Wound Healing
Wound Healing
- Wound healing is a natural restorative response to tissue injury. Healing is the interaction of a complex cascade of cellular events that generates resurfacing, reconstitution, and restoration of the tensile strength of injured skin.
- Healing is a systematic process, traditionally explained in terms of 4 overlapping classic phases: hemostasis, inflammation, proliferation, and maturation. While platelets play a crucial role in clot formation during hemostasis, inflammatory cells débride injured tissue during the inflammatory phase. Epithelialization, fibroplasia, and angiogenesis occur during the proliferative phase. Meanwhile, granulation tissue forms and the wound begins to contract. Finally, during the maturation phase, collagen forms tight cross-links to other collagen and with protein molecules, increasing the tensile strength of the scar.
Hemostasis
- Hemostasis starts within the very first moments of the injury, where platelets play a role by aggregating, as well as by releasing cytokines, chemokines, and hormones.
- Vasoconstriction occurs to limit blood loss under the effects of vasoactive mediators (epinephrine, norepinephrine, prostaglandins, serotonin, and thromboxane), causing temporary blanching of the wound.
- Exposed subendothelium, including collagen and tissue factor, activates platelet aggregation and leads to clot formation (primary plug).
- Aggregation and attachment to exposed collagen surfaces activates the platelets. Activation enables platelets to degranulate and release chemotactic and growth factors, such as platelet-derived growth factor (PDGF), proteases, and vasoactive agents (eg, serotonin, histamine).
- Chemokines released by platelet activation attract inflammatory cells to the area, leading to the next phase in the healing process.
Inflammatory Phase
- In addition to activation of fibrin, thrombin activated by the coagulation cascades facilitates migration of inflammatory cells to the site of injury by increasing vascular permeability. By this mechanism, factors and cells necessary for healing flow from the intravascular space and into the extravascular space.
- At this time, clot formation dissipates as its stimuli dissipate. Plasminogen is converted to plasmin, a potent enzyme that aids in cell lysis.
- The initial vasoconstriction period, typically only 10-15 minutes in duration, is followed by a more persistent period of vasodilation mediated by histamine, prostaglandins, kinins, and leukotrienes. Vasodilation is an important means by which the wound can be exposed to increased blood flow, accompanied by the necessary inflammatory cells and factors that fight infection and débride the wound of devitalized tissue. Alterations in pH (secondary to tissue and bacterial degradation), swelling, and tissue hypoxemia at the injury site contribute to the sensation of wound pain.
- The cellular aspect of the inflammatory phase occurs within hours of injury, and it includes neutrophils, macrophages, and lymphocytes.
- Neutrophils are the predominant cell type for the first 48 hours after injury but do not appear essential to the wound-healing process. Neutrophils cleanse the wound site of bacteria and necrotic matter and release inflammatory mediators and bactericidal oxygen free radicals. The absence of neutrophils does not prevent healing.
- Macrophages are essential to wound healing and perhaps are the most important cells in the early phase of wound healing. Macrophages phagocytose debris and bacteria. Macrophages also secrete collagenases and elastases, which break down injured tissue and release cytokines. In addition, macrophages release PDGF, an important cytokine that stimulates the chemotaxis and proliferation of fibroblasts and smooth muscle cells. Finally, macrophages secrete substances that attract endothelial cells to the wound and stimulate their proliferation to promote angiogenesis.
- Macrophage-derived growth factors play a pivotal role in new tissue formation, as evidenced by the fact that new tissue formation in macrophage-depleted animal wounds demonstrates defective repair. In studies in which experimental wounds are rendered monocytopenic, subsequent stages of fibroplasia and granulation tissue formation are impaired and the overall rate of wound healing is delayed.
- T lymphocytes migrate into the wound during the inflammatory phase, approximately 72 hours following injury. T lymphocytes are attracted to the wound by the cellular release of interleukin 1, which also contributes to the regulation of collagenase. Lymphocytes secrete lymphokines such as heparin-binding epidermal growth factor and basic fibroblast growth factor. Lymphocytes also play a role in cellular immunity and antibody production.
