Inflammation and ssue ReVair

MS, PA-C,PT,OCS,SCS, ATC,CSCS JulieA. Pryde,

SUM,T,IARY O1 lNFOR
-nflammation Phase(Days 1-Q lroliferation Phase(Days 3-20) -\laturation Phase(Day 9 on) lhronic Inflammation

WATlOIV

COVERED

Iactors Affecting the Healing Process Healing of SpecificMusculoskeletalTissues Clinical CaseStudy Chapter Review

OBJECTIVES
Uponcomyletion this chaVtet, readerwill beable to: of the Define inflammation and identify its possible causes. Identify the five cardinalsignsof inflammation and tfeir causes. List the phasesof tissueinflammation and repair and their relative time ftames. Describethe four responses the inflammatory of phase. Discussedemaand its qualitative variability. Describethe four processes that occur in the oroliferation phaseof healing. 7 . Differentiate between the different types of collagen and their rolesin tissue repair. 8. Describethe differences between the cellular fesponses acute and chronic inflammation. in 9. Identify local and systemicfactorsthat can affect tissuehealing. 10. Discusshow different types of musculoskeletal tissue heal. 11. List the physical agentsthat can affect or modify tissuehealing.

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Trauma or injury to vascularized tissueresultsin a coordinated,complexJand dynarnic seriesof events collectively refered to as inflammatiotl and re7air. Although there are variationsbenveenthe responses of different tissue t)?es, overall the processes are remarkably similar The sequelaedepend on the sourceand site of injury, the stateof local homeostasis, and whether the injury is acute or chronic.The ultimate goal of inflammation and repair is to restore function by eliminating the pathologicalor physical insult,replacing damaged destroyedtissue,and the or promoting regeneration noImal tissuestructure. of Rehabilitation professionalstreat a variety of inflammatory conditionsresultingftom trauma, surgical procedures, problematic healing.The clinior cianwho is calledupon to managesuchinjuriesneeds to understandthe physiology of inflammation and healingand how it canbe modified. The cliniciancan enhancehealing by the appropriate application of various physical agentsJtherapeutic exercises,or manual techniques. The foundation for a successful rehabilitation program requiresan understanding of biomechanics, phasesof tissuehealing,and the the effects of immobilization and therapeuticinterventions on the healingprocess.
Common Causesof Inflammation Soft tissue trasma (spfains, stfains, and contusions) Fractures Foreign bodies (sutures) Autoirnmune diseases (rheurnatoid arthritis) Microbial agents (bacteria) Chemical agents (acid, alkafi) Thermal agents fturns or frostbite) Irradiation (fV or radiation)

This chapterwill provide readers with information about the processes involvedin inflammationand tissue repair so they can understand how physical agentsmay be used to modify these processes and rmprovepatrentoutcome. The process inflammationand repairconsists of of three phases: inflammation, proliferation,and maturation. The inflammation phaseprepares wound the for heaiing;the proliferationphaserebuildsthe damaged structuresand strengthens wound; and the the marurationphasemodifiesthe scar ussueinto it' matureform (Fig.2-1).The durationof eachphase variesto some degree, and the phases generallyover-

2-1. Flow diagram of the normal phasesof inflamFigure

-^-r^^-J -^-^:-

One o PATHOLOGY AND PATIENTPROBLE\4S

15

Iap. Thus the timetables for the various phasesof healing provided in this chapter are only general not guidelines, precisedefinitions(Fig.2-2).

1-6) PHASE INFLAMMATION (DAYS

Inflammation, from *re Latrn inllamel meaning "to when the normal physiologyof tisseton fire," begins ot sue is alteredby disease trauma.l This immediate dilute, or isoattemptsto destroy, protectiveresponse late the cellsor agentsthat may be at fault. It is a norprerequisite healing.Ifthere is no to nal andnecessary Inflammationcan inflammation,healingcannotoccur. aisobe harmful, particularlywhen it is directedat the '.vrong tissue or is overly exuberant.Ior example, directedinflammatory reactionsthat :nappropriately '-rnderlie such as rheumatoid autoimmune diseases scarrinq,which can be :nhritis can causeexcessive

ul

(9

10 15 20 25 30 35 40 45 s0DAYS FROM TIME INJURY OF

: gure2-2. Time line of the phasesof inflammation and .,1air.

disfiguring and limit joint mobility. Although the inflammatory process follows the same sequence tesultin of of regardless the cause injury somecauses or exaggeration prolongationof certalnevents. the CorneliusCelsusfirst described inflammatory by phasenearly2000yearsagoasbeingcharacterized rubor, tumor,anddolor the four cardinal signsof calor, (Latin terms for heat, redness,swelling, and pain). (lossof function) was later addedto this laesa Functio list by Virchow, bringingthe numberof cardinalsigns of inflammationto five (Table2-1). An increasein blood in a given area, known as temhyyeremia, accountsprimarily for the increased and redness the area of acute inflammain perature tion. The onset of hyperemiaat the beginningof the inflammatory responseis conffolled by neurogenic Localswelling resultsfrom and chemicalmediators.2 of permeabiliryand vasodilatation the local increased blood vessels infiltration of fluid into the interstiand of tial spaces the injured area.Pain resultsftom the pressureof the swelling and from irritation of painreleased from damby sensitivestructures chemicals agedcells.2 Both pain and swellingmay result in loss of function. in There is somedisagreement the literatureabout the duration of the inflammationphase.Someinvestigatorsstatethat it is relativelyshort,lastingfor less and than 4 days,3'a othersbelieveit may last for up to may be the resultof indiThis discrepancy 6 days.5,6 variationor the overlapping vidual and injury-specific natureof phases inflammationand tissuehealing. of The inflammatory phase involves a complex sequence of interactive and overlapping events cellular,hemostatic,and immune includingvascular, processes. Humoral and neuralmediatorsact to control the inflammatorv phase.

Z-t Cu.airral Signs Inflammation of

Sign (Bnglish) Sign (Latin)

Heat Redness Swelling Pain LamLossof function

Calar Rubar Tumor Dolor Functio laesa

vascularity Increased vasculariry lncreased Blockage lymphatic drainage of pressure and/or chemical Physrcal structures iIIitation of pain-sensitive Painand swelling

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2 . Inllamnratiou nnd fi,,ue kfnir

Vascular Response
Alterations in the anatomy and function of the microvasculature, inciuding the capillaries, post-

capiliary venules and lymphatic vessels, among are the earliest responses the inflammatory phase.T in Trauma.such as a lacerarion. sprain.or contusion physicallydisruptsthesestructures and may produce bleeding, fluid loss,cell injury and exposure tissues of to foreign matedal,including bacteria.The damaged vessels respondrapidiy with transientconstdctionin an attempt to minimize blood loss. This response, which is mediatedby norepinephrine, generailylasts for 5 to 10 minutesbut can be prolongedin the small vesselsby serotonin releasedfrom mast cells and platelets. Followingthe transientvasoconstriction iniured of vessels,the noninjured vesselsnear the injured areadilate.Capillarypermeability also increased is by injury of the capillary walls and in responseto released chemicals from injured tissues(Fig.2,3). The vasodilation and increase in capillary permeability are initiated by histamine, Hageman f a c t o r . b r a d y k i n i n .p r o s r a g l a n d i n a . d c o m p l e sn ment fractions.Vasodilationand increased capil lary permeabilitylast for up to t hour after tissue damage.

Histamine is released by mast cells, platelets, and basophils at the injury site.dHistamine causesvasodilation and increased vascular permeability in venules, which contributes to local edema (swelling) formation. Histamine also attracts leukocytes to the damagedtissuearea.9 Histamine is activefor approximately t hour after tissue injury10 (Iig. 2-4). Separation of endothelialcell junctions creates gapsallowing leukocyte escape to

Erythrocytes

lvlargination leukocytes of on endothelialsudace Figure 2-3. Vascular responseto wound healing.

I
VasoactiveMediators . Histamine . Serotonin . Bradykinin . Anaphylatoxins . Leukotrienes/ Prostaglandins . PlateletActivating Faclors{PAF) Chemolactic Factors . Formylated Peptides . LymPhokines . Monoklnes Activation ol Plateletsand CoagulationSystem

tt
Thfombus Formatron
vasoaclrve Mediators tl

FlecruitrnenV of Stimulation Inflammatory Cells

Increased Vascular Pemeability Acute lnflammation . PMNS . Platelets Chfonic lnflammalion . Macrophages . Lymphocytes . PlasmaCells

Pe-rea5rlity

Fiqure 2-4. Mediatorsofthe inflammatoryresponse.

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Hagemanfactor (also known as dotring faaor Xll), an enzyme found in the blood, is activated by contact with the negatively charged surfaces of the endothelial lining of vesselsthat are exposed when vessels damaged. are The role of Hagemanfactor is wvofold. First,it activatesthe coagulationsystem to stop local bleeding. Second, it causes vasoconstriction and increased vascularoermeabiliw by actlvating other plasma proreins. conuert" lt plasminogen to plasmin and prekallikrein to kallikrein, and it activates the altemative complement Dath. w a y r l ( F i 82 - 5 ) . Plasmin augmentsvascularpermeability in botlL the skin and lungs by inducing breakdown of fibrin and by cleavingcomponentsof the complementsystem. Plasminalso activatesHageman factor, which initiatesthe cascade generates that bradykinin. Plasmakallikrein attractsneutrophils and cleaves kininogen to generate severalkinins suchasbradykinin. The ability of a chemical to attuactcells is known as cheffiotaxis. Kinins, suchas bradykinin,are biolog! cally active peptides that are potent inflammatory substancesderived lrom plasma. Kinins function similarly to histamine,causinga marked increasein permeability of the microcirculation.They are most prevalentin the early phasesof inflammation, after

wfif

they ge rapidly destroyedby tissueproteases

oI Ktnlnases.'"

