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Keywords:

  • hydrogels;
  • stimuli-sensitive polymers;
  • thin films;
  • swelling;
  • gels;
  • gelation

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography

This review highlights recent developments in the field of stimuli-responsive hydrogels, focusing primarily on thin films, with a thickness range between 100 nm to 10 μm. The theory and dynamics of hydrogel swelling is reviewed, followed by specific applications. Gels are classified based on the active stimulus—mechanical, chemical, pH, heat, and light—and fabrication methods, design constraints, and novel stimuli-responses are discussed. Often, these materials display large physiochemical reactions to a relatively small stimulus. Noteworthy materials larger than 10 μm, but with response times on the order of seconds to minutes are also discussed. Hydrogels have the potential to advance the fields of medicine and polymer science as useful substrates for “smart” devices. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2013, 51, 1084–1099


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography

Hydrogels are prevalent in nature as an excellent support scaffold for an immense diversity of life on Earth, with cells as the chief example.[1-7] Following nature's successful model, a wide array of research, from tissue cultures to nanosize actuators,[8] has demonstrated the diverse assortment of physical properties attributed to these materials.

Hydrogels have become a popular platform for the fabrication of smart devices because of their overall biocompatibility, high storage capacity for cells and small molecules, and low interfacial tension at the gel-aqueous solution interface.[9] Hydrogels respond to a large range of stimuli and offer a medium where spatially immobilized chemical functionalities may be manipulated under aqueous conditions. Several review articles have been dedicated to the application of stimuli-responsive hydrogels.[10-13] For example, previous work by Tokarev and Minko outlined burgeoning technologies, addressing a wide range of interesting applications of responsive hydrogel thin films,[9] while Buengera et al. summarized the use of hydrogels as stimuli-responsive sensors.[14]

This review includes a survey of noteworthy advances in thin film hydrogels, ranging from ∼100 nm to 10 μm, developed in the past 5 years, and is not meant to be an exhaustive review of hydrogel technology. Thin films find commercial use today in familiar products such as paints, stains, surface cleaners, mirrors, and electroplated metals to name a few. Recent advancements in organic thin films may help improve performance and reduce future production costs for a variety of existing technologies including photovoltaics, sensors, membrane technology, and drug delivery systems. Herein, we have classified the gels based on the stimulus response (i.e., “light-responsive” hydrogels); therefore, this review outlines the general theory of hydrogels, followed by a discussion of how these materials respond to the various stimuli: mechanical, chemical, pH, heat, and light.

THEORY OF SWELLING

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography

Typically, hydrogels are three-dimensional networks of either chemically or physically crosslinked polymers that swell upon the addition of water. The ratio of the swollen volume to the dry volume of the polymer matrix is often referred to as the “degree of swelling,” and is a common parameter for describing many hydrogels.[9] The degree of swelling of poly [acrylamide-stat-(acrylic acid)] hydrogels, for example, may be as high as 20,000, which indicates a volumetric expansion greater than four orders of magnitude.[15] The degree of swelling is dependent on polymer composition and architecture, as well as inherent properties of the aqueous solution such as temperature or ionic strength.

Equilibrium Swelling Theory

The equilibrium swelling theory of neutral, isotropic polymer networks in the presence of small molecules was first described by Flory and Rehner.[16] The Flory–Rehner model was proposed for the structure of a crosslinked polymer network immersed in a good solvent where the free energy of mixing from osmotic pressure induces solvent migration into the network. The model assumes both a Gaussian distribution of polymer chain lengths and average crosslinks to be tetrafunctional. The theory considers forces arising from three sources:

  1. the entropy change associated with mixing of polymer and solvent
  2. the entropy change arising from reduced polymer conformations upon swelling
  3. the enthalpy of mixing the polymer and solvent[15]

The entropy change from polymer-solvent mixing is positive and favors swelling, while the entropy change from chain stretching (reduction of the number of possible conformations) is negative and opposes swelling. The enthalpy of mixing, which is dependent on the gel composition, can be either positive (opposing mixing), negative (favoring mixing), or zero.

Swelling of the gel is a function of elastic retractive forces of the polymer chains and the expansive thermodynamic contribution of mixing of polymer and solvent. From this, the free energy of a neutral hydrogel in the absence of charged species can be expressed as:

  • display math(1)

where ΔGel is the free energy of elastic retractive forces and ΔGmix is the free energy of polymer and solvent mixing. The term ΔGmix is a measure of the compatibility of the polymer with the surrounding solvent molecules.[17] At equilibrium conditions, the net chemical potential (μ) must equal zero:

  • display math(2)

Therefore, any changes in the chemical potential due to mixing (μmix) are balanced by elastic retractive forces (μel) of the network. The change in chemical potential due to such forces can be expressed by the theory of rubber elasticity proposed by Edwards.[18]

Polymer Volume Fraction

Among the many parameters used to characterize hydrogels, the polymer volume fraction in the swollen state (ν2,s), the molecular weight of the polymer chain between crosslinks ( inline image), and the mesh size of the gel (ξ) are among the most informative, especially for drug delivery applications (Fig. 1).[17] These three parameters can be determined using the equilibrium swelling theory of rubber elasticity modified by Flory.[19]

image

Figure 1. Schematic representation of a polymeric hydrogel where the molecular weight of the polymer chain between crosslinks ( inline image), and the mesh size of the gel (ξ) are represented.

