Proliferative Phase
Formation
of granulation tissue is a central event during the proliferative
phase. Inflammatory cells, fibroblasts, and neovasculature in a matrix
of fibronectin, collagen, glycosaminoglycans, and proteoglycans comprise
the granulation tissue. Granulation tissue formation occurs 3-5 days
following injury and overlaps with the preceding inflammatory phase.
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. The extracellular wound matrix over which epithelial cells migrate has received increased emphasis in wound-healing research. Migrating epithelial cells interact with a provisional matrix of fibrin cross-linked to fibronectin and collagen. The matrix components may be a source of cell signals to facilitate epithelial cell proliferation and migration. 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.
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 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.
The synthesis and deposition of collagen is a critical event in the proliferative phase and to wound healing in general. Collagen consists of 3 polypeptide chains, each twisted into a left-handed helix. Three chains of collagen aggregate by covalent bonds and twist into a right-handed superhelix, forming the basic collagen unit. A striking structural feature of collagen is that every third amino acid is glycine. This repeating structural feature is an absolute requirement for triple-helix formation. Collagen is rich in hydroxylysine and hydroxyproline moieties, which enable it to form strong cross-links. The hydroxylation of proline and lysine residues depends on the presence of oxygen, vitamin C, ferrous iron, and α -ketoglutarate. Deficiencies of oxygen and vitamin C, in particular, result in underhydroxylated collagen that is less capable of forming strong cross-links and, therefore, is more vulnerable to breakdown.
Collagen is secreted to the extracellular space in the form of procollagen. This form is then cleaved of its terminal segments and called tropocollagen. Tropocollagen can aggregate with other tropocollagen molecules to form collagen filaments. Filaments consist of tropocollagen molecules arrayed in a staggered fashion, joined by intermolecular cross-links. Filaments aggregate to form fibrils. Collagen fibrils, in turn, aggregate to form collagen fibers.
Filament, fibril, and fiber formation occur within a matrix gel of glycosaminoglycans, hyaluronic acid, chondroitin sulfate, dermatan sulfate, and heparin sulfate produced by fibroblasts. Intermolecular cross-links within the collagen fiber stabilize it, making it resistant to destruction. Age, tension, pressure, and stress affect the rate of collagen synthesis. Collagen synthesis begins approximately 3 days after injury and may continue at a rapid rate for approximately 2-4 weeks. Collagen synthesis is controlled by the presence of collagenases and other factors that destroy collagen as new collagen is made.
Approximately 80% of the collagen in normal skin is type I collagen; the remaining is mostly type III. In contrast, type III collagen is the primary component of early granulation tissue and is abundant in embryonic tissue. Collagen fibers are deposited in a framework of fibronectin. An essential interaction seems to exist between fibronectin and collagen; experimental wounds depleted of fibronectin demonstrate decreased collagen accumulation.
Elastin is also present in the wound in smaller amounts. Elastin is a structural protein with random coils that allow for stretch and recoil properties of the skin.
Fibronectin is chemotactic for endothelial cells. Capillaries bud from existing capillaries in response to these growth factors. Endothelial cells coalesce and bind fibrin, which adds support to the vessel wall. 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.
New blood vessel formation is a complex process that relies on several angiogenic factors such as vascular endothelial growth factor, angiogenin, and angiotropin.
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.
Epithelialization
Epithelialization is the formation of epithelium over a denuded surface. Epithelialization of an incisional wound 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. The extracellular wound matrix over which epithelial cells migrate has received increased emphasis in wound-healing research. Migrating epithelial cells interact with a provisional matrix of fibrin cross-linked to fibronectin and collagen. The matrix components may be a source of cell signals to facilitate epithelial cell proliferation and migration. 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.
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.
The synthesis and deposition of collagen is a critical event in the proliferative phase and to wound healing in general. Collagen consists of 3 polypeptide chains, each twisted into a left-handed helix. Three chains of collagen aggregate by covalent bonds and twist into a right-handed superhelix, forming the basic collagen unit. A striking structural feature of collagen is that every third amino acid is glycine. This repeating structural feature is an absolute requirement for triple-helix formation. Collagen is rich in hydroxylysine and hydroxyproline moieties, which enable it to form strong cross-links. The hydroxylation of proline and lysine residues depends on the presence of oxygen, vitamin C, ferrous iron, and α -ketoglutarate. Deficiencies of oxygen and vitamin C, in particular, result in underhydroxylated collagen that is less capable of forming strong cross-links and, therefore, is more vulnerable to breakdown.
Collagen is secreted to the extracellular space in the form of procollagen. This form is then cleaved of its terminal segments and called tropocollagen. Tropocollagen can aggregate with other tropocollagen molecules to form collagen filaments. Filaments consist of tropocollagen molecules arrayed in a staggered fashion, joined by intermolecular cross-links. Filaments aggregate to form fibrils. Collagen fibrils, in turn, aggregate to form collagen fibers.
Filament, fibril, and fiber formation occur within a matrix gel of glycosaminoglycans, hyaluronic acid, chondroitin sulfate, dermatan sulfate, and heparin sulfate produced by fibroblasts. Intermolecular cross-links within the collagen fiber stabilize it, making it resistant to destruction. Age, tension, pressure, and stress affect the rate of collagen synthesis. Collagen synthesis begins approximately 3 days after injury and may continue at a rapid rate for approximately 2-4 weeks. Collagen synthesis is controlled by the presence of collagenases and other factors that destroy collagen as new collagen is made.
Approximately 80% of the collagen in normal skin is type I collagen; the remaining is mostly type III. In contrast, type III collagen is the primary component of early granulation tissue and is abundant in embryonic tissue. Collagen fibers are deposited in a framework of fibronectin. An essential interaction seems to exist between fibronectin and collagen; experimental wounds depleted of fibronectin demonstrate decreased collagen accumulation.
Elastin is also present in the wound in smaller amounts. Elastin is a structural protein with random coils that allow for stretch and recoil properties of the skin.
Angiogenesis
A rich blood supply is vital to sustain newly formed tissue and is appreciated in the erythema of a newly formed scar. These blood vessels disappear as they become unnecessary, as does the erythema of the 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.Fibronectin is chemotactic for endothelial cells. Capillaries bud from existing capillaries in response to these growth factors. Endothelial cells coalesce and bind fibrin, which adds support to the vessel wall. 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.
New blood vessel formation is a complex process that relies on several angiogenic factors such as vascular endothelial growth factor, angiogenin, and angiotropin.
Contraction
Wound contraction begins almost concurrently with collagen synthesis. Contraction, defined as the centripetal movement of wound edges that facilitates closure of a wound defect, is maximal 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.
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