Degradation Behavior of Polymer Gels Caused by Nonspecific

Sep 2, 2014 - ABSTRACT: We report a systematical study of degradation behavior of hydrogels that suffer from the nonspecific cleavage on the network ...
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Degradation Behavior of Polymer Gels Caused by Nonspecific Cleavages of Network Strands Xiang Li,† Shinji Kondo,† Ung-il Chung, and Takamasa Sakai* Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan S Supporting Information *

ABSTRACT: We report a systematical study of degradation behavior of hydrogels that suffer from the nonspecific cleavage on the network strands. The volume of the gel specimens increased with the degradation progress, and denoted the temperature dependence and the network strand length dependence. Our new model based on the pseudo-first-order cleavage kinetics of the chemical bonds on the network strands well agreed with the degradation behavior. The estimated apparent degradation rate constants of the network strands were linear function of their length, corresponding to the network strand length dependence on the macroscopic volume change of the gel specimens. The estimated degradation rate constants of the chemical bonds on the network stand, which were ether and amide bond, obeyed the transition state theory. The calculated activation enthalpy of each bond was in the range of the values in previous studies, indicating the validity of our modeling.

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INTRODUCTION Hydrogels are promising materials for biomedical application,1−3 and their desired fate depends on the purpose. Nondegradable hydrogels on a long-term basis are required in the case of the artificial cartilage, whereas hydrogels with precisely controlled degradation behavior are required in the case of drug delivery system and tissue regeneration. Numerous studies have been done on control of the degradation rate, which also resulted in significant changes to the other important properties including elastic modulus, water content, etc.4−8 Recently, we proposed a simple system that enables the precise control of degradation rate without changing the other properties of gels, based on Tetra-PEG gel.9−18 The Tetra-PEG gel system employs two different kinds of mutually reactive four-armed prepolymers, forming the extremely homogeneous network with defined network strand length (Figure 1). By using a third prepolymer with cleavable sites, we for the first time succeeded in controlling the degradation behavior without changing the other physical properties.19 The degradation behavior agreed well with the theoretical model based on the pseudo-first-order kinetics.20 Our methodology was extended to the other system, and achieved a precise control of degradation following the model.21 Through further analysis on this model, we recognized that polymer gels inevitably degrade on a long-term basis, in the case that chemical bonds in the network strand suffer from “non-specific cleavage”. The nonspecific cleavage of the polymer chain is caused by common stimuli in the practical © 2014 American Chemical Society

applications, such as the oxidation in vivo, the UV irradiation exposure and the mechanical stress.22−24 The degradation caused a serious problem on a long-term basis.25 However, as far as we know, the degradation behavior of polymer gels suffering from nonspecific cleavage has never been discussed in detail. In this study, using Tetra-PEG gel as a model system, we systematically investigated degradation behavior of gels with tuned network strand lengths. To investigate the long-term stability, we performed the accelerated tests using H2O2 solution at different temperatures. The volume of the gel specimens increased with time, showing the bulk degradation behavior. We proposed a new model predicting the degradation behavior caused by the nonspecific cleavage of network strands, based on the previous model. Our new model well agreed with the experimental data, and the degradation rate constants of bonds in the network strands were estimated. The degradation rate constants obeyed the transition state theory, indicating the validity of our modeling.26

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EXPERIMENTAL SECTION

Synthesis of Prepolymers. Tetra-amine-terminated poly(ethylene glycol) (Tetra-PEG-NH2) and tetra-OSu-terminated poly(ethylene glycol) (Tetra-PEG-OSu) with molecular weights (Mn = 10, 20, 40 kg/mol) were prepared from tetrahydroxyl-terminated poly(ethylene glycol) with equal arm lengths. Here, OSu stands for Received: July 8, 2014 Revised: September 1, 2014 Published: September 2, 2014 5352

