Basic principles of wound healing

INTRODUCTION — A wound represents a disruption of the normal structure and function of the skin with its associated underlying soft tissue structures [1]. Wounds might be caused by a variety of mechanisms, including both acute and chronic etiologies. Acute injuries are generally caused by trauma and include abrasions, punctures, crush injuries, thermal injury, gunshots, animal bites, and surgery, among others. However, any mechanism that decreases blood flow within the skin for a prolonged period has the potential to cause ischemic breakdown. Skin perfusion may be impaired due to chronic proximal arterial obstruction (eg, peripheral artery disease), vascular compression (eg, hematoma, immobility causing focal pressure), or microvascular occlusion and thrombosis (eg, vasculitis, cholesterol crystals).

Wound classifications and the basic principles of wound healing are reviewed here. The factors responsible for impaired wound healing and wound complications, as well as the clinical assessment and management of wounds, are reviewed elsewhere. (See "Risk factors for impaired wound healing and wound complications" and "Clinical assessment of chronic wounds" and "Basic principles of wound management".)

WOUND ETIOLOGY AND CLASSIFICATION — Wounds are generally classified as acute or chronic in nature (figure 1).

Acute wounds — Acute wounds usually have an easily identifiable mechanism of injury leading to disruption or skin integrity and are typically due to some form of trauma. Acute traumatic skin disruption can result from blunt or penetrating mechanisms with an array of wound sizes, depths, and locations. Because of these varying mechanisms, individualized management and care are required. (See "Basic principles of wound management", section on 'Acute wounds'.)

Surgical wounds are a controlled form of acute wound that are created in the operating room. Surgical wounds are classified into four categories according to the degree of bacterial load or contamination. The four categories are clean, clean-contaminated, contaminated, and dirty. The majority of clean and clean-contaminated wounds are closed primarily at the completion of surgery, while contaminated and dirty wounds as well as surgical wounds are generally left open and require wound care. The classification of surgical wounds is presented in more detail separately. (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults", section on 'Wound classification' and "Overview of the evaluation and management of surgical site infection".)

Chronic wounds — Chronic wounds affect a substantial proportion of the population and contribute to a significant economic burden when considering inpatient treatment. (See "Overview of treatment of chronic wounds".)

Chronic wounds can develop over time from acute traumatic or surgical skin injuries or might result from the breakdown of previously intact skin (table 1). Patients with impaired pain sensation are vulnerable to acute and chronic repetitive injuries, as these might go unnoticed if the injured area is not routinely inspected [2]. This specifically includes patients with diabetes and peripheral arterial disease and patients with neurological injury who are immobilized and at risk for pressure-induced injury.

Although there is no specific time frame that clearly differentiates an acute from a chronic wound, chronic wounds are generally associated with physiological impairments that slow or prevent wound healing (figure 2) [3]. For foot ulcers due to diabetes, there is some evidence to suggest that wounds that do not demonstrate approximately 15 percent surface area reduction on a weekly basis or approximately 50 percent reduction over a one-month period indicate a chronic state [4]. (See "Risk factors for impaired wound healing and wound complications".)

WOUND HEALING — Wound healing occurs as a cellular response to tissue injury and involves activation of keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets (figure 3). The process involves organized cell migration and recruitment of endothelial cells for angiogenesis. The many growth factors and cytokines released by these cell types coordinate and maintain wound healing (figure 4). Once hemostasis is achieved, acute wounds normally heal in an orderly and efficient manner characterized by overlapping phases of inflammation, epithelialization, fibroplasia, and maturation [5-7].

Acute wounds transition through the stages of wound healing as a linear pathway, with clear start and endpoints (figure 5). As an example, the restoration of skin integrity following the development of an acute surgical wound in normal individuals is usually complete within two to four weeks. However, following initial successful surgical skin closure, open wounds or dehiscence may result due to technical error, infection, or the presence of foreign material within the wound.

Chronic wounds are arrested in one of the wound healing stages, usually the inflammatory stage, and fail to progress further (picture 1). In these situations, the normal physiology of the linear pathway is transformed into the pathophysiology of a chronic cycle, without a clear wound closure endpoint. Healing of a surgical wound can also be delayed or prolonged in patients with disease states that impair the healing process. (See 'Impaired wound healing' below and "Risk factors for impaired wound healing and wound complications".)

