Advanced Wound Healing

Advanced wound healing product categories: Growth factors; Collagen products; Cellular and tissue-based products (CTPs)

Chronic wounds often remain stuck in a state of ongoing inflammation. In this
environment, enzymes called proteases can become overactive. Instead of only clearing
damaged tissue, they can also break down proteins and structures that are needed for
healing, including growth factors and collagen. This creates a challenging environment for
both the wound itself and for advanced wound healing products targeting the problem.

The core problem for all three

This protease-rich environment can affect growth factors, collagen products, and cellular
and tissue-based products. Earlier studies reported MMP activity to be roughly 30-fold
higher in chronic than in acute wound fluid. In another analysis, average protease activity
was reported to be more than 100 times higher. The exact level varies between wounds and
between individual proteases, but the overall pattern is clear: excessive or dysregulated
protease activity can interfere with normal healing and break down important components
such as growth factors and extracellular matrix.

Growth factors

Growth factors are particularly vulnerable to a protease-rich wound environment. In vitro testing found significantly higher degradation of epidermal growth factor (EGF) in chronic wound fluid, with a mean degradation of 28.1%, compared with only 0.6% in acute wound fluid. This degradation was associated with reduced biological activity of EGF.

The problem is not limited to EGF. Chronic wound fluid has also been shown to degrade other growth factors, including PDGF-BB and TGF-β1. This degradation was associated with increased elastase activity. Topically applied growth factors, such as becaplermin (PDGF-BB), therefore enter the same protease-rich environment that can degrade the wound’s own growth factors.

Collagen products

Collagen products face a similar challenge because collagen itself is a target of proteolytic enzymes. In wounds with excessive protease activity, these enzymes can contribute to breakdown of the extracellular matrix (ECM), including collagen. Continued breakdown of the ECM can interfere with normal wound healing and delay progression to the proliferative phase.

This principle is also used therapeutically. Some collagen-based matrices are designed to bind or inactivate excessive proteases, helping to protect the patient’s own ECM and growth factors. In this way, the applied collagen can function partly as a sacrificial substrate or protective decoy, rather than simply as material that directly rebuilds tissue.

Cellular and tissue-based products (CTPs, including skin substitutes, allografts, and amniotic products)

CTPs are also applied to the same wound environment. Their cells, extracellular matrix, growth factors, and other bioactive components may all be affected when protease activity is excessive.

High MMP levels have also been associated with failure of dermal graft integration in diabetic foot ulcers, supporting the importance of the wound environment for these therapies. More generally, excessive protease activity can break down matrix proteins and bioactive molecules and interfere with the signals needed for normal tissue repair.

This helps explain why careful wound-bed preparation is important before applying CTPs. Reducing factors that maintain excessive inflammation and protease activity can help create a more favorable environment for these products to function.

The underlying challenge is therefore relevant to all three product categories: growth factors, collagen products, and CTPs. All depend, to some extent, on a wound environment in which their active or structural components can remain functional.

Key literature

1. Trengove NJ, Stacey MC, Macauley S, Bennett N, Gibson J, Burslem F, Murphy G, Schultz G. Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. *Wound Repair and Regeneration*. 1999;7(6):442-452. doi:10.1046/j.1524-475X.1999.00442.x.

2. Schultz GS, Mast BA. Molecular Analysis of the Environments of Healing and Chronic Wounds: Cytokines, Proteases and Growth Factors. *Primary Intention*. 1999;7:7-15.

3. Yager DR, Chen SM, Ward SI, Olutoye OO, Diegelmann RF, Cohen IK. Ability of chronic wound fluids to degrade peptide growth factors is associated with increased levels of elastase activity and diminished levels of proteinase inhibitors. *Wound Repair and Regeneration*. 1997;5(1):23-32. doi:10.1046/j.1524 475X.1997.50108.x.

4. Cullen B, Watt PW, Lundqvist C, Silcock D, Schmidt RJ, Bogan D, Light ND. The role of oxidised regenerated cellulose/collagen in chronic wound repair and its potential mechanism of action. *International Journal of Biochemistry & Cell Biology*. 2002;34(12):1544-1556. doi:10.1016/S1357-2725(02)00054-7.

5. Smeets R, Ulrich D, Unglaub F, Wöltje M, Pallua N. Effect of oxidised regenerated cellulose/collagen matrix on proteases in wound exudate of patients with chronic venous ulceration. *International Wound Journal*. 2008;5(2):195-203. doi:10.1111/j.1742-481X.2007.00367.x.

6. Wiegand C, Schönfelder U, Abel M, Ruth P, Kaatz M, Hipler UC. Protease and pro-inflammatory cytokine concentrations are elevated in chronic compared to acute wounds and can be modulated by collagen type I in vitro. *Archives of Dermatological Research*. 2010;302(6):419-428. doi:10.1007/s00403-009-1011-1.

7. Izzo V, Meloni M, Vainieri E, Giurato L, Ruotolo V, Uccioli L. High matrix metalloproteinase levels are associated with dermal graft failure in diabetic foot ulcers. *International Journal of Lower Extremity Wounds*. 2014;13(3):191-196. doi:10.1177/1534734614544959.

8. Serena TE, Cullen BM, Bayliff SW, et al. Defining a new diagnostic assessment parameter for wound care: Elevated protease activity, an indicator of nonhealing, for targeted protease-modulating treatment. *Wound Repair and Regeneration*. 2016;24(3):589-595. doi:10.1111/wrr.12431.

9. Trøstrup H, Holstein P, Karlsmark T, Moser C, Ågren MS. Uncontrolled gelatin degradation in non-healing chronic wounds. *Journal of Wound Care*. 2018;27(11):724-734. doi:10.12968/jowc.2018.27.11.724.

10. Mikosiński J, Kalogeropoulos K, Bundgaard L, et al. Longitudinal Evaluation of Biomarkers in Wound Fluids from Venous Leg Ulcers and Split-thickness Skin Graft Donor Site Wounds Treated with a Protease-modulating Wound Dressing. *Acta Dermato-Venereologica*. 2022;102:adv00834. doi:10.2340/actadv.v102.325.

Sabino F, auf dem Keller U. Matrix metalloproteinases in impaired wound healing. Metalloproteinases in Medicine (Dove Press), 2015.

Rayment EA, et al. / general MMP reviews — Matrix metalloproteinases: the sculptors of chronic cutaneous wounds. Biochim Biophys Acta, 2017. (ScienceDirect S0167488917302082)

Nwomeh BC, et al. / Caley MP, et al. Proteases and Delayed Wound Healing. Adv Wound Care, 2015. (PMC3842891, PubMed 24688830)

Ramey-Ward AN, et al. Human Keratin Matrices Suppress Matrix Metalloproteinase Activity to Support Wound Healing. Int J Mol Sci. 2024;25(23):12898.

WoundSource. Matrix Metalloproteinases in Chronic Wound Healing. 2021.

WoundCare Portal. Protease in Wound Care: What It Is, Why It Matters, and How to Manage It. 2025.

Video of Wound Healing

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