wound healing =)

Mechanism of wound healing /case 9   Definition A wound occurs when the integrity of any tissue is compromised (e.g. skin breaks, muscle tears, burns, or a bone fractures). A wound may be caused as a result of a fall, or a surgical procedure; or by an infectious disease; or by an underlying condition. Restorative process Regeneration: replacement of exa ct specialize d structure and function; injured tissue replaced with ECM and specialized cells of the same type/organization Repair : stop gap mechanism by which injured tissue is replaced with connective tissue resulting in scar formation (imperfect structure/function) *often, wound healing is a combination of repair and regeneration process Wound heals in 4 phases that part ially overlap: Hemostasis Inflammation Proliferation (fibroplasia) phase Remodeling (maturation) phase HOMEOSTASIS Major Cell Player : -Platelets Adhesion ,Activation , and aggreg ation Major Events: -Tissue trauma results in disruption of vasculature; components of blood come in contact with cells and ECM components -Vascular spasm; vasoconstriction (slow blood flow) -Platelet plug formation -Activation of clotting cascade (enzyme series) -Formation of fibrin clot Stops bleeding Provisional scaffold for cell attachment and migration Clot retraction (condensatio n) -Fibrinolysis (clot digestion / removal) 1

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Mechanism of wound healing /case 9


A wound occurs when the integrity of any tissue is compromised

(e.g. skin breaks, muscle tears, burns, or a bone fractures). A

wound may be caused as a result of a fall, or a surgical procedure;

or by an infectious disease; or by an underlying condition.

Restorative process

Regeneration: replacement of exact specializedstructure and function; injured tissue replaced withECM and specialized cells of the same


Repair : stop gap mechanism by which injured tissue isreplaced with connective tissue resulting in scarformation (imperfect structure/function)

*often, wound healing is a combination of repair andregeneration process

Wound heals in 4 phases that partially overlap:

• Hemostasis

• Inflammation• Proliferation (fibroplasia) phase

• Remodeling (maturation) phase


Major Cell Player :


• Adhesion ,Activation , and aggregation

Major Events:

-Tissue trauma results in disruption of vasculature;components of blood come in contact with cells andECM components

-Vascular spasm; vasoconstriction (slow blood flow)

-Platelet plug formation

-Activation of clotting cascade (enzyme series)

-Formation of fibrin clot

• Stops bleeding

• Provisional scaffold for cell attachment andmigration

• Clot retraction (condensation)

-Fibrinolysis (clot digestion / removal)1

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After the initial insult and resultant vasoconstriction,vascular permeability is then increased. The classic signs of inflammation are generated by these metabolites. For

example, the redness caused by vasodilation is primarily aresult of prostacyclin (PGI2). Others include prostaglandin A,prostaglandin D, and prostaglandin E (PGE). Swelling iscaused by the leakage of plasma proteins through gaps inthe vascular endothelium. This edema is potentiated byPGE2 and prostaglandin F2-alpha (PGF2-alpha). PGI2 andPGE2 promote local blood flow, causing the localizedwarmth in the area of inflammation, but also allow for entryof inflammatory cells into the wound, which is due toincreased vascular permeability. These cells then release

cytokines responsible for fever production. Pain is elicited bythe effects of PGI2, PGE, and PGE2 on peripheral sensorynerve endings. Eicosanoids thus exert mediatory actions on

the injured tissue's platelet plug formation, vascularpermeability, and cellular chemotaxis to influence woundhealing. Another class of mediators involved in this stage of wound healing is the cytokines. After hemostasis has beenobtained,   polymorphonuclear (PMN) leukocytes enter thearea of injury, drawn by chemotactic substances such asthose released with the degranulation of platelets. These

are then the predominant cells for the first 3 days afterwounding, with the number peaking at approximately 48hours . They are the first to begin bactericidal activitiesusing inflammatory mediators and oxygen free radicalmetabolites. However, PMN leukocytes have been shown tonot be crucial to the wound healing process, with normalhealing progression occurring experimentally in theirabsence. Other leukocytes, specifically helper T cells, arethe source of the cytokine interleukin (IL)–2. IL-2 promotesthe proliferation of further T cells to aid in the immunogenic

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response to injury. IL-1 is a cytokine produced bymacrophages. Circulating monocytes enter the wound afterthe PMN leukocytes and reach their maximum numbers 24-36 hours later . They mature into tissue macrophages,which carry the major load of wound debridement.