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Figure 1. Schematic picture of Tetra-PEG gels and the degradation test. N-hydroxysuccinimide. The detailed preparation methods were reported elsewhere.13,15,16,27 Fabrication of Tetra-PEG Gels. Tetra-PEG-NH2 and Tetra-PEGOSu with various Mn were dissolved in phosphate buffer (PB, pH7.4) and citric phosphate buffers (CPB, pH5.8) with tuned ionic strength at different final polymer volume fractions (ϕ) as shown in Table 1.

estimated elastic moduli (G0) of the gel specimens as the initial slopes on the stress−elongation curves. The polymer volume fraction of the gel specimens in as-prepared state (ϕ0) was set within the range where the elastic moduli well obey the phantom network model.28 According to the phantom network model, G0 is related to the cycle rank density of gels in asprepared state (ξ0) as

Table 1. Condition of Fabrication of Tetra-PEG Gels sample name

Mn [g/mol]

10k 20k 40k

10k 20k 40k

ϕ 0.081 0.050 0.034

Tetra-PEG-NH2

Tetra-PEG-OSu

PB 100 mM PB 25 mM PB 12.5 mM

CPB 100 mM CPB 25 mM PB 12.5 mM

G0 = ξ0RT

(1)

The cycle rank densities estimated by eq 1 are shown in Table 2. Table 2. Cycle Rank Density of Gels in As-Prepared State (ξ0)

The stoichiometric ratios of two Tetra-PEG prepolymer solutions with corresponding Mn and ϕ were mixed with conditioning mixer (AR-100, Thinky, Japan). The mixture of two prepolymers solution was filled into a rectangular mold (30 mm high, 5 mm wide, 2 mm thick) for stretching test, and into glass capillary with inner diameters 640 μm for degradation observation. After filling, the mixture of prepolymers solution was placed at room temperature for 1 day to allow the gelation reaction to finish. The resulting gels made of the specific prepolymers (Mn 10, 20, 40, kg/mol) had the corresponding polymerization degree of network strands (N 114, 228, 456). Stretching Test. The stretching test was performed using a mechanical testing apparatus (Autograph AG-X plus; SHIMADZU, Kyoto, Japan) at a crosshead speed of 1 mm/s. The gel samples were used in the as-prepared state at room temperature. More than 3 samples were tested for each gel condition, and the observed moduli were arithmetically averaged. Degradation Observation. The gel specimens were first immersed in H2O at room temperature for 1 h to make the gel specimens equilibrium-swollen, and then were immersed in 30 w/w% H2O2 solution at room temperature for 1 h to exchange the solvent inside the gel from the phosphate buffer to the H2O2 solution (see the Supporting Information, SFigure 1). After the solvent exchange, the gel specimens were placed in a thermal glass chamber filled with the 30w/w% H2O2 solution at predetermined temperatures 60, 64, 70, and 80 °C. The thermal glass chamber was covered with a glass hot plate and the space between the glass hot plate and the thermal glass chamber was filled with vacuum grease to prevent the evaporation of H2O2 solution. The glass hot plate was set at 90 °C to prevent condensations on the plate. The diameters of the gel specimens were measured using an optical microscope (M165C, Leica).

sample name

N

ϕ0

ξ0(mol/m3)

10k 20k 40k

114 228 456

0.081 0.050 0.034

7.16 ± 0.15 2.07 ± 0.06 0.75 ± 0.01

Second, we measured the equilibrium-swelling ratio of the gel specimens (Qe) in the H2O2 solution at the predetermined temperatures (T: 60, 64, 70, and 80 °C) (Figure 2). Here, swelling ratio of gels is defined as the volume ratio of gels in measurement state to that in as-prepared state. Qe were calculated as the average values of the swelling ratio of the gel specimens in the period t = 15−30 min, where the temperature-

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RESULTS & DISCUSSION 1. Characteristics of Tetra-PEG Gels. First, we performed stretching test for the gel specimens in as-prepared state, and

Figure 2. Equilibrium-swelling ratio of Tetra-PEG gel (Qe) in the 30w/w% H2O2 solution as a function of T. The error bars smaller than the size of symbols are hidden behind the symbols. 5353

