Responsive Polymer Gels1 - CiteSeerX

208

Polymer Science, Ser. C, Vol. 42, No. 2, 2000, pp. 208–228. Translated from Vysokomolekulyarnye Soedineniya, Ser. C, Vol. 42, No. 12, 2000, pp. 2328–2352.Original Russian Text Copyright © 2000 by Philippova.English Translation Copyright © 2000 by

MAIK “Nauka

/Interperiodica” (Russia).

INTRODUCTION Polymer gels are three-dimensional crosslinked

polymers swollen in a solvent. These systems can be ofboth natural (e.g., vitreous body of the eye) andsynthetic (polyacrylamide and poly(acrylic acid) gels)origin.

The content of solvent in a gel may be very high,reaching up to 99.9%. Despite the fact that polymergels consist predominantly of water, these objects arecapable of retaining their shape like solids. This prop-erty is due to the polymer chains being crosslinked soas to form a common spatial skeleton called the poly-mer network. The crosslinks between polymer chainscan be provided both by labile entanglements formedby weak bonds (e.g., by micelles, multiplets, crystal-lites, etc.) and by stable covalent bonds (Fig. 1.). Thepolymer gels with crosslinks of the first kind arereferred to as physical gels, while those crosslinked bycovalent bonds are called chemical gels. In this review,consideration is restricted to the gels based on cova-lently crosslinked polymer networks.

The first chemical gels studied were based on poly-mer networks with a high density of crosslinks, whichexhibited very small swelling in solvents. These gelsare widely used in many fields, in particular, as carriermedia in chromatography. In recent decades, the atten-tion of researchers was drawn to the so-called slightlycrosslinked gels, with the density of crosslinks on theorder of one per 50–400 polymer chain units. Thesesystems are capable of absorbing and retaining verylarge amounts of a solvent, the mass of solvent beinggreater by several orders of magnitude than that of thepolymer involved in the gel network. In other words,these gels possess superabsorbent properties or arecapable of superstrong swelling. Another characteristicproperty of slightly crosslinked gels is their ability toundergo collapse, where the gel volume drops by a fac-tor of several tens or hundreds in response to small

changes in the external conditions (temperature, pH,etc.). Both characteristic features of the slightlycrosslinked gels (superstrong swelling and collapse)are most pronounced in polyelectrolyte gels containingionogenic groups capable of dissociating with the forma-tion of charged units and counterions (Fig. 2) [1, 2].

What physical laws stand behind these properties ofslightly crosslinked gels? The ability to undergo strongswelling is related primarily to the effective repulsionbetween polymer network units in the gel. The repul-sion is most frequently caused by the “exerting”osmotic pressure of mobile counterions contained inthe gel. The collapse is possible if attractive forces,capable of effectively counteracting the “exerting”osmotic pressure, are also operative between the gelnetwork units. The collapse takes place when an exter-nal factor (temperature, pH, etc.) stimulates the growthof attraction between units, which results in theabsorbed solvent being abruptly released from the gel.Owing to this behavior, slightly crosslinked polymergels are frequently called responsive gels [3]. This termmeans the ability of a gel to respond to external factorscapable of inducing the collapse.

The aforementioned competition between attractiveand repulsive forces can both modify the gel state on amacroscopic level (swelling or collapse) and produce

Responsive Polymer Gels

1

O. E. Philippova

Department of Physics, Moscow State University,Vorob’evy gory, Moscow, 119899 Russia

Received March 22, 2000; Revised Manuscript Received April 19, 2000

Abstract

—Experimental data on the fundamental properties of polymer gels—ability to undergo superstrongswelling and collapse—are reviewed. The main types of “responsive” gels are presented and the main possibleapplications of these systems are considered.

1

The work was supported by the Russian Foundation for BasicResearch, project no. 99-03-33447a.

Fig. 1.

Schematic diagram of a polymer gel. Blackcircles indicate crosslinks between polymer chains.

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RESPONSIVE POLYMER GELS 209

microscopic changes manifested by the formation ofregular microstructures on a 1–100 nm scale [2]. Thelatter microstructures also exhibit a “responsive” char-acter and can be controlled by external factors.

In order to control the properties of polymer gels onboth macroscopic and microscopic levels, it is neces-sary to study the fundamental laws governing thebehavior of these systems. Below we will consider theprincipal factors determining this behavior and discusstheir role in manifestations of the properties of respon-sive polymer gels.

FACTORS DETERMINING THE BEHAVIOR OF POLYMER GELS

Uncharged Gels

The behavior of a gel containing no ionogenicgroups is determined by non-Coulomb interactions.These include van der Waals forces, hydrophobic con-tacts, and hydrogen bonds.

Van der Waals forces.

These forces determine theinteraction between dipole moments induced in ini-tially uncharged atoms or molecules approaching oneanother. The energy of these interactions is rathersmall, being on the order of 4 kJ/mol [4, 5] (cf. room-temperature

kT

~ 2.5 kJ/mol). The mutual attraction due to the van der Waals

forces between uncharged network units in a gel can beenhanced by adding a thermodynamically poor solventto the system. As a result, the gel shrinks as a whole. Anexample is offered by the contraction of a water-swol-len polyacrylamide gel upon adding acetone [6, 7].However, it is not excluded that a certain role in stabi-lization of the compact gel configurations in this sys-tem belongs to hydrogen bonds between acrylamideunits.

Hydrogen bonds.

A hydrogen atom covalentlybound to an electronegative atom A (e.g., O or N) hasa deficit of electron density that can be compensated byshifting the H atom toward another electronegativeatom B possessing an unshared electron pair. As a result,the H atom forms a hydrogen bond between atoms A andB (A–H···B) with an energy of 12–38 kJ/mol [8].

Single hydrogen bonds usually cannot modify thegel state to a significant extent. The role of hydrogenbonds markedly increases if these contacts acquire acooperative character, as, for example, is the case ofhydrogen bonds between the units of two complemen-tary macromolecules. These intermacromolecular reac-tions may take place between crosslinked and linear poly-mers (e.g., in a PMAA gel–linear PEG system [9–19]) orbetween two crosslinked polymers (e.g., in interpene-trating networks of poly(acrylic acid) with polyacryl-amide [6, 20–22] and with polyethylene oxide [23]).

Hydrophobic contacts.

The energy of hydrophobicinteractions is on the order of several kJ/mol, which iscomparable with or somewhat lower than the energy ofhydrogen bonds.

In contrast to the interactions of other types, hydro-phobic interactions are closely related to the structureof water as a solvent. When a hydrophobic substance isbrought in contact with an aqueous medium, the ther-modynamic parameters exhibit a change such that

∆

S

< 0,

∆

H

< 0, and

∆

F

> 0 [4]. In other words, the lowsolubility of hydrophobic substances in water isa consequence of large decrease in the entropy of thesystem. This experimental fact is explained within theframework of the following model. Water molecules inthe liquid phase are known [5, 24] to form a systemwith hydrogen bonds, whereby each molecule has fournearest neighboring water molecules. On coming intowater, hydrophobic molecules induce enhanced struc-turization of water in their surroundings, which isrelated to an increase in the electric potential resultingfrom a decrease in the local dielectric permittivityaround the hydrophobic group. This structurization isunfavorable from the standpoint of entropy. In order todecrease the area of contact with water, the moleculesof hydrophobic substances tend to combine with oneanother. The greater the area of contact between sepa-rate hydrophobic molecular groups and water, the morepronounced is this trend.

Thus, the main driving force of hydrophobic inter-actions is the gain in entropy achieved by decreasingthe structurization of water in the environment of thehydrophobic groups. Since the entropy contribution tothe total free energy of a system increases with temper-ature, the role of hydrophobic contacts grows with tem-perature as well.

The hydrophobic interactions in a polymer gel canbe controlled by varying the ratio of hydrophilic andhydrophobic groups in the system. The hydrophobicproperties of macromolecules can be enhanced, in par-ticular, by introducing hydrophobic substituents (e.g.,

n-

alkyl groups) into their side chains. The longer the

n

-alkyl chain, the more pronounced are the hydropho-bic properties. As is known [25],

n

-alkyl chain transfer

Free ions

Fig. 2.

Schematic diagram of a polyelectrolyte gelcontaining positively charged chain segments andlow-molecular-weight negative counterions free totravel over the entire gel volume.

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from an aqueous to a hydrocarbon medium leads to afree energy gain of 1.29

kT

per CH

2

group.

Ion-Containing Gels

An important part in the behavior of gels containingionogenic groups belongs to electrostatic interactions.These interactions play a determining role in stronglycharged polymer gels. In weakly charged gels, wheremost of the monomer units are uncharged, a consider-able contribution to the free energy of the system maybe due to non-Coulomb interactions.