PHASES OF WOUND HEALING

Hemostasis — Immediately after injury to the skin, small vessels within the wound constrict to provide a measure of hemostasis for 5 to 10 minutes. Platelets aggregate in the severed vessels, trigger the clotting cascade, and release essential growth factors and cytokines that are important for the initiation and progression of wound healing (eg, platelet-derived growth factor, transforming growth factor beta). The resulting fibrin matrix stabilizes the wound and provides a provisional scaffold for the wound healing process. Hemostasis is discussed in detail elsewhere. (See "Overview of hemostasis".)

Larger vessels may require pressure, ligation, hemostatic agents, electrocautery, or other hemostatic strategies to achieve hemostasis. (See "Overview of topical hemostatic agents and tissue adhesives" and "Overview of electrosurgery".)

Inflammation — The inflammatory phase of healing is sometimes referred to as the lag phase, because wound strength does not return immediately. The inflammatory phase is generally completed within three days except in the presence of infection or other factors associated with impaired wound healing. (See "Risk factors for impaired wound healing and wound complications", section on 'Infection' and "Overview of the evaluation and management of surgical site infection".)

Key components of this phase are increased vascular permeability and cellular recruitment. Multiple events contribute to these processes, including:

●Mononuclear leukocytes accumulate and are transformed into macrophages [8]. The maturation of blood-derived monocytes into macrophages is heralded by several events, including secretion of vimentin, which is a structural filament protein involved in wound healing [9].

●Mast cells degranulate, releasing histamine and other mediators of vasodilation and cellular migration.

●Release of vasoactive substances from stromal mast cells makes small vessels permeable to molecular and cellular mediators of the inflammatory response. The resulting accumulation of plasma and cellular elements is noted clinically as edema or swelling.

●Chemotaxis results in migration and concentration of polymorphonuclear leukocytes that digest bacteria, foreign debris, and necrotic tissue with lysosomal enzymes.

In chronic wounds, the normal healing progression usually becomes arrested in this inflammatory stage. The presence of necrotic tissue, foreign material, and bacteria results in the abnormal production of matrix metalloproteases, which alter the balance of inflammation and impair the function of the cytokines described above.

Epithelialization — Epithelialization (also referred to as migration) refers to basal cell proliferation and epithelial cell migration occurring in the fibrin bridgework inside a clot [10]. Proliferation continues until individual cells are surrounded by cells of a similar type. In a clean surgical wound, the epithelial cells migrate downward to meet deep in the dermis (figure 6). Migration ceases when this layer is rejuvenated. Following surgery, this process is normally complete within 48 hours. The superficial layer of epithelium creates a barrier to bacteria and other foreign bodies. However, it is very thin, easily traumatized, and possesses little tensile strength.

The process of epithelialization is physiologically challenged in wounds that are not primarily closed or require healing by secondary intention (picture 2). In these wounds, the physical distance of epithelial migration is increased across the length, width, and depth of the wound.

This process may be further impaired by the presence of biofilm and senescent cells on the wound edge or base. Biofilm is an extracellular matrix produced by bacteria that irreversibly binds to the wound base, promoting inflammation and impairing epithelialization. Epithelial cells at the wound edge may also become senescent or mitotically inactive and unable to perform the DNA replication necessary for the process of proliferation [11].

Fibroplasia — During the stage of fibroplasia, fibroblast proliferation, accumulation of ground substance, and collagen production occur.

Fibroblasts are transformed from local mesenchymal cells (picture 3) and are usually present in the wound within 24 hours and predominate by the tenth postoperative day [12]. They attach to the fibrin matrix of the clot, multiply, and produce glycoprotein and mucopolysaccharides, which make up ground substance. Fibroblasts additionally produce contractile proteins, designated myofibroblasts (picture 4), which have characteristics of smooth muscle cells with the ability to contract and are present in the wound by the fifth day. Pulling the edges of the wound together is dependent upon tissue mobility. Myofibroblastic cells are lost via apoptosis as repair resolves to form a scar.

