新型壳聚糖水凝胶的制备及其凝胶机理的研究
摘要
作为一种新型的反向温敏性水凝胶,壳聚糖/β-磷酸甘油二钠盐(CS/β-GP)体系能在pH值中性及室温条件下保持溶液状态,但在温度升至体温(37℃)时发生凝胶化转变,而且这种水凝胶具有较小的生物毒性、良好的生物相容性、生物可降解性以及细胞粘附性,在生物医药领域,特别是用于作为注射型水凝胶进行局部缓释给药方面具有相当的应用前景。
在本论文中,我们首先通过动态流变方法、核磁共振技术、荧光光谱、动态光散射以及原子力显微镜等多种表征手段对CS/GP体系的凝胶机理进行了研究。尿素和异丁醇被用于对凝胶化过程中CS和GP两组分间的相互作用进行考察。研究发现,由于尿素对分子间氢键的破坏作用,它的加入延缓了CS/GP体系凝胶化的进行；而异丁醇的加入则增强了CS分子间的疏水相互作用,从而促进CS/GP体系的溶胶-凝胶转变。我们的研究结果表明,分子间氢键相互作用和疏水相互作用都是CS/GP凝胶形成的重要驱动力,氢键的形成有利于疏水区域的聚集,而两者的协同作用导致CS/GP凝胶的形成。本工作在原子水平上对CS/GP体系的凝胶机理进行研究,为CS/GP体系凝胶性能的调控和优化提供了理论基础。
在此基础上,我们研制出一种新型的CS/GP/乙二醇(EG)三元体系水凝胶。这种新型水凝胶在保留了CS/GP体系反向温敏特性的同时,还具有可低温成型(4℃)的优点,且形成的低温凝胶具有明显优于CS/GP凝胶的力学性能。论文采用小振幅振荡剪切流动(Small Amplitude Oscillatory Shear Flow, SAOS)和大振幅振荡剪切流动(Large Amplitude Oscillatory Shear Flow, LAOS)实验,结合31PNMR技术,以GP为探针,对CS/GP/EG体系的凝胶机理进行研究。结果表明小分子化合物GP和EG在这种低温(4℃)凝胶的形成过程中起着至关重要的作用,体系的凝胶动力学明显受到EG和GP含量的影响,两者的协同作用诱导凝胶的形成。在凝胶化初期,GP与CS的分子间氢键及GP本身的位阻效应保证了体系的稳定性,并且体系凝胶化进程随着GP含量的增加而减缓；但EG的加入会破坏了原本CS与GP之间的相互作用,最终导致新凝胶网络的形成。研究还发现,GP和EG本身并不参与该凝胶网络的构建,生成的新三维凝胶网络仅由CS分子链构成,与前面研究的CS/GP体系不同。同时31P NMR的研究还发现CS/GP/EG体系在37℃下的凝胶机理完全不同于低温时的情形(4℃),CS与GP分子间的相互作用仍然可能是其凝胶网络形成的主要驱动力。
我们的研究还发现,采用聚乙烯醇(PEG)代替EG,制得的CS/GP/PEG三元体系低温(4℃)水凝胶,相比小分子EG,较长分子链的PEG能够进一步加速凝胶的形成,并且凝胶模量随着PEG分子量的增加而提高。研究还表明,PEG分子可能参与了凝胶三维网络的构建。
As a novel reverse thermosensitive hydrogel, chitosan/β-glycerolphosphate (CS/β-GP) system remains as solution state at room temperature with neutral pH and turns into a gel upon heating at physiological temperature (37℃). As a biocompatible and biodegradable biomaterial, CS/β-GP has wide potential applications for drug delivery, tissue engineering and cell encapsulation.