In analysis of the electrostatic interactions, we mayseparately consider several factors, including the trans-lational energy of counterions, the Coulomb interac-tions between charged groups, and the formation of ionpairs and multiplets.

Translational entropy of counterions.

When apolyelectrolyte gel is placed into a medium with high

dielectric permittivity (e.g., water), the ionogenicgroups undergo dissociation with the formation ofcharged units and counterions (Fig. 2). The counterionsmay travel over the entire gel volume, that is, acquire atranslational entropy. From the standpoint of a gain inthe translational entropy, the counterions must tend tooccupy the maximum possible volume (without leav-ing the gel to obey the electroneutrality condition).As a result, the counterions remain in the gel, creatingan exerting osmotic pressure responsible for gel swell-ing [26].

The translational entropy of counterions, determin-ing the osmotic pressure in a gel, is one of the mostimportant characteristics of the polyelectrolyte gels.

Coulomb interactions.

It must be pointed out thatthe polyelectrolyte gels are macroscopically electro-neutral systems, in which the number of charged mono-mer units is equal to that of counterions. These systemsshould be described by taking into account the Cou-lomb interactions between charges of all types.

In weakly charged polyelectrolyte gels, the role ofCoulomb interactions is not as significant as that of thetranslational entropy of counterions [27]. On the con-trary, in strongly charged polymer gels, Coulomb inter-actions play a determining role and may impart addi-tional electrostatic rigidity to the polymer chain andgive rise to the effect of counterion condensation nearthe strongly charged chain [28–30].

Ion pairs and multiplets.

In weakly charged poly-mer gels in low-polarity media, the counterions are notfree but form ion pairs with the corresponding chargedgroups of the network chains [31, 32]. Once formed,these ion pairs may significantly the affect behavior ofthe polymer gel. The significant effect of even a smallnumber of ion pairs is related to their strong dipole–dipole attraction (with a characteristic energy

E

~10

−

25

kT

depending on the pair type and the dielectricproperties of the medium) [1]. These interactions leadto the aggregation of ion pairs into multiplets [33] act-ing as additional crosslinks in the gel (Fig. 3).

GEL SWELLING

An illustrative example of the osmotic pressureexerted by the mobile counterions is offered by the phe-nomenon of superstrong swelling of polyelectrolytegels in water, where the amount of absorbed water mayreach several kilograms per gram of dry polymer. Theimportant role of counterions in the swelling of poly-electrolyte gels was established long ago. At the begin-ning of the 1950s, Katchalsky

et al.

[34, 35] showedthat polyelectrolyte gel swelling is determined by thebalance between the elastic energy of polymer chainsand the osmotic pressure of counterions. Figure 4shows a typical plot of the degree of gel swelling versusthe degree of ionization [36]. As is seen, an increase in

Ion pairs Multiplets

Fig. 3.

Schematic diagram of an ionomer gel.

20 60 100

100

200

300

α

m

/

m

0

Fig. 4.

A plot of the degree of gel swelling

m

/

m

0

vs.the degree of ionization

α

for a poly(acrylic acid) gel(1 crosslink per 150 units) in water at 25

°

C [36] (

m

/

m

0

is the swollen to dry gel weight ratio;

α

is the percent-age of charged units in the polymer chain).

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the content of charged units leads to a growth in thedegree of swelling by two orders of magnitude. Notethat the main effect is observed in the region with asmall content of charged units (~10%), where the con-tribution due to the Coulomb repulsion between theseunits is not significant because they are far apart. Themain contribution to the swelling of these weaklycharged polymer gels is due to the osmotic pressure ofcounterions. This conclusion is consistent with theresults of theoretical calculations [27].

Owing to their ability to undergo superstrong swell-ing, polyelectrolyte gels can be used as superabsor-bents for water. Superabsorbent hydrogels are usuallydefined [37] as hydrogels capable of acquiring a watercontent above 95%, which implies that the amount ofsolvent absorbed by a dry gel swollen in water is20 times the initial polymer weight.

The absorption properties of the polymer gelsdepend not only on the degree of ionization (determin-ing the osmotic pressure of counterions), but also on thedegree of crosslinking and the affinity of a given poly-mer for the solvent [38, 39]. The superabsorbents forwater are usually based on highly hydrophilic macro-molecules. Most of the commercial superabsorbentsare based on salts of polyacrylic and polymethacrylicacids and polyacrylamide derivatives.

The superabsorbents should not only absorb a con-siderable amount of solvent, but effectively retain thissolvent in the swollen gel as well. For this purpose, thesuperabsorbent gels must possess sufficiently goodmechanical characteristics (strength and elasticity).However, an increase in the water content in the gelusually leads to a decrease in their strength [38]. Thus,creation of a superabsorbent gel involves the search fora compromise between its absorption properties andstrength.

In modern superabsorbent materials, this compro-mise is achieved by forming a strong shell with a suffi-ciently high density of crosslinks on the surface ofslightly crosslinked polymer granules [40]. However,this modification may somewhat decrease the ability ofthe gel to swell. Sometimes the mechanical propertiesare improved by introducing a certain proportion ofcovalently bound rigid chains (e.g., in the form of acrosslinking agent [41–43]) into the polymer network.The reinforcing rigid chains may also be tightly held inthe gel even without forming covalent bonds [44]. Thisis possible provided that the rigid chains are capable ofaggregating with each other to form large aggregateswith dimensions exceeding the gel mesh size. Pinchingof a part of the network chains in the aggregates leadsto effective immobilization of the rigid-chain polymerin the gel and a considerable increase in the elasticmodulus [44].

An alternative way to improve the mechanical prop-erties of a polymer gel and retain its good absorptioncapacity consists in forming a composite gel structure

comprising a rigid framework embedded into a flexi-ble-chain network. Such gels were obtained, for exam-ple, by acrylamide polymerization in aqueous suspen-sions of a finely dispersed crystalline mineral (sodiummontmorillonite) [45, 46]. In the course of polymer-ization in this system, the polyacrylamide gel is incor-porated immediately into the mineral platelets, whichaccounts for the formation of a sufficiently strongcomposite structure with good mechanical characteris-tics [45].

SOME APPLICATIONS OF STRONGLY SWELLING POLYMER GELS

One of the main fields of application for superabsor-bent gels is the fabrication of various hygienic materi-als and articles for the absorption of physiological liq-uids (diapers, etc.) [47]. This field consumes severalhundred tons of polymers for hydrogels per year [39].

Another important application field is agriculture,where superabsorbent gels are used as a means ofretaining ground water in drought-prone regions [39].This problem is extensively studied in Egypt [48] inattempts to increase fertility of the desert soils. Theapplication of superabsorbent gels in this field is basedon their ability to swell in the soil pores and retainwater, preventing both rapid evaporation and infiltra-tion into deep underground layers. The plants mayabsorb water both from closed pores and from the swol-len gel: the osmotic apparatus in most cultivated plantsis capable of extracting most of the water stored inhydrogels [49]. Possessing this property, hydrogels canalso be used as a base of nutritional media for plantgrowing by hydroponics.

The superabsorbent gels are successfully applied incivil engineering. The related water-absorbing materi-als are employed for coating the concrete blocks usedin the construction of tunnels. As soon as water perme-ates the structure walls, the superabsorbent gel swellsto tightly fill the gaps between the blocks and preventwater from penetrating into the tunnel. This method iswidely employed in the construction of tunnels for rail-roads and highways in Japan, and it was successfullyused for constructing the Channel tunnel [48]. Thesuperabsorbent gels enter into the composition of poly-meric ribbons used for protecting underground cablesin optical communication lines [50].

Superabsorbent gels are employed for the produc-tion of a special laminated material comprising twopaper sheets separated by a thin layer of a superabsor-bent gel powder. This laminated material is used, forexample, for packing fresh meat and poultry products.The gel absorbs excess liquid; at the same time it pre-vents the stored product from overdrying [51]. Super-absorbent gels form the base of synthetic coating mate-rials capable of substituting for snow; these materialsare used, for example, in Japan where the first sport hallwith artificial snow hills (50 m wide and 120 m long)

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was opened in 1991. The artificial snow is composed ofgel granules swollen in water and frozen. The frozengel granules retain their properties at a temperature ofup to +15

°

C (in contrast to finely crushed natural icethat can serve only up to +5

°

C) [52]. Specialists con-sider the possibility of using superabsorbent gels as ameans of strengthening soils, offering protectionagainst slides and sels [48]. It was also suggested [48]that wallpaper based on a nonwoven material filledwith superabsorbent gel powder can maintain a presetlevel of humidity in a room.

Thus, polyelectrolyte gels are highly valuablesuperabsorbent materials that can be employed in vari-ous fields. The area of application will significantlyexpand when strong composites of superabsorbent gelswith nonwoven materials, rubbers, etc. are created [48].

