Wound healing

We all know (hopefully) that organisation and repair of acute inflammation lead to healing by a collagenous scar. Organisation is when the inflammatory exudate is replaced by granulation tissue and fibrous repair is when the granulation tissue is then replaced by fibrous scar tissue.

Healing of wounds (for example, when surgeons cut people open) is also achieved by organisation, repair and scar formation. Van de Graaff should have some introduction to wound healing somewhere and it might be best to have a look at that to get a general idea of what happens. This handout is primarily aimed at going through the steps of what happened to Ben's wound when it eventually got round to healing.

Ideally, healing of a surgical wound is when the edges are held closely together by suture material. The steps in a classic surgical wound healing scenario is given in the box below. Ben, however, had Pseudomonas aeruginosa to contend with, so the healing process didn't go exactly as planned.

 Classic Surgical Wound Scenario

The key feature is that there is only a narrow space between adjacent tissues with only a small bit of dead tissue at the edges of the wound.

On with the scenario:

Day 1	Neutrophils appear at the margins of the incision and there is an acute inflammatory response on each side of the narrow incisional space, leading to swelling, redness, and pain at the wound site. Epithelial cells at edge of wound undergo mitosis and begin to migrate across wound

Day 2	Macrophages begin to infiltrate the incisional space and eat the fibrin. Surface epithelial continuity is re-established in the form of a thin surface layer.

Day 3	Granulation tissue begins to invade tissue space. Surface epithelial continuity is reinforced by thickening of epithelial layer.

Day 5	Incisional space is filled with vascular granulation tissue with collagen being progressively deposited. Surface epithelium achieves normal thickness. The acute inflammatory response at the wound margins begin to subside (packs up and goes home), and swelling and redness of adjacent tissues is reduced.

Day 7	Sutures commonly removed from skin wounds. Wound has approximately 10% of tensile strength of normal skin.

Day 10	Further fibroblast proliferation and collagen deposition occur in granulation tissue in the incisional space, adding to strength of wound.

Day 15	Collagen deposition follows the lines of tissue stress. Granulation tissue loses some of its vascularity, but still appears pinker than adjacent tissues.

Day 30	Wound now has 50% of tensile strength of normal skin.

3 months	Wound achieves maximal 80% of tensile strength of normal skin. It now appears only marginally more vascular than adjacent skin. Complete blanching of scar takes several more months.

When the wound is rather big and messy with an extensive loss of cells (e.g. large surface ulcers or open wounds that cannot be sutured) a large tissue defect results, which has to be filled by granulation tissue.  There is going to be an intense inflammatory response at the edges of the wound, and because a large amount of granulation tissue is needed, it's going to take a long time.

The ultimate size of the collagenous scar is reduced by shrinkage of the healing wound (wound contraction). Myofibroblasts contract when the granulation tissue forms and this reduces the surface area of the open wound to 10% of its original size.

Healing by primary intention is the healing of closely opposed surfaces whereas healing by secondary intention is the healing of open wounds. The difference is mainly how much tissue you need to grow back to fill the gap rather than any mechanistic differences.

Factors that influence healing

	Nutrition : proteins, vitamin C and zinc are all required for collagen synthesis. Malnutrition can therefore inhibit wound healing (as we saw with Mr. Murray and Kelly)
	Ischaemia to tissue markedly impairs repair
	Infection of tissues (like with Ben) leads to continued tissue damage, promoting a continued acute inflammatory response. (Using the right antibiotics is therefore essential.)
	Steroids (glucocorticoids), from stress or drugs, inhibit granulation tissue formation and since they suppress the immune system too, local infections can spring up.
	If you zap the area with radiation, it won't heal as well
	Bits of foreign material and dead tissue can encourage infections and promote inflammation. (Doctors therefore take out necrotic material from large wounds to stop it festering etc...)
	Diabetics get a poor deal with wound healing - they are more prone to vascular disease and ischaemia plus they get infections more easily
	Ripping out, cutting or otherwise damaging the nerves of an area impairs healing

Final comments

	The molecular events that occur during this has (fortunately) not been fully sorted out yet, but if you really want to know something about all the little things that happen, then look in a pathology book. There you'll find details on platelet-derived growth factor, transforming growth factor, IL-1, tumour necrosis factor and chums. 
 
  A potentially boring fact
The molecular type of collagen secreted early on in granulation tissue formation is type III, which is later replaced by degradation and secretion of type I collagen.

	Scar tissue is very strong but it lacks flexibility and elasticity. This can cause problems with muscle injuries. It interferes with the muscle's ability to contract and can also mess with the normal excitation by the nervous system. Adhesions (e.g. during abdominal surgery) can connect adjacent organs together. If the intestines lose their normal mobility, it can lead to obstruction of flow through them.

	Granulation tissue grows from the edge towards the centre at rate of roughly 0.2 mm/day.

 Some other potentially boring facts
Neutrophils can do harm
	They can die before they finish the job and leave unkilled bacteria lying about
	They're messy eaters, known to regurgitate at times
	At migration to the site of inflammation, they can get overexcited and spill their contents