Swelling behaviors of thermoresponsive hydrogels cross-linked with acryloyloxyethylaminopolysuccinimide
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- Yu, Y., Xu, Y., Ning, H. et al. Colloid Polym Sci (2008) 286: 1165. doi:10.1007/s00396-008-1878-y
Based on a biodegradable cross-linker, acryloyloxyethylaminopolysuccinimide (AEA-PSI), a series of looser cross-linked poly(N-isopropylacrylamide-co-acrylic acid) [P(NIPAAm-co-AAc)] hydrogels were prepared, and their water content, swelling/deswelling kinetics, and the morphology of the gels were investigated. The swelling behaviors of AEA-PSI-cross-linked P(NIPAAm/AAc) hydrogels were investigated in Dulbecco’s phosphate-buffered saline (pH = 7.4), in the distilled water, and in the simulated gastric fluids (pH = 1.2), respectively. The water contents of the hydrogels were controlled by the monomer molar ratio of NIPAAm/AAc, swelling media, and the temperature. In the swelling kinetics, all the dried hydrogels exhibited fast swelling behavior, and the swelling ratios were influenced significantly by the amounts of AEA-PSI and AAc content. The deswelling kinetics of the hydrogel were independent of the content of AAc and cross-linker. Lastly, the morphology of the hydrogels was estimated by the field scan electron microscopy.
KeywordsThermoresponsive hydrogelWater contentSwelling kineticsDeswelling kineticsMorphology
Poly(N-isopropylacrylamide; PNIPAAm) hydrogel has been extensively studied as an intelligent polymeric matrix. The reversible phase transition of PNIPAAm hydrogel can be induced by a small external temperature change about its volume phase transition temperature (VPTT; ~32 °C) in aqueous media [1–3]. When the external temperature is below the VPTT, the hydrogel hydrates and absorbs plenty of water, but it dehydrates quickly at the temperature above its VPTT. Because of this unique property, significant attention has been focused on its application in the biotechnology and bioengineering fields [4–8]. However, the PNIPAAm homopolymeric hydrogel is not a favored matrix for biomedical applications because of its transition temperature and rigid network structure. A desirable phase transition temperature of the three dimensional matrix should be at or near the physiologic temperature (37 °C). In addition, the gel matrix should possess high water content but still exhibit temperature sensitive properties at 37 °C . Thus, incorporating a hydrophilic monomer, acrylic acid (AAc), into the PNIPAAm backbone is a good approach to modulate the properties of PNIPAAm hydrogel.
However, an important limitation of PNIPAAm hydrogel for biomedical application is their lack of bioactivity and biodegradability. By incorporating degradable linkages into hydrogel, the material can accomplish a number of interesting biomedical applications such as temporary implants . Such degradable hydrogel comprises of cross-linking molecules with degradable segments. As degradation occurs, degradable linkages in each “arm” of the cross-linking molecules are cleaved systematically, lowering the average number of cross-links per kinetic chain with time and causing eventual mass loss . One of our work’s objectives was to develop a new biodegradable cross-linker. In previous studies , we synthesized the biodegradable cross-linker, acryloyloxyethylaminopolysuccinimide (AEA-PSI) and prepared a series of looser cross-linked P(NIPAAm-co-AAc) hydrogels using AEA-PSI as cross-linker. Their phase transition behavior, lower critical solution temperature or volume phase transition temperature, was investigated. By alternating the NIPAAm/AAc molar ratio, hydrogels were synthesized to have VPTT in the vicinity of 37 °C. The VPTT of the hydrogels was significantly influenced by monomer ratio of the NIPAAm/AAc but not by the cross-linking density within the polymer network.
In this paper, the swelling behaviors of AEA-PSI-cross-linked P(NIPAAm/AAc) hydrogels in Dulbecco’s phosphate-buffered saline (PBS; pH = 7.4), in the distilled water (DW), and in simulated gastric fluids (SGF; pH = 1.2) were investigated, respectively. The swelling/deswelling kinetics of the hydrogels were measured gravimetrically and the morphology of the hydrogels was estimated by the field scan electron microscopy (SEM).
The AEA-PSI cross-linker was synthesized according to the literature . The materials were N-isopropylacrylamide (Tokyo Kaset Kogyo), acrylic acid (analytic ultrapure grade), ammonium persulfate (APS; analytic ultrapure grade), N,N,N′,N′-tetramethylethylenediamine (TEMED; analytic ultrapure grade), Dulbecco’s phosphate-buffered saline (pH = 7.4±0.1), and simulated gastric fluids (pH = 1.2±0.1). All materials excepted AEA-PSI and NIPAAm were purchased from Shanghai Fine Chemical, China, used as received without further purification.
Synthesis of P(NIPAAm-co-AAc) hydrogels
Water contents of the hydrogels depending on temperature and swelling media
NIPAAm/AAc molar ratio
Cross-linker feed (wt.%)
Phase transition determination
The phase transition of the hydrogel samples was measured by ultraviolet–visible (UV–VIS) spectrophotometer (723 P, Shanghai Spectrum Instruments, China) attached to high constant temperature bath (CH-1015, The DC Instrument of Shanghai Precision Scientific Instrument, China). The transmittance of visible light (λ = 546 nm, path length = 3 cm) through the hydrogel was recorded as a function of temperature. Distilled water was used to calibrate the spectrophotometer. The heating rate was 0.5 ~1 °C every 10 min. The VPTT of the hydrogel samples was determined as the abscissa of the inflection point of the transmittance vs. temperature curves.