Fibroblasts also synthesize collagen, the primary structural protein of the body. Collagen production begins on the second postoperative day, when it is secreted as an amorphous gel devoid of strength. Maximum collagen production does not begin until day 5 and continues for at least six weeks [13]. The developing collagen matrix stimulates angiogenesis. Granulation tissue is the result of the combined production of collagen and growth of capillaries (figure 7).

In pathological fibrosis, myofibroblasts persist and are responsible for fibrosis via increased matrix synthesis and for wound contraction. The exuberant scarring may impede normal organ function or, in the case of skin, result in keloid [14]. (See "Keloids and hypertrophic scars" and "Hypertrophic scarring and keloids following burn injuries".)

Maturation — Key elements of the maturation stage include collagen cross-linking, collagen remodeling, wound contraction, and repigmentation (picture 5).

The tensile strength of any wound is directly proportional to the amount of collagen present [15]. Although numerous types of collagen have been identified, types I and III predominate in the skin and aponeurotic layers. Initially, a triple helix (tropocollagen) is formed by three protein chains; two are identical alpha-1 protein chains, and the third is an alpha-2 protein. Bundles of tropocollagen combine to form collagen. As disorganized collagen is degraded and reformed, covalent cross-links are formed that enhance tensile strength (figure 8).

The maximum strength of the healed wound depends upon the interconnection of collagen subunits. Approximately 80 percent of the original strength of the tissue is obtained by six weeks after surgery (figure 9), but the diameter and morphology of collagen fibers do not have the appearance of normal skin until approximately 180 days [16]. Wounds slowly continue to get stronger but may never actually achieve 100 percent of their previous strength [5,6].

The quality of healing that is achieved also depends upon the severity of tissue trauma and the presence of factors that may delay healing or reduce the tensile strength of the final scar. For surgical wounds, the suture material used in repair may contribute as well. Rest and immobility are important during the immediate postoperative period for successful healing to occur. However, some physical activity is essential during the maturation phase because light tension increases tensile strength by remodeling, which may continue for years.

IMPAIRED WOUND HEALING — There is usually not a single primary factor that contributes to impaired wound healing; in fact, the overlapping intricacy of the pathway serves to prevent this from happening. Instead, there are most often multiple, smaller contributing issues that might disrupt the process. As examples, local tissue ischemia and neuropathy can impair chemotaxis during the hemostasis and inflammatory stages. Tissue necrosis and infection alter the balance of inflammation and compete for oxygen. Uncontrolled periwound edema and wound instability disrupt myofibroblast activity and collagen deposition and cross-linking. The risk factors associated with impaired wound healing and wound complications are reviewed separately. (See "Risk factors for impaired wound healing and wound complications".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Minor wound management" and "Society guideline links: Chronic wound management".)

SUMMARY AND RECOMMENDATIONS

●A wound is a disruption of the normal structure and function of the epidermis and associated underlying tissues. Wounds may be caused by a variety of mechanisms, including acute traumatic injury to the skin (abrasion, puncture, crush, burns, gunshot, animal bite, surgery) or other etiologies that cause initially intact skin to break down. (See 'Introduction' above.)

●There is no specific time frame that clearly differentiates an acute from a chronic wound. Chronic wounds are generally associated with physiologic imbalances that impair the wound healing process. (See 'Chronic wounds' above.)

●After hemostasis has been achieved, acute wounds normally heal in an orderly and efficient manner characterized by four distinct but overlapping phases: inflammation, epithelialization, fibroplasia, and maturation. Chronic wounds are arrested in one of the wound healing stages, usually the inflammatory stage, and fail to progress further unless the underlying causes are addressed. (See 'Wound healing' above.)

●Many disease states alter the process of wound healing, the most common of which are peripheral artery disease, diabetes, and chronic venous disease. Small vessel arterial diseases (the vasculitides) are also associated with the development of skin ulcers and poor wound healing due to vascular obstruction or vascular thrombosis. Other factors that contribute to skin or surgical wound breakdown or nonhealing ulcers include infection, smoking, aging, malnutrition, immobilization, immunosuppressive therapy, chemotherapy, and radiation therapy. (See 'Impaired wound healing' above and "Risk factors for impaired wound healing and wound complications".)