GEL COLLAPSE

If repulsive forces dominate in the interactionsbetween polymer chain units in the gel network, the gelexhibits strong swelling and behaves as a superabsor-bent. Should the attractive forces contribute (in addi-tion to the repulsive forces) to the interaction betweennetwork units, the gel may exhibit a collapse.

The phenomenon of collapse consists in the gel vol-ume strongly decreasing (by a factor of several tens orhundreds) in response to a rather small change in theexternal factors such as temperature, pH, various addi-tives (thermodynamically poor solvent, surfactant, lin-ear polymer), light, electric field, etc. The gel volumevariations during collapse are reversible and, in macro-scopic samples, visually observable.

A driving force for the transition from swollen tocollapsed state is the violation of the balance betweenattractive and repulsive interactions in the gel under theaction of external factors. The most effective repulsiveinteractions are related to the long-range electrostaticforces (the main one of which is the osmotic pressureof counterions). The van der Waals forces, hydrophobiccontacts, hydrogen bonds, and attractive forcesbetween oppositely charged ions contribute to theattractive interactions that may give rise to gel collapse.

The collapse belongs to phenomena that were firstpredicted theoretically and only later observed in

experiment. The possibility of collapse in gels wasoriginally predicted in 1968 by Dusek and Patterson[53]. They pointed out that the volume of a gel samplemay exhibit a jumplike change upon application ofexternal pressure to the sample. Using the Flory–Hug-gins equation of state, it was demonstrated that thepresence of an external force may lead to the appear-ance of a Maxwell loop on the gel isobar. A similar phe-nomenon in a single polymer chain in solution, knownas the coil–globule transition, was theoretically studiedby Ptitsyn and Eizner [54], de Gennes [55], and Lifshitz

et al.

[56]. It was suggested that gel collapse is essen-tially a macroscopic manifestation of the coil–globuletransition in the network subchains. This process can beconsidered as a first-order phase transition [53, 57, 58]between two phases differing in their subchain confor-mations and concentration of the crosslinked polymer,one phase representing the swollen gel and the other—the same gel in the collapsed state (Fig. 5).

It was not until 1978 (i.e., ten years after the firstprediction) that the collapse was experimentallyobserved by Tanaka [59], who studied the swelling ofslightly crosslinked polyacrylamide gels in water–ace-tone mixtures (water being a thermodynamically goodsolvent and acetone—a precipitant) and establishedthat adding a certain amount of acetone led to a jump-like decrease in the volume of water-swollen gel.

There was one interesting point in this experiment:numerous attempts (including those of Tanaka) atreproducing the effect were unsuccessful. The resultsconfirmed that the gel exhibited contraction, but thetransition from swollen to collapsed state was continu-ous rather than jumplike as in the first experimentTanaka reported in [59]. Only after a few months ofexperimental work was it established that the characterof the transition (discrete versus continuous) dependson the gel prehistory—the conservation time intervalfrom polymerization to the beginning of gel washingfrom residues of the polymerization mixture. Anincrease in the conservation time to a certain valueleads to the phenomenon of discrete collapse.

Figure 6 illustrates the collapse in polyacrylamidegel observed in water–acetone mixtures of variouscompositions. The gel samples swollen in water exhibitcontraction when acetone is added to the external solu-tion. As is seen, the contraction in freshly preparedsamples has a continuous character. As the time of con-servation of the gel samples increases, the acetone con-centration inducing the collapse tends to grow and achange in the gel volume upon collapse increases. Fora gel sample stored over 60 days, the sample volumeupon collapse drops by a factor of about 500 [26].

Tanaka [26] suggested that the phenomenon of“aging” during the conservation time interval is relatedto charging of the gel network chains. Later, Ilavsky

et al.

[60] showed that the charges appear as a result ofthe partial hydrolysis of amide groups. Indeed, potenti-ometric titration [61] of a linear polyacrylamide formed

Collapsed stateSwollen state

Fig. 5.

Schematic diagram illustrating two states of apolymer gel: collapsed (subchains in a globular con-formation) and swollen (subchains in a coiled confor-mation) [51].

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under similar conditions showed that about 1% of thechain units occur in a charged state. Thus, it was sug-gested that the character of the collapse is significantlyaffected by the presence of even a small fraction ofcharged units in the network chains [26].

This hypothesis was experimentally confirmed bythe results observed on specially synthesized gels with

charged network chains. It was demonstrated that thehigher the fraction of charged groups, (i) the greater thegel volume change upon collapse, (ii) the higher theconcentration of thermodynamically poor solventinducing the collapse, (iii) and the more pronouncedthe collapse is (Fig. 7). In order to explain these facts,it is necessary to take into account the osmotic pressureof mobile counterions in charged gels [26]. This factoraccounts for the strong gel swelling in a thermodynam-ically good solvent (water). On the other hand, the col-lapsed gel phase (formed as a result of the attractionbetween uncharged monomer units in a poor solvent) isless affected by the motion of counterions, because thisphase is stabilized by non-Coulomb interactionsbetween the chain units (the region of stability for thisphase must decrease with increasing fraction ofcharged chains in the gel network).

Thus, the difference in volume between the swollenand collapsed phase in charged gels may reach threeorders of magnitude. A transition between these highlydifferent gel states (strongly swollen or collapsed) sep-arated by a high potential barrier may proceed only in ajumplike manner. Moreover, a transition of the chargedgel from strongly swollen into collapsed state wouldrequire a greater amount of the precipitant (comparedto that required for the transition in the uncharged gel)to be added in order to ensure that the non-Coulombattraction of uncharged units would exceed the osmoticpressure (repulsion) of counterions. This circumstanceexplains a shift of the collapse toward greater concen-trations of the thermodynamically poor solvent withincreasing content of charged units in the gel (Fig. 7).

The phenomenon of collapse was studied in a largenumber of synthetic polymer gels, including polyan-

Fig. 6.

Collapse in polyacrylamide gels swollen inwater–acetone mixtures and observed after gelconservation for various times: (a) 0 (initial gel);(b) 2 days; (c) 6 days; (d) 60 days.

V

/

V

*

is the swollento initial gel volume ratio; [C

3

H

6

O] is the acetoneconcentration.

10

–1

10

0

10

1

10

2

10

2

10

1

10

0

10

–1

70

50

30

100

70

50

30

10

V

/

V

*

[C

3

H

6

O],

vol

%

(a)

(b) (d)

(c)

V

/

V

*

0

20

40

60

800.1 0.3 1 3 10 30 0.1 0.3 1 3 10 30

V

/

V

*

[C

3

H

6

O],

vol

%

0 2 8 32 128 0 2 8 32128

(a) (b)

Fig. 7.

Collapse in (a) positively and (b) negatively charged polyacrylamide gels with different contents of chargedunits (indicated by figures at the curves, mmol/l) swollen in water–acetone mixtures: (a) methacrylamidopropyltrime-thylammonium chloride gel; (b) sodium acrylate gel. Total monomer concentration, 700 mmol/l [62].

V

/

V

*

is the swol-len to initial gel volume ratio.

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ionic [26, 59, 62–73], polycationic [62, 72, 74–77],polyampholytic [72, 78–91], and neutral [70, 82–95]. Itwas demonstrated that the collapse can be observed innatural polymer gels as well. There are three maingroups of the natural polymer : proteins, polysaccha-rides, and nucleic acids. Amiya

et al.

[96] prepared andstudied covalently crosslinked gels of gelatin (protein),agarose (polysaccharide), and DNA. The resultsshowed that the gels of all three types exhibit collapseon a decrease in the quality of solvent (water–acetonemixture). Thus, the phenomenon of collapse can beobserved in any polymer gels of both synthetic and nat-ural origin [7, 51, 96].

Recently, Verdugo

et al.

[51, 97] presented a con-vincing example to demonstrate the phase transition ina polymer gel occurring in the biological world. As isknown, slugs contain mucin in an extremely compactform. Once secreted into the external medium, mucinabsorbs water and swells to increase in volume by afactor exceeding 1000. In this way, slugs are capable ofstoring water and maintaining the humid medium nec-essary for their survival. For a long time, it was unclearto biologists how slugs could store mucin in a compactform in their bodies full of water. Verdugo

et al. [51, 97]established that mucin exhibits collapse on adding cal-cium ions and suggested that this secretion is stored inthe slug’s body in a collapsed state due to a high con-centration of calcium ions. A similar mechanism formaintaining a humid medium is apparently employedby some other animals (e.g., eels). It was suggested thatanalogous mechanisms are inherent in mucins liningthe internal walls of the gastrointestinal tract in thehuman organism [51].

Thus, the phase transitions in polymer gels repre-sent a universal phenomenon. These effects were

observed in all the gels studied (irrespective of theirnature and chemical structure) and are widely occur-ring in nature.

