Progress in Polymer Science Future perspectives and recent ...

Progress in Polymer Science 35 (2010) 278–301 

Contents lists available at ScienceDirect 

Progress in Polymer Science 

journal homepage: www.elsevier.com/locate/ppolysci 

Future perspectives and recent advances in stimuli-responsive 

materials 

Debashish Roy, Jennifer N. Cambre, Brent S. Sumerlin ∗ 

Department of Chemistry, Southern Methodist University, 3215 Daniel Avenue, Dallas, TX 75275-0314, USA 

article info 

Article history: 

Received 2 September 2009 

Received in revised form 20 October 2009 

Accepted 22 October 2009 

Available online 3 November 2009 

Keywords: 

Stimuli-responsive polymers 

Smart polymers 

Drug delivery 

Dynamic covalent chemistry 

Hydrogels 

Controlled release 

Contents 

abstract 

Interest in stimuli-responsive polymers has persisted over many decades, and a great deal 

of work has been dedicated to developing environmentally sensitive macromolecules that 

can be crafted into new smart materials. However, the overwhelming majority of reports 

in the literature describe stimuli-responsive polymers that are sensitive to only a few common 

triggers, including changes in pH, temperature, and electrolyte concentration. Herein, 

we aim to highlight recent results and future trends that exploit stimuli that have not 

yet been as heavily considered, despite their unique potential. Many of the topics represent 

clear opportunities for making advances in biomedical fields due to their specificity and the 

ability to respond to stimuli that are inherently present in living systems. Recent results 

in the area of polymers that respond to specific antigen–antibody interactions, enzymes, 

and glucose are specifically discussed. Also considered are polymeric systems that respond 

to light, electric, magnetic, and sonic fields, all of which have potential in the area of controlled 

release as a result of their ability to be applied in a non-invasive and easily controlled 

manner. Thiol-responsive and redox-responsive polymers are also highlighted, with particular 

attention being devoted to their reversible dynamic covalent chemistry. It is our goal 

to emphasize these underutilized adaptive behaviors so that novel applications and new 

generations of smart materials can be realized. 

© 2009 Elsevier Ltd. All rights reserved. 

1. Introduction ........................................................................................................................ 279 

2. Biologically responsive polymer systems ......................................................................................... 279 

2.1. Glucose-responsive polymers .............................................................................................. 280 

2.1.1. Glucose-responsive systems based on glucose-GOx ............................................................. 280 

Abbreviations: APBA, 3-acrylamidophenylboronic acid; ATRP, atom transfer radical polymerization; ConA, concanavalin A; CRP, controlled/“living” radical 

polymerization; DDOPBA, 4-(1,6-dioxo-2,5-diaza-7-oxamyl) phenylboronic acid; DTT, dithiothreitol; DMAPA, N,N-(dimethylamino)propylacrylamide; 

FITC, fluorescein isothiocyanate; GOx, glucose oxidase; GSH, glutathione; IgG, immunoglobulin G; IPN, interpenetrating network hydrogel; LCST, lower 

critical solution temperature; MBA, N,N-methylene-bis-acrylamide; NMP, nitroxide mediated radical polymerization; NSA, N-succinimidylacrylate; NIR, 

near-infrared; PAA, poly(acrylic acid); PMAA, poly(methacrylic acid); PNIPAM, poly(N-isopropylacrylamide); PHEMA, poly(2-hydroxyethyl methacrylate); 

PDMAEMA, poly(N,N-dimethylaminoethyl methacrylate); PEG, poly(ethylene glycol); PDMA, poly(N,N-dimethylacrylamide); PVA, poly(vinyl alcohol); 

PHPMA, poly(N-hydroxypropyl methacrylamide); PEO, poly(ethylene oxide); PNVP, poly(N-vinylpyrrolidone); PDEGA, poly(di(ethylene glycol)ethyl ether 

acrylate); PPO, poly(propylene oxide); RAFT, reversible addition-fragmentation chain transfer; TCEP, tris(2-carboxyethyl)phosphine; VPGVG, valineproline-glycine-valine-glycine; 

UV, ultraviolet. 

∗ Corresponding author. 

E-mail address: bsumerlin@smu.edu (B.S. Sumerlin). 

0079-6700/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. 

doi:10.1016/j.progpolymsci.2009.10.008

D. Roy et al. / Progress in Polymer Science 35 (2010) 278–301 279 

2.1.2. Glucose-responsive systems based on ConA ..................................................................... 281 

2.1.3. Glucose-responsive systems based on boronic acid–diol complexation ........................................ 281 

2.2. Enzyme-responsive polymers.............................................................................................. 283 

2.3. Antigen-responsive polymers .............................................................................................. 285 

2.4. Redox/thiol-responsive polymers.......................................................................................... 286 

3. Field-responsive polymers......................................................................................................... 288 

3.1. Electro-responsive polymers ............................................................................................... 289 

3.2. Magneto-responsive polymers ............................................................................................. 290 

3.3. Ultrasound-responsive polymers .......................................................................................... 291 

3.4. Photo-responsive polymers ................................................................................................ 293 

4. Conclusions ........................................................................................................................ 294 

Acknowledgement ................................................................................................................. 294 

References ......................................................................................................................... 294 

1. Introduction 

At their most fundamental level, many of the most 

important substances in living systems are macromolecules 

with structures and behaviors that vary according 

to the conditions in their surrounding environment. A 

variety of biological processes rely on feedback-controlled 

communication involving nucleic acids, proteins, and 

polypeptides that have the ability to adopt conformations 

specific to their surroundings. Similar adaptive behavior 

can be imparted to synthetic (co)polymers such that their 

utility goes beyond providing structural support to instead 

allow active participation in a dynamic sense. Incorporating 

multiple copies of functional groups that are readily 

amenable to a change in character (e.g., charge, polarity, 

and solvency) along a polymer backbone causes relatively 

minor changes in chemical structure to be synergistically 

amplified to bring about dramatic transformations in 

macroscopic material properties. 

The “response” of a polymer can be defined in various 

ways. Responsive polymers in solution are typically 

classified as those that change their individual chain 

dimensions/size, secondary structure, solubility, or the 

degree of intermolecular association. In most cases, the 

physical or chemical event that causes these responses 

is limited to formation or destruction of secondary 

forces (hydrogen bonding, hydrophobic effects, electrostatic 

interactions, etc.), simple reactions (e.g., acid–base 

reactions) of moieties pendant to the polymer backbone, 

and/or osmotic pressure differentials that result from such 

phenomena. In other systems, the definition of a response 

can be expanded to include more dramatic alterations 

in the polymeric structure. For example, degradation of 

hydrogels upon the application of a specific stimulus can 

occur by reversible or irreversible bond breakage of the 

polymeric backbone or pendant cross-linking groups. For 

the sake of this review, both concepts will be included, with 

particular attention being paid to those that hold promise 

in the areas of biomedical, sensing, and electronics applications. 

Interest in stimuli-responsive polymers has persisted 

over many decades, and a great deal of work has been dedicated 

to devising examples of environmentally sensitive 

macromolecules that can be crafted into new smart materials. 

However, the overwhelming majority of reports in the 

literature describing stimuli-responsive polymers are ded- 

icated to macromolecular systems that are sensitive to a 

few common stimuli, usually changes in pH, temperature, 

and electrolyte concentration. The purpose of this review 

is not to describe every stimulus being employed to induce 

a response in polymer systems. Rather, we aim to highlight 

recent results and future trends of a few particularly useful 

stimuli that have, in our opinion, not yet been exploited 

to a similar extent, despite their unique potential. In many 

cases, the topics represent clear opportunities for making 

advances in biomedical fields due to their specificity and 

the ability to respond to stimuli that are inherently present 

in biological systems. Indeed, designing synthetic polymers 

with the ability to adapt their properties in response 

to specific interactions with biomacromolecules and small 

molecules commonly associated with healthy or diseased 

states (e.g., glucose) may facilitate the application of smart 

polymers in drug delivery, diagnostics, sensing, separations, 

etc. Additionally, it is often advantageous to utilize 

a stimulus that is specifically applied from an external 

source so that the location and rate of response can be easily 

adjusted, as opposed to a stimulus that is encountered 

as an inherent feature of the system under consideration 

(e.g., change in pH occurring upon endocytosis). The ability 

to apply these sorts of stimuli in a non-invasive manner 

particularly lends itself to applications in vivo. The discussion 

that follows will focus on recent research in the 

area of smart materials by emphasizing these underutilized 

adaptive behaviors that have the ability to affect polymer 

conformation, solubility, degradability, and self-assembly 

behavior in aqueous media. The first areas covered will 

pertain to specific responses that may be encountered 

in biological systems. Polymers that alter their properties 

in response to glucose, enzymes, antigens/antibodies, 

and thiol/redox conditions are described. Secondly, we 

highlight recent results in the areas of field-responsive 

polymers, specifically macromolecules that exhibit adaptive 

behaviors when exposed to irradiation with light, 

electric, magnetic, or sonic energy. 

