evident because the focus of newer materials selection criteria has shifted to materials that are comprised of organic substituents.176,179 A strategy was recently reported in which physically cross-linked hydrogel networks composed of poly(L-lactide-co-glycolide)-bpoly(ethylene glycol)-b-poly(L-lactide-co-glycolide) (PLGA-bPEG-b-PLGA) could be transformed into a photoresponsive material by incorporating biologically derived melanin nanoparticles (MelNP) as efficient photothermal sensitizers.176 Melanins belong to a broad class of ubiquitous pigments that are found in many living organisms in the plant and animal kingdoms.203,204 A consequence of their unique chemical and structural properties is photon−phonon conversion with near ideal efficiency.205−207 The low toxicity of benign melanins used in some biomedical applications has been previously reported.173,208 More recently, Viger and co-workers hypothesized that a universal strategy for phototriggered drug release O


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Figure 11. Light-controlled motions of hydrogel actuators doped with graphene oxide photothermal sensitizers. NIR laser that is focused on specific locations result in (a) bending and unbending of fingers on a hand-shaped hydrogel, or (b) direction-dependent folding of a circular composite hydrogel (1 mm tick marks). (c) Schematic and images of hydrogel curling and uncurling in response to laser. A hydrogel was molded with a slight curvature and placed with porous side facing down. Gel curling is induced upon photothermal actuation using external laser light. Subsequent uncurling occurs upon recovery after the laser is removed. Reproduced with permission from ref 200. Copyright 2013 American Chemical Society.

gels can also be used as actuators that respond to stimuli with rapid response times.200 Wang et al. have demonstrated lightcontrolled motions of hydrogel actuators doped with graphene oxide photothermal sensitizers, for example, bending and unbending of macroscopic finger-like structures on a handshaped hydrogel in response to a near-IR laser that is focused on a specific location (Figure 11). This material is potentially applicable in various technological fields such as light-controlled dynamic cell culture, microfluidics, and soft robotics.200 There is a wide variety of available photothermal sensitizers, both natural and synthetic, that can be combined with functional hydrogels to create thermally responsive hydrogel networks. The specific properties of the prospective networks can be tailored for specific application by choosing the appropriate combination of photothermal sensitizer and hydrogel composition. Choosing benign, nontoxic materials for each component of the system can increase the prospect for rapid clinical translation for applications in controlled release, for example. Other ancillary risks must be assessed beyond the intrinsic toxicity of the materials. For example, the impact of local heating on surrounding tissue must be addressed. Other practical considerations include the logistics of deploying the optical signal to confined locations within the body.

using near-IR light can be achieved without incorporating additional photothermal sensitizers by exposing materials to light that is in resonance with the vibrational overtone of water.179 Confined water pockets within hydrated hydrogels such as nonlight-sensitive PLGA absorb optical energy and convert it into heat.179 Localized heating of small water droplets trapped inside microstructures of a hydrogel heats the surrounding polymer matrix by thermal conduction. Heating the polymer matrix above its glass transition temperature results in glassy−rubbery transitions that increase the mesh size of the hydrogel network and permit diffusion of encapsulated particles.179 Novel materials synthesis and design strategies that obviate the use of synthetic, metal photosensitizers may be more desirable than counterparts that do contain these materials because the timeline for clinical translation could be accelerated in the case of the former. Preliminary parameters for use of such systems have been established but still require significant effort for use in specific biomedical applications. 4.4. Applications of Photothermal Reconfigurable Networks. Photothermal hydrogels have been studied primarily in the context of programmable matrices for applications in controlled release.174,177,179,181,184,186,188,191,193,195,196 Spatiotemporal control of drug release rates using low intensity laser irradiation can achieve arbitrary release profiles that can be tailored to match patient-specific dosing schedules. For example, insulin therapy for diabetes requires a low baseline with periods of peak delivery after food ingestion.209,210 Photothermal triblock copolymers that exhibit sol−gel transition near body temperature may be suitable as an injectable hydrogel for applications in wound healing, tissue regeneration, or endovascular applications. Incorporating photothermal sensitizers increases the potential spectrum of cues that can induce reconfiguration of the network.186,211 The proposed mechanism for UVinduced photothermal phase transitions in reconfigurable PLGA−PEG−PLGA hydrogels loaded with melanin nanoparticles is described in Figure 10. Micelles formed from pristine PLGA−PEG−PLGA in the solutions aggregate as the temperature increases above the sol−gel transition to form a physically cross-linked network.178,184,185 UV irradiation of the material is converted into local heating by incorporated melanin nanoparticles forming precipitates and leading to disruption of the macroscopic network. Finally, photoreconfigurable hydro-

5. FUTURE PERSPECTIVES Photoresponsive polymers must be designed to exhibit properties that are optimized for their intended applications. Prospective applications of these materials, including programmable matrices for controlled release, templates for biomolecular/cell micropatterning, and programmable scaffolds for tissue engineering, all present unique materials selection criteria. The macroscopic form factor such as micelles, crosslinked hydrogel networks, and two-dimensional surfaces can utilize the same photosensitive chemistry to achieve different capabilities. In general, photoresponsive polymers targeted for biomedical applications should meet several basic criteria: (1) both precursors and macromolecules should be prepared using synthetic routes that are facile, robust, and scalable; (2) the chemical and mechanical stability of the network should be established and preserved prior to and in the absence of exogenous light cues; (3) light-induced reactions should proceed rapidly in aqueous conditions while using the lowest possible amount of irradiation energy to prevent collateral P


