双网络交联水凝胶在骨组织再生领域的研究进展

doi:10.13591/j.cnki.kqyx.2025.01.011

摘要/Abstract

摘要：

双网络交联水凝胶具备精准调节理化性质的能力,能够改变生物材料与细胞或分子的相互作用,更好地匹配临床实际应用的需要,在组织工程和再生医学中已得到广泛应用。本文总结了应用于骨组织再生双网络交联水凝胶的性能优势,介绍了双网络交联水凝胶系统在骨修复中对负载细胞行为的影响、药物递送能力及其在微环境构建、生物活性复合材料、抗菌性的应用。

关键词: 双网络交联, 水凝胶, 骨组织工程, 理化性质, 骨再生

Abstract:

Double network(DN) hydrogels have the ability to precisely adjust physical and chemical properties, change the interaction between biomaterials and cells or biomolecules, which can better fulfill clinical needs. DN have been widely used in tissue engineering and regenerative medicine. This article summarizes the advantages of DN hydrogels used in bone tissue regeneration, and introduces the effect of DN hydrogel systems on the behavior of loading cells, drug delivering in bone reparation, and the application of DN hydrogel system in microenvironment construction, bioactive composite materials, and antibacterial activity to meet the needs of bone regeneration.

Key words: double network cross, hydrogel, bone tissue engineering, physicochemical property, bone regeneration

中图分类号:

R783.1

张天翼, 郑义, 吕雯昊, 马宁. 双网络交联水凝胶在骨组织再生领域的研究进展[J]. 口腔医学, 2025, 45(1): 69-74.

ZHANG Tianyi, ZHENG Yi, LYU Wenhao, MA Ning. Research progress of double network hydrogel in the field of bone regeneration[J]. Stomatology, 2025, 45(1): 69-74.

