壳聚糖交联温度和pH双重敏感水凝胶的合成和性质研究
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摘要
水凝胶是由亲水性高分子交联而成的三维网络结构,它不溶于水,但可吸收大量水分。智能水凝胶是对外界刺激如温度、pH值、电场等能产生敏感响应性行为的一类水凝胶。智能水凝胶因其生物相容性、柔软性和组织相似性,目前在药物控制释放、生物材料和组织工程等生物医学领域中得到了广泛应用。聚N-异丙基丙烯酰胺(PNIPAAm)温敏类水凝胶在32 oC左右能发生可逆的非连续体积相转变,称之为低临界溶解温度(LCST),因此目前得到了广泛的研究与应用。
本文通过壳聚糖和马来酸酐酰化反应合成了水溶性良好的可生物降解的交联剂—N-马来酰化壳聚糖(N-malely chitosan,N-MACH),以N-异丙基丙烯酰胺(NIPAAm)、羧甲基纤维素钠(CMC)、丙烯酰胺(Am)为原料,通过水溶液中的自由基聚合反应,分别合成了聚N-异丙基丙烯酰胺(PNIPAAm)均聚水凝胶,聚N-异丙基丙烯酰胺/丙烯酰胺[P(NIPAAm-co-Am)]共聚水凝胶和聚N-异丙基丙烯酰胺/羧甲基纤维素钠(PNIPAAm/CMC)半互穿网络水凝胶。研究了水凝胶的温敏性、pH敏感性、溶胀和退溶胀动力学、盐溶液中的溶胀现象、热力学性质和水凝胶结构形态,并对水凝胶样品的可生物降解性做了初步的研究。
1、交联剂和CMC的用量对水凝胶的LCST值无明显的影响。但随着Am的加入,水凝胶的LCST值明显变化,Am的用量越大,水凝胶的LCST值越高,二者几乎成线性关系。
2、在25 oC的蒸馏水中,所有水凝胶均能快速达到饱和溶胀状态。溶胀率随着Am和CMC增加而升高,随着交联剂用量的增加而降低。
3、LCST值低于37 oC的水凝胶在37 oC蒸馏水中均发生快速失水的退溶胀现象,在1 h左右达到平衡。退溶胀率随交联剂、CMC和Am的用量增加而降低。
4、在25 oC时,在浓度低于0.05 mg/mL的NaCl溶液中水凝胶仍然有较好的溶胀性,但是当NaCl溶液的浓度高于0.05 mg/mL时,水凝胶的溶胀率明显下降,说明水凝胶对于盐溶液有一定敏感性。
5、在25 oC时,缓冲溶液的pH值对水凝胶的饱和溶胀率有很大影响,PNIPAAm和P(NIPAAm-co-Am)水凝胶在酸性和碱性缓冲溶液中饱和溶胀率较大,而在中性缓冲溶液中较低。而CMC的引入使PNIPAAm/CMC半互穿网络水凝胶pH敏感性明显不同于PNIPAAm和P(NIPAAm-co-Am)水凝胶。
6、水凝胶的热失重实验表明,N-MACH交联的水凝胶具有良好的热降解稳定性,在100 oC内稳定性良好。
7、P(NIPAAm-co-Am)和PNIPAAm/CMC半互穿网络水凝胶的玻璃化转变温度高于PNIPAAm水凝胶,证明了Am和CMC成功引入到PNIPAAm体系内。
8、通过扫描电镜观察可以看出,水凝胶具有较大的孔径结构,有利于水分子的自由进出。
9、在37 oC时,P(NIPAAm-co-Am)水凝胶在含溶菌酶的模拟肠液(SIF)和含胃蛋白酶模拟胃液(SGF)中较短时间内有较大程度的降解。水凝胶降解的速度随着交联剂和Am用量的增加而降低,随着酶浓度的升高而降解速度加快。
Hydrogels are insoluble, cross-linked three dimensional network structure composed of hydrophilic polymer, which do not dissolve in water but absorb a great deal of water. Intelligent or smart hydrogels are a class of polymers which undergoing a volume phase transition in response to environmental stimulus, such as pH, temperature, electric fields and so on. Intelligent hydrogels have promising potential application in the field of drug delivery system, biomaterial culture and tissue engineering because of their biocompatibility,flexibility and similarity to natural tissues,etc. Poly(N-isopropylacryamide) (PNIPAAm) is a thermosensitive hydrogel that has received much attention and application because of its lower critical solution temperature (LCST) behavior at around 32°C in an aqueous solution, which is close to the physiological temperature.
