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J. Phys. Chem. B 2008, 112, 1112-1118
A Novel Thermoresponsive Hydrogel with Ion-Recognition Property through Supramolecular Host-Guest Complexation Xiao-Jie Ju,† Liang-Yin Chu,*,†,‡ Li Liu,† Peng Mi,† and Young Moo Lee§ School of Chemical Engineering, Sichuan UniVersity, Chengdu, Sichuan 610065, China, Institute for Nanobiomedical Technology and Membrane Biology, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan UniVersity, Chengdu, Sichuan 610041, China, and School of Chemical Engineering, Hanyang UniVersity, Seoul 133-791, Korea ReceiVed: October 5, 2007; In Final Form: NoVember 8, 2007
A novel thermoresponsive hydrogel with ion-recognition property was prepared via free-radical cross-linking copolymerization of N-isopropylacrylamide (NIPAM) with benzo-18-crown-6-acrylamide (BCAm) as host receptor. Both chemical structures and stimuli-sensitive properties of the prepared poly(N-isopropylacrylamideco-benzo-18-crown-6-acrylamide) P(NIPAM-co-BCAm) hydrogel were characterized. The smart hydrogel could respond to both temperature and ion stimuli. When the crown ether units captured Ba2+ and formed stable BCAm/Ba2+ host-guest complexes, the lower critical solution temperature (LCST) of the hydrogel increased due to the repulsion among charged BCAm/Ba2+ complex groups and osmotic pressure within the hydrogel. Whereas crown ethers captured Cs+, the LCST shifted to a lower temperature because of the formation of 2:1 sandwich complexes. Unexpectedly, the LCST of the cross-linked P(NIPAM-co-BCAm) hydrogel in K+ solution did not shift to a higher temperature, which was definitely different from the previously reported linear P(NIPAM-co-BCAm) copolymer in K+ solution. The results of this work provide valuable information for development of dual thermo- and ion-responsive hydrogels which have potential applications in drug controlled-release systems or biomedical fields.
Introduction Stimuli-responsive hydrogels exhibit reversible volume change in response to small changes in the external environment, such as temperature,1,2 pH,3,4 light,5,6 electric field,7 solvent composition,8 and glucose.9 Because of their “smart” nature, these hydrogels have attracted increasing interest and considerable research attention in recent years. Poly(N-isopropylacrylamide) (PNIPAM), a typical and widely studied thermosensitive polymer, exhibits a lower critical solution temperature (LCST) due to the presence of both hydrophilic amide groups and hydrophobic isopropyl groups in its side chains.10,11 Cross-linked PNIPAM hydrogel undergoes a reversible volume change as surrounding temperature varies across its LCST.12 Below the LCST, the hydrogel is swollen and absorbs a significant amount of water, while above the LCST, the hydrogel dramatically releases free water and begins to shrink. Because of the dramatic thermosensitive properties, PNIPAM hydrogels have attracted great interest for a wide variety of applications, including controlled drug and gene delivery,13-15 immobilization of enzymes,16 separation of proteins,17 biomedical materials,13,18 and recyclable absorbents.19 For more favorable applications like drug controlled-release systems or bioseparations, hydrogels need to respond to several stimuli such as temperature, pH, and ions, which are all important environment factors in biomedical and other systems. During the past decades, the most investigated multistimuli responsive hydrogels are dual thermo- and pH-responsive * Corresponding author. E-mail:
[email protected]. † Sichuan University. ‡ West China Medical School. § Hanyang University.
hydrogels.20-24 However, few studies are found on the dual thermo- and ion-responsive hydrogels. Crown ethers have remarkable properties of selectively recognizing specific ions and forming stable “host-guest” complexes. If the crown ether groups are introduced into the thermosensitive PNIPAM hydrogel, it is able to prepare an ion-recognition hydrogel that responds to both temperature and specific ion stimuli. A molecular-responsive copolymer of PNIPAM with a pendant crown ether groups had been designed and synthesized in 1993.25 PNIPAM acts as an actuator, and benzo-18-crown6-acrylamide (BCAm), with a crown ether cavity, is used as an ion-signal sensing receptor. When the crown ether receptors capture specific ions, the LCST of the copolymer could shift to a higher temperature. Recently, investigations have reported on poly(N-isopropylacrylamide-co-benzo-18-crown-6-acrylamide) (P(NIPAM-co-BCAm)) copolymers, but all those were linear copolymers or linear-grafted copolymers.25-32 However, if the polymeric chains were cross-linked, will the effect of “host-guest” molecular recognition on the LCST shift of P(NIPAM-co-BCAm) still be active? Is it possible to achieve an ion-recognition smart device using cross-linked P(NIPAMco-BCAm) hydrogels? To the best of our knowledge, the study of dual thermo- and ion-responsive behaviors of cross-linked PNIPAM hydrogels with BCAm receptors has not been reported yet. The aim of the present work is to prepare cross-linked P(NIPAM-co-BCAm) copolymeric hydrogels and to investigate their ion-recognition and thermoresponsive behaviors. This kind of cross-linked smart hydrogels would serve as a materials candidate for dual temperature- and ion-responsive smart devices or systems.