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The swollen state polymer volume fraction ν2,s (analogous to the degree of swelling) is the ratio of the polymer volume (Vp) to the swollen gel volume (Vg). These terms are related to the volumetric swollen ratio (Q), which is dependent on the densities of the solvent (ρ1) and polymer (ρ2), and the mass swollen ratio (Qm) as in the following equation:[20]

  • display math(3)

The architecture of a swollen hydrogel can be quantified by the molecular weight between crosslinks in the absence of solvent and is expressed by:[21]

  • display math(4)

where inline image is the number average molecular weight of the polymer chains prepared in the absence of crosslinkers. inline image and V1 are the specific and molar volume of polymer and solvent, respectively. ν2,s is the volume fraction of polymer in the swollen mass, and χ1 is the Flory–Huggins polymer-solvent dimensionless interaction term.

Equation (4) describes gels that are swollen from the dry state; however, many gels are prepared in the presence of water. A new term was introduced by Peppas and Merrill to account for the presence of water and subsequent changes in chemical potential, which describes the volume fraction density of the chains during crosslinking.[21] The original Flory–Rehner model was revised to incorporate a term describing the polymer in the relaxed, unstretched state (ν2,r):

  • display math(5)

When ionic groups are present in the network, the swelling equilibrium becomes more complicated. In addition to the entropic contributions described in eq (1), a contribution from ions to the total change in Gibbs free energy is:

  • display math(6)

At equilibrium, the net chemical potential still equals zero, and expressions for the ionic contribution to this potential are added to eq (5). Terms for the ionic strength, I, and the dissociation constants Ka and Kb have been added to account for the strong dependency on the ionic strength of the surrounding medium and the nature of these ions.[22-24]

  • display math(7)
  • display math(8)

For polyelectrolyte gels, eqs (7) and (8) are equivalent expressions for anionic and cationic hydrogels prepared in the presence of a solvent. Artificially engineered protein-based hydrogels present a challenge in polymer physics; however, work by Kim et al. reviews some of the progress on the physics of the dynamic intermolecular interactions of protein hydrogels.[25]

Dynamic Swelling of Hydrogels

The theories described above address the equilibrium swelling state of hydrogels; however, an understanding of the swelling dynamics through volume phase transitions may be useful for predicting the behavior of the hydrogel with time. There are many various models that simulate volume transitions, some of which have been recently reviewed.[26, 27] Recently, work by Li et al.[28] and Lai et al.[29] investigated the swelling dynamics of hydrogels by the multieffect-coupling ionic-strength-stimulus model (MECis), which integrates the Nernst–Planck equation for mobile ion concentrations and the Poisson equation for the electric potential associated with the fixed charges to describe the mechanical displacement of a deformable network and the phase field variable. The MECis model is designed to study hydrogels stimulated by changes in ionic strength in two dimensions.

Both linear and nonlinear theories have been developed to describe the swelling kinetics and the processes of mass transport and mechanical deformation. Tanaka et al. derived a linear diffusion equation for polyacrylamide gels treated as a mixture of solid and liquid.[30, 31] A second linear theory by Scherer treats the gel as a continuum phase with pore pressure as a state variable.[32, 33] Recent work by Yoon et al. examines experimental swelling kinetics of thin layers of poly(N-isopropylacrylamide) with the model of linear poroelasticity.[34] Through fluorescent particle tracking with an optical microscope, these experiments were able to accurately monitor thickness changes on the order of 100 μm in good agreement with a linear model of poroelasticity. The linear theory works well for small deformations; however, Hong et al. formulated a nonlinear theory for coupled mass transport and large deformations on the macroscopic scale.[35] Recent work by Bouklas et al. presents a good comparison between the linear theory and the more recent nonlinear theory of poroelasticity for polymer gels.[36] In this work, the dynamics of swelling of a gel affixed to a substrate as well as free swelling are both addressed.

Calculation of the Mesh Size

Many of the target applications for the stimuli-responsive gels outlined in this review are for drug delivery, where mesh size, sometimes referred to as the “pore” size, becomes important. The mesh size is described by the correlation length (ξ) which is defined as the linear distance between two adjacent crosslinks (Fig. 1) and is calculated by:

  • display math(9)

where α is the elongation ratio of the polymer chains in any direction and inline image is the root-mean-squared, unperturbed end-to-end distance of the polymer chain between crosslinks.[17, 37] For gels swollen to isotropic equilibrium, the elongation ratio can be related to the swollen polymer volume fraction, ν2,s, by:

  • display math(10)

The end-to-end distance of network chains between two adjacent crosslinks in the unperturbed state may be determined from the Flory characteristic ratio, CN, the length of the bond along the backbone, l (1.54 Å for vinylic polymers), and the number of links per chain, N, calculated by eqs (10) and (11).

