Basic research

Fabrication of self-healing injectable hyaluronic acid hydrogel for promoting angiogenesis

  • Shu YANG ,
  • Wenguo CUI ,
  • Jie WEI ,
  • Zhengwei CAI
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  • 1.School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, China
    2.Shanghai Key laboratory for Prevention and Treatment of Bone and Joint Disease, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
CAI Zhengwei, E-mail: caizhengwei@shsmu.edu.cn.
WEI Jie, E-mail: jiewei7860@sina.com

Received date: 2023-11-08

  Accepted date: 2023-12-11

  Online published: 2024-02-01

Supported by

National Natural Science Foundation of China(32101104);Foundation of Shanghai Municipal Health Commission(202140127)

Abstract

Objective ·To construct a self-healing injectable hyaluronic acid (HA)-based hydrogel (HAPD-Cu) and investigate the effects of different copper ions on the properties of the hydrogel and its vasogenic efficacy to evaluate its feasibility for clinical wound healing. Methods ·Bisphosphonated hyaluronic acid (HAPD) was prepared via a blue-light mediated thiol-ene click reaction between thiolated hyaluronic acid (HASH) and acrylated bisphosphonate (Ac-PD) in the presence of photoinitiator 2959. Then, HAPD was further interacted with Cu2+ through metal coordination to prepare HAPD-Cu hydrogels with different Cu2+ concentrations, i.e. HAPD-Cu1, HAPD-Cu2, HAPD-Cu3 and HAPD-Cu4. The molecular structures of HASH, Ac-PD, HAPD and HAPD-Cu were verified with 1HNMR and FTIR. Microscopic morphology of HAPD-Cu was observed under SEM. The shear-thinning and self-healing properties of HAPD-Cu were verified by rheometer. The Cu2+ release from HAPD-Cu was determined with ICP. Live-dead staining and CCK-8 assay were applied to evaluate the biocompatibility of HAPD-Cu. The in vitro vasculogenic activity of HAPD-Cu was determinedby a tubule-forming assay with human umbilical vein vascular endothelial cells and the in vivo vasculogenic activity of HAPD-Cu was assessed by CD31 tissue staining. A rat wound defect model was established in vitro to evaluate its actual repair effect. Results ·The preparation of the materials was demonstrated through chemical qualitative and quantitative analytical means. In vitro studies showed that all HAPD-Cu with a loose porous internal structure exhibited outstanding self-healing, injectability and degradability, with a one-week degradation cycle and abrupt release behavior, which can meet the needs of wound healing cycle. All HAPD-Cu showed good biocompatibility except HAPD-Cu4, due to its high Cu2+ concentrations. Moreover, its angiogenic effect in vitro or in vivo was enhanced with increasing Cu2+ concentrations within the permissible Cu2+ concentration range. In vitro wound model experiments also showed that the HAPD-Cu hydrogel significantly promoted wound healing compared with the control group. Conclusion ·HAPD-Cu hydrogel constructed via the metal coordination shows excellent shape plasticity, allowing the filling of defective sites in a minimally invasive form, and the release of Cu2+ greatly facilitates the establishment of early vascular networks, with giant potential for use in the repair of clinically irregular wounds.

Cite this article

Shu YANG , Wenguo CUI , Jie WEI , Zhengwei CAI . Fabrication of self-healing injectable hyaluronic acid hydrogel for promoting angiogenesis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023 , 43(12) : 1480 -1492 . DOI: 10.3969/j.issn.1674-8115.2023.12.003