2. Biologically responsive polymer systems 

Smart polymers are becoming increasingly important 

in the context of biomedical applications. Whether 

for the purpose of controlled drug delivery, biosensing/diagnostics, 

smart films/matrices for tissue engineering, 

or for the in situ construction of structural networks,

280 D. Roy et al. / Progress in Polymer Science 35 (2010) 278–301 

Fig. 1. (a) In the absence of glucose, the PAA chains are extended which lowers the permeability of the membrane. (b) Addition of glucose leads to a 

lowering of local pH and chain collapse due to a reduction in electrostatic repulsion [4]. 

it is often advantageous to employ polymers that can 

respond to stimuli that are inherently present in natural 

systems. This approach is a form of biomimicry, since 

many biomacromolecules are known to dramatically alter 

their conformation and degree of self-assembly in response 

to the presence of specific chemical species in their surroundings. 

While great strides have been made in the 

design and implementation of new stimuli-responsive 

polymers, many of these suffer from adaptive behaviors 

that are inherently non-specific. Additionally, some of 

the more commonly considered stimuli (e.g., changes in 

temperature) are challenging to apply in vivo. Therefore, 

recent attention has been devoted to endowing synthetic 

polymers with functionality [1] that allows responsive 

behavior when exposed to biological small molecules or 

biomacromolecules. In some cases, this arises from including 

common functional groups that are known to interact 

with biologically relevant species, and in others adaptive 

behavior is the result of the synthetic polymer being conjugated 

to a biological component. Examples of both of these 

concepts are provided below. 

2.1. Glucose-responsive polymers 

While a variety of specific biological responses can be 

envisioned and have been reported in the literature [2], 

polymers that respond to glucose have received considerable 

attention because of their potential application in both 

glucose sensing and insulin delivery applications. Diabetes 

mellitus, commonly referred to as diabetes, is a chronic disease 

characterized by insufficient production or ineffective 

usage of insulin. Treatment generally involves regular monitoring 

of blood sugar concentrations and subcutaneously 

administering insulin several times per day. This need for 

consistent patient vigilance often leads to poor compliance 

with the prescribed therapy. One potential route proposed 

to increase patient compliance is the development and 

use of smart delivery systems in which insulin delivery is 

automatically triggered by a rise in blood glucose levels. 

While a variety of approaches can be envisioned to achieve 

this objective, considerable research has been dedicated to 

developing self-regulated insulin delivery systems based 

on glucose-responsive polymers [3]. Glucose-responsive 

polymeric systems are typically based on enzymatic oxidation 

of glucose by glucose oxidase (GOx), binding of glucose 

with concanavalin A (ConA), or reversible covalent bond 

formation between glucose and boronic acids. 

2.1.1. Glucose-responsive systems based on glucose-GOx 

The majority of reports detailing glucose-responsive 

polymers are based on the GOx-catalyzed reaction of 

glucose with oxygen. Typically, glucose-sensitivity is not 

caused by direct interaction of glucose with the responsive 

polymer, but rather by the response of the polymer 

to the byproducts that result from the enzymatic oxidation 

of glucose. The enzymatic action of GOx on glucose is 

highly specific and leads to byproducts of gluconic acid and 

H 2O 2. Therefore, incorporation of a polymer that responds 

to either of these small molecules can indirectly lead to 

a glucose-responsive system. Typically, a pH responsive 

polymer is loaded or conjugated with GOx, and the gluconic 

acid byproduct that results from the reaction with glucose 

induces a response in the pH-responsive macromolecule. 

For applications specifically intended for diabetes therapy, 

the pH-response generally causes swelling or collapse of 

hydrogel matrix that contains insulin. For example, Imanishi 

and co-workers reported the covalent modification 

of a cellulose film with GOx-conjugated poly(acrylic acid) 

(PAA) [4]. At neutral and high pH levels, the carboxylate 

units of the PAA chains were negatively charged and 

extended due to electrostatic repulsion, which resulted 

in occlusion of the pores in the cellulose membrane. 

The gluconic acid that resulted from the addition of glucose 

led to a local pH reduction, protonation of the PAA 

carboxylate moieties, and concomitant collapse of the 

chains obscuring the membrane pores, with the latter 

event facilitating the release of entrapped insulin (Fig. 1). 

Similar glucose-responsive gating membranes based on 

PAA-grafted poly(vinylidene fluoride) have been reported 

[5]. 

Peppas and co-workers exploited a similar concept 

to prepare glucose-responsive hydrogels [6]. 

Poly(methacrylic acid (PMAA)-graft-ethylene glycol) 

gels were synthesized in the presence of GOx. At neutral 

and high pH values, the gels were swollen by repulsion 

between negative charges on methacrylate units. The


Scheme 1. Aqueous ionization equilibria of boronic acids. As the concentration of diol increases, the equilibria shift toward the anionic boronate forms of 

the boronic acid. 

reduction in pH upon oxidation of glucose by GOx led to gel 

collapse. In addition to a reduction in electrostatic repulsion, 

the efficient response of the gel was also attributed 

to enhanced hydrogen bonding between the carboxyl and 

ether groups of the ethylene glycol units. Similar hydrogels 

prepared by copolymerization of N-isopropylacrylamide 

(NIPAM) with methacrylic acid [7] or a sulfadimethoxine 

monomer with N,N-dimethylacrylamide (DMA) have also 

been reported [8]. 

As opposed to gluconic acid production leading to chain 

collapse in carboxylate-containing polymers, the lowering 

of pH could also lead to chain expansion in the presence 

of a polybase [9–11]. For example, Kost and co-workers 

examined the glucose-responsive nature of crosslinked 

poly(2-hydroxyethyl methacrylate-co-N,N-dimethylaminoethyl 

methacrylate) (poly(HEMA-co-DMAEMA)) 

that contained entrapped GOx, catalase, and insulin [12]. 

In this case, as the pH of the hydrogel was lowered during 

exposure to glucose, amines in the DMAEMA units assumed 

a positive charge, and electrostatic repulsion caused hydrogel 

swelling and insulin escape. A similar system has been 

reported by Narinesingh and co-workers [13]. 

The need for increased biocompatibility in GOx-based 

responsive materials has recently led to the incorporation 

of poly(ethylene glycol) (PEG) grafts [9–11,14,15] and other 

nontoxic, nonimmunogenic, biocompatible polymers, such 

as chitosan [15,16]. Additionally, while the examples above 

were largely hydrogels that rely on changes in pH resulting 

from production of gluconic acid during the oxidation of 

glucose, it is also possible to prepare other pH-responsive 

polymer morphologies. For example, Han and co-workers 

synthesized pH-sensitive liposomes using �-palmitoyl-�decyl-l-�-phosphatidylethanolamine 

and oleic acid [17]. 

The liposomes were infused with GOx and insulin, and 

the acidic environment that resulted from glucose oxidation 

destabilized the liposomes and led to insulin 

delivery. Moreover, it is also possible to prepare polymers 

that respond to the increased concentration of the H 2O 2 

byproduct instead of gluconic acid [18]. 

2.1.2. Glucose-responsive systems based on ConA 

Another type of glucose-responsive system utilizes 

competitive binding of glucose with glycopolymer–lectin 

complexes, as reported by Brownlee and Cerami [19]. 

Lectins are proteins that specifically bind carbohydrates. 

Because most lectins are multivalent, glycopolymers 

tend to crosslink and/or aggregate in their presence; 

however, this aggregation can be disrupted by introducing 

a competitively binding saccharide [3]. Numerous 

glucose-responsive materials have been reported based 

on competitive binding between lectins and glucose. The 

lectin most heavily employed to impart sensitivity to glucose 

is concanavalin A (ConA). 

Kim and co-workers reported the synthesis of monosubstituted 

conjugates of glucosyl-terminal PEG (G-PEG) 

and insulin [20]. The G-PEG-insulin conjugates were 

bound to ConA that was attached pendantly along a PEGpoly(vinylpyrrolidone-co-acrylic 

acid) backbone. When 

the concentration of glucose in the surrounding aqueous 

solution increased, competitive binding of glucose with 

ConA led to displacement and release of the G-PEG-insulin 

conjugates. Sambanis reported a ConA-glycogen gel that 

underwent a gel–sol transition in the presence of glucose 

due to the preferred binding of ConA with free glucose over 

the glycogen containing gel [21]. The authors indicated the 

possibility of creating a hybrid pancreas substitute from 

constitutively secreting cells and a glucose-responsive 

material that could mimic physiologic regulation of insulin 

release. Hoffman and co-workers synthesized a glucoseresponsive 

hydrogel via copolymerization of ConA vinyl 

macromonomers with a monomer modified with pendent 

glucose units [22]. The addition of free glucose caused the 

glycopolymer–ConA complex to dissociate and the gel to 

swell, with the degree of swelling depending on glucose 

concentration. Responsive systems in which ConA is simply 

entrapped in the hydrogel can lead to leakage of the protein 

and irreversible swelling. However, the copolymerized 

hydrogel described above prevented ConA leakage, and the 

hydrogels were demonstrated to be reversibly responsive. 

The response of these polymers was specific for glucose or 

mannose, while other sugars caused no response [23–25]. 

2.1.3. Glucose-responsive systems based on boronic 

acid–diol complexation 

While the glucose-responsive systems based on GOx 

and lectins are versatile and highly specific, the reliance on 

protein-based components may limit applications under 

non-biological conditions or over longer time spans that 

might promote denaturation. An alternative mechanism of 

glucose-response relies on polymers endowed with purely 

synthetic components, namely boronic acid moieties. The 

ability of boronic acids to reversibly complex with sugars 

has led to their being heavily employed as glucose sensors 

and as ligand moieties during chromatography [26]. 