Macrophages secrete substances such as bFGF, achemotactic and mitogenic factor for fibroblasts andendothelial cells, and IL-1. IL-1 stimulates the proliferation of multiple cells of inflammation and induces the replication of endothelial cells, promoting angiogenesis. The depletion of macrophages causes a severe alteration in wound healing,with poor debridement and inadequate fibroblastproliferation and angiogenesis. As eicosanoids accumulatein the wound during the progression of the inflammatoryphase, they begin to interact with the cells present. Forexample, a rise in the ratio of PGF2-alpha to PGE2 duringlate inflammation is a stimulus for fibroblasts to begin to

synthesize collagen and ground substance. Additionally, themacrophage-derived growth factors are now at optimallevels, strongly influencing the influx of fibroblasts, thenkeratinocytes and endothelial cells, into the wound. Thecellular population of the wound becomes predominantlymononuclear, with a declining number of neutrophils andmacrophages, signaling the end of the inflammatory phaseand the initiation of the proliferativePhase

Major Events:

• Vasodilation and increased capillary permeability• Chemotaxis of neutrophil and monocyte induced by

fibrinopeptides and fibrin degradation products

• Phagocytosis of bacteria and other microorganisms

• Debridement (removal of tissue debris)

• Provisional matrix (e.g., fibrin) replaced byproteoglycans, glycosaminoglycans, and collagen


The proliferative phase of wound healing begins approximately 2-3days after wounding and is signaled by the arrival of fibroblasts intothe wound. Fibroblasts migrate from the wound margins using the

fibrin-based provisional matrix established during the inflammatoryphase. Within the first week after wounding, fibroblasts are driven bymacrophage-derived bFGF, TGF-beta, and PDGF to proliferate andsynthesize glycosaminoglycans and proteoglycans, the buildingblocks of the new extracellular matrix of granulation tissue, andcollagen. Because macrophage numbers have begun to diminish inthe acute wound by this time, fibroblasts start to produce bFGF,TGF-beta, and PDGF. They also begin producing keratinocytegrowth factor and insulinlike growth factor-1. Fibroblasts become thedominant cell type, reaching their peak numbers at 7-14 days. After secretion of collagen molecules, fibroblasts then assemble themextracellularly into collagen fibers. These fibers are then cross-linked

and organized into bundles. Collagen is the major component of acute wound connective tissue, with net production continuing for thenext 6 weeks. The increasing content of wound collagen correlateswith increasing tensile strength. During fibroblast proliferation,keratinocyte and endothelial cell populations are also stimulated toincrease their numbers. In turn, keratinocytes and endothelial cellsproduce their own growth factors stimulatory for their respective cellproliferation. Simultaneously with cellular proliferation, angiogenesisin the developing granulation tissue occurs through budding fromintact vessels at wound margins and requires endothelial cellproduction from factors described previously. Thisneovascularization accompanies the advancing line of fibroblasts

into the wound to provide them with nutrients and to produceplasminogen activator and collagenase. This begins the degradationof the fibrin clot and provisional matrix once the new granulationtissue (ie, extracellular matrix, collagen, capillaries) is laid down.Granulation tissue production continues until the defect is covered.Finally, as the hyaluronic acid–containing provisional matrix isbroken down, the decreasing hyaluronic acid concentration andrising chondroitin sulfate levels signal the slowing of fibroblastmigration and proliferation. This shift in the ratio of theseglycosaminoglycans acts to inhibit fibroblast activity, inducing them

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to differentiate, and thus initiating the maturation phase of woundhealing.

