journal of scientific & industrial research vo l. 60, june...
TRANSCRIPT
Journal of Scientific & I ndustrial Research Vol . 60, June 200 I , pp 45 1 -462
Swelling Studies on Hydrogel Networks -A Review
S K Bajpai
Department of Chemistry, Government. Autonomous Science College, Jabalpur 482 00 I , India
The pa�er d.escribes �he wide spectra of studies that have been carried out in the recent past on the swel l ing behaviour of
external stimuli responsIve polymer�c hydrogel networks, both naturally occurring as wel l as synthetic. It also highlights the condensed mathemal1c�1 approach of Flory � Rehner theory describing the equi librium-swollen state of hydrogels. A most widely accepted mechamsm of swellmg process of both ionic and non-ionic hydrogels has also been mentioned.
Introduction
Hydrogels are macromolecular networks which have abil i ty to swell in water or aqueous solvent systems. The polymer network is able to retain the solvents, forming a gel phase and will not dissolve, if cross-l inked, regardless of the solvent . The abi l i ty of hydrogels to absorb water arises from hydrophilic functional groups attached to the polymeric backbone and the difference in swelling osmotic pressure between gel phase and solvent phase which is created in the case of ionic hydrogels. The resistance to dissolution arises from crosslinks between network chains. Many materials, both natural ly occuring and synthetic, are examples of hydrogels. Crossl inked guar gum and collagens are examples of natural polymers that are modified to produce hydrogels . Classes of synthetic hydrogels include poly (hydroxyalkyl methacrylates), poly (acrylamide), poly (N-vinyl pyrrolidone), poly (acrylic acid) etc .
Synthetic hydrogel networks are useful for applications that require a material with good compatibility with aqueous solvents, without getting dissolved into it . Some of the major applications include biomaterials, chromatographic packings, controlled-release devices and electrophoresis gels. Many properties of synthetic hydrogels make them suitable for biomedical applications that require contact with l iving tissue. Their abi lity to retain aqueous media gives them a strong superficial resemblance with l iving t issues and also makes them permeable to small molecules such as oxygen, nutrients and metabol i tes. The low interfaci al tension between the hydrogel surface and the aqueous solution has been found to minimize protein adsorption and cell adhesion . Moreover, synthetic hydrogels can be fabricated in various
shapes (e.g. cylindrical, disc, s lab, nanoparticles) and can be easily washed to remove residual in itiators and monomers or other undersirable byproducts.
The first polymer which gained aceptance for manmade plastics was poly (methyl methacrylate) . It was observed that many pilots ended the war with PMMA splinters from their aircraft canopies embeded in their eyes, which was surprisingly tolerated by their eyes. But the first polymer of choice, precursor of the broad class of materi a l s known today as h ydrogel s , was polyvinylalcohol (PVA) appl ied in surgery under the trade name Ivalon. It was crosslinked with formaldehyde, and could withstand autoclaving temperatures. Tissue reaction to the implanted Ivalon is very mild, but after prolonged periods shrinkage and calcification were observed. However, its application in plastics surgery or as bone and postenucleation implants have been reported .
In the 50s Wichterle and Lim I synthesized a hydrophil ic polymer based on hydroxyethyl methacrylate, and corosslinked with diesters of methacrylic acid and mono, di-, and tri-ethylene glycols. Despite some technological problems in the beginning, poly HEM A was successful ly used as a biotolerable material, primari ly as a main component of contact lenses, but also in many other medical fields. HEMA and its various combinations with others, both hydrophi l ic and hydrophobic polymers, are t i l l now the most often used hydrogelic materials for medical purposes.
The high solute permeabi lity of hydrogels has led to their use in devices for controlled release of drugs or other active agents. The release of drugs from these hydrogels ( in i tially dried) involves the absorption of
452 J SCI IND RES VOL 60 JUNE 200 1
water into the matrix and simultaneous desorption of drugs via diffusion, as governed by Fick's law. The process can be modelled using a free-volume approach or a swel l ing-control led release mechanism. Furthermore, controlled release of drugs from hydrogel nanoparticles and microspheres, allows the possibi l i ty of targeting the drug to the specific sites in the body where the drug is needed. This targeting may make optimum use of expensive drugs while minimizing system-wide toxic effects.
Bes ides their use in biomedical filed, hydrogels have also been used as extraction solvents, enzyme reactors, in the removal of metal ions from the solutions, in adsorption of proteins etc. In fact, several reviews have appeared from time to time, describing the appl ications
. of hydrogels in different fields. Shai laja and Yaseen2 have reviewed the appl ications of polymer monolithic systems for control led release of agrochemicals, and Kazanskii and Dubrovski i3 have reviewed the chemistry of hydrogels in agricultural appl ications . Davies and Tighe4 have reviewed the potential of hydrogels in sensor appl ications and Singh ef ai. 5 and Corkhi l l ef al. ° have reviewed the design of hydrogels for various medical appl ications .
Synthesis of Hydrogels
The syntehsis of polymeric hydrogles is typically accomplished by one of two wel l-establ ished schemes : (a) Polymerization of hydropohi l ic monomers and (b) Modification or functionalization of ex isting polymers. Various reviews have d iscussed in detai l the synthetic methods of hydrogels . For example, a comprehensive review, describing the chemistry and various synthetic schemes have appeared in various chapters of a compilation edited by Peppas 7 - 10. More recently, Rosiak ef al. I I and Mathur et al. J 2 have reviewed methods for synthesis of hydrogel networks . Table I describes the commonly used monomers for synthesis of hydrogels.
Theory of Swelling Equilibrium
The state of equi l ibrium swell ing of a polymer network immersed in a solvent is obtained when the sol-
vent inside the network is in thermodynamic equil ibrium with the outside. This equi l ibrium state i s described by the equal ity of the solvent chemical potential ).1 1 in both phase. Thus, at swelling equ i l ibrium, we have :
. . . ( I )
where the subscripts g and s denote the gel and solution phases, respecti vely. In terms of the osmotic pressure 7t Eq.( I ) can be written as
JisJ - J1s J 7r = ----- = 0, . . . (2)
VI where V I is the molar volume of sol vent . Osmotic pressure 7r of a gel determines whether the gel tends to expand or shrink. When nonzero, 7rprovides a driving force for the gel volume change. Within the framework of the Flory-Rehner theory, the osmotic pressure 7r of the gel is the sum of three contributions 1 3 :
. . . ( 3 )
In above equation, 7rmix represents the tendency of mixing of the polymer and solvent; while 7rcJ accounts for the elastic response of the network due to crossl inking which opposes the dissolution. Moreover, 7r denotes 1011 the osmotic pressure resulting from the difference in the ion concentrations between the swollen gel and the external solution .
