Based on extensive studies of tissue injury and current knowledge of growth factor biology, four distinct phases of wound healing can be identified: inflammatory, migratory, proliferative — and late.
The inflammatory phase occurs in the first 24 hours. Platelets immediately form a plug by adhering to the collagen exposed by damage to blood vessels. The wound is then filled by a blood clot containing platelet aggregates, red blood cells, and white blood cells trapped in a fibrin meshwork. During blood clotting, aggregated platelets release chemicals that initially constrict blood vessels and prevent further bleeding. Subsequently, local blood vessels dilate, increasing the blood supply to the wound, bringing in the neutrophils — the white blood cells, which remove bacteria or other foreign materials. This acute inflammation hastens healing and is seen as reddening, swelling, and warmth around a wound.
In the migratory phase, fibroblasts and macrophages infiltrate the wound to initiate reconstruction. Polypeptide growth factors released from platelets stimulate the proliferation of fibroblasts at the site of a wound; these make the new fibres of collagen which will bridge the gap and form the scar. Macrophages begin to digest the blood clot. Under the influence of epidermal growth factor (EGF), epithelial cells advance across the clot to form a scab. It is interesting that the submandibular salivary glands are a major source of EGF. This provides a scientific basis for the expression ‘licking one's wounds’.
In the proliferative phase, activated macrophages release substances including growth factors which stimulate sprouting from nearby capillary blood vessels. The capillary sprouts eventually join together to form a new network, with arterioles supplying them and venules draining them. This process is of prime importance to the success of wound healing, as it contributes to the metabolic demands of the damaged tissue; delivering nutrients, allowing gaseous exchange, and disposing of waste products.
In the late phase, fibroblasts continue to produce new and stronger collagen to remodel the scar while the epithelium on the surface heals. Excessive fibrous tissue formation in a healing skin wound may form a raised and ugly scar, known as keloid, especially if the edges of a wound have not been held together effectively.
In normal situations new blood vessel growth (angiogenesis) stops after completion of wound repair, and the new vessels may regress. However, inadequate or excessive angiogenesis often leads to problems. It can be inadequate for example, in limbs with poor circulation, where wounds may lead to gangrene and eventual amputation. In cancer, excessive angiogenesis enables tumours to grow and to metastasize to other parts of the body. For this reason, tumours have been coined ‘wounds that never heal’.
There appear to be quantitative and qualitative differences in the angiogenic response in health and disease. It is possible that inadequate or excessive angiogenesis is the result of an imbalance between the production of angiogenic inducers and inhibitors, or due to differential expression of receptors for these molecules. Researchers are currently working to determine if there are indeed such differences. If so, these differences may provide future targets for pharmacological manipulations to enhance angiogenesis in chronic wounds or heart attacks. Conversely, it would be possible to suppress excessive angiogenesis in cancer and rheumatoid arthritis.
The powers of healing or regeneration vary from one tissue to another. The skin epithelium is not as efficient as the epithelia of the mucous membranes that line the gut and airways. For a skin injury, scar tissue is covered by epidermis, but specialized structures such as hair follicles and sweat glands are not regenerated. In contrast, complicated glandular structures of the stomach lining can and do regenerate after injury. In chronic septic ulcers, however, the damaged gastric epithelium does not heal — unless drug treatment is given to reduce gastric acid secretion, thus allowing growth factors to promote the healing process.
The liver is an exceptional organ, in that it can undergo complete and rapid regeneration in response to surgery or disease. A specific growth factor for liver cells is thought to stimulate their vigorous proliferation. Remarkably, after removal of 75% of the liver, the original mass can be restored in about two weeks. However, in chronic alcoholism or serious liver infections, excessive fibrous repair (cirrhosis) often outweighs regeneration, dividing the liver up into irregular islands. Such cirrhosis can lead to liver failure.
Wound healing can be affected by many factors, including medications and the state of health. Malnutrition delays healing; in particular, if the supply of vitamin C (ascorbic acid) is inadequate. Certain drugs (steroids or anticancer drugs for example) can adversely affect the process. Kidney or liver failure, and poor circulation owing to arteriosclerosis, all delay healing. A high blood glucose concentration in diabetic patients can impair healing and predispose wounds to infection.
Tai Ping Fan
See also blood; injury; scars; skin.
"wound healing." The Oxford Companion to the Body. . Encyclopedia.com. (February 27, 2017). http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/wound-healing
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