The skin is the largest organ of the body and performs many functions

The skin is the largest organ of the body and performs many functions. Healthy skin provides a barrier against pressure, friction, chemicals, heat, cold, UV, radiation and micro organisms. In addition, the skin is essential for maintaining the body's fluid balance and providing thermoregulation, and communicates external stimuli to the body via touch, pressure, temperature and pain receptors. In addition, we externalise our emotional state through the skin: we blush, turn pale, our hair stands on end and we emit scents (pheromones).

The need to perform these numerous and diverse tasks accounts for the intricate structure of the skin. The skin is made up of three layers of tissue:

the epidermis (outermost layer) the dermis

the subcutaneous tissue.

Together, these layers form the body's outer covering.

EpidermisThe epidermis has an average thickness of only about 0.1 mm andit is normally composed of four different layers (Figure 3):

horny layer (stratum corneum)

granular layer (stratum granulosum)

prickle-cell layer (stratum spinosum)

basal layer (stratum basale).

Where exposure to friction is greatest, such as in the palms of the hands and soles of the feet, the epidermis has five layers. This extra layer is called the clear layer (straum lucidum), situated between the horny layer and the granular layer.

Dermis

The dermis is the layer that gives the skin its tensile strength and elasticity. These characteristics are derived from the high proportion of loosely interwoven connective tissue fibres (collagen and elastin). Histologically, two layers are distinguished:

the papillary layer (stratum papillare)

the reticular layer (stratum reticulare).

The dermis is firmly intermeshed with the epidermis via the connective tissue papillae of the papillary layer. These papillae are interspersed with fine capillary loops, which provide the nutrient supply of the epidermis. The papillary layer also contains numerous free nerve endings branching into the epidermis as well as heat, cold and touch receptors (Meissner's cells).

The free connective tissue cells comprise fibroblasts, macrophages, mast cells, lymphocytes, plasma cells, eosinophils and monocytes. The free space between the cellular and fibrous elements is filled with a gelatinous fluid in which the cells are able to move freely. The mobile fibroblasts differentiate into fibrocytes, which link via elongated processes to form a three-dimensional network. These fibrocytes synthesise components of the intercellular fluid (eg hyaluronic acid) as well as collagen and elastin fibres, which are interspersed within the network of cells. The other free cells of the connective tissue are components of the endogenous defence system and play a major role in inflammation and in the immune regulation of the skin.

The reticular layer (stratum reticulare) contains fewer free cells than the papillary layer. The collagen fibres within this layer form a dense network running parallel to the body surface. Between this collagen mesh, the fibres of the elastin connective tissue branch out, giving the skin its extensibility. The direction ofmaximum extensibility is indicated by Langer's lines. This is why incisions made perpendicular to these lines cause gaping wounds. In surgical operations, therefore, incisions should be made along these lines wherever possible to improve the cosmetic result.

Special modifications of the skin, the hair follicles, sebaceous, sweat and scent glands, are embedded in the dermis.

Subcutaneous tissue layer

The dermis merges into the subcutaneous tissue layer without a clear boundary. The loose connective tissue of the subcutaneous layer is interspersed with many of the firm fibres of the dermis, which anchor the skin to the underlying structures, eg the fascia or periosteum. If these retaining bands arefew in numberthe skin moves on its substrate to create a skinfold. For example, on the soles of the feet or the scalp the skin is almost immovable since the fibrous bands are highly developed and numerous.

The entire subcutaneous tissue layer contains pads of fat, which are either readily mobilisable fat stores or non-mobilisable, structural fatty cushions providing insulation against heat loss, and reducing pressure on underlying structures.

Below the subcutaneous tissue layer is the general fascia.Below thatdepending upon the part of the body, there is muscle, fat, bone or cartilage (Figure 5).

Blood Composition

As well as supplying the organs and tissues with oxygen and nutrients and transporting endogenous messenger substances and enzymes, the blood has two further important tasks associated with wound healing; it contains cells of the defence system that recognise and remove foreign particles which have invaded the body and, in addition, the blood contains components of the coagulation system that seal leaks resulting from injury.

Dissolved componentsBlood plasma is a slightly yellowish fluid containing 90% water. Dissolved in it are many proteins (7-8%) such as albumins, which are responsible for maintaining the osmotic pressure in the blood and act as transport proteins for water-insoluble materials and globulins that play a role as antibodies (eg IgG, IgA, IgM) in humoral immunity. The plasma also contains:

nutrients (proteins, fats, sugars)

inorganic salts

metabolic waste products (especially urea)

enzymes

hormones

Fibrinogen is a component of plasma essential for blood coagulation. It is a 2-globulin that is normally present at a concentration of 2-4 g/l.

Cellular componentsErythrocytesBlood cells make up about 45% of the blood. Erythrocytes (red blood cells), which contain haemoglobin, are the most numerous at 4-5 million/l. They take the form of a flat, biconcave disk with a diameter of 7-8 m (1 m = 1/1000 mm), are non-nucleated and very flexible.

Red blood cells contain haemoglobin and are responsible for oxygen and CO2 transport. They are produced in the bone marrow and are broken down in the spleen and liver. They have a lifetime of about 120 days.

LeucocytesLeucocytes (also known as white blood cells) are present in the blood in much smaller numbers, 4000 - 11000 /l. Their diameter is more than twice that of the erythrocytes. White blood cells always have a nucleus and exhibit amoeboid movement. They are produced in the bone marrow and mature in the different lymphatic organs (spleen, lymph nodes, tonsils, bone marrow, thymus) into cells with a variety of functions and structural appearance.

Non-specific defence is provided by cells referred to as phagocytes. These cells can recognise,engulf and digest foreign organisms such as fungi, bacteria and viruses. They include:

granulocytes

mononuclear phagocytes or monocytes.

Granulocytes (11-14 m) (also known as polymorphonuclear leucocytes) are the most numerous phagocytic cell type. They circulate in the blood and derive their name from their granular cell inclusion (granulae) easily recognisable under a light microscope. When foreign organisms invade the body, granulocytes leave the blood capillaries, migrate into the affected area and eliminate the invader by phagocytosis.

The mononuclear phagocytes are also involved in the general defence activities. Depending upon their localisation, we distinguish between monocytes (in the blood) and macrophages (in the tissue). Macrophages, as their name suggests, are the largest phagocytic cells with a diameter of 12-20 m. As well asdestroying invading microorganisms they also removedegenerating orageing endogenous tissue.

A more specific and developed form of the general defence system (specific immunity) is provided by the lymphocytes. These are specific defence cells since they possess on their cell membrane, structures allowing them to recognise specific pathogens (antigens), which they eliminate rapidly, and selectively, after contact.

Stem cells of the lymphocytes, like those of other leucocytes, are produced in the bone marrow. During embryonic development they migrate into the lymphatic organs. Here they mature to produce two different types of lymphocytes:

T-lymphocytes

B-lymphocytes

The maturation of the T-lymphocytes depends on the thymus gland (thus the name T-lymphocyte). Here they differentiate further into the following agents of cell-mediated defence:

killer cells, which release toxins, cytolytic enzymes orcomplement factors and thereby selectively destroy invading pathogens

helper cells which, after contact with the antigen, assist the production of antibodies in the B-lymphocytes and activate phagocytic cells byemitting chemotactic agents

supressor cells that inhibit the activity of other lymphocytes and thereby regulate the immune response.

B-lymphocytes mature in the lymphatic tissue of the intestine and liver. In birds, this function is performed by a rectal gland, the bursa of Fabricius, hence the name B-lymphocyte. B-lymphocytes have specific antigen receptors on their cell surface and in the event of infection can transform into memory cells (large plasma cells) after stimulation by the respective antigen. These cells constitute the immunological memory since they "memorise" the antigen and, in the event of a repeat infection, immediately trigger the appropriate immune response. Plasma cellsproduce an antibody which is releasedinto the blood. Here they bind to their target antigen and either render it harmless directly or "mark" it for destruction by the phagocytic cells.

The platelets, (150,000 - 450,000 /l) are not cells in the true sense. The non-nucleated disk-shaped platelets have a diameter of 2-3.5 m. They can clump together, ie aggregate, in response to specific stimuli.

Once platelets have aggregated, platelet factors are released and these initiate blood coagulation.

Module 2

A wound is generally defined as a pathological state in which tissues are separated from each other and/or destroyed. This event is associated with a loss of substance and impairment of function.

Wounds can occur in all tissues of the body but most often affect the skin. The term "wound" is most frequently used to describe damage of the body's outer covering, whereas the term injury tends to be used more for damage to internal organs. Wounds heal by the same biochemical mechanisms in all tissues. Wounds to the skin and their healing are described below as examples.