According to the Flory-Huggins theori4, 7rmix is given as,
RT
--- In ( I - v2 ) + v2 + Xv\ ) , . . . (4)
VI where '\)2 is the volume fraction of polymer in the hydrogel, X is the polymer - solvent interaction parameter, R
is the gas constant, and T is the temperature . To describe the elastic contribution 7reJ to the swel l ing pressure, several theories are available I 5- 1 7 . However, according to the simplest network model 1 4 describing the behaviour of gels,
Dr S K Bajpai is A.uistalll ProFessor ill Department of Chemistrv, ill the Govel'lllllent A u
tOlW1110llS Science College, la/Jalpw; having 20 y teaching experience. He ohtained his Ph
D ill Chemistry jimn lahalpur Univer.fity ill 1 997 on 'Adsorption Behaviour (d' Polymers '. Presently, he is working on si/e specific drug delivery syslems. He has puh/ished over 15 research papers in various jo II l'Ila Is of inlernational repUle.
BAJPAI : SWELLING STUDIES ON HYDROGEL NETWORKS 453
Table 1- Commonly used synthetic monomers for hydrogel synthesis
Monomer
Hydroxyethly methacrylate
Methoxyethyl methacrylate
Ethylene glycol dimethacrylate
Acrylic acid
Methacrylic acid
Methyl methacrylate
N-vinyl-2-pyrrolidone
Vinyl acetate
Acrylamide
N-isopropylacrylamide
RT
trel = - N-I (v/3 V2 02/3 - '\)2 /2) , VI
Abbreviation
HEMA
MEMA
EGDMA
AA
MA
MMA
NVP
VAc
AAam
NIPA Aam
. . . (5)
where N is the average number of segments in the network chain and v20 is the volume fraction of polymer after preparation. Here it should be made clear that '\)7 and v20 are quite different terms. The former represent� fraction of polymer in the swollen gel whereas the later term gives the volume fraction of polymer just after it has been synthesized.
Ionic contribution trion to the swel ling pressure is caused by the concentration difference of counterions between the gel and the outer solution . To describe this effect completely, one should consider the ion-ion, ionsolvent and ion-polymer interactions. However, the ideal Donnan theory ignores these interactions and gives trion as the pressure difference of mobile ions inside and outside the geJ l 4 :
tr. = RT ( O. - 0. ), IOn I I . . . (6)
where Ci is the mobile ion concentration of species i . According to ideal Donnan equi librium, the chemical
Chemical structure
CH2 = CHCOOH
CH2 = CHCOOCH3
potential of an ionic species i inside the hydrogel must be equal to that outside.
Thus, for aqueous solutions of univalent salts, we have:
. . . (7)
Where C\alt represents the salt concentration in the external solution. On the other hand the condition of electroneutrality inside the ionic hydrogel requires.
and
o = C g + c- ' - + fix
. . . (8)
. . . (9)
where Cfix is the concentration of the fix charges in the gel and Eq. (8) and (9) holds for anionic and cationic hydrogels, respectively.
Eqs ( 1 -9) can be used to get expressions for equil ibrium value of v2 for the hydrogels and the distribution
454 J SCI IND RES VOL 60 JUNE 200 1
coefficient K of the counter ions between the gel and solution phases .
In the case of swelling of hydrogels in water, free of ionic species (CSsall = 0), the above set of Eqs ( 1 -9) may yield the fol lowing equation:
. . . ( 1 0)
Moreover, for highly swollen gels, s ince v2 < I the final equation can be written as :
[pCliX )2 Clix ] where K =: 0.5
- .. - + 4 - � C'salt salt
Mechanism of Penetrant Uptake
. . . ( I I )
Dynamic penetrant sorption into initially glassy nonionic polymers genrally involves a complex set of mass transport steps when the penetrant/polymer pair have comptabi l i ty. As the penetrant invades the polymer from the sample surface, a sharp boundary or moving front is commonly observed separating the unsolvated glassy polymer region ahead of the front from the swol len and reubbery get phase behind i t l 8 . Just ahead to the front the presence of solvent plasticizes the polymer and causes it to undergo a glass-to-rubber transition that init iates chain relaxation process and swell ing l9.
The time duration of overal l penetrant uptake often deviates from classical Fickian diffusion behaviour when sorption is accompanied by a glass-to-rubber transition in the polymer2o. In Fickian sorption the in itial uptake in polymeric slabs is proportional to to.5 and is commonly observed in penetrant sorpiton into polymers well above T, (ref.2 1 ) . In glassy polymer, however, sorption is oft;n proportional to tn, when the kinetic exponent n can take on values between 0.5 and 1 .0. This non-Fickian or anomalous sorption behaviour is general ly associated with the concurrent process of inward diffusion of penetrant from the solution/gel interface and the process of
polymer relaxation that occurs in response to penetrant invasion and plastic ization at the moving front22.
This swel l ing process of gels in excess electrolyte solutions become more complex when sorpiton of water is accompanied by ionization of gel itself. For gels that contain weakly acidic or basic groups the ionization state of the gel wi l l depend upon the electrolyte composition of the bulk solutions. During the process of dynamic water sorption in gels containing weakly basic groups, transport of mobile ions into the gel from the bulk solution is necessari ly coupled to water sorption as the gel becomes hydrated and ionized. This coupl ing is required to maintain electroneutrality in the swol len gel phase . Furthermore, when the gel i s in itially glassy, polymer relaxation process wi l l also contribute to the over all dynamics of water sorption as mentioned earl ier.
Studies on Swelling Behaviour
In fact, several studies have been carried out in the past three decades, thus unfolding various aspects of swel l ing behavior of hydrogels . Here some of the most s ignificant studies carried out in the recent past are critical ly presented so that a concrete base can be formed for those who wish to explore further possibil ities of using swelling based properties of various types of polymeric systems in different technological, b iomedical and other related fields in near future.
Studies With Chemical Signals - Responsive Gels Some of the s ign ificant studies carried out wi th
hydrogels sensit ive to chemical signals in the swel l ing media are discussed. The Swell ing behaviour of these polymer matrices depends upon factors l ike pH, ionic strength of the external solution.
However, most of the studies are based or pH- responsive gels which contain certain groups that undergo protonation/ionization with varying pH of the solution , thus cansing a change in osmotic swel l ing pressure and hence swell ing capacity.
