Wound healing is a complex biological process that involves a sequence of molecular and cellular events to restore damaged tissue. These events occur within the extracellular matrix, a complex three-dimensional acellular environment that is present within all tissue and essential for life. Remodeling within this extracellular matrix is necessary for tissue repair throughout the wound healing process, including during the inflammatory phase.¹ Tissue repair is a linear process that begins at the onset of a lesion. The biochemical events in wound repair on the cellular level are often broken down into four different stages. Frequently, these stages overlap one another, as the various processes of healing occur.²

• Hemostasis: The process in which the blood platelets come into contact with collagen and aggregate to form a fibrin mesh that successfully clots the wounds and stops the bleeding. The clot, comprised of a fibrin network, forms a barrier against microorganisms and organizes a temporary matrix for cell migration
• Inflammation: The inflammatory phase of healing is characterized by the influx of leukocytes to the wound area, resulting in edema and erythema. Inflammatory cells are integral in wound healing and assist with the release of lysosomal enzymes and reactive oxygen species, and facilitate the clean up of cell debris.
• Proliferation: The proliferative stage is responsible for the closure of the wound itself and includes the angiogenesis, fibroplasia, and reepithelialization processes.³
• Tissue remodeling: Tissue remodeling is often recognized by the appearance and minimization of scar tissue. The goal in this phase of healing is to achieve the maximum tensile strength through reorganization, degradation, and resynthesis of the extracellular matrix.³

The healing process can be impacted at any stage, resulting in the stalling of healing or worsening of the wound. Many exogenous and endogenous factors can affect a wound's ability to heal and the rate it progresses through the stages of healing.³ During the inflammatory phase, several key elements impair a wound’s ability to progress.

Biofilm

The presence of biofilm in the inflammatory phase of healing is one of the most common causes of a failure to heal. Biofilm is often identified in routine clinical assessments by the presence of excessive moisture or drainage, poor quality granulation tissue, other signs of local infection, antibiotic failure, and a failure to heal despite accounting for other comorbidities. In addressing the presence of biofilm, diagnostic testing can indicate whether the bacteria in the wound are biofilm or planktonic and identify which bacteria are present, including the dominant species (although most biofilm is polymicrobial).⁴ This information is crucial in determining treatment options.

Addressing biofilm in a non-healing wound can include various treatment options, most commonly mechanical debridement and topical antiseptics. It is crucial to understand that systemic antibiotics cannot eradicate a wound biofilm.⁴

Excessive Matrix Metalloproteinase (MMP)

MMPs are expressed by cells in the inflammatory phase, and their activity is regulated by the activation of pro-enzyme or inhibition through endogenous tissue inhibitors of metalloproteinases. MMPs involved in tissue repair cut proteins in the extracellular matrix, including collagens, gelatin, laminin, and fibronectin. They also regulate vascular remodeling by controlling angiogenic molecules.¹ While MMPs play a key role in normal tissue repair processes, elevated levels are correlated with impaired wound healing and fibrosis. This can be indicative of the presence of disease, and MMP-inhibition measures may be necessary for achieving better healing outcomes.¹

Depletion of Thrombospondins (TSPs)

Thrombospondins are a glycoprotein that contributes to linking matrix proteins and facilitating matrix organization. TSPs can also facilitate reepithelialization by organizing matrix structure and fibrils. During the inflammatory stage of healing, TSPs are necessary for collagen fibrillogenesis and platelet aggregation. Therefore, an insufficient or depleted TSP presence can result in a prolonged inflammatory response and delay the healing process.¹

Conclusion

In addition to these common causes of protracted or stalled healing, many other factors can impact the wound’s ability to move from the inflammatory stage to the proliferative stage. The healing process is remarkably complex, with many processes occurring simultaneously. It is also susceptible to a wide variety of systemic and local factors. Understanding the factors that can contribute to a failure to move out of the inflammatory phase of healing is the first step in identifying how to best improve the healing environment and promote the formation of granulation tissue that occurs in the proliferative stage.

References

1. Keane, T.J., Horejs, C. & Stevens, M.S. (2018). Scarring vs. functional repair: Matrix-based strategies to regulate tissue healing. Advanced Drug Delivery Reviews, 129, 407-419.

2. Singh, S., Young, A., & McNaught, C. (2017). The physiology of wound healing. Surgery (Oxford), 35(9), 473-477.

3. De Oliveira Gonzalez, A.C., Costa, T.F., de Araujo Andrade, Z., & Madrado, A.R.A.P. (2016). Wound healing: A literature review. Anais Brasileiros de Dermatologia, 91(5), 365-596.

4. Schultz, G., Bjarnsholt, T., James, G.A., et. al. (2017). Consensus guidelines for the identification and treatment of biofilms in chronic nonhealing wounds. Wound Repair and Regeneration, 25, 744-757.