Protease Dynamics in Chronic Wound Healing

Protease dynamics underpin the progression from acute injury to chronic wounds through intricate regulation of inflammation, cell migration and extracellular matrix remodelling. In healthy healing, a tightly controlled cascade of proteases—chiefly matrix metalloproteinases and serine proteases—facilitates debridement and tissue regeneration, tempered by endogenous inhibitors. Chronic wounds arise when this balance is disrupted by persistent inflammation, pathogenic biofilms or systemic factors, resulting in excessive proteolytic activity that degrades growth factors, matrix proteins and cell-surface receptors. Advances in mass-spectrometry-based peptidomics and positional proteomics have begun to characterise the temporal and spatial profiles of protease action in wound fluids, revealing distinct cleavage signatures associated with non-healing ulcers. Understanding these dynamics is critical to developing diagnostic biomarkers and targeted therapies that restore protease-inhibitor equilibrium, improve wound care and reduce the global burden of chronic ulcers.

Research from Nature Portfolio

Recent studies have leveraged advanced peptidomic algorithms to cluster peptides from wound fluid and define signature proteolytic events at early stages of infection. This approach has reduced data complexity, enhanced inter-sample comparability and pinpointed phenotype-specific protease activity in both animal models and human non-healing wounds. Complementing this, degradomic analyses of wound exudates have mapped specific cleavage patterns of key proteins such as thrombin, distinguishing endogenous and bacterial protease contributions. These proteolytic signatures have revealed biomarkers unique to non-healing ulcers, offering potential for diagnostic assays that report on infection status and healing trajectories.

Protease Dynamics in Chronic Wound Healing publication trend

The graph below shows the total number of articles in protease dynamics in chronic wound healing across all publications each year (not limited to Nature Index journals).

Technical terms

Protease: Enzyme that hydrolyses peptide bonds in proteins.

Matrix metalloproteinases (MMPs): Zinc-dependent enzymes that degrade extracellular matrix components.

Serine proteases: Proteases with a serine residue at the active site, involved in inflammation and coagulation.

Peptidomics: Large-scale study of endogenous peptides generated by proteolysis.

Degradomics: Proteome-wide analysis of proteolytic cleavage events.

Antiprotease: Molecule that inhibits the activity of one or more proteases.

References

1. Peptide clustering enhances large-scale analyses and reveals proteolytic signatures in mass spectrometry data. Nature Communications (2024).
2. Proteolytic signatures define unique thrombin-derived peptides present in human wound fluid in vivo. Scientific Reports (2017).
3. The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing. Clinical and Translational Medicine (2025).
4. Multifunctional Casein-Based Wound Dressing Capable of Monitoring and Moderating the Proteolytic Activity of Chronic Wounds. Biomacromolecules (2024).