The swel ling response of these gels depends on size and shape of the hydrogels. A pioneering theory of gel swell ing is developed ofTanoka-Fi llmore23 (TF) according to which :
R2
I =: D
where t, R and D are characterstic time for the gel swelling, the size of the gel and cooperative diffusion coeffi -
BAJPAI : SWELLING STUDIES ON HYDROGEL NETWORKS 455
cient respectively. As it is not easy to increase value of D by a factor of 1 02 or more, the reduction of gel s ize is the only way to achieve quick response. For example, microgels ( 1 - 1 0 flm in diam) show a faster response than the slab gels, 0.5 s vs h to d, to reach swel ling equi l ibrium with change in their chemical surroundings.
The smal l-size and quick response of microsphere hydrogels have promoted their use in drug delivery and therapeutic appl ications24. Moreover, they may be targeted to certain diseased tissues and even be taken up into the intracellular compartment of target cel ls . The micrometer sized (4-7 flm diam) poly (mtehacryl ic acid) (PMMA) hydrogel microspheres25 exhibit a sharp volume change with pH-change in a very short period of 300 ms. This indicates that swell ing rate is determined by the diffusion of the polymer matrix and not of ions into and out of the microsphere. Moreover, such quick pH-responsive volume change may have physiological importance as the time course of swel ling for natural ly occuring mast cell granules is also of the similar order.
Likewise, a pH-responsive hydrogel membrane, obtained by the copolymerization ofN-isopropylacrylamide and acrylic acid26 demonstrates pulsati le lengthwise swell ing-deswelling similar to heart beat when placed in a contineous flow stirred tank reactor (CSTR) in which regular supply of the reactants hydrogen peroxide, hydrogen sulphi te and hexacyanoferrate(II) is made. Such self-osci l lating gel system may contribute to further understanding of biological phenomena. Simi larly, a blend hydrogel, made of poly (allyguanidino-co-al lylamine) and poly (vinyl alcoholf7 shows pH dependent swel l ing behaviour. The membrane shrinks below pH 3 and above pH 1 0 while it is l i ttle affected in the range 3- 1 0. Moreover, with the variation in ionic strength, the size of the membrane changes gradual ly. The mult iple protanation states displayed by PAG and the shielding of electrostatic interaction among the charges on the polymer backbone by the added electrolyte play a key role in explaining above phenomena.
Polymer supports with complexing groups have been widely investigated by a number of workers2ll.29 for the removal of metals in the homogeneous phase. A poly (N, N' - diethylacrylamide - co- acrylic acid) membrane hydrogef�O shows a fair tendency to udergo complexation with metal ions l ike Co (II) Ni (II) etc. , which form stable complexes with gels in the pH range 5-7. The complexation abi lity of the hydrophi l ic polymer depends upon pH and the filtration factor. The carboxylic acid
moieties interact more strongly with the metal ions than do the tertiary amide moiety, particularly at pH 5 and 7 . Simi larly, the poly (N-vinylimidozole) hydrogels also bind with metal ions such as Cu(II), Co(II), Ni(II) etc as well as uranyl, vanadium, rehenium and molybdenum complexes3 1 . The binding abi l i ty of the hydrogels with metal ions depends upon the crossl in king degree of the gel, solution pH, concentration of the cation and the time of the cation-hydrogel equi l ibrium.
The crosslinked poly(acryl ic acid) hydrogels32 show a pH-dependent tendency to retain chromium. The chromium retention increases with pH in accordance with the two mechanisms. In the low pH range soluble chromium species are retained via ion-binding in the whole volume of the gel while at higher pH, the retehtion of insoluble chromium hydroxide is due to adsorption at the surface of the gel . The desorption of chromium species depends on the retention mechanism. When retention occurs via ion-binding, only partial desorption is achieved at very short aging time, while a fast desorption is achieved when retention occurs via adsorption at the surface.
When a polyeletrolyte gel i s placed in a salt solution, the binding of counterions with the poly ions of the network influences the state of the hydrogel . The swel ling of poly (sodium acrylate-acrylic acid) hydrogels33 in dilute copper sulfate solution is associated with the presence of up to three coexisting phases: a dry phase, a swollen phase and a collapsed one due to the binding of metal ions to polyions. However, in the concentrated copper sulphate solution the hydrogel just absorbs a small amount of solvent.
The hydrogels, synthesized from natural proteins and polysaccharides also exhibit a fair swell ing tendency depending upon various external conditions l ike pH, ionic strength etc. The interpenetrating network of gelatin and polyacrylamide34 show a pH and temperature dependent swelling behaviour. At low pH, max imum swell ing is observed due to larger presence of carboxylic groups which increases the diffusional flux of the carrier species into the hydrogel . With further increase of pH, the swelling decreases and finally it attains constant value in the alkaline range. Moreover, the swell ing in creases with the temperature upto 50°C and than attains constant value. This may possibly be due to the formation of a complex structure between the amide and carboxyl ic groups produced due to the partial hydrolys i s of polyacry lamide. S im i larly, the hemoglobin-
456 J SCI IND RES VOL 60 JUNE 200 1
crossl inked polyacrylamide hydrogels35 also exhibit maximum swell ing at pH 7.0 while it decreases on either sides along the pH scale. Here also the possible hydrolysis of polyacrylamide seems to be responsible for pH-dependent swell ing. The gels also undergo a number of swell ing-drying cycles without undergoing any structural deformation .
The ge la t in - sod ium carboxymethy l c e l l u lose (NaCMC) hydrogels36 also exhibit pH and temperature dependent swell ing behaviour. The increare in the swel ling capacity with pH is due to the ionization of carboxyl ic groups in NaCMC, whereas the swel l ing increases with temperature up to 50°C and then starts decreasing, possibly due to degradative process in the protein chain. The eneray of activation for the swel ling process is found to be on higher side as it involves the entire process of solvent entry, stretching of the network segments and consequent large scale dimensional change in the network.
The hydrogels containing carboxyl ic groups are suitable for the oral drug delivery of peptides as they can protect the encapsulated drug from the acidic environment of stomach by minimum swel l ing. The hydrogels composed of poly (methacryl ic acid) (PMAA) grafted with poly (ethylene glycol) (PEG) can be used as drug del i very carriers for the oral admin i strat ion of the polypeptide harmone saloman calc itonin (CST)37. The gels release the polypeptide harmone at pH 7.0 at 37°C with the ionic strength 0. 1 M. The release behaviour is not much affected by the amount of di luent used during the polymer preparation . The devices follow relaxation controlled transport mechanism.
