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Preparation and swelling studies of biocompatible hydrogel systems by using gamma radiation-induced polymerization
ARTICLE IN PRESS
Radiation Physics and Chemistry 72 (2005) 483–488
Preparation and swelling studies of biocompatible hydrogel systems by using gamma radiation-induced polymerization Hatice Kaplan Can, Betul Kirci Denizli*, Serap Kavlak, Ali Guner Faculty of Science, Department of Chemistry, Hacettepe University, Beytepe, Ankara TR-06532, Turkey Received 3 October 2003; accepted 14 December 2003
Abstract Hydrogels with varying cross-linking densities and average molecular weights between two consecutive cross-links were prepared from the binary poly(N-vinyl-2-pyrrolidone)/water and ternary poly(N-vinyl-2-pyrrolidone)/water/ K2S2O8 systems by irradiation with g rays at ambient temperature. Both hydrogel systems were employed for diffusion and swelling experiments in 0.1 g/100 ml Bovine Serum Albumin (BSA) solution at room temperature. Diffusion of BSA solution into hydrogels has been found to be of the Fickian type. The percent swelling, equilibrium swelling, initial rate of swelling, swelling rate of constant, equilibrium water/BSA content, and diffusion constant values were evaluated for PVP and PVP/K2S2O8 hydrogel systems at 0.1 g/100 ml BSA solution. r 2004 Elsevier Ltd. All rights reserved. Keywords: Bovine serum albumin (BSA); Hydrogels; g-irradiation; Poly(N-vinyl-2-pyrrolidone); Swelling
1. Introduction Hydrogels are water swollen polymer networks of either natural or synthetic origin; of these, it is the crosslinked covalently bonded synthetic hydrogels that have grown most dramatically in use. Hydrogels maybe sensitive to their environment and their structure may change according to the conditions around them. The interaction of polymers with blood and body fluids is of interest because of their high potential in the production of biomaterials. Many hydrogels obtained from synthetic polymers display good biocompatibility that can be used for drug delivery systems (Hoffman, 2002). Charlesby and Alexander (1955), first reported crosslinking of poly(N-vinyl-2-pyrrolidone) (PVP) under irradiation of aqueous solutions. Many researchers investigated gel formation in irradiated solutions of PVP in later studies. Chapiro and Legris (1985, 1986) *Corresponding author. Tel.: +90-312-2976448; fax: +90312-2992163. E-mail address: [email protected] (B.K. Denizli).
studied the effect of radiation dose, molecular weight, polymer concentration, and the influence of the nature of the solvent on cross-linking of PVP. Recently, the effects of radiation on the conversion of monomer and gelation of polymer (Darwis et al., 1993), the gelation of PVP in the presence of agar and poly(ethylene oxide) (PEO) (Hilmy et al., 1993), preparation of PVP hydrogels in the presence of cross-linking agents (ethylene glycol dimethacrylate and trimethyolpropane triacrylate) (Guven . and S- en, 1993) were studied and various characteristics (gelation dose, degree of swelling, equilibrium water content, elongation at break, tensile strength, diffusion behavior, etc.) of PVP hydrogels were evaluated. Water-soluble polymers, PEO, dextran, and PVP are known to form association complexes in aqueous solutions. Obviously, different types of additives (inorganic and organic cosolutes) can change molecular association already existing between polymer and solvent molecules. Previously, the effects of inorganic salts on dynamic and thermodynamic properties of PVP (Guner . and Ataman, 1994; Guner, . 1997) and the effects of special organic cosolutes on ifferent solution
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properties of PVP (Kırcı and Guner, . 2001, 2002; Kavlak and Guner, . 2000) were studied in aqueous solutions. These studies revealed that the dynamic and thermodynamic behavior of water-soluble PVP mainly depends on the nature of cosolute and the temperature. Persulfate anion has a different behavior on PVP and its monomer. It is commonly known that the persulfate anion is an initiator for the polymerization of vinyl type monomers and exhibits a more distinguished behavior than the other initiatiors (Senaglos and Thomas, 1979). Another unusual behavior is the effect of persulfate anion on the polymer chain structure in aqueous solutions. Two different trends; that is, cross-linking and chain scission of PVP, can be observed in aqueous solutions of polymer in the presence of persulfate anion, depending on the content of persulfate in the mixture (Anderson et al., 1979; Tenhu and Sundolm, 1984). In addition, some other reactions, oxidative degradation and ring opening lactam ring were also proposed by the same research groups. The interaction mechanism of persulfate anion with PVP chains has not been explained until now. Recent studies have revealed that significant changes occur in the hydrodynamic volume of PVP, which may be interpreted by probable chain scission in the polymer chain in the presence of persulfate anion (Tenhu and Sundolm, 1984). This observation is also supported by the gelation of PVP in aqueous solutions in the presence of different concentrations of persulfate (Kaplan Can and Guner, . submitted). Serum albumin is the most abundant protein in the circulatory system, accounting for 60% of the total serum albumin. Its principal function is to transport fatty acids, a great variety of metabolites and drugs such as anti-coagulants, transquilizers and general anesthetics. Bovine serum albumin (BSA) displays approximately 76% sequence homology and a repeating pattern of disulfides which are strictly conserved: the molecular weight is 66267 g/mol for BSA. In our previous studies, average molecular weights between two consecutive cross-links (Mc ) for PVP and PVP/K2S2O8 hydrogel systems and swelling of water (Kaplan and Guner, . 2000a), urea (Kaplan and Guner, . 2000b), lactose (Kaplan Can et al., 2003a) and some textile dyes (Kaplan Can et al., 2003b) by PVP and PVP/ K2S2O8 hydrogels have been investigated. In this study, the effect of BSA solution on swelling characteristics of PVP and PVP/K2S2O8 hydrogels has been investigated.
weight of 700,000 g mol1. The weight average molecular weight of sample was determined from light scattering measurements in chloroform at 30 C by Brice-Phoenix Light Scattering Photometer, 2000 series. The specifications of instrument and determined characteristics and second virial coefficient, root-meansquare, radius of gyration were reported previously (Guner . and Ataman, 1994). The interpretation of light scattering data was based on the Zimm method. It has a weight average molecular weight of 548,000 g mol1. Potassium persulfate (K2S2O8) was obtained from Merck and BSA was obtained from BDH. K2S2O8 and BSA were of analytical grade and were used without further purification. Deionized and double-distilled water was used for the preparation of BSA solution.