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volume and requires a highly focused laser beam that could damage tissue by heating. Tremendous progress in the use of light as a cue for smart polymeric materials has been achieved in recent decades. However, there are still major technical challenges that remain. One advantage for designing photofunctional polymeric biomaterials for medicine is that this application space is exempt from many of the traditional cost pressures that face commodity polymers that may be used in applications such as clean energy or consumer products. However, incorporating novel chemistries with photofunctionality into polymeric biomaterials offers additional constraints in prospective medical applications such as toxicity and regulatory considerations. Therefore, enthusiasm with novel chemistries and mechanisms must be tempered by the potential hurdles that these materials face prior to regulatory approval and clinical adoption for specific indications. Novel materials that pose unknown risk to long-term health face a gauntlet of regulatory hurdles and economic barriers to clinical translation. The most likely scenario for expedited approval is the case where a photofunctional material can provide a novel capability that is essential for treating an indication for which satisfactory treatment options are not currently available. This realistic constraint motivates the use of alternative light-sensitive chemistries that may utilize different mechanisms for modulating network properties. Strategies using materials that are either biologically inert (metallic structures such as gold), endogenous (melanin granules, confined water pockets intrinsically within hydrated hydrogels, etc.), or generally recognized as safe (PLGA and copolymers of PLGA) offer an increased likelihood for clinical adoption; however, they still suffer from specific limitations for widespread applications. At present, photoresponsive materials are likely to have the greatest impact as tools for constructing unique experimental platforms for fundamental research in biology. The materials described herein could have a formative role in precisely defining both the soluble factors and extracellular matrix analogues in synthetic designer cellular microenvironments. Light-responsive materials confer the ability to control the extracellular environment across four dimensions. Further collaboration is required with biologists to devise interesting and relevant questions in which novel photoresponsive polymeric materials can provide unique insight and capabilities.

damage to surrounding cells and tissues; (4) the polymer, in addition to the prospective byproducts, should be benign and present minimal cytotoxicity.38 Byproducts should be either biodegradable or bioexcretable with rapid elimination rates from the body. Minimizing toxicity is a key consideration when leveraging photoresponsive polymeric materials for biomedical applications. The use of organic solvents, exotic catalysts, free radicals, and transition metal complexes must be minimized during material synthesis. The use of these potentially toxic components should be minimized or, where possible, eliminated altogether. Meanwhile, “green” polymerization methods have been developed in recent years and can be potentially applied for photoresponsive polymer synthesis.212 Activator generated by electron transfer (AGET) ATRP can conduct polymerization reactions using metal complex concentrations no higher than ppm.213 Polymerizations may also be conducted in aqueous medium to eliminate the use of toxic organic solvents.214,215 The cytotoxicity of byproducts after light irradiation is another major concern of photoresponsive polymer design. The nitrosobenzaldehyde and coumarin groups discussed in this work have been previously reported as possessing potential toxicity to human body.216−219 The toxicity risk of light-induced macromolecular fractions and side group moieties can be mitigated if they are used in applications that prevent accumulation. For example, potential applications in the endovascular, digestive, or urinary systems could minimize the buildup of potentially cytotoxic byproducts. Although light is a desirable cue based on its temporal and spatial precision, potential for remote application, and convenience, there are still many challenges and open questions that are being addressed in ongoing research on photoresponsive polymers. Instantaneous responses to irradiated light sources at benign wavelengths and low intensities would be ideal for prospective biomedical applications. However, most photofunctional chemistries require activation using light at high intensities and long exposure times. Furthermore, most of the photosensitive moieties only respond to UV light, which could cause potential DNA damage to cells. The rapid attenuation of the intensity of irradiated light over a path length governed by the Beer−Lambert law is a potential concern for controlling the uniformity of stimuli-responsive networks that are modulated by light for use in functional biomedical materials.220 Homogeneous polymers networks are essential for ensuring reproducibility and facile physical characterization. However, passive spatial control of light intensity within a network can produce unique features such as gradients, which may be biologically relevant. Therefore, it is critical to not only improve the absorption efficiency of materials to light exposure but also seek new methods of preparing polymers that are sensitive to light with red-shifted wavelengths. Near-IR two-photon absorption appears to be a promising alternation of UV light considering its deep tissue penetration and high three-dimensional resolution. Near-IR light exhibits reduced cytotoxicity and cell damage compared to light in the UV spectrum and is widely used in various therapeutic treatments and biological imaging techniques.221,222 Polymers with near-IR sensitivity have been intensively developed and studied in recent years. However, there are many practical challenges with using near-IR as an external stimulus. Two-photon absorption processes are based on a photon crowding effect that limits the overall irradiation

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to acknowledge the work of authors that could not be included in this article due to space and formatting limitations. Funding provided by the following organizations: the Berkman Foundation; the American Chemical Society Petroleum Research Fund (ACS PRF #51980-DNI7); the American Heart Association Scientist Development Grant (12SDG12050297); and the Carnegie Mellon University School of Engineering.

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