- Email: [email protected]
Novel oscillating swelling-deswelling dynamic behaviour for pH-sensitive polymer gels
Materials Science and Engineering
C 4 ( 1996) 107-l 13
Novel oscillating swelling-deswelling dynamic behaviour for pHsensitive polymer gels Ryo Yoshida, Tomohiko Yamaguchi, Hisao Ichijo National Institute of Materials and Chemical Research, l-l, Higashi, Tsukuba, Ibaraki, 305 Japan Received 18 June 1995
Abstract Novel dynamics for polymer gel membranes demonstrating rhythmic swelling-deswelling oscillations were achieved by coupling temperature and pH-sensitive poly(N-isopropylacrylamide-co-acrylicacid-co-butyl methacrylate) gels with non-linear oscillating chemical reactions. In a pH-oscillating solution these gels exhibited a repetitive pulsatile mechanical motion with a constant period and amplitude similar to that of a heartbeat. The oscillating s,welling and deswelling kinetics of gels have been analysed theoretically for characteristic response times for gel swelling and deswelling and for external pH changes. The experimentally observed oscillation profiles are well simulated by superposition of theoretical equations modified by introduction of an external pH change to the intrinsic swelling4eswelling behaviour for the gels. The novel gel dynamics generating rhythmical pulsatile motion may create new possibilities for applying polymer gels as a functional materials that work under dynamic oscillating states similar to autonomous phenomena in living systems. Keywords:
Stimuli-responsive
pokymer; Poly(N-isopropylacrylamide-co-acrylic
1. Introduction Stimuli-responsive polymer hydrogels are a major interest in biomaterials and controlled release research. They have been widely studied for applications as artificial muscles (actuators) [ 1,2], intelligent delivery systems exhibiting onoff drug release and autofeedback dynamics [ 3-61 and bioseparations [ 7-101. Appropriate gel architectures have been investigated to optimize their applications [ 11,121. Recently, new gel types with comb structures have been developed to improve their swelling and: deswelling characteristics and dynamics [ 13,141. In these conventional systems using stimuli-responsive hydrogels, pulsatile (on-off) outputs, e.g. reversible changes in gel motion, surface properties, solute permeability and release rate, have been achieved by supplying pulsatile input as external stimuli, including electric fields [1,15], temperature [2-121 and pH changes [14,16,17]. Such systems generate output in response to external changes and are similar to some self-regulating functions in living systems. On the other hand, many natural physiological control systems maintain a dynamic control of physiological homeostasis under equilibrium conditions, manifested by rhythmic oscillations with a constant period, as represented by the autonomic heartbeat., brain waves, pulsatile potential of nerve cells, concentration changes in glycolysis and 24 h biorhythm cycles (circadihn rhythms). 0928-4931/96/$15.00 0 1996 Elsevier Science S.A. All rights reserved PIISO928-4931(96)00138-5
acid-co-butyl
methacrylate)
gel; pH-oscillating
reaction; CSTR
We have been exploring new gel systems similar to these physiological systems in which gels periodically repeat swelling and deswelling cycles under constant input and generate a pulsatile output [ 181. In particular, pulsatile mechanical motion similar to that of a heartbeat has been approximated by converting oscillating chemical reactions such as the Belousov-Zhabotinsky reaction [ 191 to mechanical volume changes with stimuli-responsive gels. These self-oscillating gel systems can function as new transducers, generating pulsatile signals from constant inputs, and may establish a new concept for functional materials that work under dynamic oscillating states similar to life’ systems. Applications to selfwalking actuators, new pacemakers and timers and drug delivery systems synchronized with human circadian rhythms are expected. Additionally, they may contribute to further understanding of biological and physical phenomena. Especially for controlled release drug therapies, pulsatile drug adminstration empirically can lead to better drug efficacy than continuous administration over long periods by avoiding drug tolerance and by matching the body’s release cycles of specific relevant peptides or hormones. In conventional stimuli-responsive systems designed to achieve pulsatile drug release, external stimuli are required as on-off switches. However, pulsatile drug release with preprogrammed release periods without external stimuli require-
108
R. Yoshida et al. /Materials Science and Engineering C 4 (1996) 107-113
ments could be achieved by self-oscillating gel systems. In the design of such oscillatory drug release devices of monolithic or membrane regulation types, gels are required to periodically repeat swelling and deswelling to reversibly change their diffusivity or permeability for drugs. Although the design concepts for these devices has been discussed [ 201, there have been no reports actually achieving novel gel oscillations nor analysing their dynamic behaviour. In a previous paper [ 181 we achieved gel swelling and deswelling self-oscillations using temperature- and pH-sensitive poly(N-isopropylacrylamide-co-acrylic acid) hydrogels by coupling the gels with a pH-oscillating reaction in a continuous flow stirred tank reactor (CSTR) . In these oscillating systems the mechanisms of cyclic swelling-deswelling changes for gels must be understood in order to control pulsatile output patterns. In this study the oscillation patterns of gels have been theoretically analysed by measuring the characteristic response time for gels and external pH changes. Oscillation kinetics have been compared with these theoretical simulations.
2. Experimental
details
2.1. Synthesis of cross-linked poly(IPAAm-co-AAc-coBMA) gels
attached pH 4.7 quickly changes
to one end was suspended in the buffer solution at (or 6.9) and equilibrated. The gel was transferred into the other buffer solution at pH 6.9 (or 4.7) and in gel length were monitored with a CCD camera.
