Preparation and Characterization of Fast Response Macroporous Poly

Sep 7, 2001 - Macroporous temperature-sensitive poly(N-isopropylacrylamide) (PNIPAAm) hydrogels have been successfully synthesized by using poly(ethyl...
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Preparation and Characterization of Fast Response Macroporous Poly(N-isopropylacrylamide) Hydrogels Xian-Zheng Zhang,† Yi-Yan Yang,*,† Tai-Shung Chung,*,†,‡ and Kui-Xiang Ma† Advanced Polymers and Chemicals, Institute of Materials Research and Engineering, 3 Research Link, Singapore 117602, Singapore, and Department of Chemical and Environmental Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore Received January 18, 2001. In Final Form: July 18, 2001 Macroporous temperature-sensitive poly(N-isopropylacrylamide) (PNIPAAm) hydrogels have been successfully synthesized by using poly(ethylene glycol) (PEG) as the pore-forming agent. Scanning electron microscope graphs reveal that the macroporous network structure of the hydrogels can be adjusted by applying different molecular weights of PEG during the polymerization reaction. The surface roughness of the hydrogels is also investigated using atomic force microscopy, and the results indicate that the surface of the PEG-modified gel is much rougher compared to that of the conventional PNIPAAm gel. The newly invented macroporous hydrogels exhibit much better properties as temperature-sensitive intelligent polymers. For instance, at a temperature below the lower critical solution temperature (LCST), they absorb larger amounts of water and show obviously higher equilibrated swelling ratios in the aqueous medium. Particularly, due to their unique macroporous structure, the PEG-modified hydrogels show a tremendously faster response to the external temperature changes during deswelling and reswelling processes as the temperature cycles across the LCST. They can also shrink and lose water with dramatically rapid rates at temperatures above the LCST. The macroporous PNIPAAm gel has potential applications in controlled release of macromolecular active agents.

Introduction Intelligent polymers which have the capability to respond to small external stimulus changes, such as temperature,1 pH,2 photo field,3 and antigen,4 have attracted significant attention from both academia and industry. A considerable number of studies have been undertaken.5-10 Poly(N-isopropylacrylamide) (PNIPAAm) is a well-known temperature-sensitive polymer and demonstrates a transition temperature (Ttr) or lower critical solution temperature (LCST) at about 32 °C.11 PNIPAAm in an aqueous solution has reversible solubility and exhibits a remarkable hydration-dehydration change in response to temperature. Below the LCST, PNIPAAm is well soluble in water. However, as the temperature is increased above the LCST, it becomes hydrophobic and precipitates out from the aqueous solution. The PNIPAAm hydrogel possesses a three-dimensional network structure, which is insoluble but has characteristics of reversible swelling. The polymer chains undergo a coil (soluble)* To whom correspondence should be addressed. Tel: 65-8748373. Fax: 65-8727528. E-mail: [email protected]; [email protected]. † Institute of Materials Research and Engineering. ‡ National University of Singapore. (1) Chen, G. H.; Hoffman, A. S. Nature 1995, 373, 49-52. (2) Qu, X.; Wirse´n, A.; Albertsson, A. C. Polymer 2000, 41, 45894598. (3) Suzuki, A. Nature 1990, 346, 345-347. (4) Miyata, T.; Asami, N.; Uragami, T. Nature 1999, 399, 766-769. (5) Sen, M.; Uzun, C.; Gu¨ven, O. Int. J. Pharm. 2000, 203, 149-157. (6) Sun, Y. M.; Chen, J. P.; Chu, D. H. J. Biomed. Mater. Res. 1999, 45, 125-132. (7) Torres-Lugo, M.; Peppas, N. A. Macromolecules 1999, 32, 66466651. (8) Risbud, M. V.; Hardikar, A. A.; Bhat, S. V.; Bhonde, R. R. J. Controlled Release 2000, 68, 23-30. (9) Podual, K.; Doyle, F. J., III; Peppas, N. A. Polymer 2000, 41, 3975-3983. (10) To¨ro¨k, G.; Lebedev, V. T.; Cser, L.; Zrinyi, M. Physica B 2000, 276-278, 396-397. (11) Taylor, L. D.; Cerankowski, L. D. J. Polym. Sci.: Polym. Chem. Ed. 1975, 13, 2551-2569.

