Fetal wound healing during the first two trimesters differs from the normal wound healing process and is the subject of much research because of the perceived potential for scarless healing. The process is more of a regenerative process than a repair process often with the absence of an inflammatory phase.1 Wound healing after birth represents a highly evolved and complex defense mechanism that helps to limit infection and further injury. The normal wound healing process is comprised of three (not five) phases. These are the inflammatory, the fibroproliferative, and the remodeling phases. The phases are not distinct entities and have overlap both in terms of timing and function. Each phase has a different duration and it can be quite variable. The inflammatory phase typically lasts for 1 week, the fibroproliferative phase lasts for 2–3 weeks, and the remodeling phase lasts for up to 1 year. Vasoconstriction is the initial response to injury in order to limit blood loss and lasts for 5–10 minutes after injury. Vasodilatation and increased tissue permeability follow this as part of the inflammatory phase to promote cellular access to the injured area. Knowledge of the key processes in wound healing is often tested in examinations and a solid understanding of these principles is important for clinical practice with respect to the management of different wound types.2–5
There are a number of key cell types involved in the wound healing process and they are generally specific to a particular phase of wound healing. For example, the neutrophil is the dominant cell type in the first 24 hours after injury. It serves to produce inflammatory mediators and undertake phagocytosis of damaged cells but is not actually critical to wound healing. After 48 hours the macrophage becomes the dominant cell type. In contrast to neutrophil, this is critical to wound healing because it orchestrates growth factors such as TGF-beta, which promotes collagen production, remodeling, epithelialization, and chemotaxis. Lymphocytes are involved in the inflammatory phase, although their role is poorly defined. They are typically present toward the end of the first week after injury. The fibroblast is key to wound healing and moves into the wound after 48 hours. By the end of the first week, it represents the dominant cell type. Along with the myofibroblast, it has a key role in the fibroproliferative phase with the production of collagen.1
Type I collagen is the most abundant collagen in humans, representing 90% of all body collagen. It predominates in the skin, tendon, and bone. Type II is found in the cornea and articular cartilage. Type III is found in the vessel and bowel walls. Type IV is found in the basement membrane only.
At 6 weeks, the healing wound should be in the remodeling phase of wound healing. During this phase, net collagen production is static because an equilibrium is reached between collagen breakdown and collagen synthesis. Although there is no change in quantity, collagen continues to undergo remodeling with increased organization and formation of stronger cross-links. The ratio of different collagen subtypes also changes. Glycosaminoglycan production and vasculogenesis decrease as does the water content and cellular population.1,2
There are more than 20 different types of collagen with type I representing 90% of all total body collagen. The normal adult ratio of type I to type III collagen within the skin is around 4:1. However, in the healing wound, type III collagen is made first and this subtype predominates in the proliferation and early remodeling phases until it is gradually replaced by type I collagen.
In spite of the impressive ability of wounds to heal, tissues never regain 100% of their preinjury tensile strength. It is estimated that a completely healed wound will have, at best, around 80% of its preinjury tensile strength and this will be achieved between 60 days and 1 year after the injury, typically around 90 days. The evidence for this stems from a 1965 study by Levenson et al1 where healing in rat skin wounds was assessed at various time intervals. Knowledge of skin strength at various time points following repair is clinically useful when considering suture selection, such that the suture is able to satisfactorily support the wound until adequate strength has been regained. For example, placement of buried dermal sutures in the face allows for external skin sutures to be removed at 5 days although the repair will still be weak at this stage. It also helps guide the clinician and patient with regard to resumption of normal activities following surgery.1
Many growth factors are involved in the wound healing process and most of these positively influence cell proliferation and migration. Similarly, TGF-beta will promote fibroblast migration and proliferation. FGF will increase both fibroblast and keratinocyte proliferation. It also affects fibroblast chemotaxis. VEGF will promote endothelial cell proliferation and is produced by many different cell types in response to hypoxia or injury. EGF promotes keratinocyte and fibroblast division rather than endothelial cell proliferation. PDGF promotes fibroblast, endothelial cell, and smooth muscle proliferation rather than keratinocyte proliferation.