Regeneration versus repairThe body naturally attempts to close a wound and restore the functions of the damaged tissue as quickly as possible. All tissues of the body are capable of wound healing with the sole exception of the teeth. The original state can be restored by two different mechanisms: regeneration or repair.

Physiology of wound healingHow does the body respond to a bleeding skin wound? Two main problems first have to be solved: the invasion of infectiousorganisms must be halted and bleeding stopped. Once this has been accomplished, foreign bodies and tissue detritus have to be broken down and new tissue produced. In simplified terms, the processes involved can be divided into four phases:

vascular response

blood coagulation

inflammation

formation of new tissue.

These phases overlap and are to some extent interdependent.

Vascular responseA fresh wound usually bleeds rather profusely if cutaneous and deeper lying vessels are damaged. The bleeding has the effect of cleansing the wound as the blood washes foreign bodies and organismsaway.

To prevent further blood loss, the affected vessels narrow within a few minutes of the injury occurring. This vasoconstriction lasts for only a few minutes, however, long enough for the leaks to be sealed by blood clots. The ends of the vessels also turn inwards.

Vasoconstriction is followed by widening of the vessels, reaching a maximum after about 10 minutes.

The vasodilation increases the blood circulation in the wound area. This causes an increasedproduction of heat and an associated rise in the temperature of the skin around the wound. In this phase, the permeability of the capillary walls to components of the blood is increased. As a result, blood constituents such as erythrocytes, leucocytes and plateletsenter the wound. Furthermore, the increased capillary pressure associated with vasodilation allows increased amounts of blood plasma to escape into the interstitium.

Finally, vascular stasis (stoppage) occurs and persists for several hours. The oxygen deficiency in the tissue causes the CO2 pressure to rise, and consequently the pH falls into the acidic range. This acidosis causes a charge reversal of the chemical components in the connective tissue. As a result, the collagen components depolymerise and lose their capacity to bind water. The accumulation of fluid - especially the plasma - within the wound causes swelling of the collagen fibres. The outcome of all these processes, ie the intensified blood flow, the increased leakage of blood from the capillaries and the accumulation of fluid in the tissue, is wound oedema.

Obviously, these vascular responses do not take place in an uncoordinated manner. They are controlled by a number of substances. Platelets adhering to the damaged vessels release thromboxane A2, which causes vasoconstriction. The tissue hormones, histamine and serotonin that are released by the mast cells present in the connective tissue and especially in the vicinity of small vessels stimulate the dilation of the capillaries. They also cause the endothelial cells in the vessels to move apart, thereby increasing their permeability to blood components.

Mast cells are in turn stimulated to release histamine and serotonin by other substances in the wound area released from various cells and the blood plasma. These mediators include the complement factors in the blood serum. Complement factors are made up of about 209 proteins, which are involved in the defence against foreign bodies. Other mediators are the prostaglandins (eg PGF2a); these hormone-like substances are particularly important for the inflammation process.

RegenerationThis refers to the tissue-specific replacement of a lost part of the body or organ. The animal kingdom contains many examples of this process, for example, the regeneration of a complete earthworm from the anterior segments of its body or the complete replacement of a severed extremity in the salamander. Among mammals, and especially in man, complete regeneration is only possible in epithelial tissue (epidermis, mucous membranes of the gastrointestinal tract and the female genitals) and is only possible to a limited degree in parenchymatous organs such as the liver.

Thus, in man, tissue defects are remedied mainly by repair. In this process, lost or damaged tissue is replaced by unspecific elements of connective and supportive tissue, which form a scar. Only defects in supporting tissue, for example in bones, cartilage and tendons, are regenerated with the typical structure of the tissue.

Wound healing can therefore be defined as the closure of a defect by scar-forming supporting tissue associated with epithelial regeneration, ie epithelialisation. Its aim is to restore the form and functions of the damaged tissue.

Blood coagulationA fresh wound rapidly fills with blood, which coagulates andtemporarily closes the defect (Figure 3). The scab formed protects the wound, reducing the risk of infection and dehydration.

Provisional wound closure by scab formation.Damage to the skin results in the wound rapidly filling with blood. A process called coagulation (clotting) then occurs which involves a large number of chemical reactions resulting in a 'scab' (eschar), which provisionally closes the defect.

Underlying this process of blood coagulation are complicated biochemical reactions involving various factors:

the blood vessel walls

the platelets

damaged connective tissue cells

the coagulation system.

Coagulation begins both in the opened vessels and in the wound gap. It starts when cells are damaged, as these release certain substances (mediators) that activate the biochemical reactions necessary for blood clot formation.

When a vessel wall is damaged, blood platelets - stimulated by mediators such as Von Willebrand factor- immediately adhere to the exposed collagen of the vessel wall. In this activated state, the platelets first change their form and change from flat, discs to spherical structures with long extended processes known as pseudopods. These activated platelets also release a number of substances that induce further reactions (the coagulation "cascade"). At first, even more platelets from the blood adhere to those that are already adhering to form a clot.

This process is known as platelet aggregation (Figure 4). It is initiated by adenosine diphosphate (ADP), thromboxane A2 and platelet activating factor (PAF) released from the activated platelets.

The clustered platelets partially coalesce with each other and release the platelet factors that initiate the actual clotting process. During the clotting process a fine line network of fibrin forms around the platelet plug and finally fills the entire wound gap. The purpose of this fibrin network is to "catch" erythrocytes and other solid components of the blood, retain them and thereby form a clot that provisionally seals the wound against the external environment and stops the bleeding. Its surface rapidly dries in the air and a dense, protective scab forms.

Flowing blood understandably contains no solid fibrin, only its water-soluble precursor, fibrinogen. Fibrinogen is only converted to fibrin at the wound surface, by the enzyme thrombin. This is also present in the blood as an inactive precursor called prothrombin. Prothrombin and fibrinogen are among the coagulation factors whose biochemical interaction ultimately leads to the formation of the blood clot. The clotting factors are distinguished by Roman numerals; fibrinogen (I) and prothrombin (II) are part of what is referred to as the coagulation cascade, a complex chain reaction, which is set in motion by injury.

Coagulation is initiated firstly by the platelet factors released from the adhering platelets, and secondly by substances liberated from damaged tissue cells. These thromboplastins activate the conversion of prothrombin into thrombin with the involvement of various other coagulation factors and calcium ions. Thrombin is now able to convert the water-soluble fibrinogen present in the blood into fibrin monomers. These polymerise spontaneously to fibrin chains, which are finally interlinked by coagulation factor XIII to form the stable fibrin mesh.

Fibrinogen, prothrombin and the other coagulation factors are formed in the liver. The synthesis of prothrombin and three other factors is vitamin K dependant. This is why vitamin K deficiency leads to disturbances of blood coagulation. On the other hand, this dependence can also be utilised therapeutically eg for thrombosis or infarction prophylaxis: vitamin K antagonists (eg coumarin derivatives) are administered to prolong the coagulation time, leading to a fall in prothrombin level and delayed clot formation.

Inhibitors of the coagulation factors present in the blood ensure that coagulation is restricted to the wound area in the event of injury. They inactivate the thrombin molecules entering the circulation. The most important of these inhibitors is antithrombin III.

InflammationThe substances released from the cell debris resulting from tissue destruction are responsible for causing the characteristic inflammatory reactions. The vascular changes previously described also contribute to this reaction. They create the preconditions for the body's inflammation:

redness (rubor)

heat (calor)

swelling (tumour)

pain (dolor)

functional disturbance (functio laesa).

Inflammation is not the same as infectionRedness and heat are consequences of the increased blood flow in the wound area, causing an influx of immune defence cells into the site of injury (Figure 5).

Wound Oedema. This photograph of oedema, after the skin has sustained a bleeding wound, displays the classic signs of the inflammatory process ie redness (rubor), swelling (tumour) and functional disturbance (functio laesa) with associated heat (calor) and pain (dolor).

The swelling or wound oedema results from collections of fluid in the soft tissue. These accumulations of fluid in the tissue exert increased pressure on the small nerves, and nerve endings, causing the wound to hurt. The pain, in turn, causes the inflamed part of the body to assume a protective posture. This and the disturbed physiological processes account for the functional disturbance of the injured organ.

The inflammatory reaction is induced independently of invasion by foreign organisms, and therefore "sterile" inflammations can also develop in closed injuries, for example bruises in which the skin remains intact. Open skin wounds are usually contaminated. Even in surgical wounds, the invasion by millions of microorganisms cannot be prevented even under the strictest sterile conditions. In such cases infection can develop initiating both the cellular and humoral immune responses.