图/表 1

参考文献 50

[1]	Bhattacharjee M, Escobar Ivirico JL, Kan HM, et al. Injectable amnion hydrogel-mediated delivery of adipose-derived stem cells for osteoarthritis treatment[J]. Proc Natl Acad Sci U S A, 2022, 119(4): e2120968119.
[2]	Zhao XD, Yang YX, Yu J, et al. Injectable hydrogels with high drug loading through B-N coordination and ROS-triggered drug release for efficient treatment of chronic periodontitis in diabetic rats[J]. Biomaterials, 2022, 282: 121387.
[3]	Liu ZW, Tang WZ, Liu JY, et al. A novel sprayable thermosensitive hydrogel coupled with zinc modified metformin promotes the healing of skin wound[J]. Bioact Mater, 2023, 20: 610-626. doi: 10.1016/j.bioactmat.2022.06.008 pmid: 35846848
[4]	Li DZ, Chen KW, Tang H, et al. A logic-based diagnostic and therapeutic hydrogel with multistimuli responsiveness to orchestrate diabetic bone regeneration[J]. Adv Mater, 2022, 34(11): e2108430.
[5]	Su GH, Yin SY, Guo YH, et al. Balancing the mechanical, electronic, and self-healing properties in conductive self-healing hydrogel for wearable sensor applications[J]. Mater Horiz, 2021, 8(6): 1795-1804. doi: 10.1039/d1mh00085c pmid: 34846508
[6]	Zhou XH, Sun JW, Wo KQ, et al. nHA-loaded gelatin/alginate hydrogel with combined physical and bioactive features for maxillofacial bone repair[J]. Carbohydr Polym, 2022, 298: 120127.
[7]	Gong JP, Katsuyama Y, Kurokawa T, et al. Double-network hydrogels with extremely high mechanical strength[J]. Adv Mater, 2003, 15(14): 1155-1158.
[8]	Arkenberg MR, Nguyen HD, Lin CC. Recent advances in bio-orthogonal and dynamic crosslinking of biomimetic hydrogels[J]. J Mater Chem B, 2020, 8(35): 7835-7855. doi: 10.1039/d0tb01429j pmid: 32692329
[9]	Xu XW, Jerca VV, Hoogenboom R. Bioinspired double network hydrogels: From covalent double network hydrogels via hybrid double network hydrogels to physical double network hydrogels[J]. Mater Horiz, 2021, 8(4): 1173-1188.
[10]	Whitehead J, Griffin KH, Gionet-Gonzales M, et al. Hydrogel mechanics are a key driver of bone formation by mesenchymal stromal cell spheroids[J]. Biomaterials, 2021, 269: 120607.
[11]	Mainardi VL, Rubert M, Sabato C, et al. Culture of 3D bioprinted bone constructs requires an increased fluid dynamic stimulation[J]. Acta Biomater, 2022, 153: 374-385. doi: 10.1016/j.actbio.2022.09.011 pmid: 36108964
[12]	Chen ZH, Lv ZD, Zhuang YP, et al. Mechanical signal-tailored hydrogel microspheres recruit and train stem cells for precise differentiation[J]. Adv Mater, 2023, 35(40): e2300180.
[13]	Szarpak A, Auzély-Velty R. Hyaluronic acid single-network hydrogel with high stretchable and elastic properties[J]. Carbohydr Polym, 2023, 320: 121212.
[14]	Sánchez-Fernández MJ, Rutjes J, Félix Lanao RP, et al. Bone-adhesive hydrogels based on dual crosslinked poly(2-oxazoline)S[J]. Macromol Biosci, 2021, 21(12): e2100257.
[15]	Ding HC, Li BQ, Liu ZL, et al. Nonswelling injectable chitosan hydrogel via UV crosslinking induced hydrophobic effect for minimally invasive tissue engineering[J]. Carbohydr Polym, 2021, 252: 117143.
[16]	Vo TN, Ekenseair AK, Spicer PP, et al. In vitro and in vivo evaluation of self-mineralization and biocompatibility of injectable, dual-gelling hydrogels for bone tissue engineering[J]. J Control Release, 2015, 205: 25-34.
[17]	Shrestha S, Li FY, Truong VX, et al. Interplay of hydrogel composition and geometry on human mesenchymal stem cell osteogenesis[J]. Biomacromolecules, 2020, 21(12): 5323-5335. doi: 10.1021/acs.biomac.0c01408 pmid: 33237736
[18]	Vo TN, Tatara AM, Santoro M, et al. Acellular mineral deposition within injectable, dual-gelling hydrogels for bone tissue engineering[J]. J Biomed Mater Res A, 2017, 105(1): 110-117. doi: 10.1002/jbm.a.35875 pmid: 27557993
[19]	Plotnikov SV, Pasapera AM, Sabass B, et al. Force fluctuations within focal adhesions mediate ECM-rigidity sensing to guide directed cell migration[J]. Cell, 2012, 151(7): 1513-1527. doi: 10.1016/j.cell.2012.11.034 pmid: 23260139
[20]	Zhao YR, Zhu TJ, Han S, et al. Construction of processable ultrastiff hydrogel for periarticular fracture strutting and healing[J]. Biomacromolecules, 2023, 24(5): 2075-2086. doi: 10.1021/acs.biomac.2c01503 pmid: 37018617
[21]	Yu TT, Zhang LY, Dou XY, et al. Mechanically robust hydrogels facilitating bone regeneration through epigenetic modulation[J]. Adv Sci, 2022, 9(32): e2203734.
[22]	Xiong A, He YJ, Gao L, et al. The fabrication of a highly efficient hydrogel based on a functionalized double network loaded with magnesium ion and BMP2 for bone defect synergistic treatment[J]. Mater Sci Eng C Mater Biol Appl, 2021, 128: 112347.
[23]	Zhang MH, Qian TB, Deng ZW, et al. 3D printed double-network alginate hydrogels containing polyphosphate for bioenergetics and bone regeneration[J]. Int J Biol Macromol, 2021, 188: 639-648. doi: 10.1016/j.ijbiomac.2021.08.066 pmid: 34390746
[24]	Wang R, Che LB, Feng Q, et al. Tough, flexible, and bioactive amphoteric copolymer-based hydrogel for bone regeneration without encapsulation of seed cells/simulating cues[J]. ACS Appl Mater Interfaces, 2022, 14(10): 12038-12049.
[25]	Stagnaro P, Schizzi I, Utzeri R, et al. Alginate-polymethacrylate hybrid hydrogels for potential osteochondral tissue regeneration[J]. Carbohydr Polym, 2018, 185: 56-62.