Major Events:

• Deposition of extracellular matrix componentsincluding collagen, proteoglycans, etc.

• Replacement of provisional matrix

• Increase in tensile strength

• Angiogenesis

• Epithelialization

• Wound contraction (e.g., myofibroblast)


New collagen production remains the dominant process inwound healing from the first week after wounding untilapproximately 6 weeks. Collagen is deposited randomly inacute wound granulation tissue. Remodeling of the collageninto a more organized structure occurs during woundmaturation, increasing the wound's tensile strength. Duringthe formation of the scar, the type III collagen of thegranulation tissue is replaced by type I collagen until thenormal skin ratio of 4:1 for type 1 collagen to type IIIcollagen is present. With the remodeling process, a dynamicturnover of collagen occurs but collagen synthesis equals

that of collagenolysis. This results in a tensile strengthplateau achieved after approximately 2 years postinjury of approximately 80% of normal strength, beyond whichwound strength cannot exceed. The wound is eventuallyclosed by the migration of epithelial cells from the woundedge, filling the defect until they reach other epithelial cellsand halt their advance due to contact inhibition. This addsnothing to wound strength, and remodeling continuesbeneath the epithelial cover. When wound fibroblasts reacha concentration with which their density causes contactinhibition, they differentiate into myofibroblasts containing

alpha-smooth muscle actin fibrils. These cells tightly bind toeach other and to the wound margins, drawing the woundedges closer together. The extent of importance of the roleof myofibroblasts in wound contraction is, at present,equivocal. Some investigators believe the myofibroblast are

the principal controller of wound contraction, while othersmaintain they are only the precursors to cell apoptosis anddo not serve in contraction. By whatever means, as woundcontraction proceeds, the volume of injured tissue isreduced by replacement with uninjured tissue.


Major Cell Players:

• Fibroblast

•  Tissue-specific cells

Major Events:

• Last and longest phase of healing

• Cellular differentiation

• ECM production/degradation

• Structural modification and maturation of ECM

• Receding of angiogenesis (decrease in number of capillaries)

• Increase collagen type I:type III ratio

• Decrease in GAG content• Decrease water content

• Decrease fibroblast number

• Increase tensile strength; fibril/fiber reorganization


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•  The development of a wound infection depends onthe complex interplay of many factors.

• If the integrity and protective function of the skin isbreached, large quantities of different cell types willenter the wound and initiate an inflammatoryresponse.

•  This may be characterised by the classic signs of redness, pain, swelling, raised temperature and fever

 This process ultimately aims to restore homeostasis.•  The potential for infection depends on a number of 

patient variables such as the state of hydration,nutrition and existing medical conditions as well asextrinsic factors, for example related to pre-, intra-,and post-operative care if the patient has undergonesurgery.

• Infections of the surgical wound are one of the mostcommon HAIs and are an important cause of morbidity and mortality.

•  The delay in recovery and subsequent increasedlength of hospital stay also has economicconsequences.

• It has been estimated that each patient with asurgical site infection will require an additional 6.5

days in hospital, which results in the doubling of hospital costs associated with that patient

Historical background 

• Wound infection is not a modern phenomenon. Asearly as 14-37AD there is documentary evidence thatCornelius Celsus (a Roman physician) described thefour principal signs of inflammation and used'antiseptic' solutions. Another Roman physician,Claudius Galen (130-200 AD) had such an influence

on the management of wounds that he is stillthought of by many today as the 'father of surgery'.It should also be remembered that he and some of his followers instigated the 'laudable pus' theory,which incorrectly considered the development of pusin a wound as a positive part of the healing process.Further historical references are listed in .