Boronic acids are unique because their water-solubility can 

be tuned by changes in pH or diol concentration (Scheme 1). 

In aqueous systems, boronic acids exist in equilibrium 

between an undissociated neutral trigonal form (1) and a 

dissociated anionic tetrahedral form (2) [2,27–30]. Inthe 

presence of 1,2- or 1,3-diols, cyclic boronic esters between


Scheme 2. Synthesis of boronic ester-containing block copolymers via RAFT followed by deprotection (Route 1) and direct RAFT polymerization of an 

unprotected monomer to yield boronic acid-containing block copolymers [63–65]. 

the neutral boronic acid and a diol are generally considered 

hydrolytically unstable [27]. On the other hand, the 

anionic form (2) is able to reversibly bind with diols to form 

a boronate ester (3), shifting the equilibria to the anionic 

forms (2 and 3) [30]. Polymers containing neutral boronic 

acid groups are generally hydrophobic, whereas the anionic 

boronate groups impart water-solubility [28]. As the concentration 

of glucose is increased, the ratio of the anionic 

forms (2 and 3) to the neutral form (1) increases, and the 

hydrophilicity of the system increases. Therefore, as a result 

of the interrelated equilibria discussed above, the solubility 

of boronic acid-containing polymers is dependent not 

only on pH, but also on the concentration of compatible 

diols in the surrounding medium [2]. By exploiting the 

complexation behavior between boronic acids and a particularly 

relevant 1,2-diol (i.e., glucose), the possibility for 

glucose-responsive materials exists [2]. 

As with many of the glucose-responsive systems 

discussed above, most examples of boronic acid-based 

responsive polymers have been hydrogels that swell or 

collapse when exposed to glucose. Sakurai and co-workers 

reported the synthesis of a glucose-responsive hydrogel 

composed of terpolymers of 3-acrylamidophenylboronic 

acid (APBA), (N,N-dimethylamino)propylacrylamide 

(DMAPA), and DMA [31]. The boronic acid groups present 

in the terpolymer were allowed to complex with poly(vinyl 

alcohol) (PVA) at physiological pH. Addition of glucose led 

to competitive displacement of the PVA, and the resulting 

decrease in crosslink density led to swelling of the gel. In 

similar systems, responsive hydrogels were made by complexing 

PVA with poly(N-vinyl-2-pyrrolidone-co-APBA) 

[32] or poly(DMA-co-3-methacrylamidophenylboronic 

acid-co-DMAPA-co-butyl methacrylate) [33]. Sakurai 

reported another glucose-responsive polymeric hydrogel 

prepared via copolymerization of NIPAM with APBA and 

N,N-methylene-bis-acrylamide (MBA) as a crosslinker 

[29]. Glucose-responsive polymer gel particles have been 

reported using a similar system [34], and PNIPAM-based 

comb-type grafted hydrogels with rapid response to 

glucose concentration were recently reported by Xie and 

co-workers [35]. In addition to conventional hydrogels, 

several glucose-responsive microgels [36–41] and fluorescent 

nanospheres based on poly(NIPAM-co-APBA) [42] 

have been reported. 

As shown in Scheme 1, modulation in solubility of 

most polymeric boronic acids occurs because of an apparent 

reduction in pKa of the boronic acid moiety in the 

presence of glucose. For this reason, potential therapeutic 

applications require boronic acids with a pKa near physiological 

pH. Most phenylboronic acids reported in the 

literature have pKa > 8. However, Kataoka recently reported 

the synthesis of a glucose-responsive copolymer of 4-(1,6dioxo-2,5-diaza-7-oxamyl) 

phenylboronic acid (DDOPBA) 

(pKa ≈ 7.8) and NIPAM [43,44]. Because of its more physiological 

relevant pKa, this copolymer is perhaps more 

appropriate for use in biological systems. 

Most glucose-responsive boronic acid-based (co)polymers 

have been synthesized by conventional radical 

polymerization to yield random copolymers [45,46], gels 

[37], or other crosslinked materials [47,48]. To fully capitalize 

on the unique properties of boronic acid-containing 

polymers, especially sensing and delivery applications 

that may rely on supramolecular self-assemblies, it is 

important to prepare well-defined copolymers with 

predictable molecular weights, narrow molecular weight 

distributions, and retained chain end functionalities, 

the latter of which facilitates block copolymer synthesis 

[49,50]. Controlled/“living” radical polymerization (CRP) is 

a synthetic technique that offers control over these aspects. 

CRP methods such as atom transfer radical polymerization 

(ATRP) [51–53] and reversible addition-fragmentation 

chain transfer (RAFT) polymerization [54–58] have been 

used to prepare well-defined organoboron polymers. 

Jäkle and co-workers reported the efficient synthesis of 

organoboron vinyl (co)polymers via ATRP, either from silylated 

precursors that were subsequently borylated [59–61] 

or from the polymerization of organoboron monomers 

[62]. We employed RAFT polymerization for the synthesis 

of well-defined boronic acid block copolymers by two 

different methods. The first approach involved the polymerization 

of the pinacol ester of 4-vinylphenylboronic 

acid followed by a mild deprotection procedure (Scheme 2) 

[63]. More recently, we reported the synthesis of welldefined 

block copolymers via direct RAFT polymerization 

of unprotected APBA [64,65]. 

The block copolymers of hydrophilic DMA and responsive 

boronic acid-containing monomers were hydrophilic 

and fully soluble above the pKa of the boronic acid


Fig. 2. PAPBA-b-PNIPAM self-assembly/dissociation in response to changes in pH, glucose concentration, and temperature [65]. Reproduced by permission 

of The Royal Society of Chemistry. 

units. However, at pH < pKa the block copolymers selfassembled 

to form micelles. The boronic acid functionality 

within the hydrophobic core caused these micelles to 

dissociate with increasing pH or glucose concentration. 

Replacing the hydrophilic poly(DMA) (PDMA) block 

with temperature-responsive PNIPAM [66–68] led to 

triply-responsive “schizophrenic” block copolymers that 

responded to changes in pH, glucose concentration, and 

temperature [65]. Depending on the combination of stimuli 

applied, these block copolymers were capable of forming 

micelles or reverse micelles (Fig. 2). 

2.2. Enzyme-responsive polymers 

A relatively new area of research in stimuli-responsive 

polymeric systems is the design of materials that undergo 

macroscopic property changes when triggered by the 

selective catalytic actions of enzymes [69,70]. Sensitivity 

of this type is unique because enzymes are highly 

selective in their reactivity, are operable under mild conditions 

present in vivo, and are vital components in many 

biological pathways. Enzyme-responsive materials are typically 

composed of an enzyme-sensitive substrate and 

another component that directs or controls interactions 

that lead to macroscopic transitions [70]. Catalytic action 

of the enzyme on the substrate can lead to changes in 

supramolecular architectures, swelling/collapse of gels, or 

the transformation of surface properties [70]. 

Similarity in properties with extracellular matrix 

make hydrogels especially promising materials for tis- 

sue engineering, and this in vivo applicability makes the 

incorporation of enzyme-sensitivity particularly intriguing. 

Hydrogels that are enzyme-responsive can be used for 

the non-invasive formation of hydrogels in situ. Xuand 

co-workers reported the use of enzymatic dephosphorylation 

to induce a sol–gel transition. The small molecule 

fluorenylmethyloxycarbonyl (FMOC)-tyrosine phosphate 

was exposed to a phosphatase, and the resulting removal 

of phosphate groups led to a reduction in electrostatic 

repulsions, supramolecular assembly by �-stacking of the 

fluorenyl groups, and eventual gelation [71,72]. In a similar 

example, Kaplan and co-workers reported the modification 

of a genetically engineered variant of spider dragline silk via 

enzymatic phosphorylation and dephosphorylation [73]. 

Another approach to convey enzyme-sensitivity to a 

material is the incorporation of functional groups that react 

under enzymatic conditions. Exposure of the groups to a 

specific enzyme can lead to the creation of new covalent 

linkages that cause a change in macroscopic properties. For 

example, Ulijin and co-workers used proteases to cause 

self-assembly of hydrogels via reversed hydrolysis (ligation) 

of peptides [74]. Transglutaminase, a blood clotting 

enzyme, has the ability to crosslink the side chains of 

lysine (Lys) residues with glutamine (Gln) residues within 

or across peptide chains [70]. This process was exploited 

by Griffith and Sperinde for the synthesis of hydrogels 

of crosslinked functionalized PEG and lysine-containing 

polypeptides [75,76]. Controlled gelation kinetics were 

observed under rather moderate conditions, indicating this 

route may allow hydrogel formation in the presence of 

Fig. 3. (a) Solution mixture of a peptide-PEG bioconjugate, calcium-loaded liposomes, Factor XIII, and thrombin; (b) heating to 37 ◦ C led to calcium release 

from liposomes, thrombin activation, and Factor XIII activation by thrombin; (c) activated Factor XIII crosslinked the peptide-PEG resulting in hydrogel 

formation. Reprinted from [78], Copyright (2002), with permission from Elsevier.


