Strategy to Introduce a Pendent Micellar Structure into Poly(N

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Langmuir 2007, 23, 4231-4236

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Strategy to Introduce a Pendent Micellar Structure into Poly(N-isopropylacrylamide) Hydrogels Xiao-Ding Xu,† Xian-Zheng Zhang,*,† Jie Yang,† Si-Xue Cheng,† Ren-Xi Zhuo,† and Ya-Qun Huang‡ Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan UniVersity, Wuhan 430072, P. R. China, and Colloid and Interface Science Laboratory and Department of Chemistry, Wuhan UniVersity, Wuhan 430072, P. R. China ReceiVed December 1, 2006. In Final Form: February 2, 2007 A novel class of functional poly(N-isopropylacrylamide) (PNIPAAm) hydrogels with pendent micellar structure resulting from the pending amphiphilic polymers was designed and prepared. The influence of the pendent micellar structure on the properties of the resulted PNIPAAm hydrogels was examined in terms of morphology observed by scanning electron microscopy, thermal response through differential scanning calorimetry, and deswelling/reswelling kinetics upon external temperature changes. In comparison with the conventional ones, the novel PNIPAAm hydrogels with pendent micellar structure presented improved temperature-sensitive properties, i.e., enlarged water containing capability at room temperature, as well as improved deswelling rate upon heating.

Introduction Polymeric hydrogels have been widely explored for biomedical applications due to the similarity between the highly hydrated three-dimensional networks and the hydrated body tissues, as well as favorable biocompatibility.1,2 In particular, great interest has been focused on the intelligent ones, which can change their volumes as a result of a slight variation of external stimuli, such as temperature,3 light,4 chemical environment,5 electric field,6 antigen,7 etc. In order to meet various applications, several strategies were proposed to improve the properties of hydrogels, such as design of microporous structure,8,9 macroporous structure,10 combtype network structure,11,12 etc. Recently, tailoring hydrogel architecture is one of the vigorous research subjects in hydrogel fields.13-16 Several kinds of hydrogels with particular structures exhibit unique properties and specific functions. For example, hydrogels with supermolecular structure, e.g., a topological hydrogel with figure-eight * To whom correspondence should be addressed. Tel: 86-27-6875 4061. Fax: 86-27-6875 4509. E-mail: [email protected]. † Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry. ‡ Colloid and Interface Science Laboratory and Department of Chemistry. (1) Hoffman, A. S. AdV. Drug DeliV. ReV. 2002, 43, 3-12. (2) Hirano, Y.; Mooney, D. J. AdV. Mater. 2004, 16, 17-25. (3) Hoffman, A. S. J. Control. Rel. 1987, 6, 297-305. (4) Suzuki, A.; Tanaka, T. Nature 1990, 346, 345-347. (5) Torres-Lugo, M.; Peppas, N. A. Macromolecules 1999, 32, 6646-6651. (6) Tanaka, T.; Nishio, I.; Sun, S. T.; Ueno-Nishio, S. Science 1982, 218, 467-469. (7) Miyata, T.; Asami, N.; Uragami, T. Nature 1999, 399, 766-769. (8) Antionietti, M.; Caruso, R. A.; Goltner, C. G.; Weissenberger, M. C. Macromolecules 1999, 32, 1383-1389. (9) Takeoka, Y.; Watanabe, M. Langmuir 2002, 18, 5977-5980. (10) Zhang, X. Z.; Yang, Y. Y.; Chung, T. S.; Ma, K. X. Langmuir 2001, 17, 6094-6099. (11) Kaneko, Y.; Sakai, K.; Kikuchi, A.; Yoshida, R.; Sakurai, Y.; Okano, T. Macromolecules 1995, 28, 7717-7723. (12) Yoshida, R.; Uchida, K.; Kaneko, Y.; Sakai, K.; Kikuchi, A.; Sakurai, Y.; Okano, T. Nature 1995, 374, 240-242. (13) Okumura, Y.; Ito, K. AdV. Mater. 2001, 13, 485-487. (14) Gong, J. P.; Katsuyama, Y.; Kurokawa, T.; Osada, Y. AdV. Mater. 2003, 15, 1155-1158. (15) Kumashiro, Y.; Lee, W. K.; Ooya, T.; Yui, N. Macromol. Rapid Commun. 2002, 23, 407-410. (16) Nakamura, K.; Murray, R. J.; Joseph, J. I.; Peppas, N. A.; Morishita, M.; Lowman, A. M. J. Control. Rel. 2004, 95, 589-599.