Table 1: Historical background (1510-1994)

Ambrose Pare (1510-1590)

Encouraged wounds to suppurate

Semmelweiss (1818-1865), Pasteur (1822-1895) and Lister (1827-1912)

Accepted germ theory andintroduced antiseptics

Florence Nightingale(1894)

'Not in bacteriology but looking intodrains (for smells) is the thingneeded'. Held a firm belief in thebenefit of hand-washing and stricthygiene

Mary Ayton (1985) Defined terminology in current use

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for wound infection

Vincent Falanga (1994) Identified the concept of 'criticalcolonisation' with fresh insights intochronic wound healing and non-healing wounds


It is important to have a clear understanding of the termsused for wound infection. Since 1985 the most commonlyused terms have included wound contamination, woundcolonisation, wound infection and, more recently, criticalcolonisation. These terms can be defined as:

• Wound contamination - the presence of bacteria

within a wound without any host reaction• Wound colonisation - the presence of bacteria

within the wound which do multiply or initiate a hostreaction

• Critical colonisation - multiplication of bacteriacausing a delay in wound healing, usually associatedwith an exacerbation of pain not previously reportedbut still with no overt host reaction

• Wound infection - the deposition and multiplicationof bacteria in tissue with an associated host reaction

Potential wound pathogens

 The majority of micro-organisms are less than 0.1mm indiameter and can therefore only be seen under amicroscope. They can be categorised into different groups,such as bacteria, fungi, protozoa and viruses, depending ontheir structure and metabolic capabilities


 These are relatively simple cells that can be furthercategorised according to differences in their shape and cellwall.

• Cocci (spherical shaped cells),

• bacilli (rods) and

• sprirochaetes (spirals)

gram staining

• gram - positive : purple

• gram - negative : red

Fungi These are composed of larger more complex cells than

bacteria. They are either single-celled yeasts or multi-

cellular organisms with a nuclei contained within a cell

membrane. Fungi can be responsible for superficial

infections of the skin, nails and hair and, although they have

been isolated from wounds, they are rarely pathogenic in

this setting


 These are single celled organisms within a fragilemembrane and without a cell wall. They are mostsignificantly associated with infected skin ulcers. 

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 These are composed of genetic material (nucleic acid)enclosed within a protein coat or a membranous envelope.Although viruses do not generally cause wound infections,

bacteria can infect skin lesions formed during the course of certain viral diseases.

It is important to remember that different micro-organismscan exist in polymicrobial communities and this is often thecase within the margins of a wound .

Table 2: Examples of potential wound pathogens



• Beta Haemolytic Streptococci(Streptococcus pyogenes)*

• Enterococci (Enterococcusfaecalis)

• Staphylococci (Staphylococcusaureus/MRSA)*



aerobic rods

• Pseudomonas aeruginosa*


Gram-negativefacultative rods

• Enterobacter species• Escherichia coli

• Klebsiella species

• Proteus species


Anaerobes • Bacteroides

• Clostridium



 Yeasts (Candida)• Aspergillus


* Most common causative organisms associated with

wound infection


Methicillin-resistant Staphylococcus aureus (MRSA) was firstreported in the UK in the 1980s and remains a cause of concern for all healthcare practitioners. Anecdotal evidencesuggests that MRSA is no more pathogenic in a wound thanthe non-resistant version; however, it is accepted that if awound is infected with MRSA it is difficult to manage withantibiotics. As a general rule, practitioners should follow thelocal protocol for the management of a wound colonisedwith MRSA, with ongoing treatment based on clinical signs.

Wound contamination and the development of infection

 There are a number of ways in which micro-organisms cangain access to a wound:

• Direct contact: eg transfer from equipment or thehands of carers

• Airborne dispersal: micro-organisms depositedfrom the surrounding air

• Self-contamination: physical migration from thepatient's skin or gastrointestinal tract

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Whilst there is no definitive evidence to identify the mostcommon route of entry for a micro-organism into a wound,direct contact and poor hand-washing techniques of healthcare practitioners during pre- and post-operativephases of patient care are considered to be significant


 The presence of a micro-organism within the margins of awound does not indicate that wound infection is inevitable.Protective colonisation may play a part whereby somebacteria produce highly specific proteins that kill or inhibitother, usually closely related, bacterial species or wherecertain bacteria produce a variety of metabolites and endproducts that inhibit the multiplication of other micro-organisms .