  • display math(11)
  • display math(12)

where inline image is the molecular weight of the polymer repeat unit. By combination of eqs 9–12, the end-to-end distance and pore size of an isotropically swollen hydrogel can be calculated by:

  • display math(13)

Swelling, and therefore mesh size, is affected by numerous physiochemical conditions and structural factors.[38-42]

Many ionic hydrogels exhibit a first-order volume-phase transition where the degree of swelling can change dramatically with only a small change in conditions or application of a stimulus (Fig. 2).[15]

image

Figure 2. The first-order volumetric swelling response of hydrogels with respect to time.

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The swelling transition has a first-order response that involves the coexistence of two gel phases, the swollen and unswollen volume components. Polyelectrolyte gels often swell to a significantly greater extent when compared with neutral gels because of the additional osmotic pressure arising from mobile counter-ions, as well as the electrostatic repulsion of anchored ionizable groups.[9] Charged particles inside the gel fail to distribute evenly between the inside of the gel and the outside medium. This difference in mobile ion concentrations between the gel and the surrounding solution causes the gel to swell to a greater extent and is governed by the Donnan equilibrium.[43] For highly ionized polyelectrolyte gels, Donnan theory was modified by Rička and Tanaka to include an osmotic pressure ion contribution term to better approximate volume transitions due to the additional equilibrium swelling pressure.[24] As a result, modifications of these theories have emerged to describe hydrogel swelling behaviors.[22, 44-46] Long-range repulsive electrostatic interactions between the polyelectrolyte segments favor swelling, while attractive electrostatic interactions between counter-ions and charged polymer segments favor shrinking. Counter-ion condensation leads to anisotropic charge distribution and the formation of ion pairs. The non-Gaussian conformation of charged polymer segments, Debye screening contributions, and other gel responses are also described.[20-22]

In the interest of practicality, fast response action is required for most stimuli-responsive thin-film devices. The volume phase transition response is the most common mechanism among hydrogel-based “smart” devices. This transition is driven by a diffusion-limited process; therefore, at least one dimension of the hydrogel must be sufficiently small so that the response behavior occurs on the order of seconds to minutes. Early work by Tanaka and Fillmore shows the volumetric response time of a gel is proportional both to the square of the smallest linear dimension of a gel and to the diffusion coefficient of the gel network, D,[30] which governs response time by:

  • display math(14)

where E is the longitudinal bulk modulus of the network, and f is the coefficient of friction between the network and the solvent.[30] Stimuli-responsive materials that respond on the order of seconds are typically 10 μm or less in their smallest linear dimension, reducing the physical restrictions to response time. This is not a strict geometric limitation; however, noteworthy examples of gels with a larger dimension, but second to minute response times, are also highlighted. Furthermore, not all of the stimuli-responsive devices outlined in this review are governed by diffusion-limited processes.

MECHANO-RESPONSIVE GELS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography

Inspired by the mechanochemical transduction prevalent in biological systems, Kuksenok et al. developed a computational model to describe traveling chemical signaling waves initiated by applied mechanical pressure.[47] They proposed the use of this model to develop touch-sensitive sensors, anti-wear films, and self-reinforcing materials. Another computational model has been described to calculate the physical properties of photonic devices,[48] which are materials that may change color with an applied stimulus, such as environment sensitive fluorophores.[49]

Recently, photonic hydrogels have attracted attention for the development of sensors because of the unique optical properties arising from their periodic structure,[47] with early reports of these materials discussed by Debord and Lyon.[50] These hydrogels have alternating swelling and nonswelling polymeric layers constructed as a lamellar, one-dimensional photonic crystal with spatially tunable optical properties (Fig. 3).[47]

image

Figure 3. Example of a lamellar photonic hydrogel showing a volume-phase transition. The refractive index of the nonswelling layer (η1) remains unchanged while the refractive index of the swelling layer in the unswollen state (η2) changes upon swelling (η2′).

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These photonic devices change color in response to a geometric change in bilayers of materials with varying refractive indices. Haque et al. developed an anisotropic photonic hydrogel in which periodically ordered single-domain lamellar bilayers of self-assembled poly(dodecyl glyceryl itaconate) are organized within a polyacrylamide network.[51] These hydrogels diffract light depending on the periodic distance of the layers, which can be varied with mechanical pressure, and show almost purely reversible elastic behavior. With applied strains from 0 to 3, the thickness of these bilayers may be tuned on the order of hundreds of nanometers, such that the diffraction response of the periodic layers generates a tunable colorometric response over the visible spectrum (Fig. 4).

image

Figure 4. Stretching a photonic hydrogel with lamellar bilayers of self-assembled poly(dodecyl glyceryl itaconate) photonic hydrogel (a) stretched from strains 0 to 2.8, (b) showing the colorimetric response to strain, with (c) calculated lamellar thicknesses on the order on 160–320 nm.[51] Reprinted with permission from Chem. Mater. 2011, 23, 5200–5207. © 2011 American Chemical Society.