In our work, time-evolved gelation behavior of chitosan-β-glycerophosphate (CS/β-GP) system was elucidated from rheological investigation, NMR analysis, fluorescence measurement, and morphology observation. Urea and isobutanol were selected to assess the interactions between the two components during the gelation process of CS/β-GP system. Urea was found to be detrimental to the gelation process by both disrupting hydrogen bonding. On the contrary, the addition of isobutanol accelerated the sol-gel transition by strengthening the hydrophobic interactions. These results reveal that both hydrogen bonding and hydrophobic interactions within chitosan or between CS and P-GP molecules are the main reasons for gel formation. The results also indicate that the formation of hydrogen bonds makes the hydrophobic sites more accessible first, and then the synergistic hydrogen bonding and hydrophobic interactions lead to the final formation of CS/β-GP gel network. This work explores the gelation mechanism of CS/β-GP system at atomic level, and shows the possible methods to tune the gelling ability of such a system as well as the mechanical properties of the resulted hydrogels, providing the opportunities to optimize the performance of this promising natural thermosensitive material for practical applications in future.
Based on the gelation mechanism of CS/GP hydrogel, a novel low temperature (4℃) hydrogel of CS/GP/ethylene glycol (EG) ternary systems was achieved, with much better mechanical properties than CS/GP hydrogel. The underlying gelation mechanism was investigated by means of Small Amplitude Oscillatory Shear Flow (SAOS) and Large Amplitude Oscillatory Shear Flow (LAOS) rheological method, as well as 31P NMR spectroscopy. We found that the gelation kinetic is strongly affected by the content of GP and EG. Although the system is stabilized from precipitation by hydrogen bond between CS and GP as well as steric hindrance of GP at the initial stage of gelation, the increase of GP content will retard the gelation of system. However, the addition of EG will weaken the interaction among CS and GP, resulting in the breakage of old weak network formed by CS and GP, as well as the formation of a new solid network. In spite of the key roles playing by GP and EG during the course of gelation, both of them do not participate in the construction of the 3D hydrogel network, that is, the network of hydrogel is formed by CS alone. Besides, the results from 31P NMR spectrum indicated that the gelation mechanism of CS/GP/EG at 37℃is different from that of 4℃, that is, CS and GP probably constitute the gel network together.
In addition, when EG is substituted by polyethylene glycol (PEG), the gelation process will be accelerated, and the increase of the length of PEG molecular chains will improve the strength of CS/GP/PEG hydrogel. Moreover, PEG probably participates in the formation of 3D network of hydrogel with CS, and the elastic modulus of the formed hydrogel is much lower than that of CS/GP/EG system.
在本论文中,我们首先通过动态流变方法、核磁共振技术、荧光光谱、动态光散射以及原子力显微镜等多种表征手段对CS/GP体系的凝胶机理进行了研究。尿素和异丁醇被用于对凝胶化过程中CS和GP两组分间的相互作用进行考察。研究发现,由于尿素对分子间氢键的破坏作用,它的加入延缓了CS/GP体系凝胶化的进行；而异丁醇的加入则增强了CS分子间的疏水相互作用,从而促进CS/GP体系的溶胶-凝胶转变。我们的研究结果表明,分子间氢键相互作用和疏水相互作用都是CS/GP凝胶形成的重要驱动力,氢键的形成有利于疏水区域的聚集,而两者的协同作用导致CS/GP凝胶的形成。本工作在原子水平上对CS/GP体系的凝胶机理进行研究,为CS/GP体系凝胶性能的调控和优化提供了理论基础。
在此基础上,我们研制出一种新型的CS/GP/乙二醇(EG)三元体系水凝胶。这种新型水凝胶在保留了CS/GP体系反向温敏特性的同时,还具有可低温成型(4℃)的优点,且形成的低温凝胶具有明显优于CS/GP凝胶的力学性能。论文采用小振幅振荡剪切流动(Small Amplitude Oscillatory Shear Flow, SAOS)和大振幅振荡剪切流动(Large Amplitude Oscillatory Shear Flow, LAOS)实验,结合31PNMR技术,以GP为探针,对CS/GP/EG体系的凝胶机理进行研究。结果表明小分子化合物GP和EG在这种低温(4℃)凝胶的形成过程中起着至关重要的作用,体系的凝胶动力学明显受到EG和GP含量的影响,两者的协同作用诱导凝胶的形成。在凝胶化初期,GP与CS的分子间氢键及GP本身的位阻效应保证了体系的稳定性,并且体系凝胶化进程随着GP含量的增加而减缓；但EG的加入会破坏了原本CS与GP之间的相互作用,最终导致新凝胶网络的形成。研究还发现,GP和EG本身并不参与该凝胶网络的构建,生成的新三维凝胶网络仅由CS分子链构成,与前面研究的CS/GP体系不同。同时31P NMR的研究还发现CS/GP/EG体系在37℃下的凝胶机理完全不同于低温时的情形(4℃),CS与GP分子间的相互作用仍然可能是其凝胶网络形成的主要驱动力。