10.1021/jp709746w CCC: $40.75 © 2008 American Chemical Society Published on Web 01/08/2008
Novel Thermoresponsive Hydrogel
J. Phys. Chem. B, Vol. 112, No. 4, 2008 1113
Figure 1. Synthetic scheme of cross-linked P(NIPAM-co-BCAm) hydrogel.
Experimental Section Materials. N-Isopropylacrylamide (NIPAM, kindly provided by Kohjin Co., Ltd., Japan) was purified by recrystallization with a hexane/acetone mixture (v/v, 50/50). Benzo-18-crown6-acrylamide (BCAm) was synthesized according to previously reported procedures.33,34 N,N′-Methylenebis(acrylamide) (MBA, Chengdu Kelong Chemical Reagent Co.) was used as a crosslinker. 2,2′-Azobis(2-amidinopropane dihydrochloride) (V50, Qingdao Runxing Photoelectric Material Co., Ltd.) and 2,2′azobis(isobutyronitrile) (AIBN, Shanghai Reagent Fourth Factory) were both recrystallized with ethanol and used as initiators. All solvents and other chemicals were of analytical grade and were used as received. Deionized water (18.2 MΩ, 25 °C) from a Milli-Q Plus water purification system (Millipore) was used throughout this work. Hydrogel Preparation. Cross-linked P(NIPAM-co-BCAm) hydrogel was prepared by thermally initiated free-radical crosslinking copolymerization using V50 as initiator first. The synthetic scheme is shown in Figure 1. NIPAM (10 mmol) and BCAm (0.75 mmol) monomers, MBA cross-linker, and V50 initiator were dissolved in 10 mL of deionized water. The molar percentages of MBA and V50 in the total monomer were 1 and 0.5 mol %, respectively. Nitrogen gas was bubbled into the solution for 15 min to remove dissolved oxygen in the system. Next, the solution was immediately transferred into small glass tube with inner diameter of 6 mm. The small glass tube was sealed immediately and then immersed into a constant-temperature water bath at 70 °C. The polymerization was carried out for 8 h. After the gelation was completed, the prepared cylindrical hydrogel was pushed out from the glass tube and immersed in an excess of deionized water. The water was replaced every 12 h to remove residual unreacted components, and the washing continued for 7 days. The purified P(NIPAMco-BCAm) hydrogel was cut into thin discs and then equilibrated in deionized water or salt solutions at 25 °C. The swelling behavior of the hydrogel was studied by measuring the diameter of hydrogel discs. The schematic illustration of preparation of hydrogel samples is shown in Figure 2. PNIPAM hydrogel, which served as a reference, was also prepared and purified using the protocol described above, except that BCAm was not present. To investigate the effect of initiator on thermo- and ionresponsive behavior of P(NIPAM-co-BCAm) hydrogel, hydrogels were also prepared using AIBN or ammonium persulfate
Figure 2. Schematic illustration of the preparation of hydrogel sample.