cross-links13 and a double-network hydrogel,14 were fabricated to improve mechanical or optical properties. Grafted hydrogels with combtype structure were designed to generate a fast response rate12 or to control the degradation behavior,15 as well as the drug release pattern.16 Hybrid hydrogels with interpenetrating polymer network structure (IPN) were also prepared to increase the deswelling kinetics17 or for drug delivery.18 The ability to tailor the chemical and mechanical properties of hydrogels at the molecular level is of importance in various biotechnology applications, including the engineering of complex tissues, the development of biosensors, and the elucidation of cell-cell and cell-material interactions.19 In this regard, as a fundamental technology, the self-assembly mechanism was also widely employed to control the nano-ordered structure at the molecular level. A polymeric micelle is a typical example of nano-ordered molecular aggregates. It is well known that copolymers consisting of hydrophilic segments and hydrophobic segments are able to associate spontaneously to form core-shell micellar structures above a certain critical concentration.20,21 The self-assembled micelles have been developed as the carriers for drug delivery.22-25 To date, there are very few reports dealing with the micelles self-assembled in the porous structure of hydrogels. Furthermore, through introducing the micelles into the hydrogel networks via chemical bonds instead of physical incorporation,26,27 the network architecture and property would be controlled. As a result, the corresponding (17) Zhang, X. Z.; Wu, D. Q.; Chu, C. C. Biomaterials 2004, 25, 3793-3805. (18) Gil, E. S.; Hudson, S. M. Biomacromolecules 2006, DOI: 10.1021/ bm060543. (19) Hahn, M. S.; Miller, J. S.; West, J. L. AdV. Mater. 2006, 18, 2679-2684. (20) Inoue, T.; Chen, G. H.; Nakamae, K.; Hoffman, A. S. J. Control. Rel. 1998, 51, 221-229. (21) Chung, J. E.; Yokoyama, M.; Okano, T. J. Control. Rel. 2000, 65, 93103. (22) Otsuka, H.; Nagasaki, Y.; Kataoka, K. AdV. Drug DeliV. ReV. 2003, 55, 403-419. (23) Wei, H.; Zhang, X. Z.; Zhou, Y.; Cheng, S. X.; Zhuo, R. X. Biomaterials 2006, 27, 2028-2034. (24) Luo, L.; Eisenberg, A. Langmuir 2001, 17, 6804-6811. (25) Wu, J.; Eisenberg, A. J. Am. Chem. Soc. 2006, 128, 2880-2884. (26) Huang, G.; Gao, J.; Hu, Z. B.; John. J. V. S.; Ponder, B. C.; Moro, D. J. Control. Rel. 2004, 94, 303-311. (27) Ramanan, R. M. K.; Chellamuthu, P.; Tang, L. P.; Nguyen, K. T. Biotechnol. Prog. 2006, 22, 118-125.

10.1021/la063485z CCC: $37.00 © 2007 American Chemical Society Published on Web 03/10/2007

