Modulation of Protease Activity for Chronic Wound Healing

Background: Chronic wounds are long term non-healing wounds that can be difficult to treat and are becoming more common as the global population of elderly or diabetic patients increases. As these wounds can take months to years to heal, advanced healing techniques are often required, such as growth factors (GFs) and other bioactive biological agents. While commonly used in the field, clinical results of GFs for the treatment of chronic wounds have been limited.

Methods: Patient chronic wound fluid was collected and found to have elevated protease levels (MMPs and Neutrophil Elastase (NE)).  When these levels were tested on common GFs used for treating chronic wounds, NE was found to degrade GFs in as little as 30 minutes, suggesting the importance of protease modulation when treating chronic wounds. This need led to the development of a novel fusion inhibitory protein, consisting of a specialized peptide to improve drug delivery (ELP) and a known protease inhibitor for NE.  When tested in a rodent chronic wound model with high NE levels, the inhibitory fusion protein demonstrated improved granulation and reduced inflammation compared to untreated samples. Moreover, heterogeneous nanoparticles (NPs) comprising of GF-ELP and Protease inhibitor-ELP were created owing to the aggregating property of ELPs. These NPs extended GF preservation in the presence of NE for up to 24 hours in wound fluid collected from chronic wound patients.

Results: Our data suggest the development of a system that can successfully protect the growth factor from degradation in the harsh protease environment of chronic wounds.

Conclusion: Moreover, the modular nature of this system enables us to include other biologically relevant peptides or proteins to address required needs in the NPs there by protecting them from degradation by proteases.