Non-specific immune defenceIn the inflammatory phase, the number of white blood cells increases, manifested as leucocytosis in the blood count. The defence cells migrate from the blood vessels that have become permeable into the wound area. They are attracted by complement factors, which are part of the nonspecific defence system. These are proteins present in the blood serum in an inactive form, which are activated by invading pathogens. The presence of pathogens initiates what is known as the complement cascade; complement factors become active and in turn activate other components of the pathway finally resulting in a complement 'attack complex', which either destroys the microorganisms directly or prepares them for destruction by other defence cells (opsonisation). The activated complement factors also produce attractants (chemotaxins), which draw wandering phagocytes into the injured area.

First to appear at the site of inflammation are a type of granulocyte called neutrophils. These have the capacity to phagocytose (engulf and digest) foreign bodies. They also release enzymes that break down degenerating connective tissue (collagenases, elastase). Soon afterwards, monocytes arrive on the scene, attracted by chemoattractants released by aggregating platelets; platelet derived growth factor (PDGF) and transforming growth factor- (TGF-). Both of these growth factors stimulate the growth of new tissue. Monocytes are also capable of phagocytosis and once they have ingested foreign bodies they transform into macrophages. Macrophages produce a large number of substances, which act as mediators of other wound healing processes and attract further phagocytic cells to the wound area for example:

growth factors TGF- a, TGF- (transforming growth factor alpha and beta), TNF-a (tumour necrosis factor alpha) and FGF (fibroblast growth factor) that promote vascular and connective tissue neogenesis

prostaglandins that sustain the inflammatory process and influence vascular dilation

complement factors C1-C5 responsible for non-specific defence

interleukin-1 which induces fever and attracts further neutrophil granulocytes.

Macrophages also release enzymes, which can destroy tissues. Necrotic tissue and dead phagocytic cells filled with foreign bodies form 'pus', which surrounds the wound.

Specific immune defenseIn addition to the nonspecific immune defence provided by the complement system and phagocytes, the body is also capable of mounting a specific, targeted defence against a particular pathogen. It does this by producing substances called antibodies. Antibodies are synthesised by B-lymphocytes in response to a specific foreign bodies (antigen) and released into the blood.

Antibodies are proteins, which belong to a chemical class known as globulins and are therefore referred to as immunoglobulins. They have the ability to bind specific antigens to form antigen-antibody complexes, thereby rendering them harmless.Immunoglobulins are divided into subgroups depending on their structure and size: IgG, IgA, IgM, IgD and IgE. These different subgroups have different functions; for example IgM antibodies are specifically directed against viruses while IgE antibodies are involved in allergic reactions.

Immunoglobulins circulate freely in the serum component of the blood. If they meet their corresponding antigen, for example in a wound, they bind it and either inactivate it directly or mark it for destruction by phagocytes.

B-lymphocytes continually produce antigen specific antibodies over a period of years and often for a lifetime, resulting in the production of 'memory cells'. If the same microorganism enters the body again at some later stage, the memory cells divide with great rapidity. The newly formed B-lymphocytes transform into plasma cells and synthesise large amounts of this specific antibody to eliminate the invaders rapidly and effectively. In this way, immunity against the respective pathogen is created.This mechanism is utilised in inoculation: by non-hazardous contact with attenuated or killed pathogens the B-lymphocytes are stimulated to produce corresponding antibodies which protect the inoculated person from an outbreak of the infectious disease on renewed contact.

Other immunocompetant cells involved in specific defence are the T-lymphocytes. These differ from the B-lymphocytes in that they do not produce antibodies but, as 'killer cells', identify and selectively destroy foreign cells. This is done through direct cell contact or by release of cell toxins, complement factors or hydrolytic enzymes. As with the B-lymphocytes, certain killer cells specialise in specific pathogens, which they are able to identify by their surface properties. Here too there are memory cells that provide large numbers of specialised T-lymphocytes for defence in the event of antigen contact.

T-lymphocytes, differentiated into helper cells assist the maturation of the B-lymphocytes into plasma cells and promote their antibody production. A further T-lymphocyte subclass, the suppressor cells, regulate the action of the T-helper cells and B-lymphocytes and thereby prevent an excessive immune response.

To summarise, the inflammatory phase of wound healing is characterised by an influx of granulocytes, macrophages and lymphocytes that absorb and enzymatically degrade foreign matter and tissue detritus and thereby clean the wound. An inflammatory reaction is also induced irrespective of whether an infection is present, for example in all closed injuries such as bruises and contusions.

Whereas catabolic processes predominate in inflammation, the next phase of wound healing is characterised mainly by repair ie anabolic reactions.

Formation of new tissueThe cleansed wound, provisionally sealed by a scab, can now be covered by new tissue. Various preconditions for this have already been created:

mediators and growth factors released from different cells in the wound area (eg TNF-a and TGF-a) activate the vascularisation ie the formation of new blood vessels

blood platelets and macrophages release growth factors (TGF- and PDGF) that stimulate the production and influx of fibroblasts

the fibrin network acts as a guide structure for the cells moving into the wound area.

VascularisationThe precondition for favourable wound healing is the presence of sufficient blood circulation. This is why new blood vessels begin to grow into the wound only three days after an injury. The vascular buds are formed by existing intact vessels. Stimulated by growth factors and other substances released in the wound, the endothelial cells in the venules begin to produce enzymes that break down the basal membrane in the area of the stimulus. Endothelial cells then migrate through the resulting gap in the direction of the wound. They divide and form tubular structures that connect with other buds. During the maturation process a new basal membrane develops from the extracellular matrix components. The newly formed vascular loops then connect with intact vessels and differentiate accordingly into arterioles or venules. Superfluous vessels are broken down again.

Formation of new connective tissueParallel to vascularisation and also proceeding from the wound margins, new tissue is formed. Fibroblasts, attracted chemotactically, migrate along the fibrin network and divide at a rapid rate. They produce the connective tissue ground substance consisting of proteoglycans (protein network with carbohydrate side chains) as well as the water-soluble collagen fibres essential for tissue stability.

Collagen is a fibrous protein synthesised in several stages. Its precursors are assembled from amino acids in the endoplasmic reticulum of the fibroblast.

These protocollagen chains are twisted together in threes, in helical formation and then transferred to the Golgi complex. Here the chains are re-arranged slightly and interlinked more closely. Golgi vesicles finally transport the molecules to the cell membrane where they are released as soluble tropocollagen into the intercellular space. Here the tropocollagen molecules accumulate to form protofibrils, which then polymerise into microfibrils. Several microfibrils unite to form a collagen fibril, several of which, in turn, arrange themselves into bundles. In healthy tissue the collagen fibres are aligned in certain patterns following the main contours of tension of the skin. This organised structure is not achieved in wound healing, however, which is why the collagen fibres in scar tissue have a disorganised appearance.

Collagen synthesis is dependent on the presence of vitamin C (ascorbic acid), which acts as a coenzyme; further cofactors are iron and copper. If there is a deficiency of these substances, satisfactory wound healing is not possible.

GranulationNew highly vascularised tissue grows in from the wound margins in the manner described. Because of its granulated appearance it is known as granulation tissue and is visible to the naked eye as pin-head-sized rounded nodules of tissue in the wound bed (Figure 7). The granulation tissue is essential for permanent wound closure since it fills out defects and prepares the way for epithelialisation.

Granulation tissue: pin-head sized, dark red fleshy nodules of tissue on the wound bed make up the new, highly vascularised tissue that fills the defect and creates the preconditions for epithelialisation.

The appearance of the granulation tissue gives an indication of how the wound will be healing. Healthy granulations have a granular appearance, are moist and shiny, hyperaemic and have a dark red colour. Poor healing can be expected however, if the granulation tissue is smooth, covered with smeary fibrin deposits, soft, pale or shows a bluish discolouration.

FibrinolysisAt the same rate as the fresh, highly vascularised connective tissue develops, the provisional fibrin network is broken down and the closed vessels are recanalised. This breakdown process is known as fibrinolysis and is caused by the enzyme plasmin. Plasmin is present in the blood in the form of an inactive precursor, plasminogen. This, like prothrombin, is activated by a number of substances released from damaged cells. The most important of these is tissue plasminogen activator, t-PA.

The activators of fibrinolysis most widely used for therapeutic purposes are streptokinase and urokinase, which are administered to dissolve life-threatening blood clots in the coronary arteries of heart attack patients.

ContractionWith the formation of new fibres, the mitotic activity of the fibroblasts is concluded. They then transform either into fibroblasts or myofibroblasts. Myofibroblasts, like the muscle cells, contain contractile elements, which allow them to draw together (Figure 8). The collagen fibres become taut and, as far as possible, aligned to the main contours of tension in the tissue. As a result, the scar tissue shrinks and the functional cutaneous tissue at the wound margin contracts leaving only a small defect.

