Cellular Restoration of Leg and Foot Ulcers

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By the WoundSource Editors

Chronic wounds pose an ongoing challenge for clinicians, and there needs to be a clearer understanding of the pathophysiology of wound chronicity and treatment modalities available.

Matrix Metalloproteinases in Chronic Wounds

Wounds that become "stalled" contain excess amounts of matrix metalloproteinases (MMPs) and decreased amounts of MMP tissue inhibitors. Wounds that fail to heal over 30 days of "standard care" are considered chronic and should have their underlying pathophysiology reevaluated. Advanced treatment modalities should be used as appropriate.

There are 24 MMPs in humans, and three forms. Active MMPs are the only matrixins that play a role in wound healing.1 MMPs are known to be substrate specific and to degrade all components of the extracellular matrix (ECM). Therefore, an imbalance is a major factor in healing impediments with chronic lower extremity ulcerations. Controlled activity of MMPs in all stages of the wound healing process is vital.2

The Normal Wound Healing Cascade

The wound healing cascade should be thought of as an intensive, sequenced process that, if not followed in precise order, will stall the healing process.3,4 The process of normal healing should help form the ECM that modifies and supports cellular processes in the wound, including cell adhesion, migration, and tissue remodeling. MMPs modify the wound matrix and degrade all components of the ECM while playing a major role in the activity of various growth factors and polymorphonuclear cells.5,6 Keratinocytes either migrate through or stay in contact with the dermis underlying the wound matrix, thereby determining the integrins that are activated. The MMPs then are isolated in specific sites of the wound to provide wound repair.7

How much do you know about lower extremity wounds? Take our 10-question quiz to find out! Click here.

Understanding both the underlying pathophysiology and the mechanisms to stimulate wounds through the healing trajectory is essential to promote overall healing outcomes and decrease recurrence rates. Novel mechanisms for regulating MMPs that are being investigated use signal transduction, peptides, and microRNAs (MiRs) to modulate MMP expression and activity.2 MMPs must be active at the right amount, in the right place, and in the right time frame.8

Breaking the Cycle of Wound Chronicity

Chronic wounds become stuck in a vicious cycle of delayed wound healing. Breaking the cycle involves eradicating any factors that are contributing to the impeded healing. There is strong clinical evidence that elevated levels of MMPs and other proteases prevent wounds from healing and that treatments that lower MMP activities promote healing of wounds that have stalled.8 Treatments include:

  • Treating the cause, which reduces inflammation
  • Moist wound healing, which reduces protease activity
  • Management of microbial bioburden through the use antimicrobial dressings
  • Lowered protease and free radical activity through the use of absorbent dressings or collagen dressings

Advanced Wound Care Dressings Used in Inhibiting MMPs

The advanced wound care dressing market is extensive, with many technologies and formulations. MMP-inhibiting advanced wound care dressings are readily available, but additional evidence must be generated to differentiate types of MMP-inhibiting dressings. The goal of these dressings is to enhance wound healing times and rates. The clinician has no way to measure levels of MMPs.8

Various dressing technologies use additional ingredients to impregnate dressings for multifunctionality, including polyhexamethylene biguanide (PHMB), carboxymethyl cellulose (CMC), and ethylenediaminetetraacetic acid (EDTA).9 Some dressing technologies Incorporate polyacrylates that have a high density of ionic charges and help absorb exudate, thereby binding MMPs while reducing MMP activity in vitro.2 Collagen dressings can be impregnated with a number of substances, and they come in numerous forms: gels, pads, particles, pastes, powders, sheets, or solutions derived from bovine, equine, porcine, or avian sources.10

Mode of Actions of Various Collagen Products

Collagen dressings have a number of benefits, including:

  • Inhibition of excess MMPs
  • Increased fibroblast production
  • Encouraged migration of cells
  • Aid in uptake bioavailability of fibronectin
  • Preservation of leukocytes, macrophages, fibroblasts, and epithelial cells
  • Hydrophilic properties encouraging fibroblast permeation
  • Assistance in maintenance of the chemical and thermostatic microenvironment


Lower extremity wounds are a challenge because of their complexity; however, more evidence of current and future advanced wound care treatment modalities is needed to validate use of these products. Using a step-by-step guide in evaluation and facilitating appropriate care will help bolster continuity of care throughout the wound care healing continuum. Understanding various wound types, and molecular and cellular levels, will lead to more effective treatments and improved healability of these ulcers.

September is Lower Extremity Wounds Month

1. Nguyen Trung T, Mobashery S, Chang M. Roles of matrix metalloproteinases in cutaneous wound healing. In: Alexandrescu V, ed. Wound Healing: New Insights Into Ancient Challenges. London, United Kingdom: InTech Open, Ltd; 2016. doi: 10.5772/64611
2. Caley MP, Martins VL, O'Toole EA. Metalloproteinases and wound healing. Adv Wound Care. 2015;4(4):225-234. doi: 10.1089/wound.2014.0581
3. Maxson S, Lopez EA, Yoo D, Danilkovitch-Miagkova A, LeRoux MA. Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med. 2012;1(2):142-149. doi: 10.5966/sctm.2011-0018.

4. Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012;49(1):35-43. doi: 10.1159/000339613
5. Vitlianova K, Georgieva J, Milanova M, Tzonev S. Blood pressure control predicts plasma matrix metalloproteinase-9 in diabetes mellitus type II. Arch Med Sci. 2015;11(1):85-91. doi: 10.5114/aoms.2015.49208.
6. Serra R, Buffone G, Costanzo G, et al. Altered metalloproteinase-9 expression as least common denominator between varicocele, inguinal hernia, and chronic venous disorders. Ann Vasc Surg. 2014;28(3):705-709. doi: 10.1016/j.avsg.2013.07.026
7. Larjava H, Haapasalmi K, Salo T, Wiebe C, Uitto VJ. Keratinocyte integrins in wound healing and chronic inflammation of the human periodontium. Oral Dis. 1996;2(1):77-86.
8. Gibson D, Cullen B, Legerstee R, Harding KG, Schultz G. MMPs made easy. Wounds Int. 2009;1(1). http://www.woundsinternational.com. Accessed August 7, 2020.
9. Wounds Journal. Effect of a new purified collagen matrix with polyhexamethylene biguanide on recalcitrant wounds of various etiologies: a case series. Wounds. 2018;30(3):72-78.
10. Collagens. WoundSource Product Category. https://www.woundsource.com/product-category/dressings/collagens. Accessed July 28, 2020.

The views and opinions expressed in this blog are solely those of the author, and do not represent the views of WoundSource, Kestrel Health Information, Inc., its affiliates, or subsidiary companies.

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