Amphiphi l ic hydrogel networks, are random assemblages of hydrophobic and hyrophoblic chains and they swell in water as wel l as in non-polar solvent. The urethane acry l ate hydrogels contain ing ion ic groups (dimethylol propionic acid DMPA) with varying molecular weight of hydrophobic segment (poly ether type, PTMG) show amphiphi l ic properties38. They also show pH-responsive swelling due to the presenes of carboxyl i c groups in the polymer matri x . Owing to their amphiphil ic nature, they can release the hydrophilic drugs (e.g. riboflavin) as wel l as hydrophobic drug (e.g. indomethacin) loaded into the gel matrix .
I t is a wel l known fact that low molecular weight compounds (M.W.< 2900) can pass through membranes derived from chitosan. The release of ampici l l in from the chitosan-amine oxide39 fol lows a pH-dependent release
pattern due to the protonization of amino groups and dissociation of hydrogen bonding within the network with change in solution pH. The size of the polymer matrix decreases with time and final ly the matrix disintegrates into pieces. This suggest that erosion takes place from the surface as well as from the bulk of the matrix. Therefore, the drug releases from the device by a combination of diffusion and erosion.
One of the ways to immobil ize proteins and retain their biological acti vity is based on the complex formation between the oppositely charged protein and the polymer carrier. The polyelectrolyte hydrogels containing pendant phosphate groups are the suitable device for the loading and release of cationic protein drugs. The anionic hydrogels , synthes ized by copolymerizing 2-methacryloy loxyethyl dihydrogen phosphate and N, N, methylenebisacryl- amide 40 form complexes with the cationic protein lysozyme. The lysozyme loaded hydrogel releases the protein when placed in KCL solution of varying concentrations. This confirms that lysozyme is loaded in the hydrogel through electrostatic interactions. The ionic strength-dependence of release rate suggests that the ionic interactions of phosphate groups with the cationic charge of lysozyme are replaced with small electrolytes.
The structure-dependent swel ling of hydrophi l ic polymers has been exploited for the releare of perfumes, deodrants, essential oi IS4 1 .42 . The glassy hydrophi I ic copolymers of 2-hydroxyethly methacrylate (HEMA) and ethylene glycol dimethacrylate (EGDMA)43 demonstrate swell ing control led release of essential oi ls l ike Cal-vone, l imonene and eugenol . The zero-order release can be achieved by changing the degree of crossl inking. The minimum difference between the solubil ity paramater of hydrogel and that l imonenc clearly indicates that maximum compatibi l ity is achieved in the case of I imonenepolymer pair.
The polymer matrices may provide an attracti ve alternative for the spray of pesticides to plants/soi I to control the pests_ The less toxic pesticide, such as neem seed oil (NSO) may be released from granuler hydrogels containing cross l inked starch and guar gum44. In order to have release for shorter time with higher concetrations of NSO, crossl inked starch matrix is more effective in soil appl ications especial ly at low moisture contents, while for higher moisture containing soil appl ications, guar gum is more effective as it swel ls less as compared to starch. The FfIR results of NSO loaded devices indi-
BAJPAI : SWELLING STUDIES ON HYDROGEL NETWORKS 457
cate the absence of chemical interaction between NSO and polymer materials.
The studies involving absorption of multivalent cations in the negatively charged polyelectrolyte gels have mostly concentrated on their macroscopic swell ing behaviour and their correlation with the distribution of multivalent ions between the gel and the exterior solution. The data on the molecular mechanism of the binding of ions to the network counter charges remain rather scare. However, a study of such possible interaction of polyanionic hydrogels composed of poly(acrylic acid) and (poly methacrylic acid) with multivalent cations in the aqueous medium, as examined by using europium ions as fluorescence probes45, indicates a strong and asymmetric binding of carboxylate group of Eu3+ ions, leading to the expulsion of upto five water molecules from the solvation shel l of the ion . The relaxation studies of the non-radiative energy transfer from europium to neodymium ions inside the gel reveals the formation of aggregates consisting of ca. seven rare earth ions (together with the corresponding counter charges of the network chains). The aggregates are stabilized by high level of polarization of the quadruplets (RE3+ + 3 COO) .
Natural fibres l ike cellulose, possessing fair mechanical strength due to high degree of orientation can be provided with fair swelling tendency through graft-polymerization with some hydrophilic monomers. For example, the ozon-induced graft polymerization of acrylic acid using cotton l inters and wood pulp fibre substrates results in the formation of cellulose-fibre supported pHsensitive hydrogels46, with fair swel l ing tendency and good mechanical properties. At low pH the hydrogel shows minimum swelling which increases with the pH of the solution and finally becomes constant. Moreover, exposure of the hydrogel to alkali and subsequent drying results in a irreversible deformation of the hydrogel which, may be made reversible by addition of a bifunctional monomer, ethyleneglycol dimethacrylate into the monomer mixture at the time of grafting.
The pH-dependent swell ing property of polybasic hydrogels has been exploited by a number of workers47,4R to develope glucose sensitive insulin release devices which contain immobil ized enzyme glucose oxidase in a the matrix enclosing saturated solution of insulin. When the glucose, present in the swelling medium diffuses into the hydrogel, glucose oxidase catalyses its conversion to gluconic acid thereby lowering the pH of the gel
micro environment, and resulting in the protonation of basic groups to cause the gel to swell with the subsequent release of entrapped insul in . A mathematical model49 describing these glucose-responsive hydrogels demonstrates two important points : ( I ) Progressive response to glucose concentration over a range of glucose concentration can be achieved only with a sufficiently low loading of glucose oxidase, otherwise, depletion of the oxygen causes the system to become insensitive to glucose and (2) a significant pH decrease in the hydrogel can be achieved only if the amine concentration is sufficiently low.
Recently, attention has been focused on employing natural polymers such as cellulose5o, starch5 1 , chitosan52 etc. to compose hydrogels with specific response to biological environment. The graft-coplymerization of chitosan (CS) and D, L-Iactic acid (LA) results in the formation of pH-sensitive and biodegradable polymeric hydrogel53. These hydrogels show maximum swelling in enzyme - free simulated gastric fluid (SGF, pH 2.2) due to the protonation of amino groups which finally increase the osmotic pressure and chain relaxation process. However the gels demonstrate minimum swel ling in simulated instestinal flu id (SIF, pH 7 .4) due to deprotonization of the protonated amino groups. In this way the gels possess different structures in acid and basic medium. FTIR studies also confirm the hypothesi s .