Fibroblasts are the key cells responsible for forming extracellular matrix and collagen. They are present in both the early and late stages of wound healing and have a permanent presence in the dermis. Myofibroblasts are specialized fibroblasts that have contractile cytoplasmic microfilaments and distinct cellular adhesion structures. They are present in the early stages of wound healing and serve to collectively decrease the size of a wound. They usually remain within the wound for the first few weeks following injury. Keratinocytes are the major cells of the epidermis and are involved in wound healing and normal skin cell turnover. Macrophages and lymphocytes are both inflammatory cells that are involved in the orchestration of wound healing.
The process of healing a split-thickness skin graft donor site is termed reepithelialization. This involves a series of cellular processes that enable keratinocytes from the wound edges to proliferate and move toward the center of the wound. Cells are usually held at the wound edge by contact inhibition and this must be lost to enable cells to mobilize. Following a loss of contact inhibition, cells move across the wound until they meet cells from the other side and contact inhibition is reestablished. While cells at the wound edge are migrating, basal cells further back from the wound edge proliferate to support the cell numbers required to bridge the wound. Differentiation of keratinocytes subsequently occurs to reestablish normal epithelial layers from basal layer to stratum corneum. Margination refers to the process of leukocytes moving from the axial zone (central higher flow zone) to the plasmatic zone (peripheral lower flow zone) within blood vessels and adhering to the vessel walls in order to exit the blood stream. Diapedesis refers to the process of cells passing through vessel walls once margination has taken place during the inflammatory phase of wound healing.
Healing is defined as primary, secondary, or tertiary (delayed primary). The key factor that differentiates whether primary or secondary healing occurs is how closely the wound edges are apposed. When the wound edges are reapproximated, such as when an incised wound is sutured, primary healing can occur. This results in the least amount of scar tissue production. In contrast, where there is a gap between the wound edges, such as when a finger pulp injury with tissue loss is left open, secondary wound healing will occur in order to fill in the missing tissue. More scar tissue is formed and the process involves a combination of contraction and epithelialization. Neither the mechanism of injury, the amount of tissue damage, nor the method of wound closure, per se, define whether healing by primary or secondary intention occur, only the reapproximation of the wound edges. Even when tissue loss has occurred, primary healing is possible providing that the wound edges are debrided and well apposed. Complete healing is normally achieved most quickly in wounds that are closed primarily, but this is not a defining factor. Wound closure can be satisfactorily achieved with sutures, staples, or glue, and each of these techniques allows primary healing to take place. Tertiary healing and delayed primary healing are the same thing. They refer to wounds that are initially left open and then closed after debridement at a later stage. This is an approach commonly employed in infected wounds where closure is delayed until the infection has been satisfactorily treated.
Cutis laxa is a condition where there is a mutation in elastin fibers and this results in loose wrinkled skin and hypermobile joints. Some patients can benefit from resection of excess skin and this is safe as wound healing is normal. The other conditions are all associated with abnormal wound healing. Ehlers-Danlos syndrome is also known as cutis hyperelastica and is a genetic connective tissue disorder with abnormal collagen cross-linking. The condition is associated with thin friable skin, poor wound healing, hypertrophic scarring, and hypermobile joints. Progeria is also known as Hutchinson-Gilford syndrome and is also a genetic condition observed in children. Patients have premature aging with skin laxity and poor wound healing. Werner syndrome is adult progeria with similar features to Hutchinson-Gilford syndrome. In each of these conditions, surgery is best avoided where possible. It is well accepted that there is an association between smoking and delayed wound healing, although the precise mechanism is not well understood. The constituents implicated within tobacco smoke include nicotine, carbon monoxide, and hydrogen cyanide. Sørensen undertook a systematic review in 20121 to consider the effects of smoking on wound healing and found that smoking temporarily decreases tissue oxygenation and aerobic metabolism, while it also attenuates both the inflammatory and proliferation phases of wound healing, thereby decreasing collagen production. Cessation of smoking for 4 weeks before surgery appears to reverse some, but not all, of the processes described.