Figure 2-5. Hageman factor activation and inflammatory

tr p.li, f^r hr^.1, '.ri^-

(PCEs)are producedby nearly all Prostaglandins cellsin the body and are released response any in to damageto the cell membrane.Two prostaglandins affectthe inflammatory phase:PGEl and PGEr.PGE, increases vascuJar permeability anragonizing by vasoconstdction,and PCE2atffactsleukocytesand synergizes the effects of other inflammatory mediators such as bradykinin. Proinflammatoryprostaglandins are alsothought to be responsible sensitizing for pain receptors. the early stages the healingresponse, In of prostaglandins may regulatethe repair process; they are also responsible the later stages inflammafor of tion.13 Steroids and nonsteroidalantiinflammatory drugs inhibit prostaglandinsynthesis.Ior example, acetyisalicylic acid (aspirin) and acetaminophen (Tylenol@)disrupt the production of prostaglandins but act at different points in their synthesis.Since prostaglandins responsible febrilestates, are for these medications effectivein reducinsfever. are The anaphylatoxins C3a.C4a.andC5aareimportant products of the complement system. These complement fractions causeincreasedvascularpermeabilify andinducemastce11 basophildegranuland taion, causinga further release histamineand thus of potentiatinga further increase vascularpermeabilin iqt QabIe2-2). Aside from the chemically mediated vascular changes, changes in physical attraction betlveen blood vesselwalls also alter blood flow. Durins the initial vasoconstriction. opposingwalls oF the rhe small vessels becomeapproximated,causingthe lining of the blood vessels stick together Under norto mal physiologicconditions, cellmembranes the the of inflammatory cells and the basement membranes have mutually repulsivenegative chargesj however, after injury this repulsiondecreases the polarity and may actuallybe reversed. This resultsin a decrease in the repulsionberween the circulatinginflammatory cellsandthe vessel walls andcontributes the adherto enceof inflammatory cellsto the blood vessel linings. As blood flow slows resultins from vasoconstriction of the postcapillary venulesandincreased permeabiliry of the microvasculature, increasein the an cellularconcentration occursin the vessels, resulting in increasedviscosiry In the normal physiological state, the cellular componentsof blood within the microvasculatureare confined to a central axial column,and the blood in conractwith the vessel wall

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2 . Inflauuntion

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2-2 Mediators of the Inflammatorv Response

Response Vasodilation
Mediators

Histamine Prostaglandins Serotonin Bradykinin C3a,C5a PAF Histamine Serotonin Prostaglandins Histamrne Monokines Kallikrein Lymphokines

Increasedvascular permeabihty

Chemotaxrs

Fever Pain

Prostaglandins Prostaglandins Hagemanfactor Bradykinin

is relativelycelf free plasma. Very early in the inflammatory response, neutrophilsin the circulatingblood begin migrating to the injured area.The sequence of eventsin the journey of these cells from inside the blood vesselto the tissueoutsidethe blood vesselis known as extavasation. neutrophils,which are a The type of leukocyte(white blood cell),breakaway from t}te centralcellularcolumn of blood and start to ro11 along the blood vessellining (the endothelium)and adhere. They line the walls of the vessels a process in known as margination. Within t hour, the endothelial lining of the vessels can be completelycoveredwith leukocytes. thesecellsaccumulate, As they lay down in Iayersin a processknown as yavemetting, Certain mediatorscontrol the adherence leukocytesto the of endothelium, either enhancing or inhibiting this process. for example, fibronectin, a glycoprotein presentin plasmaand basementmembranes, has an important role in the modulation of cellular adherence to vessel walls. After injury to the vessels, increased amountsof fibronectinare depositedat the injury site. The adherenceof the leukocytesto the endotheliumor vascular basement membraneis critical for the recruitmentof leukocytesto the site of the injury.

After margination occurs, leukocytes begin to squeeze through the vessel walls in a process known The leukocytesinsert their pseudopods asdiayedesis. into the junctionsbetweenthe endothelialcells,crawl *rrough the widened junctions, and assumea position betlveen the endothelium and the basement membrane.Then, attracted by chemotacticagents, *rey escape reachthe interstitium.This process to of leukocytemigration from the blood vessels into the perivascular tissues known asezgrationFlg.2-C1. is Edema is an accumulation of fluid within the spaceand interstitial tissues.Edemais extravascular the result of increased capillaryhydrostaticpressure, increased interstitial osmotic pressure, and an overwhelmed lymphatic systemthat is unableto accommodate this substantialincrease fluid and plasma in proteins.Edemaformation and control are discussed in detail in Chapter 11.The clinicalmanifestationof edemais swelling. The fluid that first forms edemadurins inflammation has very few cells and very litcle piotein. This fluid is known astransudate. Transudate madeup of is predominandydissolvedelectrolytesand water and has a specificgravity of lessthan 1.0.As the permeability of the vessels increases, more cellsand lower molecular weight plasma proteins cross the vessel wall, making the extravascular fluid more viscousand cloudy. This cloudy fluid, known as exudate, has a gravity of greaterthan 1.0.lt is alsocharacterspecific tzed 6y a high content of lipids and cellular debris. Exudateis often observedearly in the acute inflamto matory process and forms in response suchminor injuriesasblistersand sunburns. The loss of protein-rich fluid from the plasma reducesthe osmotic pressure within the vessels and increases osmotic pressure the interstitial fluthe of the ids.which. in turn. increases outflow of fluid from the vessels, resultingin an accumulation more fluid of in the interstitial tissue.When the exudate's concenknown as prs or tration of leukocytesincreases, is it supFurative exudate. Pus consistsof polymorphonuclear neutrophils, liquefied digestion products of underlyingtissue,fluid exudate, and very often bacteria if an infection is present. When localizedsuppurative exudateoccurswithin a solid tissue,it resultsin an abscess,localized a collection pusburiedin a tisof sue,organ,or confined space. Pyogenicbacteriaproduceabscesses. Fourmechanisms responsible the increased are for vascular permeabilityseenin inflammation.The first

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19

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Chemoanractant

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Sour"" o, ,nru,, 2-6. Illustration of leukocytic events in inflammation: margination, adhesion, diapedesis,and emigration in Figure response a chemoattractantemanatingfrom the sourceof the iniury to

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lsed first

and predominantmechanismis endothelialcell conraction, which leadsto a widening ofthe intercellular iunctions or gaps. This mechanism affects venules ',vhilesparingcapillaries arterioles. is controlled and It chemicalmediators and is relatively shortJived, by The mech for lasting only 15to 30 minutes.la second anismis a resultof direct endothelialinjury and is an immediate, sustainedresponsepotentially affecting This effect is often all levelsof the microcirculation. lytic bacterial infections,andis in burnsor seen severe plateletadhesion with and thrombooften associated endothesis or clot formation. Leukocyte-dependent bind to Leukocytes iralinjury is the third mechanism. various chemicalsand lhe area of injury and release enzvmes that damase the endothelium and thus

is The final mechanism leakage increase permeability. capillariesthat lack a differentiated by regenerating endothelium and therefore do not have tight gaps. of This may accountfor the edemacharacteristic later healinginflammatror.(Frg.2-7).

Response Hemostatic
to The hemostaticresponse injury controlsthe blood or are losswhen vessels damaged ruptured.Platelets, cellsat the siteofthe injury enterthe areaand the first fibrin to stimcollagen, releasing bind to the exposed also release regulatoryproa clotting. Platelets ulate growthfaaor (PDCF), derived tein known as Vlarelet which is chemotacticand mitogenic to fibroblasts

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MECHANISM LEAKAGE OF ANDDISTRIBUTION

2 . Inflammation and TissueRepair

Endothelial contraction . venules

Direct injury . all microvessels

Leukocyte-dependant . mostly venules .lungcapillaries

Regeneraling endothelium . capillaries . olhervessels

Arteriolar dilatation

Opening of capillary beds Increased blood tlow B

Venular dilatation
I

I s s n I I b e h I( ir

s
q

Figure 2-7. A, Illustration of four mechanismsof increasedvascularpermeability in inflammation. B, Vascularchanges associated with acute inflammation

sl g

and may alsobe chemotactic macrophages, to monocytes,andneutrophils.ls Thus platelets play a role not only in hemostasis also contdbute to the control but of fibrin deposition, fibroblast proliferation, and angiogenesis.

When fibrir and fibronectin enter the injured area they form cross-links with the collagen createa fibto rin lattice.This tenuousstructurprovidesa temoorary plug in the blood and lymph vessels, limiting local bleedingand fluid drainage. The lattice sealsoff

la * 6
tn rII

ce

Ore . PATHOLOCY AND PATIENTPROBLEMS

27

damaged vessels confinesthe inflammatory reacand tion to the areaimmediately surroundingthe injury pluggedvessels not reopenuntil The damaged, do later in the heaiingprocess. The fibrin latticeserves as the wound's only source tensilestrengthduringthe of inflammatoryphaseof healing.l6

CONNECTIVE TISSUE I\,IATRIX Basement

membranel Collagentype lV Laminin Fibronectin Proteoglycans Entaclin

VESSELS

CONNECTIVE TISSUE CELLS

@
td'.\

Mastcell

Response Cellular
Circulatingblood is composed specialized of cells in suspended a fluid known as ylasma.These cells include erythrocytes (red blood cells), leukocytes (white blood cells),and piatelets. Redblood cellsplay a minor role in the inflammatory process,although they may migrateinto the tissuespaces the inflamif matory reactionis intense. The primary role of the red blood cells,oxygentransport,is carriedout within the confinesof the vessels. inflammatory exudate Art that containsblood usually indicatessevereinjury to the microvasculature. accumulation blood in a tis The of sueor organis refeffed to asa hematama; bloody fluid that is present in a joint is called a hemarthrosis. Hematomas in muscle can cause pain and limit m o r i o n r f u n c t i o nr:h e yc a na l s oi n c r e a ss c a r i s s u e o e formation. A critical function of inflammation is to deliver leukocytesto the area of iniury via *re circulatory system.Leukocytesare classifiedaccordingto their (PMNs) and structure into polymorphonucleocytes mononuclearcells. PMNs have nuciei with several lobes and contain cytoplasmic granules.They are Furthercategorized,by their preferencefor specific histological stains, as neutrophils, basophils, and eosinophiis.Monocytes are larger than PMNs and have a singlenucleus.ln the inflammatory process, leukocytes play the important role of clearing the injured site of debris and microorganisms set the to repair(Fig. stage tissue for 2-8). Migration of leukocytes into the area of injury occurswithin hours of the in1ury.Eachleukocyte is specialized has a specific and purpose. Someleukocytes aIe more prominent in early inflammation, whereas others become more impoftant during the later stages.Initially the number of leukocytes at rhe injurysiteis proporrional theirconcenrration to in the circulatingblood (Table2-3). Sinceneutrophils have the highest concentration in the blood, they predominatein the early phases of inflammation. Chemotacticagentsreleased other by cells,suchas mast cellsand platelets, attractleuko-

Elastic fibers

rioroorast Itl

n
V

Collagen fibers

rg

l\,4acrophage

d\+d
Proteoglycans

-----,--J

Basophil Figure 2-8. Intravascular cells, colnective tissue matdx, and cellsinvolved in the inflammatory response.