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hydrogels might have superior properties, including fast response to stimuli, favorable drug release profiles, etc. In this paper, we demonstrate a novel concept to functionalize hydrogels by introducing the amphiphilic polymers into hydrogels to form the networks with pendent micellar structure. A thermosensitive hydrogel was fabricated by copolymerizing N-isopropylacrylamide (NIPAAm) and a novel amphiphilic macromonomer,P(NIPAAm-co-10-undecenoicacid)-NHCOCHd CH2. Due to the self-assembly behavior of the pending amphiphilic chains in the network, the pendent micellar structure was introduced into the PNIPAAm hydrogel network by covalent bonds. The influence of the pendent micellar structure on the properties of resulted hydrogels was examined in terms of morphology via scanning electron microscopy (SEM), thermal response through differential scanning calorimetry (DSC), and deswelling/reswelling kinetics upon external temperature changes. Experimental Section Materials. N-Isopropylacrylamide (NIPAAm), 2-aminoethanethiol hydrochloride (AET‚HCl), 2,2′-dimethoxy-2-phenyl acetophenone (DMPAP), and N-acryloxysuccinimide (NAS) were purchased from ACROS and used as received. N-Methylpyrrolidone (NMP), 10-undecenoic acid (UA), and N,N′-dimethylformamide (DMF) were obtained from Shanghai Reagent Chemical Co. and used after distillation under reduced pressure. N,N′-Azobisisobutyronitrile (AIBN) and N,N′-methylenebisacrylamide (BIS) were provided by Shanghai Reagent Chemical Co. and recrystallized from ethanol and DMF, respectively. All other reagents and solvents were of analytical grade and used without further purification. Synthesis of Amino-Terminated Poly(N-isopropylacrylamideco-10-Undecenoic acid) (P(NIPAAm-co-UA)-NH2). P(NIPAAmco-UA)-NH2 was prepared by radical polymerization using AET‚ HCl as a chain transfer agent.28 NIPAAm (50 mmol, 5.65 g), UA (5 mmol, 0.94 g), AET‚HCl (2.2 mmol, 0.25 g), and AIBN (0.24 mmol, 39.5 mg) were dissolved in 20 mL of DMF. The solution was degassed by bubbling with nitrogen for 30 min. The mixture reacted at 70 °C for 24 h under nitrogen. Then, the product was precipitated by the addition of chilled diethyl ether. Finally, P(NIPAAm-coUA)-NH2 (5.28 g) was obtained after precipitation and dried in vacuum for 24 h. Synthesis of Amphiphilic P(NIPAAm-co-UA)-NHCOCHd CH2. The amphiphilic macromonomer, P(NIPAAm-co-UA)NHCOCHdCH2 was synthesized by the nucleophilic substitution reaction between NAS and P(NIPAAm-co-UA)-NH2. In brief, NAS (1.72 mmol, 0.29 g) and P(NIPAAm-co-UA)-NH2 (1.51 g) were dissolved in 10 mL of DMF. The reaction was carried out at 4 °C for 2 days. Then the product was precipitated by the addition of chilled diethyl ether. The final product was dried in vacuum for 24 h to obtain the colorless macromonomer, P(NIPAAm-co-UA)NHCOCHdCH2 (1.37 g). GPC Measurements. Number- and weight-average molecular weight (Mn and Mw, respectively) of the macromonomer were determined by gel permeation chromatographic (GPC) system equipped with Waters 2690D separations module, Waters 2410 refractive index detector. THF was used as the eluent at a flow rate of 0.3 mL/min. Waters millennium module software was used to calculate molecular weight on the basis of a universal calibration curve generated by a polystyrene standard of a narrow molecular weight distribution. FT-IR Measurements. The macromonomer sample was analyzed by FT-IR (Perkin-Elmer Spectrum One) spectrophotometer. Before the measurement, the sample was pressed into potassium bromide (KBr) pellet. 1H NMR Measurement. The 1H NMR spectrum of P(NIPAAmco-UA)-NHCOCHdCH2 was recorded on a Mercury VX-300 (28) Soppimath, K. S.; Tan, D. C. W.; Yang, Y. Y. AdV. Mater. 2005, 17, 318-320.