RESPONSIVE GELS

When in the vicinity of the collapse transition, poly-mer gels may change their volume in a very sharp andreversible manner in response to very small variationsin the properties of the medium (temperature, pH, sol-vent composition, etc.) capable of inducing the col-lapse. Owing to this possibility, these polymeric sys-tems are called responsive gels. Sometimes they arealso referred to as smart or intelligent materials; theseterms reflect their ability to follow in a preset (pro-grammed) way some small changes in the medium [98].

Sensitivity of the polymer gels with respect to achange in one or another external factor is determinedby the chemical composition, namely, by the presenceof atomic groups affected by this factor. Depending onthe factor inducing the phase transition, responsive gelscan be divided into several major groups sensitive totemperature (thermosensitive gels), solvent composi-tion, pH, ions, light (photosensitive gels), electric field,biochemical factors, etc.

Thermosensitive Gels

The thermosensitive gels can be subdivided intothree groups [74, 88, 99], depending on whether anincrease in temperature leads to swelling, collapse, orcombined (so-called convexo) behavior. Differentresponses of the gel to temperature are determined bythe nature of interactions involved in the phase transi-tion. If the collapse is due to the van der Waals forcesor hydrogen bonds, the hydrogel exhibits an increase inthe degree of swelling with temperature, since heatingdecreases both the van der Waals attraction and thestrength of hydrogen bonds. On the contrary, the gelsfeaturing the collapse related to hydrophobic interac-tions exhibit contraction on heating because anincrease in the temperature favors stronger hydropho-bic attraction.

Heating a gel in which the collapse is determined byan interplay of interactions of several types may beaccompanied by phase transitions of both types–swell-ing and collapse [88, 100]. Here, increasing tempera-ture may induce sequential (phase reversal) transforma-tions of the collapse–swelling–collapse and swelling–collapse–swelling types. The former sequence wasobserved, for example, in the anionic gel of acryla-mide–sodium vinylsulfonate copolymer swollen in a65% aqueous acetone solution [100] and in the cationicgels of acrylamide–trimethyl-(N-acryloyl-3- aminopro-pyl)ammonium iodide copolymer swollen in a 40%aqueous acetone solution (Fig. 8) [74]. The lattersequence was reported for the uncharged gels based onsome N-(alkoxyalkyl)acrylamides swollen in water. As

0.1 1.0 10.0

0

20

40

60

V/V*

T, °C

Fig. 8. The temperature-induced swelling and col-lapse in the cationic gel of an acrylamide–trimethyl-(N-acryloyl-3-aminopropyl)ammonium iodide copo-lymer in a 40% aqueous acetone solution [74]. V/V*is the swollen to initial gel volume ratio.

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the temperature increases, these gels first collapse (at25–30°C) and then swell (at 40–45°C) [101].

A volume-phase transition in a thermosensitive gelwas originally observed by Tanaka et al. [83] in apoly(N-isopropylacrylamide) (PNIPA) gel swollen inwater. At present, this gel is one of the most thoroughlystudied thermosensitive polymer systems. The PNIPAgel occurs in a swollen state in water at room tempera-ture, but exhibits collapse on heating to 33°C [83]. Thiseffect is explained by a temperature-induced increase inthe hydrophobic interactions between nonpolar groupsin the polymer. This is accompanied by release of thewater molecules structurized at the surface of thesegroups, which results in an increase in the total entropy ofthe system. It was demonstrated [102] that dehydration ofa single monomer unit in PNIPA is accompanied by lib-eration of 13 water molecules. A number of other poly-mer gels exhibiting collapse on heating were reportedlater [7, 88], representing for the most part gels based onpoly(N-alkylacrylamides) [7, 103], as well as poly(vinylmethyl ether) [87, 93, 95, 104] and poly(N-vinyl capro-lactam) [105].

Since it is known that hydrophobic interactions arethe main driving force for gel collapse with increasingtemperature, the behavior of thermosensitive gels canbe controlled by varying the ratio of hydrophobic andhydrophilic units in the polymer chain. Based on theresults of investigations, it is possible to synthesize gelswith any preset temperature of the phase transition. Thestudy of a series of poly(N-alkylacrylamide) gels withvarious alkyl substituents, showed that the gels withhydrophobic groups possessing a greater area in con-tact with water exhibit collapse at a lower temperature[88, 103]. Using various N-alkyl-substituted polyacryla-mides, Hirasa et al. [87] obtained various thermosensi-tive hydrogels with phase transition temperatures rang-ing from 19.8°C for poly(N-methyl-N-propylacryl-amide) to 72.0°C for poly(N-ethylacrylamide).

The phase transition temperature in neutral ther-mosensitive gels can be controlled by adding smallfractions of charged units [106, 107]. The greater thefraction of charged units in the gel, the more pro-nounced the shift in the phase transition temperature[108, 109]. Adding charged units not only affects thetemperature but changes the character of the phase tran-sition as well: the transition becomes sharper andincreases in amplitude (Fig. 9). For a sufficiently largecontent of the charged units, the gel may lose tempera-ture sensitivity because the hydrophobic attraction willno longer overcome the electrostatic repulsion.

Gels Sensitive to Solvent Composition

For almost any gel, we may select a poor solventwhose additives may induce the gel to collapse. Theclassical example of polyacrylamide gel collapsing in awater–acetone mixture was considered in detail above.

In these gels, the point of collapse can be shifted byadding small amounts of charged units (Fig. 7).

It should be borne in mind that components of amixed solvent may be nonuniformly distributedbetween gel and solution. For a swollen gel, the com-position of the mixed solvent inside the gel usuallycoincides with that of the external solution, whereas thecollapsed gel is enriched with the thermodynamicallygood solvent component as compared to the externalsolution [110]. The results of a theoretical analysis[110] showed that such a redistribution of the solventcomponents between collapsed gel and solution is morepronounced in a system with a greater value of theparameter of interaction χAB between the solvent com-ponents. This is related to the fact that an increase in theχAB value reflects the growing tendency to phase sepa-ration in the solvent, whereby preferential solvation ofthe thermodynamically good solvent component in thenetwork becomes energetically favorable (leading tothe free energy variation in the same direction as thatupon the phase separation).

A number of gels were reported that featured twophase transitions in the course of gradual change of thecomposition of a mixture of two solvents (the relativecontent of each component varied from 0 to 100%).Figure 10 shows the variation of the degree of swellingof a PNIPA gel in a water–DMSO mixture of variablecomposition [83, 92]. Both water and DMSO takenseparately are thermodynamically good solvents forPNIPA, in which the polymer gel is in the swollen state.However, adding water to a gel swollen in DMSO (orvice versa) results in gel collapse. Under similar condi-tions, a polyacrylamide gel does not undergo any phasetransitions at all (Fig. 10).

Reentrant phase transitions of the same type (swell-ing–collapse–swelling) were also observed in a weaklycharged gel based on a NIPA–sodium acrylate copoly-mer swollen in a water–methanol mixture [70] and in

30 40 50

1

212345

T, °C

d/d*

Fig. 9. The pattern of temperature-induced collapse inpoly(N-isopropylacrylamide) (PNIPA) gels with vari-able content of charged sodium acrylate units: (1) 0;(2) 8; (3) 32; (4) 50; (5) 70 mmol/l [109] (d/d* is theratio of gel diameters in the swelled and initial state).

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PHILIPPOVA

an N,N-diethylacrylamide–sodium acrylate copolymerswollen in a water–DMSO mixture [68]. These phasetransitions are related to the fact that interactionsbetween the molecules of both solvent componentsproduce a greater gain in the free energy than do inter-actions between each solvent and the network mono-mer units. As a result, the network undergoes a collapsethat decreases the area of the polymer in contact withsolvent. These experimental data are in complete agree-ment with the results of theoretical analysis of polymernetwork collapse in a two-component solvent [110].

It should be noted that the theory [110] predicts thepossibility of reentrant phase transitions of both swell-ing–collapse–swelling (described above) and collapse–swelling–collapse types in mixed solvents. The lattersituation takes place if a network is swollen in a mix-ture of two solvents, each of them being thermodynam-ically poor for the polymer. Then the network is in acollapsed state in each solvent taken separately, whilebeing capable of swelling in their mixture.

Under certain conditions, we may observe a doublereentrant transition. For example, a weakly charged gelbased on NIPA–sodium acrylate copolymer swollen ina water–methanol mixture [70] doubly undergoes thereentrant phase transition when the ethanol concentra-tion is gradually increased. This behavior is fully con-sistent with predictions of the theory [110] and isexplained by redistribution of the solvent componentsbetween gel and solution, whereby leveling of the sol-vent compositions inside and outside the gel at equalvolume fractions of both solvent components is causedby a gain in the entropy of mixing.

pH-Sensitive Gels

Sensitivity with respect to pH is observed in gelscontaining weak acid or weak base groups capable ofionizing in response to pH variations. The unchargedgels occur in the collapsed state, while ionization leadsto gel swelling caused by the osmotic pressure ofmobile counterions. The hydrogels containing acidgroups exhibit swelling in an alkaline medium but col-lapse in an acid solution, where ionization is sup-pressed. In contrast, the hydrogels with base groupsswell in an acid medium and collapse on increasing pH(Fig. 11).