2.3. Oscillations in gel length and pH A CSTR (volume 35 ml) was designed using a glass cell with a water jacket. Premixed solutions of sulphuric acid ( [H+]o=3.5X10-4 M), sodium sulphite ([SO:-],= 2.0X 10e3 M) and potassium hexacyanoferrate(I1) trihydrate ([Fe(CN)~-]c,=1.0X10-3 M) (all agents were obtained from Kanto Chemical Co., Inc., Tokyo) and pure hydrogen peroxide solution (Wako Pure Chemical Industries, Ltd., Osaka) ( [ H,OJO = 3.1 X low3 M) were continuously supplied to the reactor with a liquid chromatography pump at a constant flow rate (vi = Y*= 1.5 ml min-‘) (Fig. 1). Effluent was forced to overflow the top of the reactor. The pH changes in the reactor were monitored continuously with a pH meter (Model HM-12A, TOA Electronics Ltd., Tokyo). The rectangular gel membrane was suspended in the reactor and the dimensional changes of the gels were recorded on video tape with a CCD camera over the course of repeated gel swelling-deswelling. Gel oscillation profiles were generated from video image processing.
Purified N-isopropylacrylamide ( IPAAm) monomer (Eastman Kodak Co., Rochester, NY), purified acrylic acid ( AAc) (Wako Pure Chemical Industries, Ltd., Osaka), distilled butyl methacrylate (BMA) (Tokyo Kasei Kogyo Co., Ltd., Tokyo) ( IPAAm: AAc: BMA = 90:5:5 wt.%) and ethylene glycol dimethacrylate (EGDMA) (Nakarai Chemicals Ltd., Kyoto) (cross-linker 1.Omol%) were dissolved in purified 1,6dioxane (Kant0 Chemical Co., Inc., Tokyo) (1 ml per 1 g monomer) and bubbled with dry nitrogen gas for 15 min. t-Butyl peroxyoctanoate (BPO) (Nippon Oil and Fats Co., Ltd., Tsukuba) as an initiator (2.75 ~1 ml-‘) was added to the solution and then the solution was injected between two Mylar sheets separated by a gasket spacer of 100 pm thickness and backed by glass plates. The solution was polymerized at 80 “C for 18 h. The cross-linked copolymer gel membrane was then washed in methanol-water mixtures by methods already reported [ 121.
3. Results and discussion
2.2. Swelling and deswelling measurements
and similarly for deswelling
Equilibrium swelling ratios were measured for the synthesized poly (IPAAm-co-AAc-co-BMA) gels in buffer solutions with various pH values (pH 3-5.5, potassium phthalate; pH 6-7, phosphate) at constant temperature. The gel swelling ratio is defined as the weight of adsorbed solution per weight of dried polymer disk ( W,,,,/ W,) . For measurement of swelling and deswelling kinetics the rectangular gel membrane (desiccated gel length 10 mm, width 1 mm, thickness 0.1 mm) with a weight (0.5 g)
3. I. Theoretical analysis of swelling and deswelling kinetics In aqueous solution, swelling kinetics of polymer gels in response to environmental changes are generally described by the diffusion equation for slab-type gels [ 2 11
-+1-g 0
8 ,,d_ (2”: 1)‘) “=,(2n+ l)‘,rr*
(1)
where ris the characteristic time of swelling given by T= 41*/ ( rr*D) . Eq. ( 1) can be reduced to a single exponential expression
42 1
+!-,, 0
Al 8 pb=;;iex
7
4
-;
t 1
(2)
(3)
These equations are derived from an assumption of constant boundary, i.e. stepwise environmental changes followed by time-independent conditions. Here, however, we consider that the external media condition does not change instantaneously. In the case that the surface condition changes with time exponentially, represented as C = Co exp( t/b), Fq ( 1) becomes [ 221
R. Yoshida et al. /Materials
Science and Engineering C 4 (1996)
107-113
109
Recorder
Na2S03 1K,,[Fe(CN)6].3H20 H2S04
+G
. . __ :7-l pump
Monitor
’ Weinht
‘Gel
.._.J...
[I
CSTR (volume : 35ml) 1 Video printer Fig.
I, Continuous monitoring system for oscillations in both medium pH and gel length in a CSTR.
(4) When b = w, the surface condition changes instantaneously to C, and Eq. (4) becomes Eq. (1). 3.2. pH-oscillating
pattern
Non-linear chemical systems generating pH oscillations have been produced using a closed batch reactor and a CSTR
z
6
-
and the oscillation mechanisms have been investigated in detail [ 23-261. In the CSTR consisting of Fe( CN)i-, H202 and HzS04, hydrogen sulphite ions are oxidized by hydrogen peroxide with production of hydrogen ions, while hexacyanoferrate( II) ions are oxidized by hydrogen peroxide with consumption of hydrogen ions [ 231. Under certain conditions the production and consumption of hydrogen ions occur at comparable rates, generating pH oscillations in the reactor with a constant amplitude and period. The amplitude and period depend on feed concentration, flow rate and temperature [ 241. Fig. 2 shows a typical pH-changing pattern for one cycle of continuous oscillation at 22 “C. Here the pH oscillates with a period of 8 min and a ApH amplitude between 4.7 and 6.9. For analysis of the characteristics for pH changes, the pulsatile pattern was separated into two regions - pH increase (a) and pH decrease (b) - and each curve was approximated by the equation APH
-=A
AP%
lp 5
4
-
I
I
I
1
I
I
I
I I I I
I
I , I
I
4-w
1 min Time [min] Fig. 2. Typical pulsatile pattern for pH oscillations
in a CSTR at 22 “C.
exp $ 0
(5)
where ApH is the absolute difference between the initial pH and the pH after time t and ApHo is the overall pH amplitude (i.e. 6.9 - 4.7 = 2.2). The factor b expresses the characteristic times for pH changes related to experimental conditions. Curve fitting by a least-squares method yields b values of 1.12 min (r=0.991) and 0.286 min (r=0.988) for pH increase and decrease respectively.