globule (insoluble) transition when the external temperature cycles across the LCST at about 33 °C.12-16 Thus, at a temperature below the LCST, PNIPAAm hydrogel absorbs water and exists in a swollen state, but it shrinks and displays an abrupt volume decrease when the environmental temperature is higher than the LCST. Generally, the main reason for this distinctive property of the PNIPAAm hydrogel has been attributed to its uniquely rapid alteration in hydrophilicity and hydrophobicity.11,17-20 When the hydrophilic groups in the side chains of the PNIPAAm hydrogel connect with water molecules through hydrogen bonds, these hydrogen bonds act cooperatively to form a stable hydration shell around the hydrophobic groups, which leads to the great water uptake of the PNIPAAm hydrogel at temperatures below the LCST. However, as the external temperature increases, the hydrogen bonding interactions become weakened or destroyed; thus, the hydrophobic interactions among the hydrophobic groups grow to be stronger which induces the freeing of the entrapped water molecules from the network. When the temperature reaches or is above the LCST, the hydrophobic interactions become fully dominant. With a rapid water release, the polymer chains (12) Hirokawa, Y.; Tanaka, T. J. Chem. Phys. 1984, 81, 63796380. (13) Pekcan, O ¨ .; Kara, S. Polymer 2000, 41, 8735-8739. (14) Oh, J. S.; Kim, J. M.; Lee, K. J.; Bae, Y. C. Eur. Polym. J. 1999, 35, 621-630. (15) Wu, S.; Jorgensen, J. D.; Skaja, A. D.; Williams, J. P.; Soucek, M. D. Prog. Org. Coat. 1999, 36, 21-33. (16) Qiu, X. P.; Kwan, C. M. S.; Wu, C. Macromolecules 1997, 30, 6090-6094. (17) Feil, H.; Bae, Y.; Feijen, J.; Kim, S. W. Macromolecules 1993, 26, 2496-2500. (18) Inomato, H.; Goto, S.; Saito, S. Macromolecules 1990, 23, 48874888. (19) Tokuhiro, T.; Amiya, T.; Mamada, A.; Tanaka, T. Macromolecules 1991, 24, 2936-2943. (20) Bokias, G.; Hourdet, D.; Iliopoulos, I.; Staikos, G.; Audebert, R. Macromolecules 1997, 30, 8293-8297.

10.1021/la010105v CCC: $20.00 © 2001 American Chemical Society Published on Web 09/07/2001

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Table 1. Feed Compositions of the Conventional and PEG-Modified PNIPAAm Hydrogels sample ID NIPAAm (mg) BIS (mg) PEG (g) H2O (mL) 10 wt % APS (ul) TEMED (ul) conversion (%)b a

NG

NE-300a

NE-600

NE-1000

NE-2000

100 2.0 0 1.2 30 5 96.5

100 2.0 0.2 (PEG-300) 1.2 30 5 60.83

100 2.0 0.2 (PEG-600) 1.2 30 5 51.95

100 2.0 0.2 (PEG-1000) 1.2 30 5 59.57

100 2.0 0.2 (PEG-2000) 1.2 30 5 64.28

Molecular weight of PEG used during the polymerization. b Weight percentage of the synthesized gel from the NIPAAm monomer.

