wound healing 2008

7/27/2019 Wound Healing 2008

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FOCUSING ON INJ URIES ARTICLE

THE BIOM EDICAL SCIENTIST 609JULY 2008

A wound occurs when the integrity of anytissue is compromised (eg skin breaks, muscletears, burns or a bone fracture). A woundmay be caused as a result of a fall, a surgicalprocedure, an infectious disease or anunderlying pathological condition.

Types and causes of wounds are wide

ranging, and healthcare professionals haveseveral different ways of classifying them.They may be chronic, such as the skin ulcerscaused by diabetes mellitus, or acute, suchas a gunshot wound or animal bite.

Wounds can be open, in which the skinhas been compromised and underlyingtissues are exposed, or closed, in which theskin has not been compromised, but traumato underlying structures has occurred(eg a bruised rib or cerebral contusion).Emergency personnel and first-aid workersgenerally place acute wounds in one ofeight categories:

Abrasions, also called scrapes, whichoccur when the skin is rubbed away byfriction against another rough surface(eg rope burns and skinned knees)

Avulsions occur when an entire structureor part of it is forcibly pulled away, suchas the loss of a permanent tooth or an earlobe; animal bites may cause avulsions

Contusions (bruises) are the resultof a forceful trauma that injures aninternal structure without breaking theskin; blows to the chest, abdomen or headwith a blunt instrument (eg footballor fist) can cause contusions

Crush wounds occur when a heavy object

falls on a person, splitting the skin andshattering or tearing underlying structures

Cuts are slicing wounds made with a sharpinstrument, leaving even edges; they may

Mechanisms involvedin wound healing

Wounds and s kin dam ag e are subjects of great importance to the derma l

pharma ceutical and skin ca re industries, b ut the injuries caus ed and the

repair mec hanisms involved a re also important in the labo ratory setting,

as Pasca l Mallefet and Anthony C Dw eck explain.

be as minimal as a paper cut or assignificant as a surgical incision

Fish-hook wound: an injury caused bya fish-hook becoming embedded in softtissue

Incised wound: any sharp cut in which thetissues are not severed; a clean cut caused

by a keen cutting instrument the woundmay be aseptic or infected, depending onthe circumstances

Lacerations (tears) are separating woundsthat produce ragged edges; they areproduced by a tremendous force againstthe body, either from an internal sourceas in childbirth, or from an external sourcesuch as a punch

Open wound (contusion) in which the skinis also broken, such as a gunshot, incisedor lacerated wound

Penetrating wound in which the skin isbroken and the agent causing the woundenters subcutaneous tissue or a deep lyingstructure or cavity (the agent might bea nail, splinter or spike)

Punctures are deep, narrow woundsproduced by sharp objects such as nails,knives and broken glass.1,2

WOUND HEALINGSkin trauma will start an organised andpredictable sequence of events that has acascade effect until the wound is bridged byscar tissue that binds and holds the wound

in stasis.Successful treatment minimises the

formation of scar tissue and reduces theamount of necrotic tissue that is producedduring this process. The use of hydrogel helpsto produce more rapid healing by creatinga moist environment that reduces the buildup of necrotic tissue through apoptosis(programmed cell death). The beneficial

Clockwise from top left: Abrasions on knees, hands, incised w ound a nd puncture wo und.


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610 THE BIOM EDICAL SCIENTIST JULY 2008

effects of a moist versus a dry woundenvironment include the prevention of tissuedehydration and cell death, acceleratedangiogenesis, increased breakdown of deadtissue and fibrin (ie pericapillary fibrin cuffs)and potentiating the interaction of growthfactors with their target cells.3

The response to injury, either surgically

or traumatically induced, is immediate and thedamaged tissue or wound then passes throughphases in order to effect a final repair. Thesephases are barrier protection, the inflammatoryphase, the fibroplastic phase and theremodelling phase.

PHYSICAL BARRIERThe most important action to take in thecase of any wound is to protect it from theexternal environment and apply some formof a dressing. Modern thinking suggeststhat wounds should be kept in a moistenvironment, and hydrogel is a perfect

medium to apply.Wound care should support the natural

healing process, and such care should providea moist dressing/wound interface, absorbor remove excess exudate, provide thermalinsulation, prevent contamination and providean environment conducive to the bodysnatural defence mechanisms.