Studies with Physical Signals - Responsive Hydrogel.\·
Some of the most s ignificant studies based on hydrogels responding to physical signals such as temperature, electric field, magnetic field, etc. are discussed. Out of these, temperature-sensitive gels have been studied most widely because of their special characterstic of undergoing drastic volume change at a definite temperature called lower critical solution temperature (LCST). Such hydrogels have a variety of applications in medical , pharmaceutical, industrial and technological fields.
In most of the applications, of such hydrogels, a fast swel ling-shrinking is required. Although microgels or thin gel membranes exhibit this property but they possess a poor mechanical strength. On the the other hand hydrogels with porous structure swell or shrink very fast as compared with non porous gels of the same size. The free radical polymerization of N-isopropylacrylamide (NIPAAm) or N,N diethylacrylamide (DEAAm) results in the formation of hydrogels54 consisting of aggregated microgel praticles, namely a porous structure. The gels
4 5 8 J S C I IND R E S VOL 6 0 J U N E 200 1
swell below their LCSTs and the swel l ing degree increases with lowering temperature. Furthermore, these gels swel l or shrink very fast in response to the change in temperature of the swelling media, and the shrinking rate is larger than the swelling rate.
The shrinking/swel l ing behaviour of the charged thermosensitive gels is rather more sophisticated, as the solvent molecules are highly localized near the charged groups, thus leading to a discrete volume transi tion, bubble formation and microphase separation. The swelling/shrinking for cylindrical gels made of weakly charged ploy (N-isopropylacrylamide-co-acrylic acid) (NIPA-coAAc) and uncharged poly(N-isopropy lacry lamide) (NIPA) unfolds some interesting aspects)) . In the case of (NIPA-co-AAc) gels, the shrinking takes place through a three-stage process, namely a uniform shrinking stage with the exponential decrease of the diameter a plateau stage where the gel shrinks further from both ends of the cylinder and final ly a col lapse stage where the middle parts shrinks l inearly with time. This unique behaviour is explained on the basis of the concept of microphase separation, and spatial inhomogeneities . In the case of uncharged poly NIPA gels, the shrinking process is greatl y declerated by phase separation. However, both type of gels show the single-exponential type swel l ing behaviour.
The applications of hydrogels such as, artificial muscle and rapidly acting actuators, requ ire a fast swellingdeswell ing which may be achieved through modification of the molecular structure by incorporating hydroph i l i c graft chai n s . The copo lymeri zation of isopropylacrylamide with a-acryloy I-(J)-methox y-ethy 1 -ene ox ide resu l t s in the format ion of po ly (Nisopropylacylamide) (PIPAAm) gels with poly (ethy lene oxide) (PEO) chains as graft chains, thus maintaining free mobi le ends in hydrogel56. The deswel ling response of this hydrogel above the gel phase transition temperature (Tp) takes place within 1 0 min, whereas conventional ly crossl inked PIPAAm gel of the same dimension requires one month for deswel l ing. This difference is due to the formation of water-release channels within the skin layer by the hydrophilic PEO graft chains.
The interpenetrating polymer network, comprising both pH and temperature sensitive properties may be formed through chain interpenetration of pH and temperature sensitive polymeric materials. The interpenetrating polymer network, (IPN) composed of temperature
sensitive poly (N-isopropylacrylamide) and pH sensitive poly (methacrylic acid) exhibits a combined pH and temperature sensitivity57 at the temperature range of 3 1 -32" C and pH value of approx S .S , thus suggesting the independent response of each network in these lPNs, which is also verified by differential scanning calorimetry (DSC) measurements. The permeation study results indicate a significant size exclusion behaviour while model drugs with different sizes permeate through the JPN membranes.
The condition of synthesis of a hydrogel effects its properties s ign i ficant ly . The po ly (Nisopropylacrylamide) (PNIPA) gels58, prepared in the form of rods and slabs by solution and inverse polymerization techniques exhibit different swel ling properties. The solution polymerization technique at temperatures as high as 3SoC leads to the formation of heterogeneous PNIPA gels with high water retaining capacity. The swelling capacity further increases for the gels prepared in the form of beads using inversion suspension polymerization method. The PNIPA gels, synthesized by solution suspension polymerization demonstrate greater extraction efficiency in concentrating dilute solutions bovine serum albumin (BSA) as compared to the gels prepared by suspension polymerization.
The sharp volume phase transition, exhibited by thermoresponsive gels is often used for the removal of metal ions from the aqueous solutions. The microgel dispersions of poly (N-isopropylacryl amide»)'), with cationic or anionic surface charge groups absorb sign ificant amount of ions from aqueous solutions at 2S"C. Under these conditions the microgel particles can be envisaged as porous-like materials with spherical conformation consisting of numerous interstial spaces. At SO°C a reversible contraction of microgel takes place thus causing a large amount of the retained material to be released from within the closed interstial spaces of the structures. The nature of ionic in itiator used in the polymerization of microgel particles shows a considerable influence on the affinity of each ionic species.
The thermosensitive gels , having promising potential for being used as a molecular device for self regu lating drug delivery60 suffer from the disadvantage of poor mechanical strength, which however may be increased by the attachment of gel to some ceramic surface. The composite crosslinked poly (N-i sopropylacrylamide) (PNIPAAm) gel layer6 1 , after being attached covalently to the glass plate possess a good mechanical strength .
B AJPAI : SWELLING STUDIES ON HYDROGEL N ETWOR KS 459
The glass plate as a substrate increases not only the strength of composite gels , especial ly with a lower crosslinking density, but also keeps the size of the composite gels unchanged in the horizontal direction . The composite gel s exhibit hydrophi l ic property below 25°e and change to hydrophobic above 40°C.
The poly (N-isopropylacrylamide) (NIPAAm) and poly (NIPPAAm-co-acryl ic acid) hyrogels exhibit the property to be used as injectable scaffolds for tissue engineering62. At room temperature they are transparent and extremely pl iable, while at 37°e the matrices become opaque and s i gn i fi cant l y more rig i d . The P(NIPAAm-co-AAc) hydrogels demonstrate sign ificantly less volume change between the room temperature and 37°e and possess lower critical solution temperature (LeST) . The hydrogels support bovine articular chondrocyte viabil ity for atleast 28 d of in vitro culture, and carti lage-like tissue are formed in the matrices. These hydrogels can be injected through a small diameter aperture.