(APS) as initiator. The preparation recipe and conditions were the same as that mentioned above with V50 as initiator. To show the gelation process in the polymerization, hydrogels were also prepared in transparent glass cuvettes using the same preparation recipes at 70 °C, and photographs at certain time intervals were taken by a digital camera (Nikon CoolPix 4600, Japan) before or during the reactions. FT-IR Characterization and Elemental Analysis. The chemical structures of both P(NIPAM-co-BCAm) and PNIPAM hydrogels were determined by Fourier transform infrared spectroscopy (FT-IR, Nicolet 560, PE Com., US) using the KBr disc technique in the range of 4000-400 cm-1. Carbon, nitrogen, and hydrogen contents in the hydrogels were obtained by elemental analyses (EA, 1106, Carlo Erba Co., Italy). The hydrogel specimens were prepared by a freeze-drying method. Measurement of Ion-Recognition and Thermoresponsive Behaviors of P(NIPAM-co-BCAm) Hydrogels. Because of the selective ability of benzo-18-crown-6 to recognize certain metal ions, the effects of various metal ions on the thermosensitivity of P(NIPAM-co-BCAm) hydrogels were investigated. The ionrecognition and thermoresponsive behaviors of P(NIPAM-coBCAm) hydrogels were studied by evaluating the volume-phase transition behaviors in different salt solutions at various desired ambient temperatures in the range from 25 to 50 °C. The concentrations of metal cations in salt solutions were all 0.02 mol L-1. We simply expressed volume change of hydrogel using diameter change of the thin hydrogel discs. To minimize saltingout effects, nitrate was chosen as the model salt.35 Deionized water was used as a reference. The temperature at which the diameter decreased half of the total change value was taken as the LCST. Experiments on the equilibrium swelling behaviors of hydrogels were performed in a transparent glass culture dish with
1114 J. Phys. Chem. B, Vol. 112, No. 4, 2008
Ju et al. TABLE 1: Elemental Analyses of PNIPAM and P(NIPAM-co-BCAm) Hydrogels elemental analysis (%) hydrogel
C
N
H
[C]/[N] ratio
PNIPAM P(NIPAM-co-BCAm)
54.91 55.41
10.91 9.58
9.84 9.30
5.03/1 5.78/1
TABLE 2: 1:1 Complex Stability Constant, log K, of Benzo-18-crown-6 with Metal Ions in Water metal ion
log Ka-c
Ba2+
2.90d 1.74 1.38 0.88
K+ Na+ Cs+
a Izatt, R. M.; Pawlak, K.; Bradshaw, J. S. Chem. ReV. 1991, 91, 1721-2085. b Takeda, Y.; Kohno, R.; Kudo, Y.; Fukada, N. Bull. Chem. Soc. Jpn. 1989, 62, 999-1003. c Takeda, Y. J. Inclusion Phenom. Mol. Recognit. Chem. 1990, 9, 309-313. d With NO3- anions.
Figure 3. FT-IR spectra of BCAm (a), cross-linked PNIPAM hydrogel (b), and cross-linked P(NIPAM-co-BCAm) hydrogel (c).
Figure 4. Temperature dependence of diameter change of cross-linked P(NIPAM-co-BCAm) hydrogels that initiated by V50 in nitrate solutions contain different cations.
a calibrated scale, which was placed in a temperature-controlled water bath of (0.1 °C. P(NIPAM-co-BCAm) thin hydrogel discs were immersed in the culture dish that filled with sufficient nitrate solutions to reach swelling/deswelling equilibrium. The measurement was carried out using an optical method, through a digital camera, which was placed vertically to the gel surface with a fixed height. The photos of the hydrogel disc with a calibrated scale were then analyzed by graph-processing software to determine the measurements of diameter. The measurements were carried out at least three times, and the data were in good agreement within a standard deviation of 2%. Results and Discussion FT-IR Characterization and Elemental Analysis. From comparative analysis of the FT-IR spectra (Figure 3), the copolymerization of NIPAM and BCAm is confirmed. Specifically, the appearance of the following characteristic bands in the FT-IR spectrum of P(NIPAM-co-BCAm) hydrogel suggested a successful copolymerization: (1) a strong 1516 cm-1 band for CdC skeletal stretching vibration of the phenyl ring, (2) a