In this paper, the cross-linker N-maleyl chitosan (N-MACH) was synthesized with chitosan (CS) and maleic anhydride (Ma) as materials. Poly(N-isopropylacryamide) (PNIPAAm) hydrogels, Poly(N-isopropylacryamide-co-acrylamide) [P(NIPAAm-co-Am)] hydrogels and Poly(N-isopropylacryamide)/Sodium carboxymethyl cellulose (PNIPAAm/CMC) semi-interpenetrating polymer network (semi-IPN) hydrogels have been synthesized by the free radical polymerization in distilled water, with the soluble and biodegradable N-MACH cross-linker. The temperature and pH sensitive behavior, swelling/deswelling kinetics, swelling ratio in NaCl solution, the thermodynamics and the morphology of the hydrogels were investigated. At last, the biodegradable behaviors of P(NIPAAm-co-Am) hydrogels in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF) were investigated.
1. The content of the N-MACH cross-linker and CMC did not influence the lower critical solution temperature (LCST) of hydrogels evidently, but it was significantly influenced by monomer ratio of the NIPAAm/Am. The LCST increased with the increase of the content of Am.
2. All the hydrogels exhibited fast swelling kinetics in DW at 25°C, the swelling ratio of the hydrgels was increased with the increase of Am and CMC content, but decreased with the increase of N-MACH cross-linker content.
3. The hydrogels deswelled fast in DW when the temperature was above their LCSTs. The deswelling rate of the hydrogels was decreased with the increase of N-MACH cross-linker、Am and CMC content.
4. The swelling ratio of the hydrogels was decreased sharply with increasing NaCl concentration to 0.05 mg/mL at 25°C.
5. The swelling ratio of the hydrogels was strongly dependent on the pH of the swelling medium. The swelling ratio of the PNIPAAm and P(NIPAAm-co-Am) hydrogels in acid/alkaline buffer solutions was higher than that in the neutral solution. The pH sensitive behavior of PNIPAAm/CMC semi-IPN hydrogels was different from PNIPAAm and P(NIPAAm-co-Am) hydrogels because of the introduction of CMC.
6. The thermodynamic stability of the hydrogels was characterized by thermogravimetry. The result showed that the hydrogel had a good thermal stability.
7. The glass temperature (Tg) of P(NIPAAm-co-Am) and PNIPAAm/CMC semi-IPN hydrogels was higher than that of PNIPAAm hydrogels. It was intimated the successful introduction of Am and CMC.
8. The morphology of hydrogels was estimated by field scan electron microscopy (SEM). The hydrogels contained open and well-structure orientated porous network.
9. In enzymatic degradation studies, the weight loss of the P(NIPAAm-co-Am) hydrogels was strongly dependent on the cross-linking density, the content of Am, and the concentration of the lysozym and pepsin.
本文通过壳聚糖和马来酸酐酰化反应合成了水溶性良好的可生物降解的交联剂—N-马来酰化壳聚糖(N-malely chitosan,N-MACH),以N-异丙基丙烯酰胺(NIPAAm)、羧甲基纤维素钠(CMC)、丙烯酰胺(Am)为原料,通过水溶液中的自由基聚合反应,分别合成了聚N-异丙基丙烯酰胺(PNIPAAm)均聚水凝胶,聚N-异丙基丙烯酰胺/丙烯酰胺[P(NIPAAm-co-Am)]共聚水凝胶和聚N-异丙基丙烯酰胺/羧甲基纤维素钠(PNIPAAm/CMC)半互穿网络水凝胶。研究了水凝胶的温敏性、pH敏感性、溶胀和退溶胀动力学、盐溶液中的溶胀现象、热力学性质和水凝胶结构形态,并对水凝胶样品的可生物降解性做了初步的研究。
1、交联剂和CMC的用量对水凝胶的LCST值无明显的影响。但随着Am的加入,水凝胶的LCST值明显变化,Am的用量越大,水凝胶的LCST值越高,二者几乎成线性关系。
2、在25 oC的蒸馏水中,所有水凝胶均能快速达到饱和溶胀状态。溶胀率随着Am和CMC增加而升高,随着交联剂用量的增加而降低。
3、LCST值低于37 oC的水凝胶在37 oC蒸馏水中均发生快速失水的退溶胀现象,在1 h左右达到平衡。退溶胀率随交联剂、CMC和Am的用量增加而降低。
4、在25 oC时,在浓度低于0.05 mg/mL的NaCl溶液中水凝胶仍然有较好的溶胀性,但是当NaCl溶液的浓度高于0.05 mg/mL时,水凝胶的溶胀率明显下降,说明水凝胶对于盐溶液有一定敏感性。
5、在25 oC时,缓冲溶液的pH值对水凝胶的饱和溶胀率有很大影响,PNIPAAm和P(NIPAAm-co-Am)水凝胶在酸性和碱性缓冲溶液中饱和溶胀率较大,而在中性缓冲溶液中较低。而CMC的引入使PNIPAAm/CMC半互穿网络水凝胶pH敏感性明显不同于PNIPAAm和P(NIPAAm-co-Am)水凝胶。
6、水凝胶的热失重实验表明,N-MACH交联的水凝胶具有良好的热降解稳定性,在100 oC内稳定性良好。
7、P(NIPAAm-co-Am)和PNIPAAm/CMC半互穿网络水凝胶的玻璃化转变温度高于PNIPAAm水凝胶,证明了Am和CMC成功引入到PNIPAAm体系内。
8、通过扫描电镜观察可以看出,水凝胶具有较大的孔径结构,有利于水分子的自由进出。