2. Experimental
S% ¼ ½ðMt M0 Þ=M0 100;
2.1. Chemicals
where M0 is the initial weight and Mt is the weight of swollen gel at time, t: In this study, measurements have been achieved at optimum BSA concentration.
The PVP sample used in this study was obtained from British Drug House (BDH) with nominal molecular
2.2. Preparation of hydrogels Aqueous solutions of PVP (6%) and PVP aqueous solutions containing 4% K2S2O8 were prepared using double distilled deionized water. The prepared polymer solutions (PVP/water and PVP/water/K2S2O8) were then placed in PVC straws and irradiated with a dose of 26, 64, 96, and 124 kGy in air at ambient temperature in a Gamma Cell 220 type 60Co g irradiator at a fixed dose rate of 0.40 kGy h1, the radiation dose being determined by Fricke dosimeter previously. The PVP/ K2S2O8 ratio value and the irradiation doses mentioned previously were preferable since the exact cylindrical geometry of the gels had been obtained under these optimum conditions. 2.3. Measurement of swelling Cross-linked PVP samples have been obtained in long cylindrical shapes cut into pieces B0.5 cm long and stored for later studies. Gels thus prepared were immersed in distilled water for a week to remove uncross-linked polymers and low molecular-weight substances, and dried to constant weight. Dried hydrogels were left in BSA solutions at room temperature (20 C) and they were removed from the BSA solutions. After a certain time, they are weighed and placed in the same solutions. The percentage swelling (S) was determined gravimetrically by the following equation: ð1Þ
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3. Results and discussion 3.1. Swelling A fundamental relationship exists between the swelling of a cross-linked polymer in a solvent and the nature of the polymer and solvent. Swelling of the cross-linked polymers in the chosen and/or suitable solvent is the
26 kGy 64 kGy 96 kGy 124 kGy
1200
1000
% Swelling
800
600
400
200
PVP/(0.1g/100mL) BSA
0 0
100
200
300
400
500
Time (min) Fig. 1. Swelling percent values of PVP gels in 0.1 g/100 ml BSA solution at different radiation doses.
1400
26 kGy 64 kGy 96 kGy 124 kGy
1200
% Swelling
1000 800 600 400 200
PVP/K2S2O8 /(0.1g/100mL) BSA 0 0
100
200
300
400
Time (min) Fig. 2. Swelling percent values of PVP/ K2S2O8 gels in 0.1 g/ 100 ml BSA solution at different radiation doses.
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most important parameter (especially since one of the most important parameters is mass swelling) (Horkay and Zrinyi, 1998; Mencer and Gomzi, 1994) for swelling studies. The intake of initially dry hydrogels was followed for a long period of time in BSA solutions. Swelling curves of PVP and PVP/K2S2O8 hydrogels are plotted and representative swelling curves at 0.1 g/100 ml BSA solutions are shown in Figs. 1 and 2. As can be seen from these figures, swelling capabilities of PVP and PVP/K2S2O8, hydrogels are increased by time, reaching constant swelling (equilibrium swelling) after a certain period of time. Another observation is the swelling of the gels depend on the irradiation dose. It is obvious that increasing the total radiation dose increases the cross-linking density, resulting in lower maximum swelling percent. As shown in these curves (Figs. 1 and 2), the swelling capabilities of PVP and PVP/K2S2O8 hydrogels vary in the range 310–1300% in BSA solutions. In order to make a better comparison, the determined equilibrium swelling percentages are given in Table 1. It can be clearly seen that the highest swelling percentages are observed in the PVP/K2S2O8 hydrogel system. Before explanation of the swelling of hydrogels in the presence of BSA, it is better to discuss the effect of additives on the structure of water and interactions between polymer and solvent molecules. In the presence of K2S2O8, the cross-link density of the gel is decreasing. For this reason swelling behavior of the gel system bears in better. It is known that the Mark-Houwink exponent, a, depends on the nature of solvent, temperature, and the molecular weight of the polymer. At the theta temperature, a is equal to 0.50. This exponent has been found as 0.55 in the Mark-Houwink equation for the system PVP/H2O, which is close to 0.50, showing the characteristic of a theta solvent. It is obvious that the additives can change and /or disturb the hydrogenbonded structure of water and the molecular association of the water-soluble polymer in aqueous media, as well as the swelling behavior of cross-linked PVP chains (Kırcı and Guner, . 2001). In the presence of BSA, swelling of hydrogels can easily follow the change of the hydrogen-bonded structure of water and polymer–solvent interaction. Equilibrium swelling percentages were indicated as
Table 1 Equilibrium swelling (ES) and equilibrium BSA content (EC-BSA) values (%) of PVP and PVP/K2S2O8 hydrogels in 0.1 g/100 ml BSA solutions Dose (kGy)
ES (PVP)
ES(PVP/K2S2O8)
EC-BSA (PVP)
EC-BSA (PVP/K2S2O8)
26 64 96 124
1100 610 460 310
1300 700 520 440
91.8 86.5 83.4 77.5
92.9 87.9 85.2 84.2
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1300, 700, 600, and 500% for PVP/K2S2O8 hydrogel systems in water (Kaplan, 2000a). In the case of 0.1 g/ 100 ml of aqueous BSA solutions, these percentages are very close to the results with aqueous solutions such as 1300, 700, 520, and 440% for the same hydrogel system, respectively. In the higher cross-link density of gel system (96 and 124 kGy) swelling (%) value is lower than in water. This can be explained by the diffusion of high molecular weight BSA substance into hydrogel system. 3.2. Diffusion The swelling curves of PVP and PVP/K2S2O8 hydrogels in aqueous BSA solutions were used for the calculation of a certain diffusion characteristics. The following equation was used to determine the nature of diffusion of BSA solution into hydrogels (Crank, 1970): F ¼ Mt =MN ¼ ktn ;