This extensive wound after melanoma excision on the thigh cannot undergo primary closure by surgical means because of its extent and depth. It heals by secondary intention and closes mainly by formation of new tissue and contraction. Subsequent coverage by skin grafting was not performed at the patient's request.

EpithelialisationAt the end of the wound healing process the surface of the wound is closed by epithelialisation. The preconditions for this are an increased rate of cell division in the basal layer of the epidermis and migration of the epithelial cells, which move towards each other from the wound margins until the defect is covered by a fine skin. New epithelial cells are also formed by the appendages of the skin ie the hair follicles, sebaceous glands and sweat glands.

The mechanisms underlying this cell migration are still largely unknown. Migration requires the presence of a moist substrate, well perfused with blood, as is the case with granulation tissue. If this migratory layer becomes dehydrated, the epithelial cells cannot travel. Recent experiments suggest that the glycoproteins, fibronectin and vitronectin serve as a substrate across which the cells are able to move. However, the way in which epithelial cells are stimulated to migrate in a specific direction and how the reorganisation of the cell network necessary for this motion is induced is still unknown.

Scar formationDue to the repair and regeneration processes, the wound margins are bridged over by connective tissue and a scar is formed. At first it is still elevated above the level of the skin and has a reddish colour. With time, however, the connective tissue grows tauter and the vascularisation decreases. As a result, the scar becomes slightly recessed and turns pale. Since the pigment producing cells, the melanocytes, cannot be regenerated, the scar tissue does not turn brown but remains white. Its surface is more or less smooth, since the ridged and tessellated pattern of the epidermis is not restored. This tissue contains no hairs, sebaceous or sweat glands.

RemodellingThe process of remodeling is the reorganisation of the scar tissue and is the longest phase of wound healing, and can continue for up to 20 years after an injury. It consists mainly of restructuring of the collagen fibres, which are partially broken down again by enzymes contained in the tissue (collagenases) or newly cross-linked.

Remodelling can be influenced to a certain extent by external factors. For example, the application of compression bandages can reduce scar formation and so provide a better cosmetic result.

Time Course of Wound HealingAs already mentioned, the individual processes of wound healing do not occur one after the other but overlap to varying degrees:

the vascular response begins only seconds after the injury, reaches its peak after three to seven days, and then slowly subsides

blood coagulation also begins immediately after the injury. The fibrin network is formed within 24 hours

the peak of the inflammatory processes, initiated immediately after the injury, is reached between the third and fifth day. These events are normally complete after 14 days

the formation of new connective tissue starts after only 10 to 12 hours, and reaches its peak after 6 to 16 days. The mechanical strength of the scar ie its tearing resistance, increases parallel to the collagen content. It reaches its maximum after 12 to 15 days. However, only about 80% of the strength of normal healthy tissue is restored. The scar may take several years to become fully differentiated.

epithelialisation of superficial wounds occurs within the first 24 hours and is generally complete after 12 days. In the case of deeper, more extensive wounds however, it only starts after new connective tissue has formed and takes correspondingly longer.

Module 3

Chronic wounds are often indicative of a serious long term condition in a patient. They have a complex nature, and, unlike acute wounds, do not undergo the ordered molecular and cellular processes of normal tissue repair (inflammation, proliferation, re-epithelialization and remodelling.) Wounds may remain stuck in the inflammatory phase, for example, or specific cells will become senescent, preventing healing.

Wound bed preparation, a new paradigm in wound care, is a concept that has developed current practice for the treatment of chronic wounds by removing the barriers to healing. These barriers have recently been defined as 4 clinical observations within the wound: Non viable tissue (T), infection or inflammation (I), moisture imbalance (M), and a non advancing wound edge (E). The goal of wound bed preparation is to accelerate endogenous healing and facilitate the effectiveness of other therapeutic measures; in other words, to create a viable wound bed where healing can take place.

Wound Bed Preparation was developed in 2000 by Drs Vincent Falanga and Gary Sibbald as a means of preparing the chronic wound to accept advanced wound healing therapies.

Many nurses and other healthcare professionals have now adopted this concept and are using it successfully to further develop their clinical practice. Wound bed preparation is still evolving, but initial definitions are cited below.

Wound bed preparation is defined as the management of wounds to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures. Falanga V. Wound bed preparation and the role of enzymes: a case for multiple actions of therapeutic agents. Wounds: A Compendium of Clinical Research and Practice; 14(2);2002.

Dr. Gary Sibbald has also cited wound bed preparation as a changing paradigm that links treatment of the cause and focuses on three components of local wound care: debridement, wound-friendly moist interactive dressings and bacterial balance. Sibbald RG et al, Preparing the wound bed debridement, bacterial balance and moisture balance Ostomy Wound Management; 46(11):2000.

This module begins with an overview of wound healing, explaining the processes involved in the acute wound model and comparing these to the processes that take place in chronic wounds. The components of wound bed preparation (represented by the acronym T.I.M.E, mentioned above) are then explained, together with a discussion of cellular dysfunction and biochemical imbalance, which contribute to the damaging microenvironment in the chronic wound bed.

A wound is only likely to heal when the right cellular and molecular mechanisms are in place to promote the healing process. Chronic wounds are less likely to heal, even with sophisticated wound management products, if the wound bed is not prepared properly.

The first step in wound management is to assess the patient as a whole, identify any underlying causes (pathogenic abnormalities) and consider the patients overall physical condition.

Next, the wound must be carefully evaluated, before any treatment is undertaken, and regularly thereafter, until healing is achieved. Constant attention to the appearance and condition of the wound bed will prepare the wound for healing.

Proper wound bed preparation and evaluation are essential components of wound care. This is especially true with chronic wounds, where signs of delayed healing or underlying infection may be atypical and, therefore, easily overlooked.

In wound care it is important to identify all the potential barriers to wound closure. There are a number of systemic factors that should be considered.

Age as we age the density of collagen decreases, fewer fibroblasts and mast cells are produced and elastin fibres begin to fragment

Body build body size is important, and both obese and thin people are at risk of pressure ulcer development and impaired healing

Stress psychological stress, pain and noise are major factors and the accepted mechanism is thought to be stimulation of the sympathetic nervous system and the outflow of vasoactive substances causing vasoconstriction

Nutrition impaired wound healing is usually associated with protein-calorie malnutrition as opposed to a single depleted nutrient

Medication various medications have the potential to effect healing, but the ones most noted are steroids. This is attributed to the anti-inflammatory action of steroids which may interrupt the inflammatory phase of wound repair

Tissue oxygenation the deposition of collagen and phagocytic activity of white blood cells is hindered if the oxygen levels in the tissue are inadequate

Concomitant Disease conditions such as diabetes, renal failure, peripheral vascular disease and autoimmune disease can have a significant impact on the patients healing process

Normal wound healing

Normal wound healing (which applies to acute wounds) starts as soon as an injury involving blood vessel damage occurs. Essentially there are four main healing phases (outlined below), when several molecular and cellular processes are initiated. There is significant overlap between activities in these phases.

HemostasisIn the minutes following acute injury, clot formation and platelet aggregation occurs. Once aggregated, platelets degranulate releasing several growth factors; platelet-derived growth factor (PDGF), insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF) and transforming growth factor beta (TGF-).

InflammationIn the first 2-3 days post-injury, inflammatory cells (neutrophils and macrophages) are drawn into the injured area (chemotactic migration) where they engulf and destroy bacteria and debris by phagocytosis. Neutrophils release proteases, which break down damaged extracellular matrix (ECM) components in a process called proteolysis. Activated macrophages release growth factors, which stimulate fibroblasts, epithelial cells and endothelial cells. In addition, macrophages release a controlled amount of the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-) and interleukin-1 beta (IL-1), which stimulate endothelial cells to express cell adhesion molecules (CAMs). CAMs are cell surface proteins which enable inflammatory cells to enter the tissues. IL-1 also draws fibroblasts into the wound and up-regulates matrix metalloproteinase (MMP) enzyme levels. Importantly, there is a balance between levels of MMPs and tissue inhibitors of metalloproteinases (TIMPs). TIMPs bind to MMPs and cause them to become inactive.

ProliferationPlatelets and macrophages release growth factors, such as TGF- and PDGF, which activate the formation of new blood vessels (vascularisation or angiogenesis). In addition, the pro-inflammatory cytokines TNF- and IL-1 and growth factors released by activated macrophages induce fibroblasts to produce collagen. In the healing wound bed there is a high level of mitogenic activity. Blood vessel repair (angiogenesis) and granulation tissue formation occur over several weeks.

Epithelialisation, scar formation and remodelling New tissue formation is followed by epithelialisation; increased cell division in the basal layer of the epidermis results in the wound being covered by a fine layer of skin. A scar is formed when the wound margins are bridged over by connective tissue. The last phase in wound healing is remodelling which involves scar tissue reorganisation by restructuring of collagen fibres. Collagen fibres in the scar are reorganized to improve tensile strength. This final healing phase may take several years. Wound healing occurs in a cascade of events.