Fig. 4. Collapse of enzyme-responsive hydrogels due to reduced electrostatic repulsion upon cleavage of pendant tripeptides [69]. Reproduced by permission 

of The Royal Society of Chemistry. 

living cells. Transglutaminase can similarly be used to 

crosslink naturally occurring polymers in the presence 

of cells [77]. Escherichia coli cells entrapped in a protein 

gelatin mixture continued to grow within the hydrogel 

and even survived after hydrolytic gel degradation induced 

by exposure to a protease enzyme. Because some transglutaminase 

enzymes are only active in the presence of 

calcium ions, exposure to Ca 2+ can also trigger enzymatic 

crosslinking [70]. Messersmith and co-workers used this 

phenomenon with a four-arm star-shaped PEG that contained 

a 20-residue fibrin peptide sequence at the end of 

each arm [78]. When the copolymer was mixed with Ca 2+ - 

loaded liposomes designed to release their contents at body 

temperature, crosslinking of the peptide–PEG conjugates 

led to gels with potential applications as drug/gene delivery 

agents and tissue adhesives (Fig. 3). 

A wide variety of approaches have been employed to 

prepare hydrogels that respond to the presence of proteases. 

Typically the preformed network is exposed to a 

protease enzyme, and hydrolysis of protein or peptidebased 

crosslinkers in the network leads to gel degradation 

and subsequent release of encapsulated contents. Hubbell 

and co-workers formed hydrogels in the presence of cells, 

using a Michael-type reaction between vinyl sulfonefunctionalized 

multi-armed telechelic PEG macromers and 

mono-cysteine adhesion peptides or bis-cysteine matrix 

metalloproteinases [79]. The resulting hydrogels locally 

degraded in response to cell-surface proteases, which 

provided a route to gels with templated paths for cell 

migration. Moore and co-workers prepared chymotrypsinresponsive 

materials by incorporating a degradable CYKC 

tetrapeptide sequence as a crosslinker within polyacrylamide 

hydrogels [80]. The CYKC sequence contains a 

terminal cysteine conjugation site, a tyrosine residue which 

can be cleaved at the carboxyl side by chymotrypsin, and 

a lysine residue. When subjected to flowing or stationary 

solutions of �-chymotrypsin, the micron-sized gels 

dissolved in a matter of minutes due to the degradation 

of CYKC by �-chymotrypsin, while a control hydrogel 

with a non-cleavable tetrapeptide sequence showed no 

appreciable degradation under similar conditions. Ulijin 

and co-workers reported protease-responsive hydrogels 

that potentially have applications for the removal of toxins 

or entrapment of drug molecules [69]. In this case 

the response was caused by a change in osmotic pressure 

instead of crosslink degradation. Copolymer beads 

composed of acrylamide and PEG-macromonomers were 

modified via an enzyme cleavable tripeptide comprising 

combinations of glycine, phenylalanine, and positively 

charged arginine residues that imparted swelling due to 

electrostatic repulsions. Upon the addition of proteases, 

the tripeptide was cleaved, and the resulting loss of arginine 

groups led to a reduction in electrostatic repulsions 

and subsequent collapse of the hydrogel (Fig. 4). The 

beads could alternatively be functionalized with zwitterionic 

peptides that left the hydrogel uncharged in its initial 

state due to charge neutralization [81]. Enzyme-catalyzed 

hydrolysis of the pendant peptide resulted in a charge 

imbalance that caused significant swelling. 

Polymers that respond to a variety of other proteins 

have also been reported. For instance, Thayumanavan 

and co-workers recently demonstrated that supramolecu-


Fig. 5. Non-reversible (a) and reversible (b) antigen-responsive hydrogels. The response in (a) is non-reversible as a result of loss of the antibody crosslinks 

after addition of free antigen. Reversibility is possible in (b) because the antibody is covalently immobilized within the network. Reprinted by permission 

from Macmillan Publishers Ltd. [87], copyright (1999). 

lar polymer–surfactant complexes can self-assemble into 

micellar structures and that these aggregates can be 

induced to dissociate upon the addition of bovine serum 

albumin, lysozyme, avidin, chymotrypsin, �-glucosidase, 

and other proteins [82,83]. It is important to note, however, 

that in this case protein sensitivity did not arise from 

enzymatic activity but was instead the result of competitive 

complexation caused by the ability of polyelectrolytes 

to effectively bind globular proteins. 

2.3. Antigen-responsive polymers 

Antigen–antibody interactions are highly specific and 

are associated with complex immune responses that help 

recognize and neutralize foreign infection-causing objects 

in the body. Binding between antigens and antibodies can 

rely on a variety of non-covalent interactions, such as 

hydrogen bonding, van der Waals forces, and electrostatic 

and hydrophobic interactions. Antibodies are employed 

in a number of immunological assays for the detection 

and measurement of biological and non-biological substances 

[84], and the high affinity and specificity of their 

interactions with antigens have been harnessed to yield a 

variety of responsive synthetic polymeric systems. In most 

cases, antigen–antibody binding has been used to induce 

responses in hydrogels prepared by physically entrapping 

antibodies or antigens in networks, chemical conjugation 

of the antibody or antigen to the network, or using 

antigen–antibody pairs as reversible crosslinkers within 

networks [85]. 

Miyata et al. prepared antigen-sensitive hydrogels by 

coupling rabbit immunoglobulin G (Rabbit IgG) to Nsuccinimidylacrylate 

(NSA). The modified monomer was 

polymerized in the presence of goat anti-rabbit IgG as 

an antibody, acrylamide, and MBA to result in the formation 

of a hydrogel crosslinked both covalently and 

by antigen–antibody interactions. Upon the addition of 

rabbit IgG as a free antigen, competitive binding of the 

goat anti-rabbit IgG antibodies resulted in loss of the 

antigen–antibody crosslinkers and concomitant swelling 

of the hydrogel (Fig. 5a) [86]. While this represented one 

of the first examples of an antigen-responsive polymeric 

system, the antibody was lost upon hydrogel swelling, and 

antigen–antibody crosslinks could not be reformed [84]. 

In a later report, Miyata et al. reported a similar hydrogel 

that was reversibly responsive [87]. The antigen (rabbit 

IgG) and antibody (goat anti-rabbit IgG) were each functionalized 

to contain vinyl groups. The modified antibody 

Fig. 6. Chemical structure of Fab ′ -containing antigen-responsive hydrogels. Addition of free sodium fluorescein led to competitive binding and loss of 

antigen–antibody crosslinks. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission [85].


Scheme 3. Redox/thiol-responsive behavior capable of being exploited in polymeric systems. 

was polymerized with acrylamide, and the modified antigen 

was polymerized with acrylamide and MBA in the 

presence of the polymerized antibody to synthesize an 

antigen–antibody semi-interpenetrating network hydrogel 

(semi-IPN). Addition of free rabbit IgG antigen resulted 

in competitive binding with the antibodies in the hydrogel, 

which disrupted the antigen–antibody crosslinks and 

led to swelling of the hydrogel (Fig. 5b). Due to both antigen 

and antibody being covalently bound within the semi-IPN, 

swelling was reversible. Stepwise changes in the antigen 

concentration induced pulsatile permeation of a protein 

through the network. 

Kopeček and co-workers reported the synthesis of antigen 

responsive hydrogels based on polymerizable antibody 

Fab ′ fragments [85]. The polymerizable Fab ′ fragment was 

copolymerized with NIPAM and MBA, and binding of antigens 

to the Fab ′ fragment caused reversible changes in 

volume (Fig. 6). The response of the hydrogels was shown 

to be dependent on Fab ′ content, pH, and temperature. 

Hubble and co-workers reported an antigen-responsive 

hydrogel membrane based on a crosslinked dextran backbone 

grafted with both a fluorescein isothiocyanate (FITC) 

antigen and a sheep anti-FITC IgG antibody [88]. When 

free sodium fluorescein was added to the hydrogel, 

antibody–antigen crosslinks were broken by competitive 

binding of the free antigen. The disruption of the crosslinks 

resulted in reversible hydrogel swelling. Potential applications 

were envisioned in which the responsive membranes 

could serve as gates for selective diffusion in response to 

the presence of an antigen. 

2.4. Redox/thiol-responsive polymers 

Redox/thiol sensitive polymers are another class of 

responsive polymers that have recently received increased 

attention, especially in various fields of controlled drug 

delivery [89–98]. The interconversion of thiols and disulfides 

is a key step in many biological processes, plays an 

important role in the stability and rigidity of native proteins 

in living cells [99], and has been harnessed synthetically 

for various bioconjugation protocols [100,101]. Because 

disulfide bonds can be reversibly converted to thiols by 

exposure to various reducing agents and/or undergo disulfide 

exchange in the presence of other thiols, polymers 

containing disulfide linkages can be considered both redoxand 

thiol-responsive (Scheme 3) [101,102]. 