contract or collapse abruptly and the phase separation of the PNIPAAm hydrogel system occurs. This phase separation is thermoreversible, which makes this hydrogel especially useful for biomedical and bioengineering applications such as protein-ligand recognition,21 on-off switches for modulated drug delivery22-24 or artificial organs,25 and immobilization of enzyme.26 Since the rapid response rate to temperature variation is the most essential function for their applications, the response rate of the hydrogels has to be improved. In this regard, several strategies have been proposed in order to increase the response kinetics. One strategy is to form a heterogeneous network structure of the hydrogel through a phase separation method.27,28 T. Okano’s research group suggested another strategy to synthesize rapid deswelling PNIPAAm hydrogels by graft-copolymerizing a comblike structure.29-31 In recent years, R. X. Zhuo’s team also reported that the response rate of the PNIPAAm hydrogel could be improved via incorporating siloxane linkage, cold polymerization, and cross-linking methods.32-35 In this paper, a new strategy is proposed to prepare rapid response PNIPAAm hydrogels with a macroporous network structure by using poly(ethylene glycol) (PEG) as a pore-forming agent36 during the polymerization reaction. The influence of PEG molecular weight on porous structure is further investigated. The PEG-modified PNIPAAm hydrogels are characterized by swelling ratio, deswelling/reswelling kinetics, Fourier transform infrared spectroscopy (FT-IR), and differential scanning calorimetry (DSC). The morphology of the PNIPAAm hydrogels is analyzed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The PEG-modified PNIPAAm hydrogels may have potential applications in (21) Stayton, P. S.; Shimobji, T.; Long, C.; Chilkoti, A.; Chen, G.; Harris, J. M.; Hoffman, A. S. Nature 1995, 378, 472-474. (22) Ramkissoon-Ganorkar, C.; Liu, F.; Baudysˇ, M.; Kim, S. W. J. Controlled Release 1999, 59, 287-298. (23) Gutowska, A.; Bae, Y. H.; Jacobs, H.; Mohammad, F.; Mix, D.; Feijen, J.; Kim, S. W. J. Biomed. Mater. Res. 1995, 29, 811-821. (24) Vakkalanka, S. K.; Brazel, C. S.; Peppas, N. A. J. Biomater. Sci., Polym. Ed. 1996, 8, 119-129. (25) Osada, Y.; Okuzaki, H.; Hori, H. Nature 1992, 355, 242-244. (26) Liu, F.; Tao, G. L.; Zhuo, R. X. Polym. J. 1993, 25, 561-567. (27) Kabra, B. G.; Gehrke, S. H. Polym. Commun. 1991, 32, 322323. (28) Wu, X. S.; Hoffman, A. S.; Yager, P. J. Polym. Sci., Part A: Polym. Chem. 1992, 30, 2121-2129. (29) Yoshida, R.; Uchida, K.; Kaneko, Y.; Sakai, K.; Kikuchi, A.; Sakurai, Y.; Okano, T. Nature 1995, 374, 240-242. (30) Kaneko, Y.; Nakamura, S.; Sakai, K.; Aoyaji, T.; Kikuchi, A.; Sakurai, Y.; Okano, T. Macromolecules 1998, 31, 6099-6105. (31) Kaneko, Y.; Sakai, K.; Kikuchi, A.; Yoshida, R.; Sakurai, Y.; Okano, T. Macromolecules 1995, 28, 7717-7723. (32) Zhang, X. Z.; Zhuo, R. X. Colloid Polym. Sci. 1999, 277, 10791082. (33) Zhang, X. Z.; Zhuo, R. X. Langmuir 2001, 17, 12-16. (34) Zhang, X. Z.; Zhuo, R. X. Macromol. Chem. Phys. 1999, 200, 2602-2605. (35) Zhang, X. Z.; Zhuo, R. X. J. Colloid Interface Sci. 2000, 223, 311-313. (36) Lin, J. K.; Ladisch, M. R.; Patterson, J. A.; Noller, C. H. Biotechnol. Bioeng. 1987, 29, 976-981.