[26]	Guo F, Huang KQ, Niu JJ, et al. Enhanced osseointegration of double network hydrogels via calcium polyphosphate incorporation for bone regeneration[J]. Int J Biol Macromol, 2020, 151: 1126-1132.
[27]	Liu YW, Wang G, Luo HT, et al. Phosphoserine enhanced Cu-doped bioactive glass dynamic dual-network hydrogel for craniofacial bone defect repair[J]. Regen Biomater, 2023, 10: rbad054.
[28]	Wang L, Zhao W, Zhao YN, et al. Enzymatically-mineralized double-network hydrogels with ultrahigh mechanical strength, toughness, and stiffness[J]. Theranostics, 2023, 13(2): 673-684. doi: 10.7150/thno.77417 pmid: 36632214
[29]	Zhao FJ, Yang Z, Xiong HC, et al. A bioactive glass functional hydrogel enhances bone augmentation via synergistic angiogenesis, self-swelling and osteogenesis[J]. Bioact Mater, 2023, 22: 201-210.
[30]	Li XM, Liu SB, Han SS, et al. Dynamic stiffening hydrogel with instructive stiffening timing modulates stem cell fate in vitro and enhances bone remodeling in vivo[J]. Adv Healthc Mater, 2023, 12(29): e2300326.
[31]	Jiang W, Hou FS, Gu Y, et al. Local bone metabolism balance regulation via double-adhesive hydrogel for fixing orthopedic implants[J]. Bioact Mater, 2022, 12: 169-184. doi: 10.1016/j.bioactmat.2021.10.017 pmid: 35310387
[32]	Nonoyama T, Wada S, Kiyama R, et al. Double-network hydrogels strongly bondable to bones by spontaneous osteogenesis penetration[J]. Adv Mater, 2016, 28(31): 6740-6745.
[33]	Nonoyama T, Wang L, Tsuda M, et al. Isotope microscopic observation of osteogenesis process forming robust bonding of double network hydrogel to bone[J]. Adv Healthc Mater, 2021, 10(3): e2001731.
[34]	Li JY, Ma JJ, Feng Q, et al. Building osteogenic microenvironments with a double-network composite hydrogel for bone repair[J]. Research, 2023, 6: 0021. doi: 10.34133/research.0021 pmid: 37040486
[35]	Long J, Wang YT, Lu MX, et al. Dual-cross-linked magnetic hydrogel with programmed release of parathyroid hormone promotes bone healing[J]. ACS Appl Mater Interfaces, 2023, 15(30): 35815-35831.
[36]	Li DH, Yang ZY, Zhao X, et al. A bone regeneration strategy via dual delivery of demineralized bone matrix powder and hypoxia-pretreated bone marrow stromal cells using an injectable self-healing hydrogel[J]. J Mater Chem B, 2021, 9(2): 479-493.
[37]	Liu BB, Wu JN, Sun XD, et al. Sustained delivery of osteogenic growth peptide through injectable photoinitiated composite hydrogel for osteogenesis[J]. Front Bioeng Biotechnol, 2023, 11: 1228250.
[38]	Miao YL, Liu X, Luo JS, et al. Double-network DNA macroporous hydrogel enables aptamer-directed cell recruitment to accelerate bone healing[J]. Adv Sci, 2024, 11(1): e2303637.
[39]	Tang SY, Liu K, Chen JS, et al. Dual-cross-linked liquid crystal hydrogels with controllable viscoelasticity for regulating cell beha-viors[J]. ACS Appl Mater Interfaces, 2022, 14(19): 21966-21977.
[40]	Chen G, Deng SH, Zuo MX, et al. Non-viral CRISPR activation system targeting VEGF-A and TGF-β1 for enhanced osteogenesis of pre-osteoblasts implanted with dual-crosslinked hydrogel[J]. Mater Today Bio, 2022, 16: 100356.
[41]	Jeon O, Lee K, Alsberg E. Spatial micropatterning of growth factors in 3D hydrogels for location-specific regulation of cellular behaviors[J]. Small, 2018, 14(25): e1800579.
[42]	Dutta SD, Ganguly K, Randhawa A, et al. Electrically stimulated 3D bioprinting of gelatin-polypyrrole hydrogel with dynamic semi-IPN network induces osteogenesis via collective signaling and immunopolarization[J]. Biomaterials, 2023, 294: 121999.
[43]	Choi JH, Choi OK, Lee J, et al. Evaluation of double network hydrogel of poloxamer-heparin/gellan gum for bone marrow stem cells delivery carrier[J]. Colloids Surf B Biointerfaces, 2019, 181: 879-889.
[44]	Xin TW, Gu Y, Cheng RY, et al. Inorganic strengthened hydrogel membrane as regenerative periosteum[J]. ACS Appl Mater Interfaces, 2017, 9(47): 41168-41180.
[45]	Yang CC, Han B, Cao CL, et al. An injectable double-network hydrogel for the co-culture of vascular endothelial cells and bone marrow mesenchymal stem cells for simultaneously enhancing vascularization and osteogenesis[J]. J Mater Chem B, 2018, 6(47): 7811-7821. doi: 10.1039/c8tb02244e pmid: 32255027
[46]	Zhou ZZ, Liu Y, Li WJ, et al. A self-adaptive biomimetic periosteum employing nitric oxide release for augmenting angiogenesis in bone defect regeneration[J]. Adv Healthc Mater, 2024, 13(3): e2302153.
[47]	Jin MQ, Sun NN, Weng WX, et al. The effect of GelMA/alginate interpenetrating polymeric network hydrogel on the performance of porous zirconia matrix for bone regeneration applications[J]. Int J Biol Macromol, 2023, 242(Pt 3): 124820.
[48]	Xu Y, Xu C, He L, et al. Stratified-structural hydrogel incorporated with magnesium-ion-modified black phosphorus nanosheets for promoting neuro-vascularized bone regeneration[J]. Bioact Mater, 2022, 16: 271-284. doi: 10.1016/j.bioactmat.2022.02.024 pmid: 35386320
[49]	Jian GY, Li DZ, Ying QW, et al. Dual photo-enhanced interpenetrating network hydrogel with biophysical and biochemical signals for infected bone defect healing[J]. Adv Healthc Mater, 2023, 12(25): e2300469.
[50]	Yao QQ, Liu Y, Pan YN, et al. Long-term induction of endogenous BMPs growth factor from antibacterial dual network hydrogels for fast large bone defect repair[J]. J Colloid Interface Sci, 2022, 607(Pt 2): 1500-1515.