Mechanism of wound healing examined

Pascal Mallefet MD – Novartis Healthcare, UK Anthony C. Dweck FLS FRSC FRSH – Technical Editor

Wounds and skin damage are subjects of great importance to both the dermal pharmaceutical and skin care products industries – the two sectors, of course, focus on different levels of damage.

A wound occurs when the integrity of any tissue is compromised (e.g. skin breaks, muscle tears, burns are suffered, or a bone fractures). A wound may be caused as a result of a fall, a surgical procedure, an infectious disease, or an underlying condition.

Types and causes of wounds are wideranging, and healthcare professionals have several different ways of classifying them. They may be chronic, such as the skin ulcers caused by diabetes mellitus, or acute, such as a gunshot wound or animal bite.

Wounds may also be referred to as open, in which the skin has been compromised and underlying tissues are exposed, or closed, in which the skin has not been compromised, but trauma to underlying structures has occurred (e.g. a bruised rib or cerebral contusion).

Emergency personnel and first-aid workers generally place acute wounds in one of eight categories:
 


Wound healing

A skin trauma will start an organised and predictable sequence of events that has a cascade effect until the wound is bridged by scar tissue that binds and holds the wound in stasis.

The successful treatment is one that minimises the formation of scar tissue and reduces the amount of necrotic tissue that is produced during this process. The use of an hydrogel helps to produce a more rapid healing by creating a moist environment that reduces the build-up of necrotic tissue through the apoptosis of cells (cell death). The beneficial effects of a moist versus a dry wound environment include: prevention of tissue dehydration and cell death, accelerated angiogenesis, increased breakdown of dead tissue and fibrin, i.e. pericapillary fibrin cuffs, and potentiating the interaction of growth factors with their target cells. [Field et al].

The response to injury, either surgically or traumatically induced, is immediate, and the damaged tissue or wound then passes through phases in order to effect a final repair:


Physical barrier

The most important action to take in the case of any wound is to protect it from the external environment and apply some form of a dressing. The modern thinking is to keep wounds in a moist environment and a hydrogel is a perfect medium to apply.

Wound care should support the natural healing process; i.e. such care should provide a moist dressing / wound interface, absorb or remove excess exudate, provide thermal insulation, prevent contamination, and provide an environment conducive to the body’s natural defence mechanisms. Furthermore, dressings should cause little or no discomfort to the patient, and be able to remain in place for a number of days to facilitate the healing process and reduce the cost of care [Wijetunge].

Occlusion dressings can minimise necrotic tissue by preventing desiccation, aiding debridement, and providing a barrier against exogenous pathogenic organisms, thus limiting the resulting inflammatory cascade [Baxter].

The use of more moisture-retentive dressings generally achieves environments supportive of earlier healing outcomes when compared to less moisture-retentive dressings.

Maceration, an unwelcome occurrence with moisture-retentive dressing use on highly exuding wounds, is not consistently associated with increased adverse events. Evidence further suggests that greater dressing moisture retention is associated with fewer clinical infections, greater patient comfort, and reduced scarring. [Bolton et al.]. Concerns that moisture in wounds would increase the risk of clinical infection over traditional therapies are unfounded. [Field et al; Smith (2)].

Wounds will readily acquire bacteria unless protective measures are taken. The bacterial protection afforded by conventional absorbent cellulose dressings has been shown to be limited, particularly in the presence of serous exudate that may compromise dressing integrity. In addition, dressings may shed particles that remain in the wound. By contrast, many modern dressings are impermeable to bacteria, are removed completely, have been found to optimise re-epithelialisation rates, and reduce the incidence of wound sepsis. Further, the numbers of bacteria per litre of air following removal of the hydrocolloid dressing were approximately 20% of those observed for gauze [Lawrence].

The sense of touch is the name given to a network of nerve endings that reach just about every part of the body. These sensory nerve endings are located just below the skin and register light and heavy pressure on the skin and also differences in temperature. These nerve endings gather information and send it to the brain. A graze to the skin will likely remove both the stratum corneum and, in more severe cases, the underlying epidermis as well. This will almost certainly expose nerve endings in the skin and so heighten their sensitivity so that they become extremely sensitive.

The application of a hydrogel will provide a soothing barrier that insulates the wound against hot and cold stimuli and also will act as a cushion against external physical influences such as pressure and touch. (see Fig. 1)

The application of a hydrogel provides a cooling barrier that allows for water to evaporate from the surface and so produce a cooling effect. It is this cooling effect that helps to reduce the microcapillary circulation to the surface of the skin, so encouraging a reduction in erythema (skin redness), and that may lessen the build-up of oedema and so reduce swelling to allow a more even cicatrisation (wound healing) to develop at the site. This cooling effect will bring a soothing comfort [Smith et al]. Pain is significantly reduced when wounds are covered with an occlusive dressing. [Field et al; Metzger; Rheinecker]. Frequent dressing changes are time-consuming and sometimes painful, and, at the same time, patients are able to move freely and take showers, and nursing time spent on changing post-operative dressings is greatly reduced [Hulten et al.]. Dressings with large absorptive capacity reduce pain related to maceration of surrounding tissues and to pressure caused by the excess exudates [Ferrell & Coyle].