the controlled release of macromolecular active agents such as proteins and peptides since the macroporous structure may be able to provide enough space for the loading and releasing of macromolecular active agents. Experimental Section Materials. N-Isopropylacrylamide (NIPAAm, Aldrich Chemical Co., Inc., USA) was recrystallized from benzene/n-hexane. N,N′-Methylenebisacrylamide (BIS, Bio-Rad Laboratories, USA), ammonium persulfate (APS, Bio-Rad Laboratories), N,N,N′,N′tetramethylethylenediamine (TEMED, Bio-Rad Laboratories), and poly(ethylene glycol)s with molecular weights of 300, 600, 1000, and 2000 (defined as PEG-300, PEG-600, PEG-1000, and PEG-2000, respectively; Aldrich) were used as supplied. Synthesis of PNIPAAm Hydrogels. The polymerization of the conventional and PEG-modified PNIPAAm hydrogels was carried out in deionized water solution at room temperature (22 °C) for 6 h using APS and TEMED as a pair of redox initiators with the cross-linker BIS. The difference between the PEGmodified and conventional PNIPAAm hydrogels is the addition of PEG during the polymerization reaction of the former hydrogels. Here, PEGs with different molecular weights are employed as the pore-forming agent, which does not react with other chemicals during the polymerization. After the reaction, the resultant hydrogels were cut into disks (10 mm in diameter and 3 mm in thickness). The disk samples were immersed in deionized water at room temperature for at least 48 h, and the water was changed every several hours to wash out PEG and the unreacted materials. The feed compositions of monomers and other chemicals are listed in Table 1. FT-IR Measurements. The hydrogel samples were analyzed by FT-IR (Perkin-Elmer Spectrum 2000, USA) in the region of 2000-1000 cm-1. Before the measurement, the originally swollen hydrogel samples were kept at room temperature for 48 h and then freeze-dried (-48 °C, 38 × 10-3 mbar) for at least 24 h. LCST Determination. The LCST of the hydrogel samples was determined using a Perkin-Elmer 7-Series differential scanning calorimeter (model DSC 4, Perkin-Elmer, CT). All samples were immersed in deionized water at room temperature and allowed to swell for at least 24 h to reach the equilibrium state. The thermal analyses were performed from 25 to 45 °C (heating rate, 3 °C/min) on the swollen hydrogels under a dry nitrogen atmosphere with a flow rate of 40 mL/min. Deionized water was used as reference. Scanning Electron Microscopy. The surface morphology of the hydrogels was studied using a scanning electron microscope (XL Series-30, Philips, USA). Specimens of the freeze-dried gels were glued to the brass holders and coated with gold for 40 s using a coating machine (JFC-1200 Fine Coater, Japan) prior to the SEM examination. Atomic Force Microscopy. An atomic force microscope (Park Scientific, CA) was employed to investigate the surface roughness of the hydrogels. AFM studies were carried out on an AutoProbe CP Research model, supplied by ThermoMicroscopes. The sample surfaces of the freeze-dried conventional and PEG-300-modified PNIPAAm hydrogels were scanned in a noncontact mode, using a 100 µm scanner and AutoProbe mounted Si tip with a force constant of 2.1 N/m and a frequency of 95 kHz, respectively. All topography images were processed by flattening under IP 1.3 Imaging Processing software, provided by the manufacturer.

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Swelling Ratio Measurement. The swelling ratios of the hydrogels were measured gravimetrically after wiping off the excess water on the surface with moistened filter paper in the temperature range from 22 to 45 °C. The gel samples were incubated in deionized water for at least 24 h at each particular temperature. The swelling ratio was calculated from the following formula:

swelling ratio ) Ws/Wd

(1)

where Ws is the weight of water in the swollen hydrogel at the particular temperature and Wd is the dry weight of the hydrogel. Deswelling Kinetics Measurement. The deswelling of the hydrogels after a temperature jump from the equilibrated swollen state at room temperature to the hot water at 48 °C was measured after wiping off the excess water on the surface with moistened filter paper. The weight changes of the hydrogels were recorded during the shrinking course at regular time intervals. Water retention was defined and calculated from the following formula:

water retention ) 100(Wt - Wd)/Ws

(2)

where Wt is the weight of the wet hydrogel at regular time intervals and the other symbols are the same as defined above. Reswelling Kinetics Measurement. The reswelling kinetics of the shrunk samples was determined gravimetrically at 22 °C after wiping off the water on the surface with moistened filter paper. The swollen gels shrank in the hot water (48 °C) for 8 h prior to this measurement. The weight of the hydrogels was recorded at predetermined time intervals. Water uptake was defined and calculated from the following formula:

water uptake ) 100(Wt - Wd)/Ws

Figure 1. FT-IR spectra of the conventional and PEG-modified PNIPAAm hydrogels: (a) ∼1644 cm-1, (b) ∼1538 cm-1, and (c) ∼1386 and ∼1367 cm-1.