R. Yoshidu et ul. /Materials
110
2
3
4
5 PH
6
7
Science und Engineering C 4 (1996) 107-113
8
[_I
Fig. 3. pH dependence of equilibrium swelling ratio for poly( IPAAm-coAAc-co-BMA) gels at a con&t temperature of 22 “C.
1.0 0.8
changes at lower critical solution temperature (LCST, 32 “C) [ 5,271. By incorporating AAc into PIPAAm as a copolymer, the LCST varies depending on the external pH [ 161. At higher pH the LCST shifts to higher temperature owing to ionization and electrostatic repulsion between anionic AAc carboxylate groups. At lower pH, however, the LCST shifts to lower temperature owing to polymer interactions enhanced by hydrogen bonding between protonated AAc carboxyl groups. As a result, at a certain constant temperature the gels undergo substantial swellingdeswelling changes in response to external pH changes. Fig. 3 shows the pH dependence of the gel equilibrium swelling ratio for our synthesized poly (IPPAAm-co-AAc-co-BMA) gels at 22 “C. Our hydrogels include a small amount of hydrophobic BMA to increase their mechanical strength; however, their pH sensitivity is maintained. The gel phase transition occurs near pH 4.0 and swelling increases with an increase in external pH. For stepwise pH changes, gels swell or deswell with their intrinsic time response as expressed by Eq. ( 1) . The gel swelling and deswelling kinetics after stepwise pH increases from 4.7 to 6.9 and stepwise pH decreases from 6.9 to 4.7 are demonstrated in Fig. 4 and Fig. 5 respectively. From Eq. (2) and Eq. (3) the characteristic time of swelling or deswelling, T, can be calculated from the slope of the semilogarithmic plots (lower part in each figure). The obtained rvalues for swelling
0.6
z 0.4
1.0
s :
0.8
c
0.6
s 5 ul
0.4
0.2 0.0 0 -1 -2 -3 -4 -5 0
0.5
1.0
1.5
2.0
Time [min] Fig. 4. Swelling kinetics of poly(IPAAm-co-AAc-co-BMA) gel in buffer solutions in response to stepwise pH changes from 4.7 to 6.9 at a constant temperature of 22 “C.
3.3. Swelling and deswelling responses to pH changes for poly(IPAAm-co-AAc-co-BMA) gels Poly(IPAAm) sitive properties,
gels are well known for their thermosenexhibiting dramatic swelling-deswelling
Time [min] Fig. 5. Deswelling kinetics of poly( IPAAm-co-AAc-co-BMA) gel in buffer solutions in response to stepwise pH changes from 6.9 to 4.7 at a constant temperature of 22 “C.
R. Yoshida et al. /Materi&
Science and Engineering C 4 (19%) 107-113
111
7
Fig. 6. Oscillations Table 1 Characteristic
in poly(IPAAm-co-AAc-co-BMA)
times for pH changes and swelling-deswelling
From pH 4.7 to 6.9 From pH 6.9 to 4.7
gel length (upper)
changes of gel
b (min)
r(min)
1.12 0.286
0.399 2.72
1.0
z ;
0.8
‘;;
$ s
0.2
5 0.0 0
12
3
4
5
60
and pH (lower) in an oscillating
CSTB at 22 “C.
gels demonstrate rhythmic swelling and deswelling changes synchronized with the pH oscillation. In contrast with the observed asymmetric pulsatile pattern for pH changes, the gel oscillation profiles are symmetric, similar to a trigonometric function. Even though the pH only increases gradually after a sharp decrease to the minimum value in each cycle, the gel still continues to shrink as long as the rate of pH increase is slow at each initial stage. After the sharp pH decrease a time of about 3 min is required for the gel length to exhibit a minimum value. This delay may be attributed to the longer response time characteristic of gel deswelling. Since the pH gradient is small at the initial stage of each pH increase, it is suggested that gel deswelling exhibits the same behaviour as that in response to stepwise pH decrease. The theoretical curves calculated from Eq. (4) using estimated b and rvalues (Table 1) are demonstrated in Fig. 7. In the pHincreasing region (a), calculated values for Eq. ( 1) based on characteristic deswelling responses are shown in addition to those for Eq. (4) which express the swelling kinetics synchronized with the external pH changes. In this region these
1
Time [min] Fig. 7. Theoretical curves calculated from Eqs. (1) and (4) using obtained b and r values (see text and Table 1)
-
: Experimental
----
: Calculated
and deswelling are 0.339 min (I= 0.986) and 2.72 (r = 0.999) respectively (Table 1). Deswelling rates are much slower than swelling rates. Since a gel shrinks gradually from its surface inwards [ 4,5], a dense, collapsed polymer network that decreases the outward permeability of solvent is formed at the gel surface, retarding subsequent gel deswelling. 3.4. Analysis of swelling and deswelling oscillations
e
4
5 min Tlme [min]
Fig. 6 shows typical patterns for pH oscillation in the medium and corresponding gel dynamics in the CSTR. The
Fig. 8. Experimental deswelling.