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following analyses, because these points were irrelevant to the degradation behavior. The subsequent increase in Q(t) indicates the progress of bulk degradation over time. The increase in Q(t) was accelerated by increasing N, indicating the degradation behavior has N-dependence. The elevated temperature also accelerated the increase in Q(t). Assuming that the swelling rate is much faster than the degradation rate, and that elution of dissociated sol fractions from the gel are negligible, we treated Q(t) as that in the equilibrium-swelling state at a certain time t, and ϕ0 as a constant value during the degradation. The first assumption may be valid because the time for the gel to swell from the asprepared state to a given swelling state (e.g., Q = 1−2, t ≈ 30 min (see the Supporting Information, SFigure 1)) was much shorter than the time for the degradation-induced swelling (e.g., Q = 1−2, t ≈ 3 h (Figure 4)). The second assumption is valid under the condition that the existence probability of sol fraction (P(X0)) is negligible (≈ 1 × 10−2), which corresponds to the range where the cycle rank density of the degrading gel ξ(t) are larger than half of ξ(0) (see the Supporting Information for detailed information). In addition, we have confirmed the applicability of the Flory−Rehner equation under these assumptions to the degrading gel system in our previous paper.19 Under these assumptions, we can estimate ξ(t) from Q(t), ϕ0, and χ, according to eq 2. Figure 5 shows the time course of ξ(t) of the gel specimens. ξ(t) decreased over time, reflecting the cleavage of the network strand. 3. A Model for Degradation. The network strand of the polymer network of Tetra-PEG gels consists of three different kinds of chemical units (Figure 1): carbon−carbon bond, ether bond, and amide bond. Among these bonds, the ether bond and amide bond may suffer from degradation in H2O2 solution by oxidation and/or hydrolysis.24,32 Because the molar amount of H2O2 was much larger (105 times) than the total molar amount of ether and amide bonds, we can neglect the consumption of H2O2 accompanying the degradation of the gels and apply the pseudo-first-order kinetics for the cleavage of the network strand. According to the pseudo-first-order kinetics, the possibilities that an ether (pether) or an amide (pamide) bond still exist after a period of time can be expressed as

induced volume change of the gel specimen completed and the degradation-induced volume change was negligible (see the Supporting Information, SFigure 2). Qe decreased with increasing T, indicating the solvent quality deteriorated at higher temperature. This tendency is commonly seen in PEGwater system, because PEG has lower critical temperature (LCST) around 100 °C in water.29 According to the Flory−Rehner equation that is based on the phantom network model,30 the Flory interaction parameter (χ) can be estimated from the parameters ξ0, ϕ0, and ϕe, which is the polymer volume fraction of the gel in the equilibriumswelling state as ⎛ ϕ ⎞1/3 −V ⎜⎜ e ⎟⎟ ξ0 = ln(1 − ϕe) + ϕe + χϕe 2 ⎝ ϕ0 ⎠

(2)

where V is the molar volume of solvent (30w/w% H2O2 aqueous solution, 18.89 cm3/mol). Notably, the term ϕ0/ϕe (= Qe) in eq 2 indicates the volume change from the asprepared state to the equilibrium-swelling state, and ξ0 represents the cycle rank density of the gel with the initial volume. By substituting the value of ϕ0, ξ0, and Qe (= ϕ0/ϕe) into eq 2, we obtained χ of the different gel specimens at each temperature. As shown in Figure 3, χ increased with increasing

Figure 3. Flory interaction parameter (χ) of the different gel samples as a function of T. The error bars smaller than the size of symbols are hidden behind the symbols.

