Continuing Education Activity
Wound healing is a natural physiological reaction to tissue injury. However, wound healing is not a simple phenomenon and involves a complex interplay between numerous cell types, cytokines, mediators, and the vascular system. This activity reviews the evaluation and treatment of wounds and discusses the various wound healing phases, highlighting the role of the interprofessional team in evaluating and treating patients with a wound.
- Describe the initial phases of wound healing.
- Identify the mediators of the inflammatory phase of wound healing.
- Outline the physiologic processes involved in the proliferative phase of wound healing.
- Summarize the factors that promote the development of chronic wounds.
Wound healing is a natural physiological reaction to tissue injury. However, wound healing is not a simple phenomenon but involves a complex interplay between numerous cell types, cytokines, mediators, and the vascular system. The cascade of initial vasoconstriction of blood vessels and platelet aggregation is designed to stop bleeding. This is followed by an influx of a variety of inflammatory cells, starting with the neutrophil. These inflammatory cells, in turn, release a variety of mediators and cytokines to promote angiogenesis, thrombosis, and reepithelialization. The fibroblasts, in turn, lay down extracellular components which will serve as scaffolding. 
The inflammatory phase is characterized by hemostasis, chemotaxis, and increased vascular permeability which limits further damage closes the wound, removes cellular debris and bacteria, and fosters cellular migration. The duration of the inflammatory stage usually lasts several days. 
The proliferative phase is characterized by the formation of granulation tissue, reepithelialization, and neovascularization. This phase can last several weeks.
The maturation and remodeling phase is where the wound achieves maximum strength as it matures. 
When an injury occurs, the initial phase is always an outpouring of lymphatic fluid and blood. It is during this process that adequate hemostasis is achieved. Both the extrinsic and intrinsic coagulation pathways are activated and play a role in stopping the loss of blood. Aggregation of platelets follows the arterial vasoconstriction to the damaged endothelial lining. A release of adenosine 5´ diphosphate (ADP) results in the clumping of platelets and initiates the process of thrombosis. The vasoconstriction is a short-lived process that is soon followed by vasodilation, which allows the influx of white cells and more thrombocytes.
The inflammatory phase begins with hemostasis and chemotaxis. Both the white cells and thrombocytes speed up the inflammatory process by releasing more mediators and cytokines. Besides the platelet-derived growth factor, there are other factors that promote collagen degradation, the transformation of fibroblasts, the growth of new vessels, and re-epithelialization. All of the processes occur at the same time but in a synchronized fashion. Mediators like serotonin and histamine are released from platelets and increase cellular permeability. The platelet-derived growth factor attracts fibroblasts and, along with transforming growth factor, enhance division and multiplication of fibroblasts. The fibroblasts, in turn, synthesize collagen.
Inflammatory cells, such as neutrophils, monocytes, and endothelial cells, adhere to a fibrin scaffold that is formed by platelet activation. The neutrophils enable phagocytosis of cellular debris and bacteria, allowing for decontamination of the wound. 
The proliferative or granulation phase does not occur at a discrete time but is occurring all the time in the background.
By days 5 through 7, the fibroblasts have started to lay down new collagen and glycosaminoglycans. These proteoglycans form the core of the wound and help stabilize the wound.
Reepithelialization starts to occur with the migration of cells from the wound periphery and adjacent edges. Initially, only a thin superficial layer of epithelial cells is laid down, but with time, a thicker and more durable layer of cells will bridge the wound.
Neovascularization occurs through both angiogenesis, which is the formation of new blood vessels from existing vessels, and vasculogenesis, which is the formation of new vessels from endothelial progenitor cells (EPCs).
Once collagen fibers have been laid down on the fibrin framework, the wound starts to mature. The wound also begins to contract and is facilitated by continued deposition of fibroblasts and myofibroblasts.
The maturational or remodeling phase starts around week 3 and can last up to 12 months. The excess collagen degrades, and wound contraction also begins to peak around week 3. Wound contraction occurs to a much greater extent in secondary healing than in primary healing. The maximal tensile strength of the incision wound occurs after about 11 to 14 weeks. The ultimate resulting scar will never have 100% of the original strength of the wound, and only about 80% of the tensile strength. 
Issues of Concern
Wounds generally heal in 4 to 6 weeks. Chronic wounds are those that fail to heal within this timeframe.
Many factors can lead to impaired healing. The primary factors are hypoxia, bacterial colonization, ischemia, reperfusion injury, altered cellular response, and collagen synthesis defects. These may be the result of a systemic illness, such as diabetes, or chronic conditions, such as smoking or malnutrition. Local factors that can impair wound healing are pressure, tissue edema, hypoxia, infection, maceration, and dehydration.
Bacterial biofilm, which is a slime created by a bacterial community to protect against host defenses and allow bacterial proliferation, is another inhibitory factor of wounding healing. Biofilm can produce low oxygen, low pH environment for the wound. This film also can create a physical barrier that prevents cellular migration and prevents antibiotic and antibody penetration. 
Clinical considerations in wound management include preventing and controlling infection and contamination, maintaining adequate moisture, treating edema, and preventing further injury.
Wounds should be cleansed prior to closure. Wounds can be cleaned with either irrigation or scrubbed and irrigated with a 0.9% saline solution. Alternately, wounds can be scrubbed with pluronic plyols and irrigated with normal saline. Tap water is frequently used by patients to irrigate wounds prior to seeking out medical attention. The advantage is that copious amounts of irrigant can be rapidly used, however, irrigation pressure may be difficult to control. A study by Mosacati found that infection rates for wounds irrigated with tap water were comparable to those irrigated by a 0.9% saline solution. 
Wound dressings should create a moist environment to prevent wound desiccation but allows for absorption of additional exudate. It should allow for airflow, prevent particulate contamination, and be impermeable to bacteria or microbiota.
There are several techniques used to reconstruct or surgically repair wounds, the simplest of which is primary closure. Other techniques are closure via secondary intention, negative pressure wound therapy, and grafting.
Wound Healing Controversies and the Future
- Fetal tissue has been shown to heal without scars, but its clinical role has yet to be determined.
- Transforming growth factor and several other cytokines all have a role in healing but when to add or how much of the cytokine is needed for adequate healing is still being debated.
- Hyperbaric oxygen can promote healing, but the technique and success rate is not well established.
- Even though there are many anecdotal reports on honey and wound healing, controlled studies show that the benefits of honey are marginal at best.
- Finally, medications that can adversely affect healing include anticonvulsants, steroids, antibiotics, angiogenesis inhibitors, and NSAIDs. Drugs known to promote healing include insulin, vitamins, thyroid hormone, and iron.
- The new frontier for wound healing is the use of stem cells, but there are ethical issues regarding the widespread use of this technology. 
Enhancing Healthcare Team Outcomes
Current studies on wound healing focus on identifying molecular level target genes that can be enhanced to expedite natural wound healing. The hedgehog signaling pathway has been used in multiple studies due to its role in epithelial-mesenchymal interaction in wound healing.  Laser techniques are being explored to enhance cell proliferation and accelerate wound healing.  A multifaceted approach to wound healing focusing on adequate dressing and local care, nutritional support, and hyperbaric oxygen therapy in severe cases is necessary to ensure proper wound healing in the most difficult of cases.