Furthermore, dressings should cause littleor no discomfort to the patient and be ableto remain in place for a number of days tofacilitate the healing process and reducethe cost of care.4

Occlusion dressings can minimise necrotic

tissue by preventing desiccation, aidingdebridement, and providing a barrier againstexogenous pathogenic organisms, thus limitingthe resulting inflammatory cascade.5 The useof more moisture-retentive dressings generallyachieves environments supportive of earlierhealing when compared to less moisture-retentive dressings.

Maceration, an unwelcome occurrencewith moisture-retentive dressings on highlyexuding wounds, is not consistently associatedwith increased adverse events. Evidencesuggests that greater dressing moistureretention is associated with fewer clinical

infections, greater patient comfort and reducedscarring.6 Concerns that moisture in woundswould increase the risk of clinical infectionover traditional therapies are unfounded.3,7

Wounds will readily acquire bacteria unlessprotective measures are taken. The bacterialprotection afforded by conventional absorbentcellulose dressings is limited, particularly in

the presence of serous exudate that maycompromise dressing integrity. In addition,dressings may shed particles that remain inthe wound. In contrast, many moderndressings are impermeable to bacteria, areremoved completely, have been found tooptimise re-epithelialisation rates and reducethe incidence of wound sepsis.

Furthermore, the numbers of bacteria perlitre of air following removal of hydrocolloiddressings were approximately 20% of thoseobserved with gauze.8

The sense of touch is provided by a networkof nerve endings that reach just about every

part of the body. These sensory nerve endingsare located just beneath the skin and registerlight and heavy pressure on the skin and alsodifferences in temperature. These nerveendings gather information and send it to the

brain. A graze to the skin will likely removeboth the stratum corneum and in more severecases the underlying epidermis as well. Thiswill almost certainly expose nerve endingsin the skin and so heighten their sensitivityso that they become extremely sensitive.

The application of hydrogel will providea soothing barrier that insulates the woundagainst hot and cold stimuli and also act as

a cushion against external physical influencessuch as pressure and touch.Hydrogel provides a cooling barrier that

permits water to evaporate from the surface

and so produce a cooling effect. It is thiscooling effect that helps to reduce themicrocapillary circulation to the surface of theskin, so encouraging a reduction in erythema

(redness), may lessen the build up of oedemaand so reduce swelling to allow more evenwound healing. This cooling effect will bringsoothing comfort.9

Pain is significantly reduced when woundsare covered with an occlusive dressing.3,10,11

Frequent dressing changes are time consumingand sometimes painful, but patients are ableto move freely and take showers, and nursingtime spent on changing post-operativedressings is greatly reduced.12 Dressings withlarge absorptive capacity reduce pain relatedto maceration of surrounding tissues and topressure caused by the excess exudates.13

INFLAMMATORY PHASEThe inflammatory phase prepares the area forhealing and immobilises the wound by causingit to swell and become painful, so thatmovement becomes restricted. The fibroplasticphase rebuilds the structure, and then theremodelling phase provides the final form.

Tissues can heal at different rates, andeven one wound can show various areashealing rapidly or slowly. The more rapid thehealing process can be made leads to the betterlikelihood of a satisfactory outcome. The useof a moist healing environment has been

demonstrated to speed up the healing processwhen compared to a dry dressing scenario.Scar quality is significantly superior in

those wounds treated with a moist dressing.14

Haemostasis and inflammatory phase

Epidermis

Dermis

Subcutaneous

tissue

Injured tissue and inflammation

Fibroplastic phase Remodelling phase

New vessel and tissue remodelling Healing wound


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Scar assessment scores demonstrated markedprevention of unfavourable scars withimproved cosmetic results followingprophylactic use of a moist hydrogel-typedressing.15 The rate of wound infections is notincreased when occlusive dressings are usedfollowing surgery. Finally, occlusive dressingshave also been found to reduce inflammation

and subsequent scarring.12,16

Inflammation is a normal and necessaryprerequisite to healing. Changes in vascularflow are responsible for the clinical symptomsused to detect an inflammatory response.The majority of the specialised cells involvedin this phase of the wound healing processcome from blood.

Blood vessels that traversed the wound aresevered at the time of injury and it is these cut

vessels that allow whole blood into the wound,which then coagulates, seals the injured

vessels and lymphatic channels in order toclose the wound, and prevents further

haemorrhage. The simultaneous release ofhistamine and other triggers by the injuredtissue causes the intact vessels to dilate.