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image

Figure 5. Oxidative crosslinking of enzymatically degradable cAAPEG macromonomer yields rapid and simultaneous gelation and tissue adhesion. In the presence of neutrophil elastase, the Ala-Ala dipeptide linker (blue) is cleaved to provide cell-mediated structural degradation. Black arrowheads indicate continuation of the crosslinked hydrogel matrix.[91] Reprinted with permission from Biomacromolecules 2011, 12, 4326–4334. © 2011 American Chemical Society.

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Banik et al. developed hybrid polymer hydrogels comprised of two different gel types in intimate contact which showed interesting mechano-optical response behavior based on the alignment of laponite particles, leading to stress-induced birefringence.[52] The alignment of the laponite particles upon mechanical stretching induces particle stacking and a resulting change in refractive index of the material.

Hamilton et al. developed a supramolecular hydrogel that displayed thixotropic behavior, where a mechanical force (typically shaking or sonication) caused a phase transition from gel to liquid-like.[53] Unlike their traditional polymeric counterparts, supramolecular gels are a framework of non-covalent interactions among a contiguous network of small molecules.[54] These molecules can be comprised of simple alkanes to higher order structures such as large porphryins.[55]

CHEMO-RESPONSIVE GELS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography

A low molecular weight (LMW) gelator was first reported in the 19th century.[56] A supramolecular gel includes all classes of gelating species that utilize noncovalent interactions such as hydrogen bonding, van der Waals forces, and metal-ligand coordination to co-assemble or self-sort.[55, 57-76] Over the past century, these unique gels have been incorporated into many facets of daily life, from hygiene products to drug delivery agents.[77-86]

Although supramolecular hydrogels have found many commercial applications, a fundamental understanding of these complex architectures is still in the early stages. A recent review by Buerkle and Rowan critically details supramolecular gels made from multicomponent LMW species that are able to co-assemble and self-sort.[55] LMW supramolecular gels have garnered attention in recent years due to the ease of forming gels that take advantage of molecular responses through noncovalent interactions.[55]

An enzymatic process that assists in the formation of supramolecular hydrogels from a hydrophobic small molecule was reported in 2009 by Gao et al.,[87] expanding the toolbox of potential molecules for enzymatic assisted hydrogel formation.[75, 87, 88] The group demonstrated that alkaline phosphatase offers a means for the creation of hydrophobic compounds, thus, allowing for the formation of supramolecular hydrogels in 3D networks.[87]

In an investigation of degradable hydrogels,[89, 90] Brubaker and Messersmith developed a mussel-inspired adhesive hydrogel that offers potential to be used as a degradable glue or medical sealant (Fig. 5).[91-95] The enzyme-degradable hydrogel was synthesized by introducing small amounts of an elastase substrate peptide, Alanine-Alanine, into a branched poly(ethylene glycol) macromonomer, as seen in (Fig. 4). Degradation of the hydrogel was carried out after implantation of the adhesive gel onto the epidermis of mice. The surface confinement of the gel took approximately 1 min to achieve under oxidative crosslinking conditions. The crosslinked hydrogel was fabricated to degrade in the presence of the proteolytic enzyme neutrophil elastase. The subcutaneous studies confirmed the degradable adhesive hydrogel produced very little inflammatory epidermal response.[91]

The Kurisawa group reported a medically promising biodegradable hydrogel with tunable stiffness for controlling the rate of proliferation and differentiation of human mesenchymal cells.[86] The investigated hydrogels were composed of gelatin-hydroxyphenylpropionic acid conjugates formed through oxidative coupling. It was ascertained that the gel stiffness was tuned by varying the concentration of hydrogen peroxide in the matrix, without altering the precursor polymer. As the stiffness of the gel increased, cell proliferation decreased. Hydrogel degradation was carried out in the presence of type-1 collagenase, a member of the matrix metalloprotease family.[86] Although stiffness slowed cell proliferation, the hydrogel still degraded with increased rigidity.

Absorbing water is an inherent property of hydrogels, but swelling can also initiate novel responses. Work by the Tsukruk group has demonstrated spontaneous folding behavior in ultrathin (100 nm) gel films of polyvinyl-2-pyridine (PV2P).[96] A highly uniform folding pattern is formed by exposing films to acidic conditions (Fig. 6).

image

Figure 6. (a) Optical image showing the remarkable long-range uniformity of the folds along the length of the folds and (b) 3D AFM image of the folding. (c) Cross section along the folded structure showing the three discrete heights of the fold regions, the intermediate regions, and the substrate-grafted layer.[96] Reprinted with permission from S. Singamaneni, M. E. McConney, V. V. Tsukruk. ACS Nano 2010, 4, 2327–2337. © 2010 American Chemical Society.

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Hydrogels can be highly sensitive to changes in humidity. Tellis et al. have used this property to produce a hydrogel humidity sensor film containing dapoxyl sulfonic acid (DSA) as a fluorophore.[97] The sensor works by detecting a shift in DSA's fluorescence resulting from a change in local polarity brought about by absorbed water in the hydrogel. This shift can be attributed to an effect known as solvatochromism, which is caused by the ground and excited state of a fluorophore being stabilized to different degrees by the interaction of the fluorophore with solvent molecules. A change in the degree of solvation of the fluorophore will nonuniformly affect its energy levels, leading to a shift in fluorescence.