$ g

2-3 Cot ."ntration of Leukocytes in Adult Human Blood

Typ" Poly morphonuclear Cells Neutrophils Eosinophils Basophils Mononucleat Cells Monocytes Lymphocytes
Concentration

62.0./. 23% 0.4./. 5.3./. 30.0%

cytes at the time of injury. Neutrophils rid the injury site of bacteria and debris by phagocytosis. When lysed, the lysosomes of the neutrophils release proteolytic enzymes (proteases)and colwhich begin the lagenolyticenzymes(collagenases),

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2 c lttllatttttntion

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debridementprocess. Neutrophils remain at the site of the injury for only 24 houri, after which time they disintegrate.However, they help to perpetuatethe inflammatory response by releasing chemotactic agents attractother leukocytes to into the area. Basophils release histamine after injury and contribute to early increasedvascularpermeability. Eosinophils may be involvedin phagocytosis some to degree. Ior 24 to 48 hoursafteran acure rnjury. monocytes predominate. Monocytes make up bewveen 4o/o and 8% of the total white blood cell count. The predominanceof thesecellsat this staseof inflammation is thoughr to resuk in parr from rheir longer lite span.Ly'rnphocytes supply antibodiesto mediatethe body's immune response.They are prevalent in chronicinflammatory conditions.
Macrophage Products Proteases Elastase Collagenase Plasminogen activator Chemotactic factors fot other leukogztes Complement components of the alternative and classical pathways Coagulation factors Growth-promoting factors for fibroblasts and blood vessels Cl'"tokines Arachidonic acid metabolites Monocytes are converted into macrophages when they migrate from the capillaries into the tissue spaces. The macrophage is considered the most important celi in the inflarnmatory phase and is essen-

tial for wound healing.Macrophages important are becausethey produce a wide range of chemicals. They play a major role in phagocytosis producing by enzymes such as collagenase(Fig. 2-9). These enzymesfacilitatethe removal of necrotictissueand bacteria.Macrophages also produce factors that are chemotactic other leukocytes. for Macrophages probablyplay a role in localizing also the inflammatory process attractingfibroblasts and to the injuredareaby releasing chemotactic factorssuch as fibronectin. Macrophages chemically influence the number of fibroblastic repak cells activated; therefore,in the absence macrophages, of fewer, less mature fibroblastsmigrateto the injuredsite. Platelet derived growth factor (PDGI) releasedby platelets during clotting is also released macrophages by and canactivatefibroblasts.In the later stages fibroplaof sia,macrophages may also enhancecollagendeposition by causing fibroblasts adhereto fibrin. to As macrophages ingest microorganisms, they excrete productsof digestionsuchashydrogenperoxide, ascorbic acid, and lactic acid.17Hydrogen peroxideassists the control of anaerobic in microbial growth. The other two products signal the extent of the damagein the area, and their concentration is interyreted by the body as a need for more macrophages the area.l8This, in turn, causes in increasedproduction of by-products, which then resuitsin an increased macrophage population and a more intenseand prolongedinflammatoryresponse. Macrophages most effectivewhen oxygen is are presentin the injured tissues. However,they can toleratelow oxygen conditions,as is apparentby their presencein chronic inflammatory states.Adequate oxygentensionin the injuredareais alsonecessary to minimizethe riskof infecrion. issue I oxygentension

Macrophage

Figure 2-9. Diagrammatic represntationof the processof phagocl,tosis.

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depends the concentration atmospheric on of oxygen available for breathing, the amount of oxygen by absorbed the respiratoryand circulatorysystems, and the volume of blood availablefor tlansDortation. as well as rhe stare of the tissues. Local topical application of oxygen to an injured area does not influencetissueoxygen tension as much as the level of oxygenbrought to the injured areaby the circuiating blo6d.le-2t

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lmmune Response
The immune responseis mediated by cellular and humoral factors. The roles of lyrnphocytes and phagocyticleukocytesin the immune response were previously. discussed The other mechanisminvolved in the immune responseis the complementsystem which is an important source vasoactive of mediators. The complementsystemis one of the most important plasmaprotein systemsof inflammation as its components participate in virtually every inflammatory

Let
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response. The complementsystem can be activated by antigen-antibody complexes and by bacteria,foreignmaterial,and other cellularproducts. The complementsystem is a seriesof enzymatic plasma proteins that is activated by two different pathways, the classical and the alternative.22 Activation of the first componentof either pathway of the cascaderesults in the sequentialenzymatic activationof the downstreamcomponents the casof cade(Fig.2-10).The end product of the cascade, by either pathway, is a complex of C6, C7, C8, and C9, which form the membraneattack complex (MAC). The MAC creates pores in plasma membranes, *rereby allowing water and ions into the cell. This causes loss of membraneintegrity and cell lysis. The subcomponents generated earlier in the cascade also have important functions. Activation of components C1-C5 produces subunits that enhance inflammationby making bacteria more susceptible to phagocytosis (known asopsonization), attracting leukocytes by chemotaxisand acting as anaphylatoxins.

en ral :nt on )re ;es en la e. is of eir

Ite

Classical Pathway Activated immune by complexes antibodies of withantigens

Alternative Pathway Activated cell by surfaces

ActivatesClr+C1s

to on

ActivatesC6, C7, C8, C9 to form membraneattack complex (MAC)

Figure 2-10. Overview of the complement system- classical and alternativeactivation pathways.

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2 . ltrflarnrnatiortntt/1 li.,ttc Rcfatr

Anaphylatoxins inducemastcellandbasophil degranu- the classical pathway, C1, C2, and C4 are not pathway. lation, causing the release of histamine, platelet involved in the alternative activatingfactot and leukotrienes. Thesefurther proln summary therearethreemajor consequences of vascuiar mote increased permeability. the inflammatory phase.Iirst, fibrin, fibronectin,and The classicalpathway of the complement cas- collagencross-linkto form a fibdn lattice that limits cade is activated by an antigen antibody complex blood loss and providesthe wound widr some initial interactingwith *re first componentof the complestrengdr.Then macrophages begin to remove damment cascade, C1 consists threeproteins: C1. of C1q, aged tissue.finally, endothelialcells and fibroblasts C l r . a n d C l s . C i q b i n d s t o t h e a n t i g e n - a n t i b o d y are recruitedand stimulatedto divide. This sets the complex, resultingin a conformationalchange.Clr 2-4). stage the proliferationphaseof healing(Table for enzymaticallyactivatesC1s so that it can act on C4 and C2. C4 and C2 are cieaved form C4bC2a, ro a PR0LtFERATt0N (DAYS PHASE 3-20) complex that acts as a C3 convertase. is cleaved C3 into C3b and C3a by the C3 convertase. C3b then The secondphaseof tissuehealingis known as the cleaves producingC5aand C5b. C5b activates C5, yhase.Thisphasegenerallylastsfor up to the Vroliferation production of the terminal products of the cascade, 20 daysand involvesboth epithelialcellsand connecc6-c9. tive tissues.lo purpose to coverthe wound and Its is The alternativepathway of the complementcas- impart strengthto the injury site. cadeis activatedby a variety of cellularand microbial Epithelial ceils form the covedng of mucous and productsand by foreign material.The binding of C3 serousmembranes,and the epidermis of the skin. with tlvo plasmaproteins,factorsB and D, catalyzes Comective tissueconsists fibroblasts, of ground subthe conversionof C3 to C3bBbwhich functionsas a stance, and fibrous strandsand providesthe structure generating C3 convertase additional C3a and C3b in for other tissues. The structure,strength,and elastican amplificationstep.C3b then cleaves C5, resulting ity of connctivetissuevariesdependingon the type in the formation of the MAC, C6-C9. In contrastto of tissue comorises. orocesses it Four occur simultane-

,-O ,"--ary
Response

of Events the InflammatoryPhase of

Changes in the injured area

Vascular

Vasodilation followed by vasoconstnction the capillaries, postcaprllary venules, and lymphatics at Vasodilation mediatedby chemicalmediators histamine,Hageman factor,bradykimn, prostaglandins, complementf ractions Slowingofblood flow Margination,pavementing, ultimatelyemigrationof leukocytes and Accumulationof fluid in the interstitialtissues resultingin edema Retractron sealing of blood vessels and off Platelets form clotsandassist burldingoffibrin lattice,which serves the wound's source in oftensile as strengthin the inflammatoryphase Delivery ofleukocytesto the areaof injury to rid the areaof bacteria and debrisby phagocl,tosrs Monocytes,the precursors macrophages, considered most important cellin the of are the inflammatoryphase Macrophages producea numberofproducts essentral the healingprocess to Mediatedby both cellularand humoralfactors Activationof the complement pathwaysresultingin systemvia the alternative and classical components that increase vascuiar permeability, stimulatephagocytosrs, act aschemotactic and stimuli for leukocytes