Polyampholytic gels swell on acidification or alkal-ization of the medium, while occurring in the most con-tracted state in the intermediate pH range (Fig. 11) cor-responding to an equimolar ratio of positively and neg-atively charged units (isoelectric point) [80, 111]. Gelcontraction at the isoelectric point is related both to adecrease in the osmotic pressure of counterions and tothe Coulomb attraction of oppositely charged networkunits.

By simultaneously introducing thermosensitivemonomer units and a small fraction of units withgroups capable of pH-induced ionization, we mayobtain a gel combining the properties of pH and tem-perature sensitivity. Such gels were synthesized, forexample, using the NIPA–sodium acrylate copolymers(negatively charging gel) [106] and the NIPA copoly-mers with 2-dimethylaminoethylmethacrylate [106]

10–2 10–1 100 101 102

20

40

60

80

100

1 2

V/V*

[DMSO], vol %

Fig. 10. Variation of the swelling ratio of (1) PNIPAand (2) polyacrylamide gels in the DMSO–water sol-vent mixture of variable composition [83]; V/V* is theswollen to initial gel volume ratio.

2 6 10pH

–COO–

–COOH

Deg

ree

of s

wel

ling (a)

2 6 10pH

–NH3+

–NH2

(b)

2 6 10pH

–COOH–NH+

3–COO–

–NH2

(c)

Fig. 11. Schematic diagrams illustrating the possible effects of pH on the swelling of gels containing network units of(a) weak acid, (b) weak base, and (c) both acid and base types (polyampholytic gel).



and diethylaminoethylmethacrylate [112] (positivelycharging gels).

It is interesting to note that the situation of ionization-induced swelling is not the only one possible. Figure 12shows a series of plots of the degree of swelling versusdegree of ionization for a PMAA gel in various solvents[113]. As is seen, there are three main types of gelbehavior on ionization. The first regime, in which thegel swells with increasing charge, is observed in a polarmedium (polyelectrolyte regime). The second regime,when the gel collapses upon charging, takes place in alow-polarity medium (ionomer regime). The thirdregime characterized by the passage from swelling tocollapse with increasing degree of ionization isobserved for an intermediate solvent polarity (mixedpolyelectrolyte–ionomer regime).

The different character of variation of the degree ofswelling in the course of ionization in these regimes isexplained by different states of counterions in the gel.When the counterions formed due to the ionization arefree (polar medium), the gel exhibits swelling due totheir osmotic pressure (polyelectrolyte regime). In thelow-polarity medium, the counterions are not free butcondense at the oppositely charged chain units to formion pairs (Fig. 3). These ion pairs tend to aggregate withthe formation of multiplets acting as additionalcrosslinks in the gel, which causes gel collapse in theionomer regime. The gel immersed in a medium ofintermediate polarity contains both free ions and ionpairs. The initial swelling at low degrees of ionizationis related to a growth in the osmotic pressure of freecounterions with increasing network charge. The col-lapse transition is observed when the concentration ofion pairs becomes sufficient for the formation of mul-tiplets. In this state, the equilibrium between free ionsand ion pairs shifts toward the latter and the gel col-lapses. The collapse is caused both by a decrease in the

osmotic pressure of mobile counterions and by theadditional network crosslinking related to ion pairaggregation into multiplets (mixed polyelectrolyte–ionomer regime). Thus, ionization of the gel may leadto either collapse or swelling, depending on the polarityof the medium [113].

Ion-Sensitive Gels

Adding low-molecular-mass salts may significantlyaffect the swelling behavior of polymer gels, mostly ofthe polyelectrolyte type, by screening the networkcharge.

Let us first consider the polyelectrolyte gels inwhich the network units possess charges of the samesign. Here, the salt effect depends on the thermody-namic quality of a solvent into which the gel isimmersed. In the case of a thermodynamically goodsolvent, adding a monovalent salt usually leads to grad-ual contraction of the gel, while the same salt added toa relatively poor solvent may induce a jumplike col-lapse (Fig. 13) [65]. The salt effect is manifested whenthe additive concentration becomes comparable withthe concentration of free counterions (determining theosmotic pressure) inside the gel [114]. The gel contrac-tion is related primarily to a decrease in the osmoticpressure difference inside and outside the gel. In addi-tion, establishing the Donnan equilibrium results in thatthe low-molecular-mass salt concentration inside thepolyelectrolyte gel is always lower than that outside[115]. In contrast to the case of swollen gels, introduc-ing salts into a system with a collapsed gel does notaffect the gel state.

Gel contraction or collapse upon adding a multiva-lent salt is usually observed at a markedly lower addi-tive concentration than that necessary for a monovalentsalt (Fig. 13) [65, 116, 117]. The difference is explained

10

20

30

0.2 0.6 1.0 α

1

2

3

4

2

3

456

7

240

160

80

0.2 0.6 1.0 α

m/m0 m/m0

(a) (b)

Fig. 12. Plots of the degree of swelling vs. degree of ionization for a PMAA gel in various solvents: (a) methanol–water mixtures containing (1) 0, (2) 20, (3) 50, (4) 65, (5) 80, (6) 90, and (7) 95 vol % of methanol; (b) methanol–dioxane mixtures containing (1) 90, (2) 75, (3) 65, and (4) 20 vol.% of methanol [113]. (m/m0 is the swollen to initialgel mass ratio).

1

218


PHILIPPOVA

O

OO

O

OO

NH

C

CH CH2

O

O

OO

O

OO

NH

C

CH CH2

O

K+K+

by several factors. First, by a decrease in the total num-ber of counterions inside the network, which are neces-sary to compensate for the network charging. Second,by the multivalent ions being attracted stronger thanmonovalent ones to the oppositely charged groups inthe network (this decreases the mobility of counterionsand, hence, their ability to produce osmotic pressure).Third, by the polyvalent ions electrostatically bindingsimultaneously to several gel network units, which isequivalent to the formation of additional crosslinks inthe network. The greater the multivalent ion charge, thelower the salt concentration necessary to induce the geltransition to the collapsed state.

A qualitatively different pattern is observed on add-ing low-molecular-mass salts to the polyampholyticgels. Here, establishing the Donnan equilibrium resultsin that the salt concentration inside the gel is higherthan that outside. Inside the gel, the salt shields attrac-tion of the oppositely charged network units, thusfavoring swelling of the gel [115].

Irie [89] synthesized gels possessing selective sensi-tivity with respect to certain ions. For this purpose, spe-cial groups selectively interacting with the given ionwere introduced into the polymer gel. For example, a gelsensitive to potassium ions was obtained by immobiliz-ing a benzo-18-crown-6 in a PNIPA gel (Fig. 14) [89].The size of the ring cavity in this crown ether moleculeis just suited to accommodating the potassium ion. Thisaccounts for the tight binding of potassium ions tocrown ether by means of the ion–dipole interactions

between potassium cations and electronegative oxygenatoms of the ring.

This gel, occurring in a contracted state at the col-lapse threshold, exhibits abrupt swelling upon theappearance of potassium ions in solution. This isexplained by the fact that the gel converts fromuncharged to polyelectrolyte upon binding K+ ions tocrown ether fragments. The potassium ions sorbed by thegel attract an equivalent amount of counterions, whichenter the gel and produce the exerting osmotic pressureleading to gel swelling. No such effect was observed forthe salts of other alkali metals (lithium and sodium) thatdid not bind to the crown ether employed [89].

60%

50%40%

30%

20%

25%

10%

0%

0.1 1.0 10.0

Φ/Φ*

0.1 1.0 10.0

Φ/Φ*

10–6

10–4

10–2

100

[NaCl], mol/l

60%

70%

50%

40%

30%20%0%

(a) (b)

10%

Fig. 13. Effect of the low-molecular-mass salts (a) NaCl and (b) MgCl2 on the swelling behavior of acrylamide–sodiumacrylate copolymer gels in water–acetone mixtures of various compositions (acetone concentrations in vol.% indicatedat the curves) [65]; Φ/Φ* is the final to initial polymer volume fraction ratio.

[MgCl2], mol/l

Fig. 14. A schematic diagram illustrating potassiumion binding to a crown ether.