Histamine causes brief vasodilation inneighbouring non-injured vessels and it isthis combination of whole blood exudate andserous transudate that creates a reddened,hot, swollen and painful environment.Bradykinins, derived from plasma in the areaof the injury, contribute to more prolonged

vascular permeability.Prostaglandins are produced by all cells

in the body and are released when there is anydisruption of cell membrane integrity. Certain

prostaglandins further contribute to long-termvascular vasodilation. The fibrin plugs thatclot in the wound to seal leakage also formin the lymphatic vessels. The blocking of thelymphatic flow not only seals the wound butalso helps to stop the spread of infection.They remain closed until later in the healingprocess.

Mast cells also release hyaluronic acidand other proteoglycans into the cocktail ofchemicals accumulating within the woundand these bind with the watery wound fluidto create a non-flowing gel that slows downleakage and fluid loss. The inflammatory

oedema fills up all the spaces in the woundand surrounds all the damaged or repairedstructures and binds them together.

This type of oedema causes loss of dermalfat, thus thinning normal skin in the area.Some swelling in a wound is inevitable and toa degree it is required for successful healing tooccur. If there is no inflammation then healingdoes not begin, and if too little inflammationoccurs then healing may be slow. However,if too much inflammation occurs then thelikelihood of excessive scarring increases. Thisinflammatory fluid, derived from the blood,is high in fibrinogen, which coagulates in thewound and in the surrounding tissues that are

now filled with fluid. Later, the coagulatedfibrin will mature into a dense, binding scar.

The soluble protein fibrinogen circulatesin the blood and provides the material from

which the insoluble fibrin clot is formedduring blood coagulation. Fibrinogen, as anacute-phase reactant, responds to infection

and other short-term inflammatory stressors.Excessive swelling, therefore, must not

be permitted. Primary wound care ensuresthat all blood vessels have been repaired,cauterised or clotted. Haematomas, the resultof ongoing bleeding in the wound, createextra exudate, which is a powerful stimulusto scar formation.

The application of hydrogel provides avehicle into which the exudates may migrateand dissolve, thus removing it from thewound site without drying out the woundand allowing the formation of potential scartissue to be reduced. The use of hydrocolloid

dressings facilitates granulation tissueformation. Also, the use of these dressingssolves many of the practical problemsassociated with traditional methods ofkeeping metal plates, exposed bone andtissues moist.17

Secondary wound care addresses thecontribution made by induced vasodilation,which continues in relation to the severityof the wound. This serous transudate can

be diminished by a regimen of rest, ice,compression and elevation.

Pharmacological use of steroids andaspirin affects the transudative oedema, andtheir action inhibits prostaglandin release.

All wounds, and even controlled surgicalprocedures, require oedema care.

For healing to commence, the wound mustbe decontaminated by phagocytosis, and a

new blood supply (neovascularisation) mustthen be available.

PHAGOCYTOSISWithin blood vessels adjacent to the wound,white blood cells start to adhere to the dilatedendothelial walls. Chemical changes in thewound induce and attract these cells to slipthrough the enlarged capillary pores andmigrate to the site of injury. The mainpurpose of this phase is to prevent infectionor rid the wound of infective agents. Allwounds, even under meticulous sterileconditions, are contaminated.

Fortunately, the system of defence isperfectly adequate to prevent a minorcontamination from developing into a major

infection. Certain conditions can encouragean infection to develop. The types of bacteriapresent, the presence of foreign objects,necrotic tissue, poor oxygen supply,malnutrition, certain vitamin deficiencies,radiated tissues, and immunosuppressionmay all lead to complications.

The first white blood cells to reach thewound are polymorphonuclear leucocytes.These short-lived cells begin the processof phagocytosis by fixing to bacteria,extending their membrane around them,then enzymatically dissolving and digestingthe invaders.

Phagocytosis is the cellular process of

engulfing solid particles by the cell membraneto form an internal phagosome (food vacuole)and is a major mechanism used to removepathogens and cell debris.