The addi t i on of hydroph i l ic , hydrophobic and amphiphilic comonomers into the thermosensitive homopolymer can cause a great change in its volume phase transition behaviour. For example, the addition of smal l amount of anionic or cationic comonomers (sodium acrylate and methacrylamidopropyl trimethlylammon ium chloride) to the hydrogel of N-i sopropylacrylamide (NIPAAm) affects their thermosensitive and collapsing behaviour during d iscontineous volume trans i t ions occuring at their criticial points63. Swel l ing ratios in the swollen gel states below the critical points are significantly greater than those of pure NIPAAm gels and collapsed state becomes much more condensed. This behaviour i s explained by a gel structural model that considers the effect of hydrophil ic constituents on the water transport in transition state network undergoing critical phenomena.
The addition of ionic surfactants also causes a change in the volume phase transition temperature of poly (Nisopropylacrylamide) (PNIPA) gels64 which depends on the chemical structure of the surfactants i .e. hydrophobic chain length and hydrophil ic head group65 . S imilarly to the interaction between surfactants and water soluble l inear polymers66, the effectiveness of the hydrophi l ic groups on the elevation of phase-transition temperature is roughly in the order of anionic > cationic > non-Ionic . Even among the anionic surfactant, su lphate-type surfactant elevates more than 600e whereas phosphate-type
surfactant elevates by 2 to 3°C. This elevation is due to the ionization of polymer chains of PNIPA gel by absorption of ionis surfactant molecules64. However, this may not be the sufficient cause to explain the appreciable elevation in temperature. The study of binding isotherms of surfactants onto the po lymer ge l of po ly (Nisopropylacrylamide) (PNIPA) reveals67 that the amount of surfactant binding onto the PNIPA gel changes reversibly and discontinuously through the volume phase transition of the gel . The hysteresis in the binding isotherm is also observed. These results mean that the affinity of surfactant to the polymer chain alters by the conformational change of the polymer just l ike the functions of haemoglobin, enzyme etc .
The isotropic swel ling behaviour of hydrogels may be changed by an external constraint such as streching, and surface bonding68. Such anisotropic gels have been obtained by incorporating l iquid crystals into gel networks69. A recent approach to get anisotropic hydrogels is to anisotropically constrain one of the network components before the gelation of the other network takes place. For example, the interpenetrated network of Nisopropylacrylamide and polyacrylamide with the former component prestressed during the gelation of the other one results in the formation of anisotropic gels 71l . The swell ing properties of these gels along the prestressed direction is different from that along other directions. The change in ratio of gel length (non pre-stressed) to its diameter (prestressed) on heating the sample from below to above the volume phase transition temperature is proportional to the degree of initial stress.
There is not much information about the restriction on movement of counterions in a col lapsing hydrogel . Some information about the degree of this restriction is provided by the measurment of dielectric spectra for the polymer gel of N-isopropylacrylamide (NIPA) and sodium styrenesulfonate (NIPA-SS) in the swollen and col lapsing states 7 1 in the frequency range from 1 00 kHz to 2MHz. The characterstics of dispersions in the collapsing gels are different from those in the swol len gels, whi le former characterstic are very similar in NIPA and NIPA-SS gels, thus suggesting that countersions of NIP ASS gels bind tightly to the ionized groups. The di spersion analysis confirms the prescnce of electrical ly disconnected clusters, of water molecules.
In the hydrogels, sensi tive to the electric current the mechanical energy is triggered by an electric signal72. Electrically controlled drug del ivery system 71 offer
460 J SCI IND RES VOL 60 JUNE 200 1
unique advantage for providing on-demand release of drug molecules. For example the interpenetrating network (IPN) composed of poly (vinyl alcohol) (PVA) and poly (acrylic acid) (PAAc), loaded with ionic drugs (i .e . cefazoline) and nonionic drug (i .e. theophyll ine) demonstrate electric field responsive release behaviour74. The amount of loaded drug increases significantly with the contents of PAAc in IPN. As an electric stimulus is turned on and off, the release of drug molecules loaded within the IPN is switched on and off in a pulsati le pattern. The released amount and the release rate of drug are influenced significantly by the applied voltage, ionic group contents in lPN, ionic properties of the drug solute and ionic strength of the release medium.
The small-angle X-ray scattering (SAXS) techniques are often used to understand the structure of the ful ly ionized gels at the point of volume transition in a salt so lu t ion . The po ly ( al l y lamine hydroch l oride) (PAAMHCL) gels collapse when equilibrated with sodium salts of various organic acids 7.S. and a less precipitous volume change is observed with NaCI and Nal. The SAXS studies, carried out with col lapsing gels show a single broad peak for the collapsed gels with the sodium salts of organic acids, whereas no peak is observed for inorganic salts . The strong maximum in the SAXS pattern is attributed to the ordered structure in the collapsed gels due to electrostatic and hydrophobic interactions.
The mechan ical strength and degradation time of hydrogels may be utilized to use them as cell-delivery vehicles for replacement of damaged tissues. One typical ly desires to time the rate of hydrogel degrdation to the rate of new tissue formation. The mechanical strength enables these hydrogels to create and maintain a space for new tissue formation. For example, the poly (aldehyde guluronate) (PAG) gels, crosslinked with adipic acid dihydrazide (AAD) exhibit degradative behaviour76 due to the hydrolysis of hydrazone bonds formed between the aldehyde of PAG and the hydrazide of AAD. The mechanical properties and degradation time of hydrogels vary wi th the degree of cross l i nk ing . Moreover, hydrogels with many dangl ing single-end molecules show a retarded degradation behaviour.
It may be interesting to investigate the behaviour of charged rigid rods embeded in the flexible hydrogel network and their influence on the hydrogel properties. The incorporation of stiff-chain polyelectrolyte rods composed of poly (4,4"-disodium 2,5-dimethyl- I ', 1 ' 04' I "-
terpheny 1 -3',2"-disulfonate) into the flexible network of polylacrylamide results in the improvement of me chan ical strength and water absorbing capacity of the hydrogel77 due to enhanced osmotic swel ling pressure. The study of the release kinetics of polyelectrolyte rods shows that the rods, though not covalently attached, are effectively retained by the gel due to formation of aggregates with the network chains.
The swel l ing tendency of hydro gels is used in extracting water from the aqueous solutions of proteins. The po lymer matr i x , composed of po ly (N-v iny l -2-pyrrolidone-acrylamide) concentrates protein solutions like bovine serum albumin, hemoglobin, etc.78• The protein molecules, being larger in size, can not penetrate into the gel matrix . The swollen gel, after drying in vaccum oven at 400C, returns to its original state and hence can be reused. In this way, using the same sample a number of times, the protein solution can be concentrated. The extraction efficiency varies with the degree of crosslinking and the concentration of protein solutions.