and simulated oscillation patterns for gel swelling and
R. Yoshida et ul. /Materuls Science and Engineering C 4 (1996) 107-113
I12
two curves intersect at a time of 3.1 min, which agrees with the time for exhibiting minimum gel length by changing from gel deswelling to swelling observed in Fig. 6. By superimposing these theoretical curves, the swellingdeswelling oscillation profiles were simulated (Fig. 8). By introduction of Eq. ( 1) for deswelling, these curves become discontinuous at the boundary between pH-increasing and pH-decreasing regions. At the boundary the error also becomes larger, because the pH-changing profiles deviate from the exponential approximation. Therefore the superimposed curves, except for the boundary region (expressed by the bold broken curve in Fig. 8), may be treated as reasonable simulation approximations. The curve provides symmetric pulsatile patterns and closely simulates the observed experimental oscillation profiles, with good agreement for times exhibiting minima and maxima in gel length. In this study, periodic swelling+leswelling oscillations of polymer gels have been realized without applying pulsatile stimuli from the exterior. For these novel gel dynamics the oscillation pattern was simulated by using the theoretical equations with the characteristic response times for external pH changes as well as swelling~eswelling changes of gels. This theoretical analysis for oscillating kinetics will be applied for prediction of output patterns in the design of new devices utilizing self-oscillation of gels.
4. Conclusions Novel gel dynamics demonstrating periodic swellingdeswelling oscillations have been achieved under constant conditions without applying external pulsatile stimuli. This response is distinct from conventional stimuli-responsive gel dynamics, exhibiting only either swelling or deswelling in response to stepwise external stimuli. The oscillating swelling-deswelling kinetics have been analysed theoretically and the observed gel behaviours can be explained by model equations based on the characteristic response times for both external pH changes and gel swelling and deswelling.
Acknowledgements The authors gratefully acknowledge Associate Professor David W. Grainger, Department of Chemistry, Colorado State University, USA for valuable discussions.
Appendix b C CO
D
1 l0
A. Nomenclature
time constant of pH increase and decrease(s) polymer concentration (g cm-3) initial polymer concentration (g cmm3) diffusion coefficient of polymer network (cm* s-’ ) characteristic length of gel (cm) initial gel length (cm)
Al t 7 W HZ0
WP
change in gel length total change in gel length time(s) characteristic time of swelling and deswelling( weight of absorbed water (g) weight of dry gel (g)
s)
References [ 1] Y. Osada, H. Okuzaki and H. Hori, A polymer gel with electrically driven motility, Nurture, 355 ( 1992) 242-244. [2] R. Kishi, H. Ichijo and 0. Hirasa, Thermo-responsive devices using poly( vinyl methyl ether) hydrogels, J. Intell. Mnrer Sysr. Strucf., 4 (1993) 533-537. [3] J. Kost (ed.), Pulsed and Se&Regulated Drug Delivery, CRC Press, Boca Raton, FL, 1990. [4] R. Yoshida, K. Sakai, T. Okano and Y. Sakurai, Pulsatile drug delivery systems using hydrogels, A&. Drug Delivery Rev., I I ( 1993) 85-108. [5] T. Okano, Y.H. Bae, H. Jacobs and S.W. Kim, Thermally on-off switching polymers for drug permeation and release, J. Controlled Release, II ( 1990) 255-265. [6] R. Yoshida, Y. Kaneko. K. Sakai, T. Okano, Y. Sakurai, Y.H. Bae and S.W. Kim, Positive thermosensitive pulsatile drug release using negative thermosensitive hydrogels, J. Cortrrolled Release, 32 ( 1994) 97-102. [7] T. Okano, N. Yamada, H. Sakai and Y. Sakurai, A novel recovery system for cultured cells using plasma-treated polystyrene dishes grafted with poly(N-isopropylacrylamide), J. Biomed. Mater. Rex, 27 (1993) 1243-1251. [S] Y.G. Takei, T. Aoki. K. Sanui, N. Ogata. T. Okano and Y. Sakurai, Temperature-responsive bioconjugates. 2. Molecular design for temperature-modulated bioseparations, Bioconjug. Chem., 4 ( 1993) 341-346. [ 91 G. Chen and A.S. Hoffman, Synthesis of carboxylated poly( NIPAAm) oligomers and their application to form thermo-reversible polymerenzyme conjugates, J. B&rater. Sci. Polym. Edn., 5 (1993) 371-382. [ IO] M. Matsukata, Y. Takei, T. Aoki, K. Sanui, N. Ogata. Y. Sakurai and T. Okano, Temperature modulated solubility-activity alternations for poly(N-isopropylacryIamide)-iipase conjugates, I Biochem., f/6 ( 1994) 682-686. [ 1 I] T. Aoki, M. Kawashima. H. Katano, K. Sanui, N. Ogata, T. Okano and Y. Sakurai, Temperature-responsive interpenetrating polymer networks constructed with poly(acrylic acid) and poly(N,N’dimethylacrylamide), Macromolecules, 27 ( 1994) 947-952. [ 121 R. Yoshida, K. Sakai, T Okano and Y. Sakurai, Modulating the phase transition temperature and thermosensitivity in N-isopropylacrylamide copolymer gels, J. Biomarer. Sci. Polym. Edn., 6 ( 1994) S85-598. [ 13 ] R. Yoshida, K. Uchida, Y. Kaneko, K. Sakai, A. Kikuchi, Y. Sakurai and T. Okano, Comb-type grafted hydrogels with rapid de-swelling response to temperature changes, Nature, 374 ( 1995) 240-242. [ 141 G. Chen and AS. Hoffman, Graftcopolymers that exhibit temperatureinduced phase transitions over a wide range of pH, Nature, 373 ( 1995) 49-52. [ 151 I.C. Kwon, Y.H. Bae and S.W. Kim, Heparin release from polymer complex, J. ControlledRelease, 30 (1994) 155-159. [ 161 L.C. Dong and A.S. Hoffman, A novel approach for preparation of pH-sensitive hydrogels for enteric drug delivery, J. Controlled Release, 15 (1991) 141-152. [ 171 R.A. Siegle, M. Falamarzian, B.A. Firestone and B.C. Moxley, pHcontrolled release from hydrophobic/polyelectrolyte copolymer hydrogels, J. Controlled Release, 8 ( 1988) 179-182. [ 181 R. Yoshida, H. Ichijo, T. Hakuta and T. Yamaguchi, Self-oscillating swelling and deswelling of polymer gels, Macromol. Rapid Commun., 16(1995)305-310.