1230 cm-1 band for C-O asymmetric stretching vibration in Ar-O-R, (3) a 1130 cm-1 band for C-O asymmetric stretching vibration in R-O-R′, and (4) a 1057 cm-1 band for C-O symmetric stretching vibration in Ar-O-R. Corresponding bands also appeared in the FT-IR spectrum of BCAm (Figure 3a). Furthermore, the characteristic double peaks at 1388 and 1366 cm-1 for isopropyl group of NIPAM appeared in both FT-IR spectra of PNIPAM and P(NIPAM-co-BCAm) hydrogels (Figure 3b,c). These feature peaks suggested a successful fabrication of P(NIPAM-co-BCAm) copolymeric hydrogel. Further evidence to copolymer formation is provided by carbon, hydrogen, and nitrogen contents of P(NIPAM-coBCAm) hydrogel measured by elemental analyses (Table 1). Because the elemental [C]/[N] ratio of BCAm ([C]/[N] ) 16.29/ 1) is clearly larger than that of NIPAM ([C]/[N] ) 5.14/1) and MBA ([C]/[N] ) 3.00/1), the increase in the elemental [C]/[N] ratio of P(NIPAM-co-BCAm) hydrogel supported to confirm the successful incorporation of BCAm into PNIPAM chains. Ion-Recognition and Thermoresponsive Behaviors. Figure 4 shows the diameter changes of P(NIPAM-co-BCAm) hydrogels in different nitrate solutions as a function of temperature. All P(NIPAM-co-BCAm) hydrogels underwent a rapid diameter change when the ambient temperatures changed across a corresponding temperature region. The diameter-change trend of P(NIPAM-co-BCAm) hydrogel in Ba2+ or Cs+ solution was significantly different compared with that in deionized water. The LCST of cross-linked P(NIPAM-co-BCAm) hydrogel in deionized water was around 33.5 °C. In Ba2+ solution, the LCST of P(NIPAM-co-BCAm) hydrogel shifted to a higher temperature and increased ∼6 °C (LCST ≈ 39.5 °C), whereas, it shifted to lower temperature and decreased ∼2 °C (LCST ≈ 31.5 °C) in Cs+ solution. The change of LCST in K+ or Na+ solutions was not obvious. The LCST of cross-linked P(NIPAM-co-BCAm) hydrogel in K+ solution increased only about 0.8 °C. The reason for these phenomena should be the formation of crown ether/metal-ion complexes. BCAm receptors in the crosslinked hydrogel selectively recognized specific ions, which bound with the cavities of crown ethers tightly and effectively. The order of the complex stability constant, log K, of benzo18-crown-6 with metal ions in water was Ba2+ > K+ > Na+ > Cs+,36-38 as listed in Table 2. The stability constant of complex of Ba2+ with benzo-18crown-6 is the largest. A very stable BCAm/Ba2+ complex was formed. The polymer chain, attached to ionic “host-guest” complexes, behaves like an ionic polymer chain. The repulsion
Novel Thermoresponsive Hydrogel among charged BCAm/Ba2+ complex groups counteracted the shrinkage of the hydrogel network with the increase of temperature, thereby resulting in the LCST changing to a higher temperature. Additionally, osmotic pressure within the hydrogel due to a Donnan potential, which arises from mobile counterions to the crown ether bound Ba2+, also made the hydrogel swell more.39-41 So, it can be also seen in Figure 4 that the P(NIPAMco-BCAm) hydrogel in Ba2+ solution has a larger degree of swelling than that in deionized water, and the diameter of P(NIPAM-co-BCAm) hydrogel in Ba2+ solution was always larger than that in deionized water at any temperature throughout the experiment. The charge repulsion among the captured Ba2+ ions could cause larger interspaces in the internal structure of hydrogel so that more water may be contained inside the polymer networks and result in a larger volume change. Linear and linear-grafted P(NIPAM-co-BCAm) copolymers have been reported to present a significant LCST shift in K+ solutions.25-32 When the BCAm groups capture K+ ions, the LCST of the linear copolymer shifts to a high temperature.25-32 Surprisingly, in this work, the LCST of cross-linked P(NIPAMco-BCAm) hydrogel did not increase remarkably in K+ solution. The reason for the different phenomena may be the result of the following: if the copolymer chains were cross-linked, the cavities of crown ethers were close to each other; because the stability constant of BCAm/K+ complex is not high enough, therefore the electrostatic repulsion among K+ ions affected the formation of stable BCAm/K+ complexes inside the cross-linked P(NIPAM-co-BCAm) hydrogel. Thus, the effect of K+ on the LCST of cross-linked P(NIPAM-co-BCAm) hydrogel was different from that of linear P(NIPAM-co-BCAm) copolymer. The stability constant of complex of benzo-18-crown-6 with Ba2+ is larger than that with K+; therefore, a significant LCST shift of cross-linked P(NIPAM-co-BCAm) hydrogel was observed in Ba2+ solution. The stability constant of complex of benzo-18-crown-6 with Na+ is also small, so the effect of Na+ on the LCST shift of cross-linked P(NIPAM-co-BCAm) hydrogel was nearly negligible. When Cs+ ions were added in the solution, the LCST of