Stimulus-responsive hydrogels: Theory, modern advances, and applications

Abstract

Over the past century, hydrogels have emerged as effective materials for an immense variety of applications. The unique network structure of hydrogels enables very high levels of hydrophilicity and biocompatibility, while at the same time exhibiting the soft physical properties associated with living tissue, making them ideal biomaterials. Stimulus-responsive hydrogels have been especially impactful, allowing for unprecedented levels of control over material properties in response to external cues. This enhanced control has enabled groundbreaking advances in healthcare, allowing for more effective treatment of a vast array of diseases and improved approaches for tissue engineering and wound healing. In this extensive review, we identify and discuss the multitude of response modalities that have been developed, including temperature, pH, chemical, light, electro, and shear-sensitive hydrogels. We discuss the theoretical analysis of hydrogel properties and the mechanisms used to create these responses, highlighting both the pioneering and most recent work in all of these fields. Finally, we review the many current and proposed applications of these hydrogels in medicine and industry.

Keywords: Biosensors; Chemically-responsive; Drug delivery; Electrically-responsive; Hydrogels; Molecularly imprinted polymers; Photo-responsive; Polymers; Scaffolds; Shear stress; Smart materials; Stimulus-responsive; Swelling; Temperature responsive; Tissue engineering; pH responsive.

Fig. 1

Equilibrium swelling behaviors of anionic and cationic hydrogels. Behavior is dependent on the ionic pendant groups. Reprinted with permission from Khare et al. [53].

Fig. 2

Insulin release from P(MAA-co-NVP) at both low pH (~3) and neutral pH (~7) conditions. Reprinted with permission from Carr and Peppas [86].

Fig. 3

Volume swelling ratio, Q, as a function of pH for Cationic PDBP nanogels of various crosslinking ratios: ●, 0.01; ○, 0.025; ▲, 0.05; △, 0.1. Reprinted with permission from Fisher and Peppas [106].

Fig. 4

(a) Inverse polymer volume fraction as a function of time. (b) Polymer interaction parameter in ethanol. (c) polymer interaction parameter in water. (d) Enthalpic contribution to the polymer interaction parameter in water. (e) Entropic contribution to the polymer interaction parameter in water. ○ poly(acrylamide), ▲ poly(dimethyl acrylamide), □ poly(ethyl acrylamide), ■ poly(acrylroylpyrolidine), △ poly(diethylacrylamide), ● poly(N-isoproylacrylamide). Reprinted with permission from Bae et al. [117].

Fig. 5

Zipper-like hydrogen bonding of PAA-PAAm IPN. Reprinted with permission from Katono et al. [118]. Copyright 1991 Elsevier.

Fig. 6

Thermo-gelling schematic for injectable PNIPAAm based hydrogels. Reprinted with permission from Hacker et al. [137]. Copyright 2008 American Chemical Society.

Fig. 7

Stimulus-responsive membrane: (a) temperature-triggering, comparison of nanogel particle size in suspension (blue data, right y-axis) and differential flux of sodium fluorescein through the nanogel-loaded membranes (red data, left y-axis) as a function of temperature; (b) magnetic triggering, temperature profile in the sample chamber and differential flux of sodium fluorescein out of membrane-capped devices as a function of time over four successive on/off cycles of the external magnetic field; (c) schema of the proposed mechanism of membrane function. Reprinted with permission from Hoare et al. [141]. Copyright 2009 American Chemical Society. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Fig. 8

Concanvalin A-based glucose-responsive hydrogel swelling mechanism.

Fig. 9

Reaction of glucose with phenylboronic acid (PBA). Binding of glucose to PBA yields more negatively charged and thus hydrophilic hydrogel, leading to the observed swelling response.

Fig. 10

Effect of exposure time and degradation on (a) Wettability of poly(Hydroxyethylacrylate-co-2-nitrobenzyl acrylate (p(HEA-co-2-NBA)). (b) Swelling ratio of P(HEA-co-2-NBA). (c) Elastic modulus of P(HEA-co-2-NBA). (d) Cell concentration in P(HEA-co-2-NBA) with fluorescent imagages of (a) 0, (b) 15, and (c) 90 min exposure times. Reprinted with permission from Ramanan et al. [311]. Copyright 2010 The Royal Chemical Society.