Ultimately the development of an infection will be

influenced largely by the virulence of the organism andimmunological status of the patient; for example, patientsconsidered most at risk are those being treated with long-term steroids and those receiving chemotherapy. Virulencedescribes both the pathogenicity ( Table 3) and invasivenessof the relevant micro-organism. A number of specific factorshave also been identified in relation to infection rates insurgical wounds . These include:

• Presence of an existing chronic infection

•  Time interval between skin preparation and surgery

•Nature of the invasive procedure - especially if involving the bowel

• Extent of tissue loss and/or trauma to tissues duringsurgery

• Adequacy of wound drainage

• Appropriate use of wound management materials.

Specific wound-related factors that may predispose to thedevelopment of an infection include:

• Poor application of the principles of asepsis at thetime of wound dressing changes

• Presence of devitalised tissue within the woundmargin - necrotic tissue or slough, particularly if over50%

• Nature and prolonged presence of exudate notmanaged by a closed wound drainage system.

Table 3: Pathogenic effects of virulent micro-


 Toxin production Vigorous stimulation of immune cells


release within the

blood stream that

initiates an


proliferation of T


Stimulation of T (thymus maturing) cell

subsets allowing the release of cytokines

that initiate cell and tissue damage



Some species of micro-organisms such as

the exotoxins of Staphylococcus and

Streptococcus produce superantigens

Presence of 


A microbial colony encased in an adhesive

polysaccharide matrix that is usuallyattached to a wound surface . Biofilms

present in the form of a transparent sticky

film covering the wound surface. Cells in

biofilms exhibit a decreased sensitivity to

host immunological defence mechanisms,

decreased susceptibility to antimicrobial

agents and increased virulence. They

have also been implicated in persistent

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Recognition of wound infection

 The inflammatory response is a protective mechanism thataims to neutralise and destroy any toxic agents at the siteof an injury and restore tissue homeostasis . There are anumber of indicators of infection, these include the classicsigns related to the inflammatory process and further moresubtle changes as highlighted by Cutting and Harding. Theclassic signs of infection include:

• Localised erythema

• Localised pain

• Localised heat

• Cellulitus• Oedema.

Further criteria include:

• Abscess

• Discharge which may be viscous in nature,discoloured and purulent

• Delayed healing not previously anticipated

• Discolouration of tissues both within and at thewound margins

• Friable, bleeding granulation tissue despite gentlehandling of and the non adhesive nature of woundmanagement materials used

• Unexpected pain and/or tenderness either at thetime of dressing change or reported by the patient asassociated specifically with the wound even whenthe wound dressing is in place

• Abnormal smell

• Wound breakdown associated with woundpocketing/bridging at base of wound, ie when a

wound that was assessed as healing starts todevelop strips of granulation tissue in the base asopposed to a uniform spread of granulation tissueacross the whole of the wound bed.

 The above criteria should be used as discriminating factorswhen the 'classic' signs of wound infection do not appear tobe present but the presence of a wound infection issuspected, usually as a result of a delay in wound healingthat was not anticipated from the patient's medical historyor knowledge of the patient's wound.

Confirming a diagnosis of wound infection

If, after careful assessment, it is apparent that the wound isinfected, it is important to confirm this and identify thecausative organism(s) and possible sensitivities toantibiotics.

Wound swabbing is the most common sampling methodused throughout the UK although its clinical value has beenquestioned by a number of authors . It has been suggestedthat routine swabbing, such as at weekly intervals or at thetime of frequent dressing changes, is neither helpful norcost effective . Further investigations include:

• Serum investigations. These involve smallamounts of blood being obtained from the patient to

identify elevated white cell counts and elevatedlevels of serum C-reactive protein (CRP), a proteinnormally not found in the serum, but present inmany acute inflammatory conditions and withnecrosis. However, it should be remembered that thelatter is not diagnostic of a chronic wound infection .