Pushing the boundaries of responses, the Tsukruk group has contributed a new single material consisting of Poly-(N-isopropylacrylamide) (PNIPAM) and titanium(IV) isopropoxide, with variants consisting of composites of these materials, which respond to humidity by changing their refractive index.[98] By switching between 1.5% relative humidity and 95% relative humidity, refractive index changes as large as 0.03 can be observed on time scales as short as 2 s.

pH-RESPONSIVE GELS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography

Stimuli-responsive polymer systems that drive efficient transduction pathways enable them to be suitable for sensor applications. pH-sensitive hydrogels are known for their ability to undergo dramatic changes that affect their volume, elasticity, and mass by slightly altering the pH of the system.[84, 99-121] These types of hydrogels can be used in a wide range of applications that include sensors and actuators.[122, 123]

Tokareva et al. reported pH-responsive hydrogels fabricated on gold nanoparticles or gold substrates, that behave as highly sensitive pH sensors with short response times.[122] Effective tuning was achieved by the use of a swellable thin film of poly(2-vinylpyridine) (P2VP). The authors demonstrated a 50-nm shift in the plasmon resonance by lowering the pH from 5 to 2, which in turn increased the film thickness by about 70%.[122]

Minko and Tokarev have produced porous gel films by fabricating thin films with the ability to phase separate.[10, 124-128] Porous membranes were fabricated using several techniques, the most common of which networked the weak cationic polyelectrolyte P2VP by crosslinking with 1,4-diiodobutane (DIB). After spin-coating of the polymer network to produce a smooth, homogeneous thin film, the substrate was thermally annealed to evaporate unreacted DIB, leaving a porous membrane. Once the pore diameter reached a controlled size, the films were exposed to various pH conditions. Figure 7 illustrates the concept used by Minko et al. to decrease pore size by changing the pH of the matrix. A pH near 2 collapsed the pores, while an increase in pH to 3 opened the pores, which allowed diffusion through the membrane. It should be noted that even though the pores were closed at pH 2, the membrane demonstrated slight permeability. They also investigated several more P2VP membranes, alginate gel membranes, and electrochemical gate stimuli-responsive membranes based on a gold electrode. [10, 122, 124, 125]

image

Figure 7. SPM topography images (10 × 10 μm2) of the swollen (a) and shrunken (b) pH-responsive polyelectrolyte membrane.[124] Reprinted with permission from ACS Appl. Mater. Interfaces 2009, 1, 532–536. © 2009 American Chemical Society.

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In a more recent study by Minko and Tokarev, a biocompatible hydrogel porous membrane was developed via phase separation of polyvinyl alcohol and sodium-alginate.[129] pH-responsive membranes were prepared by an ionically crosslinked hydrogel thin film with controlled pore diameter and an even pore size distribution. After crosslinking of the alginate matrix with divalent calcium ions, the hydrogel film was sensitive to changes in pH, which led to an ability to open and close the pores (Fig. 8).[129]

image

Figure 8. Schematic representations of a single pore of the polyelectrolyte membrane switched between the closed (a) and open (b) states. The structure of the alginate hydrogel comprised of d-mannuronic acid and l-guluronic acid residues crosslinked with divalent ions (Ca2+) in part (d) to give an egg-carton-like conformation (c). The swelling and shrinking of the hydrogel is attributed to the ionization (a) and protonation (b) of the unbound carboxyl groups at pH > 5 and pH < 4, respectively.[124] Reprinted with permission from ACS Appl. Mater. Interfaces 2009, 1, 532–536. © 2009 American Chemical Society.

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Hydrogels comprised of multilayered poly(methacrylic acid) (PMAA) capsules, prepared from hydrogen-bonded PMAA/poly-N-vinylpyrrolidone (PMAA/PVPON) multilayer layer-by-layer (LbL) precursors through crosslinking with ethylenediamine (EDA), can be used to synthesize gold nanoparticles inside hydrogel shells.[130] The Tsukruk group produced composites with pH dependant properties without a need for pretreatment or the addition of buffers to a borate solution under ambient conditions. Dimensions of the gold nanoparticles were controlled through the pH-dependant release of amine groups through the crosslinks, without affecting the film integrity. At pH 7, the walls of the hydrogels demonstrate a folding pattern that collapses uniformly upon drying. With more robust hydrogel walls the capsule morphology changes dramatically as shown in Figure 9.[130]

image

Figure 9. AFM images (height, left; phase, right) of the EDA-PMAA hollow capsules (a) with Au nanoparticles reduced in borate buffers at pH 10 (b), pH 5 (c), and pH 3 (d). The scan size is 5 μm, and the z-scale is 400 nm for all images (height).[130] Reprinted with permission from Chem. Mater. 2009, 21, 2158–2167. © 2009 American Chemical Society.

