Introduction

The mechanisms our bodies utilize to heal wounds are relatively well understood and involves complex interactions between inflammatory mediators and cells. Wounds can be left to fill in on their own through secondary intention, or the wound edges can be approximated with sutures, staples, or other tools which allow the wound to heal by primary intention. 

Immediately after the damage occurs, the healing process begins. Injured tissue is repaired, missing tissue replaced, and the epithelial layer restored. Keratinocytes, fibroblasts, vascular endothelial cells, and immune cells all play important roles to support inflammation, cell migration, and angiogenesis.

A superficial laceration confined to the epidermal layer heals quickly and regenerates from adnexal appendages such as hair follicles, sweat, and sebaceous glands housed in the dermal layer. This method of repair is relatively quick and takes mere days. More extensive injuries that involve the dermis require much more time to heal and leave a noticeable scar. [1]

Issues of Concern

If the healing process goes as intended without any complications, the tissue is restored to a relatively similar state as before the injury. Sometimes this process is interrupted, and chronic wounds or infections occur. Wounds that do not heal after 3 months are considered chronic. Chronic wounds may predispose patients to further complications such as disfigurement, sepsis, loss of function, or amputation. 

Other times the healing process may be overactive and form excess scar tissue creating complications such as hypertrophic scars and keloids. [1] Both hypertrophic scars and keloids may be associated with itching, burning, or tenderness. [2]

Function

One of the primary functions of wound healing is to restore the protective epithelial barrier. Without this defense, our initial protection against infection is gone, which leaves us vulnerable to outside pathogens and fluid loss. Later stages of wound healing are important for regaining tissue volume and strength.

Mechanism

Wound healing occurs in an organized sequence of overlapping phases that results in tissue reconstitution. This process involves hemostasis, inflammation, proliferation, and ends with the formation of mature scar tissue.

Hemostasis

Hemostasis begins immediately after the injury. Bleeding from the wound is controlled with vascular constriction, the formation of a platelet thrombus, propagation of the coagulation cascade, termination of clotting, and lastly removal of the clot by fibrinolysis. [3]

Damage to the vascular endothelium brings blood to the wound site and exposes the basal lamina. Activated platelets then bind to the exposed collagen which stimulates the release of various growth factors, inflammatory mediators, and cytokines. The intrinsic and extrinsic coagulation pathways are activated, and a fibrin clot forms a seal to prevent further blood loss. [4]

Cytokines released during the hemostasis phase go on to play a role in extracellular matrix deposition, chemotaxis, epithelialization, and angiogenesis. These include transforming growth factor-beta, platelet-derived growth factor, fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor. [3]

Inflammation

Inflammatory cells migrate to the wound site after platelet activation during the first several days following injury. Mast cells release vasoactive cytokines such as prostaglandins and histamine which increase capillary permeability and promote local dilation to aid the migratory process.

Initially, neutrophils predominate and are attracted to the wound bed by bacterial products. Neutrophils engulf the bacteria along with any dead tissue, forming the pus seen in wounds after the first 48 to 72 hours. Next, monocytes become macrophages and debride the wound further, clearing the matrix and other cell debris such as fibrin and spent neutrophils. Macrophages are also responsible for releasing most of the inflammatory cytokines such as transforming growth factor-beta, platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor. These tasks make macrophages essential to successful wound repair; inhibition of macrophage function causes delayed wound healing. [3][4]

Through these mechanisms, the inflammatory phase creates a clean wound bed for the basis of further repair mechanisms. 

Proliferation

The proliferative phase occurs 3 to 21 days after injury and involves processes of angiogenesis, granulation tissue production, collagen deposition, and epithelialization. The primary outcome of this phase is the filling of the wound defect. Hypoxic conditions in the wound bed lead to the synthesis of nitric oxide (NO) by endothelial cells which stimulate vascular endothelial growth factor to release and promotes angiogenesis. [4]

The release of fibroblast growth factor and platelet-derived growth factor also triggers angiogenesis, which supplies the new wound with oxygen, glucose, and other factors necessary for proper healing. Here, thin-walled endothelium branch from preexisting vessels and lay their foundation on the newly synthesized extracellular matrix. As blood flow returns to the area, oxygen saturation normalizes and NO levels along with vascular endothelial growth factor decrease to slow the process of angiogenesis. This autoregulatory mechanism plays a role in preventing excess collagen production and abnormal scar formation.