Structure of the skin

The epidermis

Capillaries

Epidermis

(100 m)

Dermis

(1200 m)

Subcutaneous

fat

Stratum

corneum

Stratum lucidum Stratum corneum

Stratum spinosum

Basement

membrane

Stratum granulosum

Stratum basale

Sweat gland A rrector pili muscle

Sweat

duct

Hair

follicle

Hair

Sebaceous

glandPore

Papilla


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Within a few days of the injury, anothertype of phagocyte will predominate and remainin the wound until all signs of inflammationcease. This cell, the macrophage, has twoimportant roles in the process of repair.Macrophages are cells in the tissues thatoriginate from specific white blood cellscalled monocytes. Their role is to phagocytose

cellular debris and pathogens, either asstationary or mobile cells, and to stimulatelymphocytes and other immune cells torespond to the pathogen.

The macrophage has considerableinfluence on scar production. As a scavengercell, the macrophage not only attacks andengulfs bacteria but also disposes of necrotictissue in the wound. It is also capable ofphagocytosing in poorly nourished tissueswith low oxygen levels or can consume oxygenat over 20% of the basal rate for enhancedphagocytosis. Because ischaemic tissues aremore prone to infection than normal tissues,

the oxygen state of the wound is a criticalfactor.

Ischaemia is a restriction in blood supply,generally due to factors in the blood vessels,with resultant damage or dysfunction of tissue.

The maintenance of an adequate arterialoxygen supply for optimum phagocytosis isdependent on a sufficient blood volume andis also a function of the percentage ofatmospheric oxygen breathed (as opposed tolocal, topically applied oxygen). Macrophagesingest microorganisms and excrete products ofdigestion (ie ascorbic acid, hydrogen peroxideand lactic acid) as a result of phagocytosis.

Hydrogen peroxide aids in controllinganaerobic microbial growth, while the levelof ascorbic acid and lactic acid are interpretedas a need for more macrophages. The cycleinvolves more macrophages producing more

by-products and so leads to a more intenseand prolonged inflammatory response.

Most wounds heal without infectionbecause of the microbiocidal capacity of themacrophage population. Chronically activatedmacrophages create a chronically inflamedwound. Hydrogel can mitigate this process

by assisting the macrophage in its work byproviding a moist, exudate-solubilising

environment.Soon, fibroblasts respond to the chemicalsignals issued by macrophages. Fibroblastsprovide a structural framework for manytissues, play a critical role in wound healingand are the most common cells of connectivetissue. They secrete the precursors of all thecomponents of the extracellular matrix,

primarily the ground substance and a varietyof fibres.

The macrophage influences repair bychemically influencing the number offibroblastic repair cells activated. It is a localplatelet-derived growth factor released fromthe platelets during clotting and frommacrophages that signals fibroblasts. Themacrophage is a key factor in regulating thestages of the inflammatory period. Its presenceis vital as a phagocytic agent and an appraiserof damage, and the presence of fibroblasts

is significantly related to the final amountof scar produced.

It is of interest to note that the use ofsteroids may inhibit the macrophage leveland result in a lowering in the rate of wounddebridement and so lead to a delay in scarproduction.

Neovascularisation is the growth of newblood vessels, as healing will not proceedunless new, functioning blood vessels arepresent to supply oxygen and nourishment tothe injured tissue. It is likely that macrophagessignal this vascular regeneration to begin.Patent vessels in the outlying wound area

develop small buds or sprouts that growinto the wound area and it is these outgrowthsthat eventually will come into contact and joinup with other arteriolar or venular buds toform a functioning capillary loop.

These new circulatory loops fill the wound,creating a pink/red colour throughout thewound. As a result, the young wound will

remain much redder in contrast to adjacenttissues throughout healing because of the highconcentration of capillary loops. Those areasthat remain grey in appearance or showdelayed whitening following pressure havean inadequate circulation. As the woundapproaches final maturity the majority ofthese loops cease to function and they retract.

As a result, the fully matured scar appearswhiter than adjacent tissue.

The success of wound healing may thereforebe determined by the colour of the scar and bea guide to the prognosis of any further changesin scar characteristics. The capillary sprouts,when first formed, lack full thickness, whichrenders them delicate and easily disrupted,so immobilisation is essential during this phaseto permit vascular regrowth and prevent theformation of microhaemorrhages. As this phasecomes to a close, fibrinolysin in blood vesselsis produced to assist in dissolving clots and thelymphatic channels open to assist in reducing

the wound oedema.Under normal conditions, all these events

happen within the first four days after injuryand the main objective in treatment is tominimise all the factors that can preventor prolong inflammation.

