Wound healing is a fundamental part of recovery from surgery. After tissue damage, the body responds in a predictable manner to repair and restore function. Wound healing involves blood clotting factors, inflammatory mediators, connective tissue formation, and remodeling processes. In the fetus some wounds will heal without a scar, but after birth scar formation is expected. Individuals respond to wound healing differently, resulting in differences in scar formation. Some chronic (eg, diabetes, malnutrition) and genetic (eg, Ehlers–Danlos) conditions negatively affect the healing of a wound.

The repair process after tissue injury from trauma or surgically created wounds has been divided into 3 phases: inflammation, proliferation, and remodeling (Fig. 12-1). These 3 phases overlap, but each has identifiable characteristics that will be discussed in more detail. Wound healing is the tissue’s ability to restore function after injury. There is an urgency to restore function, minimize loss of fluid, and avoid infection. This may explain why perfect repair, or regeneration, is not possible. Regeneration is a term used for restoration of the tissue without a scar or signs of previous injury. It is found to take place only in fetal tissue and in certain organs such as liver and bone.

All wounds undergo the same 3 steps (inflammatory, proliferative, and remodeling phases) progressing toward repair and restoration of function. Acute wounds heal in a predictable fashion, progressing through these 3 phases. Chronic wounds do not proceed past the inflammatory phase.

Inflammatory Phase

The inflammatory phase starts immediately after injury or incision and lasts for approximately 6 days. This phase represents the body’s attempt to limit blood loss by creating a seal over the wound and is followed by removal of necrotic tissue and debris. During the inflammatory phase there is an increase in vascular permeability. Cells migrate into the tissue stimulated by chemotaxis. These cells release several cytokines and growth factors which activate migrating cells (Fig. 12-2).

Hemostasis, Inflammation, and Increased Vascular Permeability

Hemostasis is triggered by the exposure of subendothelial collagen to platelets; this is mediated by Von Willebrand factor. Platelet adhesion to the endothelium is facilitated by integrin receptor GPIIb-IIIa. This results in aggregation of platelets, vasoconstriction, and activation of the coagulation cascade. The binding of platelets results in the release of biologically active proteins from the platelets’ α granules and dense bodies (eg, platelet-derived growth factor [PDGF], transforming growth factor β [TGF-β], insulin-like growth factor type I [IGF-I], fibronectin, fibrinogen, thrombospondin, Von Willebrand factor, and vasoactive amines). The increased vascular permeability observed is a result of the release of these biologically active proteins by platelets and mast cells. The most important mediators are histamine and serotonin. Prostaglandin and thromboxane A2 are released from the breakdown of cell membranes and assist in platelet aggregation and vasoconstriction.

Both the intrinsic and extrinsic clotting pathways are activated. Thrombin activates platelets and triggers fibrin formation from fibrinogen. The resulting fibrin strands trap erythrocytes and other cells in the blood to form a blood clot (Fig. 12-3). Ultimately, this results in the formation of a scaffold for inflammatory cells, fibroblasts, and endothelial cells, allowing hemostasis and the wound healing process.

Macrophages and neutrophils are the predominant cell types to migrate into tissue in response to injury. Neutrophils (polymorphonuclear cells or PMNs) appear first, followed by macrophages. Integrin molecules, a family of cell surface receptors, are important for the migration and activation of neutrophils and macrophages.

Monocytes and endothelial cells increase the migration of PMNs into the injured tissue through the release of interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α). The PMNs release lysosomes, elastase, and other proteases, promoting further migration of PMNs and facilitating the breakdown of damaged tissue. PMNs and macrophages are phagocytes, which have the ability to remove damaged tissue and dead cells in preparation for the synthesis of new tissue.

Macrophages are very important to the wound healing process. They appear in the wound when PMNs are dwindling and induce apoptosis of the PMNs. Within 24 to 48 hours of injury, monocytes from the blood migrate into the tissue and become macrophages. Chemotactic agents from the initial response to the wound (complement c5a, thrombin, fibronectin, collagen, TGF-β) recruit monocytes into the wound. The process of transforming monocytes into macrophages is facilitated by specific integrins in the tissue, which control adhesion-mediated gene induction in monocytes. The macrophages release matrix metalloproteinases, collagenases, and other enzymes to break down the damaged tissue in preparation for regeneration. In addition, macrophages release numerous cytokines and growth factors important for the wound healing process (see Table 12-1).

After about 5 days, T lymphocytes appear in the wound. They stimulate other cells (primarily macrophages) and process the antigens presented by macrophages. These antigens include foreign material from bacteria, viruses, and other pathogens.

Proliferative Phase

The proliferative phase begins after the initial inflammatory response has subsided and is characterized by angiogenesis, fibroplasia, and epithelialization (Fig. 12-4).

Angiogenesis is an important part of wound healing. Without new vessels to support the energy and oxygen demands of the cells taking part in healing, the wound cannot heal quickly. Angiogenesis is dependent on angiogenic growth factors. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are 2 of the most potent stimulants of angiogenesis. In addition, TGF-β, TGF-α, and hypoxia-inducible factor-1α (HIF-1α) are important for angiogenesis.

Fibroplasia is the process of collagen synthesis performed by fibroblasts for use in the extracellular matrix (ECM). Collagen synthesis starts 3 to 5 days after injury. This is the amount of time needed for undifferentiated mesenchymal cells to migrate into the tissue and differentiate into fibroblasts. It appears that the initial proliferation of fibroblasts comes from tissue-derived mesenchymal cells capable of differentiation. These cells are not as pluripotent as the mesenchymal cells found in bone marrow. The bone marrow-derived mesenchymal cells respond later.

The factors involved in the differentiation of mesenchymal cells to fibroblasts are not well characterized, but most likely involve connective tissue growth factor (CTGF). Interestingly, TGF-β and CTGF differentiate fibroblasts into the myofibroblasts responsible for wound contraction. The presence of a large number of myofibroblasts can lead to hypertrophic scars and keloids.

Epithelialization takes place very soon after an injury to the skin and replaces the clot that initially protects the wound (Fig. 12-4). Epidermal cells migrate from the basal layer of the residual epidermis or the epithelium-lined dermal appendages to form a fine layer over the wound. The migrating epidermal cells are guided by dermal integrins, allowing them to migrate between the fibrinous eschar and the underlying dermal tissue. The migrating epidermal cells use phagocytosis to remove debris as they migrate.