Xu et al. Table 1. Feed Compositions of the PNIPAAm Hydrogels sample ID NIPAAm (mg) macromonomer (mg) BIS (mg) photoinitiator (mg) H2O (mL) NMP (mL) conversion (%)a a

CGel

Gel20

Gel30

Gel40

200 0 10 10 1 1.2 85.6

180 20 10 10 1 1.2 78.3

170 30 10 10 1 1.2 69.4

160 40 10 10 1 1.2 62.8

Weight percentage of the resulted hydrogel from the monomers.

spectrometer at 300 MHz (Varian) by using CDCl3 as a solvent and TMS as an internal standard. Preparation of Hydrogels. The polymerization of the novel PNIPAAm hydrogel was initiated by the photoinitiator (DMPAP). Particular amounts of NIPAAm, P(NIPAAm-co-UA)-NHCOCHd CH2, and the crosslinker, BIS, were dissolved in mixed solvent (distilled water/NMP) to obtain a clear solution. The feed compositions of the monomers and other reactants are listed in Table 1. The monomer solution was irradiated by a portable long-wavelength UV lamp (356 nm, 16 W) at room temperature (22 °C) for 24 h. The resulted PNIPAAm hydrogel was taken out and immersed in distilled water to leach out the unreacted chemicals for 3 days. During this period, the distilled water was replaced with fresh water every 4 h. The hydrogels prepared were labeled as Gelx, where x means the amount of the macromonomer P(NIPAAm-co-UA)-NHCOCHd CH2. Herein, the conventional PNIPAAm hydrogel was used as a control and designated as CGel, which was fabricated under the same condition without the macromonomer. The hydrogels were cut into disks with a 10 mm diameter and a 8 mm thickness for the following characterizations. Interior Morphology. The swollen hydrogel samples, after reaching equilibrium swelling ratios in the solvent (distilled water or DMSO) at room temperature, were quickly frozen in liquid nitrogen and then freeze-dried in a freeze drier (Labconco) under vacuum at -45 °C for 3 days. The freeze-dried samples were then fractured carefully in liquid nitrogen, and the interior morphology of the hydrogel samples was studied by a scanning electron microscope (SEM, FEI-QUANTA 200). Before SEM observation, the hydrogel specimens were coated with gold for 7 min. Brunauer-Emmett-Teller (BET) Surface Area. The surface area of the hydrogels was investigated via nitrogen adsorption isotherms at 77 K on a Micromeritics ASAP 2020 volumetric adsorption analyzer. All the freeze-dried bulk hydrogel samples (∼10 mg) were degassed under vacuum for 6 h at 313 K prior to measurements. The BET surface area was calculated using data in a relative pressure range from 0.05 to 0.25 by the BET method. LCST Behavior. LCST (lower critical solution temperature) behavior of the hydrogel was determined by using DSC (DSC822e, METTLER). Each sample was immersed in distilled water at room temperature and allowed to reach the equilibrium state. Then, the swollen sample was placed in a hermetic sample pan and sealed. The thermal analysis was performed at a heating rate of 3 °C/min on the swollen sample under a dry nitrogen atmosphere with a flow rate of 50 mL/min. Temperature Dependence of Swelling Ratios. The gravimetric method was employed to study the temperature dependence of swelling ratio of the hydrogels. The samples were equilibrated in distilled water at a temperature ranging from 22 to 45 °C. The samples were allowed to swell in the distilled water for at least 24 h at each predetermined temperature by a thermostated water bath. After 24 h immersion in the distilled water, the samples were weighed after wiping off the excess water on the surfaces by moistened filter paper. Each sample was measured three times, and the average value of three measurements was taken. After this weight measurement, the samples were re-equilibrated in distilled water at another predetermined temperature, and then their wet weights were determined as above. The dry weight of each sample was obtained after dried in vacuum at 45 °C for 24 h. The swelling ratio at each

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Langmuir, Vol. 23, No. 8, 2007 4233 [Water uptake]t ) [(Wt - Wd)/Ws] × 100

(3)

where Wt is the weight of the wet hydrogel at time t at room temperature and the other symbols are the same as defined above.