where B ¼ 1=Seq is the reciprocal of the maximum or 2 equilibrium swelling, A ¼ 1=ðks Seq Þ is the reciprocal of the initial swelling rate of the gel (r1 ), and ks is the swelling rate constant. This relation represents second order kinetics (Peniche et al., 1998). Figs. 3 and 4 exhibit the linear regression of the swelling curves obtained by means of Eq. (3) for PVP and PVP/K2S2O8 hydrogels in 0.1 g/100 ml BSA solution. The initial rate of swelling (r1 ), swelling rate constant, and equilibrium swelling (or as commonly used, theoretical equilibrium swelling) of PVP and PVP/K2S2O8 hydrogels are calculated from the slope and intersection of the lines given in Table 3 both for hydrogel systems in 0.1 g/100 ml BSA solutions. The values of theoretical equilibrium swelling of the hydrogels are in good agreement with the results of equilibrium swelling of PVP and PVP/K2S2O8 hydrogels (Fig. 1). Swelling process of PVP/K2S2O8 hydrogels is
ð2Þ
140
where Mt MN denote the amount of BSA solution diffused into the gel at time, t; and infinite time (at equilibrium), respectively, k is a constant related to the structure of the network, and the exponent n is a numerical value to determine the type of diffusion. For a cylindrical shapes, np0:50 and corresponds to Fickian diffusion, whereas 0:50ono1:00 indicates that diffusion is non-Fickian (Frisch, 1980). Eq. (2) was applied to various stages of swelling and plots of ln F against ln t yielded straight lines from which the exponents n and k were calculated from the slope and intercept of the lines listed in Table 2 at 0.1 g/100 ml aqueous BSA solutions. It can be clearly seen from the table that the values of the diffusion exponent range between 0.305 and 0.446 and are known to be lower than 0.50. Hence, the diffusion of BSA solutions into PVP and PVP/K2S2O8, hydrogels was assumed to be Fickian in character. It can also be noticed from Table 2 that diffusion of BSA is higher at irradiation doses (64, 96 and 124 kGy) of PVP/ K2S2O8 because of the higher cross-linking density. For extensive swelling of PVP and PVP/K2S2O8 hydrogels in BSA solutions the following equation (Peniche et al., 1998; Katime et al., 1996) can be used:
120 100
t/S
80 60 40 20
0
60
26 64 96 124
k 102
0.446 0.401 0.319 0.305
9.26 12.34 21.20 24.41
0.401 0.408 0.372 0.372
10.86 11.74 13.52 14.31
500
50 40
10
n
400
124 kGy 96 kGy 64 kGy 26 kGy
70
Dose (kGy)
k 102
300
80
30
n
200
Fig. 3. t=S vs. t graphs plotted for PVP gels in 0.1 g/100 ml BSA solution at different radiation doses.
Table 2 Diffusion characteristics of PVP and PVP/K2S2O8 hydrogels in 0.1 g/100 ml BSA solutions PVP/K2S2O8
100
Time (min)
ð3Þ
PVP
PVP/(0.1g/100mL) BSA
0
t/S
t=S ¼ A þ Bt;
124 kGy 96 kGy 64 kGy 26 kGy
20
PVP/K2S2O8/(0.1g/100mL) BSA
0 0
100
200
300
400
Time (min) Fig. 4. t=S vs. t graphs plotted for PVP/ K2S2O8 gels in 0.1 g/ 100 ml BSA solution at different radiation doses.
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Table 3 Calculated ri {g water/g gel)/min}, ks {g gel /g water)/min}, Seq {(g water/g gel)} and correlation constant (R2 )values of PVP and PVP/ K2S2O8 hydrogels in 0.1 g/100 ml BSA solution Dose (kGy)
26 64 96 124
PVP
PVP/K2S2O8
ri
ks 102
Seq
R2
ri
ks 102
Seq
R2
0.228 0.157 0.243 0.223
3.82 5.54 9.22 13.1
12.52 7.14 5.35 3.61
0.994 0.992 0.996 0.998
0.262 0.163 0.125 0.138
3.40 4.93 5.29 6.28
15.04 8.20 6.67 5.92
0.992 0.990 0.988 0.990
Table 4 Diffusion coefficient (cm2 min1) of PVP and PVP/K2S2O8 hydrogels in 0.1 g/100 ml BSA solutions Dose (kGY)
PVP/K2S2O8
PVP 4
26 64 96 124
D 10
D 104
8.52 8.55 11.19 11.25
7.35 7.62 8.16 8.24
0.1 g/100 ml aqueous BSA solution vary from 7.35 104 to 8.24 104 cm2 min1, respectively. And it has been found that D values determined for PVP hydrogels change between the ranges 8.52 104 and 11.25 104 cm2 min1. 3.3. Equilibrium content BSA (EC-BSA) Equilibrium BSA content has been calculated from Eq. (5), EC-BSA ¼ ½ðWeq Wdry Þ=Wdry 100;
quicker than the swelling rate of PVP hydrogels. It is well known that swelling is directly related to the structure of the cross-linked polymer and/or the density of the hydrogel. The study of diffusion phenomenon in hydrogel and solvent is of importance as it clarifies the polymer behavior (Buckley and Berger, 1962). For the characterization of hydrogels, the diffusion coefficient (D) can be determined by different methods (Polishchuck et al., 1993; Li and Tanaka, 1990). The short-time approximation method is used for the calculation of diffusion coefficients of hydrogels. This method is used for the first 60% of swelling of cross-linked polymers in a chosen solvent. Commonly, the diffusion coefficient of cylindrical hydrogel is determined by the following equation: F ¼ Mt =MN ¼ 4½Dt=pr2 1=2 p½Dt=pr2 p=3½Dt=pr2 3=2 þ
ð5Þ
where Weq is the BSA content diffused into the gel at equilibrium state and Wdry is the weight of initially gel. The determined EC-BSA values are presented in Table 1. Along with the increase of irradiation dose, the equilibrium BSA content is decreased for both hydrogel systems. Equilibrium BSA content, as well as the swelling behavior of hydrogel, mainly depends on the nature of network structure, that is, hydrophilicity, cross-linking density, and the average molecular weight between two consecutive cross-links. When two different hydrogel systems are compared, it is clearly seen that the values of EC-BSA of PVP/K2S2O8 hydrogels in 0.1 g/ 100 ml aqueous BSA solution are higher than the values of EC-BSA for PVP hydrogels in the same solutions. This observation is also in good agreement with the swelling results of these two hydrogel systems and with that of equilibrium swelling and initial swelling rate values mentioned previously.
