Preparation And Investigation Of Smart Self-Healing Hydrogel Based On Multivalent Coordination Between Polyhistidine And Ni²⁺

Stimuli-responsive hydrogels can change their chemical or physical structures and undergoes tunable volume phase transition(such as gel-sol transition)or other gel property changes,when they suffered from the stimuli of external environment.These transition will extend to meaningful applications such as stimuli-responsive shape-memory and drug controlled release.With a pKa near the physiological conditions,polyhistidine became an important biocompatible pH responsive polymer.Together with the coordination ability of polyhistidine,it's really urgent to develop a facile preparation method for polyhistidine and introduce this polyhistidine into the field of responsive hydrogels.Due to the dynamic exchangeability of the polyhistidine coordination and pKa of the polymer,the formed hydrogel showed a self-healing,pH and some other stimuli responsive properties,which matter for the drug delivery hydrogels.Meanwhile,the multivalent coordination structure of the polyhistidine related metal coordination help this dynamic hydrogel in the poor stability under neutral water environment.In this thesis,synthetic polyhistidine was introduced into the responsive hydrogels.The formed hydrogel will be stable in aqueous environment with sensitive responsiveness.Applications in responsive drug delivery was also studied.The dissertation includes the following three parts:1.We introduced polyhistidine into the field metal coordination hydrogels by using the coordination ability between polyhistidine chains.The designed coordination hydrogels showed a physiologically relevant pH responsiveness and injectability and stability in neutral buffer.Through the novel and facile synthesis of polyhistidine,a 4-arm polyhistidine block polymer was prepared using amino terminated 4-arm PEG as macro-initiator.The nickel coordination hydrogel was formed in neutral.Due to the protonation ability of nitrogen atom on imidazole ring of polyhistidine,the hydrogels showed a physiological mild acid triggered gel-sol transition and an injectability to neutral buffer benefitting from the fast gelation.The dynamic nature of the coordination structure allows the gel to self-heal in neutral conditions.The multivalent coordination between polyhistidine blocks increased the stability of the coordination structure and more important,the stability of the gel.2.According to His-tag chemistry,the Ni2+ coordination of polyhistidine and chelator IDA was introduced into metal coordination hydrogels and modified to PEG and oligochitosan,respectively.By changing the ratio of polyhistidine and IDA groups in the gel component,a similar multivalent coordination structure is formed,which succeed in tuning the relaxation time of gel to adjust the stability.Moreover,by introducing polyhistidine to the side chain of oligochitosan and IDA to the ends of PEG,an opposite structure of the coordination hydrogel was prepared for comparison.It was found that this gel can only form monovalent coordination and exhibited an opposite trend of relaxation time under the same conditions as the previous gel,which further verified the effect of multivalent coordination on the stability of the coordination structure.Benefitting from the multivalent coordination,the gel with different relaxation time showed a different stability in neutral buffer,while the stable hydrogel maintained the pH responsiveness.Using this pH-responsive stable hydrogel,a pH-responsive release of the His-tag-containing molecule was performed.The drug release exhibited a limited leakage of the His-tagged cargo under neutral condition and a sensitive release of that cargo under weak acid condition.3.The commercial available temperature-responsive triblock polymer F127(PEOioo-PPO65-PEO100)was introduced into the Ni2+ coordination hydrogel,which exhibited a pH/temperature dual responsiveness.The chelating ligand IDA was modified at both ends of F127 to obtain a temperature-induced aggregation of IDA ligands.The hydrogel was formed by mixing the IDA-modified F127 and polyhistidine-terminated PEG with Ni2+ after adjusting the pH of the system to neutral.The gel still had the responsiveness of weak acidity in the previous system.Due to the aggregation of the IDA ligand by elevating the temperature,the coordination structure was changed from the original monovalent coordination to multivalent coordination,which enhanced the gel strength,and also increased the relaxation time and stability of the gel.Utilizing the above-mentioned temperature responsiveness,the gel behaved a shear-thinning injectability and thermo induced gel strengthening.The system achieves a dual pH/temperature responsiveness and injectability and is expected to have potential applications in responsive drug release fields.