我们的研究还发现,采用聚乙烯醇(PEG)代替EG,制得的CS/GP/PEG三元体系低温(4℃)水凝胶,相比小分子EG,较长分子链的PEG能够进一步加速凝胶的形成,并且凝胶模量随着PEG分子量的增加而提高。研究还表明,PEG分子可能参与了凝胶三维网络的构建。
As a novel reverse thermosensitive hydrogel, chitosan/β-glycerolphosphate (CS/β-GP) system remains as solution state at room temperature with neutral pH and turns into a gel upon heating at physiological temperature (37℃). As a biocompatible and biodegradable biomaterial, CS/β-GP has wide potential applications for drug delivery, tissue engineering and cell encapsulation.
In our work, time-evolved gelation behavior of chitosan-β-glycerophosphate (CS/β-GP) system was elucidated from rheological investigation, NMR analysis, fluorescence measurement, and morphology observation. Urea and isobutanol were selected to assess the interactions between the two components during the gelation process of CS/β-GP system. Urea was found to be detrimental to the gelation process by both disrupting hydrogen bonding. On the contrary, the addition of isobutanol accelerated the sol-gel transition by strengthening the hydrophobic interactions. These results reveal that both hydrogen bonding and hydrophobic interactions within chitosan or between CS and P-GP molecules are the main reasons for gel formation. The results also indicate that the formation of hydrogen bonds makes the hydrophobic sites more accessible first, and then the synergistic hydrogen bonding and hydrophobic interactions lead to the final formation of CS/β-GP gel network. This work explores the gelation mechanism of CS/β-GP system at atomic level, and shows the possible methods to tune the gelling ability of such a system as well as the mechanical properties of the resulted hydrogels, providing the opportunities to optimize the performance of this promising natural thermosensitive material for practical applications in future.
Based on the gelation mechanism of CS/GP hydrogel, a novel low temperature (4℃) hydrogel of CS/GP/ethylene glycol (EG) ternary systems was achieved, with much better mechanical properties than CS/GP hydrogel. The underlying gelation mechanism was investigated by means of Small Amplitude Oscillatory Shear Flow (SAOS) and Large Amplitude Oscillatory Shear Flow (LAOS) rheological method, as well as 31P NMR spectroscopy. We found that the gelation kinetic is strongly affected by the content of GP and EG. Although the system is stabilized from precipitation by hydrogen bond between CS and GP as well as steric hindrance of GP at the initial stage of gelation, the increase of GP content will retard the gelation of system. However, the addition of EG will weaken the interaction among CS and GP, resulting in the breakage of old weak network formed by CS and GP, as well as the formation of a new solid network. In spite of the key roles playing by GP and EG during the course of gelation, both of them do not participate in the construction of the 3D hydrogel network, that is, the network of hydrogel is formed by CS alone. Besides, the results from 31P NMR spectrum indicated that the gelation mechanism of CS/GP/EG at 37℃is different from that of 4℃, that is, CS and GP probably constitute the gel network together.
In addition, when EG is substituted by polyethylene glycol (PEG), the gelation process will be accelerated, and the increase of the length of PEG molecular chains will improve the strength of CS/GP/PEG hydrogel. Moreover, PEG probably participates in the formation of 3D network of hydrogel with CS, and the elastic modulus of the formed hydrogel is much lower than that of CS/GP/EG system.
引文
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