Water content studies
Measurement of swelling kinetics
Measurement of deswelling kinetics
Scanning electron microscopy analysis
For the morphological studies, the hydrogel samples were first immersed in PBS or DW for 0.5 h. Then, the swollen hydrogel samples were freeze dried for 24 h. Finally, the freeze-dried specimens were fractured in liquid nitrogen and coated with gold for 30 s. The morphology of the freeze-dried hydrogels was investigated by using a scanning electron microscope (6700F, JEOL).
Results and discussion
Table 1 showed the water contents of AEA-PSI-cross-linked P(NIPAAm-co-AAc) hydrogels in different swelling media at 25 °C and 37 °C. At 25 °C, all of the hydrogel samples exhibited water contents of >15 g/g in DW, PBS, and SGF. The water contents of the hydrogels were lower in PBS and SGF than in DW. This tendency was greater above the VPTT as delineated in Table 1. The effect of the media on the swelling behavior could be attributed to the shielding of COO– repulsion, which prevented collapse of the hydrogels, by the interactions between COO– groups in AAc and the ions present in the PBS. As discussed previously, the hydrophilic –COO– groups hinder the dehydration of the polymer chains, expanding the collapsed structure. But in PBS, ions were introduced into P(NIPAAm-co-AAc)-based systems, ionic shielding of the –COO– groups occurred. This ionic shielding disrupted the solubility and repulsion of the –COO– groups, and the –COO– groups were unable to effectively counteract the hydrophobic NIPAAm interactions. As a result, the water contents decreased . The swelling behavior in SGF was low due to the ionization/deionization of the carboxylic acid groups. At low pH, such as pH value about 1.2, the –COOH groups were not ionized and less hydrophility than when –COOH groups were ionized. The hydrogel was less swollen. At high pH values, the –COOH groups were ionized, and the charged –COO– groups generated electrostatic repulsive forces between the polymer chains, which leaded to swelling of the hydrogel network. Also, the ionized groups created an osmotic pressure in the network and therefore prompted the swelling process.
In addition, the water contents of AEA-PSI-cross-linked hydrogels (feed of AEA-PSI = 2.5 wt.%) decreased with increasing the AAc contents in the hydrogels in SGF, probably due to the presence of additional –COOH hydrogen bonds, whereas the water contents of the hydrogels in the DW and PBS gradually increased with the AAc content in the hydrogels (see sample 3, 6, 7, 8, and 9 in Table 1) at room temperature, below the VPTT. When heated to 37 °C, the water content of the hydrogels dropped significantly regardless of the swelling media. At 37 °C, the water contents of the hydrogels in SGF did not change significantly with the monomer molar ratio, whereas the water contents of the hydrogels in the DW and PBS gradually increased with the AAc content in the hydrogels. The results proved that the hydrogels with higher AAc contents were not in the collapsed state in the DW and PBS at 37 °C (which corresponded with the results of the VPTT measurement in Table 1); however, the hydrogels with higher AAc contents were also in the collapsed state in SGF at 37 °C because the –COOH groups were not ionized in SGF.
The effect of the amounts of the AEA-PSI cross-linker on the water contents of the hydrogels with the same NIPAAm/AAc molar ratio of 97.5/2.5 was also investigated (see sample 1, 2, 3, 4, and 5 in Table 1). As the amounts of the AEA-PSI cross-linker within the hydrogels increased, the water content difference was not statistically significant regardless of swelling media.
When samples are freeze dried, movement of polymer chains is highly restricted since the entire sample is in the solid state (both polymer chains and water molecules). Thus, as water molecules are removed by sublimation, the polymer chains cannot move and remain in the same conformation .
In summary, with a novel biodegradable AEA-PSI cross-linker, cross-linked P(NIPAAm-co-AAc) hydrogels were prepared in phosphate-buffered saline. The swelling behaviors of AEA-PSI-cross-linked P(NIPAAm/AAc) hydrogels were investigated in PBS (pH = 7.4), in DW, and in SGF (pH = 1.2), respectively. The water contents of the hydrogels were controlled by the monomer molar ratio of NIPAAm/AAc, swelling media, and the temperature. In the swelling kinetics, all the dried hydrogels exhibited fast swelling behavior. The swelling rate of the hydrogel in distilled water was higher than that in PBS, and it was also influenced by the amounts of the AEA-PSI and AAc content. The hydrogels deswelled fast in PBS at 45 °C. The deswelling rate of the hydrogel was independent of the content of AAc and AEA-PSI. The surface of the hydrogel was smooth but the hydrogel contained open and well-structure orientated porous network. The AEA-PSI-cross-linked hydrogels were potentially biodegradable in PBS.
This research was supported by the National Natural Science Foundation of China (No.20476049), the program for New Century Excellent Talents in the Universities (No. NCET-04-0649), and the Science Foundation of Shandong Province (No.Y2006B10).