FIBROPLASTIC PHASEWith the inflammatory phase completed,rebuilding can commence. This phase isnamed after the primary cell of scarproduction, the fibroblast.

Many different cells are involved in theinflammatory phase, but fewer types of cell

operate in the fibroplastic phase, which lastsfor about three weeks. During this phase thewound is resurfaced and strength is impartedto the wound. The fibroblasts originate frommesenchymal cells located in loose tissuearound blood vessels and fat. In response tochemotaxis, fibroblast precursors transforminto cells with migratory ability.

These migratory fibroblasts follow the fibrinmeshwork created earlier in the wound fluidmilieu, which enveloped all injured structures,and thus the fibroblasts have access to alldepths of the wound. Once in place, thefibroblast initiates its synthesis of the collagen

molecule. During this phase, three processesoccur simultaneously to achieve coalescenceand closure, and these processes areepithelialisation, wound contraction andcollagen production.

Topical application of hydrogel to a woundsite enhances wound healing and it has beendemonstrated that L-arginine increases

The epithelial cycle

Dead cornified cells of horny layer

Keratinocytes of prickle cell layer

Cells of granular layer early keratinisation

Kerati nocytes (daughters of basal cells)

Dead cells of clear layer keratinisation complete

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Join biomedical scientists in working to improve standards and communications in the pathology laboratory field.

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collagen biosynthesis18 and reduces apoptosis19

Arginine is the physiological substrate forNO synthesis, and systemic arginineadministration improves wound healing innormal individuals as well as in individualswith impaired wound healing.20

Arginine enhances wound healing andlymphocyte immune responses in humans21

and stimulates wound healing and immunefunction in the elderly.22Administration ofagents known to enhance T-lymphocytefunction, such as thymotrophic arginine,leads to increases in wound breaking strengthand collagen deposition.23,24

Several studies have reported impaired

wound healing after trauma and shock.Wound immune cell dysfunction seems to

be responsible for altered wound healing aftertrauma/haemorrhage. In this respect,administration ofL-arginine normalised woundimmune cell function under those conditions,25

and was also shown to support the successfulwound healing of diabetic ulcers.26Arginine is

beneficial in enhancing wound healing, andwas shown to reduce hospital stay in severetrauma patients, with few side effects.27

EPITHELIALISATIONThe factors critical to tissue survival are

phagocytosis, blood flow and the provisionof a surface covering. These events occur earlyin the healing process. The provision of evena one-cell layer will provide protection frominvading organisms. Neuropathic ulcersrespond well to reducing the pressure thatcaused the ulcer, removing necrotic materialsand to secure protection with a hydrocolloiddressing. Such wounds have been found toheal, on an out-patient basis, afterapproximately six weeks. All diabetic footulcers are contaminated with a varietyof organisms, but antibiotic treatmentis usually unnecessary.28

Within hours of injury, undamaged

epithelial cells at the wound margin beginto reproduce. Epithelial mitosis causesaccelerated reproduction and leads to a ridgeforming around the periphery of the wound.

These new cells are true epithelial cells and

therefore this represents a regenerationprocess.

Surviving epidermal structures such ashair shafts and sweat glands also give rise toepithelial mitoses. If the wound bed is viableand a good blood supply is available, thenmigration of these new cells begins, with thosefrom the periphery moving in and those fromappendages moving out. These migratory cellsremain attached to their parent cells and theirmovement causes tension on the normal skinaround the wound edge. The advancing edgeof the epithelium seeks out moist, oxygen-richtissue.

If the epithelial edge meets eschar, foreignmaterial, sutures or blood clots, it will plungeunder it in order to maintain contact with the

vascular loop network in the wound.The epithelial margin must release lytic

enzymes, which act to cleave the attachmentof non-viable tissue from the viable wound bed.Thus, this epithelial margin graduallyundermines and loosens the eschar, whicheventually detaches from the wound.

A red, highly vascular wound with a thin,almost transparent covering appears oncethe eschar is detached. A scab forms as atemporary barrier for the wound and should

not be disturbed until epithelialisation iscomplete.If necrotic tissue or the wound is too

extensive or oxygen availability is poor,epithelial migration cannot proceed. Ifsufficient capillary circulation is not availableto maintain epithelial integrity then wounddehiscence can occur.

