How Do Wounds Heal? Four Overlapping Phases and a Lot of Collagen

The first phase begins immediately and lasts minutes. Blood vessels at the wound edge constrict sharply, reducing flow, while platelets arriving at the exposed collagen of the damaged vessel wall stick to it and to each other, forming a temporary plug. That triggers the coagulation cascade, a chain of enzyme activations ending in the conversion of soluble fibrinogen into insoluble fibrin, which forms a mesh through the platelet plug and turns it into a stable clot. The clot does two jobs beyond stopping blood loss: it seals the surface against bacteria, and it is itself the temporary scaffold that the repair cells will crawl along. The platelets also release signalling molecules, including growth factors, that summon the next wave of cells, which is why this phase is not merely plumbing but the start of the instructions for everything that follows.

Within hours the inflammatory phase begins and runs for several days. Blood vessels around the wound now dilate and become leaky, which produces the redness, heat, swelling and pain that people associate with infection and which are, in moderation, the normal signs of repair. Neutrophils arrive first in large numbers and destroy bacteria and debris, dying in the process and contributing much of what becomes pus. Macrophages follow at around two to three days and are the more important cell, because they both clear the remaining debris, including the spent neutrophils, and release the signals that drive the rebuilding stage; experiments removing macrophages show healing stalling almost completely. This phase is a balance rather than a nuisance to be suppressed: too little and infection takes hold, too much and prolonged inflammation damages surrounding tissue and delays everything, which is one reason chronic wounds stay open.

From about day three the proliferative phase constructs new tissue, and several things happen at once:

• •Fibroblasts migrate into the clot and begin secreting collagen, mainly the weaker type III initially, building the temporary matrix called granulation tissue, which is red and bumpy because it is full of new vessels
• •Angiogenesis grows new capillaries into the wound, since no tissue survives without a blood supply, and this is why granulation tissue bleeds readily
• •Epithelial cells at the wound edges lose their attachments and crawl across the surface beneath the scab until they meet cells coming the other way, at which point contact stops them, a mechanism called contact inhibition
• •Myofibroblasts, fibroblasts that have acquired muscle-like contractile fibres, pull the wound edges together and can reduce the area substantially, which is efficient and is also what causes disabling contractures across joints after burns
• •The scab is a temporary cover that is undermined and shed once the new epithelium is continuous beneath it

The final phase begins at around three weeks and continues for months or years, and it is where the quality of the repair is decided. The hastily laid type III collagen is gradually broken down by enzymes and replaced with stronger type I, the density of blood vessels falls, which is why a scar fades from red to pale, and the fibres are progressively realigned along the lines of mechanical stress. Even at its best the result reaches only around eighty percent of the original tensile strength. The reason it is a scar rather than replacement skin is the arrangement: normal dermal collagen is woven in a basketweave that distributes force in every direction, while scar collagen is laid down in parallel bundles, which is quicker and mechanically inferior and also lacks hair follicles, sweat glands and normal pigmentation. Excessive collagen production produces raised hypertrophic scars, and when the process overshoots the wound boundary entirely it produces keloids, which are more common in darker skin and are difficult to treat because excising them creates a new wound.

A chronic wound is one that has stalled, usually in the inflammatory phase, and the causes are mostly circulatory or metabolic. Diabetes impairs healing through several routes at once, including damaged small blood vessels, reduced immune cell function and peripheral nerve damage that removes the pain signal warning of pressure or injury, which is why diabetic foot ulcers are a leading cause of amputation. Venous insufficiency in the legs raises pressure in the capillaries and produces ulcers that can persist for years. Pressure sores arise where sustained compression cuts off blood supply in immobile patients. Other contributors include poor nutrition, since collagen synthesis requires protein, vitamin C and zinc, smoking, which constricts vessels and reduces oxygen delivery, corticosteroids, which suppress the inflammatory phase deliberately, and infection with bacteria growing as a biofilm that ordinary immune cells cannot clear. Treatment now emphasises moist wound healing, which speeds epithelial migration compared with letting a wound dry and scab, a finding from the 1960s that took decades to displace the traditional advice to let air get to it.

Healing runs in four overlapping phases: a clot of platelets and fibrin forms within minutes and acts as a scaffold, inflammatory cells clear debris and bacteria over several days with macrophages directing what follows, fibroblasts and new capillaries build granulation tissue while epithelial cells crawl across the surface, and remodelling replaces weak collagen with stronger collagen for up to two years. A scar forms because the new collagen is laid in parallel bundles rather than the original basketweave, and wounds stall chiefly from poor circulation, diabetes and infection.