Results and Discussion

Figure 1. FT-IR spectrum of P(NIPAAm-co-UA)-NHCOCHd CH2. temperature was calculated as follows SReq ) Ws/Wd

(1)

where Ws is the weight of water in the equilibrium swollen hydrogel (wet weight - dry weight) and Wd is the dry weight. Deswelling Kinetics at 50 °C. The deswelling kinetics of the equilibrated swollen hydrogel was measured gravimetrically in distilled water at 50 °C. At predetermined time intervals, the samples were taken out from the hot water (50 °C) and weighed after removing the excess water on the surfaces with wet filter paper. Similarly, each sample was measured three times, and the average value of three measurements was used. Water retention was defined as follows [Water retention]t ) [(Wt - Wd)/Ws ] × 100

(2)

where Wt is the weight of the wet hydrogel at time t at 50 °C, Ws is the equilibrium water weight at room temperature, and the other symbols are the same as defined above. Reswelling Kinetics at 22 °C. The dried sample was immersed in distilled water at room temperature and removed from water at regular time intervals. After removing the water on the surface with wet filter paper, the weight which was the average value of three measurements was recorded. The water uptake at time t was defined as follows

Synthesis of the Macromonomer. During the synthesis of amphiphilic P(NIPAAm-co-UA)-NHCOCHdCH2, NIPAAm and UA were randomly copolymerized to obtain the macromonomer (Mn ) 13 200 g/mol, Mn/Mw ) 1.8 by GPC measurement). The chemical structure of the resulted macromonomer was characterized by FT-IR (Figure 1) and 1H NMR (Figure 2) spectroscopy, respectively. As shown in Figure 1, the typical amide I and II bands of NIPAAm units were obvious at 1648 and 1547 cm-1. Besides, the stretching variation absorbance of CdO in carboxylic groups of UA units existed at 1712 cm-1. From the FT-IR spectrum, we can conclude that the resulted macromonomer contained NIPAAm and UA units. Herein, in order to exactly determine the molar ratio of UA units to NIPAAm units in the macromonomer, the 1H NMR measurement was carried out. The corresponding 1H NMR spectrum is exhibited in Figure 2. From the spectrum, the amide protons (-NH, signal f) of NIPAAm units and the protons of carboxylic groups (-COOH, signal h) of the UA units were at 6.4-7.2 and 8.68.8 ppm, respectively. The chemical shifts at 6.3 (signal e) and 8 ppm (signal g) were mainly associated with the terminal protons of -CHdCH2 and -NH, respectively. Other peaks and their chemical shifts were consistent with the literature report.29 On the basis of the above 1H NMR spectrum analysis, the actual molar ratio of UA units to NIPAAm units in the resulted macromonomer could be calculated from the peak intensities of signal h (UA units) and d (NIPAAm units). The peak intensities of signal h and d were 0.41 and 4.33, respectively. That is, the molar ratio of UA to NIPAAm was 1:10.5 in the polymeric chain of the resultant macromonomer, which nearly coincided with the feed composition (1:10). Preparation of Hydrogels. In general, block copolymers consisting of hydrophilic NIPAAm units and hydrophobic UA units are able to form a core-shell micellar structure in aqueous solution at the temperature below the LCST of PNIPAAm. In this study, in order to avoid the self-assembling of the

Figure 2. 1H NMR spectrum of P(NIPAAm-co-UA)-NHCOCHdCH2.

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Figure 3. Synthesis scheme of the novel PNIPAAm hydrogels.