Glutathione (GSH), the most abundant reducing agent 

in most cells [95], has a typical intracellular concentration 

of about 10 mM, whereas its concentration is only 

about 0.002 mM in the cellular exterior [103]. This significant 

variation in concentration has been utilized to 

design thiol/redox-responsive drug delivery systems that 

specifically release therapeutics upon entry into cells. For 

instance, Lee and co-workers synthesized polymer micelles 

with shells crosslinked via thiol-reducible disulfide bonds 

to serve as biocompatible nanocarriers that preferentially 

release anticancer drugs in the reducing conditions characteristic 

of cancer tissues [104]. Redox-sensitive disulfide 

groups can also be directly introduced into side chains 

or backbones by using an appropriate monomer, initiator, 

or chain transfer agent [95,105–108]. For instance, 

Stayton and co-workers synthesized a drug carrier by 

copolymerization of a pyridyl disulfide containing acryloyl 

monomer with methacrylic acid and butyl acrylate [94,95]. 

The resulting terpolymers were thiol- and pH-sensitive and 

demonstrated membrane-disruptive properties necessary 

for effective endosomal escape in gene delivery. Tsarevsky 

and Matyjaszewski synthesized redox/thiol-sensitive polymers 

using a disulfide-containing difunctional ATRP 

initiator [109], and later employed a disulfide-functional 

dimethacrylate monomer (Fig. 7) to synthesize redox sensitive 

nanogels via inverse miniemulsion ATRP [102,110]. 

Fig. 7. (a) Difunctional disulfide-containing ATRP initiator and (b) a disulfide-containing monomer employed to prepare redox/thiol-responsive polymers.


Scheme 4. Preparation of hollow nanocapsule vesicles from redox-responsive block copolymers. The addition of reducing agent DTT into a hetero-PEGdetachable 

polyelectrolyte complex micelle solution resulted in a morphology transition to polymeric vesicles. Reprinted with permission from [115]. 

Copyright 2009 American Chemical Society. 

Synthesis of the nanogels by ATRP led to increased colloidal 

stability, higher swelling ratios, and enhanced control of 

degradability on treatment with tributyl phosphine or 

GSH, as compared to analogs prepared by conventional 

free radical polymerization in inverse miniemulsion. Li 

and Armes used the disulfide-functional dimethacrylate 

as a branching agent during the polymerization of N-(2hydroxypropyl)methacrylamide 

(HPMA) via ATRP [111]. 

Disulfide bonds within the branched copolymers were efficiently 

cleaved either upon exposure to dithiols or by 

treatment with benzoyl peroxide. 

Incorporating cleavable disulfides within both micelle 

cores and shells has proven to be a feasible mechanism of 

stabilizing multimolecular aggregates. For example, Stenzel 

and co-workers used RAFT to synthesize thiol-sensitive 

core crosslinked micelles consisting of poly(polyethylene 

glycol methyl ether methacrylate)-block-poly(5 ′ -O-methacryloyluridine) 

and a dimethacrylate crosslinker [92]. The 

resulting nanoparticles demonstrated a drug release efficiency 

of up to 70% in 7 h in the presence of dithiothreitol 

(DTT). Liu and co-workers also synthesized redoxresponsive 

core crosslinked micelles of poly(ethylene 

oxide) (PEO)-b-poly(NIPAM-co-N-acryloxysuccinimide) 

via RAFT [112]. After reacting the micelles with cystamine, 

the disulfide bonds within the hydrophobic core were 

cleaved by treatment with DTT and reformed again upon 

addition of cystamine as a thiol/disulfide exchange promoter. 

McCormick and co-workers synthesized disulfide 

based cystamine-containing triblock copolymer micelles 

that were shell crosslinked [113]. Reversible cleavage 

of the micelles was accomplished with either DTT or 

tris(2-carboxyethyl)phosphine (TCEP), and the degraded 

micelles could be re-crosslinked using cystamine as a 

thiol-exchanger. Shell crosslinked micelles of poly(lcysteine)-b-poly(l-lactide) 

were also synthesized via 

ring-opening polymerization [114]. When treated with 

DTT, the crosslinks within the micelle shells were lost, but 

when DTT was removed by dialysis, the shell crosslinked 

micelles were reformed. Disulfide crosslinked polymer 

capsules based on poly(N-vinylpyrrolidone) (PNVP) and 

PMAA have also been reported [97]. The resulting hydrogen 

bonded multilayer films were stable at physiological pH but 

could be induced to disassemble when treated with DTT. 

Kataoka and co-workers most recently demonstrated 

that disulfide reduction could be used to induce morphological 

transitions of block copolymer aggregates in 

solution [115]. Polymeric micelles with interpolyelectrolyte 

complexed cores composed of positively and 

negatively charged chains contained a PEG corona linked 

by disulfide bonds. Upon reduction with DTT, the PEG 

segments were detached from the micelles, leading to 

homopolymer complexes that adopted a vesicular structure 

due to the small curvature that resulted from the 

absence of shielding from PEG. The decreased free energy 

of the corona, due to the loss of the PEG chains from the 

polyion complex surface, is thought to be the driving force 

(Scheme 4). 

While the examples above rely on block copolymer selfassembly 

into micelles or vesicles that can be subsequently 

(de)stabilized by thiol-disulfide chemistry, redox-response 

can also be induced in aggregates that do not involve block 

copolymers. For examples, Thayumanavan and co-workers 

demonstrated that supramolecular polymer-surfactant 

complexes can form micelles susceptible to thiol-induced 

dissociation (Fig. 8) [116]. A polymer decorated with pendant 

carboxylates attached via disulfides was allowed to 

complex with a cationic surfactant. When micelles of the 

supramolecular complex were treated with GSH, cleavage 

of the polymer side chains resulted in aggregate dissociation 

and release of a model hydrophobic compound. 

Thiol-responsive triblocks composed of PNIPAM or 

PHPMA and PMPC have also been reported using the 

disulfide-based ATRP initiator described above (Fig. 7a). 

Because the integrity of the gels relied on disulfide linkages,


Fig. 8. A glutathione induced cleavage reaction and the result on the solution morphology of the polymer–surfactant complexes. Copyright 2009. Reprinted 

with permission of John Wiley & Sons, Inc. [116]. 

controlled degradation could be induced under physiologically 

relevant conditions using GSH or DTT [90,117]. 

Rapid dissociation of PHMA–PMC–PHMA triblock copolymer 

gels was observed under mild reducing conditions, 

indicating that materials prepared from such polymers 

may have potential applications as wound dressing [90]. 

Vogt and Sumerlin recently reported RAFT-generated ABA 

triblocks copolymers capable of forming hydrogels that 

were both temperature- and redox-responsive (Scheme 5) 

[118]. A difunctional trithiocarbonate chain transfer agent 

was used to synthesize symmetrical triblock copolymers 

of PNIPAM-b-PDMA-b-PNIPAM and poly(di(ethylene glycol)ethyl 

ether acrylate) (PDEGA)-b-PDMA-b-PDEGA. In 

each case, heating above the LCST of the outer thermoresponsive 

block led to gelation. However, because 

the hydrophilic bridging PDMA chains contained labile 

trithiocarbonate linkages, aminolysis led to a free-flowing 

solution of thiol-decorated polymeric micelles. Under 

oxidizing conditions, the thiols on the termini of the 

micelle corona chains coupled to form disulfide-containing 

hydrogels. Reduction with either DTT or GSH led to gel 

degradation. Other examples of redox-responsive gels and 

block copolymers have also been reported. Plunkett et al. 

synthesized polyacrylamide hydrogels using a tetrapeptide 

crosslinker responsive to reducing agents such as 

TCEP [80], and Winnik and co-workers reported a redox 

sensitive nanogel prepared via RAFT polymerization of 

NIPAM mediated by a polysaccharide (pullulan)-based 

chain transfer agent [119]. Self-assembly of the PNIPAMgraft-polysaccharide 

with thiol end groups rendered the 

nanogel responsive to changes in the redox environment, 

with both chemical and physical cross-linking points being 

destroyed upon treatment with TCEP. Monteiro and coworkers 

reported the synthesis and redox-sensitivity of 

reversible crosslinked polystyrene networks. Aminolysis 

of RAFT-generated polymers led to telechelic thiol polymers 

that could reversibly assemble into responsive cyclic, 

bicyclic, multiblock, and network architectures [120,121]. 

Star, block, and multiblock copolymers can also be 

rendered thiol-responsive by incorporating redox-labile 

linkages at block junction points. For instance, Liu et al. 

used RAFT to prepare thiol-sensitive biodegradable threearmed 

star polymers using both “core-first” and “arm-first” 

approaches [122]. Jeong and co-workers synthesized 

a disulfide-containing multiblock copolymer of PEO-bpoly(propylene 

oxide) (PPO)-b-PEO [93]. Drug release 

was significantly faster after treatment with GSH. Similarly, 

Oupicky and co-workers reported redox-responsive 

multiblock copolymers of PNIPAM and PDMAEMA that 

were readily reduced to the constituent starting blocks 

due to the presence of disulfide bridge between the 

blocks [89]. Börner and co-workers investigated controlled 

disassembly of a polymeric drug carrier composed of 

disulfide-linked poly(amidoamine) and PEO [123]. Release 

of the monodisperse poly(amidoamine) segments was 

observed by mass spectrometric analysis. Hubbell reported 

the design and characterization of block copolymers with 

hydrophilic PEG tethered to hydrophobic poly(propylene 

sulfide) via a disulfide bridge [91,124–127]. Because they 

should undergo sudden vesicular burst within the early 

endosome, polymeric vesicles assembled from such block 

copolymers may have promise for potential cytoplasmic 

delivery of biomolecular therapeutics such as peptides, 

proteins, oligonucleotides, and DNA. 