cross-linked P(NIPAM-co-BCAm) hydrogel shifted to a lower temperature. Although Cs+ is too large to fit into the crown ether cavity of BCAm, it could form a stable 2:1 complex with the crown ethers.34,42 Two crown ether cavities from adjacent polymer chains form a 2:1 “sandwich” complex with one Cs+.34,42 Such complexation causes the cross-linked P(NIPAMco-BCAm) hydrogel to contract, which increases the elastic restoring force of the network and decreases the LCST of the hydrogel. Therefore, the volume of the swollen P(NIPAM-coBCAm) hydrogel in Cs+ solution was smaller than that in the deionized water. From these results, we can conclude that the ion recognition, which was achieved by the capture of special ions within crown ether receptors, caused the shift in LCST of cross-linked P(NIPAM-co-BCAm) hydrogel. In other words, Ba2+ and Cs+ could be used as special stimuli for controlling the phase transition of cross-linked P(NIPAM-co-BCAm) hydrogels. The cross-linked P(NIPAM-co-BCAm) hydrogel could swell or shrink in response to Ba2+ or Cs+ ions isothermally at a temperature fixed between the LCST in deionized water and that in a corresponding ion solution. By using the swelling and shrinking actions, cross-linked P(NIPAM-co-BCAm) hydrogel can control the release of loading substance inside the hydrogel responding to dual thermo- and ion-stimuli. The photographs and comparisons of the swelling/deswelling behaviors of PNIPAM and P(NIPAM-co-BCAm) hydrogels in
J. Phys. Chem. B, Vol. 112, No. 4, 2008 1115
Figure 5. Photographs of cross-linked PNIPAM and P(NIPAM-coBCAm) hydrogels that initiated by V50 in different nitrate solutions at 25 and 35 °C. “PNB” represents “P(NIPAM-co-BCAm)” in the lower two rows. Scale bar 0.5 cm.
nitrate solutions containing different cations are shown in Figures 5 and 6, respectively. The data in Figure 6 present the influences of metal cations on the diameters of cross-linked P(NIPAM-co-BCAm) and PNIPAM hydrogels. The influences were expressed by diameter ratio, Dion/DH2O, where Dion and DH2O were the diameters of hydrogels in solutions containing different cations and in deionized water, respectively. The diameters of PNIPAM hydrogel discs in nitrate solutions were almost the same as that in deionized water at every selected temperature. That is to say, the nitrate or metal ions scarcely affected the phase transition behavior of PNIPAM hydrogel. Similarly, as seen in Figure 4, the diameter of cross-linked P(NIPAM-co-BCAm) hydrogel in Ba2+ solution was always larger than that in deionized water due to the repulsion among charged BCAm/Ba2+ complex groups and osmotic pressure within the hydrogel. On the other hand, except the complete deswelling state, the diameter of cross-linked P(NIPAM-coBCAm) hydrogel in Cs+ solution was always smaller than that in deionized water because of the formation of a 2:1 sandwich BCAm/Cs+ complexes. For the cross-linked P(NIPAM-coBCAm) hydrogel in K+ solution, the diameter of the hydrogel disc was not always larger than that in deionized water because of the instable complex formation of K+ with BCAm. Preparation of P(NIPAM-co-BCAm) Hydrogels Using Other Initiators. To investigate whether the positive charges from initiator V50 will affect the formation of BCAm/K+ complexes in cross-linked P(NIPAM-co-BCAm) hydrogel or not, cross-linked P(NIPAM-co-BCAm) hydrogels were also prepared using AIBN or APS as initiator. Figure 7 shows the photographs of the gelation processes. The gelation phenomenon using AIBN as initiator was similar to that using V50 as initiator. Before reaction, the solution of NIPAM, BCAm and MBA was transparent and colorless. After AIBN was added, the solution quickly turned opaque during heating. When the gelation was completely, an opalescent P(NIPAM-co-BCAm) hydrogel was obtained. The polymerization initiated using APS was unsuccessful. The monomer solution was transparent and colorless, too. After adding APS and heating for 30 s, the solution quickly turned into orange. Finally, despite being heated for 8 h or more, the
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Ju et al.
Figure 6. Comparisons of the swelling/deswelling behaviors of cross-linked PNIPAM and P(NIPAM-co-BCAm) hydrogels initiated by V50 in various solutions, where Dion/DH2O is the ratio of diameter of hydrogel disc in nitrate solutions containing different ions to that in deionized water.