Proliferative Phase
- Formation of granulation tissue is a central event during the proliferative phase. Its formation occurs 3-5 days following injury and overlaps with the preceding inflammatory phase. Granulation tissue includes inflammatory cells, fibroblasts, and neovasculature in a matrix of fibronectin, collagen, glycosaminoglycans, and proteoglycans.
Epithelialization
- Epithelialization is the formation of epithelium over a denuded surface. It involves the migration of cells at the wound edges over a distance of less than 1 mm, from one side of the incision to the other. Incisional wounds are epithelialized within 24-48 hours after injury. This epithelial layer provides a seal between the underlying wound and the environment.
- The process begins within hours of tissue injury. Epidermal cells at the wound edges undergo structural changes, allowing them to detach from their connections to other epidermal cells and to their basement membrane. Intracellular actin microfilaments are formed, allowing the epidermal cells to creep across the wound surface. As the cells migrate, they dissect the wound and separate the overlying eschar from the underlying viable tissue. In superficial wounds (eg, wounds due to laser resurfacing, dermabrasion, chemical peel treatments) adnexal structures (eg, sebaceous glands, hair follicles) contribute to reepithelialization.
- Epidermal cells secrete collagenases that break down collagen and plasminogen activator, which stimulates the production of plasmin. Plasmin promotes clot dissolution along the path of epithelial cell migration. Migrating epithelial cells interact with a provisional matrix of fibrin cross-linked to fibronectin and collagen. In particular, fibronectin seems to promote keratinocyte adhesion to guide these cells across the wound base.
- Wounds in a moist environment demonstrate a faster and more direct course of epithelialization. Occlusive and semiocclusive dressings applied in the first 48 hours after injury may maintain tissue humidity and optimize epithelialization. Studies have shown that occlusive dressings in the form of silicone sheeting, or other forms of occlusive dressing, limit epidermal inflammatory factors that contribute to epidermal hyperplasia, by restoring barrier function and increasing skin hydration. [1]
- When epithelialization is complete, the epidermal cell assumes its original form, and new desmosomal linkages to other epidermal cells and hemidesmosomal linkages to the basement membrane are restored.
Fibroplasia
- The fibroblast is a critical component of granulation tissue. Fibroblasts are responsible for the production of collagen, elastin, fibronectin, glycosaminoglycans, and proteases Fibroblasts grow in the wound as the number of inflammation cells decrease. The demand for inflammation disappears as the chemotactic factors that call inflammatory cells to the wound are no longer produced and as those already present in the wound are inactivated.
- Fibroplasia begins 3-5 days after injury and may last as long as 14 days. Skin fibroblasts and mesenchymal cells differentiate to perform migratory and contractile capabilities. Fibroblasts migrate and proliferate in response to fibronectin, platelet-derived growth factor (PDGF), fibroblast growth factor, transforming growth factor, and C5a. Fibronectin serves as an anchor for the myofibroblast as it migrates within the wound.
Angiogenesis
- A rich blood supply is vital to sustain newly formed tissue and is appreciated in the erythema of a newly formed scar. The macrophage is essential to the stimulation of angiogenesis and produces macrophage-derived angiogenic factor in response to low tissue oxygenation. This factor functions as a chemoattractant for endothelial cells. Basic fibroblast growth factor secreted by the macrophage and vascular endothelial growth factor secreted by the epidermal cell are also important to angiogenesis.
- Angiogenesis results in greater blood flow to the wound and, consequently, increased perfusion of healing factors. Angiogenesis ceases as the demand for new blood vessels ceases. New blood vessels that become unnecessary disappear by apoptosis.
Contraction
- Wound contraction, defined as the centripetal movement of wound edges that facilitates closure of a wound defect, essentially begins concurrent with collagen synthesis, and reaches maximal activity at 5-15 days after injury. Contraction results in a decrease in wound size, appreciated from end to end along an incision; a 2-cm incision may measure 1.8 cm after contraction.