Photosensitive Gels

Light-sensitive gels were synthesized [85, 118, 119]using a copolymer of NIPA with photosensitive mole-cules of bis(4-(dimethylamino)phenyl)(4'-vinylphe-nyl)methyl leukocyanide capable of dissociating underUV irradiation [118]. The action of light on this gel isbased on the photoionization effect. In the absence ofthe UV light, a PNIPA gel containing 1% of these pho-tosensitive groups exhibits a phase transition to the col-lapsed state at 30.0°C. Upon exposure of the sample toUV radiation, this temperature increases to 32.6°C dueto ionization of the photosensitive groups (Fig. 15). Ina gel maintained at a constant temperature in the inter-val between 30.0 and 32.6°C, for example at 31.0°C,the UV irradiation produces a reversible jumplike tran-sition from collapsed to swollen state [118]. The effectwas explained by the osmotic pressure of cyanide ionsappearing as a result of the UV-induced photoioniza-tion of the sample. As soon as the UV irradiation isswitched off, the charged groups vanish and the gelpasses back to the collapsed state.

Suzuki and Tanaka [85] also reported on the synthe-sis of gels sensitive to visible light. The structure ofthese samples consists of a PNIPA network withcovalently bound molecules of a chromophore(Cu-chlorophyllin). The gel, occurring initially in aswollen state at a temperature close to that of the phasetransition (31.5°C), collapses under illumination at aradiant power exceeding 85 mW. It was suggested thatthe light induces a local temperature increase inside thegel due to absorption and thermal dissipation of thelight energy by the chromophore molecules.

Gels Sensitive to Electric Field

Charge transfer under the action of an applied elec-tric field may induce a change in the degree of swellingin ion-containing gels. Consider a strip of a weaklycharged anionic gel. Upon electric field application,both polyions and small counterions in the gel are sub-ject to electric forces acting in opposite directionsdepending on the charge sign. Since the negativecharges are fixed in the polymer network, the electricfield predominantly transfers the counterions (cations)moving toward the cathode. As a result, the concentra-tion of mobile ions producing the osmotic pressure nearthe cathode markedly increases, leading to gel swellingin this region. In contrast, the gel at the other electrode(anode) shrinks and the whole sample strip exhibitsbending [66, 120, 121].

Similar manipulations with a gel in a sufficientlypoor solvent (in the vicinity of a collapse threshold) canlead to the collapse induced by the electric field [66].This process is reversible and the gel exhibits swellingwhen the electric field is switched off.

Gels sensitive to electric field were also obtainedusing the process of reversible complex formationbetween a polyelectrolyte gel and an oppositely

charged surfactant [122]. In this system, the surfactantions transferred by the electric field concentrate at oneof the electrodes to form complexes with oppositelycharged gel network units. The complex formation isaccompanied by surfactant ion aggregation to micelles,which results in gel contraction at the site of complex-ation. This eventually leads to bending of the gel plate.On changing the polarity of the electrodes, theabsorbed surfactant molecules desorb, while new sur-factant molecules concentrate at the opposite electrodeand form complexes with the gel. Thus, the polymer gelplate can be driven to repeated bending and straighten-ing by alternating the electrode polarity [122].

Biochemically Sensitive Gels

Special investigations were devoted to the synthesisof gels exhibiting phase transitions in the presence ofcertain biopolymer molecules [7, 20–22, 51, 108,123−125]. This task is solved using special interactionsof various types, such as antigen–antibody, ligand–receptor, etc. Molecules of a biochemically active sub-stance (e.g., an enzyme or a receptor) are immobilizedin a gel occurring in the state close to the collapsethreshold. The target molecules falling within the gelinteract with the active substance, thus breaking theequilibrium and leading to gel swelling or collapse.

Kokufuta et al. [125] used a PNIPA gel to immobi-lize an enzyme (concanavalin A) possessing specificbinding sites for polysaccharides. On binding a chargedpolysaccharide (dextran sulfate), the gel swells due tothe osmotic pressure of ions. Replacing the dextran sul-fate by an uncharged polysaccharide (α-methyl-D-mannopyranoside) causes the gel to collapse.

1 3 10 30

28

32

36

V/V*

1

2

3

T, °C

Fig. 15. Effect of temperature on the swelling of aNIPA copolymer with photosensitive molecules ofbis(4-(dimethylamino)phenyl)(4'-vinylphenyl)methylleukocyanide capable of dissociating under UV irra-diation [118]: (1) heating and cooling in the absenceof UV radiation; (2) cooling under UV irradiation;(3) heating under UV irradiation. V/V* is the swollento initial gel volume ratio.

220


PHILIPPOVA

SOME APPLICATIONS OF RESPONSIVE GELS

The ability of hydrogels to react in a sharp andreversible manner in response to changes in the exter-nal conditions determines their use as functional mate-rials in various fields. Below we will mention onlysome of these applications

Membranes with Controlled Permeability

There are two principal mechanisms determiningthe passage of substances through polymeric mem-branes [107]: (i) diffusion in the polymer matrix and(ii) diffusion through pores. In the former case, a sub-stance dissolves in the membrane material and diffusesin the polymer medium. In the latter case, the mem-brane is considered as a sieve comprising a system ofinterpenetrating channels and pores, through which themolecules diffuse without interacting with the polymer.In hydrogels, the second mechanism is usually domi-nating. This implies that the lower the degree of gelswelling, the smaller the membrane permeability [22].A collapse of the gel completely blocks diffusionthrough the polymeric membrane [22]. In membranesfabricated from responsive gels, we may change thepermeability in a reversible manner by varying thehydrogel swelling with the aid of some controlledexternal parameter (e.g., temperature) [21, 22].

If a gel exhibits collapse on heating (thermosensi-tive gels based on PNIPA or poly-N-acryloylpyrro-lidine), the permeability of the gel decreases withincreasing temperature [21, 22]. The permeability oftemperature-insensitive gels (e.g., poly-2-hydroxy-ethylmethacrylate gel) increases on heating, which isrelated [21] to the diffusion rate of dissolved substancesincreasing with temperature. Using this approach, Baeet al. [21] obtained membranes, the permeability ofwhich increases or decreases with temperature(depending on the gel composition employed).

Catalysts with Controlled Activity

The ability of gels to collapse can be used for creat-ing reversible catalysts using catalyst molecules immo-bilized in the gel network. The action of such catalystscan be readily halted by inducing collapse of the geland then restored by allowing the gel to swell again.The catalytic process termination is related to a sharpdecrease in the gel permeability with respect to thereagents, whereby the catalyst becomes inaccessible.As the gel swells, the diffusion process is restored andthe reaction proceeds further.

Polymer gels capable of collapsing under “mild”conditions (in aqueous media at temperatures notexceeding 40–45°C and neutral pH values) can be usedfor preparing reversible biocatalysts with the activecomponents represented by enzymes [108, 123, 126,127]. Such a reversibly swelling biocatalyst acquiresthe advantages of immobilized enzymes (whereby the

enzyme becomes more stable and can be readily sepa-rated from the reaction mixture and repeatedly used).However, this system may possess certain disadvan-tages related primarily to diffusion hindrances to thesubstrate permeation inside the gel and the removal ofreaction products to the external solution (even in theswollen gel). These disadvantages can be eliminatedusing the characteristic ability of responsive gels tochange their volume depending on the external factors.An interesting method for solving the task was pro-posed by Park and Hoffman [123, 128, 129]. The ideais to create a microscopic pump exhibiting swelling andcontracting cycles to absorb a liquid in the gel pores (onswelling) or drive it back to the surrounding solution(on shrinking), thus markedly enhancing the masstransfer. For this purpose, the authors used a ther-mosensitive gel in which the swelling and contractioncycles were induced by small periodic temperaturevariations in the vicinity of the collapse threshold [123,128, 129].

Carriers for Controlled Drug Release

Polymer matrices have been used for a long time todevelop new medicinal forms. Polymeric carriersensure prolonged drug action by allowing the parentcompound to release slowly from a matrix to the organ-ism. However, a polymer matrix can not only control therate of drug release, but may provide for drug delivery toa target site in the organism that has to be treated [22].

Systems for the targeted delivery of drugs aredesigned taking into account the fact that the gas-trointestinal tract of humans contains compartmentswith markedly different pH levels. For example, thestomach contains an acid medium (pH 1.4) while thatin the intestine is close to neutral (pH 6.7–7.4). For thisreason, the drug carriers are frequently based on thepH-sensitive gels [130]. When such a gel carrying adrug enters the organism, the drug is released at the sitewhere the conditions favor gel swelling.

pH-Sensitive weak-base gels. Polymer gels con-taining weak base groups collapse in neutral or alkalinemedia (Fig. 11) and swell in an acid medium (e.g., inthe stomach). Therefore, these gels can be used for thetargeted transport of drugs to the stomach. Owing to thefact that these gels collapse at a neutral pH value typicalof the oral cavity, they can also be used for makingshells protecting drugs against dissolution in saliva andprotecting patients against the bitter taste of manydrugs (taste-masking application) [131]. In particular,special gels for these applications were developedbased on a copolymer of methyl methacrylate andN,N-dimethylaminoethylmethacrylate (a weak base capa-ble of charging in acid media).

pH-Sensitive weak-acid gels. Polymer gels con-taining weak base groups collapse in acid media andswell in an alkaline medium (Fig. 11). Therefore, carri-ers based on these gels retain a parent drug inside the



gel in the stomach (at pH 1.4), thus acting as protectiveshell [130]. Upon reaching the intestine (pH 6.7–7.4),the gel swells and releases the drug.