Figure 7. Photographs of the gelation process of P(NIPAM-co-BCAm) hydrogel preparation. The a-series show the reaction using AIBN as initiator, and b-series show that using APS as initiator.
solution was still transparent and gelation never occurred, but only the solution color became deeper. The reason could be that APS is a peroxide initiator and has strong oxidation ability, which could oxidize the crown ether but could not initiate the gelation reaction.
Figure 8. Temperature dependence of diameter change of cross-linked P(NIPAM-co-BCAm) hydrogels initiated by AIBN in aqueous nitrate solutions containing different cations.
The thermo- and ion-responsive behavior of cross-linked P(NIPAM-co-BCAm) hydrogel initiated by AIBN was also studied using the same method. The diameter-change trends of the P(NIPAM-co-BCAm) hydrogel initiated by AIBN in different nitrate solutions (Figure 8) are similar to those in Figure 4. That is to say, the initiator in the reaction system, whether or not it has charged groups, scarcely influences the thermoand ion-responsive behavior of cross-linked P(NIPAM-coBCAm) hydrogels.
Novel Thermoresponsive Hydrogel
J. Phys. Chem. B, Vol. 112, No. 4, 2008 1117 recognition property and was able to respond to both temperature and metal-ion stimuli. The results of this work provide interest for further investigations. Acknowledgment. This work was supported by the National Natural Science Foundation of China (20674054), the NSFCKOSEF Scientific Cooperation Program, and the Key Project of the Ministry of Education of China (106131). X.-J. Ju thanks the Student Innovation Foundation of Sichuan University (2006G007). The authors also thank Kohjin Co., Ltd, Japan, for kindly supplying the N-isopropylacrylamide. References and Notes
Figure 9. Temperature dependence of the ratio of diameter of crosslinked P(NIPAM-co-BCAm) hydrogel (initiated by AIBN) in Ba2+ solution to that in deionized water, where DBa2+/DH2O is the ratio of the diameter of hydrogel disc in Ba2+ solution to that in deionized water.
Figure 9 shows the effect of Ba2+ on the swelling behavior of cross-linked P(NIPAM-co-BCAm) hydrogel initiated by AIBN as a function of temperature. The effect was expressed as a ratio of the diameter of hydrogel disc in Ba2+ solution to that in deionized water, DBa2+/DH2O. At first, the ratio value increased with the temperature rising and then deceased. As mentioned above, because of the formation of BCAm/Ba2+ complex, the hydrogel swelled more and had a higher LCST in Ba2+ solution than that in deionized water. At 38 °C, the value of DBa2+/DH2O reached the maximum. When temperature increased above 38 °C, the value of DBa2+/DH2O decreased sharply as cross-linked P(NIPAM-co-BCAm) hydrogel in Ba2+ solution began to shrink rapidly. The results indicated that the optimal operating temperature for Ba2+-recognition application of crosslinked P(NIPAM-co-BCAm) hydrogel was about 38 °C, at which the hydrogel could spontaneously swell in response to Ba2+ and had the optimal ion-responsibility. Conclusions Cross-linked P(NIPAM-co-BCAm) smart hydrogel exhibiting both ion-recognition and thermoresponsive characteristics was successfully prepared via thermally initiated free-radical crosslinking copolymerization. When BCAm receptors in the hydrogel capture special ions such as Ba2+ or Cs+, the LCST of P(NIPAM-co-BCAm) hydrogel shifted. In Ba2+ solution, the hydrogel swelled more and had a higher LCST than that in other solutions, due to the repulsion among charged BCAm/Ba2+ complex groups and the osmotic pressure within the hydrogel. In Cs+ solution, the LCST of P(NIPAM-co-BCAm) hydrogel shifted to a lower temperature because of the formation of 2:1 sandwich complexes. On the other hand, because the crosslinked structure affected the formation of stable BCAm/K+ complexes, the LCST of cross-linked P(NIPAM-co-BCAm) hydrogel did not increase remarkably in K+ solution, which is somewhat unexpected. The residual groups of initiator at the end of copolymeric chains, whether it was charged or not, scarcely influenced the thermo- and ion-responsive behavior of the cross-linked P(NIPAM-co-BCAm) hydrogel. The copolymerization initiated by APS was unsuccessful due to its oxidative effect on the crown ether. In summary, the prepared cross-linked P(NIPAM-co-BCAm) hydrogel in this study demonstrated ion-
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