• Quantative analysis (eg through wound biopsies). This can assist with the recognition of an increasedbacterial burden; however, this is not regularlyundertaken in the UK and previous studies have

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shown that wounds can heal despite high bacterialcounts .


Once a diagnosis of wound infection has been confirmedand antibiotic sensitivities identified, appropriatemanagement regimens should be considered, with a highpriority given to reducing the risk of cross infection. It isimportant to treat the patient as a whole and not theinfection alone, so management strategies must be basedon data derived from an holistic assessment of the needs of the individual . The main treatment objective will be toreduce rather than eradicate the bacterial burden within thewound margins. In addition to antibiotic therapy, there aretwo main generic groups of wound management productsthat have the potential to reduce the bacterial burden in thewound, these are compounds containing silver or iodine .

Antibiotic therapy

Antibiotics are chemical substances produced by a micro-organism that have the capacity, in dilute solutions, toselectively inhibit the growth of or to kill other micro-organisms . Whereas it is now generally accepted thatsystemic antibiotics are essential for the management of 

clinically infected wounds, the choice of antibiotic to beused is not always apparent. Only after a comprehensiveassessment process including consideration of patientcharacteristics, the results of microbiological investigationsand the identification of both the nature and location of thewound, can the most appropriate antibiotic be identified.

  The routine use of topical antibiotics is not justified forcolonised or infected wounds. In addition, a recentsystematic review of antimicrobial agents has concluded

that systemic or topical antimicrobials are not generallyindicated for the management of chronic wound infections .However, there may be some value in the prophylactic useof topical antimicrobials for the initial management of acutecellulitus, whilst awaiting clarification of antibiotic sensitivity

and the establishment of a therapeutic regimen.

Resistance to antibiotics has become a serious problem inrecent years particularly with the rise of epidemic strains of MRSA. The overuse of broad-spectrum antibiotics will onlyserve to exacerbate the situation. It could therefore beargued that all antibiotic use should be based on knownsensitivities.


Iodine is an element that has antiseptic properties. It isactive against a number of pathogens. In the past its usehas been limited by the fact that elemental iodine can beabsorbed systemically, is almost insoluble and can be anirritant to the skin.

In wound management iodine is used in two forms:

• Cadexomer iodine - a polysaccharide starch latticecontaining 0.9% elemental iodine that is released onexposure to wound exudate.

• PVP-1 (Povidone iodine) - an iodophor composed of 

elemental iodine and a synthetic polymer

Both have different physical characteristics that relate tothe component parts and the iodine concentration of available iodine that is released when in use. Clinicallyiodine is indicated for wound cleansing, wound bedpreparation (the stimulation and influence of specific cellsinvolved with the immune system) and the prevention andmanagement of wound infection

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Further interventions

Other appropriate wound management interventions thatcan be considered to help reduce the bacterial burden onthe wound surface include autolytic or enzymatic

debridement, surgical debridement, maggot therapy andthe use of topical negative pressure (TNP) for example,vacuum-assisted closure (VAC), in conjunction with the useof appropriate secondary dressings as required .


 The importance of wound infections, in both economic andhuman terms, should not be underestimated. Practitionersneed to know how to recognise and manage the signs andconsequences of clinically infected wounds. The key

principles for the management of a patient with a woundinfection can be summarised as follows:

•  Treat the patient holistically

• Recognise the signs of inflammation/increasedbacterial burden/clinical infection

• Be able to take 'reliable' wound swabs

• Be able to interpret culture reports

•  Treat the infection - causative organism(s)

• Consider antibiotic sensitivities

• Consider which wound management products aresuitable and appropriate

• Minimize the risk of cross infection

• Reduce the risk of any complications

• Educate the patient and his/her family and carers

 The incidence of wound infections will only be reduced overtime if all practitioners keep these principles in mind whendealing with patients and plan interventions based onappropriate assessment techniques.