These preparations are especially important for thetreatment of disorders such as pancreatitis. Patientswith pancreatitis must permanently receive enzymeswith meals, otherwise the products are not properlydigested and absorbed in the small intestine. At present,pancreatitis is usually treated with drug preparationsbased on the enzyme amylase. However, pharmacolog-ical investigations showed that only a small fraction(<10%) of the drug administered by a patient reachesthe intestine in the active state. The reason for the drugactivity loss is enzyme inactivation by a low-pHmedium in the stomach. The weak-acid hydrogels areof no less importance for administration of the anti-inflammatory drug indomethacin, but here the task is toprotect the stomach against the undesired drug action(indomethacin produces strong irritation of the stom-ach tissues and may even lead to their perforation[107]), rather than to shield the drug from the aggres-sive medium of stomach. The gel matrix completelyblocks the release of indomethacin in the stomach.

It was suggested that a shell for peroral drugs to pro-tect them in the stomach can be formed by hydrogelssynthesized through copolymerization of NIPA, acrylicacid, and a polydimethylsiloxane (PDMS) macromo-nomer with vinyl terminal groups [107, 130]. Thesecopolymers are sensitive with respect to both pH (dueto the acrylic acid units) and temperature (due to theNIPA units). In addition, the hydrogels contain hydro-phobic PDMS domains that may serve as a depot forstoring hydrophobic drugs.

Thus, the pH-sensitive hydrogels not only play therole of a matrix ensuring controlled drug release at adefinite site of the organism, but perform an additionalprotective function as a shell for peroral drugs.

Pathological processes taking place in the organismusually involve variations in pH, temperature, and theconcentrations of certain substances. Taking this intoaccount, it is possible to create drug release systemswith feedback, whereby a given pathological processinitiates the drug release. The creation of such a self-controlled drug preparation—an artificial pancreas rep-resenting a device capable of secreting insulin inresponse to a change in the glucose concentration—may help in meeting serious problems of patients suf-fering from diabetes mellitus. Certain success in solv-ing this task was achieved with the aid of hydrogels. Asa rule, the glucose sensors are based on the enzyme glu-cose oxidase. The enzyme is immobilized in a pH-sen-sitive weak-base gel containing a saturated insulinsolution. Glucose diffusing from the external solutioninto the hydrogel is oxidized by glucose oxidase to glu-conic acid. Formed in the course of the reaction, thisacid produces ionization of the pH-sensitive gel and,hence, its swelling. The gel swelling favors the outdif-fusion of insulin from gel to external solution. Thus, the

system provides for the controlled release of insulin inresponse to the glucose content in the external solution[128, 132–134].

For further progress in this field, it is necessary todevelop methods for the synthesis of pH-sensitivehydrogels with different pH of transition from col-lapsed to swollen state. This would allow us to selectwith greater precision the site and rate of drug release.A possible way of solving this task was proposedin [36, 77]. According to this approach, a small numberof units with nonpolar n-alkyl side groups are intro-duced into a weak-acid or weak-base polymer gel.A typical structure of the resulting system is schemati-cally depicted in Fig. 16. When the gel is not charged,the hydrophobic attraction of n-alkyl groups leads tothe formation of micelle-like aggregates stabilizing thecollapsed state. Acting as additional effectivecrosslinks in the gel structure, these hydrophobicaggregates hinder the network swelling triggered byionization induced by pH variations [36]. Thus, thetransition to swelling in this gel requires a greaterchange in pH (i.e., a greater number of charged units)such that the electrostatic repulsion forces would besufficient to destroy the aggregates. By varying the con-tent of units with hydrophobic groups or the length ofthe side n-alkyl chain, it is possible to change in a con-trolled manner the threshold pH level corresponding tothe gel transition from collapsed to swollen state(Fig. 17) [36]. In addition, the hydrophobic aggregatesformed by the nonpolar groups in a collapsed gel mayserve as “reservoirs” for nonpolar drugs. As the degree

–

–

–

–

–

–

–

+

+ +

+

++

+

–(–CH2–CH–)100 –q– (–CH2–CH–)q–

–

COOH

–

C = O

–

O

–

(CH2)n–1–

CH3

Fig. 16. The chemical formula and schematic diagramof the structure of a poly(acrylic acid) gel modified byhydrophobic groups. The hydrophobic groupscovalently bound to the network chains are capable ofinteracting with one another to form micelle-likeaggregates.

222


PHILIPPOVA

of network ionization increases, the hydrophobic aggre-gates are destroyed and the drug is released from the gel.

Soft Manipulators

All living organisms move due to the isothermalconversion of chemical energy into mechanical work,which is expressed, for example, by the contractions ofmuscles or the motions of cilia in microorganisms[135]. These systems can be modeled by hydrogelsbased on “responsive” polymers capable of stronglyswelling (expanding) or contracting in response toexternal stimuli in the form of thermal, chemical, orelectric energy. The history of creating the first systemsof this type dates back to the 1950s and is related to thenames of Kuhn and Katchalsky—well known authori-ties in polymer chemistry [136, 137].

At present, works on the development of variousdevices employing the ability of hydrogels to changetheir volume and/or shape in response to the action ofexternal factors are in progress; the most extensiveinvestigations are being performed in Japan [11, 120,138, 139]. In particular, Kurauchi et al. [120] used apolyelectrolyte gel deformed by an electric field to con-struct a “soft” manipulator, consisting of a robot armwith soft gel fingers, which was capable of carefullytaking and transferring an egg without damaging it.Another device had the form of an artificial fish with asoft gel tail, the motion of which was controlled by anelectric field [120] so that the fish was able to swim.

A disadvantage of gels as materials for manipulatorsis their relatively slow response to external actions: therate of this response is frequently determined by thenetwork reaction rate (depending on the rate of diffu-sion processes in the network) rather than by the rate ofchange of the external stimulus itself. As is known, the

time necessary to reach the equilibrium gel swelling orcollapse is proportional to the square of the characteristicgel size [1], reaching several days for macroscopic sam-ples with dimensions on the order of ~1 cm. In order toaccelerate the gel response to the external action, it ispossible to use small-size gel elements (thin films orballs). For a spherical gel with a diameter on the orderof a few microns, the time of response to externalactions is measured in milliseconds.

However, a more promising approach consists inusing alternative external factors, the response to whichdoes not depend on the diffusion process inside the net-work. A possible method was proposed by Zrinyi et al.[140–144], according to which magnetite (Fe3O4)nanoparticles possessing pronounced ferromagneticproperties are introduced into the gel structure. Theresponse time of such a gel upon a change in theapplied magnetic field is very fast (~1 s) and indepen-dent of the gel size. The “magnetic” gels are capable ofperforming complicated motions in response to a com-puter-controlled magnetic field [142].

The gel manipulators controlled by such externalactions exhibit soft, flexible, and noiseless operations.Constructing gel-based soft manipulators is a rapidlydeveloping direction of polymer network technology,which has good prospects for creating robots withhuman-like motions [122].

MICROSTRUCTURE OF RESPONSIVE GELS

The competition between opposing attractive andrepulsive forces may not only change the macroscopicproperties of a gel (collapse versus swelling), but favorself-organization of the network units in the gel volumeas well, with the formation of regular microstructuresof various types.

Let us consider a weakly charged polyelectrolytegel occurring in an aqueous medium in a state close tothe collapse threshold. The gel is subject to two com-petitive forces: repulsive (related primarily to the trans-lational entropy of counterions) and attractive (causedby non-Coulomb interactions). The translationalentropy of counterions tends to retain the gel in theswollen state. At the same time, a decrease in the ther-modynamic quality of the solvent would enhance thenon-Coulomb attraction of monomer units to eachother, leading eventually to a collapse.