(3)

Wt, Wd, and Ws are the same as defined above.

Results and Discussion Hydrogel Synthesis. Both conventional and PEGmodified PNIPAAm hydrogels can be easily synthesized. However, the existence of PEG influences the conversion efficiency from the NIPAAm monomer. The conversion efficiency of the hydrogels in terms of weight percentage is summarized in Table 1. For instance, the conversion efficiency of the conventional PNIPAAm gel is 96.5 wt %, while it drops to proximately 60 wt % with the presence of PEG. This decrease in conversion efficiency is probably attributed to the spatial hindrance that PEG provides during the polymerization. At the end of polymerization, the NE-2000 gel appears to be translucent with obviously fine opaque domains in the matrix, indicating that its network structure may be heterogeneous and the pore size within the gel is probably relatively large.28 This may be arisen from the phase separation of the formed PNIPAAm chains and PEG molecules. FT-IR Spectra of PNIPAAm Hydrogels. The FT-IR spectra of the conventional and PEG-modified PNIPAAm gel samples, which have been freeze-dried, are shown in Figure 1. The FT-IR spectra of all the gels are similar. There exists a typical amide I band (∼1644 cm-1), consisting of the CdO stretch of PNIPAAm and the amide II band (∼1538 cm-1), including N-H vibration in each spectrum. One can also observe two typical bands of C-H vibration with the nearly same intensity at ∼1386 and ∼1367 cm-1 in each spectrum which belong to the divided bands of the symmetric -CH(CH3)2 group. On the other hand, if there exists PEG in the PEG-modified gel system, a typical and strong peak positioned at around 1100 cm-1, which belongs to the C-O stretch of PEG, would appear. From Figure 1, there is no obvious peak appearing around 1100 cm-1 in the spectra of PEG-modified gels. These findings suggest that the PEG-modified PNIPAAm gel has the same chemical composition as the conventional

Figure 2. DSC thermograms of the conventional and PEGmodified PNIPAAm hydrogels at a heating rate of 3 °C/min from 25 to 45 °C.

PNIPAAm gel and PEG does not exist in the PEG-modified gels after they are extensively washed. PEG acts as a pore-forming agent and does not participate with the polymerization. DSC Behaviors of PNIPAAm Hydrogels. Figure 2 exhibits the DSC thermograms of the conventional and PEG-modified PNIPAAm gels. Here, the temperatures at the onset point of the DSC endotherms are referred to the LCSTs37 as illustrated in the figure. Clearly, all the PNIPAAm gels show a similar LCST around 35 °C. For instance, the LCST for the NG gel and the NE-2000 gel are 35.0 and 34.8 °C, respectively. The invariance of LCST with PEG content reconfirms our previous hypotheses that PEG acts as a pore-forming agent during the polymerization and it has been easily removed by washing with freshwater. SEM Micrographs of PNIPAAm Hydrogels. Figure 3 shows the SEM photos of the surface structure of the (37) Otake, K.; Inomata, H.; Konno, M.; Saito, S. Macromolecules 1990, 23, 283-289.

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Figure 3. SEM micrographs of the conventional and PEG-modified PNIPAAm hydrogels. The size of the bar is 20 µm.

Figure 4. AFM images of the conventional (NG) and PEG-300 modified (NE-300) PNIPAAm hydrogels: (a) NG and (b) NE-300.