The synthesis of a gel sensitive to some molecular species has been a chal lenge before the researchers. Even the glucose-responsive gels function by responding to gluconic acid formed in gel 's microenvironment by the enzymatic reaction of glucose oxidase. Tanaka7,! suggested that swel ling behaviour of hydrogels is also governed by the crosslink density. Using this concept, Okano et aL. 80 synthesized IPN of poly (acrylamide-co-butyl acrylate) and poly (acrylic acid) which showed temperature sensitivity due to reversible complex formation between acrylamide and acrylic acid. Similarly, the complex formation between polysaccharides and lectin at cross-l inking points resulted in the formation glucoseresponsive of hydrogels l . The Antigen-sensitive hydrogel has also been prepared82 by the application of antigen-antibody complex formation at the cross linking points. Here Rabbit immunoglobulin G (Rabbit IgG) and Goat anti-Rabbit IgG has been selected as antigen and antibody respectively. The Rabbit IgG-sensitive swelling of the antigen-antibody hydrogel is attributed to the decrease in the crosslink density due to the dissociation of the antigen-antibody bonding in the presence of a free antigen on the basis of the complex exchange between the polymerized antigen and free antigen. However, the complex does not dissociate due to addition of Goat IgG and hence the swelling ratio of hydrogel remains constant.
B AJPAI : SWELLING STUDIES ON HYDROGEL NETWORKS 46 1
Conclusions
Owing to their wide range of appl ications in biomedical, agricultural and biotechnological fields, hydrogels have proved to be good friend of mankind. Some of the major appl ications include contact lenses, wound dressings, monolithic drug delivery systems, membrane materials, chromatographic packing materials, water-blocking tapes , seal ing composit ies , art ific ia l snow, gel actutators, immobi l ization of enzymes, phase transition catalysis etc . In fact, al l such applications have emerged from a large number of swel l ing studies which were carried out under different experimental conditions.
However, it is sti l l required into investigate more aspects of swel l ing behaviour of hydrogels so that the may be used as site-specific drug delivery systems, for releasing the drug in the desired amount and for the desired time at a particular site in human body. Similarly, it is suggested to fabricate such plant nutrients-loaded release devices which can be put inside the "sprinklersystems" to release the contents at the time of i rrigation so that crops can be provided with the desired neutrients with minimum cost and maximum protection of environment from toxic effects. The unique swel ling property of hydrogel s can be successful ly util ized for the preparation of new commercial products with designed functions which satisfy expectations of mankind .
References I Wichterle 0 & Lim 0, Nall/re, 165 ( 1 960) 1 77.
2 Shailaja 0 & Yaseen M, J PO/YIIl Mater, 11 ( 1 994) 73.
3 Kazanskii K S & Dubrovski i , Adv PolYIIl Sci, 104 ( 1 992) 97.
4 Davies M L & Tighe B J, Sel Electrode Rev, 13 (2) ( 1 99 1 ) 1 59.
5 Singh H, Vasudevan P & Ray A R, J Sci Ind Res, 39 ( 1 (80) 1 62.
6
7
8
9
1 0
Corkhi l l P H, Hamilton C J & Tighe B J, Crit Rev Biocompat, 5(4) ( 1 990) 363.
Peppas N A & M i kos A G, in Hydrogels in Medicine and Pharmacy, Vol. 1, edited by N A Peppas (CRC Press, Boca Raton, FL) 1 987, p. 1 .
Peppas N A , in Hydrogel.� ill Medicine and Pharmacy, Vol. 3, edited by N A Peppas (CRC Press, Boca Raton, FL) 1 987, p . 1 .
Gombotz W R & Hoffman A S, i n Hydrogels in Medici/le & Pharmacy, Vol. 1, edited by N A Peppas ( CRC Press, Boca Raton, FL) 1 987, p.95 .
Graham N B, i n Hydrogel.� ill Medicine & Phamzac\', Vol. 3,
edited by N A Peppas (CRC Press, Boca Raton, FL) 1 987, p.95 .
I I
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
20
2 1
22
23
24
25
26
27
28
29
30
3 1
3 2
33
34
35
36
37
38
39
40
4 1
Rosiak J M , Ulanski P, Pajewski L A, Yoshii F & Makuuchi K, Radiant Ph)'s Chem, 46(2)( 1 996) 405.
Mathur A M , Moorjani S K & Scranton A B, J M S - Rev
Macromol Chem Phys, C 36 (2)( 1 996) 405 .
Flory P J & Reimer J (1r) , .I Chem Ph,'s, 11 ( 1 943) 52 1 .
Flory P J , in Principals of Polymer Chemistr,l' (Cornell University Press, Itchaca, NY) 1 953 .
Flory P J , Macromolecules, 1 2 ( 1 979) 1 1 9.
Erman B & Flory P J, Macromolecules, 15 ( 1 982) 806,
Edwards S F & Vilgis Th, Pol\,mer, 27 ( 1 986) 483,
Alfrey T, Gurnee E F & Lloyd W G, .I Polym Sci, C 12 ( 1 966) 249.
Davidson G W R & Peppas N A, .I Cont ReI, 3 ( 1 986) 243,
Thomas N L & Windle A H, Polymer, 21 ( 1 980) 6 1 3 .
Crank J, in The Mathematics of Diffusion, 2nd ed (Oxford University Press, Oxford) 1 975, Chap, I I ,
Park G S, in Diffusioll in Polymers, edited by J Crank and G S Park (Academic Press) 1 968, Chap. 2.
Tanaka T & Fi l lmore 0 J , .I Chem Ph),s, 711 ( 1 979) 1 2 1 4,
Shiroya, T, Tamura N, Yasui M , Fuj imoto K & Kawaguchi H , Colloids Sill/. B 4 ( 1 995) 267.
Eichenbaum G M, Kiser P F, S imon S A & Needhol11 0, Macromolecules, 31 ( 1 998) 5084.
Yoshida R, Ichijo H , Hakuta T & Yamaguchi T, Macl'OlI1ol Rapid Commu, 16 ( 1 995) 305,
Lio K & Minoura N, Polym Cds Net, 5 ( 1 997) 3 1 7 ,
Geckelet K E, Zhou R, Fi nk A & Rivas B L, .I Appl POII'III
Sci, 60( 1 996) 2 1 9 1 .
Geckeler K E, Rivas B L & Zhou R, Angew Makcmll10l Chon,
197 ( 1 992) 1 07.
Rivas B L, Pooley S A. Soto M. M aturana H A & Gcckclcr K E, J Appl Polym Sci, 67 ( 1 998) 93.
Rivas B L, Maturana H A, Molina M J , Gomezanton & Pierula I F, J Appl PolYIIl Sci, 67 ( 1 998) 93.