macromonomers before the hydrogel formation, the mixed solvent of distilled water and NMP was used. The synthesis scheme of the novel PNIPAAm hydrogels is presented in Figure 3. Interior Morphology. In order to confirm the presence of pendent micellar structure originated from the self-assembly behavior of the grafted amphiphilic polymers, the hydrogel samples were immersed in distilled water (Figure 4a) and DMSO (Figure 4b) and then freeze-dried for SEM observation. From Figure 4a, it was found that different kinds of pendent micellar structures (sphere or dumbbell) appeared in the networks of Gel20, Gel30, and Gel40. As mentioned above, the conventional amphiphilic copolymers consisting of PNIPAAm segments and hydrophobic segments can form core-shell micellar structure below the LCST. Recently, it was reported that random copolymers of NIPAAm and UA could self-assemble into coreshell nanoparticles.28 Similarly, in this paper, the grafted amphiphilic P(NIPAAm-co-UA) chains would self-assemble in water to form the pendent micellar structure in the resulted hydrogel networks, which is demonstrated in Figure 4a. In contrast, as shown in Figure 4b, the restrained network structure instead of the pendent micellar structure of the hydrogels can be observed when immersed in DMSO. This difference in morphology of the hydrogels under different conditions was reasonable, and similar findings were also reported in other studies.22,23 The core-shell structure, i.e., pendent micellar structure, could be destroyed in organic solvent, such as DMSO,

Xu et al.

to form dispersed polymeric chains. As a result, no pendent micellar structure would exist in the hydrogel networks in DMSO. Simultaneously, the initial porous structure in water was also changed to the heterogeneous and collapsed morphology in DMSO. The disappearance of the micellar structure further confirmed that the pendent micellar structure in Figure 4a resulted from the self-assembling of the amphiphilic polymeric chains in water. Importantly, the micellar structure was introduced into the network via chemical bond instead of traditional physical incorporation. The chemical incorporation of the micellar structure into the hydrogel network would overcome the leakage problem of the traditional composite hydrogel, where nanoparticles were incorporated physically into bulk hydrogel networks.30 Among the SEM micropictures in Figure 4a, the average pore size of the hydrogels increased from CGel to Gel40. Generally, in order to prepare macroporous networks, pore-forming agents, such as cellulose31 and PEG,10 were added physically to the monomer solution, although pore-forming agents did not participate in the polymerizing/cross-linking reaction. Due to the existence of pore-forming agents, the resultant networks exhibited macroporous or expanded network structures. In this study, during the formation of hydrogels, the grafted amphiphilic polymers would lead to spatial hindrance and the similar effect of pore-forming agents to form macroporous network structures. BET Surface Area. The BET surface areas of the novel PNIPAAm hydrogels determined via nitrogen adsorption isotherms are shown in Figure 5. It was easily found that the BET surface area of the hydrogel almost linearly decreased with the increasing content of the amphiphilic polymers. For example, the BET surface area of CGel was 4.96 m2/g, while those of Gel20, Gel30, and Gel40 were 3.08, 0.73, and 0.34 m2/g, respectively. As we know, there was a tendency that the microporous materials had the lager BET surface area. The decreasing BET surface area in Figure 5 indicated that the number of the pores reduced from CGel to Gel40. On the other hand, this decreasing BET surface area simultaneously demonstrated that the pore size increased from CGel to Gel40, which was also confirmed by the SEM micropictures in Figure 4a. In the same way, the conclusion of the BET surface area also demonstrated that the grafted amphiphilic polymers acted as a pore-forming agent during the hydrogel formation. LCST Behavior. The LCSTs of the novel PNIPAAm hydrogels determined from the DSC thermograms are exhibited in Figure 6. As shown in Figure 6, all the hydrogels regardless of content of the grafted amphiphilic polymers showed relatively

Figure 4. SEM micropictures of the novel PNIPAAm hydrogels and the conventional hydrogel in distilled water (a) or DMSO (b).

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Figure 7. Temperature dependence of the swelling ratio of the novel PNIPAAm hydrogels and the conventional hydrogel over a temperature range from 22 to 45 °C. Figure 5. BET surface areas of the novel PNIPAAm hydrogels and the conventional hydrogel.

