General Principles of Wound Healing in Animals
Wound healing occurs through a similar process in most tissues in the body. It consists of three major stages: inflammation, proliferation, and remodeling.
Inflammation, the first stage of wound healing, can be divided into several phases. Hemorrhage is controlled with vasoconstriction , followed within minutes by vasodilation. During the second phase, cells adhere to the vascular endothelium. To resolve infection, leukocytes migrate through the vascular basement membrane into the newly created wound within 30 minutes. Initially, neutrophils predominate (as in the peripheral blood); later, the neutrophils die off and monocytes become the predominant cell type in the wound.
Debridement is the next phase of inflammation. Although neutrophils phagocytose bacteria, monocytes, rather than neutrophils, are considered essential for wound healing. Monocytes secrete a number of growth factors required for wound healing. Additionally, after migration out of the blood vessels, monocytes are considered macrophages. In addition to the phagocytosis of necrotic debris, macrophages also attract mesenchymal cells. Finally, mononuclear cells may coalesce to form multinucleated giant cells found in chronic inflammation. Lymphocytes may also be present in the wound and contribute to the immunologic response to foreign debris.
Proliferation is the second stage of wound healing. It consists of fibroblast, capillary, and epithelial proliferation phases. During the proliferation stage, mesenchymal cells transform into fibroblasts, which lay fibrin strands to act as a framework for cellular migration. In a healthy wound, fibroblasts begin to appear ~3 days after the initial injury. These fibroblasts initially secrete ground substance and later collagen. The early collagen secretion allows an initial rapid increase in wound strength, which continues to increase more slowly as the collagen fibers reorganize according to the stress on the wound.
Migrating capillaries deliver a blood supply to the wound. The center of the wound is an area of low oxygen tension that attracts capillaries following the oxygen gradient. Because of the need for oxygen, fibroblast activity depends on the rate of capillary development. As capillaries and fibroblasts proliferate, granulation tissue is produced. Because of the extensive capillary invasion, granulation tissue tends to be both very friable and resistant to infection.
Epithelial cell migration begins within hours of the initial wound. Basal epithelial cells flatten and migrate across the open wound. The epithelial cells may slide across the defect in small groups or “leapfrog” across one another to cover the defect. Migrating epithelial cells secrete mediators, such as transforming growth factors α and β, which enhance wound closure. Although epithelial cells migrate in random directions, migration stops when contact is made with other epithelial cells on all sides (ie, contact inhibition). Epithelial cells migrate across the open wound and can cover a properly closed surgical incision within 48 hours. However,in an open wound, epithelial cells must have a healthy bed of granulation tissue to cross. Epithelialization is retarded in desiccated wounds.
Remodeling is the final stage of wound healing. During this period, the newly laid collagen fibers and fibroblasts reorganize along lines of tension. Fibers in a nonfunctional orientation are replaced by functional fibers. This process allows wound strength to continue to increase slowly over a long period (as long as 2 years). Most wounds remain 15%–20% weaker than the original tissue. However, the urinary bladder and bone regain 100% of their original strength after wounding and repair.