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Bassik et al. introduced a photo-patterned actuator composed of N-isopropyl acrylamide (NIPAM), acylic acid (AAc), and poly-ethylene oxide diacrylate (PEODA) thin films.[123] The actuator fabrication is dependent on the swelling behavior of individually patterned hydrogels. By varying the pH and ionic strength, bilayer structures were prompted to fold and unfold. The actuation mechanism of the gel in solution was predicted by the high differential swelling characteristics of the bilayer, resulting from specific acrylate layers (Fig. 10).[123]

image

Figure 10. Schematic of the bilayer actuation mechanism. (a) A hydrogel bilayer is placed in aqueous solution 1 with specific pH and IS. It comes to equilibrium. (b) The bilayer is transferred to solution 2 which has different pH and IS. (c) Gel 1 swells in response to the environmental changes while Gel 2 does not swell, causing the bilayer to fold. (d) The bilayer is transferred back into solution 1. (e) Gel 1 deswells in response to the environmental changes and the bilayer unfolds.[123] Reprinted from Polymer 2010, 51, 6093–6098. © 2010, with permission from Elsevier.

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In early 2010, Cameron et al. introduced a dipeptide amphiphile that was electrochemically self-assembled into thin surface-supported hydrogels and gap-spanning hydrogel membranes (Fig. 11).[131] The voltage change enabled rapid lowering of the pH inducing a controlled volume response near the electrode, which allowed for controlled diffusion rates of particles inside the gel as well as erosion of the gel surface.[131]

image

Figure 11. Cryo-SEM image of the top surface of an electrochemically grown gel film. The scale bar is 1 μm. Reprinted with permission from J. Am. Chem. Soc. 2010, 132, 5130–5136. © 2010 American Chemical Society

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HEAT STIMULUS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography

Responsiveness to heat is a popular paradigm in stimuli-responsive materials. PNIPAM dominates research in heat-responsive polymers due to its low cost, reversibility, and physiological temperature response range.[132-135] PNIPAM hydrogels respond to an increase in temperature above its lower critical solution temperature (LCST) by expelling water because of a temperature dependence of the hydrogen bonding between polymer and water. This response allows water content and volume of PNIPAM hydrogels to be regulated thermally.

As previously discussed, transport across membranes is an important surface phenomenon, and “gated” pores have attracted interest in drug release and biomimetics.[136-139] Work by Wang et al. took advantage of the temperature dependant volume changes in PNIPAM to synthesize a polycarbonate-g-PNIPAM porous membrane[140]. Imposing a temperature gradient allowed for fine control of the water flux in this material. A temperature increase caused the membrane pores to dilate as the gel shrank in volume by expelling water, which raised the flowrate. The open/closed state water flux ratio can be augmented by moderately increasing initial monomer concentration.

PNIPAM thin films can also be used to initiate drastic morphological changes in films. The Hayward group used halftone lithography to fabricate PNIPAM gel sheets that produced predictable 3D structures in response to heating above the LCST.[141] These “responsive buckling” sheets were made with a copolymer of NIPAM and benzophenoneacrylamide. The buckling pattern is generated by lightly crosslinking a large area of the film with 360 nm UV light, followed by intense UV irradiation of a smaller, detailed pattern within the lightly crosslinked area. A wide variety of morphologies were obtained by varying the intensity, location, and pattern of the second crosslinking step (Fig. 12).

image

Figure 12. Half-toned disks with axisymmetric metrics. Patterned sheets programmed to generate (a) a piece of saddle surface (Sa), (b) a cone with an excess angle (Ce), (c) a spherical cap (Sp), and (d) a cone with a deficit angle (Cd). (Top) 3D reconstructed images of swollen hydrogel sheets and (bottom) top-view surface plots of Gaussian curvature. Initial thicknesses and disk diameters are 9 and 390 μm, respectively, although the apparent thickness of sheets is enlarged due to the resolution of the LSCM. (g–j) Patterned sheets programmed to generate Enneper's minimal surfaces with n = (g) 3, (h) 4, (i) 5, and (j) 6 wrinkles upon swelling. Three-dimensional reconstructed images (top) and top-view surface plots of squared mean curvature h2 and Gaussian curvature k (bottom). Initial thicknesses and disk diameters are 7 and 390 μm, respectively. From Science 2012, 335, 1201–1205. Reprinted with permission from AAAS.

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The swelling/deswelling behavior of PNIPAM is a result of the pendant isopropyl group-backbone interaction becoming more favorable at raised temperature than the amide-water hydrogen bonding interaction, which drives a switch from hydrophilicity to hydrophobicity. As an extension of earlier work by Okano et al.,[142] Canavan et al.[143] used this surface energy change to grow endothelial cells, which have a high affinity for hydrophobic surfaces, on PNIPAM above its LCST. The cells were released from the surface by lowering the temperature below the LCST to form a hydrophilic surface. For more information on cell detachment using PNIPAM, Canavan et al. contributed an excellent review in 2010.[135]

Another adaption of a responsive PNIPAM gel is a system which creates mechanical motion. Using a PNIPAM hydrogel loaded with single-walled carbon nanotubes (SWNT), Zhang et al.[144] fabricated reversible heat-responsive actuators. The actuator material consists of PNIPAM loaded with 0.75 mg mL−1 SWNT, and responds 5 times faster (∼35 s) than a pure PNIPAM actuator (∼150 s). The actuator operates on the simple principle that above LCST, the film will expel water and decrease in volume. By strategically orienting films, a reversible folding mechanism can be activated in the presence of water above 32 °C. By layering the actuators, full response times can be lowered to ∼10 s. This folding mechanism can also be activated by near IR light, which is highly absorbed by the embedded SWNTs, generating localized heating.