Figure 8. Deswelling kinetics of the novel PNIPAAm hydrogels and the conventional hydrogel at 50 °C. Figure 6. LCSTs of the novel PNIPAAm hydrogels and the conventional hydrogel (the onset temperature of endotherm was referred as LCST).

similar LCSTs at around 33 °C (ranging from 32.7 to 33.4 °C). In fact, from Figure 6, although the LCST of the hydrogel had the tiny tendency to increase with the increasing content of grafted amphiphilic polymers, no apparent difference was found. That is, the pendent micellar structure had no apparent impact on the LCST. A widely recognized mechanism to explain the LCST behavior of PNIPAAm hydrogels is that the phase transition resulted from a balance between hydrophilicity and hydrophobicity in the polymeric backbone.32,33 When a hydrophilic moiety was copolymerized into PNIPAAm hydrogel network, the hydrophilic/hydrophobic balance shifted to a more hydrophilic nature and the corresponding LCST shifted to a higher temperature. In contrast, if the hydrophobic moiety was copolymerized into the polymeric chain, its LCST became lower. Here, the amphiphilic P(NIPAAm-co-UA)-NHCOCHdCH2 moiety was incorporated into PNIPAAm hydrogel network as the pendent chains, instead of the backbone. Thus, the initial hydrophilic/ hydrophobic balance of the backbone did not change apparently. Consequently, the LCST of the resulted hydrogel did not change obviously. Temperature Dependence of Swelling Ratios. The temperature dependence of swelling ratio of the novel PNIPAAm hydrogels was examined to evaluate their temperature-sensitive properties. Figure 7 exhibits the temperature-dependent swelling (29) Li, Y. Y.; Zhang, X. Z.; Kim, G. C.; Cheng, H.; Cheng, S. X.; Zhuo, R. X. Small 2006, 2, 917-923. (30) Xu, X. D.; Wei, H.; Zhang, X. Z.; Cheng, S. X.; Zhuo, R. X. J. Biomed. Mater. Res. 2006, DOI: 10.1002/jbm.a.31063. (31) Wu, X. S.; Hoffman, A. S.; Yager, P. J. Polym. Sci., Part A: Polym. Chem. 1992, 30, 2121-2129. (32) Vernon, B.; Kim, S. W.; Ba, Y. H. J. Biomed. Mater. Res. 2000, 51, 69-79. (33) Shibayama, M.; Fujikawa, Y.; Nomura, S. Macromolecules 1996, 29, 6535-6540.

ratios over the temperature range 22-45 °C. As shown in the figure, all the hydrogels demonstrated a similar swelling profiles, i.e., the swelling ratio of all the hydrogels decreased rapidly as the temperature increased toward their LCSTs. Traditionally, in terms of swelling ratio changing, the phase-separation temperature or LCST is regarded as the temperature at which the phaseseparation degree, swelling ratio change vs temperature change (∆SR/∆T), is the greatest, or the temperature at which the swelling ratio of hydrogel decreases most dramatically. From Figure 7, it was clear that the LCSTs of the hydrogels were around 33 °C, irrespective of presence of the pendent micellar structure, which was in agreement with the LCSTs determined from the DSC. Even though the LCSTs of the hydrogels were not virtually affected by the pendent micellar structure, the data in Figure 7 show that, at a temperature below the LCST, the equilibrium swelling ratio of hydrogels increased from CGel to Gel40. For example, at room temperature the equilibrium swelling ratio of CGel was 53.5, while those of Gel20, Gel30, and Gel40 were 80, 232, and 255, respectively. Due to the increasing average pore size from CGel to Gel40 as indicated in Figure 4a, the capacity of holding water increased correspondingly. As a result, the swelling ratio of hydrogels improved from CGel to Gel40. On the basis of our experiments, due to the increasing of water content from CGel to Gel40, the macroscopic mechanical property of resulted hydrogel decreased correspondingly. Furthermore, it was interesting to note, at the temperature above their LCSTs, there was no effect of the pendent micellar structure on the swelling ratio of hydrogels, which suggested that, with or without the pendent micellar structure, all the hydrogels would collapse into the similar structure at the temperature above their LCSTs. Deswelling Kinetics at 50 °C. The temperature dependence of the swelling ratios only demonstrated the equilibrium hydration state of hydrogels at different temperatures. In practical applications, the temperature response kinetics or deswelling kinetics upon the suddenly altered stimulation is more important. Figure 8 presents the deswelling kinetics of these novel PNIPAAm