Dehiscence is the premature bursting orsplitting of a wound along natural or surgicalsuture lines. It is a complication of surgery thatoccurs secondary to poor wound healing. Riskfactors include diabetes, advanced age, obesityand trauma during the post-surgical period.

When epithelial cells from one direction

meet similar migratory cells from anotherdirection, contact inhibition causes cessationof movement. Although clean, approximatedwounds are clinically resurfaced within

48 hours, larger open wounds require a longer

period of repair. Several weeks are requiredfor this thin covering to become multilayeredand to differentiate into the various strataof the normal epidermis.

The thickening process of skin healing istermed intussusceptive growth. However, skinhealed in this manner never truly developsa full basal layer of cells and will always bethinner in appearance.

WOUND CONTRACTIONEpithelialisation closes the wound surface,

but contraction pulls the entire woundtogether, in effect shrinking the defect.

A successful contraction results in a smallerwound that needs to be repaired by scarformation.

Minimising the area to be healed is trulybeneficial in certain tissues with fixed, deepstructures covered by mobile, loose skin.Wound contraction, however, may be harmfulin those areas that require every millimetreof skin and tissue length, such as the handsand face.

Allowing uncontrolled contraction is apotential problem as it will distort thetopography of the skin and cause the tissueto be drawn abnormally towards the site

of healing, causing disfigurement anddiscomfort. A specialised cell called amyofibroblast is involved in this contractionprocess. In terms of differentiation, themyofibroblast lies between a fibroblast anda smooth muscle cell.

Myofibroblasts attach to the skin margins,pull the entire epidermal layer inward, andare a feature in hypertrophic scars. Controlof wound contraction and scar formationat the time of wound formation is usefulin order to control the direction of woundcontraction and thus prevent distortion.29

COLLAGEN PRODUCTIONThe conclusion to the wound healing processis collagen production, which is essentialif wound healing is to occur. Migratoryfibroblasts are now present throughout the

The dermis

Dermis

Sub-

cutaneous

fat

Epidermis

Fat cell Collagen fibre

Capillary Fibroblast

cell

Arrector

pili muscle

Elastic fibre Hair

M acrophage M ast cell Sebaceousgland

The subcutaneous layer (hypodermis)

Hair shaft

Free nerveendings

Sm all bloodvessels

Hair root

Hair follicle

O il gland

Artery

Vein

Smoothmuscle

Adiposetissue

Epidermis

Dermis

Hypodermis

Sweat gland Nerve Receptors


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wound and it is this environment thatstimulates the fibroblasts to synthesise andsecrete collagen. The build up of lactic acidinfluences the amount of collagen produced.Adequate supplies of oxygen, ascorbic acidand other cofactors such as zinc, iron andcopper are needed to create the properbackground for fibroplasia, which is the

production of fibrous tissue, usually implyingan abnormal increase of non-neoplasticfibrous tissue.

The fibroblast synthesises threepolypeptide chains that coil to form aright-handed helix. These spiralled chains(procollagen) are then extruded from thefibroblast into the extracellular space. Onceexocytosed, the triple-helical moleculeundergoes cleavage at specific terminalsites and becomes tropocollagen.

Tropocollagens associate spontaneously inan overlapping array and eventually convolvewith other tropocollagen molecules to form

a collagen fibril. These filaments laydisorganised in the wound and are in agelatinous state. There is little strength in thiscollagen mass, which requires crosslinks andother bonding to be formed before wounddurability or tensile strength can be achieved.

Fibroblast also synthesisesglycosarninoglycans (GAG), which fill in thespace between and around collagen. ThisGAG ground substance, combined with water,provides lubrication and acts as a spacerbetween moving collagen fibres. Newcrosslinks are formed that convert mobiletissue into immobile tissue. The relationship

between GAG ground substance and collagendictates the scar architecture. A bulky, rough,tender, red scar is visible and palpable.

Oedema, infection and rough handlingcan cause the wound to become re-inflamed.Any mobilisation aimed at breaking scar tissuemay create a new wound, with further scarformations. A secondary inflamed wound willresult in collagen deposition in addition tothat already present and so the quantity ofscar produced is an indication of the finaloutcome.

SYNTHESISLYSIS BALANCE

Despite the fact that collagen synthesiscontinues at a high rate, no further increasein scar mass occurs. At this point, newcollagen is created and old collagen is brokendown in a balanced fashion as a result of theaction of the enzyme collagenase.