Hemostatic

Cellular

lmmune

One . PATHOLOCY AND PATIENT PROBLEMS

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d
rd o. )le c)e e-

perpendicuthey begin to align themselves increases, lar to the capillaries. composed The fibroblastssynthesizeprocollagen, polypeptide chainscoiled and held together of three bondsinto a triple helix. These by weak electrostatic chains undergo cleavageby coilagenaseto form Epithelialization tropocollagen.Multiple tropocollagen chains then of :oithelialization, *re reestablishment the epider- coil together to form collagen fibrils, which then make up collagenfilaments and ultimately combine ::ris,is initiated earlyin prolilerationwhen a wound is ..rperficial. often within a few hours of injury73 to form collagen fibers (Fig. 2-13). CrossJinking .\tLena wound is deep,epithelialization occurslater, between collagenmoleculesprovides further tensile =:ter collagen production and neovascularization. strengthto the injuredarea. Tissue containing the newly formed capillaries, :oithelialization providesa protectivebarrierto pre-.ent fluid and electroly'te and to decrease risk to the fibroblasts, andmyofibroblastsis referced asgranuloss by lation tissue.As the amount of granulation tissue :i infection.Healingof the wound surface epithethereis a concurrent reductionin the sizeof -:alizationalone doesnot provide adequatestrength increases, the fibrin clot, allowing for the formation of a more 3 meet the mechanicaldemandsplacedon most tisTheseeventsare medipennanentsupportstructure. :ues. Suchstrengthis provided by the collagenproated by chemotacticfactorsthat stimulate increased :uced duringfibroplasia. During epithelialization,uninjured epithelial cells fibroblasticactivity and by fibronectinthat enhances The fibrobof misration and adhesion the fibroblasts. :om the margins of the injured area reproduceand tasas initially produce a thin, weak-structuredcolla:rigrate over the injured area,coveringthe surfaceof --rewound and closingthe defect.It is hypothesized genwith no consistent organizationknown asty7eIII Thrs period is the most tenuoustime during rat the stimulusfor this activity is the lossof contact collagen. due to the limited tensilestrength the healingprocess :rhibition that occurswhen epithelial cells are norof the tissue. During the proliferation phase an =ally in contact with one another. The migrating yet :rithelial cells stay connectedto their parent cells, injured areahas the greatestamount of collagen, -:rerebypulling the intact epidermisover the wound its tensile strensth can be as low as 15% of that of normaltissue.2i :Cge. When epithelial cells from one edge meet Iibroblasts also produce hyaluronic acid, a glyrigrating cellsfrom the other edge,they stop moving (CAC), which draws water into *re :ue to contactinhibition (Iig. 2-11).Aithough clean, cosaminoglycan matrix, and the :.oproximatedwounds can be clinically resurfaced area,increases amount of intracellular '.,.'ithin hours, larger open wounds take longer to 48 facilitatescellularmigration. It is postulatedthat the is compositionof this substance relatedto the num]t :esurface,24 *ren takes severalweeks for this thin thereby implyber and location of the cross-bridges, ,ayerto becomemultilayeredand to differentiateinto (Frg.2-12). ing rhat the relationship benveenCAC and collagen strata normalepidermis of =e various 17'28 dictates scar the architecture. allows the newly The formation of cross-1inks Production Collagen formed tissueto tolerateearly,controlledmovement without disruption. However, infection, edema, or ibroblasts make collagen. Fibroblast growth, may resultin further stress onthe healing area takesplacein connective tissue. excessive :nown asfibroplasra. hflammation and additional depositionof collagen. mesenchy:ibroblastsdevelopfrom undifferentiated collagendepositionwill result in excessive Excessive ral cells located around blood vesselsand in fat. that may lirnit the functional outcome. 1ey migrate to the injured areaalongfibrin strands, scarring By the seventhday afterinjury thereis a significant to influences, arepresent and :r response chemotactic causing tensile the increase the amount of collagen, in Adequatesuppliesof i.rroughoutthe injured area.25 strength of the injured area to increasesteadily.By :>,ygen,ascorbicacid, and other cofactorssuch as day 12, the initial immature ty?e IIl collagenstartsto and copper are necessary for inc, iron, manganese, As :broplasia to occur.26 the number of fibroblasts be replacedby type I collagen,a more mature and :us1y in the proliferation phase to achieve coales:ence and closureof the injured area:epithelializa:on, collagenproduction, wound contraction, and ::eovascularization.

26

2 o Itflannation

anl7'issra

Refair

With Injurybasal cells detach irom the basementmembrane.

ce s

The cells migratewhile holdingon to their 'parent'cells and pulllhem into the center to close the wound. Contact Inhibition

when thetwosrdes meet, movement ceases,

Basalcells differenliate and proliferate...

...1o becomemultilayered and restorethe epidermis.

Figure . Schematic 2-11 diagramof epithelialization.

strongerform.16,29,30 ratio of type I to type III colThe lagen increases sreadily from chis pojnron.

Wound Contraction
Wound contractionis the finai mechanismfor repairing an injured area.In contrast to epithelialization, which coversthe wound surface, contraction pullsthe edgesof the injured site toged-rer, effect shrinking in the defect.Successful contractionresultsin a smaller areato be repairedby scarformation. Contractionof the wound beghs approximately5 days after injury

and peaksafter about 2 weeks.31 Myofibroblastsare the primary cel1s responsible wound contraction. for Myofibroblasts,identified by Gabbianiet aI rn 1971, are derived from the same mesenchymaicells as fibroblasts.32 Myofibroblastsare similarto fibroblasts exceptthat they alsopossess contractile the properties of smooth muscle.Myofibroblastsattachto the margins of the intact skin and pull the entire epithelial layerinward.The rateof contraction proportionalto is the number of myofibroblastsat and under the cell marginsandis inversely proportionalto the latticecol lagenstructure.

Otc . PATHOLOCY AND PATIENTPROBLEMS

27

HEALING PRIIVARY BY INTENTION 24 hours

HEALING SECONDARY BY INTENTION

3 to 7 days

lvlitosis Granulationtissue lvlacrophage Fibroblast New capillary

Fibrous union
Wound contraction

; ale rion.

)7r,
iasts rties :rar_ :e1ial ral to :cell : colFigure2-l2 Diagrammatic comparison of healing by primary intention (left) and secondaryintention (right).

Accordins

rn

rhc

.'.t,''o

tr:mc

th"^^,

.h"

'.vound margin beneath the epidermis is the location :f myofibroblast action.33 A ring of myofibroblasts noves inward from the wound margin. Although :ontractile forces are initially equal, the shape of the

picture frame predictsdre resultantspeedof closure (Frg.2-14).Linear wounds with one narrow dimension contract rapidly;square rectangular or wounds, wi*r no close edges, progress a moderate at pace; and circularwounds contractmost slowly.34

28

2 . lrrflotnrnationnnd li..tc Rcynir

Collagen filament Collagen fibril

Primitive coUagen fiber Collagen fibers

Wounds that are rapidly closedwith sutureswith minimallossoltissueandminimalbacterial contamination can heal without wound contraction.This is known a, healing yrimaryunionytimaryinrenrion bv or When thereis significant lossof tissueor frst ixtention. bacterialcontamhation,wound contractionis necessaryto close wound. Wound contraction the feathe is ture that most clearly differentiatesprimary ftom secondary healing,alsoknown as healing secondary by intentiox iadirect or uniou.36 Later approximationof a wound's edges with sutures the application skin or of graftscan reducewound contraction and is krrown as healiug delayed by yrimatyintention '38 minimize con.37 fo traction,graftsmust be appliedearlyil the inflammatory phase, beforethe process ofcontractionbegins.39 As scartissuematures, develops it pressure and tension-sensitive nerveendingsto protect the immature vascular system, which is weak and can bleed easilywith any insult. During the proliferationphase, the scaris red and swollen due to the increase vasin cularity and fluid, the innervationof the healingsite, and the relativeimmatudty of the tissue.The tissue can easily be damagedand is tender to tension or pressure.

Figure 2-13.Dragran-matic representalion one uopocolof lagenunit joinirg wirh orhersro lorm collagen tilamenrs and, ultimately, collagenfibers.

Neovascularization
Neovascularization, developmentof a new blood the supply to the injured area, occurs as a result of angiogenesis, the growth of new blood vessels. Healing cannot occur without angiogenesis. These new vessels are needed to suppiy oxygen and nutrients to the injured and healing tissue. It is thought that macrophages signal the initiation of neovascularizatron. Angiogenesis can occur by three different mechanisms: generation of a new vascular network, anastomosts to preexisting vessels,or coupling of the vessels the injured area.4o in Vesselsin the wound periphery develop small buds that grow into the wound area. These outgrowths eventually come in contact with and join other arterial or venular buds to form a capillary loop. These vesselsfill the injured area,giving it a pinkish to bright red hue. As the wound heals, many of these capillary loops ceaseto function and retract, giving the mature scar a more whitish appearance than the adjacent tissues. Initially the walls of these capillaries are thin, making them prone to injury Therefore immobilization at this stage may help to protect these vesseis and permit further regrowth, whereas excessiveearly

Figure2-14. Illustration of the picture frame theory of wouno contlactron.