The following model has been hypothesised to explain the key events that occur in chronic wounds, although there is still much that is not fully understood. A chronic wound differs from an acute normal-healing wound because it has a persistent pro-inflammatory stimulus, often caused by one or several of the following factors (Mast BA and Schultz GS 1996):

repetitive trauma

local tissue ischaemia

necrotic tissue

heavy bacterial burden

tissue breakdown.

Inflammatory cells (neutrophils and macrophages) are drawn to the wound bed. In chronic wounds the controlled stimulation of inflammatory cytokines is disrupted. This leads to an elevated secretion of TNF- and IL-1, which causes an increase in MMP production and reduced synthesis of TIMPs. Elevated levels of MMPs cause degradation of extracellular matrix, resulting in impaired cell migration and connective tissue deposition. Furthermore, MMPs degrade growth factors and their target cell receptors.

These processes prevent a wound from entering the proliferative phase of healing, and continue the vicious cycle of the chronic wound.

Biochemical differences between healing wounds and chronic ulcersNormal Acute

Chronic Wound

In healing wounds, there is a high level of mitogenic activity. Fluids collected from acute mastectomy wounds were found to stimulate DNA synthesis when added to cell cultures (Schultz GS and Mast B, 1998). Conversely, fluids collected from chronic venous leg ulcers did not stimulate DNA.

Distinct differences in cytokine environments between wound types. In a healing wound there is a balance of pro-inflammatory cytokines and their natural inhibitors. In chronic wounds, the balance is disrupted and the levels of pro-inflammatory cytokines increase.

Pro-inflammatory cytokines influence MMP levels. In healing wounds MMPs and TIMPs are in equilibrium, but MMP levels are significantly higher in chronic wounds. High MMP levels also degrade various growth factors.

What is wound bed preparation?

Wound bed preparation has been defined as the process of removing the barriers to the healing. Removal of these barriers is thought to allow the wound repair process to progress normally. Wound bed preparation represents a combination of both scientific knowledge and practical skill; its application can help correct abnormalities in chronic wounds and stimulate the healing process (Schultz, Sibbald, Falanga et al 2003). Wound bed preparation addresses the following four clinical observations listed below: and can be summarized by the acronym TIME which unite the cellular and clinical components of wound healing.

Insert interactive box with links to appropriate sections.

Tissue, non-viable or deficient

Infection or inflammation

Moisture imbalance

Edge of wound non-advancing or undermined

The principles of TIME have been formulated to help clinicians gain a better understanding of the pathogenesis of chronic wounds and can be used as a framework to guide clinical practice (Schultz, Sibbald, Falanga et al 2003).

Tissue non viable or deficient

Tissue management is defined as the removal of non viable tissue and the encouragement of viable, well vascularised tissue to grow. The removal of non viable tissue can be achieved by the process of debridement. This involves the removal of dead or necrotic tissue and foreign material from the wound and is an important step in wound bed preparation. Debridement enhances wound assessment, decreases the likelihood of infection and removes necrotic tissue, which otherwise would delay the formation of granulation and epithelial tissue.

Devitalized tissues (eschar and slough) in the wound bed reduce the clinicians ability to assess the wounds depth, or the condition of tissue and surrounding structures

Necrotic tissue may mask signs of infection ( it supports significant bacterial growth and is a physical barrier to healing

Devitalized tissue may also cause excessive amounts of proteases to be released, which has an extremely detrimental effect on healing

A necrotic wound containing dead black tissue and yellow fibrinous slough

DebridementNatural mechanisms facilitate debridement, but wounds heal more rapidly if this process is accelerated. Methods of debridement: can be grouped into five categories: surgical, enzymatic, autolytic, mechanical and biologic. In some cases, more than one method may be appropriate, depending on the clinical circumstances.

Surgical (or sharp) debridementSurgical or sharp debridement is the fastest way to remove debris and necrotic tissue from the wound bed. Surgical debridement is sometimes performed where there is an extensive amount of necrotic tissue in the wound. This is often the case when the depth of the wound cannot be judged or if there is widespread infection requiring bone and infected material to be removed. Other than being an efficient method, surgical debridement causes minimal damage to surrounding tissue, and minor bleeding following the procedure can release inflammatory mediators, such as cytokines, that can assist the wound repair process. Surgical debridement does however, have limitations. It cannot be used for patients with bleeding disorders or who are immunocompromised. The procedure may be painful, cause transient bacteraemia and damage to nerve and tendons. Add hydrosurgical awaiting text

Enzymatic debridementEnzymatic debridement is the most selective method of debridement employing the use of manufactured proteolytic enzymes. When these are applied directly onto the wound surface, they work together with naturally occurring enzymes to degrade necrotic tissue.Some enzymatic debriding agents may cause minor transitory discomfort. Insert text on agents

Autolytic debridementAutolytic debridement is a process, which to some extent, occurs naturally in all wounds. Phagocytic cells (such as macrophages) and proteolytic enzymes in the wound bed, liquefy and separate necrotic tissue and eschar from healthy tissue. Wound dressings, which maintain a moist wound bed, can provide an optimal environment for debridement, as they cleanse the wound by allowing phogocytic cells to liquefy necrotic tissue thereby promoting granulation. Unsurprisingly, the process of autolytic debridement can result in significant wound fluid, which should be considered when selecting an appropriate dressing.Autolytic debridement is easy to perform and does not damage healthy tissue surrounding the wound. Furthermore, the pain experienced by the patient when using this method is minimal. As autolytic debridement occurs naturally, the process requires limited technical skill.

Mechanical debridementMechanical debridement is a non-selective method that physically removes debris from the wound. Examples of mechanical debridement include wet-to-dry dressings, wound irrigation and whirlpool therapy. Wet-to-dry dressings are the simplest form of mechanical debridement. These dressings cause mechanical separation of eschar from the wound bed once the dressing is removed. This can, however, cause the patient significant discomfort and damage newly formed tissue. Wound irrigation involves the use of a pressurised stream of water. High-pressure irrigation removes bacteria and necrotic debris from the wounds but could drive bacteria into soft tissue. Whirlpool therapy is another form of powered irrigation which loosens and removes necrotic tissue, debris and wound exudate. This is suitable for use in inflammatory wounds but not those with fragile granulation tissue.

Hydrosurgical DebridementHydrosurgical Debridement utilises a high-pressure jet of sterile saline that travels parallel to the wound surface. This high-speed jet creates a Venturi effect that enables the surgeon to hold cut and remove tissue, while irrigating and aspirating the wound, with a single instrument. This new technology allows the surgeon to differentiate between tissue types through technique as well as by varying power settings. Therefore sparing viable tissue while precisely targeting and removing debris and damaged tissue. Rapid and effective hydrosurgical debridement can help to reduce procedure times as well as potentially reducing the number of debridements each wound requires compared to traditional modalities eg the use of scalpel and pulsed lavage. This modality is suitable for surgical debridement of Chronic and Acute wounds in the Operating Room with the patient undergoing General Anesthesia

Biologic (Larval) TherapyLarval therapy using specially bred, sterile maggots offers an effective approach to wound debridement and removing bacteria. These maggots break down and liquefy dead tissue using powerful proteolytic enzymes. This treatment seems to have no adverse side effects. Although initially viewed by clinicians as a treatment of last resort, reports of the success of larval therapy has spread and its use is becoming more common.

Why a prolonged debridement is beneficialIt is unlikely that a single method of tissue debridement would be adequate to prepare the wound bed of a chronic wound for the next stage or repair. In chronic wounds it is generally not possible to remove the underlying pathogenic abnormalities, and consequently necrotic burden continues to accumulate. Therefore, an important part of wound bed preparation is the recognition that continual removal of necrotic burden is necessary throughout the lifespan of the wound, and debridement should be viewed as an extended, ongoing process often referred to as maintenance debridement. Autolytic and enzymatic methods of debridement, compared with other methods, are more selective and may be less aaggressive therefore , generally less painful to the patient. Within the context of maintenance debridement, autolytic and enzymatic agents that can be used for extended periods of time can be extremely beneficial (Falanga V 2002)

Infection or inflammation

Wound bed preparation also identifies infection or inflammation as a barrier to healing .When preparing the wound bed it is critical to assess the nature and extent of the infection or inflammation component also referred to as bioburden so that these can be corrected or optimize wound healing.

Bacteria present in the wound may prevent healing, even when there are no obvious signs of infection. The clinician needs to identify when bioburden is acceptable, and when it reaches a level where bacteria contribute to impaired healing.