steroids? Vitamins are vital to normal wound healing processes, but supplements typically help wound healing only when there is a deficiency present. Vitamin A is also known as retinol and has important functions in immunity, vision, and wound healing. It can help reverse delayed wound healing due to steroids and increase epithelialization in healing wounds. It is well accepted that steroids delay wound healing and animal and human studies have shown these negative effects to be reversed when vitamin A is used either topically or systemically. The mechanism is not well understood, and the benefit of using vitamin A is absent when steroids are not being given. Given this evidence, it may be particularly useful to prescribe vitamin A during the perioperative period in patients on long-term steroids such as for rheumatoid arthritis or ulcerative colitis.1 There are a number of different B vitamins including thiamine, folic acid, pyridoxine, and cobalamin which have important roles in metabolism and oxygen transport. Deficiencies of the B vitamins can therefore result in a broad range of conditions. Vitamin C is vital for hydroxylation reactions in collagen synthesis and a deficiency leads to scurvy, with immature fibroblasts, deficient collagen synthesis, capillary hemorrhage, and decreased tissue strength. Vitamin D is important for calcium regulation and a deficiency can lead to rickets in children or osteomalacia in adults. Vitamin E is an antioxidant that stabilizes membranes. Large doses inhibit healing and may cause dermatitis.
The single most common reason for a wound not to heal is tissue hypoxia. This can occur secondary to a number of causes such as poor vascularity, smoking, previous injury, or radiation therapy. The presence of infection with microorganisms greater than 105 per gram of tissue will decrease oxygen tension, lower the pH, and increase collagenase activity. Denervation of a wound will make it more susceptible to pressure damage and is a major factor in the development of sacral sores in paraplegic patients and foot ulcers in diabetic patients. A moist wound is thought to be beneficial to healing so wounds are often kept moist until reepithelialization is complete, but a dry wound is not the most significant factor in failure of a wound to heal. Radiation injury is a significant factor in wound healing and results from damage to blood vessels, which in turn causes poor oxygen supply to local tissues. Nutritional status is a key component in wound healing and needs to be considered pre- and postoperatively, with dietician support requested in more complex cases.
Cotinine is the body’s key metabolite of nicotine and is considered the gold standard biomarker for smoking assessment. It has a half-life of up to 20 hours in contrast to nicotine which has a half-life of up to 2 hours. Measurement of nicotine itself is therefore less useful than cotinine because it is more rapidly metabolized from the body, so would only be measurable very shortly after a recent cigarette. In contrast, cotinine levels would remain elevated some weeks following a patient’s last cigarette if he or she is a regular smoker. Cotinine levels can be measured in the urine, blood, saliva, or hair follicles. Urine testing is generally preferred because blood testing of cotinine can be affected by diet due to the presence of thiocyanate, which is found in green vegetables such as broccoli and cabbage. Hair or saliva testing of cotinine is less commonly used. One advantage of the hair sampling over saliva is that longer exposure estimates may be obtained.1 Exhaled carbon monoxide (not carbon dioxide) is another useful measurement for assessing smoking. It is recorded in parts per million (ppm). It is generally accepted that a level of 7 ppm is the upper limit to show evidence of recent smoking. Measurement of exhaled carbon monoxide has some drawbacks including the fact it is not specific to tobacco intake as it is influenced by atmospheric carbon monoxide, passive smoking, occupational exposure, or smoke from biomass or coal burning. It too has a short half-life so tends to provide an assessment of smoking behavior primarily over a 6–8 hours period.2 Smoking can lead to increased platelet adhesiveness due to nicotine itself; however, the platelet count would not be expected to be measurably altered. Some other blood parameters can be affected by smoking and these include hemoglobin, white cell count, and mean corpuscular volume.3 Hydrogen cyanide inhibits oxygen transport and is increased in smokers. However, it is not routinely measured in relation to smoking cessation.