Another example of temperature-dependent mechanical motion is a recent addition to the gel field by Thérien-Aubin et al.,[145] using composite polymer sheets of two different hydrogel materials, such as PNIPAM and PNIPAM-co-polyhydroxyethylacrylamide. The primary gel (PG) is photopolymerized from the first monomer, then swollen with water and an aqueous solution containing the second monomer or monomer mix. Photopolymerization is induced in the primary gel matrix to form the second gel layer. This technique generates overlapping sheets of polymer which have different LCSTs. By specifically photopatterning each layer, a thermo-responsive morphological change can be elicited (Fig. 13). Other polymers which respond to ionic strength or pH, such as poly(2-acrylamido-2-methyl-1-propanesulfonic acid) can also be included in one of the layers to give additional modes of response.

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Figure 13. Three-dimensional configurations adopted by composite gel sheets under the action of various stimuli. (a and b) Dome-shape structures formed in a 1 M NaCl solution by PNIPAM/PAMPS hydrogel disks patterned using a photomask of two-dimensional projection of a truncated icosahedron (a) or a photomask with a shade of gray increasing from the center to the circumference (b). (c) An hourglass structure generated in deionized water at 45 °C by a rectangular gel sheet composed of a central PNIPAM stripe and two outer PNIPAM/PNIPAM stripes. (d) A saddle-like structure formed by a poly(acrylamide-co-butylmethacrylate) hydrogel disk patterned with circular rings of poly(NIPAM-co-dimethylamino-ethylmethacrylate) when CO2 is bubbled in the liquid medium. The insets show corresponding photomasks, in which the dark regions yield the regions of PG. The thickness of the gel films was 0.44 mm. The scale bars are 0.5 cm. In panels (a) and (c), the white color corresponds to the strongly shrunk PG regions. Reprinted with permission from J. Am. Chem. Soc. 2013, 135, 4834–4839. © 2013 American Chemical Society.

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Although much work has focused on PNIPAM, other temperature-sensitive polymers have advantages over PNIPAM, such as the better biocompatibility seen in poly(N-vinylcaprolactam) (PVCL) because of its resistance to hydrolysis.[146] Depending on the molecular weight and concentration, PVCL has a widely tunable native LCST temperature from 32 to 50 °C. Liang et al. have taken advantage of these properties by building up a PVCL-co-polyaminopropylmethacrylamide (PVCL-co-PAPMA), polymer film using LbL deposition with PMAA, then crosslinking with glutaraldehyde.[146] By varying the percentage of PAPMA and the amount of crosslinking, a range of LCSTs can be achieved.

LIGHT STIMULUS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography

Spatial, wavelength, and intensity parameters of light can be varied quickly, easily, and remotely, enabling light to be one of the most controllable stimuli. Research has taken advantage of this unique control to synthesize gels that use the fine spatial and time resolution afforded by photo-irradiation. In the context of hydrogels, light is most often used to induce crosslinking, which can be used to produce novel results, such as in the aforementioned work by Hayward.[141] In terms of responses, light can stimulate a variety of useful responses, such as cleavage of crosslinks, diffraction shifts in the presence of analytes, biomolecule, and nanoparticle uptake and release, and ion detection.[147-152]

The Kanamori group has used the high spatial-resolution of light to form microscopic surface motifs on poly(N-isopropylacrylamide-co-acrylospiropyran) films with N,N-methylene-bis(acrylamide) included as a crosslinker.[153] Acidifying the gel in the dark can induce ring opening into the protonated merocyanine isomer. After exciting the acidified gel with 436-nm light, micromotifs could be created from the decrease in swelling caused by the switching of merocyanine in irradiated domains to the ring-closed hydrophobic spiropyran isomer (Fig. 14). Depending on irradiation time (1–3 s), motifs were formed which varied in height up to 130 μm. The pattern completely faded after 3 hours in the dark, and a new one could be installed on the same gel.

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Figure 14. (a and b) Images of the pSPNIPAAm hydrogel layer just after the micropatterned light irradiation. Duration of irradiation was (•, red) 0 s, (◊) 1 s, and (○, green) 3 s. (c) Height change of the hydrogel layer in (b) nonirradiated and (O) irradiated region as a function of time after 3-s blue light irradiation. Reprinted with permission from Chem. Mater. 2007, 19, 2730–2732. © 2007 American Chemical Society.

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Photodegradable crosslinks are critical tools for designing responsive gels. Pioneering work by the Anseth group,[147] using acrylates connected by a nitrobenzyl ether photodegradable moiety to PEG crosslinks, has opened new avenues of research. Degrading the crosslinks uniformly can alter the overall material properties; however, local photoirradiation with either a single photo 405 nm laser or a two photon 740 nm laser can form 3D structures in the material. Anseth's work focused on creating a unique and tunable cell culture environment, but broader work in this area promises powerful new applications.