ContaminationBacteria are present on intact skin, but infection is rarely problematic because the following mechanisms control the bioburden.

The hard outer layer of skin is a physical barrier to invasion

Skin has a slightly acidic pH, which is not conducive to bacterial growth

Skin normally secretes fatty acids and antibacterial polypeptides which inhibit bacterial growth

Normal flora on the skin help to prevent potentially pathogenic bacteria from becoming established

Although a wound creates a portal of entry for bacteria, an inadequate blood supply is one of the most significant predisposing factors for wound infection (eg in pressure ulcers or ischaemic leg ulcers).

Contamination-infection continuumChronic wounds exist along a bacterial continuum, ranging from contamination to infection (see below figure). The challenge is to establish where the wound is positioned on this continuum, and which clinical strategies are appropriate at that point. Bacteria present within a wound can be divided into four distinct categories.

Contamination

Colonization

Critical colonization

Infection

Contamination: defined as the presence of non-replicating bacteria. This is a normal condition in chronic wounds and does not contribute to impaired healing.

Colonization: defined as the presence of replicating bacteria without a host reaction. Replicating bacteria colonise and contaminate all chronic wounds, but this does not mean that these wounds are infected. Bacterial colonisation does not contribute to impaired healing.

Critically colonized wounds: defined as the presence of replicating microorganisms, which are beginning to cause local tissue damage. There may be subtle local indications that a change in the equilibrium, or increasing bioburden, could be contributing to delayed healing.

Infection: occurs when healing is impaired because bacteria have invaded tissue, are multiplying, and are causing a host reaction.

When is bioburden a problem?Bacterial bioburden can be defined as the metabolic load imposed by bacteria in the wound bed. Bacteria compete with normal cells for oxygen and nutrients, and bacteria and their by-products (eg endotoxins) can cause disturbances in all phases of wound healing. A high bacterial bioburden can cause the following:

increased metabolic load

production of endotoxins and proteases

stimulation of a pro-inflammatory wound environment

delayed or impaired healing.

Chronic wounds are always contaminated and colonised with bacteria, so it can be difficult to identify when bacterial loads reach levels where wound healing is impaired. Although there are no firm guidelines on how to quantify bacterial levels within a wound, the clinician should consider host resistance, wound characteristics and wound fluid (also known as exudate) when assessing the bacterial burden.

Studies have shown (Robson MC 1997, Dow G 2001) there is a negative effect on wound healing when the quantity of bacteria in a wound reach levels greater than 1 x 105 colony forming units per gram of tissue. This effect has been seen in acute traumatic wounds, skin grafts, surgical wounds and chronic wounds.

Wound infectionAcute wound infection, and often severe chronic wound infection, classically demonstrate the following signs and symptoms:

purulence

advancing erythema

warmth

edema/periwound swelling

pain

fever

leukocytosis.

It has become apparent that the classic signs and symptoms of the acute wound model may be diminished or altered in a chronic wound, despite heavy bacterial burden. The precise mechanisms of chronic wound infection remain unclear, and the clinical presentation and impact of bacterial burden in chronic wounds remains a key focus for research. However, the following secondary signs may alert a clinician to consider that a chronic wound has an increased bacterial burden, which is delaying healing. This is sometimes referred to as critical colonisation. Some of these secondary signs are listed below:

delayed healing

change in colour of granulation tissue

abnormal appearance of granulation tissue (ie it becomes friable). The tissue is sometimes described as pocketing (where areas at the wound base fail to granulate) or as having a cobblestone appearance

increased or abnormal wound odour increased serous drainage. (Sibbald, 2002)

Effects of infection in the chronic woundOnce a chronic wound becomes infected, progress towards healing is severely hindered because infection can:

prolong the inflammatory phase of healing

disrupt normal clotting mechanisms

lead to disordered leukocyte function

lead to less efficient angiogenesis

alter the formation of granulation tissue (fibroblasts are reduced in number, have reduced metabolic activity and form weak collagen in disorganised patterns in chronically infected wounds).

It may be appropriate for the clinician to monitor blood values and undertake X-rays in a patient with an infected chronic wound, to investigate whether there could be any underlying osteomyelitis.

Bacterial balance: relationship between host resistance and bacterial quantity and virulenceBacteria are present in all chronic wounds but, for healing to occur, the balance between host resistance and the quantity and virulence of bacteria must be maintained.

Host resistance: this is an important variable in determining the risk of infection in chronic wounds, because local and systemic factors can impair healing. Perfusion is an important factor that is associated with the pathophysiology of chronic wounds, and can increase the risk of wound infection.The following equation demonstrates that although bacterial quantity and virulence are significant in assessing a wound for infection, host factors are of over-riding importance.

Risk of infection = Bacterial dose x virulenceHost resistance

Other factors such as immunosuppression, diabetes and concomitant medications, can all influence whether bacteria present will impair wound healing.

Bacterial quantity and virulence: The following factors listed below may tip the equilibrium, thereby increasing bacterial burden. Adhesins bacteria contain heterologous proteins on their cell surface, which mediate cell adherence to and invasion of the host.

Cell capsules - these cell surface polysaccharides present on the surface of bacteria confer protection against phagocytosis by host immune cells.

Biofilms - the importance of biofilms as an element of wound infection has recently become apparent (Sibbald RG et al, 2000). When bacteria proliferate in wounds they form microcolonies, which attach to the wound bed and secrete a glycocalyx or biofilm that protects the organisms. These bacterial colonies undergo several changes, which can then alter the organisms antimicrobial sensitivity. Organisms may exist as clusters of individual bacterial types or as mixed bacterial colonies such as Pseudomonas and Staphylococcus sp. The periodic release of motile bacteria from these colonies may result in infection. Biofilms are protected foci of infection and bacterial resistance within the wound, protecting bacteria from the effects of antimicrobial agents such as antibiotics and antiseptics (Davey ME and OToole GA, 2000).

Antibiotic resistance overuse use of antibiotics contributes to the development of antimicrobial-resistant bacterial strains.

Moisture Imbalance

The management of moisture within the wound environment is the third consideration for wound bed preparation. The goal is to identify factors which:

contribute to exudate

provide absorption

maintain a moist wound environment.

Why manage exudate?Increased exudate in a chronic wound is often associated with other underlying complications in the patient. For example, when bacterial burden increases, wound drainage also increases. Both oedema (particularly in the lower extremities) and the breakdown of necrotic tissue can increase the amount of exudate.

A comprehensive approach to exudate management should address underlying factors and ensure that the wound environment remains moist. A moist wound environment is one where the optimal level of moisture is maintained to allow for efficient cellular division and migration, while ensuring the wound bed does not dry out or stay wet. In a moist wound environment, collagen synthesis and granulation tissue formation improve; cell migration and epithelial resurfacing occur faster; and scabs, crusts and eschar do not form.

Maintaining a moist wound environment has several additional benefits such as those listed below.

Decreased healing time

Capacity for autolysis

Decreased infection rates

Reduced wound trauma

Decreased pain

Fewer dressing changes

More cost-effective (when defined as the total cost of care to achieve the desired outcome, and not simply the cost of dressings).

Achieving moisture balance should begin with an assessment of factors that contribute to increased levels, for example:

as bacterial burden increases, the amount of drainage may also increase, and intervention should manage the microbial load in the wound environment

edema in the lower extremity can cause increased amounts of exudate and use of compression therapy may be indicated

breakdown of necrotic tissue can increase the exudate produced, making debridement of devitalized tissue essential.

This decision concerning choice of topical dressing should be based on several factors, including the amount of moisture present in the wound.

Moisture levelTopical dressings

LowFilm dressings these semi-permeable polyurethane dressings that are coated with an adhesive, are able to help manage bacterial infection and absorb low amounts of exudate, while maintaining a moist wound environment.

Hydrogel dressings these dressings gently re-hydrate dry necrotic tissue, facilitating autolytic debridement, while being able to loosen and absorb slough and exudate. Hydrogels are best used to treat wounds with low exudate levels (Sibbald RG et al, 2000). They can also be used to provide a moist wound management environment during the later stages of wound closure.

LowModerate Hydrocolloiddressings contain absorbent material to absorb low levels of exudate while maintaining a moist wound environment. Hydrocolloid dressings are indicated for the management of partial thickness wounds, which are mildly to moderately exuding.

Moderate-heavy Alginatedressings highly absorbent dressings, which can be used to cover moderate to heavily exuding wounds. The action of exudate on the alginate fibres produces a gel, which creates a moist wound environment.

Foam (hydrocellular) dressings provide thermal insulation, high absorbency, a moist wound environment, and are gas permeable. They are available as non-adherent or adherent and easy to shape to the wound. Speciality absorbent dressings can be used as secondary dressings.