Nicotine is a vasoconstrictor that reduces nutritional blood flow to the skin, resulting in tissue ischemia and the potential for impaired healing of injured tissues. Nicotine also increases platelet adhesiveness (not decreases it), raising the risk of thrombotic microvascular occlusion and further tissue ischemia. In addition, it can reduce red blood cells, fibroblast, and macrophage proliferation. Nicotine is therefore one of the components within cigarette smoke that may be responsible for the increased risk of wound complications associated with tobacco smoking. There have been a number of studies to explore the precise role of nicotine in wound healing, both as a single agent and as part of cigarette smoking. However, the mechanisms involved are complex and remain incompletely understood. At present, in spite of the effects of nicotine on wound healing, there is no clinical evidence to show that nicotine replacement therapy in patients abstaining from smoking will significantly affect their wound healing. In high-risk procedures such as face lifting, it is still probably best to avoid both smoking and nicotine replacement therapy in order to minimize risk of wound complications. Other products in cigarette smoke such as carbon monoxide and hydrogen cyanide are responsible for reduced oxyhemoglobin concentrations, altered inflammation, and toxic cellular effects.1–3
wound? It is well accepted that antineoplastic agents affect wound healing. This evidence is based on both lab-based animal studies and clinical studies in humans. However, there is unlikely to be any significant effect on wound healing, providing that chemotherapy treatment is delayed for 10–14 days after the wound has been closed. This makes sense given the anticipated healing time for a typical soft tissue wound.1,2
Biofilms have a significant role in plastic surgery, particularly where implants are used. They can be a major saboteur to wound healing and the reconstructive process. In addition, there has been much debate as to their importance in formation of capsular contracture in breast augmentation, where their presence has been implicated as a key causal factor.1 One of the most challenging factors in managing biofilms is their effectiveness at evading the host’s immune system. Biofilms are fundamentally different from free floating bacteria (termed the planktonic state). They require a surface for growth, which can be either a prosthetic implant or one occurring within the body’s own soft tissues. They are difficult to detect and treat. Routine culture is not effective at detection of biofilms and they are recalcitrant to treatment with systemic antimicrobials. Even following debridement, they have a tendency to recur.
Keloid and hypertrophic scars each represent abnormal scarring processes and are differentiated clinically. The key defining feature of a keloid scar is that it grows beyond the original scar border, whereas a hypertrophic scar does not. Both keloid and hypertrophic scars are typically elevated and erythematous. The histological appearances are similar with high concentrations of type III collagen in each. Keloid scars are only seen in humans, and typically observed in younger patients, i.e., 10–30 years of age. They can occur spontaneously or secondary to injury or infection. They tend to affect patients with darker skin tones most commonly. Females are more commonly affected than males. They commonly occur on the ear or anterior chest and rarely regress spontaneously. Hypertrophic scars have an equal sex ratio, are typically seen in younger age groups (less than 20 years of age), and appear soon after injury such as in children who have sustained a burn. All skin tones can be affected (Fig. 1.1).1,2
Recurrence rates tend to be high in many cases, so multimodality or combination therapy is generally accepted as the best practice approach for their treatment.1,2 In this case, initial treatment with steroid injection followed by surgical excision or debulking may be effective. Additional scar management therapies such as silicone sheeting or pressure may also be helpful. Alternatively, surgical excision combined with radiotherapy may provide the most effective solution if this treatment is available. Radiation treatment for keloids is typically commenced on the same day as surgery with dose ranges of 12–30 gray (Gy), delivered over 5–7 days.3,4 Silicone sheeting would be recommended for wounds as soon as epithelialization is complete so it would be too late for this duration of scar as primary treatment and would be unlikely to show any effect. Steroid injections can reduce collagen synthesis and inflammatory mediators to soften keloid scars. Radiation inhibits angiogenesis and fibroblasts and can be associated with lower rates of recurrence than some treatments.