Fig. 11

(a) exposure sensitivity, (b) 2 D patterning, and (c) 3 D patterning of (1) photo-modified and (2) photodegradeable hydrogels. Reprinted with permission from DeForest and Anseth [295]. Copyright 2011 Macmillan Publishers Limited.

Fig. 12

(a) Chemical schematic for swellable photoresponsive micro-well patterning. (b) Photoresponsive microchannel formation schematic. (c) Microvalve photo-actuation schematic. Reprinted with permission from Sugiura et al. [302]. Copyright 2009 The Royal Chemical Sociery.

Fig. 13

Time lapse of micrographs of photo-actuated microchannels. (a), (c), (e), and (g) are irradiation steps. (b), (d), (f), and (h) are subsequent visualizations of latex flow through the formed microchannels. Reprinted with permission from Sugiura et al. [302]. Copyright 2009 The Royal Chemical Sociery.

Fig. 14

Fractional release of rhodamine, AMCA, and fluorescein from a hydrogel as a function of light exposure (λ = 436 nm, I₀ = 44.6 ± 1.0 mW/cm², t = 5 min; λ = 405 nm, I₀ = 21.4 ± 1.1 mW/cm², t = 5 min; and then λ = 365 nm, I₀ = 5.53 ± 0.14 mW/cm², t = 5 min); solid lines depict predicted release, actual release shown as data points. Reprinted with permission from Griffin and Kasko [313]. Copyright 2012 American Chemical Society.

Fig. 15

Relative hydrogel weight change for various degrees of swelling, q. Top: simulated results; Bottom: experimental results with PAMPS hydrogel. ◊, q = 25; ○, q = 70; ■, q = 100; △, q = 200; ●, q = 256; ▲, q = 512; □, q = 750. Reprinted with permission from Gong et al. [314]. Copyright 1994 American Chemical Society.

Fig. 16

Relative hydrogel weight change as a function of quantity of electric flow. Top: simulated results; Bottom: experimental results with PAMPS hydrogel. Symbols are the same as in Figure MK3. Reprinted with permission from Gong et al. [314]. Copyright 1994 American Chemical Society.

Fig. 17

Schematic of hydrogel bending mechanism by association of surfactant molecules in electric field. Reprinted with permission from Osada et al. [315]. Copyright 1992 Nature Publishing Group.

Fig. 18

PAMPS hydrogel bending and movement from application of electric field. The front hook and rear hooks can only slide forward along the rail, as prevented by ratchet teeth. Thus, with repeated on/off application of a 20 V electric field and the bending mechanism shown in Figure MK5, the hydrogel slides unidirectionally forward. Reprinted with permission from Osada et al. [315]. Copyright 1992 Nature Publishing Group.

Fig. 19

Release rate of model drug (edrophonium chloride) as a Function of Electric Current. Edrophonium chloride was released from a 14 mm P(AMPS/BMA) hydrogel disk with various electric currents applied. Reprinted with permission from Kwon et al. [354]. Copyright 1991 Elsevier

Fig. 20

Schematic of electrode system used for In Vivo test of electrically-responsive PDMAPAA hydrogel insulin delivery system in rats. Reprinted with permission from Kagatani et al. [360]. Copyright 1997 Wiley-Liss, Inc. and the American Pharmaceutical Association.

Fig. 21

Plasma Glucose Concentration Profile with Insulin Administration by PDMAPAA Electrically-Responsive Hydrogel. Current of 1.0 mA was applied for 1 min at t = 0 h and for 10 min at t = 2 h. A noticeable decrease in glucose levels is observed at each time, indicating pulsatile release. ○, PBS; □, PDMAPAA gel only; ■, PDMAPAA gel with current; △, insulin-loaded PDMAPAA gel; ▲, insulin-loaded PDMAPAA gel with current. Reprinted with permission from Kagatani et al. [360]. Copyright 1997 Wiley-Liss, Inc. and the American Pharmaceutical Association.

