Abstract：The development of injectable dynamic hydrogels has been one hot issue in recent years, and the preparation of catalyst-free fast-crosslinked injectable dynamic hydrogels is still one big challenge. In this paper, reversible dynamic Schiff base bonds and electrostatic interactions, formed by amine groups on methylacrylated chitosan (CHMA) molecules with aldehyde groups and carboxyl groups on Aldehyde hyaluronic acid (ALHA) molecules respectively, were utilized to prepare a novel catalyst-free hydrogel. The gelation rate, shear thinning behavior and self-healing characteristics of the hydrogel were characterized by dynamic rheological analyzer, the cytocompatibility was evaluated by the cell three-dimensional culture experiment, and the wound healing rate was evaluated through the acute full-thickness skin wound repair experiment. Results showed that the hydrogel quickly formed in 5 seconds the aqueous solution of CHMA and ALHA were mixed. In addition, the hydrogel was an injectable one with shear thinning and rapid self-healing. The complex viscosity gradually decreased from 0.4 kPa to 8 Pa, when the scanning frequency increased from 10-1 s-1 to 102 s-1. Meanwhile, the values order of its storage modulus and loss modulus switched quickly between 1% and 1000% of the strain, yet the modulus had no significant decrease. The hydrogel also exhibited excellent cytocompatibility and fast wound healing rate, evidenced by the high cell survival rate (>95%) in the 3D culture of cells, and a reduction in the wound healing time of 5-7 days in the hydrogel group compared to the blank control based on a model of acute full-thickness skin defect in male ICR mice. The injectable chitosan-hyaluronate hydrogel showed broad application perspectives in the fields of regenerative medicine.
吴益栋, 洪丹, 郝文娟, 叶栋. 超快动态交联的可注射壳聚糖-透明质酸水凝胶及促创伤愈合研究[J]. 中国生物医学工程学报, 2021, 40(5): 590-596.
Wu Yidong, Hong Dan, Hao Wenjuan, Ye Dong. Ultra-Rapid Fabrication of Dynamic-Crosslinked Injectable Chitosan-Hyaluronate Hydrogel for Wound Healing. Chinese Journal of Biomedical Engineering, 2021, 40(5): 590-596.
[1] Ren P, Zhang H, Dai Z, et al. Stiff micelle-crosslinked hyaluronate hydrogels with low swelling for potential cartilage repair [J]. J Mater Chem B, 2019, 7(36): 5490-5501. [2] Zhang H, Cong Y, Osi AR, et al. Direct 3D printed biomimetic scaffolds based on hydrogel microparticles for cell spheroid growth [J]. Adv Funct Mater, 2020, 30(13): 1910573-1910583. [3] Pei X, Zhang H, Zhou Y, et al. Stretchable, self-healing and tissue-adhesive zwitterionic hydrogels as strain sensors for wireless monitoring of organ motions [J]. Mater Horiz, 2020, 7(7):1872-1882. [4] Mao X, Cheng R, Zhang H, et al. Self‐healing and injectable hydrogel for matching skin flap regeneration [J]. Adv Sci, 2019, 6(3): 1801555-1801565. [5] Wang S, Zheng H, Zhou L, et al. Nanoenzyme-reinforced injectable hydrogel for healing diabetic wounds infected with multi-drug resistant bacteria [J]. Nano Lett, 2020, 20(7): 5149-5158. [6] Li J, Chen G, Xu X, et al. Advances of injectable hydrogel-based scaffolds for cartilage regeneration [J]. Regen Biomater, 2019, 6(3): 129-140. [7] Yang C, Gao L, Liu X, et al. Injectable schiff base polysaccharide hydrogels for intraocular drug loading and release [J]. J Biomed Mater Res A, 2019, 107(9): 1909-1916. [8] 史传英,马小越,黄晓文,等. 基于可逆酰腙键的自修复聚氨酯的制备与性能研究 [J]. 高分子通报, 2019(9): 45-57. [9] 吴宝意,徐亚文,乐晓霞,等. 基于动态硼酸酯键的水凝胶的模块化组装和智能形变 [J]. 高分子学报, 2019, 50(5): 496-504. [10] 李进,赵梓年,李征征,等. 自愈合水凝胶的合成机理及生物医学应用 [J]. 材料导报, 2019,33(19): 3328-3346. [11] Liang S, Zhang Y, Wang H, et al. Paintable and rapidly bondable conductive hydrogels as therapeutic cardiac patches [J]. Adv Mater, 2018 30(23): 1704235-1704245. [12] Jiang Z, Diggle B, Shackleford ICG. Tough, self‐healing hydrogels capable of ultrafast shape changing [J]. Adv Mater, 2019, 31 (48): 1904956-1904966. [13] Fan B, Zhang K, Liu Q, et al. Self-healing injectable polymer hydrogel via dynamic thiol-alkynone double addition cross-Links [J]. ACS Macro Lett, 2020, 9 (6): 776-780. [14] Lou J, Liu F, Lindsay CD, et al. Dynamic hyaluronan hydrogels with temporally modulated high injectability and stability using a biocompatible catalyst [J]. Adv Mater, 2018, 30(22): 1705215-1705225. [15] Zhang Z, He C, Rong Y, et al. A fast and versatile cross-linking strategy via o-phthalaldehyde condensation for mechanically strengthened and functional hydrogels [J]. Nat Sci Rev, 2020, 8 (4): 128-139. [16] Yesilyurt V, Webber M, Appel E, et al. Injectable self-healing glucose-responsive hydrogels with pH-Regulated mechanical properties [J]. Adv Mater, 2016, 28(1): 86-91. [17] Feng Q, Wei K, Lin S, et al. Mechanically resilient, injectable, and bioadhesive supramolecular gelatin hydrogels crosslinked by weak host-guest interactions assist cell infiltration and in situ tissue regeneration [J]. Biomaterials, 2016, 101: 217-228. [18] Loebel C, Rodell C, Chen M, et al. Shear-thinning and self-healing hydrogels as injectable therapeutics and for 3D-printing [J]. Nat Protoc, 2017, 12(8): 1521-1541. [19] Mealy J, Chung J, Jeong H, et al. Injectable granular hydrogels with multifunctional properties for biomedical applications [J]. Adv Mater, 2018, 30(20): 1705912-1705922 [20] Rodell C, Kaminski A, Burdick J, et al. Rational design of network properties in guest-host assembled and shear-thinning hyaluronic acid hydrogels [J]. Biomacromolecules, 2013, 14(11): 4125-4134. [21] Felt O, Carrel A, Baehni P, et al. Chitosan as tear substitute: A wetting agent endowed with antimicrobial [J]. J Ocul Pharmacol Th, 2000, 16(3): 261-270. [22] Ueno H, Mori T, Fujinaga T, et al. Topical formulations and wound healing applications of chitosan [J]. Adv Drug Deliver Rev, 2001, 52(2): 105-115. [23] Yaling Z, Lei T, Shuxi L, et al.Synthesis of multiresponsive and dynamic chitosan-based hydrogels for controlled release of bioactive molecules [J]. Biomacromolecules, 2011, 12(8):2894-2901.