Collagen turnover is accelerated as oldfibrous tissue is removed and as new fibroustissue is formed. This process continues untilthe remodelling phase ends at six months toa year, depending on the state of the injury.The high rate of collagen turnover during thisstage can be beneficial or detrimental. As longas the scar exhibits a rosier appearance thannormal, remodelling is underway. However,it should be remembered that the speed ofcollagen synthesis and the laying down of newcollagen is age-related and decreases withadvancing years.

COLLAGEN FIBRE ORIENTATION

During the remodelling phase, collagenturnover allows the randomly deposited scartissue to be arranged, in both linear andlateral orientation. Scar tissue is non-elasticand attempts to mimic the characteristics ofthe tissue that is undergoing the healingprocess. The tissue structure induces the

collagen weave dense tissues induce adense, highly cross-linked scar, while pliabletissues induce a loose, coiled, less crosslinkedscar. A scar can adapt through theremodelling forces of synthesis and lysis.Sometimes the process does not function asexpected and results in unwanted scar tissuein the form of hypertrophic or keloid scars.These types of scar are the result of anoverproduction of collagen, which causesthe scar to be raised above the surroundingskin.

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26 Arana V, Paz Y, Gonzalez A, Mendez V,Mendez JD. Healing of diabetic foot ulcersin L-arginine-treated patients. BiomedPharmacother 2004; 58 (10): 58897.

27 Peng X, Yi D, Fan SZ, et al. Analysis of theinfluence on the prognosis and safety ofarginine in patients with severe traumaand burns a multi-center randomizeddouble blinded, placebo controlled, clinicaltrail in 86 patients (in Chinese).Zhonghua Shao Shang Za Zhi 2006; 22(4): 2436.

28 Laing P. Diabetic foot ulcers.Am J Surg1994; 167: 31S36S.

29 Zitelli J. Wound healing for the clinician.Adv Dermatol 1987; 2: 24367.

Dr Pascal M allefet works for Novartis

Healthcare UK and Anthony C Dweck is

technical editor ofPersonal Care. This article

first appeared in the M ay 2008 issue and

is reproduced here by kind permission.


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ARTICLE


GLOSSARY OF TERMS

BradykininsBradykinins belong to a family of short,structurally similar peptides that areimportant metabolites of the kallikrein-kininsystem. They are vasoactive nonapeptidesformed by the action of proteases on the

high-molecular-weight kininogen during thecontact phase of blood coagulation, resultingin endothelium-dependent vasodilatation andstimulation of tissue plasminogen activatorrelease from human endothelial cells.Bradykinin is released from mast cells indamaged tissues as a pain signal, and mayact as a neurotransmitter. Bradykinin alsocontracts smooth muscles, and is a potentstimulator of nitric oxide formation by

vascular endothelium. Bradykinin is involvedin oedema resulting from trauma or injuryand aids in dissolving blood clots. When it issecreted by eccrine sweat glands, it causes

the surface of blood vessels to dilate and helpsradiate excessive heat from the body surface,making it an important peripheralthermoregulatory molecule.

ChemotaxisChemotaxis is the phenomenon by which

bodily cells, bacteria and other single-cellor multicellular organisms direct theirmovements according to certain chemicalsin their environment. This is importantfor bacteria to find food (eg glucose) byswimming towards the highest concentrationof food molecules, or to flee from poisons

(eg phenol). In multicellular organisms,chemotaxis is critical to development as wellas normal function. Chemotaxis is termedpositive if movement is in the direction ofa higher concentration of the chemical inquestion, and negative if the direction isopposite.

CollagenasesCollagenases are enzymes that break thepeptide bonds in collagen. They assist indestroying extracellular structures in

bacterial pathogenesis. They are an exotoxin(a virulence factor). Collagenase production

can be induced during an immune responseby cytokines that stimulate cells such asfibroblasts and osteoblasts, and causeindirect tissue damage.

EscharAn eschar is a piece of dead tissue (scab)that is cast off from the surface of the skin,particularly after a burn injury, but it is alsoseen in gangrene, ulcers, fungal infectionsand late exposure to anthrax. Eschar issometimes called a black wound becausethe wound is covered with thick, dry, blacknecrotic tissue. Eschar may be allowed toslough off naturally, or it may require surgical

removal (debridement) to prevent infection,especially in immunocompromised patients(eg if a skin graft is to be conducted).

