Preparation And Properties Of Double-Crosslinked Hyaluronic Acid Self-Healing Hydrogels

Hydrogel material is a soft material with high water content and three-dimensional network structure.Natural polymer hydrogels have attracted extensive attention due to their excellent biocompatibility,low immune response,low cytotoxicity,and ability to promote cell adhesion,proliferation,migration,and regeneration of new tissues.However,natural polymer hydrogels have low strength in performance,and are difficult to repair themselves after damaging,thus limiting their applications in various fields.If hydrogels are given self-healing properties,they can not only prolong the service life,but also restore and retain the original structure and performance of hydrogels,thereby expanding the range of applications for natural polymer hydrogels.Therefore,in this paper,hyaluronic acid self-healing hydrogels with good self-healing properties and mechanical strength have been constructed by using modified hyaluronic acid combined with acylhydrazone bonds crosslinking and photocrosslinking.To this end,the following three aspects of works have been carried out:（1）Aldehyde-modified maleyl hyaluronic acid/3,3’-dithiobis（propionyl hydrazide）self-healing hydrogels system.First,aldehyde-modified maleyl hyaluronic acid（AMHA）with maleyl groups substitution degree of 0.63 and oxidation degree of 0.18 was synthesized,and was crosslinked with 3,3’-dithiobis（propionyl hydrazide）（DTP）via acylhydrazone bonds crosslinking to produce single-crosslinked AMHA/DTP hydrogel.Double-crosslinked AMHA/DTP+UV hydrogel was produced by acylhydrazone bonds crosslinking and photocrosslinking.The acylhydrazone bonds crosslinking resulted in hydrogels with good self-healing properties（stress self-healing efficiencies for 3 h were 93.1 ± 5.9 % and 90.4 ±12.8 %,respectively）and p H responsiveness.Compared with the single-crosslinked hydrogel,the double-crosslinked hydrogel had higher mechanical strength and stability,with the compressive strength increasing from 107.4 ± 9.8 k Pa to 116.6 ± 12.3 k Pa and the stability time extending from three to five days.In addition,the hydrogels all had good cytocompatibility.（2）Aldehyde-modified maleyl hyaluronic acid/hydrazide hyaluronic acid self-healing hydrogels system.In this chapter,macromolecular hydrazide hyaluronic acid（DHA）with hydrazide substitution degree of 0.25 was used to replace the small molecule DTP in the previous chapter.DHA and AMHA were crosslinked by acylhydrazone bonds crosslinking to produce single-crosslinked AMHA/DHA hydrogel,and double-crosslinked AMHA/DHA+UV hydrogel was prepared by acylhydrazone bonds crosslinking and photocrosslinking.The chain entanglement and hydrogen bonding between the macromolecular DHA and AMHA significantly improved the stability of hydrogels（stability time > 7 days）.The dynamic acylhydrazone bonds endowed AMHA/DHA hydrogels and AMHA/DHA+UV hydrogels with self-healing properties（stress self-healing efficiencies for 6 h were 96.9±7.9 % and96.2±4.2 %,respectively）.Photocrosslinking improved the mechanical properties of hydrogel,resulting in double-crosslinked hydrogel with greater compressive strength（150.5±4.2 k Pa）than the single-crosslinked hydrogel（102.1±2.4 k Pa）.Meanwhile,hydrogels were p H-responsive as well as good cytocompatibility.（3）Aldehyde-modified maleyl hyaluronic acid/hydrazide hyaluronic acid/3,3’-dithiobis（propionyl hydrazide）self-healing hydrogels system.In order to improve the mechanical strength and self-healing properties of hydrogels at the same time,DTP and DHA were simultaneously introduced into the hydrogels.Single-crosslinked AMHA/DHA/DTP hydrogel was prepared by acylhydrazone bonds crosslinking,and double-crosslinked AMHA/DHA/DTP+UV hydrogel was produced by acylhydrazone bonds crosslinking and photocrosslinking.The compressive strength of hydrogels could reach149.6±2.3 k Pa and 162.2±16.2 k Pa,respectively.The cleavage and reconstruction of acylhydrazone bonds endowed the hydrogels with good self-healing properties（the stress self-healing efficiencies for 6 h were 102.6±7.5 % and 95.0±8.4 %,respectively）.The hydrogels also exhibited p H responsiveness and good cytocompatibility.In conclusion,the hyaluronic acid hydrogels were prepared by acylhydrazone bond crosslinking and photocrosslinking.They have excellent self-healing properties,good mechanical strength and cytocompatibility,and show broad application prospects in the biomedical field.