The cis-trans isomerization photoresponse of azobenzene is commonly used in photoresponsive materials.[154-156] Liu et al. examined the release kinetics, poration, and swelling kinetics of a gel containing azobenzene.[157] It was shown that the cis conformation allows widening of the pores, facilitating water release from the hydrogel.

Another adaption of this azobenzene chemistry was shown by the Tieke group with copolymerization of NIPAM and (11-(acryloyloxy)undecyl)trimethylammonium bromide gel using gamma radiation.[158] The gel was swelled with an aqueous disodium 4,4′-di(6-sulfatohexyloxy)azobenzene solution, which is electrostatically adsorbed onto the polymer matrix. Below the LCST the azo group freely isomerizes in response to light, but above the LCST the azo group cannot interconvert between isomers, likely due to the steric hindrance of a shrunken gel and the loss of optical clarity after the LCST transition. Using temperature to trap gel properties allows the building of smarter and more complex systems.

FUTURE OUTLOOK FOR HYDROGELS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography

This review outlines recent progress in the field of stimuli-responsive hydrogels. As these films improve through creative new designs, their influence is likely to expand to new areas of science, industry, and health. The rapid expansion of this field has created novel devices that stretch across disciplines including polymer science, biochemistry, tissue engineering, and medicine.[1, 75, 77, 78, 80-86, 159]

Although developing hydrogel systems that respond quickly to external stimuli is a challenge, films that have a fast, easily observable response to minimal stimuli have undergone tremendous improvement. Furthermore, developing a single system that can respond to multiple stimuli is often challenging and requires precise molecular engineering,[54, 109, 154, 160, 161] although some examples of multiple-response materials promise unforeseen applications.[154, 162-168] Some examples of multi-responsive hydrogels have been developed by the Serpe group, including unique p(NIPAM-co-AAc) microgel film assemblies on gold substrates, called etalons, capable of color tunability over 300 nm in response to temperature and pH changes,[169-171] which may find applications as microarray sensors or in display technologies.

In living systems, nature exploits the principle of partitioning: compartmentalized cells are separated by biochemically selective membranes which interact dynamically with their surrounding environment.[172] Imitating this type of hierarchal organization of complex stimuli-responses will help aide in the development of increasingly more utilitarian stimuli-response materials.

Future advances in porous membrane fabricated from hydrogels may one day provide angstrom-precise selectivity to molecule passivity. Photonic hydrogels may offer a scaffold for the development of flexible, liquid-like, color displays. The controlled stimulus, sol-gel transitions of hydrogel materials may lead to advanced biodegradable products to be used commercially. Future electricity-free biomolecule sensors constructed from hydrogels may come packaged as dry state devices, activated with the addition of water. Hydrogels present a useful substrate for functional, stimuli-responsive devices, and many more applications for these devices will develop as the technology for intelligent, stimuli-responsive materials improves.

REFERENCES AND NOTES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography

Biography

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. THEORY OF SWELLING
  5. MECHANO-RESPONSIVE GELS
  6. CHEMO-RESPONSIVE GELS
  7. pH-RESPONSIVE GELS
  8. HEAT STIMULUS
  9. LIGHT STIMULUS
  10. FUTURE OUTLOOK FOR HYDROGELS
  11. Acknowledgments
  12. REFERENCES AND NOTES
  13. Biography
  • Image of creator

    Evan M. White (second from right) is from Lilburn, GA and received his B.S. in Chemistry from Georgia College and State University in 2009. He is a doctoral candidate doing research concentrating in light-responsive hydrogels and polymer brushes. Jeremy Yatvin (middle) is from Philadelphia, PA and received his B.S. in Chemistry from the College of Charleston in 2011. He is a doctoral student researching specialized glass coatings and antimicrobial polymers. Joe B. Grubbs III (second from left) is from Eldorendo, GA and received his B.S. in Biology from Georgia Southwestern State University in 2002. Since 2008, he has been employed by DaniMer Scientific LLC in Bainbridge GA, who is partially funding his Ph.D., along with financial support from Jason Locklin. He is a doctoral candidate under the supervision of Jason Locklin studying surface-initiated polymerization and solution type chemistries of biodegradable polymers. Jenna Bilbrey (left) is from Pensacola, FL and received her B.S. in Chemistry from the University of West Florida in 2010. She is a doctoral candidate studying computational models of polymerization mechanisms. Jason Locklin (right) obtained his B.S. in Chemistry (1999) from Millsaps College and his Ph.D. in Chemistry (2004) at the University of Houston. In 2005, he moved to Stanford University as an Intelligence Community Postdoctoral Fellow, and in 2007, he joined the faculty at the University of Georgia and is currently an Associate Professor in the Department of Chemistry and College of Engineering. He has been awarded the Central Intelligence Agency Young Investigator Award (2007) and the NSF CAREER Award (2010). His group is currently investigating surface-initiated polymerization reactions, orthogonal self-assembly, Kumada-transfer polycondensation, antimicrobial polymers, and stimuli-responsive interfaces.