FibrinolysinFibrinolysis attacks and inactivates fibrinmolecules occurring in undesirable exudateson the surface of the human body and onhuman mucosa (eg in superficial woundsand burns).

FibroblastFibroblasts synthesise and maintain theextracellular matrix of many tissues. Fibroblastsprovide a structural framework (stroma) formany tissues, and play a critical role in woundhealing. They are the most common cells ofconnective tissue. The main function offibroblasts is to maintain the structural integrityof connective tissue by continuously secretingprecursors of the extracellular matrix.Fibroblasts secrete the precursors of all thecomponents of the extracellular matrix,primarily the ground substance and a variety

of fibres. The composition of the extracellularmatrix determines the physical properties ofconnective tissues. Fibroblasts can also migrateslowly over the substratum as individual cells,again in contrast to epithelial cells. Whileepithelial cells form the lining of bodystructures, it is fibroblasts and relatedconnective tissues that sculpt the bulk of anorganism.

HyaluronanHyaluronan (also called hyaluronic acidor hyaluronate) is a non-sulphatedglycosaminoglycan distributed widely

throughout connective, epithelial and neuraltissues. It is one of the chief componentsof the extracellular matrix, and contributessignificantly to cell proliferation and migration.Hyaluronan is also a major component ofskin, where it is involved in tissue repair.

Hypertrophic scar.Two types of scars are the result of the bodyoverproducing collagen, which causes thescar to be raised above the surrounding skin.Hypertrophic scars take the form of a redraised lump on the skin, but do not grow

beyond the boundaries of the original wound,

and they often improve in appearance after afew years. The other type is a keloid scar.

Intussusceptive growthIntussusceptive growth is the folding in of anouter layer to form a pocket in the surface.It is the growth in the surface area of a cell bythe deposit of new particles between existingparticles in the cell wall.

Keloid scarA keloid is the result of an overgrowth of tissueat the site of a healed skin injury. Keloids arefirm, rubbery lesions or shiny, fibrous nodulesand can vary from pink to flesh-coloured or

red to dark brown in colour. A keloid scaris benign, non-contagious and usuallyaccompanied by severe itchiness, sharp pains

and changes in texture. In severe cases,it can affect the movement of skin. Keloidsshould not be confused with hypertrophicscars, which are raised scars that do notgrow beyond the boundaries of the originalwound and may reduce over time.

Lytic cycleThe lytic cycle is one of the two cycles of viralreproduction, the other being the lysogeniccycle. These cycles should not be seen asseparate, but rather as interchangeable. Thelytic cycle is typically considered to be themain method of viral replication, as it resultsin the destruction of the infected cell.

MacrophageMacrophages are cells in tissue that originatefrom specific white blood cells calledmonocytes. Monocytes and macrophages

are phagocytes, acting in both non-specificdefence (innate immunity) and specificdefence (cell-mediated immunity) in

vertebrate animals. Their role is tophagocytose (engulf and then digest) cellulardebris and pathogens either as stationary ormobile cells, and to stimulate lymphocytesand other immune cells to respond to thepathogen.

NeovascularisationNeovascularisation is the formation offunctional microvascular networks withred blood cell perfusion, and differs from

angiogenesis in that the latter ischaracterised mainly by the protrusionand outgrowth of capillary buds and sproutsfrom pre-existing blood vessels.

PhagocytosisPhagocytosis is the cellular process ofengulfing solid particles by the cell membraneto form an internal phagosome (food

vacuole). The phagosome is usually deliveredto the lysosome, an organelle involved in the

breakdown of cellular components, whichfuses with the phagosome. The contents aresubsequently degraded and either released

extracellularly via exocytosis, or releasedintracellularly to undergo further processing.Phagocytosis is part of the immune systemand is a major mechanism used to removepathogens and cell debris. Bacteria, deadtissue cells and small mineral particles areall examples of objects that may bephagocytosed.

ProstaglandinProstaglandin is one of a number ofhormone-like substances that participate ina wide range of body functions such as thecontraction and relaxation of smooth muscle,the dilation and constriction of blood vessels,

control of blood pressure, and the modulationof inflammation. Prostaglandins are derivedfrom arachidonic acid.

wound healing 2008

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