ð4Þ
where D is the diffusion coefficient (cm2 min1), t is the time (min), and r is the radius (cm) of cylindrical polymer samples. The graphical comparison of Eqs. (2) and (4) show the semi-emprical Eq. (2) with n ¼ 0:50 and k ¼ 4½Dt=pr2 1=2 : The diffusion coefficients of PVP and PVP/K2S2O8 hydrogels were also calculated from the slope of the lines of F against t1=2 by a computational program in BSA solution. The results are listed in Table 4 for hydrogel systems. It can be seen from the table that the values of the diffusion coefficients PVP/K2S2O8 hydrogels in
4. Conclusion The swelling capabilities of PVP and PVP/K2S2O8 hydrogels, followed for a long period of time in BSA solutions, increase with immersion time. On the other hand, irradiation dose increases the cross-linking density, resulting in lower swelling percent. The diffusion of BSA solutions into PVP and PVP/K2S2O8 hydrogels was assumed to be Fickian in character. The theoretical equilibrium swelling hydrogels fitted quite well with those of PVP and PVP/K2S2O8 hydrogels, where the
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swelling rate of the PVP/K2S2O8 system was faster than that observed in PVP hydrogels. In the presence of K2S2O8, the uptake capacity of gel system is increased. Penetration of BSA solution into PVP/K2S2O8 hydrogels is the most efficient, implying that aqueous solution of BSA facilitates and consequently increase the diffusion process compared to that in water. The Mc values of PVP/K2S2O8 gels are higher than the PVP system. Because of the high adsorption capacity of the hydrogels, they can be used in protein separation from plasma. As a conclusion, it may be said that the PVP and PVP/ K2S2O8 hydrogels have shown biocompatibility with biochemical systems. References Anderson, C.C., Rodriguez, F., Thurston, D.A., 1979. Crosslinking aqueous poly(vinyl pyrrolidone) solutions by persulfate. J. Appl. Polym. Sci. 23, 2453–2462. Buckley, D.J., Berger, M., 1962. The swelling polymer systems in solvents II. Mathematics of diffusion. Polym. Sci. 56, 175–187. Charlesby, A., Alexander, P., 1955. Energy transfer in macromolecules exposed to ionizing radiations. J. Polym. Sci. 23, 355–375. Chapiro, A., Legris, C., 1985. Formation de gels de poly(Nvinyl pyrrolidone) par l’action des rayons gamma sur des solutions aqueuses de poly(N-vinyl pyrrolidone). Eur. Polym. J. 21 (1), 49–53. Chapiro, A., Legris, C., 1986. Gel formation in the radiolysis of poly(N-vinyl pyrrolidone). Radiat. Phys. Chem. 28 (2), 143–144. Crank, J., 1970. Mathematical of Diffusion. Oxford University Press, New York. Darwis, D., Hilmy, N., Hardiningsih, L., Erlina, T., 1993. Poly(N-vinyl pyrrolidone) hydrogels: 1. Radiation polymerization and crosslinking of N-vinyl pyrrolidone. Radiat. Phys. Chem. 42, 907–910. Frisch, H.L., 1980. Sorption and transport in glassy polymers— a review. Polym. Eng. Sci. 20, 2–13. Guner, . A., 1997. Spectrophotometric behavior of polyvinyl pyrrolidone in aqueous solutions. II. The effects of denaturing agents. J. Appl. Polym. Sci. 65, 1307–1311. Guner, . A., Ataman, M., 1994. Effects of inorganic salts on the properties of aqueous PVP solutions. Colloid Polym. Sci. 272, 175–180. Guven, . O., S- en, M., 1993. The dependence of enzyme leakageon crosslink density in poly(N-vinyl-2-pyrrolidone) hydrogels with immobilized urease. Die Makromol. Chem. 207, 101–109. Hilmy, N., Darwis, D., Hardiningsih, L., 1993. Poly(Nvinylpyrrolidone) hyrogels: 2. Hydrogel composites as wound dressing for tropical environment. Radiat. Phys. Chem. 42, 911–914.