Inflammatory phase

The inflammatory phase prepares the area for healing and immobilises the wound by causing it to swell and become painful, so that movement becomes restricted. The fibroplastic phase rebuilds the structure, and then the remodelling phase provides the final form.

Tissues can heal at different rates, and even one wound can show various areas healing rapidly or slowly. The more rapid the healing process can be made, the better likelihood of a satisfactory outcome. The use of a moist healing environment such as that created by a hydrogel has been demonstrated to speed up the healing process when compared to a dry dressing scenario.

Scar quality is significantly superior in those wounds treated with a moist dressing [Atiyeh (2003) et al.]. Scar assessment scores demonstrated marked prevention of unfavourable scars with improved cosmetic results following prophylactic therapy with a moist hydrogel type dressing [Atiyeh (2002) et al.].

The rate of wound infections is not increased when occlusive dressings are used following surgery. Finally, occlusive dressings have also been found to reduce inflammation and subsequent scarring [Hulten et al.; Kerstein et al].

Inflammation is a normal and necessary prerequisite to healing. Changes in vascular flow are responsible for the clinical symptoms used to detect an inflammatory response. The majority of the specialised cells involved in this phase of the wound healing process come from blood.

Blood vessels that traversed the wound were severed at the time of injury and it was these cut vessels that allowed whole blood into the wound, which then coagulated, sealing off the injured vessels and lymphatic channels in order to close the wound and prevent further haemorrhage. The simultaneous release of histamine and other triggers by the injured tissue caused the intact vessels to dilate. Histamine causes brief vasodilation in neighbouring non-injured vessels and it is this combination of whole blood exudate and serous transudate that creates a reddened, hot, swollen and painful environment. Bradykinins, derived from plasma in the area of the injury, contribute to more prolonged vascular permeability. Prostaglandins are produced by all cells in the body and are released when there is any disruption of cell membrane integrity. Certain prostaglandins further contribute to long-term vascular vasodilation. The fibrin plugs that clotted in the wound to seal off leakage also formed in the lymphatic vessels. The blocking of the lymphatic flow not only seals off the wound, but also helps to stop the spread of any potential infection and the vessels remain closed until later in the healing process.

The mast cells also release hyaluronic acid and other proteoglycans into the cocktail of chemicals building within the wound and these bind with the watery wound, fluid to create a non-flowing gel that slows down leakage and fluid loss. The inflammatory oedema fills up all the spaces in the wound and surrounds all the damaged or repaired structures and binds them all together.

This type of oedema causes loss of dermal fat, thus thinning normal skin in the area. Some swelling in a wound is inevitable, and to a degree it is required for successful healing to occur, because if there is no inflammation then healing does not begin, and if too little inflammation occurs then healing may be slow. However, if too much inflammation occurs, then the likelihood of excessive scar is produced. This inflammatory fluid, derived from the blood, is high in fibrinogen. Fibrinogen coagulates in the wound and in the surrounding tissues that are now fluid filled. The coagulated fibrin will later mature into a dense, binding scar. The soluble protein fibrinogen circulates in the blood and provides the material from which the insoluble fibrin clot is formed during blood coagulation. Fibrinogen, as an acute phase reactant, responds to infection and other short-term inflammatory stressors.

Excessive swelling, therefore, must not be permitted. Primary wound care ensures that all blood vessels have been repaired, cauterised, or clotted. Haematomas, the result of ongoing bleeding in the wound, create extra exudate, a powerful stimulus to scar formation.

The application of a hydrogel provides a vehicle into which the exudates may migrate and dissolve, so taking them away from the wound site without drying out the wound and allowing the formation of potential scar tissue to be reduced. The use of hydrocolloid dressings facilitates granulation tissue formation. Also, the use of these dressings solves many of the practical problems associated with the traditional methods of keeping the metal plates, exposed bone, and tissues moist [Sochen].

Secondary wound care addresses the contribution made by induced vasodilation, which continues in relation to the severity of the wound. This serous transudate can be diminished by the classic “RICE” regimen of rest, ice, compression, and elevation.

Pharmacological use of steroids and aspirin affects the transudative oedema. Their action aids in inhibiting prostaglandin release. All wounds, and even controlled surgical procedures, require oedema care.

For healing to commence, two prerequisite events must occur:

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