If wound contraction is uncontrolled it can result in the formation of contractures. Contracrures are con ditions of fixed high resistance to passive stretch that may ^result from fibrosis of tissues surrounding a joint.35 Contractures may also result from adhesio'ns, muscle shortening, or tissue damage. Contractures are discussed greaterdepth in Chapter 5. in

One . PATHOLOGY AND PATIENT PROBLEITIS

29

/ith
JLS

motion can causemicrohemorrhagingand increase 'he likelihood of infection.

p ,-s aou"*enTypes
Tw"
Distribution

,or 30r

PHASE I0N) MATURATToN (DAY

-\s dre transitionfrom the proliferationto the maturaion stage healingis made,changes of occurinthe size, :orm, and strengthof the scartissue.The maturation rhaseis the longestphase the healingprocess. can in It for over a year alter *re initial insult. During rersist -Jristime the number of fibroblasts,macrophages, nyofibroblasts,and capillaries decrease the water and :ontent of the tissue deciines.The scar becomes '.vhiterin appearance the collagen as maturesand the '.'ascularity decreases. ultimate goal of this phase The ofthe prior functionof the injuredtissue. :srestoration Severalfactors determine tl-terate of maturation :rrd the final physicalcharacteristics ofthe scar. These :rclude fiber odentation and the balanceof collasen .vnrhesis lysis. and Throughout the maturation phase, synthesis and lysrs of collagen occur in a balancedfashion. llormonal stimulation secondary to inflammation :ausesincreased collagendestructionby the enzyme Collagenase derived from polymoris ;ollagenase. :nogranular leukocytes, the migrating epithelium, ai-rd granuiationbed. Collagenase ableto break the is -re strong crossJinkingbonds of the tropocollagen =olecule,causingit to becomesoluble.It is then .xcretedasa wasteby-product.Although collagenase :smost activein the actualareaofthe injury its effects :an alsobe noticed,to a lesser extent,in areas adja-enr to the injury site. Thus remodelrngoccurs --:rrough process collagen a of turnover. Collagen, glycoprotein,providesthe extracellular a :amework for all multicellularorganisms. Although :ore than 27 types of collagenhave been identified, is re following discussion limited to types I, Il, and molecules madeup of are -llr' f|able 2-5).AII collagen -rree separatepolypeptide chains wrapped tighdy :ogether a triple left-handed in helix.Type I collagen is re primary collagen found in bone,skin, and tendon, andis the predominantcollagen maturescars. in Type -l collagenis the major coliagenin cartilage. Type III :ollagenis found in the gastrointestinal tract, uterus, in and blood vessels adults.It is also the first woe of :olJagen be deposited ro duringrhehealing proceis. During the maturationphase,the collagensynthe;ized and depositedis predominantlyrype I. The bal:nce between synthesisand lysis generallyslightly

Most abundantform ofcollagen:skn, bone,tendons,and most organs

:om :lary rfa skin nas ma39 and leed

II III IV

Major cartilage collagen, vitreoushumor rrterus, skin Abundantin blood vessels, Ali basement membranes Mrnor componentof most interstitial ussues

VI VII UII

Abundantin most interstitialtissues junctron Dermal-epidermal Endothelium Cartilage Cartilage

x
X

SItC,

ssue nor

looo rgionew ts to that

^-L

f the buds wths artehese

rioht

illary ature rt trstnm, tltza^ :ssels early

favors synthesis.As type I collagenis strongerthan the rype III collagendepositedin the proliferation phase,tensile strengthincreases faster than mass.If the rate of collagenproduction is much greaterthan the rate of lysis, a keloid or hypeftrophic scar can result. Both keloids and hypertrophic scarsare the result of excessive collagendepositiondue to inhibition of lysis. lt is believedthat this inhibition of lysis is due to a genetic defect. Keloids extend beyond the original boundaries of an injury and invade the suffounding tissue,whereas hypertrophic scars, although raised, remain within the margins of the original wound. The treatment of keloid scars through surgery medications,pressure, and iradia44 tion hasonly limited success.42 Collagen synthesis is oxygen dependent,while collagenlysis is not.asThus, when oxygenlevelsare low, the processof maturation is weighted toward lysis,resulting a softer,lessbulky scar. in Hypertrophic scarscan be managedclinicallywith prolongedpressure,which causes decrease oxygen,resultingin a in decreased overall collagensynthesiswhile maintaining the level of collagenlysis.37 This is one of the basesfor the use of pressuregarmentsin the treatment of patientssufferingftom bums, and for the use of elastomer the management scars hand therof in in apy. Eventually,balanceis achievedwhen the scar normal tissue. bulk is flattenedto approximate

30

2 . Inflannatiou

and fi>:uc Rerair

Collagensynthesisand lysis may last for up to 12 to 24 monthsafreran injury. The high rateof collagen turnover during this period can be viewed as both detrimentaland beneficial.As lonq as the scartissue appears redder rhanthe surrounding tissue, rernodeling is sLill occurring. AJthough joint or rissue a srructure canIosemobiliry quickly duringthis stage, sucha Ioss can still be reversedthrough appropriateinterventron. The physical structure of the collagen fibers is largely responsible the finalfunction rheinlured tor of area.Collagenin scartissueis always lessorganized than collagen in the surrounding tissue. SCarsare inelastic,so redundantfolds are necessary Demit to mobiliryof the srruturesto which they areattached. To understand this conceptbetter,onemay consider a spring,which, aithoughmadeof an inelasticmaterial, has a spiraledform that, like the redundantfolds of a scar,allows it to expandand contract.If short, dense adhesions are formed, these will restrict motion because they cannotelongate. Two theorieshave been proposedto explain the orientation of the collagenfibers in scar tissue:tlre inductiontheory and the tensiontheory.Accordingto the induction theory the scarattemptsto mimic the charactedstics the tissue it is healins.46 of Thus a dense tissue induces dense. a highlycro"s-linled scar, whereasa more pliable tissueresultsin a loose,less cross-linked scar.Densetissuetypes havea preferential status when multiple tissue types are in close proximity. Basedon this theory, surgeons attempt to designrepair fields that separate denseand soft tissues.If this is not possible,as in the caseof repaired tendonleft immobileover bone Fracrures, adhlsions and poorly gliding tendonscan result.In such cases, earlyconrrolled movement may be beneficial. According to the tension theory, the intemal and extemalstresses placedon the injuredareaduring the maturationphasedeterminethe final tissuestructure.aoMuscle tension, joint movementJsoft tissue loadingand unJoading. fascialgliding. temperarure changes, and mobilizatjon are alJ forces that are thought to affect collagensfiucture.Thus the length and mobility of cheinjuredareamay be modified-by the applicationof stress duringthe appropriate phases of healing.This theory has been supported by the work of Arem and Madden, which has shown *rat the two most important variables responsible sucfor cessful remodeirngare the phasei of the repair process which mechanjcal in forces were introduced

and the natureof the appliedforces.aT Scars needlowload, long-duration stretch during the appropriate phasefor permanentchanges occur to Studies haveshown *rat the applicationof tension duringhealingcauses increase censile an in strength. and immobilization and stress deprivation reduce tensilestrengthand collagenstructure.The recovery curves for tissue experimentally immobilized For bet:ween and 4 weeks reveal that these processes 2 cantakemonths to reverse, reversal oftennever and is complete. Eachphaseof the healingresponse necessary is and essential the subsequent to phase.In the optimal scenario,inflammation is a necessarv aspectof the healingresponse the [irst srept;ward recovery, and seting rhe stagefor the ocherphases healing. of It repeatedinsults or injury occur,however, a chronic inflammatory response may develop that can adversely afFect outcomeof the healingprocess. the Acute inflammatory processes can have one of four outcomes. Iirst, and most beneficial, the comis plete resolutionand replacement the injured tissue of with like tissue.Second, and most common,is healing by scarformation.The third is the formation of an abscess. Fourth is the possibility of progressionto 1o chronicinflammation.

CHRONIC INFLAMMATION
Chronic inflammation is the simultaneousproqression of activeinflammation. tissuedestruccion,-and healing.Chronicinflammationcanarisein oneof two ways. The first follows acute inflammation and can be due to the persistence the injurious agent(such of asa cumulativetrauma)or to someother interference with the normal healing process.The second is a resultof an immune response eitheran alteredhost to tissueor a foreign material,such as an implant or a suture,or is t}le resultof an autoimmunedisease such asrheumatoidarthritis. The normal acute inflammatory processlasts for no morethan2 weeks.II ir continues morechan for 4 weeks,it is known as subacute inflammation.3 Chronrc inflammationis inflammationthat lastsformonths or years. The primary cells presentduring chronic inflammation aremononuclear cellsincludinglymphocytes, macrophages, monocytes(Iig. 2-15).Occasionally and eosinophils alsopresent.aB progression the are The of inflammatory response a chronicstateis a resultof to

O e . PATHOLOGY AND PATIENT PROBLEMS

31

Leukocyte
e

CharacteristicsFunctions /
Associatedwith . chronic inflammation . phagocytosts ibrolyticpathways Regulatescoagulation/f Regulateslymphocyteresponse when they emigrate Ivlonocytes convertedto macrophages are from capillanesinto the tissue spaces

n
IJ

Lysosome

v
)t :S

:r

v
^l IC

a =
Associatedwith . chronic intlammation immuneresponse and cell-mediated Key cell in humoral

v'
If ic
tn

rf
:l-

te Ll' tn

Lymphocyte

Sparse endoplasmic reticulum

ro
Granules

Associatedwilh . allergicreactions . parasiticinfectionsand associatedinflammatory reactrcns reactions Modulatesmasi cell-mediated

rS-

rd
1Q

Eosinophil

ch ce
a )st :a

Assocrated with . acuteinflammation . baclerial foreign and bodyphagocytosis

ch
:OI

r4 ric
OI

m1ly he oI

@
Basophil

. Not phagocytic . Contarnshistamine,which causes increasedvascular permeabilfy

Figute 2-15, Cellular components of acute and chronic inflammation.