Heitz C, Limbele W B & Biver C, .I Appl PolYIl1 Sci. 72
( 1 999) 455.
Budtova T & Navard P, Macromolecules, 31 ( 1 998) 81;45,
Ramraj B & Radhakrishnan G . .I Appl PolYII1 Sci, 52 ( 1 (94) 837.
Baj pai S K , Asian .I Chem, 10(4) ( 1 998) 964,
Ratna G V N, Mohan Rao 0 V & Chatterj i P R, J M S-PlIre Appl Chelll A, 33 (9)( 1 996) 1 1 99,
Torres-Lugo M & Peppas N A, Macmlllolecules, 32 ( 1 999) 6646.
Lee 0 H, Kim J W & Sub K 0, J Appl PolY1l1 Sci, 72
( 1 999) 1 305.
Dutta P K, Vishwanathan p, Mimort L & Ravi Kumar M N V, .I Po/ym Mater, 14 ( 1 997) 35 1 ,
Nakamae K, Nizuka T, Miyata T, Furukawa M , Nishino T, Kato K, I noue T, Hoffman A S & Kanzaki Y, .I Biol/wter Sci, Poly Edn, 9( I ) ( 1 997) 43,
Calkin R R & Jel l i nek J S, Perfil/llelT : Practise & Principals ( Wi ley, New York) 1 994,
462
42
43
44
45
46
47
48
49
50
5 1
52
53
54
55
56
57
58
59
60
6 1
J SCI IND RES VOL 60 JUNE 200 1
Dorl W E & Rogers J A (Jr), The Fragrance and Flavour
Industry (Dorland Co, Mendham, New Jersey) 1 977.
Peppas N A & Am Ende D J, J Appl Polym Sci, 66 ( 1 997) 509.
Kulkarni A R, Soppimath K S, Aminabhavi T M, Dave A M & Mehta M H , J Appl Polym Sci, 73 ( 1 999) 2437.
Smirnov V A, Sukhadolski G A, Phi l l ipova 0 E & Khokhlov A R, J Phys Chem B, 103 ( 1 999) 5084.
Karisson J 0 & Gatenhom P, Polymer, 40 ( 1 999) 379.
Klumb 1 A & Horbett T A, J Cont Rei, 27 ( 1 993) 95.
Schwartz M, Guterman H & Kost J, J Biomed Mater Res, 41
( 1 998) 65.
Siegel R A & Firestone B A, J COll t ReI, 1 1 ( 1 990) 1 8 1 .
Oli veira W D & Glasser W G , J Appl Polym Sci, 6 1 ( 1 996) 8 1 .
Pascual B , Castell ano L, Vazquez B , Gurruchaga M & Goni I , Polymer, 37 ( 1 996) 1 005.
Guan Y L, Shao L & Yao K D, J Appl Polym Sci, 61 ( 1 996) 2325.
Qu X, Wirsen A R & Albertsson A C, J Appl Polym Sci, 74
( 1 999) 3 1 86.
Gothoh T, Nakatasie Y & Sakohara S, J Appl Polym Sci, 69
( 1 998) 895.
Hirose H & Shibayama M, Macromolecules, 31 ( 1 6)( 1 998) 5336.
Kaneko Y, Nakamura S, Sakal K, Aojagi T, Kikuchi A, Sakuai Y & Okana T, Macromolecules, 31 ( 1 998) 6099.
Zhang J & Peppas N A, Macromolecules, 33 (2000) 1 02.
Kayaman N , Kazan D, Erarslan A, Okay 0 & Baysal B M, .l Appl Polym Sci, 67 ( 1 998) 805.
Snowden M J, Thomas D & Vincent B, Analyst, 118 ( 1 993) 1 367.
Karachashi H & Furusakis S, J Chem Eng Jpll, 26 ( 1 993) 89.
Liang L, Feng X & Rieke P C, J Appl Polym Sci, 72
( 1 999) I .
62
63
64
65
66
67
68
69
70
7 1
72
73
74
75
76
77
78
79
80
8 1
82
Stile R A, B urghardt W R & Healy K E, Macromolecules, 32 ( 1 999) 7370.
Yu H & Grainger D W, J Appl Polym Sci, 49 ( 1 993) 1 367.
Sakai M, Satoh N, Tsuji i K , Zhang Y & Tanaka T, Langllllir, 11 ( 1 995) 2493.
Zhang Y, & Tanaka T, Polym M(lfer Sci Eng, 66 ( 1 992) 369.
Polymer-SI./Ifaclant Systems : Swfaclallt Sciellce Series,
edited by J C Kwak (Marcel Dekker; New York) Vol 77,
1 998.
Murasae Y, Onda T, Tsuji i K & Tanaka T, Macromolecules, 32 ( 1 999) 8589.
Li C, Hu Z & Li Y, Ph),s Rev E, 48 ( 1 993) 603.
Hikmet R A M , Lub J & Higgins J A, Polymer, 34 ( 1 993) 1 736.
Wang C, Hu Z & Chen Y, Macromolecules, 32 ( 1 999) 1 822.
Sasaki S, Koga S & Maeda S, Macl'Omolecules, 32 ( 1 999) 46 1 9.
Ma J T, Liu L R, Yang X J & Yao K D, J Appl Pol)'1II Sci. S6
( 1 995) 73.
Shin H S , Kim S Y & Lee Y M , J Appl Pol)'1Il Sci, 6S ( 1 997) 685.
Kim S Y & Lee Y M, J Appl Polym Sci, 74 ( 1 999) 1 752.
Raman Rao G V, Konishi T & Ise N, MaclVmolecules, 32
( 1 999) 7582.
Lee K Y, Bouhadir K H & M ooney D J , Macromolecules, 33
(2000) 97.
Phi l ippova 0 E, Rulkens R, Kovtunko B I, Abramchuk S S, Khokhlov A R & Wegner G, Macromolecules, 31 ( 1 998) 1 1 68.
Bajpai S K, frail Polym J, 9 ( I ) (2000) 1 9.
Tanaka T, Sci Am, 244 ( 1 98 1 ) I I ()
Aoki T, Kawashima M , Katono H, Sanui K, Ogata N, Okano T & Sakurai Y, Macl'OmoleCitles, 27 ( 1 994) 947.
Miyata T, Jikihara A, Nakamae K, & Hoffman A.S, MaclrJlllol
Chem Ph),s, 197 ( 1 996) 1 1 35 .
Miyata T, Asami N & Uragami T, Macl'Omolecules, 32 ( 1 99 1 ) 2082.