With multiple risk factors impeding wound healing and wounds often diagnosed with mixed etiology, wound healing can be complicated. Understanding the pathophysiology of wound healing can help clinicians to better comprehend the needs of a wound to help it progress through the stages of wound healing.

Wound Healing Phases

There are four basic phases of wound healing: (1) hemostasis, (2) inflammatory, (3) proliferative, and (4) remodeling or maturation.¹ These phases generally occur in order, with some overlap. If a wound is on a normal healing trajectory, it will generally heal in four to six weeks.¹ Alternately, chronic wounds are wounds that fail to heal in the normal four- to six-week standard healing time. Many factors cause stalled wounds, including lack of oxygen or perfusion, metabolic disorders that alter cellular response, smoking, malnutrition, infection, altered pH, swelling, and many others.¹ Clinicians should consider clinical and educational opportunities that will minimize or eliminate barriers to wound healing. Infection should be controlled or prevented through good hand washing; prevention, reduction, or elimination of biofilm; and prevention of cross-contamination.

The hemostasis phase is initiated when an injury occurs to the skin or tissue. Several important actions happen during this phase. Initially, vasoconstriction occurs to prevent the body from bleeding out rapidly. Platelets are delivered to the site of injury to stop bleeding, forming a clot. This starts the inflammatory response and activates inflammatory cells. Neutrophils, cytokines, and mediators promote angiogenesis, thrombosis, and epithelialization.¹ Fibroblasts provide a structure that allows extracellular components to form a scaffold that cells can migrate across. In the inflammatory phase, the wound starts to close. Cellular debris and bacteria are removed, and cellular migration is encouraged. This phase can last for several days. It is also characterized by hemostasis, as well as chemotaxis and increased vascular permeability. The inflammatory phase is where chronic wounds typically get stuck.

The proliferative phase is the phase where granulation tissue forms. Additionally, neovascularization and re-epithelialization occur. Cells involved in this stage of wound healing include macrophages, fibroblasts, endothelial cells, mast cells, B cells, and/or myofibroblasts. This phase can last several weeks and is the phase that occurs right before the remodeling phase.¹ The remodeling phase starts around week three and can take 12 to 24 months, depending on the patient's age, comorbid medical conditions, and other risk factors.¹ Once excess collagen degrades and wound contraction begins to peak, the maturation phase (remodeling) begins. Ultimately, a scar forms, leaving up to 80% tensile strength for life.

Infection and Wound Healing

The inflammatory phase is a necessary part of wound healing. White blood cells and thrombocytes release mediators and cytokines, speeding up the inflammatory process. Polymorphonuclear neutrophils enable phagocytosis of bacteria and cellular debris, thereby decontaminating the wound.¹ If the wound is not properly decontaminated, however, or if conditions are not right for the wound to continue on to the next stage of wound healing, the inflammatory stage may become prolonged and lead the wound into chronic status. There are many factors that can cause a wound to stall in the inflammatory phase, such as hypoxia, ischemia, and altered cellular response¹; infection and the presence of biofilm can also delay wound healing. Biofilms can lower the wound bed's pH and reduce oxygen levels; they can also produce a barrier that prevents cellular migration and stops antibiotic and antibody penetration.²

Pro-inflammatory cytokine levels are increased in the presence of bacteria, and if bacteria levels are not reduced, these cytokines may stay elevated, prolonging the inflammatory phase. When the inflammatory phase lasts too long, a buildup of matrix metalloproteases occurs that, at high levels, can damage the extracellular matrix.³ The extracellular matrix is a critical component of the remodeling phase and is largely created during the proliferative stage, which overlaps with and continues after the inflammatory stage.³ Stalling a wound in the inflammatory stage prevents the proliferative stage from moving forward and the remodeling stage from happening at all until the stalling factor is resolved. Resolving biofilm may require serial debridement. For infection, a wound culture and systemic antibiotics may be needed.

Other Wound Healing Factors

Evaluating the wound and choosing dressings that encourage moist wound healing are paramount to wound progression. As clinicians evaluate the wound, they should continue to identify areas that are stalling wound healing and preventing the wound from achieving closure. Remember, a wound bed that is too dry prevents cell migration and can cause other issues that delay wound healing. A wound bed that is too wet can cause maceration, encourage bacterial growth, and also delay wound healing. Wound specialists should focus on moist wound healing, infection prevention or resolution, a healthy wound bed with removal of non-viable tissue (i.e., slough, eschar), management of drainage, and mitigation of other negative causes that prevent wounds from progressing. A well-trained eye and proper assessment can lead the way to wound healing.

References

1. Wallace HA, Basehore BM, Zito PM. Wound Healing Phases. Treasure Island, FL: StatPearls; 2019. https://www.ncbi.nlm.nih.gov/books/NBK470443/. Accessed November 5, 2019.

2. van Koppen CJ, Hartmann RW. Advances in the treatment of chronic wounds: a patent review. Expert Opin Ther Pat. 2015;25(8):931-7.

3. DiPietro LA, Guo S. Factors affecting wound healing. J Dent Res. 2010;89(3):219-229.