R. Yoshida et al. /Materials Science and Engineering
[ 191 R.J. Field and M. Burger teds.), [20]
[21] [22] [23 ]
Oscillurions and Traveling Waves in
Chemical Systems, Wiley, New York, 1985. R.A. Siegle and C.G. Pitt, A strategy for~oscillatory drug release. General scheme and simplified theory, J. Controlled Release, 33 (1995) 173-188. T. Tanaka and D.J. Fillmore, Kinetics of swelling of gels, J. Gem. Phys., 70 (1979) 121&1218. J. Crank. The Mathematics of Diffkion, Oxford University Press, London, 1975. G. Rabai, K. Kustin and I.R. Epstein, A systematically designed pH oscillator: the hydrogen peroxide-sulfite-ferrocyanide reaction in a continuous-tlow stirred tank reactor, J. Am. Chem. Sot., 1 I I (1989) 3870-3874.
C 4 (1996) 107-l 13
[24] Y. Mori and 1. Hanazaki,
113
Bifurcation
oscillation in the Fe(CN)i--H20,-H$O,
structure
of the chemical
system, J. Phys. Chem., 97
(1993) 7375-7378. 1251 M. Orban and 1.R. Epstein,
A new oscillator.
oscillatrons in the bromide-thiosulfate-phenol Chem., 99 (1995) 2358-2362.
Large-amplitude
pH
flow system, J. Phys.
L261 G. Rabai and M.T. Beck, High-amplitude hydrogen ion concentration oscillation in the iodate-thiosulfate-sulfite system under closed conditions, J. Phys. Chem., 92 (1988) 48314835.
[271M. Heskins, J.E. Guillet and E. James, Solution properties of poly(Nisopropylacrylamide), 1455.
f. Macromol.
SC;. Chew., A2 (1968)
1441-
C 4 ( 1996) 107-l 13
Novel oscillating swelling-deswelling dynamic behaviour for pHsensitive polymer gels Ryo Yoshida, Tomohiko Yamaguchi, Hisao Ichijo National Institute of Materials and Chemical Research, l-l, Higashi, Tsukuba, Ibaraki, 305 Japan Received 18 June 1995
Abstract Novel dynamics for polymer gel membranes demonstrating rhythmic swelling-deswelling oscillations were achieved by coupling temperature and pH-sensitive poly(N-isopropylacrylamide-co-acrylicacid-co-butyl methacrylate) gels with non-linear oscillating chemical reactions. In a pH-oscillating solution these gels exhibited a repetitive pulsatile mechanical motion with a constant period and amplitude similar to that of a heartbeat. The oscillating s,welling and deswelling kinetics of gels have been analysed theoretically for characteristic response times for gel swelling and deswelling and for external pH changes. The experimentally observed oscillation profiles are well simulated by superposition of theoretical equations modified by introduction of an external pH change to the intrinsic swelling4eswelling behaviour for the gels. The novel gel dynamics generating rhythmical pulsatile motion may create new possibilities for applying polymer gels as a functional materials that work under dynamic oscillating states similar to autonomous phenomena in living systems. Keywords:
Stimuli-responsive
pokymer; Poly(N-isopropylacrylamide-co-acrylic
1. Introduction Stimuli-responsive polymer hydrogels are a major interest in biomaterials and controlled release research. They have been widely studied for applications as artificial muscles (actuators) [ 1,2], intelligent delivery systems exhibiting onoff drug release and autofeedback dynamics [ 3-61 and bioseparations [ 7-101. Appropriate gel architectures have been investigated to optimize their applications [ 11,121. Recently, new gel types with comb structures have been developed to improve their swelling and: deswelling characteristics and dynamics [ 13,141. In these conventional systems using stimuli-responsive hydrogels, pulsatile (on-off) outputs, e.g. reversible changes in gel motion, surface properties, solute permeability and release rate, have been achieved by supplying pulsatile input as external stimuli, including electric fields [1,15], temperature [2-121 and pH changes [14,16,17]. Such systems generate output in response to external changes and are similar to some self-regulating functions in living systems. On the other hand, many natural physiological control systems maintain a dynamic control of physiological homeostasis under equilibrium conditions, manifested by rhythmic oscillations with a constant period, as represented by the autonomic heartbeat., brain waves, pulsatile potential of nerve cells, concentration changes in glycolysis and 24 h biorhythm cycles (circadihn rhythms). 0928-4931/96/$15.00 0 1996 Elsevier Science S.A. All rights reserved PIISO928-4931(96)00138-5
acid-co-butyl
methacrylate)
gel; pH-oscillating
reaction; CSTR
