Healing and repair

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10.2 Factors affecting wound healing89

Self-assessment: questions91
Self-assessment: answers92

Chapter overview
Healing is the replacement of dead or injured tissue by healthy tissue; this can be accomplished either by regeneration, when the damage is mild and cells can multiply to replace lost tissue, or by repair, which involves the formation of granulation tissue and then a scar. Repair occurs if there is extensive tissue injury or in permanent cell populations.

10.1. The healing process

Learning objectives
You should:

• distinguish regeneration from repair
• state the components of granulation tissue and describe its production
• describe the healing process in skin and in bone
• state the consequences of fibrosis.
For regeneration to occur two conditions must be fulfilled. First, there must be little or no disruption to the intercellular matrix, because the matrix provides the ‘scaffolding’ for new cells. Second, the damage must involve cell populations capable of dividing (i.e. labile or stable cell populations). Repair by scar tissue formation occurs if:

• there is significant disruption of the connective tissue matrix
• cells cannot divide to replace lost cells (this occurs in permanent cell populations such as the heart).

When does healing occur?

Healing occurs in damaged tissues. It begins early in the inflammatory reaction, when phagocytes clear dead cells and other debris. If the injury is mild then healing may take place by regeneration; there is replacement of injured tissue with cells of the same type and normal anatomy is restored, leaving no trace of damage. An example is resolution following lobar pneumonia; there is acute inflammation associated with extensive loss of alveolar cells, but there is typically no significant destruction of lung tissue matrix and thus healing by regeneration can take place.
If regeneration is not possible, there is repair by granulation tissue formation and subsequent fibrosis (scarring). This results in loss of specialised cells and hence loss of function. The anatomy is altered, although structural integrity is preserved.
Skin healing has been extensively studied and much of our understanding of the healing process comes from observation of surgical skin wounds. The central pathological process in healing by repair is the formation of granulation tissue.

What is granulation tissue?

This bright pink, granular tissue is seen, for example, in the base of a healing skin wound, and denotes the process of repair. Granulation tissue is composed of:

• small blood vessels (capillary-sized channels)
• proliferating fibroblasts and myofibroblasts
• inflammatory cells.
The development of new blood vessels is called angiogenesis or neovascularisation. Endothelial cells initially form solid cords, but they soon open into capillary loops at the edges of the lesion accompanied by new lymphatic channels. The endothelial cells derive firstly from sprouts produced by adjacent capillaries and secondly from endothelial precursor cells (EPCs) produced in the bone marrow. EPCs are mobilised from the marrow and circulate to the site of injury where they migrate into the tissues. New arterioles and venules are formed as the proliferating capillaries become surrounded by pericytes and smooth muscle cells.
Fibroblasts migrate to the area and produce collagen and other components of the extracellular matrix, such as fibronectin and proteoglycans. Type III collagen tends to be produced first; it is gradually replaced by type I collagen, which is stronger. Many fibroblasts also have significant contractile abilities due to the presence of muscle-type intracytoplasmic filaments; such cells are called myofibroblasts and contract to reduce the wound size. Consequently, the volume of a scar is generally less than the volume of the original tissue damage.
Granulation tissue also contains a variety of inflammatory cells, the types and proportions of which depend on the cause of the tissue damage. For example, granulation tissue surrounding an abscess is rich in neutrophils.
The transformation of necrotic material or fibrin to a fibrous scar by granulation tissue is called organisation. The granulation tissue grows into the dead tissue and eventually replaces it.
The cellular events in healing are orchestrated by a large number of cytokines. For example, epidermal growth factor (EGF), produced by epidermal cells around the damaged area, is important in stimulating regeneration of epithelial cells. Neovascularisation is triggered by fibroblast growth factor (FGF) and various endothelial growth factors, which are produced by macrophages. FGF and transforming growth factor beta (TGF-β), again derived from macrophages, and platelet-derived growth factor (PDGF) from platelets in the clot in the wound, are important mediators of fibroblast activity.


Over the course of a few weeks granulation tissue matures into a scar. This process is called fibrosis. The inflammatory cells gradually disappear and the amount of collagen in the matrix increases, with type III collagen being replaced by type I. The new blood vessels are remodelled and the (myo)fibroblasts reduce in number. The final result is a mature scar mainly composed of collagen-rich matrix and scattered residual fibroblasts supplied by a new circulation. After the scar has formed, its strength increases over subsequent months through increased cross-linking of collagen and increased collagen fibre diameter. The collagen fibres also align themselves along lines of stress. This remodelling of the scar requires the production of metalloproteinases, a family of enzymes that degrade collagen, by fibroblasts and other cells such as macrophages.
Scarring provides benefit by restoring the integrity of the damaged tissue but it may have significant complications. Scar tissue tends to contract with time and will not function in the same way as the original tissue. Examples of consequences arising from fibrosis include:

• cosmetic problems produced by unsightly scar tissue
• skin contractures following severe burns that can limit movement
• obstruction of tubular structures due to fibrous narrowing (stricture formation), e.g. duodenal obstruction following healing of a peptic ulcer
• heart failure due to impaired left ventricular function following myocardial infarction and scarring
• adhesion formation – adhesions are scars that stick serosal surfaces together; they can follow organisation of fibrinous exudates in serosal cavities (occasionally, peritoneal adhesions can cause bowel obstruction).

Examples of types of tissue healing

Skin wound healing

There are two pathways by which skin wounds are repaired, named primary and secondary union. Similar principles apply elsewhere in the body. A simple incised surgical wound will heal by primary union (also called healing by primary intention). This means that the clean edges of a wound once placed together (apposed) will heal quickly with minimal granulation tissue formation and thus minimal scarring (Figure 25A). There are several stages:

1. Blood escapes from damaged vessels and fills the gap.
2. Fibrin clot binds the edges together loosely and dries on the surface, forming a scab.
3. An acute inflammatory reaction develops around the wound in 24 hours and the exudate adds more fibrin, polymorphs and macrophages to the wound. These produce lytic enzymes which start to digest any clot and remove any debris from the wound site.
4. Epithelial cells start to regenerate and bridge the gap within 48 hours.
5. Fibrin in the wound provides stability so that blood vessels can regrow. Only a small amount of granulation tissue forms and the final scar will be thin and inconspicuous.
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