References

1 WU F, YUAN Z C, SHAFIQ M, et al. Synergistic effect of glucagon-like peptide-1 analogue liraglutide and ZnO on the antibacterial, hemostatic, and wound healing properties of nanofibrous dressings[J]. J Biosci Bioeng, 2022, 134(3): 248-258.
2 SHI L Y, ZHAO Y N, XIE Q F, et al. Moldable hyaluronan hydrogel enabled by dynamic metal-bisphosphonate coordination chemistry for wound healing[J]. Adv Healthc Mater, 2018, 7(5): 10.1002/adhm.201700973.
3 RAI V, MOELLMER R, AGRAWAL D K. Stem cells and angiogenesis: implications and limitations in enhancing chronic diabetic foot ulcer healing[J]. Cells, 2022, 11(15): 2287.
4 OKONKWO U A, DIPIETRO L A. Diabetes and wound angiogenesis[J]. Int J Mol Sci, 2017, 18(7): 1419.
5 ZHANG W Y, WANG L T, GUO H Y, et al. Dapagliflozin-loaded exosome mimetics facilitate diabetic wound healing by HIF-1α- mediated enhancement of angiogenesis[J]. Adv Healthc Mater, 2023, 12(7): e2202751.
6 SIDDIQUI Z, SARKAR B, KIM K K, et al. Angiogenic hydrogels for dental pulp revascularization[J]. Acta Biomater, 2021, 126: 109-118.
7 QIU W W, HAN H, LI M N, et al. Nanofibers reinforced injectable hydrogel with self-healing, antibacterial, and hemostatic properties for chronic wound healing[J]. J Colloid Interface Sci, 2021, 596: 312-323.
8 CHANG L K, XU Y L, WU Z Y, et al. Hyaluronic acid methacrylate/laponite hydrogel loaded with BMP4 and maintaining its bioactivity for scar-free wound healing[J]. Regen Biomater, 2023, 10: rbad023.
9 BURDICK J A, PRESTWICH G D. Hyaluronic acid hydrogels for biomedical applications[J]. Adv Mater, 2011, 23(12): H41-H56.
10 LI J Y, ZHAI D, LV F, et al. Preparation of copper-containing bioactive glass/eggshell membrane nanocomposites for improving angiogenesis, antibacterial activity and wound healing[J]. Acta Biomater, 2016, 36: 254-266.
11 LIU N B, ZHU S J, DENG Y Z, et al. Construction of multifunctional hydrogel with metal-polyphenol capsules for infected full-thickness skin wound healing[J]. Bioact Mater, 2022, 24: 69-80.
12 ZHANG K Y, LIN S E, FENG Q, et al. Nanocomposite hydrogels stabilized by self-assembled multivalent bisphosphonate-magnesium nanoparticles mediate sustained release of magnesium ion and promote in situ bone regeneration[J]. Acta Biomater, 2017, 64: 389-400.
13 LIU H, CAI Z W, WANG F, et al. Colon-targeted adhesive hydrogel microsphere for regulation of gut immunity and flora[J]. Adv Sci (Weinh), 2021, 8(18): e2101619.
14 ZHOU Y, GU Z P, LIU J, et al. Arginine based poly (ester amide)/hyaluronic acid hybrid hydrogels for bone tissue Engineering[J]. Carbohydr Polym, 2020, 230: 115640.
15 LIU J, SU C Y, CHEN Y T, et al. Current understanding of the applications of photocrosslinked hydrogels in biomedical engineering[J]. Gels, 2022, 8(4): 216.
16 XIA H T, ZHANG Y, XIN H M, et al. Metal-phenolic network-based polydopamine@Cu within a polyvinyl alcohol hydrogel film for improved infected wound healing through antibacterial and pro-angiogenesis activity[J]. Mater Des, 2022, 221: 110904.
17 LEE J H, PARTHIBAN P, JIN G Z, et al. Materials roles for promoting angiogenesis in tissue regeneration[J]. Prog Mater Sci, 2021, 117: 100732.
18 FENG X Z, WANG C, SHANG S B, et al. Multicolor fluorescent cellulose hydrogels actuators: lanthanide-ligand metal coordination, synergetic color-changing and shape-morphing, and antibacterial activity[J]. Chem Eng J, 2022, 450: 138356.
19 ZHAO Z Y, LI G, RUAN H T, et al. Capturing magnesium ions via microfluidic hydrogel microspheres for promoting cancellous bone regeneration[J]. ACS Nano, 2021, 15(8): 13041-13054.
20 LUO M, WANG Y D, XIE C X, et al. Multiple coordination-derived bioactive hydrogel with proangiogenic hemostatic capacity for wound repair[J]. Adv Healthc Mater, 2022, 11(18): e2200722.
21 ZHAO Y C, CHEN Z J, SHAO W J, et al. Black phosphorus-enhanced injectable hydrogel for infected soft tissue healing[J]. APL Bioeng, 2023, 7(1): 016103.
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