9、在37 oC时,P(NIPAAm-co-Am)水凝胶在含溶菌酶的模拟肠液(SIF)和含胃蛋白酶模拟胃液(SGF)中较短时间内有较大程度的降解。水凝胶降解的速度随着交联剂和Am用量的增加而降低,随着酶浓度的升高而降解速度加快。
Hydrogels are insoluble, cross-linked three dimensional network structure composed of hydrophilic polymer, which do not dissolve in water but absorb a great deal of water. Intelligent or smart hydrogels are a class of polymers which undergoing a volume phase transition in response to environmental stimulus, such as pH, temperature, electric fields and so on. Intelligent hydrogels have promising potential application in the field of drug delivery system, biomaterial culture and tissue engineering because of their biocompatibility,flexibility and similarity to natural tissues,etc. Poly(N-isopropylacryamide) (PNIPAAm) is a thermosensitive hydrogel that has received much attention and application because of its lower critical solution temperature (LCST) behavior at around 32°C in an aqueous solution, which is close to the physiological temperature.
In this paper, the cross-linker N-maleyl chitosan (N-MACH) was synthesized with chitosan (CS) and maleic anhydride (Ma) as materials. Poly(N-isopropylacryamide) (PNIPAAm) hydrogels, Poly(N-isopropylacryamide-co-acrylamide) [P(NIPAAm-co-Am)] hydrogels and Poly(N-isopropylacryamide)/Sodium carboxymethyl cellulose (PNIPAAm/CMC) semi-interpenetrating polymer network (semi-IPN) hydrogels have been synthesized by the free radical polymerization in distilled water, with the soluble and biodegradable N-MACH cross-linker. The temperature and pH sensitive behavior, swelling/deswelling kinetics, swelling ratio in NaCl solution, the thermodynamics and the morphology of the hydrogels were investigated. At last, the biodegradable behaviors of P(NIPAAm-co-Am) hydrogels in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF) were investigated.
1. The content of the N-MACH cross-linker and CMC did not influence the lower critical solution temperature (LCST) of hydrogels evidently, but it was significantly influenced by monomer ratio of the NIPAAm/Am. The LCST increased with the increase of the content of Am.
2. All the hydrogels exhibited fast swelling kinetics in DW at 25°C, the swelling ratio of the hydrgels was increased with the increase of Am and CMC content, but decreased with the increase of N-MACH cross-linker content.
3. The hydrogels deswelled fast in DW when the temperature was above their LCSTs. The deswelling rate of the hydrogels was decreased with the increase of N-MACH cross-linker、Am and CMC content.
4. The swelling ratio of the hydrogels was decreased sharply with increasing NaCl concentration to 0.05 mg/mL at 25°C.
5. The swelling ratio of the hydrogels was strongly dependent on the pH of the swelling medium. The swelling ratio of the PNIPAAm and P(NIPAAm-co-Am) hydrogels in acid/alkaline buffer solutions was higher than that in the neutral solution. The pH sensitive behavior of PNIPAAm/CMC semi-IPN hydrogels was different from PNIPAAm and P(NIPAAm-co-Am) hydrogels because of the introduction of CMC.
6. The thermodynamic stability of the hydrogels was characterized by thermogravimetry. The result showed that the hydrogel had a good thermal stability.
7. The glass temperature (Tg) of P(NIPAAm-co-Am) and PNIPAAm/CMC semi-IPN hydrogels was higher than that of PNIPAAm hydrogels. It was intimated the successful introduction of Am and CMC.
8. The morphology of hydrogels was estimated by field scan electron microscopy (SEM). The hydrogels contained open and well-structure orientated porous network.
9. In enzymatic degradation studies, the weight loss of the P(NIPAAm-co-Am) hydrogels was strongly dependent on the cross-linking density, the content of Am, and the concentration of the lysozym and pepsin.
引文
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