As scientists and researchers have delved deeper into the causes of wounds and wound chronicity, matrix metalloproteinases, or MMPs, have come into sharper focus. MMPs are not just present in chronic wounds — they also play an essential role in acute wounds.

Matrix Metalloproteinases in Chronic Wounds

Matrix metalloproteinases signal certain functions essential to wound healing, such as debridement, angiogenesis, contraction, epithelial migration and remodeling, to name a few. Absent these vital functions, wounds cannot progress through the phases of healing and ultimately to closure. There are at least 28 different types of MMPs, and they can be divided into the following seven groups:

• Collagenases
• Gelatinases
• Stromelysins
• Matrilysins
• Metalloelastases
• Membrane-type MMPs (MT-MMPs)
• Other MMPs¹

Each one has its specific role in signaling or directing various collagen and growth factors within the wound. For example, MMP-1 (collagenase-1) has substrates of collagen I, II, III, VII and X along with aggrecan; serpins; alpha2-macroglobulin; kallikrein; and chymase. These substrates promote growth factors that signal specific processes, such as migration on collagen.¹

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Different cell types express MMPs during the wound healing process, including endothelial cells, inflammatory cells, fibroblasts and keratinocytes. Hormones, cytokines and contact with other cell types are just some of the signals that encourage MMP expression. Enzymatic activation can control MMP activity, enabling diverse functions, including degrading and remodeling of the extracellular matrix. Without MMPs, cell migration and tissue remodeling would not occur.¹ When MMPs become imbalanced or overproduced, essential proteins are destroyed, inflammation is prolonged, and ischemia and biofilm can set into the wound, causing a wound to increase in size or become infected or stalling the healing process.

Matrix Metalloproteinases and Biofilm in Chronic Wounds

When MMPs can’t signal and regulate the essential functions needed to heal a wound properly, biofilm sets into the wound. Clinical research studies show that biofilm is present in more than 80% of chronic wounds and 6% of acute wounds. The problem with biofilm is that it can lead to chronic inflammation, which can degrade the proteins essential for wound healing. Reducing inflammation in chronic wounds reduces protease levels, allowing wounds to progress through the phases of wound healing.² Clinicians can create an ideal wound environment using a variety of methods and can regulate MMPs in the wound bed using basic principles of good wound healing. For example, sharp debridement can remove senescent cells and unhealthy tissue and address the overproduction of MMPs. Some dressings can regulate MMP expression. For example, superabsorbent polymers can bind MMPs and reduce counterproductive MMP activity. Wound dressings that have high ionic charges when absorbing wound drainage can bind MMPs to downregulate their overproduction. Additionally, these types of wound dressings can inhibit the activity of bacterial proteases, further facilitating wound healing.¹

Giving MMPs a sacrificial substrate to attack, such as a collagen-based dressing or cellular and/or-tissue based products (CTPs) containing collagen, will also prevent wound healing from stalling. MMPs can attack the donated collagen instead of attacking the modulators in the wound that are trying to help the wound heal. Topical drugs, systemic antibiotics, and topical antimicrobial dressings or solutions can also help downregulate MMPs and facilitate wound healing. Modalities such as negative pressure wound therapy can help manage wound drainage, thereby suppressing the overproduction of MMPs. CTPs that contain collagen and antimicrobials may be helpful in lowering MMPs and encouraging wound closure. Utilizing a CTP that contain an antimicrobial component such as polyhexamethylene biguanide or silver can help to control bioburden.

Conclusion

MMPs are essential to wound healing when they are properly regulated. Left unchecked, they can delay wound healing. Therefore, every clinician involved in wound care should know how to support the positive functions of MMPs while reducing or eliminating MMPs’ harmful effects.

References

1. Caley, M. P., Martins, V. L. & O’Toole, E. A. (2015). Metalloproteinases and Wound Healing. Advances in Wound Care, 4(4), 225-234. https://doi.org/10.1089/wound.2014.0581

2. Mast, B. & Schultz, G. (1996). Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair and Regeneration, 4(4), 411-420.

3. Malone, M., Barjnsholt, T., McBain, A., James, G., Stoodley, P., Leaper, D., Tachi, M., Schultz, G., Swanson, T., & Wolcott, R. Prevalence of biofilms in chronic wounds; a systematic review and meta-analysis of published data. Journal Wound Care, in press.