We have been exploring new gel systems similar to these physiological systems in which gels periodically repeat swelling and deswelling cycles under constant input and generate a pulsatile output [ 181. In particular, pulsatile mechanical motion similar to that of a heartbeat has been approximated by converting oscillating chemical reactions such as the Belousov-Zhabotinsky reaction [ 191 to mechanical volume changes with stimuli-responsive gels. These self-oscillating gel systems can function as new transducers, generating pulsatile signals from constant inputs, and may establish a new concept for functional materials that work under dynamic oscillating states similar to life’ systems. Applications to selfwalking actuators, new pacemakers and timers and drug delivery systems synchronized with human circadian rhythms are expected. Additionally, they may contribute to further understanding of biological and physical phenomena. Especially for controlled release drug therapies, pulsatile drug adminstration empirically can lead to better drug efficacy than continuous administration over long periods by avoiding drug tolerance and by matching the body’s release cycles of specific relevant peptides or hormones. In conventional stimuli-responsive systems designed to achieve pulsatile drug release, external stimuli are required as on-off switches. However, pulsatile drug release with preprogrammed release periods without external stimuli require-
108
R. Yoshida et al. /Materials Science and Engineering C 4 (1996) 107-113
ments could be achieved by self-oscillating gel systems. In the design of such oscillatory drug release devices of monolithic or membrane regulation types, gels are required to periodically repeat swelling and deswelling to reversibly change their diffusivity or permeability for drugs. Although the design concepts for these devices has been discussed [ 201, there have been no reports actually achieving novel gel oscillations nor analysing their dynamic behaviour. In a previous paper [ 181 we achieved gel swelling and deswelling self-oscillations using temperature- and pH-sensitive poly(N-isopropylacrylamide-co-acrylic acid) hydrogels by coupling the gels with a pH-oscillating reaction in a continuous flow stirred tank reactor (CSTR) . In these oscillating systems the mechanisms of cyclic swelling-deswelling changes for gels must be understood in order to control pulsatile output patterns. In this study the oscillation patterns of gels have been theoretically analysed by measuring the characteristic response time for gels and external pH changes. Oscillation kinetics have been compared with these theoretical simulations.
2. Experimental
details
2.1. Synthesis of cross-linked poly(IPAAm-co-AAc-coBMA) gels
attached pH 4.7 quickly changes
to one end was suspended in the buffer solution at (or 6.9) and equilibrated. The gel was transferred into the other buffer solution at pH 6.9 (or 4.7) and in gel length were monitored with a CCD camera.
2.3. Oscillations in gel length and pH A CSTR (volume 35 ml) was designed using a glass cell with a water jacket. Premixed solutions of sulphuric acid ( [H+]o=3.5X10-4 M), sodium sulphite ([SO:-],= 2.0X 10e3 M) and potassium hexacyanoferrate(I1) trihydrate ([Fe(CN)~-]c,=1.0X10-3 M) (all agents were obtained from Kanto Chemical Co., Inc., Tokyo) and pure hydrogen peroxide solution (Wako Pure Chemical Industries, Ltd., Osaka) ( [ H,OJO = 3.1 X low3 M) were continuously supplied to the reactor with a liquid chromatography pump at a constant flow rate (vi = Y*= 1.5 ml min-‘) (Fig. 1). Effluent was forced to overflow the top of the reactor. The pH changes in the reactor were monitored continuously with a pH meter (Model HM-12A, TOA Electronics Ltd., Tokyo). The rectangular gel membrane was suspended in the reactor and the dimensional changes of the gels were recorded on video tape with a CCD camera over the course of repeated gel swelling-deswelling. Gel oscillation profiles were generated from video image processing.
Purified N-isopropylacrylamide ( IPAAm) monomer (Eastman Kodak Co., Rochester, NY), purified acrylic acid ( AAc) (Wako Pure Chemical Industries, Ltd., Osaka), distilled butyl methacrylate (BMA) (Tokyo Kasei Kogyo Co., Ltd., Tokyo) ( IPAAm: AAc: BMA = 90:5:5 wt.%) and ethylene glycol dimethacrylate (EGDMA) (Nakarai Chemicals Ltd., Kyoto) (cross-linker 1.Omol%) were dissolved in purified 1,6dioxane (Kant0 Chemical Co., Inc., Tokyo) (1 ml per 1 g monomer) and bubbled with dry nitrogen gas for 15 min. t-Butyl peroxyoctanoate (BPO) (Nippon Oil and Fats Co., Ltd., Tsukuba) as an initiator (2.75 ~1 ml-‘) was added to the solution and then the solution was injected between two Mylar sheets separated by a gasket spacer of 100 pm thickness and backed by glass plates. The solution was polymerized at 80 “C for 18 h. The cross-linked copolymer gel membrane was then washed in methanol-water mixtures by methods already reported [ 121.