T, and with decreasing N. The former tendency reflects the decrease in Qe with the increase in T. The latter tendency qualitatively corresponds to our previous study,10 and has been reported in the other study.31 The obtained values of χ were used as a fixed parameter for each experimental condition in the following section. 2. Degradation Behavior of Tetra-PEG Gels. Figure 4 shows the time course of swelling ratio of Tetra-PEG gels during the degradation (Q(t)) in H2O2 solution at different T. To accelerate the degradation rate, the 30w/w% H2O2 solution was used as a standard solution. The microscope images of the observation of gel degradation are shown in SFigure 3 in the Supporting Information. Q(t) decreased slightly at the beginning (t < 15 min), then increased over time. Finally all specimens were disintegrated and dissolved into the solution after a certain period of time. The decrease in Q(t) at the beginning was caused by the volume change induced by temperature change from the room temperature to the predetermined temperatures (T: 60−80 °C), which was equilibrated within 15 min. We ignored these points in the

pether = exp( −kethert )

(3)

pamide = exp( −kamidet )

(4)

where kether and kamide are the degradation rate constant of an ether and an amide bonds, respectively. Because there are an amide bond and N ether bonds per network strand, the probability that a network strand still exists after a period of time (P) is given by P = P0((pether )N pamide ) = P0exp[− (kamide + Nkether)t ]

(5)

where P0 is the reaction conversion (or the connectivity) of prepolymers of Tetra-PEG gels in as-prepared state. P can be related to ξ(t) by the tree-like approximation as follows33 (see the Supporting Information for the detailed information) 1/2 1/2 3 ⎛1 ⎛1 3 ⎞ ⎞⎛ 3 ⎛ 1 3⎞ ⎞ ⎜ ⎟ ⎜ ⎟ ⎜ ⎟ ⎜ ξ(t ) = U ⎜ + − ⎟⎜ − ⎝ − ⎠ ⎟⎟ ⎝P 4 ⎠ ⎠⎝ 2 P 4 ⎝2 ⎠

(6)

According to eqs 5 and 6, we finally obtain ξ(t) as below 5354

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Figure 4. Time course of swelling ratio of Tetra-PEG gels during the degradation (Q(t)) in H2O2 solution at predetermined T.

Figure 5. Time course of the cycle rank density of the degrading gel (ξ(t)) in H2O2 solution at predetermined T. The solid curves show the fitting curves with eq 7

larger than half of ξ(0) values, where U was calculated from the prepolymer concentration in as-prepared state (sample 10k, U = 10 mol/L; sample 20k, U = 3 mol/L; sample 40k, U = 1 mol/ L). kapp and P0 were set as the fitting parameters. The fit worked well for the data of all the gel specimens over a wide range (Figure 5). The estimated values of P0 were in the range of ±2% error from the values of P0 that was directly measured by IR spectroscopy (see the Supporting Information, SFigure 4). The estimated kapp were plotted against N (Figure 6). kapp linearly increased with increasing N, which agrees well with the prediction of our model (eq 8). According to eq 8, we can estimate the kamide and kether from the intercepts and the slopes in Figure 5, respectively. Figure 7 shows a semilogarithmic plot of kamide/T and kether/ T vs 1/T. Linear relationships were observed between

⎡ ⎛ ⎞1/2 ⎤ 1 1 3 ⎢ ξ(t ) = U ⎢ + ⎜⎜ − ⎟⎟ ⎥⎥ 2 P0exp( −kappt ) 4⎠ ⎝ ⎣ ⎦ 3 ⎡ ⎛ ⎞1/2 ⎤ 3 1 3 ⎢ −⎜ ⎥ ⎜ P exp( −k t ) − 4 ⎟⎟ ⎥ ⎢2 ⎝ ⎠ 0 app ⎣ ⎦

kapp = kamide + Nkether

(7) (8)

where kapp is the apparent degradation rate constant of a strand, and U is the molar concentration of the tetra-arm prepolymers in as-prepared state. 4. Estimation of Degradation Rate Constants. We fitted the data in Figure 5 with eq 7 in the range where ξ(t) values are 5355

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in our experimental condition; however, the radical generated in body can degrade PEG based polymer gels in terms of years.