32

2 . Itflafltfiatiot

awl Tissre Repair

both immunologicand nonimmunologicfactors.The macrophage an important sourceof inflammatory is a n di m m u n o l o g im e d i a c o as di s a n i m p o r t a nc o m c rn r ponent in the regulationof their actions.The role of eosinophils much lessclear, is althoughthey are often presentin chronic inflammatory conditions that are caused allergicreactions parasiticinfection.4s by or Chronic inflammation also results in increased fibroblastproliferation,which in turn increases collagen production and ultimately increases scar tissue and adhesionformation. This may lead to a loss of function asthe delicatebalance betweenootimal tensile strengthand mobility of tbe involvei tissues is lost.

Smallerwounds heal faster than larger wounds, and sursicalincisionsheal faster*ran wounds caused by blunl trauma.l6Softtissueinjuriesover bonestend preventingcontracto adhereto the bony surfaces, tion and adequate oppositionof the edges and delaying healing.l6 lnfection Infection in an injured area is the most problematic local factor that can affect healing.Among the complications of wound healing, S0'/" are due to local infection.ll Infections affect collagen metabolism, reducingcollagenproduction and increasinglysis.49 lnfectionoften preventsor delayshealingand encourl6 granulauon ages excessive tissue formation. Vascularsupply The healing of injuries largely dependson the availability of a sufficient vascular supply. Nutrition, oxygen tension, and the inflammatory responseall depend on the microcirculatory system to deliver rheir components.50 Decreasedoxygen tension blood supplycanresult resultingfrom a compromised in the inhibition of fibroblastmigration and collagen slmthesis, leadingto decreased tensilestrengthof the injured area and increasedsusceptibility to infection.2o

FACTORS AFFECTING HEALING THE PROCESS

A number of factors, either local or systemic, can impact or modify the processesof inflammation and repav (Table 2-A1.Localfactors that can affect wound healing include the type, size, and location of the injury infection, blood supply, and external physical forces.

Local Factors

Type, andlocation size, oftheiniury Injurieslocated well-vascularized in tissue, suchas the scalp, heal fasterthan thosein poorlyvascular- Extefnal forces
ized areas.16 Injuries in areas of ischemia, such as those that may be caused by arterial obstruction or pressure, excessive heal more slowly.16

h
p

2-6 FactorsInfluencing Healing

Local Systemic

Type, size,andlocationofinjury Ag" Infection Vascular supply Movement/excessive pressure Temperature deviation Topicalmedications Electromagnetic energy Retained foreignbody Infection disease or Metabolicstatus Nutrition Hormones Medication Fever Oxygen

The application of physical agents including thermal agents,electromagnetic energy,and mechanical forcesmay also influenceinflammation and healing. Cryotherapy (cold therapy), thermotherapy (heat), therapeutic ultrasound electromagnetic radiation, have all electricalcurrents,and mechanicaipressure been used by rehabilitation professionalsin an attempt to modify the healingprocess. The impact of thesephysicalagentson tissuehealingis discussed in each type of Section2 of this text, which describes physicalagent,its effects,and its clinicalapplications. Movement Early movement of a newly injured area may delay healing.Thereforeimmobilization may be usedto aid early healing and repair.However, sinceimmobiliry can result in adhesions and stiffness by altering collagencrossJinkingand elasticiry continuouspassive motion (CPM) with stricdy controlled parameters is often usedto remobilize and restorefunction safelv.)rThe use of CPM in coniunctionwi*r short-

One o PATHOLOGY AND PATIENT PROBLEMS

33

ied nd ac-

rtrc mcal
i0, -19

:erm immobilization, compared to immobilization alone, has been shown to achieve a better func:onal outcome in some studies; however, odrer only in early rangeof srudieshave found differences Ir =ocion.5753 has also been reponedrhar padents :iilizing CPM during the inflammatory phaseof soft :ssue healingafter anterior cruciateligament reconjrruction usesignificandylesspain-relieving narcotics -,:ran patientsnot usingcPMs4(Fig.2-10.

Factors Systemic
Age because variations of -\ge is a factor to be considered :r healingbetween the pediatric,adult, and geriatric :opulations.In childhood,wound closure occurs :rore rapidly than in adulthood because physiothe -rgical changesand cumulative sun exposure that -;cur wtth aging can reducethe healingrace.ss A of :ecreasein the density and cross-linking collagen, '...'hich resultsin reducedtensile strength,decreased :-umbersof mast cells and fibroblasts,and a lower s: rre oI epiLne]ializaLion. in the elderly.56 1n" occurs of :oor organization cutaneous vessels olderpeoin affectswound healing. :le alsoadversely Disease --.' number of diseasescan affect wound healing ::ther direcdy or indirectly.Ior example,poorly con:ol1eddiabetesmellitus impairs collagensynthesis, r:r.creases risk of infection due to a dampened the and -:rununeresponseJ decreases phagocytosis to due 58 irerations in leukocytetunction.S0 Peripheral vas:.rlar compromiseis alsoprevalentin this population,

ur-

-:]
ofl,

all ver ion' iult 9n

Lhe

leading to a decrease in local blood flow. Neuropathies, which are alsocommon,canincrease the potential for trauma and decrease ability of the softtissue lesions heal. to Patientswho are immunocompromised,such as those with acquired immune deficiency syndrome (AIDS) or those taking immunosuppressive drugs after organtransplantation, more prone to wound are infections because they have an inadequateinflamAIDS alsoaffectsmany other facets matory response. of the healing processthrough its impairment of phagocytosis, fibroblast function, and collagensynthesis.59 Problems involving the circulatorysystem,including atherosclerosis, sicklecell disease, and hypertension, can also have an adverse effect on wound healing since inflammation and healing depend on systemfor the delivery of compothe cardiovascular oxygen nents to the local area of injury Decreased tension resulting from a reducedblood supply can result in an inhibition of fibroblast migration and a decreased collagensynthesis,resulting in decreased tensilestrengthandmakingthe injuredareamore susceptibleto reinjury Wounds with a decreased blood supplyarealsomore susceptible infection.20'60 to Medications Patientswith injuries or wounds often take medications with systemiceffectsthat alter tissuehealing. Forexample, antibioticscanpreventor fight off infection, which can help to speedhealing but may also havetoxic effectsthat inhibit healing. Corticosteroids,such as prednisoneand dexamearly on ethasone,block the inflammatory cascade by blocking the release of arachidonic acid.61 Corticosteroids havebeenshown to impair all phases and inhibitof healingby stabilizingcell membranes ing the production of prostaglandins.They also decrease margination,migration, and accumulathe tion of monocytesat the siteof inflammation.62 They severely inhibit wound contracture, decrease rate the and decrease tensilestrength ahe of epithelialization, 66 Corticosteroids of closed, healed wounds.63 that are administeredat the time of injury have a greaterimpact because decreasing inflammatory the phases response this early stagedelayssubsequent at of healingand increases incidence infection. the of In comparisonwith corticosteroids, nonsteroidal antiinflammatory drugs (NSAIDs)such as ibuprofen are lesslikely to impair healing.They act later in the

tc-

IEI-

ical

LOn,

I AII an tof dLn rof )ns.

Figure 2-16.CIM machine. (Courtesy Thera-l(netics Jompany, Cherry Hill, New Jersey.)

34

2 . l la

Rq'ait tnaliol, oud Tis<rrc

interruptingthe production of inflammatory cascade, prostaqlandinsfrom arachidonic actd6r Fil 2-77). affectthe function ih"y Jr. ttot thorrghtto adversely NSAIDs can of fibroblastsor tissue macrophages.6T causevasoconstrictionand suppressthe intlammahowever, and some NSAIDs have tory response,l2 been found to inhibit celi proliferationduring tendon healing.6B

Nutrition Nutrition can have a profound effect on healing tissues.Deficiencyof any o[ a number of important amino acids,vitamins, minerals,or water, as well as insufficient caloric intake, can result in delayed or stress physiological impairedhealing.This is because from the injury inducesa hypermetabolicstate.Thus if insufficient "fuel" is availablefor the processof inflammationand repair,healingis slowed. ln most cases,healing abnormalities are asso- HEALINGSPECIFIC OF ciated with general protein-calorie malnutrition TISSUES MUSCULOSKELETAL rather than depletion of a single nutrient.69Such is of The primary determinants the outcomeo[ any the casewith patientswith extensivebums who are injury are the type and extent of the injury the rege-nhypermetabolicstate A protein de[iin a prolonged eritive caoaciw of the tissuesinvolved, the vascular fibroblasticproliferaciency can result in decreased lo andthe extentof damage srte, tion, reduced proteoglycanand collagensynthesis, supplvof the iniured of basicprincrples lhe framework. and disrupted collagen the extracellulai decreasedangiogenesis, all tissues;howremodeling./0Protein deficiency can also adversely inflammation and healing apply to which may lead to an increased ever, there is some tissue specificity to the healing affect phagocyto_sis, even For response. example,the liver can regenerate riskoI infection.ou

Studieshave shown that a deficiency of specific nutrients may also affect healing. Vitamin A defithe ciencvcanretardepithelialization, rateof collagen and croisJinking.TlThiamine (vitamin B) synthesis, collagenformation, and vitamin ieficiency decreases the B. deficiencydecreases tensilestrengthof healed Vitamin the ti"ssue reduces fibroblastnumber.72'73 and C deficiency impairs collagensynthesisby fibroblasts, increasesthe capillary rupture potential, arld /a the increases susceptibilityof wounds to infection Many mineralsalsoplay an important role in healthe ins. Insufficientzinc can decrease rate of epithereduce collagensynthesis,and decrease lialization, -o may also deficjency suength.-5 Magnesium tensile and copperinsutsynthesis, collagen causedecreased to ficiencymay altercrossJinking,leading a reduction in tensilestrength./a

acted on by NSAIDs and steroids 2-17, Comparison of the site in the inflammatory cascade Figure

Ore . PATHOLOCY AND PATIENT PROBLEMS

35

when over half of it is removed, while even a thin is hactureline in cartilage unlikely to heal.

