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

doi:10.3969/j.issn.1674-8115.2023.12.003

Abstract

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.

Key words: self-healing, injectable hydrogel, angiogenesis, would healing, soft tissue repair

CLC Number:

R318.08

YANG Shu, CUI Wenguo, WEI Jie, CAI Zhengwei. 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.

Figures/Tables 10

Fig 1 Chemical reaction equations of Ac-PD, HASH, and HAPD

Fig 2 Chemical characterization analysis of Ac-PD, HASH, HAPD, and HAPD-Cu

Fig 3 Microstructure of HAPD-Cu

Fig 4 Self-healing and injectable properties of HAPD-Cu

Fig 5 Rheology of HAPD-Cu

Fig 6 Swelling, degradation and ion release of HAPD-Cu

Fig 7 Biocompatibility of HAPD-Cu

Fig 8 Tube formation experiments of HAPD-Cu

Fig 9 CD31 immunofluorescence staining and optical photographs of wound repair of HAPD-Cu

Fig 10 Observation of diabetic wound healing of HAPD-Cu (n=3)

TrendMD

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