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CONCLUSION We investigated the degradation behavior of a series of TetraPEG gel specimens with different network strand length at various T in the accelerating test condition. By simply observing the diameter change of the gel specimens during the degradation, we successfully estimated the degradation rate constants of a single network strand for each Tetra-PEG gel specimen with our model. The degradation rate constants of the network strands were linear functions of N, which indicates that as the strand length becomes longer, the degradation rate becomes higher. The estimated degradation rate constant of amide and ether bonds obeyed the transition state theory. The values of resulted activation enthalpy were in the range of previous studies. Thus, we for the first time succeeded in modeling the degradation behavior of gels caused by the random scission of network strands, which inevitably occurs in the practical use. Notably, the degradation rate of polymer gel is much higher than that of the consisting chemical bond. The radical species generated in the human body or by the UV irradiation can degrade polymer gels, making it difficult to use polymer gels in a long time basis. We envision that our model will be helpful for the material design of polymer gels.

Figure 6. kapp as a function of N at different T. The dotted lines illustrate the fitting curves with eq 7

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S Supporting Information *

Figure 7. Semilogarithmic plot of kether/T and kamide/T as a function of 1/T. The dotted lines show the fitting curves of k/T = Aexp(−ΔH/ RT).

Additional experimental results, images, and theoretical background of the degradation model. This material is available free of charge via the Internet at http://pubs.acs.org/.

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logkamide/T and 1/T, logkether/T and 1/T, indicating that both kamide and kether follow the transition state theory, which predicts ⎛ ΔS* ⎞ ⎛ ΔH * ⎞ ⎟exp⎜ − ⎟ k ≈ T exp⎜ ⎝ R ⎠ ⎝ RT ⎠

ASSOCIATED CONTENT

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Author Contributions

(9)

†

X.L. and S.K.contributed equally to the work.

where k is the reaction rate constant, ΔS* is the activation entropy, ΔH* is the activation enthalpy and R is the gas constant (8.314 J mol−1 K−1).26 The estimated ΔH* values of amide bond (∼86 kJmol−1) and ether bond (∼89 kJmol−1) were comparable to the ΔH* values of the previous studies for the degradation for low molecular weight substances and linear polymers,24,34 suggesting that our analyses are valid. The A value of amide bonds was approximately 2 orders of magnitude greater than that of ether bonds. According to the transition state theory, ΔS* is an increasing function of A as A ≈ exp(ΔS*/R). Our results suggest that the activation entropy of amide bonds is much larger than that of ether bonds. The difference in the activation entropy of amide and ether bond may be due to the number of cleavage pathways; ether bonds only suffer from oxidation by H2O2, whereas amide bonds in H2O2 solution may suffer from both oxidation by H2O2 and hydrolysis by H2O.32,34 According to eq 5 and the values of ΔH* and ΔS*, we can estimate the kapp at 37 °C, which is meaningful value for biomedical applications. The value of kapp at 37 °C is roughly 1 order of magnitude smaller than that at 60 °C. Because the disintegration time is inversely proportional to kapp,19 we can roughly estimate the disintegration time at 37 °C as 1−3 weeks based on the disintegration time at 60 °C. The variance in the stability is due to N of the Tetra-PEG gels. Of course, the radical concentration in human body is much smaller than that

Notes

The authors declare no competing financial interests.

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ACKNOWLEDGMENTS The authors appreciate the advice of Prof. Naoko Yoshie and Prof. Hirotaka Ejima. This work was supported by the Japan Society for the Promotion of Science (JSPS) through the Grants-in-Aid for Scientific Research, the Center for Medical System Innovation (CMSI), the Graduate Program for Leaders in Life Innovation (GPLLI), the International Core Research Center for NanoBio, Core-to-Core Program, A. Advanced Research Networks and the Funding Program for WorldLeading Innovative R&D on Science and Technology (FIRST program); the Ministry of Education, Culture, Sports, Science, and Technology in Japan (MEXT) through the Center for NanoBio Integration (CNBI); and the Japan Science and Technology Agency (JST) through the S-innovation program and COI STREAM; and Grants-in- Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (12J07977 to X.L., 23700555 to T.S., and 24240069 to U.C.).

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