3. Results and discussion
2.2. Swelling and deswelling measurements
and similarly for deswelling
Equilibrium swelling ratios were measured for the synthesized poly (IPAAm-co-AAc-co-BMA) gels in buffer solutions with various pH values (pH 3-5.5, potassium phthalate; pH 6-7, phosphate) at constant temperature. The gel swelling ratio is defined as the weight of adsorbed solution per weight of dried polymer disk ( W,,,,/ W,) . For measurement of swelling and deswelling kinetics the rectangular gel membrane (desiccated gel length 10 mm, width 1 mm, thickness 0.1 mm) with a weight (0.5 g)
3. I. Theoretical analysis of swelling and deswelling kinetics In aqueous solution, swelling kinetics of polymer gels in response to environmental changes are generally described by the diffusion equation for slab-type gels [ 2 11
-+1-g 0
8 ,,d_ (2”: 1)‘) “=,(2n+ l)‘,rr*
(1)
where ris the characteristic time of swelling given by T= 41*/ ( rr*D) . Eq. ( 1) can be reduced to a single exponential expression
42 1
+!-,, 0
Al 8 pb=;;iex
7
4
-;
t 1
(2)
(3)
These equations are derived from an assumption of constant boundary, i.e. stepwise environmental changes followed by time-independent conditions. Here, however, we consider that the external media condition does not change instantaneously. In the case that the surface condition changes with time exponentially, represented as C = Co exp( t/b), Fq ( 1) becomes [ 221
R. Yoshida et al. /Materials
Science and Engineering C 4 (1996)
107-113
109
Recorder
Na2S03 1K,,[Fe(CN)6].3H20 H2S04
+G
. . __ :7-l pump
Monitor
’ Weinht
‘Gel
.._.J...
[I
CSTR (volume : 35ml) 1 Video printer Fig.
I, Continuous monitoring system for oscillations in both medium pH and gel length in a CSTR.
(4) When b = w, the surface condition changes instantaneously to C, and Eq. (4) becomes Eq. (1). 3.2. pH-oscillating
pattern
Non-linear chemical systems generating pH oscillations have been produced using a closed batch reactor and a CSTR
z
6
-
and the oscillation mechanisms have been investigated in detail [ 23-261. In the CSTR consisting of Fe( CN)i-, H202 and HzS04, hydrogen sulphite ions are oxidized by hydrogen peroxide with production of hydrogen ions, while hexacyanoferrate( II) ions are oxidized by hydrogen peroxide with consumption of hydrogen ions [ 231. Under certain conditions the production and consumption of hydrogen ions occur at comparable rates, generating pH oscillations in the reactor with a constant amplitude and period. The amplitude and period depend on feed concentration, flow rate and temperature [ 241. Fig. 2 shows a typical pH-changing pattern for one cycle of continuous oscillation at 22 “C. Here the pH oscillates with a period of 8 min and a ApH amplitude between 4.7 and 6.9. For analysis of the characteristics for pH changes, the pulsatile pattern was separated into two regions - pH increase (a) and pH decrease (b) - and each curve was approximated by the equation APH
-=A
AP%
lp 5
4
-
I
I
I
1
I
I
I
I I I I
I
I , I
I
4-w
1 min Time [min] Fig. 2. Typical pulsatile pattern for pH oscillations
in a CSTR at 22 “C.
exp $ 0
(5)
where ApH is the absolute difference between the initial pH and the pH after time t and ApHo is the overall pH amplitude (i.e. 6.9 - 4.7 = 2.2). The factor b expresses the characteristic times for pH changes related to experimental conditions. Curve fitting by a least-squares method yields b values of 1.12 min (r=0.991) and 0.286 min (r=0.988) for pH increase and decrease respectively.
R. Yoshidu et ul. /Materials
110
2
3
4
5 PH
6
7
Science und Engineering C 4 (1996) 107-113
8
[_I
Fig. 3. pH dependence of equilibrium swelling ratio for poly( IPAAm-coAAc-co-BMA) gels at a con&t temperature of 22 “C.
1.0 0.8
changes at lower critical solution temperature (LCST, 32 “C) [ 5,271. By incorporating AAc into PIPAAm as a copolymer, the LCST varies depending on the external pH [ 161. At higher pH the LCST shifts to higher temperature owing to ionization and electrostatic repulsion between anionic AAc carboxylate groups. At lower pH, however, the LCST shifts to lower temperature owing to polymer interactions enhanced by hydrogen bonding between protonated AAc carboxyl groups. As a result, at a certain constant temperature the gels undergo substantial swellingdeswelling changes in response to external pH changes. Fig. 3 shows the pH dependence of the gel equilibrium swelling ratio for our synthesized poly (IPPAAm-co-AAc-co-BMA) gels at 22 “C. Our hydrogels include a small amount of hydrophobic BMA to increase their mechanical strength; however, their pH sensitivity is maintained. The gel phase transition occurs near pH 4.0 and swelling increases with an increase in external pH. For stepwise pH changes, gels swell or deswell with their intrinsic time response as expressed by Eq. ( 1) . The gel swelling and deswelling kinetics after stepwise pH increases from 4.7 to 6.9 and stepwise pH decreases from 6.9 to 4.7 are demonstrated in Fig. 4 and Fig. 5 respectively. From Eq. (2) and Eq. (3) the characteristic time of swelling or deswelling, T, can be calculated from the slope of the semilogarithmic plots (lower part in each figure). The obtained rvalues for swelling
0.6
z 0.4
1.0
s :
0.8
c
0.6
s 5 ul
0.4
0.2 0.0 0 -1 -2 -3 -4 -5 0
0.5
1.0
1.5
2.0
Time [min] Fig. 4. Swelling kinetics of poly(IPAAm-co-AAc-co-BMA) gel in buffer solutions in response to stepwise pH changes from 4.7 to 6.9 at a constant temperature of 22 “C.