In weakly charged polyelectrolyte gels obeying thecondition of macroscopic electroneutrality, the transi-tion to a collapsed state is made unfavorable because ofa considerable decrease in the entropy of counterions.However, the energy gain due to a short-range interac-tion of the network chain units can also be realized inthe swollen state by forming a microphase-separatedstructure with alternating aggregates of hydrophobicuncharged units and strongly swollen regions accom-modating most of the charged units and counterions(Fig. 18). In this microphase-separated structure, the

4 8 120

100

200

300

pH

(m – m0)/m0

1 2 3 4

Fig. 17. Plots of the degree of swelling vs. equilib-rium pH of the external solution for the gels of(1) unmodified (2−4) modified poly(acrylic acid)containing (2) 2.5, (3) 10, and (4) 20% of n-octylacry-late units [36]. (m and m0 are the masses of swollenand dry gel, respectively.)



counterions do not lose their translational entropy: theyare still capable of traveling over the whole swollen gelvolume, while the number of unfavorable contactsbetween uncharged units and water is markedlydecreased (Fig. 18). The phenomenon of microphaseseparation in polyelectrolyte gels swollen in aqueousmedia was experimentally observed in 1991–1992independently by two groups of researchers headed byProf. Candau in France [145, 146] and by Prof.

Shibayama in Japan [71]. Shibayama et al. [71, 147]studied the microstructure of weakly charged polyelec-trolyte gels based on NIPA–sodium acrylate copoly-mers in heavy water by the method of small-angle neu-tron scattering (SANS). The PNIPA gels are ther-mosensitive gels exhibiting collapse on heating. Themain factors responsible for the collapse are the hydro-phobic interactions, which increase with temperature.The SANS curve showed a peak (Fig. 19) that appearedat 40°C and grew with further increase in the tempera-ture. The presence of a peak in the SANS curve at afinite value of the wavevector q0 is indicative of the for-mation of a microphase-separated structure with a char-acteristic spatial period of λ = 4π/q0 . It should beemphasized that this structure appears at 40°C, whenthe gel is still in a strongly swollen state (a discrete col-lapse in this gel is observed at 50.8°C).

Similar results were obtained by Schosseler et al.[145, 146, 148–150] for weakly charged gels of poly-acrylic and polymethacrylic acids swollen in heavywater.

The SANS data were interpreted using a theorydeveloped by Borue and Erukhimovich for microphaseseparation in a linear polyelectrolyte solution in a ther-modynamically poor solvent [151, 152]. It was demon-strated [71] that both the shape of the experimentalSANS curve and the peak position coincide with thosepredicted by the theory (Fig. 19). The spatial fluctua-tion period determined from the experimental data [71]was also close to the theoretical value [152].

The formation of microstructures (microphase sep-aration) in polymer gels may be caused by various fac-tors. The appearance of microstructures in the gels inaqueous media considered above was explained by thecompetition of electrostatic and hydrophobic interac-tions, the former factor (predominantly the osmoticpressure of counterions) being responsible for therepulsion between network chain units. Later, micro-structure formation was observed in systems where theelectrostatic factor accounted for the attraction of chainunits and non-Coulomb interactions stabilized theswollen gel state. These microstructures form under theconditions favoring strong Coulomb interactionsbetween ions, for example, in low-polarity media or insystems with large ion charge. The attraction betweencounterions and charged chain units in the gel leads tothe formation of ion pairs, followed by their aggrega-tion into multiplets as a result of the dipole–dipoleattraction (Fig. 3).

Fig. 18. Schematic diagrams illustrating the possibil-ity of microphase separation in a weakly chargedpolyelectrolyte gel swollen in a thermodynamicallypoor solvent.

Fig. 19. Plots of the SANS intensity vs. wavevector(symbols) for a NIPA–sodium acrylate copolymer gel(95 : 5, mol %) swelled in heavy water at various tem-peratures T = 32 (1); 36 (2); 40 (3); 44 (4), 46 (5);48 (6); 50°C (7) [71]. Solid curves show the theoreti-cal neutron scattering curves calculated using theBorue–Erukhimovich theory [151, 152].

7

6

5

4

3

2 1

150

100

50

0.02 0.06 0.10

q, Å–1

I, cm–1

224


PHILIPPOVA

The formation of multiplets in gels was reported forthe first time in [153–155]. The objects of investigationwere gels of polyacrylate and polymethacrylate ofeuropium. Since counterions in these gels were capableof producing fluorescence, the ion aggregates werestudied by the fluorescent spectroscopy technique. Itwas established that charged groups are nonuniformlydistributed over the gel volume, being concentrated inaggregates (multiplets) including on average about

seven counterions (with the corresponding oppositelycharged groups of chain units). Similar to the hydro-phobic aggregates in PNIPA gels, the ion aggregates(multiplets) begin to form when the gel is still in theswollen state (and are retained in the gel upon col-lapse). Thus, the formation of microstructures in poly-mer gels can be observed near the collapse threshold inthe systems featuring competition between the ten-dency to aggregation on the short-range scale and thetendency to long-range stabilization counteracting gelcollapse.

Proceeding from the analogy with microphase sepa-ration in block copolymers, it could be expected that theresulting microstructures may possess various morphol-ogies—and this assumption was confirmed in [156].Moreover, we may expect that the transitions betweenmicrostructures with different morphologies can becontrolled by varying external parameters (tempera-ture, pH, etc.). This assumption is corroborated by theresults of theoretical calculations for the collapse inweakly charged polyelectrolyte gels in a thermody-namically poor solvent with allowance for possiblemicrostructure formation [157].

Figure 20 shows a theoretical plot of the averagevolume fraction of polymer in the gel ⟨Φ⟩ (this quantityis inversely proportional to the gel volume V) versus thepolymer–solvent incompatibility parameter χ. As seenfrom this diagram, the pattern of gel contraction in thiscase (in contrast to the classical case) exhibits severalstages. As the solvent quality decreases, the gel under-goes a transition from a disordered swollen phase to anintermediate phase with lamellar microdomains; this isfollowed by the next jumplike change in the gel volumeaccompanied by the transition of microdomains fromlamellar to hexagonal structure comprising cylindricalhydrophobic micelles; finally, the last jumplike changein the gel volume gives rise to a collapsed disorderedphase. A characteristic period of the microdomainstructure formed in the intermediate stages of nontrivialmorphology variation in all cases amounts to tens ofnanometers. As seen from Fig. 20, the collapse regionmay feature a number of metastable phases (in additionto those mentioned above); therefore, nonmonotonicvariation of the parameter χ may be accompanied byhysteresis phenomena.

Thus, according to the theoretical analysis [157], thepossible existence of microdomains of stable phaseswith various morphologies in a collapsing polyelectro-lyte gel may render the collapse a multistage processinvolving the formation of microphase-separated nano-structures in the intermediate stages. These theoreticalresults may provide an explanation for the recent exper-imental data [51, 79, 94, 158, 159] indicating the exist-ence of several intermediate phases in collapsing gels.The multiple phases were originally observed byAnnaka et al. [79, 158, 159] in a gel based on a copol-ymer of cationic and anionic monomers (capable offorming hydrogen bonds with one another in the

0.2 0.4 0.6 0.8

0.7

0.9

1.1

1.3

1.5

L BCC

T

D

TD

⟨Φ⟩

χ

τ = 4, Φ0 = 0.1

Fig. 20. A plot of the average volume fraction of poly-mer in the gel ⟨Φ⟩ versus the polymer–solvent incom-patibility parameter χ calculated for a polyelectrolytegel (fraction of charged units, 0.06; number of mono-mer units in subchains between crosslinks, 1000;τ = 4; volume fraction of polymer in the gel, 0.1)[156]. Solid curve represents the equilibrium collapsecurve; dashed lines indicate metastable states featur-ing microdomain structures of various morphologies(L = lamellar; T = triangular; D = disordered; BCC =body-centered cubic).

2 6 10 14

1

2

3

4

pH

d/d0

Fig. 21. The pattern of room-temperature (25°C)phase transitions induced by pH variations in a gelbased on a copolymer of acrylic acid (460 mmol) andmethacrylamidopropyltrimethylammonium chloride(240 mmol) [25]. (d/d* is the ratio of gel diameters inthe swelled and initial state.)



uncharged state). It was found that a change in the pHor temperature of an aqueous medium is accompaniedby jumplike transitions in the gel between severalphases differing in their volumes (Fig. 21). The numberof phases and transitions depends on the ratio ofcationic to anionic monomer units in the gel network.Intermediate phases were also observed in some othergels [51, 94], but their structures were not charac-terized.

CONCLUSIONS

Thus, the behavior of swollen polymer gels hasproved to be richer and more complicated than onemight think. These objects offer wide possibilities forcontrolled variation of both their macroscopic state andmicroscopic structure. Evidently, a key point in the pos-sibility of controlled action upon polymer gels is theknowledge of the principal forces responsible for theirbehavior.

In recent years, slightly crosslinked polymer gelshave found increasing practical applications. Their useis based on two main properties: the capacity for strongswelling and the ability to sharply change their volumein response to small variations in the external condi-tions. In this review, we have briefly considered themain physical factors determining the properties ofpolymer gels and indicated some promising applica-tions of these systems.

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