3. Field-responsive polymers 

Most methods of inducing a response in smart polymeric 

systems rely on kinetically restricted diffusion of 

the stimulus. For example, polymer gels that respond


Scheme 5. Temperature and redox-responsive gelation of triblock copolymers prepared by RAFT. (a) Molecularly-dissolved unimers of PNIPAM-b-PDMAb-PNIPAM 

or PDEGA-b-PDMA-b-PDEGA; (b) hydrogels formed upon heating above the LCST of the responsive PNIPAM or PDEGA blocks; (c) free-flowing 

micellar solutions of PNIPAM-b-PDMA-SH or PDEGA-b-PDMA-SH resulting from trithiocarbonate aminolysis at T > LCST; (d) hydrogels formed from 

PNIPAM-b-PDMA-S-S-PDMA-b-PNIPAM or PDEGA-b-PDMA-S-S-PDMA-b-PDEGA upon oxidation of the thiol-terminated diblock aminolysis products [118]. 

Reproduced by permission of The Royal Society of Chemistry. 

to changes in electrolyte concentration or pH require 

transport of externally introduced ions to or from the vicinity 

of the polymer backbone. Similarly, the response of 

temperature-sensitive polymers can be significantly limited 

by issues of heat transfer. As a result, the response 

of many traditional stimuli-responsive polymers is a slow 

process [128]. An alternative mechanism of stimulation 

that overcomes this issue is the application of electric, 

magnetic, sonic, or electromagnetic (photo/light) fields. In 

addition to having the ability to be applied or removed near 

instantaneously, some of these stimuli have the added benefit 

of potentially being directional, which can give rise to 

anisotropic deformation. Indeed field-responsive polymers 

are some of the most convenient stimuli from the point of 

signal control [129,130]. 

3.1. Electro-responsive polymers 

Electro-responsive polymers can be used to prepare 

materials that swell, shrink, or bend in response to an electric 

field [131,132]. Because electro-responsive polymers 

can transform electrical energy into mechanical energy 

and have promising applications in biomechanics, artificial 

muscle actuation, sensing, energy transduction, sound 

dampening, chemical separations, and controlled drug 

delivery, these polymers are an increasingly important 

class of smart materials [132–136]. Gel deformation (gen- 

erally bending) in an electric field is influenced by a number 

of factors, including variable osmotic pressure based on 

the voltage-induced motions of ions in the solution, pH 

or salt concentration of the surrounding medium, position 

of the gel relative to the electrodes, thickness or shape 

of the gel, and the applied voltage [132,137–139]. Transforming 

the application of an electric field into a physical 

response by a polymer generally relies on collapse of a 

gel in an electric field, electrochemical reactions, electrically 

activated complex formation, ionic polymer–metal 

interactions, electrorheological effects, or changes in electrophoretic 

mobility [131]. 

Typically, electro-responsive polymers have been 

investigated in the form of polyelectrolyte hydrogels 

[131,133,140–152]. Polyelectrolyte gels deform under an 

electric field due to anisotropic swelling or deswelling 

as charged ions are directed toward the anode or cathode 

side of the gel [131]. For instance, under an electric 

field, in the case of hydrolyzed polyacrylamide gels, mobile 

H + ions migrate toward the cathode while the negatively 

charged immobile acrylate groups in the polymer networks 

are attracted toward the anode, creating a uniaxial stress 

within the gel. The region surrounding the anode undergoes 

the greatest stress while the area in the vicinity of 

the cathode exhibits the smallest stress. This stress gradient 

contributes to the anisotropic gel deformation under 

an electric field [153].


Fig. 9. Electro-response of a PDMS gel loaded with 10% TiO2 as a function of uniform field strength. Reprinted from [131], Copyright (2000), with permission 

from Elsevier. 

Both synthetic and natural polymers have been 

employed. Key naturally occurring polymers used to 

prepare electro-responsive materials include chitosan 

[140,144], chondroitin sulfate [154], hyaluronic acid [155], 

and alginate [147]. Major synthetic polymers have been 

based on vinyl alcohol [135,137,142,146], allylamine 

[143], acrylonitrile [144], 2-acrylamido-2-methylpropane 

sulfonic acid [138,156], aniline [157], 2-hydroxyethyl 

methacrylate [145], methacrylic acid [146,147], acrylic acid 

[135,157,158] and vinyl sulfonic acids [157,158]. In some 

cases, a combination of natural and synthetic components 

have been employed. For instance, Kim et al. prepared a 

semi interpenetrating polymer network (IPN) hydrogel of 

PHEMA and chitosan [140]. The response of the hydrogel 

to an applied electric field was investigated through measurements 

of bending rate and angle, with these values 

increasing with ionic strength of the medium and applied 

voltage. The same research group also reported a purely 

synthetic IPN composed of poly(methyl methacrylate) 

(PMMA)/PVA that rapidly led to significant and reversible 

bending toward the cathode when the gel was subjected to 

an electric field in an NaCl solution [146]. Yao and Krause 

investigated the electromechanical response in a direct 

current electric field of crosslinked strong acid hydrogels 

composed of sulfonated polystyrene or sulfonated 

poly(styrene-b-ethylene-co-butylene-b-styrene) in different 

electrolyte solutions of varying concentration [150]. 

Both systems led to bending toward the cathode when 

pre-equilibrated in the corresponding salt solutions. The 

bending angle of the gels increased rapidly and linearly 

before eventually leveling off. This bending behavior in 

response to the applied electric field was highly repeatable. 

In a recent study, Gao et al. reported an electro-responsive 

hydrogel based on PVA and poly(sodium maleate-cosodium 

acrylate) [137]. It was observed that hydrogel 

deformation increased when the concentration of NaCl or 

the electric voltage was increased. 

Although most polymers that exhibit electro-sensitive 

behavior are polyelectrolytes, a few neutral polymers 

have also demonstrated electric field sensitivity in nonconducting 

media. Typically such systems require the 

presence of an additional charged or polarizable component 

with the ability to respond to an applied electric field. 

For example, Zrinyi and co-workers synthesized a lightly 

crosslinked poly(dimethyl siloxane) gel containing electrosensitive 

colloidal TiO 2 particles (Fig. 9) [131]. A significant 

and rapid bending of the gel in silicon oil was observed. 

Because the TiO 2 particles were not able to exit the matrix, 

the force acting on these particles was transferred to the 

polymer, which resulted in gel deformation. 

3.2. Magneto-responsive polymers 

Polymers that respond to the presence or absence 

of magnetic fields can exist as free chains in solution, 

be immobilized to surfaces, or be crosslinked 

within networks. The majority of reports in the literature 

involve the latter and describe the rapid response 

of magneto-responsive gels swollen with complex fluids 

[128–130,159,160]. Generally, inorganic magnetic 

(nano)particles are physically entrapped within or covalently 

immobilized to a three-dimensional crosslinked 

network [161,162], leading to materials with shape 

and size distortion that occurs reversibly and instantaneously 

in the presence of a non-uniform magnetic field 

[159,161,163,164]. In this case, the magnetophoretic force 

[129] conferred to the polymeric material as a result of 

the magnetic susceptibility of the particles has led to such 

materials receiving significant attention for use as soft 

biomimetic actuators, sensors, cancer therapy agents, artificial 

muscles, switches, separation media, membranes, 

and drug delivery systems [129,161,165–167]. In uniform 

magnetic fields, a different phenomenon occurs. In this 

case, there is a lack of magnetic field–particle interactions, 

but particle–particle interactions arise from the creation 

of induced magnetic dipoles. Particle assembly within the 

surrounding polymer matrix can lead to dramatic transformations 

in material properties. 

The incorporation of magnetic nanoparticles (Fe 3O 4) 

within PNIPAM-based microgels is well documented in the 

literature [129,168–170]. Zrinyi and co-workers investigated 

magneto-responsive polymer gel beads that were


Fig. 10. 1D carbon nanostructures formed via functionalization of ferromagnetic nanoparticles with polyacrylonitrile, magnetic assembly, and pyrolysis. 

Reprinted with permission from [174]. Copyright 2007 American Chemical Society. 

prepared by incorporating the magnetic nanoparticles into 

PNIPAM and PVA hydrogels [129,171]. In uniform magnetic 

fields, the gel beads assembled into straight chainlike structures. 

However, when a non-uniform field was applied, the 

gel beads aggregated. Incorporating the magnetic particles 

into cylindrical-shaped polymer gels led to materials that 

mimicked muscular contraction by undergoing rapid and 

controllable changes in shape when exposed to a magnetic 

field. 