freeze-dried gel samples. The internal structure of gels is also investigated. It is found that the internal structure of gels is similar to that of their surface. In a comparison of these micrographs, it can be noticed that compared to the conventional PNIPAAm gel, the PEG-modified PNIPAAm gels show more porous network structures. There are two possible reasons. First, the hydration and thus exclusion volume of PEG may provide spatial hindrance during the polymerization and cross-linking process. Thus, a more porous structure is formed with the PEG-modified hydrogels. Second, due to the presence of PEG, phase separation of formed PNIPAAm chains occurs during the polymerization, leading to macroporous and heterogeneous structures. In addition, the average diameter of PEG molecules in aqueous media increases with an increase in PEG molecular weight;36 the higher the molecular weight of PEG applied during the polymerization, the larger the pores within the resultant gel. From Figure 3, it can also be observed that the stringlike polymer matrix in the gel turns to be slender and the thickness of the pore wall becomes thinner from NE-300 to NE-2000 consecutively, which is also attributed to the enlarged porous network structure of PEG-modified gels. AFM Observations of PNIPAAm Hydrogels. AFM images allow us to study polymer structure from the atomic

level with the provision of three-dimensional information and accurately quantitative proximity measurements.38-40 The conventional and PEG-300-modified PNIPAAm hydrogels are investigated with a noncontact mode. Comparing the two AFM images as displayed in Figure 4, the topography of the NE-300 hydrogel is rougher. Here, the root-mean-square (rms) roughness (Rq) is recorded and defined as the standard deviation of the z values within the given area as follows:

Rq )

∑ (Zi - Zavg)2

x

Np

where Zi is the current Z value, Zavg is the average of the Z values within the given area, and Np is the number of points within the given area. The rms of the NE-300 (38) Bronstein, L. M.; Platonova, O. A.; Yakunin, A. N.; Yanovskaya, I. M.; Valetsky, P. M.; Dembo, A. T.; Obolonkova, E. S.; Makhaeva, E. E.; Mironov, A. V.; Khokhlov, A. R. Colloids Surf., A 1999, 147, 221231. (39) Karlsson, J. O.; Henriksson, Å.; Micha´lek, J.; Gatenholm, P. Polymer 2000, 41, 1551-1559. (40) Zareie, H. M.; Volga Bulmus, E.; Gunning, A. P.; Hoffman, A. S.; Piskin, E.; Morris, V. J. Polymer 2000, 41, 6723-6727.

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Figure 5. Swelling ratios of the conventional and PEGmodified PNIPAAm hydrogels in the temperature range from 22 to 45 °C (NG, /; NE-300, 0; NE-600, O; NE-1000, 4; NE-2000, ]).

hydrogel is 25.1 Å, which is higher than that of the NG hydrogel (20.8 Å). Namely, the surface of the NE-300 gel is rougher than that of the normal-type PNIPA gel. Due to the larger surface area accessible for the external medium, the rougher surface of the PEG-modified PNIPAAm hydrogel avails improving its response rate to the external temperature as presented later. This is consistent with the results reported by L. Liang et al.41 Swelling Ratios of PNIPAAm Hydrogels. Swelling ratios at different temperatures, as shown in Figure 5, illustrate the LCST behaviors of the conventional and PEG-modified PNIPAAm hydrogels. As the temperature increases, the swelling ratios of all the gels decrease. Particularly at a temperature below the LCST, the equilibrated swelling ratio of the NG gel is lower than those of the PEG-modified gels. Among the PEG-modified gels, the NE-2000 gel has the largest swelling ratio, while the NE-300 gel yields the smallest one. This may be explainable by various porous structures that PEGs create. Figure 5 indicates that the NE-2000 gel has the highest temperature sensitivity and undergoes the fastest phase separation when the temperature increases to the LCST. This phenomenon may be due to the fact that a more porous network structure makes water easier to diffuse in or out of the matrix, and thus the effect of temperature variation on phase separation is rapidly manifested. Deswelling Ratios of PNIPAAm Hydrogels. Figure 6 shows a comparison of shrinking rate for the PNIPAAm hydrogels after a temperature jump from 22 °C (below the LCST) to 48 °C (above the LCST). As discussed above, due to the hydrogen bonds between the hydrophilic groups and water and the hydration shell around the hydrophobic groups, the whole gel network is well soluble when the external temperature is below the LCST. When the temperature is raised, these hydrogen bonds are weakened and destroyed. As a consequence, the hydrophobic groups become naked and the interactions among the hydrophobic groups strengthen, which frees the entrapped water molecules. When the temperature is raised above the LCST, the hydrophobic interactions turn to be dominant and the polymer chains contract and aggregate abruptly, which leads to the shrinkage of the gel volume. Simultaneously, a lot of freed water molecules appear and have to diffuse out. The diffusion rate of the freed water through the macroporous network determines (41) Liang, L.; Rieke, P. C.; Liu, J.; Fryxell, G. E.; Young, J. S.; Engelhard, M. H.; Alford, K. L. Langmuir 2000, 16, 8016-8023.