Cartilage
it Cartilagehas a limited ability to heal because lacks However, lymphatics, blood vessels,and nerves.77 ;artilage reactsdifferently when injured alone than -.vheninjured in conjunction with dre subchondral 'cone to which it is attached.Injuriesconfinedto the ;artilage do not form a clot or recruit neutrophilsor nacrophages,and the cells adjacent to the injury ,how a limited capacityto induce healing.This limgenerallyfails to heal the defect, and :red response -Jrese lesionsseldomresolve.Ts In injuries that involve both articular cartilage and subchondralbone, the vascularizationof the :ubchondralbone allows for the formation of fibrinibronectin gel, giving accessto the inflammatory -ells and permitting the formation of granulation :ssue. Differentiationofgranulationtissueinto choncan begin within 2 weeks. NormafappearCrocytes ng cartilagecan be seenwithin 2 months after the has njury However,this cartilage a low proteoglycan is thereforepredisposed degeneration :ontent and to changes./Y :nd erosive

r ) f

:I

Tendons Ligaments and

of Iendons and ligamentspassthrough similar stages in realing.Inflammationoccurs the first 72 hours,and :o1lagensynthesis occurs within the first week. occursfrom intrinsic sources suchasadja- ibroplasia :ent cells,and from extrinsic sourcessuch as those :rought in via the circulatorysystem. The repair potential of tendon is somewhat con=oversial.Both intrinsic cells such as epitendonous cellsand extrinsicperitendonous :nd endotendonous rells pafticipate in tendon repair.The exact role of -Jrese cellsand the final outcome dependon several :actors,including the type of tendon, the extent of the supply,and iamage to the tendonsheath, vascular -he duration of immobilization. The first two stages rftendon healing,inflammationandproliferation,are similar to the healing phasesof other tissues.The -hird phase,scarmaturation,is unique to tendonsin -iat this tissuecan achievea state of repair closeto :egeneration. During the first 4 days following an injury, the with an infiltration of nllammatory phaseprogresses

both extrinsicand intrinsic cells.Many of thesecells while othersbecome developphagocyticcapabilities, fibroblastic.Collagensynthesisbecomesevident by predominatingat around days7 to 8, with fibroblasts day 14.Earlyin this stage, both cellsand collagenare oriented perpendicularto the tendon's long axis.80 This orientation changes day 10, when new collaat parallelto the old gen fibersbeginto alignthemselves For longitudinalaxis of the tendon stumps.Bl the following 2 months,thereis a gradualtransitionofalignment, through remodelingand reorientation,parallel to the lone axis. Ultimate maturation of the tissue on loading. depends sufficientphysiological If the synovial sheathis absentor uninjured, the relative contributions of the intrinsic and extrinsic are cellsare balancedand adhesions minimal. If the synovial sheath is injured, the contributions of the of extrirsic cellsoverwhelm the capacities the intrinare sic cellsand adhesions common. Factors affectingthe repairof tendonsare different with the repair of ligaments.s2 from those associated Studieshave shown that mobilization of tendonsby and strengthcontrolled forcesaccelerates enhances ening of tendon repair, but mobilization by active contractionof the attachedmusclelessthan 3 weeks after repair generallyresultsin a poor outcome.]he poor resultsmay be a result of the fact that high tension can leadto ischemiaand tendon rupture.Recent in studieshavefound no significantdifference tendon are exposed controlledlow to strengthwhen tendons lt or high levelsof passiveforce after repair.8384 appears that mechanicalstressis neededto promote appropriate oientation of the collagen fibrils and remodelingof collageninto its mature form and to optimize strength,but the amount of tensionnecessary to promote the optimal clinical response not is
certaln."",""

Many variablesinfluencethe healing of ligamentous tissue,the most important of which are the rype of ligament,the sizeof the defect,and the amount of and loadingappiied.For example,injudesto capsular extracapsular ligaments generallystimulate an adewhile injuries to intracapsular quate repair response, ligamentsoften do not. In the knee,the medial collateral ligament often heals without surgicalintervention, whereasthe anteriorcruciateligamentdoesnot. These differencesin healing may be due to the s)movial environment, the limited neovascularizatistion, or the fibroblastmigrationfrom surrounding sues.Treatments that stabilize the iniurv site and

36

2 c Inflannatiot

atdTissue Repait

Young children have a more elastic bone structure that allows their bones to bend, accountingfor the greenstick-type fractures seenin this population. Muscle Skeletal Induction is the stage when cells that possess Muscles maybe injured blunttrauma by causing cona osteogenic capabilities activated.lnduction is the are tusion,byviolent contraction excessive or stretchcaus- least well-understood stage of bone healing. lt is ing a strain,or by muscle-wasting diseases. Although thought that the cells may be activatedby oxygen skeletal musclecellscannotproliferate, stemor reserve gradients, proteins,or nonforces,bonemorphogenic cells,known as satellite rclls,can,under some circumcollagenousproteins. Although the timing of this stances, proliferate differentiate form new skele- process not known exactly,it is thought to be initiand to is tal musclecellsafterthe deathof adultmusclefibers.79 ated after the moment of impact.The durationof this Skeletal musclereseneration beendocumented has in stage alsonot known, althoughthe influenceof the is musclebiopsy tp.ii-".rr kom patientswith diseases induction forcesseems lessen to with time. Therefore such as musculardystrophy and poll'rnyositis;howoptimizing the early conditions for healing to miniever, skeletal muscle regenerationin humans after mize the potentialfor delayed union or nonunionis traumahas not beendocumented. Followins a severe imperative. contusion. calciFied a hematoma.known is nyasiis Inflammationbeginsshordy after impact and lasts ossifcans, develop.Myositis ossificans rarefof may is until somefibrousunion at the fracturesiteoccurs. At lowing surgery hemostasis controlled. if is the time ofthe fracture, thereis disruptionofthe blood supplyand formationof a fracturehematoma, well as asa decrease oxygentensionand pH. This environin Bone ment favors the growth of the early fibrous or cartilagiBone is a specialized tissuethat is able to heal itself nous callus.This callusforms more easilythan bone with like tissue.Bone can heal by two mechanisms: and helpsto stabilizethe fracturesite, decrease pain, primary or secondary healing.Primaryhealingoccurs andlessen likelihoodof a fat embolism.lt alsorapthe with rigid internalfixation of the bone,while second- idly andefficiendyprovides scaffold furthercircua for ary healingoccursin the absence suchfixation. of latiorqandfor canilage endosteal and boneproduction. Bone goes through a seriesof four histologically The amount of movement at the fracturesite infludistinct stagesin the healing process: inflammation, encesthe amount and quality of the callus. Small soft callus,hard callus,and bone remodeling.Some amounts of movement stimulate callus formation, investigators alsoincludethe stages impactionand of while excessive movement can disrupt callusformainductionbeforeinflammationin tltis scheme. tion andinhibit bony union. Impactionis the dissipationof the energytrom an The soft callus stage begins when the pain and insult. The impact of an insult is proportionalto the swelling subsideand lasts until the bony fragments energy applied to the bone and is inverselyproporare united by fibrous or cartilaginoustissue. This tional to the voiume of the bone. Thus a fracture is period is marked by a greatincreasein vasculariry more likely to occurif the forceis greatot the bone is ingrowth of capillariesinto the fractufe callus, and small. Energydissipatedby a bone is inverselyproincreased proliferation.The tissueoxygentension cell portional to its modulus of elasticity.Therefore the remains low. but the oH returns to normal. The bone of a personsufferingfrom osteoporosis, which hematoma becomes organized with fibrous tissue has low elasticiry will sustaina fracturemore easily. cartilageand bone formation; however, no callus is

maintainthe appositionof the torn ligamentcanhelp *re ligamentheal in its optimal length and minimize scarring.However, mature ligamentousrepair tissue sT is still30% to 50olo weakerthan uninjuredligament. This does not usually clinically significantly impair joint function because the repairedtissue is usually larger than the uninjured ligament. Early, controlled loading of healingligamentscan also promote healing, althoughexcessive loading may delay or disrupt the healing process.88,89

Stages of Fractsre Healing 1. Impaction 2. Induction 3. Inflammation 4. Soft callus 5. Hard callgs 6. Remodeling

Orc t PATHOLOGY AND PATIENT PROBLEMS

37

) Clinical CaseStude a
The following casestudy summarizesthe conceptsof inflammationand repairdiscussed this chapter. in Based on the scenariopresented, evaluationof the clinical an findingsand goalsoftreatment areproposed. with pain noted especiallywi*r plantarflexion and inversion. She exhibits a decreased stance phase on the right lower extremity. Pain and weakrressoccur on strengti tests of the peroneals,gastrocnemius, and soleusmuscles.JP also exhibits a marked decrease in proprioception,as evidencedby the single-leg balance test.Her anteriordrawertestis positive,and hertalar tilt rsne8at1ve. EVALUATION CLINICALFINDINGS OF The patient presents with impairmentsof pairl loss of subtalarand talocmalmotioq decreased strengthof the evertomand plantarflexors, increased girth of the right ankle, and decreased proprioceptionresultingin functional iimitation of ambulationand sportsactivitv. She performs home activities independently,without che useof adaptiveequipment. PREFERREDPRACTICEPATTERN Impaired joint Mobiliry, Motor Function, Muscle Performance, and Range of Motion AssociatedWith Coonective TissueDysfunction,(4D). PLAN OF CARE The goals of treatment at this time are to control the pain and edema,accelerate resolutionof the acute the inflammatory phaseof haling,and speedthe recovery olJP'snormalrangeof motion, strength, proprioception, and function.

