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Peer-reviewedCC BY 4.0Frontiers in Bioengineering and Biotechnology

Sprayable phage-cocktail hydrogel promotes diabetic wound healing through macrophage M2 polarization and restoring SP and CGRP signaling axis

  • Han-Shiang Shiue1,2
  • Sheng-Jie Shiue1
  • Hsin-Yi Lin3,4
  • Ming-Shun Wu1,2,5,6,7
7 affiliations
  1. 1Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
  2. 2International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
  3. 3Graduate Institute of Chemical Engineering, National Taipei University of Technology, Taipei, Taiwan
  4. 4Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei, Taiwan
  5. 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
  6. 6International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
  7. 7TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan
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Abstract

Aims: Chronic diabetic wounds often fail to heal due to persistent infections and dysregulated immune responses. This study developed a sprayable phage-cocktail hydrogel, a hybrid living material, to provide simultaneous infection control and neuroimmune modulation.

Methods: A phage-cocktail dressing was formulated using three bacteriophage strains targeting Salmonella enterica, Escherichia coli, and Pseudomonas aeruginosa. These bacteriophages were mixed with a 1% sodium alginate solution to create a hands-free spray-produced dressing. The dressing was evaluated for antibacterial activity, cytocompatibility with 3T3 fibroblasts, and efficacy in healing sterile full-thickness skin wounds in db/db mice. The skin wound recovery, macrophage polarization, calcitonin gene-related peptide (CGRP) and substance P (SP) expression were assessed through histological analysis.

Results: The dressing achieved approximately 90% antibacterial efficacy while maintaining excellent skin cell cytocompatibility. In db/db mice, the treatment significantly accelerated wound closure (94.2% by day 14), prevented ulceration, and enhanced tissue regeneration. Mechanistic analysis revealed that the dressing induced M2 macrophage polarization and modulated neuropeptide signaling. Specifically, epidermal CGRP sustained M2 macrophages to promote re-epithelialization, while dermal SP facilitated extracellular matrix (ECM) remodeling.

Conclusion: This sprayable hydrogel integrates antimicrobial efficacy with neuroimmune modulation to accelerate diabetic wound healing. By modulating pathways associated with the SP/CGRP signaling axis, it supports functional ECM remodeling and re-epithelialization while mitigating dermal fibrosis. This layer-specific regulation provides a potent therapeutic framework for achieving regenerative tissue repair in chronic ulcers.

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Cite

BibTeXRIS
BibTeX
@article{shiue2026sprayable,
  title = {{Sprayable phage-cocktail hydrogel promotes diabetic wound healing through macrophage M2 polarization and restoring SP and CGRP signaling axis}},
  author = {Han-Shiang Shiue and Sheng-Jie Shiue and Hsin-Yi Lin and Ming-Shun Wu},
  journal = {Frontiers in Bioengineering and Biotechnology},
  year = {2026},
  month = oct,
  doi = {10.3389/fbioe.2026.1789996},
  url = {https://doi.org/10.3389/fbioe.2026.1789996},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Sprayable phage-cocktail hydrogel promotes diabetic wound healing through macrophage M2 polarization and restoring SP and CGRP signaling axis
AU  - Han-Shiang Shiue
AU  - Sheng-Jie Shiue
AU  - Hsin-Yi Lin
AU  - Ming-Shun Wu
PY  - 2026
DA  - 2026/10/12
JO  - Frontiers in Bioengineering and Biotechnology
DO  - 10.3389/fbioe.2026.1789996
UR  - https://doi.org/10.3389/fbioe.2026.1789996
AB  - Aims: Chronic diabetic wounds often fail to heal due to persistent infections and dysregulated immune responses. This study developed a sprayable phage-cocktail hydrogel, a hybrid living material, to provide simultaneous infection control and neuroimmune modulation.  Methods: A phage-cocktail dressing was formulated using three bacteriophage strains targeting Salmonella enterica, Escherichia coli, and Pseudomonas aeruginosa. These bacteriophages were mixed with a 1% sodium alginate solution to create a hands-free spray-produced dressing. The dressing was evaluated for antibacterial activity, cytocompatibility with 3T3 fibroblasts, and efficacy in healing sterile full-thickness skin wounds in db/db mice. The skin wound recovery, macrophage polarization, calcitonin gene-related peptide (CGRP) and substance P (SP) expression were assessed through histological analysis.  Results: The dressing achieved approximately 90% antibacterial efficacy while maintaining excellent skin cell cytocompatibility. In db/db mice, the treatment significantly accelerated wound closure (94.2% by day 14), prevented ulceration, and enhanced tissue regeneration. Mechanistic analysis revealed that the dressing induced M2 macrophage polarization and modulated neuropeptide signaling. Specifically, epidermal CGRP sustained M2 macrophages to promote re-epithelialization, while dermal SP facilitated extracellular matrix (ECM) remodeling.  Conclusion: This sprayable hydrogel integrates antimicrobial efficacy with neuroimmune modulation to accelerate diabetic wound healing. By modulating pathways associated with the SP/CGRP signaling axis, it supports functional ECM remodeling and re-epithelialization while mitigating dermal fibrosis. This layer-specific regulation provides a potent therapeutic framework for achieving regenerative tissue repair in chronic ulcers.
SN  - 2296-4185
ER  -