Hoffman, A., 2002. Hydrogels for biomedical applications. Adv. Drug Delivery Rev. 54, 3–12. Horkay, F., Zrinyi, M., 1998. Studies on mechanical and swelling behavior of polymer networks on the basis of the scaling concept 7. Effect of deformation on the swelling equilibrium concentration of gels. Macromolecules 21, 3260–3266. Kaplan, H., Guner, . A., 2000a. Characterization and determination of swelling and diffusion characteristics and poly(Nvinyl-2-pyrrolidone) and poly(N-vinyl-2-pyrrolidone)/ K2S2O8 hydrogels in water. J. Appl. Polym. Sci. 78, 994. Kaplan, H., Guner, . A., 2000b. Swelling behavior of poly(Nvinyl-2-pyrrolidone) and poly(N-vinyl-2-pyrrolidone)/ K2S2O8 hydrogels in urea solutions. Adv. Polym. Chem. 19, 210. Kaplan Can, H., Guner, . A. Polymer, Submitted for publication. Kaplan Can, H., Kavlak, S., Kırcı, B., Guner, . A., 2003a. Swelling behavior of poly(N-vinyl-2-pyrrolidone) and poly(N-vinyl-2-pyrrolidone)/K2S2O8 hydrogels in a-lactose solutions. Adv. Polym. Technol. 22 (3), 252–259. Kaplan Can, H., Kırcı, B., Kavlak, S., Guner, . A., 2003b. Removal of some textile dyes from aqueous solutions by (Nvinyl-2-pyrrolidone) and poly(N-vinyl-2-pyrrolidone)/ K2S2O8 hydrogels. Rad. Phys. Chem. 68 (5), 811–818. Katime, I., Valeda, J.L., Novva, R., et al., 1996. Swelling kinetics of poly(acrylamide)/poly(mono-n-alkyl itaconates) hydrogels. Polym. Int. 40, 281–286. Kavlak, S., Guner, . A., 2000. Effect of some selective aromatic cosolutes on the main thermodynamic parameters of aqueous poly(N-vinyl-2-pyrrolidone) solutions. J. Appl. Polym. Sci. 78, 507–510. Kırcı, B., Guner, . A., 2001. Effect of phenolic cosolutes on the main parameters. Phase separation and theta temperatures of the dilute poly(N-vinyl-2-pyrrolidone) solutions. Eur. Polym. J. 37, 361–364. Kırcı, B., Guner, . A., 2002. Effect of phenol derivatives on molecular dimensions of pvp in aqueous solutions. J. Appl. Polym. Sci. 84, 473–477. Li, Y., Tanaka, T., 1990. Kinetics of swelling and shrinking of gels. J. Chem. Phys. 92, 1365–1371. Mencer, H.J., Gomzi, Z., 1994. Swelling kinetics of polymersolvent systems. Eur. Polym. J. 30 (1), 33–36. Peniche, C., Cohen, M.E., Vazquez, B., et al., 1998. Water sorption of flexible networks based on 2-hydroxyethylmethacrylate-triethylenglycol dimethacrylate copolymers. Polymer 38, 5977–5982. Polishchuck, A.Y., Zaikov, G.E., Petropoulos, J.H., 1993. The modelling of the simultaneous transport of solvent and lowmolecular compounds in swelling polymers. Int. J. Polym. Mater. 19, 1–14. Senaglos, E., Thomas, R., 1979. Persulfate-initiated reactions of N-vinylpyrrolidone. J. Polym. Sci. Symp. Ser. 55, 241–247. Tenhu, H., Sundolm, F., 1984. Studies of cross-linked poly(Nvinyl-2-pyrrolidone) by calorimetry and by NMR. Macromol. Chem. 18, 2011.
Radiation Physics and Chemistry 72 (2005) 483–488
Preparation and swelling studies of biocompatible hydrogel systems by using gamma radiation-induced polymerization Hatice Kaplan Can, Betul Kirci Denizli*, Serap Kavlak, Ali Guner Faculty of Science, Department of Chemistry, Hacettepe University, Beytepe, Ankara TR-06532, Turkey Received 3 October 2003; accepted 14 December 2003
Abstract Hydrogels with varying cross-linking densities and average molecular weights between two consecutive cross-links were prepared from the binary poly(N-vinyl-2-pyrrolidone)/water and ternary poly(N-vinyl-2-pyrrolidone)/water/ K2S2O8 systems by irradiation with g rays at ambient temperature. Both hydrogel systems were employed for diffusion and swelling experiments in 0.1 g/100 ml Bovine Serum Albumin (BSA) solution at room temperature. Diffusion of BSA solution into hydrogels has been found to be of the Fickian type. The percent swelling, equilibrium swelling, initial rate of swelling, swelling rate of constant, equilibrium water/BSA content, and diffusion constant values were evaluated for PVP and PVP/K2S2O8 hydrogel systems at 0.1 g/100 ml BSA solution. r 2004 Elsevier Ltd. All rights reserved. Keywords: Bovine serum albumin (BSA); Hydrogels; g-irradiation; Poly(N-vinyl-2-pyrrolidone); Swelling
1. Introduction Hydrogels are water swollen polymer networks of either natural or synthetic origin; of these, it is the crosslinked covalently bonded synthetic hydrogels that have grown most dramatically in use. Hydrogels maybe sensitive to their environment and their structure may change according to the conditions around them. The interaction of polymers with blood and body fluids is of interest because of their high potential in the production of biomaterials. Many hydrogels obtained from synthetic polymers display good biocompatibility that can be used for drug delivery systems (Hoffman, 2002). Charlesby and Alexander (1955), first reported crosslinking of poly(N-vinyl-2-pyrrolidone) (PVP) under irradiation of aqueous solutions. Many researchers investigated gel formation in irradiated solutions of PVP in later studies. Chapiro and Legris (1985, 1986) *Corresponding author. Tel.: +90-312-2976448; fax: +90312-2992163. E-mail address: [email protected] (B.K. Denizli).
studied the effect of radiation dose, molecular weight, polymer concentration, and the influence of the nature of the solvent on cross-linking of PVP. Recently, the effects of radiation on the conversion of monomer and gelation of polymer (Darwis et al., 1993), the gelation of PVP in the presence of agar and poly(ethylene oxide) (PEO) (Hilmy et al., 1993), preparation of PVP hydrogels in the presence of cross-linking agents (ethylene glycol dimethacrylate and trimethyolpropane triacrylate) (Guven . and S- en, 1993) were studied and various characteristics (gelation dose, degree of swelling, equilibrium water content, elongation at break, tensile strength, diffusion behavior, etc.) of PVP hydrogels were evaluated. Water-soluble polymers, PEO, dextran, and PVP are known to form association complexes in aqueous solutions. Obviously, different types of additives (inorganic and organic cosolutes) can change molecular association already existing between polymer and solvent molecules. Previously, the effects of inorganic salts on dynamic and thermodynamic properties of PVP (Guner . and Ataman, 1994; Guner, . 1997) and the effects of special organic cosolutes on ifferent solution
0969-806X/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.radphyschem.2003.12.056
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properties of PVP (Kırcı and Guner, . 2001, 2002; Kavlak and Guner, . 2000) were studied in aqueous solutions. These studies revealed that the dynamic and thermodynamic behavior of water-soluble PVP mainly depends on the nature of cosolute and the temperature. Persulfate anion has a different behavior on PVP and its monomer. It is commonly known that the persulfate anion is an initiator for the polymerization of vinyl type monomers and exhibits a more distinguished behavior than the other initiatiors (Senaglos and Thomas, 1979). Another unusual behavior is the effect of persulfate anion on the polymer chain structure in aqueous solutions. Two different trends; that is, cross-linking and chain scission of PVP, can be observed in aqueous solutions of polymer in the presence of persulfate anion, depending on the content of persulfate in the mixture (Anderson et al., 1979; Tenhu and Sundolm, 1984). In addition, some other reactions, oxidative degradation and ring opening lactam ring were also proposed by the same research groups. The interaction mechanism of persulfate anion with PVP chains has not been explained until now. Recent studies have revealed that significant changes occur in the hydrodynamic volume of PVP, which may be interpreted by probable chain scission in the polymer chain in the presence of persulfate anion (Tenhu and Sundolm, 1984). This observation is also supported by the gelation of PVP in aqueous solutions in the presence of different concentrations of persulfate (Kaplan Can and Guner, . submitted). Serum albumin is the most abundant protein in the circulatory system, accounting for 60% of the total serum albumin. Its principal function is to transport fatty acids, a great variety of metabolites and drugs such as anti-coagulants, transquilizers and general anesthetics. Bovine serum albumin (BSA) displays approximately 76% sequence homology and a repeating pattern of disulfides which are strictly conserved: the molecular weight is 66267 g/mol for BSA. In our previous studies, average molecular weights between two consecutive cross-links (Mc ) for PVP and PVP/K2S2O8 hydrogel systems and swelling of water (Kaplan and Guner, . 2000a), urea (Kaplan and Guner, . 2000b), lactose (Kaplan Can et al., 2003a) and some textile dyes (Kaplan Can et al., 2003b) by PVP and PVP/ K2S2O8 hydrogels have been investigated. In this study, the effect of BSA solution on swelling characteristics of PVP and PVP/K2S2O8 hydrogels has been investigated.
