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  3. A calcitonin gene-related peptide co-crosslinked hydrogel promotes diabetic wound healing by regulating M2 macrophage polarization and angiogenesis

A calcitonin gene-related peptide co-crosslinked hydrogel promotes diabetic wound healing by regulating M2 macrophage polarization and angiogenesis

  • Acta Biomater. 2025 Feb 26:S1742-7061(25)00141-2. doi: 10.1016/j.actbio.2025.02.046.
Xiangyu Li 1,  Min Yi 2,  Ziyan Song 1,  Tianyi Ni 3,  Liying Tu 2,  Miao Yu 1,  Lantian Zhang 4,  Jingping Shi 3,  Weicheng Gao 5,  Qian Zhang 6,  Wei Yan 7
Affiliations

Affiliations

  • 1 Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China.
  • 2 Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China.
  • 3 Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China.
  • 4 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China.
  • 5 Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China. Electronic address: weicheng_gao@njmu.edu.cn.
  • 6 Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China. Electronic address: zqsummer1031@njmu.edu.cn.
  • 7 Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China. Electronic address: yan_wei@njmu.edu.cn.
PMID: 40020959 DOI: 10.1016/j.actbio.2025.02.046
Abstract

Delayed diabetic wound (DBW) healing is a severe complication of diabetes, characterized notably by peripheral sensory neuropathy. The underlying mechanism of sensory nerves and DBW remain unclear. Here, we demonstrate the role of Calcitonin gene-related peptide (CGRP) in regulating epithelialization and angiogenesis in DBW. Subsequently, we design and synthesis a gelatin methacryloyl (GelMA-CGRP) hydrogel that slowly releases CGRP, and evaluated its effect on promoting DBW healing. The results show that CGRP is abnormally downregulated in DBW, and CGRP ablation further delays DBW healing. This is due to the reduced M2 polarization and decreased angiogenesis in the absence of CGRP, whereas local application of GelMA-CGRP accelerates DBW healing. Mechanistic studies indicate that CGRP promotes M2 macrophage polarization by inhibiting the p53 signaling pathway and enhances endothelial cell function, thereby accelerating DBW healing. These findings suggest that CGRP could provide a novel therapeutic approach for diabetic wound treatment. STATEMENT OF SIGNIFICANCE: Current methods for treating diabetic wounds have many limitations. Compared to conventional dressings, hydrogels combined with drugs or biological factors to promote diabetic wound healing have become an important research direction in recent years. This study reveals the key role of CGRP in the pathogenesis of diabetic wounds. The research found that CGRP promotes M2 macrophage polarization and angiogenesis by inhibiting the p53 signaling pathway, thereby promoting diabetic wound healing. We further utilized the carrier properties of GelMA hydrogel to develop a GelMA-CGRP hydrogel material that slowly delivers CGRP and effectively treats diabetic wounds. This material demonstrates strong biocompatibility and antimicrobial properties, offering a novel approach for the treatment of diabetic wounds.

Keywords

Angiogenesis; Calcitonin gene-related peptide; Diabetic Wound; GelMA Hydrogel; Macrophage; Polarization.

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