 The extracellular matrix (ECM) is the largest component of the dermal skin layer and the synthesis of ECM is a keyfeature of wound healing, especially when there has been asignificant loss of tissue that precludes closure by primaryintention. This article discusses the proteins contained inthe ECM of normal skin that are important in the healing of acute and chronic wounds. In addition, the theory that thehigh levels of proteases found in chronic wounds impairhealing by degrading essential components of the ECM isdiscussed using data from cell culture experiments andimmunohistochemical analyses of wound biopsies.

As a consequence of this theory new dressings have beendeveloped that are designed to reduce protease levels inwound fluids by providing a competitive substrate (collagen)for the proteases and thereby reducing proteolyticdestruction of essential ECM components (fibronectin) andplatelet-derived growth factors (PDGFs). Other newapproaches include the topical treatment of chronic woundswith agents that reduce the synthesis of matrix

metalloproteinases (MMPs), such as a mixture of metalcations, and treatment with unique proteins (amelogenin) toreplace the corrupted ECM.

Clinical and laboratory data now clearly show thatcomponents of the ECM play an important role in normalwound healing and that the destruction of ECM componentsimpairs healing. This has lead to the development of newtherapies that aim to reduce the destruction of ECM or re-establish undamaged ECM.

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The extracellular matrix of normal skin

 The largest component of normal skin is the ECM, a gel-likematrix produced by the cells that it surrounds (Figure 1). The ECM is composed of a variety of polysaccharides, waterand collagen proteins which give the skin remarkableproperties. On a weight basis, the tensile (breaking)strength of normal skin approaches that of steel, yet skinalso has substantial elasticity and compressibility. Theseproperties are due to the combination of two main classesof ECM molecules, which are secreted by fibroblasts andepidermal cells. They are:

• Fibrous structural proteins, including collagens,elastin and laminin, which give the ECM strength andresilience

• Proteoglycans, such as dermatan sulfate andhyaluronan, typically consist of multipleglycosaminoglycan chains (formed from repeatingdisaccharide units) that branch from a linear proteincore. Extracellular proteoglycans are large, highlyhydrated molecules that help cushion cells in the


Figure 1 - The structure of the skin. Skin and underlyingtissues can be divided into the five major divisions of 

epidermis, corium, subcutis, fascia and muscle.

In addition to serving as a scaffold or structural support forcells, the ECM regulates cellular functions via cell adhesion,lubricates cells and provides a transport system for

nutrients and waste products.


 The components of the ECM provide strength, elasticity andcompressibility in normal skin. In acute wounds theprovisional wound matrix, containing fibrin and fibronectin,plays several key roles, including providing a scaffold todirect cells into the injury as well as stimulating them toproliferate, differentiate and synthesise new ECM. Ashealing proceeds, the initial ECM of the scar undergoesremodelling and eventually the injured tissue is repairedrather than regenerated because the architecture of the

scar never completely reproduces the pre-woundarchitecture of the skin tissue. In some wounds healing failsto progress through the sequential phases and a chronicwound develops. These wounds are often characterised byincreased levels of inflammatory cells that are associatedwith elevated levels of proteases; these appear to degradethe ECM components, growth factors and receptors that areessential for healing. Recognising and removing thesebarriers to healing has led to the concept of wound bedpreparation, which emphasises the need to debride non-viable and denatured ECM[54]. The importance of re-

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establishing a functional ECM in chronic wounds has led tothe development of dressings that reduce excessiveprotease levels, and new technologies are exploring how totemporarily replace the degraded ECM in chronic wounds tofacilitate healing.

Clearly, the optimal care and treatment of chronic woundsrequires an understanding of the key role ECM plays innormal healing, recognition of how this is altered in chronicwounds and the inclusion of appropriate clinical treatmentsto re-establish a functional ECM