weight of 700,000 g mol1. The weight average molecular weight of sample was determined from light scattering measurements in chloroform at 30 C by Brice-Phoenix Light Scattering Photometer, 2000 series. The specifications of instrument and determined characteristics and second virial coefficient, root-meansquare, radius of gyration were reported previously (Guner . and Ataman, 1994). The interpretation of light scattering data was based on the Zimm method. It has a weight average molecular weight of 548,000 g mol1. Potassium persulfate (K2S2O8) was obtained from Merck and BSA was obtained from BDH. K2S2O8 and BSA were of analytical grade and were used without further purification. Deionized and double-distilled water was used for the preparation of BSA solution.
2. Experimental
S% ¼ ½ðMt M0 Þ=M0 100;
2.1. Chemicals
where M0 is the initial weight and Mt is the weight of swollen gel at time, t: In this study, measurements have been achieved at optimum BSA concentration.
The PVP sample used in this study was obtained from British Drug House (BDH) with nominal molecular
2.2. Preparation of hydrogels Aqueous solutions of PVP (6%) and PVP aqueous solutions containing 4% K2S2O8 were prepared using double distilled deionized water. The prepared polymer solutions (PVP/water and PVP/water/K2S2O8) were then placed in PVC straws and irradiated with a dose of 26, 64, 96, and 124 kGy in air at ambient temperature in a Gamma Cell 220 type 60Co g irradiator at a fixed dose rate of 0.40 kGy h1, the radiation dose being determined by Fricke dosimeter previously. The PVP/ K2S2O8 ratio value and the irradiation doses mentioned previously were preferable since the exact cylindrical geometry of the gels had been obtained under these optimum conditions. 2.3. Measurement of swelling Cross-linked PVP samples have been obtained in long cylindrical shapes cut into pieces B0.5 cm long and stored for later studies. Gels thus prepared were immersed in distilled water for a week to remove uncross-linked polymers and low molecular-weight substances, and dried to constant weight. Dried hydrogels were left in BSA solutions at room temperature (20 C) and they were removed from the BSA solutions. After a certain time, they are weighed and placed in the same solutions. The percentage swelling (S) was determined gravimetrically by the following equation: ð1Þ
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3. Results and discussion 3.1. Swelling A fundamental relationship exists between the swelling of a cross-linked polymer in a solvent and the nature of the polymer and solvent. Swelling of the cross-linked polymers in the chosen and/or suitable solvent is the
26 kGy 64 kGy 96 kGy 124 kGy
1200
1000
% Swelling
800
600
400
200
PVP/(0.1g/100mL) BSA
0 0
100
200
300
400
500
Time (min) Fig. 1. Swelling percent values of PVP gels in 0.1 g/100 ml BSA solution at different radiation doses.
1400
26 kGy 64 kGy 96 kGy 124 kGy
1200
% Swelling
1000 800 600 400 200
PVP/K2S2O8 /(0.1g/100mL) BSA 0 0
100
200
300
400
Time (min) Fig. 2. Swelling percent values of PVP/ K2S2O8 gels in 0.1 g/ 100 ml BSA solution at different radiation doses.