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Figure 6. Deswelling kinetics of the conventional and PEGmodified PNIPAAm hydrogels at 48 °C (NG, /; NE-300, 0; NE-600, O; NE-1000, 4; NE-2000, ]).

Figure 7. Reswelling kinetics of the conventional and PEGmodified PNIPAAm hydrogels at 22 °C (NG, /; NE-300, 0; NE-600, O; NE-1000, 4; NE-2000, ]).

the deswelling rate of the hydrogel. The diffusion rate is controlled by the collective diffusion coefficient and gel morphology. When a conventional gel is immersed into the hot water with a temperature higher than the LCST, the gel may start the phase transition and shrink in the utmost surface region, resulting in a thick and dense skin layer31,35 at the beginning of the shrinking process. The resultant dense skin layer acts as a barrier for further water permeation and prevents the freed water diffusion out from the gel matrix. However, the PEG-modified PNIPAAm gels have more even heat and mass transfers because of their macroporous structures. Heat transfers from the hot water to the innermost gel matrix occur rapidly, which results in a rapid phase separation throughout the matrix. Thus, a large amount of the freed water can diffuse out quickly once the gels are immersed in the hot water (48 °C). From Figure 6, it can be seen that the NE-2000 gel shrinks with the fastest rate because of its most porous structure. Reswelling Behaviors of PNIPAAm Hydrogels. Figure 7 displays the reswelling behaviors of the conventional and PEG-modified PNIPAAm hydrogels after shrinking for 8 h in the hot water (48 °C). As presented in the previous paragraphs, all the PEG-modified gels reabsorb water or shrink more quickly than the conventional gel because their macroporous structures make transfer of water molecules easier between the gel matrix

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and the external aqueous phase. Figure 7 implies that the PEG-modified gels have superior reswelling behaviors. However, the reswelling ratio is not improved accordingly by applying an increased PEG molecular weight. PEG with a molecular weight of 600 yields the highest reswelling rate. However, the hydrogels that are modified by PEG-1000 and PEG-2000 have lower reswelling rates than that modified by PEG-300. The possible cause may be due to irreversible network collapses of the NE-1000 and NE-2000 gels during the deswelling (shrinking) process before the reswelling because of their weak mechanical strength with random stringlike and slender networks. The decrease in the porosity caused by the collapse of the gel networks definitely affects its reswelling ratios. Thus, the NE-2000 gel leads to the lowest reswelling rate among the PEG-modified hydrogels because of its highly porous and slender structure. Conclusion This study has proved that macroporous temperaturesensitive PNIPAAm hydrogels are obtained by applying PEG as a pore-forming agent during the polymerization, which own tremendously improved swelling and deswell-

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ing properties compared with the conventional PNIPAAm hydrogel. The addition of PEG does not change the chemical composition of the PNIPAAm hydrogels. However, the network structure of the PEG-modified hydrogels can be manipulated through changing PEG molecular weight. As a consequence, an increased PEG molecular weight yields a hydrogel with a more porous and slender network structure resulting in larger equilibrated swelling ratios accompanied with dramatically faster deswelling rates and higher temperature sensitivity. However, the gel macroporous network structure has to be optimized to maintain its high thermoreversibility. The macroporous and fast temperature-responsive PNIPAAm hydrogels have a potential application for controlled release of macromolecular active agents. Acknowledgment. This research was supported by the National Science and Technology Board of Singapore. We are grateful to Professor Allan S. Hoffman (Department of Bioengineering, University of Washington) and Dr. Shabbir M. Moochhala (Defence Medical Research Institute, Singapore) for their valuable discussion. LA010105V