Most examples of magneto-responsive polymer systems 

involve non-covalent interactions between polymer 

chains and magnetic particles [161,162,165,166]. However, 

recent advances in polymer synthesis have facilitated 

the covalent immobilization of polymer chains directly 

to the surface of magnetic particles. For example, Pyun 

and co-workers have employed nitroxide-mediated radical 

polymerization (NMP) to prepare polymeric surfactants 

that stabilize magnetic nanoparticles. By casting nanoparticle 

dispersions from organic media onto surfaces, a diverse 

range of mesoscale morphologies have been observed, 

ranging from randomly entangled chains, field aligned 

1D mesostructures, and nematic-like liquid crystal colloidal 

assemblies [160,172–176]. For instance, after ligand 

exchange to obtain a dispersion of polyacrylonitrilestabilized 

ferromagnetic cobalt (Co) nanoparticles, a film 

was cast under an applied magnetic field [174]. Stabilization 

and pyrolysis of the resulting nanoparticle chains led 

to 1D carbon nanoparticle chains with cobalt inclusions 

(Fig. 10). Ihara and co-workers recently reported a novel 

route to prepare magneto-responsive gels via surface initiated 

ATRP [177]. Iron nanoparticles served as crosslinkers, 

eliminating the need for a conventional cross-linking agent. 

3.3. Ultrasound-responsive polymers 

Many of the applications suggested for stimuliresponsive 

polymers involve the controlled release of 

therapeutic compounds at a specified rate or location 

within the body. In some cases, the change in environmental 

conditions necessary to impart responsive drug 

release can occur by passive or active migration of the 

polymeric carrier to an area of the body that has conditions 

that encourage release (e.g., pH-responsive polymers 

can release drugs at specific points in the digestive tract 

or within endosomes due to inherent differences in pH). 

However, the application of systems that rely on other 

stimuli may be complicated by the inability to locally apply 

the stimulus at the targeted site. For instance, a change 

in temperature could lead to release in thermoresponsive 

polymer carriers in vitro, but localized heating and cooling 

in vivo is not always trivial at sites deep within the body. 

However, ultrasound is a particularly effective stimulus 

that can be applied externally on demand and has proven 

effective at inducing drug release within the body [178]. 

The concept of using ultrasound-responsive polymers for 

controlled drug delivery is attractive because the method is 

essentially noninvasive and has been successfully used in 

other areas of medical treatment and diagnostics [179]. The 

success of ultrasonic mediation of drug delivery is generally 

ascribed to cavitation, which is the alternating growth and 

shrinkage of gas-filled microbubbles that results from high 

and low pressure waves generated by ultrasound energy 

[180]. Eventually, these cavitating microbubbles implode, 

generating local shock waves that can disrupt polymer 

assemblies in their vicinity [181].


Scheme 6. Ultrasound-responsive drug delivery from triblock copolymer micelles [198]. 

As opposed to the other stimuli-responsive polymers 

described in this review, it is difficult to pinpoint 

the specific macromolecular characteristics that allow 

response to ultrasound. As a consequence of this possibility 

for diversity, a wide variety of polymers of varying 

composition, architecture, polarity, Tg, etc. have been 

demonstrated to alter their behavior when exposed to 

ultrasonic stimulation. Additionally, as opposed to, for 

example, magneto-responsive polymers, foreign additives 

are not required to impart ultrasound-responsive behavior 

[178]. However, polymers existing in a few specific physical 

states have been most heavily considered. Polymeric 

systems that respond to ultrasound have generally been 

gels or other non-swollen macroscopic solids, polymeric 

micelles, or layer-by-layer coated microbubbles. 

The ultrasound-induced release rate of incorporated 

materials from biodegradable polyglycolides, polylactides, 

and poly[bis(p-carboxyphenoxy)alkane anhydrides with 

sebacic acid and non-biodegradable ethylene-vinyl acetate 

copolymers have been extensively studied by Langer and 

co-workers [182–185]. Each of these systems exhibited 

release kinetics that were significantly enhanced with 

increasing ultrasound intensity. It has been suggested that 

ultrasound significantly accelerates the rate of degradation 

in biodegradable polymers and enhances permeation 

through non-erodible polymers [186,187]. Poly(lactideco-glycolide) 

microspheres and poly(HEMA-co-DMAEMA) 

hydrogels have also been investigated as ultrasoundresponsive 

drug delivery systems [184,187]. Miyazaki et al. 

reported a ethylene-vinyl alcohol copolymer system that 

was capable of delivering on demand insulin at increased 

rates in diabetic rats by external ultrasound irradiation 

[188]. Stoodley and co-workers reported ultrasoundresponsive 

antibiotic release from PHEMA hydrogels [179]. 

The PHEMA hydrogels were coated to minimize passive 

release with a layer of C 12-methylene chains by reaction 

with dodecyl isocyanate. In the absence of ultrasound, 

antibiotic was retained within the polymer matrix; however, 

the application of low intensity ultrasound led to 

disruption of the alkane coating and concomitant drug 

release. Kooiman recently reported a similar system composed 

of ultrasound-responsive polymeric microcapsules 

with a shell of fluorinated end-capped poly(l-lactic acid) 

[189]. 

Acoustic destabilization of supramolecular polymer 

assemblies has also received attention [190–202]. Gener- 

ally, polymeric micelles are induced to dissociate or to 

adopt loosely associated morphologies when exposed to 

ultrasound (Scheme 6) [198]. Low-frequency ultrasound 

also enhances local cellular uptake of drugs, which indicates 

this approach could prove particularly useful for 

delivery, provided precautions are taken to prevent cavitational 

damage to vital structures in the body. 

Pitt and co-workers [191,199–202] have demonstrated 

that hydrophobic drugs can be incorporated into PEO-b- 

PPO-b-PEO micelles and that release could be induced with 

low-frequency ultrasound. Stabilization of the micelles at 

concentrations below the critical micellar concentration 

was accomplished by polymerizing N,N-diethylacrylamide 

and N,N ′ -bis(acryloyl)cystamine in the presence of the 

micelles above the LCST of poly(N,N-diethylacrylamide) 

[203]. Interpenetrating networks of this kind within the 

hydrophobic cores were capable of solubilizing doxorubicin 

that could selectively be released in tumor tissue 

only when ultrasound was applied [201]. Importantly, the 

observed efficacy enhancement could be attributed to a 

combination of synergistic effects brought about by ultrasonic 

exposure, including ultrasound-responsive release 

of the drug, ultrasound-triggered extravasation of the 

polymeric micelles, and ultrasound-enhanced uptake of 

pre-released drug into the cells. 

Another method by which polymers can contribute 

to ultrasound-responsiveness is through the coating and 

stabilization of microbubbles that result from sonication. 

Cavitation and microbubble implosion generate local shock 

waves and microjets that can temporarily perforate membranes 

to facilitate cell entry of macromolecules [180,181]. 

This process of “sonoporation” has proved effective in vitro 

and in vivo. For example, Smedt and co-workers recently 

demonstrated that the microbubbles that result from ultrasonic 

irradiation can be directly coated with a polymer 

shell and that the resulting structures can potentially be 

used for gene delivery applications [180]. Perfluorcarbon 

gas-filled microbubbles were coated via the layer-by-layer 

(LbL) approach with positively charged poly(allylamine 

hydrochloride) and negatively charged DNA, and the 

ultrasound responsiveness, physical properties, DNA binding/protection 

of the particles were investigated. Binding 

DNA on the microbubble surface ensured that it was 

proximal to the site of cell membrane poration, thereby 

enhancing the probability of DNA entering the cell by the 

generated microjets.

3.4. Photo-responsive polymers 


Scheme 7. Reversible photo-induced transformations of (a) azobenzene and (b) spiropyran derivatives. 

Photo-responsive polymers are macromolecules that 

change their properties when irradiated with light of the 

appropriate wavelength [204,205]. Typically these changes 

are the result of light-induced structural transformations 

of specific functional groups along the polymer backbone 

or side chains [206–211]. Possible applications of photoresponsive 

polymers include reversible optical storage, 

polymer viscosity control, photomechanical transduction 

and actuation, bioactivity switching of proteins, tissue 

engineering, and drug delivery [207,212–222]. An important 

aspect of photo-sensitive polymer systems is that 

using irradiation as a stimulus is a relatively straightforward, 

non-invasive mechanism to induce responsive 

behavior. These types of polymers have been investigated 

for many years, but there has been a recent expansion in 

research to create increasingly complex macromolecular 

architectures. 

The most well-studied examples of photo-responsive 

polymers are those that contain azobenzene groups 

[204,223–225]. Azobenzene is a well-known chromophore 

with an irradiation-induced cis-to-trans isomerization 

that is accompanied by a fast and complete change 

in electronic structure, geometric shape, and polarity 

(Scheme 7) [207,226]. For instance, while the more stable 

trans-azobenzene has no dipole moment, the cis 

form is quite polar, having a dipole moment of 3D 

[204]. By incorporating azobenzene derivatives into polymer 

structures, materials with variable shape, polarity, 

and self-assembly behavior can be obtained [227]. For 

instance, Wang and co-workers described photo-induced 

deformation of epoxy-based azobenzene-containing polymer 

colloids [228,229]. Depending on the wavelength 

of irradiation, these photo-responsive colloids changed 

morphology from spheres to spindles and finally to rods 

[229]. Incorporating azobenzene groups in methylcellulose 

[230] and methylcellulose-cyclodextrin inclusion complexes 

[231] allowed photo-tuning of the sol–gel transition 

and cloud points in aqueous media. Tirrell and co-workers 

prepared photochromic derivatives of elastin-like polypeptides 

[poly(VPGVG)] [232]. The inherent thermoresponsive 

nature of the polymers could be tuned by incorporating 

one azobenzene moiety for every 30 amino acid residues. 