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most important parameter (especially since one of the most important parameters is mass swelling) (Horkay and Zrinyi, 1998; Mencer and Gomzi, 1994) for swelling studies. The intake of initially dry hydrogels was followed for a long period of time in BSA solutions. Swelling curves of PVP and PVP/K2S2O8 hydrogels are plotted and representative swelling curves at 0.1 g/100 ml BSA solutions are shown in Figs. 1 and 2. As can be seen from these figures, swelling capabilities of PVP and PVP/K2S2O8, hydrogels are increased by time, reaching constant swelling (equilibrium swelling) after a certain period of time. Another observation is the swelling of the gels depend on the irradiation dose. It is obvious that increasing the total radiation dose increases the cross-linking density, resulting in lower maximum swelling percent. As shown in these curves (Figs. 1 and 2), the swelling capabilities of PVP and PVP/K2S2O8 hydrogels vary in the range 310–1300% in BSA solutions. In order to make a better comparison, the determined equilibrium swelling percentages are given in Table 1. It can be clearly seen that the highest swelling percentages are observed in the PVP/K2S2O8 hydrogel system. Before explanation of the swelling of hydrogels in the presence of BSA, it is better to discuss the effect of additives on the structure of water and interactions between polymer and solvent molecules. In the presence of K2S2O8, the cross-link density of the gel is decreasing. For this reason swelling behavior of the gel system bears in better. It is known that the Mark-Houwink exponent, a, depends on the nature of solvent, temperature, and the molecular weight of the polymer. At the theta temperature, a is equal to 0.50. This exponent has been found as 0.55 in the Mark-Houwink equation for the system PVP/H2O, which is close to 0.50, showing the characteristic of a theta solvent. It is obvious that the additives can change and /or disturb the hydrogenbonded structure of water and the molecular association of the water-soluble polymer in aqueous media, as well as the swelling behavior of cross-linked PVP chains (Kırcı and Guner, . 2001). In the presence of BSA, swelling of hydrogels can easily follow the change of the hydrogen-bonded structure of water and polymer–solvent interaction. Equilibrium swelling percentages were indicated as
Table 1 Equilibrium swelling (ES) and equilibrium BSA content (EC-BSA) values (%) of PVP and PVP/K2S2O8 hydrogels in 0.1 g/100 ml BSA solutions Dose (kGy)
ES (PVP)
ES(PVP/K2S2O8)
EC-BSA (PVP)
EC-BSA (PVP/K2S2O8)
26 64 96 124
1100 610 460 310
1300 700 520 440
91.8 86.5 83.4 77.5
92.9 87.9 85.2 84.2
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1300, 700, 600, and 500% for PVP/K2S2O8 hydrogel systems in water (Kaplan, 2000a). In the case of 0.1 g/ 100 ml of aqueous BSA solutions, these percentages are very close to the results with aqueous solutions such as 1300, 700, 520, and 440% for the same hydrogel system, respectively. In the higher cross-link density of gel system (96 and 124 kGy) swelling (%) value is lower than in water. This can be explained by the diffusion of high molecular weight BSA substance into hydrogel system. 3.2. Diffusion The swelling curves of PVP and PVP/K2S2O8 hydrogels in aqueous BSA solutions were used for the calculation of a certain diffusion characteristics. The following equation was used to determine the nature of diffusion of BSA solution into hydrogels (Crank, 1970): F ¼ Mt =MN ¼ ktn ;
where B ¼ 1=Seq is the reciprocal of the maximum or 2 equilibrium swelling, A ¼ 1=ðks Seq Þ is the reciprocal of the initial swelling rate of the gel (r1 ), and ks is the swelling rate constant. This relation represents second order kinetics (Peniche et al., 1998). Figs. 3 and 4 exhibit the linear regression of the swelling curves obtained by means of Eq. (3) for PVP and PVP/K2S2O8 hydrogels in 0.1 g/100 ml BSA solution. The initial rate of swelling (r1 ), swelling rate constant, and equilibrium swelling (or as commonly used, theoretical equilibrium swelling) of PVP and PVP/K2S2O8 hydrogels are calculated from the slope and intersection of the lines given in Table 3 both for hydrogel systems in 0.1 g/100 ml BSA solutions. The values of theoretical equilibrium swelling of the hydrogels are in good agreement with the results of equilibrium swelling of PVP and PVP/K2S2O8 hydrogels (Fig. 1). Swelling process of PVP/K2S2O8 hydrogels is
ð2Þ
140
where Mt MN denote the amount of BSA solution diffused into the gel at time, t; and infinite time (at equilibrium), respectively, k is a constant related to the structure of the network, and the exponent n is a numerical value to determine the type of diffusion. For a cylindrical shapes, np0:50 and corresponds to Fickian diffusion, whereas 0:50ono1:00 indicates that diffusion is non-Fickian (Frisch, 1980). Eq. (2) was applied to various stages of swelling and plots of ln F against ln t yielded straight lines from which the exponents n and k were calculated from the slope and intercept of the lines listed in Table 2 at 0.1 g/100 ml aqueous BSA solutions. It can be clearly seen from the table that the values of the diffusion exponent range between 0.305 and 0.446 and are known to be lower than 0.50. Hence, the diffusion of BSA solutions into PVP and PVP/K2S2O8, hydrogels was assumed to be Fickian in character. It can also be noticed from Table 2 that diffusion of BSA is higher at irradiation doses (64, 96 and 124 kGy) of PVP/ K2S2O8 because of the higher cross-linking density. For extensive swelling of PVP and PVP/K2S2O8 hydrogels in BSA solutions the following equation (Peniche et al., 1998; Katime et al., 1996) can be used:
120 100
t/S
80 60 40 20
0
60
26 64 96 124
k 102
0.446 0.401 0.319 0.305
9.26 12.34 21.20 24.41
0.401 0.408 0.372 0.372
10.86 11.74 13.52 14.31
500
50 40
10
n
400
124 kGy 96 kGy 64 kGy 26 kGy
70
Dose (kGy)
k 102
300
80
30
n
200
Fig. 3. t=S vs. t graphs plotted for PVP gels in 0.1 g/100 ml BSA solution at different radiation doses.
Table 2 Diffusion characteristics of PVP and PVP/K2S2O8 hydrogels in 0.1 g/100 ml BSA solutions PVP/K2S2O8
100
Time (min)
ð3Þ
PVP
PVP/(0.1g/100mL) BSA
0
t/S
t=S ¼ A þ Bt;
124 kGy 96 kGy 64 kGy 26 kGy
20
PVP/K2S2O8/(0.1g/100mL) BSA
0 0
100
200
300
400
Time (min) Fig. 4. t=S vs. t graphs plotted for PVP/ K2S2O8 gels in 0.1 g/ 100 ml BSA solution at different radiation doses.