Fig. 22

Models for linear viscoelastic polymer systems (top) Maxwell (bottom left) Kelvin–Voigt and (bottom right) Standard linear solid. Springs represent the elastic component and dashpots represent the viscous components of the polymer system.

Fig. 23

Within the linear viscoelastic region (bottom left) the storage and loss moduli, G′ and G″, respectively are independent of the applied strain amplitude. The resulting shear stress curve is, therefore, sinusoidal (top left). However, once entering the non-linear region (bottom right), G′ and G″ become dependent on shear amplitude, i.e. G′(γ₀) and G″(γ₀), and the shear stress curve is no longer sinusoidal (top right). This illustrates the different behaviors expected from small amplitude oscillatory shear (SAOS) and large amplitude oscillatory shear (LAOS) experiments. As a note, the distortion of the stress curve in the non-linear region can be attributed to the higher harmonics of G′ and G″. Reprinted with permission from Hyun et al. [388].

Fig. 24

(a) and (b) depict strain-sweeps from vortex-induced fibroin hydrogels with varying silk concentrations. The arrows depict yielding/thinning behavior. (c) and (d) show frequency sweeps before (open symbols) and immediately after shear-thinning by injection (closed symbols).

Fig. 25

A schematic of a coiled–coiled dimer containing the (abcdefg) motif. The ‘a’ and ‘d’ residues are typically hydrophobic amino acids, while the ‘e’ and ‘g’ residues are charged moieties. The dashed lines represent hydrophobic and charge interactions resulting in the coiled-coil structural motif. Obtained and modified from Jonker et al. [415].

Fig. 26

Network formed with a tri-block copolymer consisting of coiled-coil forming end blocks and a polyanionic linker. Reprinted with permission from Olsen et al. [413].

Fig. 27

MITCH schematic showing (top left) the WW association domains, CC43 and Nedd.3, and the proline peptide (PPxY) and (bottom left) hydrophilic spacers linking repeat units of either the WW domains or proline peptides. (Right) The two-component gel results from the mixing of the WW association domains and the respective proline peptide chains. Reprinted with permission from Foo et al. [448].

Fig. 28

(Top) Self-assembly of b-hairpin peptide and their subsequent assembly into fibrillar hydrogels. Also pictured is the reaction of the network to the application of shear force. (Bottom) Proposed mechanism of the network behavior during shear-thinning and recovery, or self-healing. Reprinted with permission from Guvendiren et al. [365] (Top) Haines-Butterick et al. [411]. (Bottom) Yan et al. [464].

Fig. 29

(Top) Distribution of fluorescently labeled C3H10t1/2 cells in a MAX1 (left) and MAX8 (right) peptide hydrogel. (Bottom left) G′ is being measured as a function of time to observe the properties of the MAX8 hydrogel before, during and after the introduction of shear flow. The cells were stained for viability before (bottom middle) and after (bottom left) being injected through a syringe. Reprinted with permission from Haines-Butterick et al. [411].

Fig. 30

Shear-thinning behavior of MDP hydrogels self-assembled in various ionic solutions. Shear is applied at t = −1 and released at t = 0. G′ is measured as a function of time and as a response to applied shear. Reprinted with permission from Aulisa et al. [395].

Fig. 31

Bimodal release of EGF-FITC and PlGF-1-TAMRA from hydrogel alone (blue) or liposome (red). Both drugs show ~100% release over a 15 day period. However, the drug from the hydrogel alone is released much more rapidly, i.e. burst release, than the drug that had been encapsulated within the liposome. These systems exhibit temporal control over drug release. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.) Reprinted with permission from Wickremasinghe et al. [483].

Fig. 32

(a) Schematic of CD, Ad and the guest host complex, either when alone or when Cd or Ad are joined to HA. (b) Synthesis of Ad-HA and CD-HA. (c) Inversion test to observe gelation between Ad-HA and CD-HA. (d) Schematic of guest–host interactions forming reversible physical crosslinks. Reprinted with permission from Chen and Jiang [501].

Fig. 33

The concentration-dependent formation of a network of the cationic telechelic polymer, MMA-DMAEMA-MMA in a salt-free environment. Concentration of polymer increases from left to right. Reprinted with permission from Bossard et al. [518].