Alonso et al. also reported the photo-responsive properties 

of azobenzene and spiropyran derivatives of elastin-like 

polypeptides [233,234]. 

The change in polarity that accompanies isomerization 

has led to azobenzene-containing block copolymers being 

used to prepare photo-responsive micelles and vesicles 

[235–241]. Azo chromophores have been incorporated into 

a variety of other polymeric systems, including poly(Nhydroxy 

propyl methacrylamide) (PHPMA) [242], PAA 

[243,244], PDMAEMA [245,246], and PNIPAM [247]. Photoresponsive 

dendrimers based on azobenzene derivatives 

have also been reported [248–251]. 

In addition to enabling photo-switching of bulk material 

properties [207], surface properties [252,253], and polymeric 

aggregates in solution [223], azobenzene groups 

can be used to control the assembly of supramolecular 

polymers. Ghadiri and co-workers reported a new 

photo-responsive peptide system composed of two ringshaped 

cyclic peptides tethered by an azobenzene moiety 

[254,255]. When the azobenzene group was in the 

trans state, the cyclic peptide units demonstrated intermolecular 

hydrogen bonding to yield extended linear 

chains. UV-induced isomerization to the cis state led 

to intramolecular hydrogen bonding and depolymerization 

of the supramolecular complex (Fig. 11). Similar 

photo-responsive supramolecular polymers based on 

diarylethene chromophores have also been reported [256]. 

The non-invasive nature in which light can be applied 

to a polymer solution has led to a variety of applications 

of photo-responsive polymers in biological systems. For 

example, Hoffman and co-workers employed azobenzenecontaining 

polymers as switches to reversibly activate 

enzymes in response to distinct wavelengths of light 

[213] and used the same concept to reversibly control 

biotin-binding by site-specific conjugation to streptavidin 

[212]. In the latter case, a polymer–streptavidin conjugate 

successfully bound biotin under UV irradiation, but 

upon exposure to visible light, the polymer was collapsed 

to block biotin association. By employing an alternative 

photo-responsive polymer, the opposite photo-tunable 

behavior was observed. 

The responsive nature of azobenzenes has been used to 

generate photomechanical effects and even macroscopic 

motion [223,257]. Photo-contraction of azobenzene-


Fig. 11. Photo-responsive supramolecular assembly/disassembly of cyclic peptides tethered by azobenzene units, as reported by Ghadiri and co-workers 

[254]. Reprinted from [223], Copyright (2006), with permission from Elsevier. 

containing polymer films leads to changes in film thickness 

[258,259] and bending/unbending motions [260–263] 

that can, in some cases, bring about remarkable macroscopic 

3D motion reminiscent of a robot arm or an 

inchworm [264]. Ikeda and co-workers recently developed 

a photo-responsive laminated film consisting of 

an azobenzene-containing crosslinked liquid-crystalline 

polymer and flexible polyethylene [264]. The laminated 

film was fully extended and flat under UV light but returned 

to its original bent shape when irradiated with visible light. 

This type of photo-responsive polymeric film may lead to 

devices capable of converting light energy into mechanical 

work, such that motion is possible without a wired 

connection to a power source. 

In addition to polymers functionalized with azobenzene 

moieties, other chromophores have also been used 

to impart photo-responsive behavior. Several examples 

exist in which spiropyran derivatives were incorporated 

terminally [265] or pendantly [217,246,266–268] to bring 

about light sensitivity. Spiropyran groups are relatively 

non-polar, but irradiation with the appropriate wavelength 

of light leads to the zwitterionic merocyanine 

isomer that has a larger dipole moment (Scheme 7b). The 

isomerization can be reversed by irradiating with visible 

light. This concept has been employed to prepare a 

variety of spiropyran-containing photo-responsive polymers, 

including, for example, PAA [217], PHPMA [267], 

and PNIPAM [266,269]. Matyjaszewski and co-workers 

used the photo-tunable change in polarity to prepare 

polymeric micelles with responsive spiropyran-containing 

blocks [268]. A block copolymer of PEO and a spiropyrancontaining 

methacrylate monomer was prepared by ATRP, 

and the polymeric micelles formed in aqueous solution 

of the resulting polymer were completely disrupted 

by UV irradiation and regenerated by irradiation with 

visible light (Fig. 12). This strategy allowed the controlled 

release of hydrophobic coumarin 102 from the 

micelle cores via UV irradiation and re-encapsulation of 

the dye upon irradiation with visible light. Laschewsky 

and Rekai modified PHPMA by copolymerization with a 

monomer containing the photo-reactive cinnamate moiety 

[270]. Photoisomerization of pendant trans-cinnamate 

groups to cis-cinnamate groups led to polymers with 

increased polarity and higher cloud points. Unlike other 

frequently used photo-reactive groups, the cinnamate 

group is easy to incorporate, rather chemically inert,


Fig. 12. Photo-responsive micellization of a spiropyran-containing block copolymer prepared by ATRP. (a) Micellar dye encapsulation, (b) UV-induced 

micelle dissociation and dye release, and (c) micelle reconstruction and dye re-encapsulation induced by visible light irradiation. Copyright Wiley–VCH 

Verlag GmbH & Co. KGaA. Reproduced with permission [268]. 

and exhibits thermal stability in both the trans- and 

cis-forms. 

While most examples of photo-responsive behavior rely 

on light-induced isomerization, another viable approach 

is to capitalize on polarity changes that result from 

cleavage of photo-labile esters that yield the corresponding 

alcohol and acid components. Such photosolvolysis 

reactions have been used to impart responsive behavior 

to methacrylate polymers. Zhao and co-workers investigated 

light-responsive amphiphilic diblock copolymers 

of PEO and a methacrylate monomer with photo-labile 

pyrenylmethyl chromophores pendantly attached [271]. 

When exposed to UV irradiation, cleavage of the pyrenylmethyl 

esters caused the pyrene-containing hydrophobic 

methacrylate units to be transformed to hydrophilic 

methacrylic acid units, resulting in micelle dissociation. 

However, while photosolvolysis of pyrenylmethyl esters 

requires nucleophilic solvents, photolysis of polymers 

containing 2-nitrobenzyl side chain moieties can take 

place both in solution and the solid state [272]. Lepage 

et al. exploited this concept with triblock copolymers 

that formed micelles with photo-labile poly(2-nitrobenzyl 

methacrylate) coronas that were capable of releasing Gdbased 

contrast agents under UV light exposure [273]. 

Most of the examples mentioned above require isomerization 

induced by UV irradiation. However, light 

of UV and visible wavelengths is readily absorbed by 

the skin, so UV/visible-light-responsive systems have 

potential limitations for some biomedical applications. 

However, IR radiation can penetrate skin with less risk 

of damage and might be more applicable for photoactivation 

of drug carriers within a living system. Therefore, 

Fréchet and co-workers investigated block copolymer 

micelles with PEG hydrophilic segments and 2-diazo- 

1,2-naphthoquinone hydrophobic blocks. Irradiation with 

IR light led to micelle dissociation as a result of the 

photo-induced rearrangement of the 1,2-naptho-quinone 

units to yield anionic/hydrophilic 3-indenecarboxylate 

groups [274]. Near-infrared (NIR) dissociable polymeric 

micelles based on diblock copolymers of PEG and poly(2nitrobenzyl 

methacrylate) have also been developed where 

the latter undergoes photolysis and is converted to 

hydrophilic poly(methacrylic acid) (PMAA) [272]. 

4. Conclusions 

With inspirations arising from a variety of sources, 

novel polymers with sensitivities to other triggers are con- 

stantly being developed. A recent report by Rowan and 

co-workers capitalized on a phenomenon observed during 

the self-defense mechanism of the sea cucumber [275]. 

A nanocomposite of cellulose nanofibers embedded in a 

rubbery ethylene oxide-epichlorohydrin copolymer was 

prepared to mimic the sea cucumber dermis known to 

be composed of rigid collagen fibrils embedded within 

a viscoelastic glycoprotein matrix. The properties of the 

synthetic composite were largely dependent on hydrogen 

bonding between surface hydroxyls on the imbedded 

nanofibers. When the material was placed in an aqueous 

medium, water acted as hydrogen bond disrupter, causing 

the composite to dramatically soften with a change 

in tensile modulus from 800 to 20 MPa. As this example 

indicates, many new advances in the area of responsive 

polymers can be achieved by reproducing inherently complex 

natural phenomena with straight-forward polymer 

science. 

The topics covered here are at various levels of maturity, 

but many opportunities remain to capitalize on their 

specificity and uniqueness. There is little doubt that many 

applications can benefit from a combination of these 

stimuli sensitivities. Indeed, for many purposes like drug 

delivery and diagnostics, hybrid materials with the ability 

to respond to several stimuli would be extremely beneficial. 

Despite many advances, numerous challenges and 

opportunities remain for making an impact in the field 

of smart polymers. While new responsive polymer compositions 

are continually being developed and the ability 

to prepare macromolecules with topological complexity is 

expanding, many underutilized stimuli will take on greater 

roles in the next generation of smart materials. 

Acknowledgement 

A portion of this material is based upon work supported 

by the National Science Foundation under Grant No. DMR- 

0846792. 

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