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Table 3 Calculated ri {g water/g gel)/min}, ks {g gel /g water)/min}, Seq {(g water/g gel)} and correlation constant (R2 )values of PVP and PVP/ K2S2O8 hydrogels in 0.1 g/100 ml BSA solution Dose (kGy)
26 64 96 124
PVP
PVP/K2S2O8
ri
ks 102
Seq
R2
ri
ks 102
Seq
R2
0.228 0.157 0.243 0.223
3.82 5.54 9.22 13.1
12.52 7.14 5.35 3.61
0.994 0.992 0.996 0.998
0.262 0.163 0.125 0.138
3.40 4.93 5.29 6.28
15.04 8.20 6.67 5.92
0.992 0.990 0.988 0.990
Table 4 Diffusion coefficient (cm2 min1) of PVP and PVP/K2S2O8 hydrogels in 0.1 g/100 ml BSA solutions Dose (kGY)
PVP/K2S2O8
PVP 4
26 64 96 124
D 10
D 104
8.52 8.55 11.19 11.25
7.35 7.62 8.16 8.24
0.1 g/100 ml aqueous BSA solution vary from 7.35 104 to 8.24 104 cm2 min1, respectively. And it has been found that D values determined for PVP hydrogels change between the ranges 8.52 104 and 11.25 104 cm2 min1. 3.3. Equilibrium content BSA (EC-BSA) Equilibrium BSA content has been calculated from Eq. (5), EC-BSA ¼ ½ðWeq Wdry Þ=Wdry 100;
quicker than the swelling rate of PVP hydrogels. It is well known that swelling is directly related to the structure of the cross-linked polymer and/or the density of the hydrogel. The study of diffusion phenomenon in hydrogel and solvent is of importance as it clarifies the polymer behavior (Buckley and Berger, 1962). For the characterization of hydrogels, the diffusion coefficient (D) can be determined by different methods (Polishchuck et al., 1993; Li and Tanaka, 1990). The short-time approximation method is used for the calculation of diffusion coefficients of hydrogels. This method is used for the first 60% of swelling of cross-linked polymers in a chosen solvent. Commonly, the diffusion coefficient of cylindrical hydrogel is determined by the following equation: F ¼ Mt =MN ¼ 4½Dt=pr2 1=2 p½Dt=pr2 p=3½Dt=pr2 3=2 þ
ð5Þ
where Weq is the BSA content diffused into the gel at equilibrium state and Wdry is the weight of initially gel. The determined EC-BSA values are presented in Table 1. Along with the increase of irradiation dose, the equilibrium BSA content is decreased for both hydrogel systems. Equilibrium BSA content, as well as the swelling behavior of hydrogel, mainly depends on the nature of network structure, that is, hydrophilicity, cross-linking density, and the average molecular weight between two consecutive cross-links. When two different hydrogel systems are compared, it is clearly seen that the values of EC-BSA of PVP/K2S2O8 hydrogels in 0.1 g/ 100 ml aqueous BSA solution are higher than the values of EC-BSA for PVP hydrogels in the same solutions. This observation is also in good agreement with the swelling results of these two hydrogel systems and with that of equilibrium swelling and initial swelling rate values mentioned previously.
ð4Þ
where D is the diffusion coefficient (cm2 min1), t is the time (min), and r is the radius (cm) of cylindrical polymer samples. The graphical comparison of Eqs. (2) and (4) show the semi-emprical Eq. (2) with n ¼ 0:50 and k ¼ 4½Dt=pr2 1=2 : The diffusion coefficients of PVP and PVP/K2S2O8 hydrogels were also calculated from the slope of the lines of F against t1=2 by a computational program in BSA solution. The results are listed in Table 4 for hydrogel systems. It can be seen from the table that the values of the diffusion coefficients PVP/K2S2O8 hydrogels in
4. Conclusion The swelling capabilities of PVP and PVP/K2S2O8 hydrogels, followed for a long period of time in BSA solutions, increase with immersion time. On the other hand, irradiation dose increases the cross-linking density, resulting in lower swelling percent. The diffusion of BSA solutions into PVP and PVP/K2S2O8 hydrogels was assumed to be Fickian in character. The theoretical equilibrium swelling hydrogels fitted quite well with those of PVP and PVP/K2S2O8 hydrogels, where the
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swelling rate of the PVP/K2S2O8 system was faster than that observed in PVP hydrogels. In the presence of K2S2O8, the uptake capacity of gel system is increased. Penetration of BSA solution into PVP/K2S2O8 hydrogels is the most efficient, implying that aqueous solution of BSA facilitates and consequently increase the diffusion process compared to that in water. The Mc values of PVP/K2S2O8 gels are higher than the PVP system. Because of the high adsorption capacity of the hydrogels, they can be used in protein separation from plasma. As a conclusion, it may be said that the PVP and PVP/ K2S2O8 hydrogels have shown biocompatibility with biochemical systems. References Anderson, C.C., Rodriguez, F., Thurston, D.A., 1979. Crosslinking aqueous poly(vinyl pyrrolidone) solutions by persulfate. J. Appl. Polym. Sci. 23, 2453–2462. Buckley, D.J., Berger, M., 1962. The swelling polymer systems in solvents II. Mathematics of diffusion. Polym. Sci. 56, 175–187. Charlesby, A., Alexander, P., 1955. Energy transfer in macromolecules exposed to ionizing radiations. J. Polym. Sci. 23, 355–375. Chapiro, A., Legris, C., 1985. Formation de gels de poly(Nvinyl pyrrolidone) par l’action des rayons gamma sur des solutions aqueuses de poly(N-vinyl pyrrolidone). Eur. Polym. J. 21 (1), 49–53. Chapiro, A., Legris, C., 1986. Gel formation in the radiolysis of poly(N-vinyl pyrrolidone). Radiat. Phys. Chem. 28 (2), 143–144. Crank, J., 1970. Mathematical of Diffusion. Oxford University Press, New York. Darwis, D., Hilmy, N., Hardiningsih, L., Erlina, T., 1993. Poly(N-vinyl pyrrolidone) hydrogels: 1. Radiation polymerization and crosslinking of N-vinyl pyrrolidone. Radiat. Phys. Chem. 42, 907–910. Frisch, H.L., 1980. Sorption and transport in glassy polymers— a review. Polym. Eng. Sci. 20, 2–13. Guner, . A., 1997. Spectrophotometric behavior of polyvinyl pyrrolidone in aqueous solutions. II. The effects of denaturing agents. J. Appl. Polym. Sci. 65, 1307–1311. Guner, . A., Ataman, M., 1994. Effects of inorganic salts on the properties of aqueous PVP solutions. Colloid Polym. Sci. 272, 175–180. Guven, . O., S- en, M., 1993. The dependence of enzyme leakageon crosslink density in poly(N-vinyl-2-pyrrolidone) hydrogels with immobilized urease. Die Makromol. Chem. 207, 101–109. Hilmy, N., Darwis, D., Hardiningsih, L., 1993. Poly(Nvinylpyrrolidone) hyrogels: 2. Hydrogel composites as wound dressing for tropical environment. Radiat. Phys. Chem. 42, 911–914.
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