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Figure 9. Reswelling kinetics of the novel PNIPAAm hydrogels and the conventional hydrogel at 22 °C.

hydrogels after transferring an equilibrated swollen sample at 22 °C (below its LCST) to hot water at 50 °C (above its LCST). It was shown that all the hydrogels tended to shrink and lost water once immersed into hot water at 50 °C. From the figure, the deswelling rate of the hydrogels improved from CGel to Gel40. For instance, the water retention of Gel40 decreased from 100% to 1.5% within 4 min, while that of Gel30, Gel20, and CGel decreased from 100% to 13.1%, 17.4%, and 24.9% within the same time frame, respectively. Yoshida et al.12 prepared the fast responsive comb-type PNIPAAm by grafting the PNIPAAm without UA units as the side chain. They reported that the grafted PNIPAAm chains in the hydrogel can easily collapsed at the temperature above the LCST due to the strong shrinking tendency of PNIPAAm chains that bear free ends. Recently, Noguchi et al.34 reported a new PNIPAAm hydrogel by using amphiphilic surfactant to modify the hydrogel properties. When the external temperature was above the LCST, the amphiphilic surfactant acted to form the micellar structure. In the shrinking procedure, the inside water was rapidly squeezed out through the hydrophilic channels between the formed micelles and consequently the hydrogel shrunk quickly. With a similar reason, the PNIPAAm hydrogels with pendent micellar structure prepared here exhibited fast response rates upon heating. In addition, the enlarged average pore size would accelerate the shrinking rate and water molecules could diffuse out from hydrogel network quickly. (34) Noguchi, Y.; Okeyoshi, K.; Yoshida, R. Macromol. Rapid Commun. 2005, 26, 1913-1917.

Xu et al.

Reswelling Kinetics at 22 °C. Figure 9 displays the reswelling behaviors of the dried hydrogel samples. From the figure, it was found that the reswelling rate of the hydrogels decreased from CGel to Gel40. For example, the water uptake of dried CGel reached 38.7% within 300 min, while within the same time frame, the water uptakes of Gel20, Gel30, and Gel40 reached 26.8%, 21.9%, and 16.4%, respectively. The reswelling procedure is complicated and involves three successive steps:35,36 (1) the diffusion of water molecules into a polymer system, (2) the subsequent relaxation of hydrated polymer chains, and (3) the expansion of polymer network into aqueous solution. In this study, steps 2 and 3 induced the different reswelling rates. Due to the existence of the grafted amphiphilic polymers in the hydrogel network, there were extra hydrophilic and hydrophobic interactions between the network and the grafted amphiphilic chains, which resulted in slow rates of relaxation of hydrated polymer chains and expansion of polymer network into the aqueous solution. The reswelling rate of the resulted hydrogel decreased accordingly. And also, due to the increasing grafted chains from CGel to Gel40, the above extra hydrophilic and hydrophobic interactions would strengthen, resulting in decreasing reswelling rate from CGel to Gel40.

Conclusions In this study, for the first time, we synthesized a series of novel PNIPAAm hydrogels by grafting amphiphilic chains to fabricate hydrogel networks with pendent micellar structure. Although the LCST did not change apparently from the conventional one, the PNIPAAm hydrogels with pendent micellar structure had large porous network structure and exhibited enlarged water-containing capability at room temperature, as well as improved deswelling rate upon heating. The improved properties in the PNIPAAm hydrogels with pendent micellar structure may find potential applications in drug delivery and biotechnology fields. Acknowledgment. This work was supported by National Key Basic Research Program of China (2005CB623903) and National Natural Science Foundation of China (20504024). LA063485Z (35) Zhang, X. Z.; Zhuo, R. X. J. Colloid Interface Sci. 2000, 223, 311-313. (36) Zhang, X. Z.; Wu, D. Q.; Chu, C. C. Biomaterials 2004, 25, 4719-4730.