Migrating fibroblasts synthesize elastin and collagen to form the new extracellular matrix necessary for vascular support and granulation tissue. Granulation tissue is a highly vascular connective tissue and is essential to the final stages of wound healing, maturation, and remodeling. [3][4]

Maturation

The final stage of wound healing is the maturation phase, and includes collagen cross-linking, remodeling, and wound contraction. Initially, fibroblasts synthesize type 3 collagen which is thinner than mature, type 1 collagen is abundantly found in healthy skin. During the maturation phase, type 1 collagen replaces the type 3 collagen found in granulation tissue, and a scar forms. This increase in type 1 collagen correlates with the increased strength of wounds seen 4 to 5 weeks after healing. A wound will regain 80% of its original strength 3 months after injury. Unfortunately, attaining the full strength of the skin before the injury is impossible. [3]

Wound contraction occurs in open wounds to decrease the amount of connective tissue required to fill in the wound bed. One proposed theory suggests that contraction occurs with the help of myofibroblasts and their synthesis of alpha-smooth muscle actin. [5] Both the location and the mobility of the tissue surrounding the wound bed plays a role in how well the wound contracts. In areas with less mobility, contraction may be troublesome and can be avoided by using a skin graft or various flaps.

The formation of a new, protective epithelial layer is synthesized by epithelial cells migrating inward from the wound edges. Varying migration rates allow for both stratification of the epithelial layer and increasing tissue depth to restore the epithelium's normal thickness. [6]

Once healed, a wound leaves behind a scar. The scar tissue will be firm, slightly raised, and red from excess collagen deposition and increased vascularity, respectively. Typically this would stay like this for the first 6 to 9 months and then begin to soften, flatten and become paler. [7]

Pathophysiology

Wounds occasionally result in an exaggerated healing response and lead to the formation of keloids and hypertrophic scars. By definition, hypertrophic scars are confined within the margins of the original wound bed whereas keloids extend beyond those borders. It is thought that excess tension from excess movement over a joint, underlying bony structures, or loss of tissue may play a role in the development of these particular scars. Keloids also occur more frequently in patients with darker skin.

The exact mechanism of how these scars form is unknown, but abnormal or hyperactive fibroblasts have been found in keloids. These fibroblasts create abundant amounts of collagen, elastin, fibronectin, and proteoglycan and respond excessively to stimulation. This response is likely related to the up-regulation of insulin-like growth factor receptors on keloid fibroblasts. Insulin-like growth factor stimulates collagen production. Unlike normal scars, collagen deposited in keloids is arranged haphazardly, and likely plays a role in their expansion beyond wound edges.

Collagen found in hypertrophic scars is bundled and arranged in wavy patterns parallel to the epithelial surface. This somewhat organized pattern differentiates hypertrophic scars from the chaotic orientation seen in keloids. Unlike the fibroblasts in keloids, fibroblasts found in hypertrophic scars normally respond to growth factors and produce only a small excess of collagen. Hypertrophic scars also contain unique nodular structures of alpha-smooth muscle actin myofibroblasts, similar to those involved with scar contraction. It is thought that over time hypertrophic scars may regress, whereas keloids will not. [2]

Clinical Significance

The many processes involved with wound healing create a large metabolic demand that is met with oxygen and glucose carried to the wound site by newly formed endothelial vessels. Factors leading to vasoconstriction limit this blood supply and thus prevent proper wound healing. Healthcare providers attending to patients with healing wounds should be aware of these factors and control for them when possible. Causes of vasoconstriction include pain, cold, fear, nicotine, alpha-1 agonists, beta antagonists, and hypovolemia. Patients should be screened for the use of substances and medications and counseled regarding their potential for impairing or delaying wound healing. 

Smoking is particularly detrimental to wound healing and affects multiple stages of the healing process. It has vasoconstrictive effects and decreases oxygen supply to the wound. Nicotine also increases the risk of thrombus formation due to increased platelet activation and decreases erythrocyte, fibroblast, and macrophage proliferation. Impairments of fibroblast and macrophage migration delay collagen production and thus wound repair. This delay puts the patient who smokes at an increased risk for infection as well. For patients undergoing elective procedures, discussion of smoking cessation is important in regards to proper wound healing. 

Diabetes, a growing concern for all physicians, can negatively impact wound repair as well. Patients with diabetes have an increased risk of microvascular disease which can impair blood flow to the wound site. Hyperglycemia affects basement membrane permeability and impedes blood flow as well. Elevated blood sugars along with decreased immunity place this population at risk for infection. [3] It is therefore essential to manage blood glucose carefully in patients with healing wounds. 

Successful wound healing relies on several factors and involves multiple high energy processes. Knowledge of the basic physiology of wound healing is vital for predicting possible complications and minimizing poor outcomes. Chronic wounds, keloids, and hypertrophic scars can be difficult to manage once they occur. Therefore, it is best to avoid these problems entirely. Awareness of and screening for common risk factors related to such complications can lead to better patient care.