Edge of wound non advancing or undermined

Epidermal edge migration is very much dependent on the overall environment of the wound. Moisture balance, together with debridement and bacterial balance, are essential to achieving wound closure. But there are also other factors which may be preventing the wound edges from advancing. In chronic wounds the molecular and cellular processes are disrupted, leading to significant differences in the microenvironment of the wound, both in terms of the cellular components of the wound bed and the constituents of the exudate.

In chronic wounds, the specific cell populations and processes that prepare the wound for repair are disrupted.

The epidermis fails to migrate across the wound tissue

Hyperproliferation of cells occurs at the wound edge and interferes with normal cellular migration

As a result, apoptosis (programmed cell death) of fibroblasts and keratinocytes is inhibited

Fibroblast cells have an altered morphology and reduced proliferation rate

Reduced response of cells to growth factors such as PDGF- and TGF-

Fluid from chronic wounds is biochemically distinct from that of acute wounds. Chronic wound fluid has a detrimental effect on healing, and can be attributed to the following:

increased levels of matrix metalloproteinases, which can degrade extracellular matrix proteins and inhibit cell proliferation

greater levels of the proteins fibronectin and thrombospondin

macromolecules present in chronic wound fluid can bind growth factors making them inactive.

Adequate debridement can remove non-viable tissue and cells that have accumulated and are no longer responsive to signals required for closure of the wound (cellular sensescence)..

This in turn reduces the disruption to the extracellular matrix and releases growth factors, which can then promote an angiogenic response leading to wound repair.

Epidermal edge migration lies at the heart of the concept of wound bed preparation, because if there is no epidermal advancement the wound is not really healing. Advancement of the wound edges means a reduction in wound area, the best visible predictor of healing.

The process of wound management cannot be fully understood unless the cellular and biochemical factors are addressed alongside issues such as debridement, infection and exudate management. Constant attention to the appearance and condition of the wound bed will prepare the wound for healing. Wound bed preparation provides clinicians with a systematic approach to achieve a stable wound with good granulation tissue that will progress assist with the efficient use of advanced wound care products.

Wound bed preparation is not intended to be viewed in isolation. It is part of the process of effective wound care, which includes close co-operation with the patient as to goal setting (and pain management, if appropriate) before careful assessment and ongoing monitoring of a comprehensive care regimen, using available resources.

Module 4When assessing a patient with a wound it is tempting to focus on the wound. However it is vital that general patient health issues, which affect healing, and the underlying pathology causing the wound are addressed. Clear, logical, systematic assessment of the wound and the wound bed, followed by communication and concise documentation using terminology that is accepted and understood, ultimately optimise the patient's chances of wound closure.

Gathered information from wound assessments can be evaluated and a realistic and clearly defined goal of care can be adopted. Furthermore, a wound management plan can be agreed upon to achieve this goal in an effective manner.

Patient wound management must be constantly re-evaluated to ensure that therapeutic interventions are both appropriate and effective. If this is not the case then changes can be made and a more suitable treatment regime can be initiated.

Assessment is worth doing

Spending time accurately assessing a wound is not time wasted since the correct diagnosis and an effective wound management plan will ultimately optimise patient care and reduce healthcare costs (Khachemoune and Phillips, 2001).

Effective monitoring of wound progress is crucial since it can shorten the duration and therefore the cost of inappropriate treatment for those that are not responding to current treatment. In addition, wound assessment can reassure the clinician and patient that the current treatment is working, which in turn can improve patient compliance.

Effective documentation of the progress of a wound allows the outcome of wound management procedures to be monitored. It is important to note that assessment must be documented for it to be communicated and acted upon if necessary.

Continual re-evaluation of the wound provides the clinician with important additional information to monitor the effectiveness of therapeutic interventions.

Assessment is only worth doing if it is done well The methodology employed in wound assessment must be consistent.

Data must be objective, precise and reproducible in order to draw any conclusions.

Interpretation should be objective (evidence-based) rather than subjective.

Assessment is only worth doing if it is acted uponThe information gathered should support the clinician in making decisions about the most effective course of wound management and therapeutic interventions.

Patient assessment factors Introduction Different facilities and expertise are available to the patient depending upon where patient care is being provided. For example, a hospital clinic may have access to more advanced measurement techniques and to wound care experts with vascular and diabetes specialities.

There are many factors related to a patient's general health that may affect wound healing. If these factors are not identified and resolved, where possible, wound healing is unlikely to be optimised. There are two main areas that should be assessed related to a patient's general health: associated conditions (see intrinsic factors) and the specific aetiology of the wound (see aetiology).

Intrinsic factorsIntrinsic Factors refer to any factor, which may affect the healing of the patient's wound regardless of its specific aetiology. These factors include those listed below.

Age - the skins capacity to regenerate decreases with increasing age. Since aged skin contains less collagen and therefore has less elasticity, it is less able to withstand mechanical stress making tissue damage more likely.

Infection - it is not just the number of bacteria but also their virulence and how these bacteria interact with the patient's immune system that determines whether a wound becomes infected. An infected wound may display classic signs of infection such as advancing erythema, oedema, and foul odour. However, in some cases, wound infection may be inapparent due to underlying pathogenesis such as diabetes, which reduces the immune response.

Concomitant Diseases - many disease processes have a negative effect on wound repair. For example, tissue repair requires oxygen and factors which decrease the availability of oxygen to a wound such as cardiac disease, anaemia or chronic breathing disorders, may result in a delay in healing. In addition, illness such as cerebrovascular accidents and spinal or femoral fractures can result in a lack of sensation and/or movement that increases the risk of pressure damage. Diseases such as rheumatoid arthritis are associated with an increased risk of ulceration and an underlying disorder such as this may complicate the healing process. The disease process of diabetes mellitus is associated with peripheral neuropathy and arteriosclerosis, which can increase the risk of ulceration. Diabetes can cause delayed wound healing due to reduced collagen levels, defective granulocyte function and chemotaxis, and reduced angiogenesis (Silhi, 1998).

Drug therapies - steroids, non-steroid anti-inflammatory drugs, immunosuppressive agents, anticoagulants and antiprostaglandins have all been shown to impair normal wound healing.

Nutrition - Successful wound management depends on appropriate nutritional support. Poor nutrition is recognised as one of the major causes of poor wound healing. Proteins, carbohydrates, vitamins and minerals are all involved in the healing process and it is possible that a higher than average daily intake of these components is needed for optimal woundhealing (Zagoren, 2001). Conversely, a reduced intake could interfere with healing. There are a number of measurements that can be made to assess and monitor a patient's nutritional status and indicate whether they are protein/calorie malnourished (PCM):

body mass index - this is probably the easiest and most useful indicator of a poor nutritional status and is calculated by dividing the patients weight in kilograms by their height in metres squared. The normal range is 20-25

serum albumin - 30-35g/litre is a possible indicator of PCM; 0.8

Capillary refill normal < 3 seconds Pulses diminished, may only be audible with Doppler or absent

ABI 0.7 or lower

Capillary refill > 3 seconds Palpable pulses

ABI may not be reliable in diabetic patients

Capillary refill normal < 3 seconds

Treatment Considerations

Improve venous return

Compression therapy

Unna Boot

Multi-Layer Compression Therapy

Tubular compression dressing

Compression stockings

Compression pumps

Leg elevation

Must rule out arterial disease before initiating compression

Vascular consult to evaluate potential for revascularisation

No smoking

Moisturise dry skin, do not apply between toes

Avoid trauma

Appropriate footwear

Moist wound healing, if adequate blood flow to support healing, present

High risk for pressure ulcers on heels Pressure relief "off loading" the plantar surface of the foot with appropriate footwear

Tight glucose control

Aggressive sharp debridement of callous

No bathroom surgery

Aggressive treatment of infection

Routine professional foot care

Wound dimensions / Size Measuring and recording the size of a wound are crucial to help clinicians make decisions about how to manage the wound most effectively. For example, clinical studies of chronic wounds have shown that the initial wound size affects the time taken to heal (Marks et al 1983). Ongoing wound measurements quantify changes in wound size and give an indication of whether the wound is healing.

Tape measurements and tracings are the most commonly used techniques for measuring wound dimensions. Length and width measurements provide valuable information about the progress of the wound, but multiplying these two-dimensional measurements will not provide an accurate measurement of area. One wound measurement protocol is to record length as the longest measurement of the wound and the width as the longest measurement perpendicular to the length. An alternative measurement protocol is the 'clock' method using the analogy of a clock face and visualising the patient's head at 12 o'clock. In this instance, the length is a measurement of the wound from head to toe and width is a side-to-side measurement. A specific disadvantage of length and width measurements are that they are unreliable for deeper wounds such as stage III and IV pressure ulcers as they are highly dependant upon the position of the patient at the time of measurement. Whichever method of wound measurement is employed, for it to be useful, method consistency and accurate documentation of how the measurements were obtained are of crucial importance.