3.3. Swelling and deswelling responses to pH changes for poly(IPAAm-co-AAc-co-BMA) gels Poly(IPAAm) sitive properties,
gels are well known for their thermosenexhibiting dramatic swelling-deswelling
Time [min] Fig. 5. Deswelling kinetics of poly( IPAAm-co-AAc-co-BMA) gel in buffer solutions in response to stepwise pH changes from 6.9 to 4.7 at a constant temperature of 22 “C.
R. Yoshida et al. /Materi&
Science and Engineering C 4 (19%) 107-113
111
7
Fig. 6. Oscillations Table 1 Characteristic
in poly(IPAAm-co-AAc-co-BMA)
times for pH changes and swelling-deswelling
From pH 4.7 to 6.9 From pH 6.9 to 4.7
gel length (upper)
changes of gel
b (min)
r(min)
1.12 0.286
0.399 2.72
1.0
z ;
0.8
‘;;
$ s
0.2
5 0.0 0
12
3
4
5
60
and pH (lower) in an oscillating
CSTB at 22 “C.
gels demonstrate rhythmic swelling and deswelling changes synchronized with the pH oscillation. In contrast with the observed asymmetric pulsatile pattern for pH changes, the gel oscillation profiles are symmetric, similar to a trigonometric function. Even though the pH only increases gradually after a sharp decrease to the minimum value in each cycle, the gel still continues to shrink as long as the rate of pH increase is slow at each initial stage. After the sharp pH decrease a time of about 3 min is required for the gel length to exhibit a minimum value. This delay may be attributed to the longer response time characteristic of gel deswelling. Since the pH gradient is small at the initial stage of each pH increase, it is suggested that gel deswelling exhibits the same behaviour as that in response to stepwise pH decrease. The theoretical curves calculated from Eq. (4) using estimated b and rvalues (Table 1) are demonstrated in Fig. 7. In the pHincreasing region (a), calculated values for Eq. ( 1) based on characteristic deswelling responses are shown in addition to those for Eq. (4) which express the swelling kinetics synchronized with the external pH changes. In this region these
1
Time [min] Fig. 7. Theoretical curves calculated from Eqs. (1) and (4) using obtained b and r values (see text and Table 1)
-
: Experimental
----
: Calculated
and deswelling are 0.339 min (I= 0.986) and 2.72 (r = 0.999) respectively (Table 1). Deswelling rates are much slower than swelling rates. Since a gel shrinks gradually from its surface inwards [ 4,5], a dense, collapsed polymer network that decreases the outward permeability of solvent is formed at the gel surface, retarding subsequent gel deswelling. 3.4. Analysis of swelling and deswelling oscillations
e
4
5 min Tlme [min]
Fig. 6 shows typical patterns for pH oscillation in the medium and corresponding gel dynamics in the CSTR. The
Fig. 8. Experimental deswelling.
and simulated oscillation patterns for gel swelling and
R. Yoshida et ul. /Materuls Science and Engineering C 4 (1996) 107-113
I12
two curves intersect at a time of 3.1 min, which agrees with the time for exhibiting minimum gel length by changing from gel deswelling to swelling observed in Fig. 6. By superimposing these theoretical curves, the swellingdeswelling oscillation profiles were simulated (Fig. 8). By introduction of Eq. ( 1) for deswelling, these curves become discontinuous at the boundary between pH-increasing and pH-decreasing regions. At the boundary the error also becomes larger, because the pH-changing profiles deviate from the exponential approximation. Therefore the superimposed curves, except for the boundary region (expressed by the bold broken curve in Fig. 8), may be treated as reasonable simulation approximations. The curve provides symmetric pulsatile patterns and closely simulates the observed experimental oscillation profiles, with good agreement for times exhibiting minima and maxima in gel length. In this study, periodic swelling+leswelling oscillations of polymer gels have been realized without applying pulsatile stimuli from the exterior. For these novel gel dynamics the oscillation pattern was simulated by using the theoretical equations with the characteristic response times for external pH changes as well as swelling~eswelling changes of gels. This theoretical analysis for oscillating kinetics will be applied for prediction of output patterns in the design of new devices utilizing self-oscillation of gels.
4. Conclusions Novel gel dynamics demonstrating periodic swellingdeswelling oscillations have been achieved under constant conditions without applying external pulsatile stimuli. This response is distinct from conventional stimuli-responsive gel dynamics, exhibiting only either swelling or deswelling in response to stepwise external stimuli. The oscillating swelling-deswelling kinetics have been analysed theoretically and the observed gel behaviours can be explained by model equations based on the characteristic response times for both external pH changes and gel swelling and deswelling.
Acknowledgements The authors gratefully acknowledge Associate Professor David W. Grainger, Department of Chemistry, Colorado State University, USA for valuable discussions.
Appendix b C CO
D
1 l0
A. Nomenclature
time constant of pH increase and decrease(s) polymer concentration (g cm-3) initial polymer concentration (g cmm3) diffusion coefficient of polymer network (cm* s-’ ) characteristic length of gel (cm) initial gel length (cm)
Al t 7 W HZ0
WP
change in gel length total change in gel length time(s) characteristic time of swelling and deswelling( weight of absorbed water (g) weight of dry gel (g)
s)
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