- The maximal rate of contraction is 0.75 mm/d and depends on the degree of tissue laxity and shape of the wound. Loose tissues contract more than tissues with poor laxity, and square wounds tend to contract more than circular wounds.
- Wound contraction depends on the myofibroblast located at the periphery of the wound, its connection to components of the extracellular matrix, and myofibroblast proliferation.
- Radiation and drugs, which inhibit cell division, have been noted to delay wound contraction. Contraction does not seem to depend on collagen synthesis.
- Although the role of the peripheral nervous system in wound healing is not well delineated, recent studies have suggested that sympathetic innervation may affect wound contraction and epithelialization through unknown mechanisms.
- Contraction must be distinguished from contracture, a pathologic process of excessive contraction that limits motion of the underlying tissues and is typically caused by the application of excessive stress to the wound.
Maturation Phase
Collagen
- Collagen remodeling during the maturation phase depends on continued collagen synthesis in the presence of collagen destruction. Collagenases and matrix metalloproteinases in the wound assist removal of excess collagen while synthesis of new collagen persists. Tissue inhibitors of metalloproteinases limit these collagenolytic enzymes, so that a balance exists between formation of new collagen and removal of old collagen.
- During remodeling, collagen becomes increasingly organized. Fibronectin gradually disappears, and hyaluronic acid and glycosaminoglycans are replaced by proteoglycans. Type III collagen is replaced by type I collagen. Water is resorbed from the scar.
- These events allow collagen fibers to lie closer together, facilitating collagen cross-linking and ultimately decreasing scar thickness. Intramolecular and intermolecular collagen cross-links result in increased wound bursting strength. Remodeling begins approximately 21 days after injury, when the net collagen content of the wound is stable. Remodeling may continue indefinitely.
- The tensile strength of a wound is a measurement of its load capacity per unit area. The bursting strength of a wound is the force required to break a wound regardless of its dimension. Bursting strength varies with skin thickness. Peak tensile strength of a wound occurs approximately 60 days after injury. A healed wound only reaches approximately 80% of the tensile strength of unwounded skin.
Cytokines
- Cytokines have emerged as important mediators of wound healing events. By definition, a cytokine is a protein mediator, released from various cell sources, which binds to cell surface receptors to stimulate a cell response. Cytokines can reach their target cell by endocrine, paracrine, autocrine, or intracrine routes.
Some important cytokines are described as follows:
- Epidermal growth factor was the first cytokine described and is a potent mitogen for epithelial cells, endothelial cells, and fibroblasts. Epidermal growth factor stimulates fibronectin synthesis, angiogenesis, fibroplasia, and collagenase activity.
- Fibroblast growth factor is a mitogen for mesenchymal cells and an important stimulus for angiogenesis. Fibroblast growth factor is a mitogen for endothelial cells, fibroblasts, keratinocytes, and myoblasts. This factor also stimulates wound contraction and epithelialization and production of collagen, fibronectin, and proteoglycans.
- PDGF is released from the alpha granules of platelets and is responsible for the stimulation of neutrophils and macrophages and for the production of transforming growth factor-β. PDGF is a mitogen and chemotactic agent for fibroblasts and smooth muscle cells and stimulates angiogenesis, collagen synthesis, and collagenase.
- Vascular endothelial growth factor is similar to PDGF but does not bind the same receptors. Vascular endothelial growth factor is mitogenic for endothelial cells and plays an important role in angiogenesis.
- Transforming growth factor-β is released from the alpha granules of platelets and has been shown to regulate its own production in an autocrine manner. This factor is an important stimulant for fibroblast proliferation and the production of proteoglycans, collagen, and fibrin. The factor also promotes accumulation of the extracellular matrix and fibrosis. Transforming growth factor-β has been demonstrated to reduce scarring and to reverse the inhibition of wound healing by glucocorticoids.
- Tumor necrosis factor-α is produced by macrophages and stimulates angiogenesis and the synthesis of collagen and collagenase. Tumor necrosis factor-α is a mitogen for fibroblasts.
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