Absolute area measurement, although key, is currently only available with computer software such as computerised planimetry (area measurement on a plane). This calculates the area within a tracing of the wound edge (either scanned from a grid or drawn with a mouse around a digital image of the wound). Because of this, healthcare professionals have often been restricted to approximations of wound area calculated by counting the number of full and half squares it takes to cover the wound, from a grid placed over the top of the wound.

It is both intuitive and widely believed that wound closure, the migration of the wound edges towards one another, is a useful parameter to monitor to help the clinician assess the progress of wound healing. Published research now provides statistically significant evidence in favour of the use of percentage area reduction for monitoring purposes. This can be done by either plotting against time (Robson et al, 2000), or evaluation of this parameter as at a specific time period (Arnold et al, 1994; Phillips 2000; van Rijswijk et al 2003). Either way there is now considerable published evidence that percentage reduction in wound area is a useful measurement within the first few weeks of treatment to help the clinician to differentiate between wounds that are responding or are not responding to treatment. The consistent message from these papers is that a percentage area reduction of less than 20-40 percent over the first two to four weeks is a reasonable indicator that the wound is showing a low response to the treatment.

In summary, obtaining wound measurements has been found to provide clinically useful and valid information provided that method consistency and documentation are rigidly adhered to.

Tunnelling / Undermining Undermining refers to tissue destruction underlying intact skin along the margins of the wound. This can often involve a significant proportion of the wound edge and in some cases may extend entirely around the wound. Undermining usually involves subcutaneous fat necrosis, and generally, there are greater quantities of aerobic and anaerobic bacteria present in these wounds than in those without undermining.

Appearance of the wound baseIt is very important to assess and document the appearance of the wound bed. For example, the presence of healthy granulation tissue and epithelialisation in the wound bed is an indication of wound healing.It is also important to note the colour of the granulation bed. Terms often used to describe this tissue include 'beefy red', 'pink', 'pale and/or 'dusky'.Similarly, the presence of necrotic tissue, eschar and sloughy tissue in the wound base needs to be documented. Necrotic tissue refers to tissue that changes to a brown or black/purple colour as it becomes more dehydrated and lacks an effective blood supply. After some time this necrotic tissue becomes thick, dry, black, and leathery in appearance, and at this point it is referred to as eschar.Slough, in contrast, is a moist, yellow, fibrinous tissue consisting of fibrin, proteinacous material that can build up on the surface of a previously clean wound bed. Slough provides an ideal culture medium for pathogenic organisms and may therefore predispose a wound to infection.Many wounds contain a combination of granulation tissue and necrotic tissue. When trying to document the effect of treatments, clinicians have quantified the percentage of tissue involved, expressing it as a percentage of the total wound area (eg 75% of the wound bed contains necrotic tissue, 25% contains granulation tissue). This type of assessment will facilitate the documentation of changes in the wound related to debridement.

Wound edgesIn addition to assessing the extent and depth of the wound, the condition of the wound edges should be a part of regular wound assessment. The clinician should assess and document for example, whether the wound edges are well defined and well supplied with blood or ragged, swollen, crushed, and undermined with a poor blood supply. Other terms commonly used to describe wound edges include: irregular, crater-like, punched-out, calloused, macerated and desiccated.

Periwound skin The condition of the surrounding or periwound skin provides very important information about the status of the wound and effects of treatment. Observation, assessment and documentation should include evaluating colour, induration, any oedema, suppleness and/or maceration. For example, redness of the periwound skin could indicate unrelieved pressure or prolonged inflammation. Furthermore, redness, tenderness, warmth and swelling are the classic signs of infection. Assessing the suppleness of the periwound skin is important since overly dry as well as overly moist skin is more prone to injury. Signs of maceration (pale, grey or white tissue) may be observed when surrounding skin has been exposed to moisture for a prolonged period of time. Documentation of the condition of the periwound skin should include the location and extent (measured in centimetres) of these characteristics.

InfectionThere are several variables that are involved in determining whether a wound becomes infected. These include the number of microorganisms present in the wound and bacterial virulence although, what is of crucial importance is the way these bacteria interact with the host ie host resistance factors. For example, immunosuppression, diabetes and medication, can lower a patient's resistance to infection.

Studies have demonstrated that numbers of bacteria above 105 per gram of tissue can cause infection (Dow, et al 1999). Conversely, some surgical studies have demonstrated that many patient's with bacterial levels greater than 105 heal normally (Robsen, et al, 1973). Therefore it is likely that the type of bacteria and their virulence increase the risk of infection rather than the number of microorganisms alone.

The way in which these factors are related can be demonstrated by the following equation:

Risk of wound infection =number of bacteria x virulence

host resistance

The classic signs and symptoms of infection are:

advancing erythema

fever,

warmth,

oedema

pain

purulence.

However, not all infected wounds display these classic signs. For example, chronic wounds may have a reduced immune response to invading microorganisms as a result of underlying pathogenic abnormalities such as diabetes. In wounds of this nature, secondary signs and symptoms could indicate that the chronic wound is infected. These include:

delayed wound healing

change in colour of the wound bed

friable granulation tissue

absent or abnormal granulation tissue

increased or abnormal odour

raised volumes of serous drainage

increased pain at the wound site.

Wound exudateWound exudate characteristics such as type and amount should be assessed because they provide important information about the status of the wound and give an indication of what would be the most appropriate treatment.

A moist wound environment has been shown to provide an optimal environment for wound healing. However, if the wound becomes too wet as a result of excessive quantities of exudate being produced, surrounding tissues become macerated and the wound may deteriorate further. Different types of wound produce different amounts of exudate. For example, compared to acute wounds venous leg ulcers are highly inflammatory wounds and produce large amounts of exudate.

When describing exudate, it is important to document the amount, consistency, odour (if applicable) and if there is a particular area of the wound bed in which the exudate produced is more pronounced.

Terms used to describe the amounts of exudate are minimal (10cc/24 hours) (Mulder, 1994).

Tissue involvement / Wound depthTissue involvement (or wound depth) can be sub divided into the categories below depending upon which tissues are involved.

Superficial wounds - damage to the epidermis, exposing the underlying dermal layer

Partial thickness wounds - damage is limited to the epidermis and superficial dermis

Deep dermal wounds - damage extending through the epidermis and dermis up to the junction with the subcutaneous fat layer

Full thickness wounds - injury involves loss of the dermis and extends into subcutaneous fat, muscle and bone

Depth refers to the depth of the wound at its deepest point. However, wound depth is difficult to ascertain, especially in irregular shaped wounds (Thomas and Wysocki, 1990; Harding 1994).PainAs well as being assessed on initial presentation, pain should also be monitored on an ongoing basis. Increasing pain could suggest further deterioration of the wound and possibly infection. Staging

Wound depth is a very important assessment variable because it has a direct impact on how long wounds take to heal. For this reason descriptive wound assessment methods/systems are based on wound depth. As a result of work by Shea (Shea, 1975) together with input from the International Association of Enterostomal Therapy and the National Pressure Ulcer Advisory Panel (NPUAP), pressure ulcer staging systems were devised, all based upon the level of tissue involved.

The following definitions of staging for pressure ulcers are the latest put forward by the NPUAP:

Stage I - an observable pressure related alteration of intact skin with indicators, as compared to an adjacent or opposite area on the body, which may include changes in one or more of the following: skin temperature (warmth or coolness), tissue consistency (firm or slack), and/or sensation (pain, itching). The ulcer appears as a defined area of persistent redness in lightly pigmented skin, whereas in darker skin tones, the ulcer may appear with persistent red, blue, or purple hues.

Stage II - partial thickness skin loss involving the epidermis, dermis or both. The ulcer is superficial and presents clinically as an abrasion, blister or shallow crater.

Stage III - full thickness skin loss involving damage to subcutaneous tissue that may extend down to, but not through, the underlying fascia. A stage III ulcer presents clinically as a deep crater with or without undermining of underlying tissue.

Stage IV - full thickness skin loss with extensive tissue destruction or damage to muscle, bone or supporting structures such as tendons or joint capsules. Undermining and sinus tracts may also be associated with Stage IV pressure ulcers.

An alternative classification system has been proposed by the European Pressure Ulcer Advisory Panel (EPUAP). This is similar to that of the NPUAP but this system 'grades' rather than 'stages' pressure ulcers as below:

Grade 1 - non-blanchable erythema of intact skin. Discolouration of the skin, warmth, oedema, induration or hardness may also be used as indicators, particularly on individuals with darker skin.

Grade 2 - partial thickness skin loss involving epidermis, dermis or both. The ulcer is superfici