Case 4
high schoolstudent.Sheinjured her JPis a 16-year-old right anlle 1 week ago playing soccerand was treated conservativelywith crurches;rest, ice. compression. and elevation (NCE); and NSAIDs. She rcports some improvement,althoughsheis unableto play soccerdue to continued complaints of right lateral ankle pain. Her x-rayfilms showedno kacture,andherfamily physician diagnosed the injury as a grade II lateral ankle sprain. Shecomesto your clinic with an order to (evaluateand treat.' JPsustainedthis injury during a cutting motion while dribblinga soccer ball. Shenoted an audiblepop, immediate pain and swelling,and an inabiliry to bearweight. Shereportsttrat herpainhas decreased intensityftom in 8/10 to 6/10 but that it incleases with weight bearing and with certain demonstrated movements. The objectiveexam reveals moderatewarmth of dre skin of the anterolateralaspect of the right ankle. Moderateecchymosis swellingare alsonoted,with and a girth measurement of 34 cm on the right ankle compared with 30 cm on the left. Her range of motion is restrictedto 0 degreesdorsiflexion,30 degreesplantarflexion,10 degrees inversio4 and5 degrees eversion,

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visible radiographically. The callusis electronegative :elative to the rest of the bone during *ris period. Osteoclasts remove*re deadbonefrasments. The hard callusstagebeginswhei a sticky.hard ;allus coversthe endsof the fracture,and endswhen 1ew bone uniteswith the fragments. This period corto periodofclinical and radiological :esponds d:)e fracrure healing.The duration of this period dependson ;he fracture location and the patient's age, and can rangeftom 3 weeksto 4 mon*ts. The remodelingstagebeginswhen the fractureis 'coth clinicallyand radiologically healed.It endswhen -,hebone has returned to its normal state and the catency of the medullary canal is restored. The ibrous bone is convened to lamellar bone, and the nedullary canalis revised. This process take sevcan eralmonths to several yearsto complete.90

CHAPTER REVIEW
The processesof inflammation and tissue repair involve a complex and dynamic seriesof events,the ultimate goal of which is the restorationof normal function. In these events the involved tissue progresses through three stages: inflammation,proliferation, and maturation. The inflammation phase involves interaction of hemostatic.vascular cellular. andimmuneresponses mediated a numberof neuby ral and chemical factors.The proliferation phaseis characterized epithelialization, by fibroplasia, wound contractior\ and neovascularization. maturation The phaseinvolvesbalancedcollagensynthesisand lysis to ultimately remodelthe injuredarea. This seriesof eventsfollows a similar timely and predictablecourse.If the normal healing processis interferedwith however, healingmay be delayedor

38

2 e ln[Iammaion

and Ti>sue Reyair

CF, RM et al: In vivo incisional 15. Pierce MustoeTA, Senia wound healingaugmented PDCF and recombinant by c-sis gene homodimeric proteins, / E^xyMed 167: 975,987,1988. in 16. Maninez-HemandezA, Amenta PS:Basicconcepts wound healing. In Leadbener \48, Buckwalter JA, lxflammatlo4 ParkRidge, GordonSL,eds:Spons-lxduced IL, 1990, AmericanAcademyof OnhopaedicSurgeons. 17. Hardy M: The biology of scar formation, Phys Ther 69:1074-1024,1989. 18. RutherfordR" RossR: Plateletfactorsstimulatefibroblasts and smooth muscle celis quiescent in plasma serumto proliferate, CellBlol69:196-203,1976. J 19. Mathes S: Roundtablediscussion:probiem wounds, References ye Pers ctPIasrrc Surg 2 :89-120, 1988 MedrcalDrcnoxaryed 25, Baltimore, 1990, L. Stedmar's 20. Whimey JD, Heiner S, Mygrant BI et al: Tissue and Williams & Wilkins. wound healingeffectsof sholt duration postoperative 2. Price SA, Wilson LM: Pathophysiology: Cliwcal o*lgen therapy, Biol Res NursJan;2(3):206-215 . ol Protesses, 2, New York, 1982, ed Coxcepts Disease ,2001 21. Davidson JD, Mustoe TA: Oxygen in wound healing: McCraw Hili. more than a nutrient, \1(/oundReValr Regen May3. KellettJ: Acute soft trssuenjunes a review of the ht5 2001,. Med St SVorts erature, Ererc18:489-504,1986. Jun;9 Q):17 - 177, ed: III, 4. Galrett WE Jr,LohnesJ: Cellularand matrix responses 22. Bell.anttJA, Imnunology ed 3, Piitadelphia,1985, WB Saunders. to mechanical injury at the myotendmousjunction. In 23. Werb A, Cordon S: Elastase secretionby stimulated Ieadbetter\48, BuckwalterJA, Cordon SL,eds:Spons' macrophages, ItducedInflammauot, Park fudge, IL, 1990,American J ExyMed 142:361-377 5 . , 197 24. Madden JW: Wound healingrbiologic and clinical feaAcademyof Orthopaedic Surgeons. DC, ed: Davk-Chrktoyher Textbook of tures.ln Sabiston 5. AndriacchiI Sabrston DeHavenK et a1:Ligament: P, ed 1997, WB Saunders. Swgety, 1L, Philadelphia, Injury andrepair InWoo SL-l BuckwalterJA, It4ury eds: of 25. Clark RA-F:Overview and general considerations and ReVait theMusculosleeletal llsaes, Parkfudge, of Saft wound repair. In Clark MF, Henson PM, eds: Tle IL, 1988, American Academyof Orthopaedic Surgeons. Molecular atd Cellular Biology of \Y/oundRepak, New 6. CarrettWE Jr:Musclestraininjuries:Clinicaland basic York, 1988,PlenumPress. aspects, Med Se Spons Exerc22:436 443,1990. 26. Stotts NA, Wipke-Tevis D: Co"factors in impaired 7. Fantone Ward PA:Inflammation.ln RubrnE, Farber JC, 1996. wound healing,Ostony42(2):44-56, Pathology, Pl'riladelphra, 1988, Lippincott. lL, eds: JB applications experimental of studS: L Wrlkerson CB: lnflammauon ln corurectlvelisoue: 27. Levenson Practical ies rn the care of primary closedwounds, An J Surg and ment.Athl Ttututkg20:298-301 . etrolog'y manage , 1985 . 104:273-282 9. ChristieAI: The tissueinjury cycleand new advances , 1962 M. A: toward its management openwounds, Athl Trafuing 28. Nemeth-Csoka Kovacsay The effect o[ glyin (CAC) on the intramolecularbindcosaminoglycans 26:274-277 , 1,991. ngs of collagen, ActaBiol30(4):303-308, 1,979. SL, Pathologic 10. Robbrns KumarV CotranRSet al: Robbins 29. Lachman SM Soft TissueInjuries ut Spotts, St. Louis, ofDisease, Basis ed5, Philadelphia, 1994,WB Saunders. 1988, Mosby. 11. Fantone JC: Basic concepts in inflammation. In Leadbetter WB, BuckwalterJA, Gordon SL, eds:S7otls- 30. Hunt TK, Van Winkle W Jr: Wound healing. In Treatment and Healing, HeppenstallR3, ed: Fracture lwlucedhflamnalox, Park tudge, IL, 1990, American Philadeiphia, 1980, WB Saunders. Academyof OrthopaedicSurgeons. 31. Daly T: The repair phase of wound healing: 1984,WB 1.2.PeacockEE\!/ound RepaLr, ed3,Phlladelphia, re-eprthehalization and contraction. In Kloth L, Saunders. in McCullochJ,Feeder eds \X/ound Healing: Abernatives 13. SalterRB,SimmonsDF,Malcom BW et al: The biologil, Management, Phl.adelphia, 1990, Davis. FA cal effectsof continuouspassive motion on the healing oI of fu1lthrckness defects arhcularcartilage, BaneJoint 32. Cabbiani C, Ryan G, Majeno Gr Presence modified in J fibroblastsin granulationtissueand their possiblerole Swg 62-A:1,232 1, 1980. 125 1971. in wound contractioo, Experiertia 27:549-550, 14. Majno G, PaladeCE: Studieson inflammauon.L The 33. Watts CT, Grillo HC, GrossJ: Studiesin wound heal effect of histamine and serotoninon vascularpermeAr?l ing: II. fhe role ofgranulationtissuein contraction, ability: an electronmrcroscoprc study,/ Bnphys Biochem - 60, 58. Surg l4B1,53 1, 1,9 Cytol ll57l,1961,. chronic inflammation may result. Various local and systemic factors can influence the progression of inflammation and tissue repair, including physical agents utilized by clinicians to facilitate the healing process. The rehabilitation specialist must assessthe state of inflammation and repair to determine the appropriate agent to incorporate into the treatment plan for an optimal outcome. The reader is referred to the Evolve Website at http://evolve.elsevier.com/ Cameron for study questions pertinent to *Lis chapter.

One . PAIHOLOGY AND PATIENT PROBLEMS

39

-VcGrath MH, Simon RHr Wound geometry and the kinetics of *re wound contraction,PlastReconstr Surg 72:66-73,1983. Taber's Cyclopedic Medical Dicuonary, 75,Philadelphia, ed 1985, Davis. FA Billngham RE, RussellPS:Studieson wound healing, with special reference the phenomena to ofconftacture rn expe mental wounds in rabbit skin, Am Surg 144:961, . , 1,956 SawhneyCP,Monga HL: Wound contracture rabbits in and the effectiveness skin graftsin preventingitJBlr of Plast urg23:318-321, S 1970. Stone PA, Madden JW: Biological factors affecting -548,197 wound contraction, SurgFotuu 26:547 5. RudolphR: Contractionand the control of contraction, VorldI Surg4:279-287, 1980. Alvarez OM: Wound healing. In Fitzpatrick T, ed: in Dermatology Ceneral Medicite,ed 3, New York, 1986, McCraw-Hill. EyreDR: The collagens musculoskeletal tissues. of 5oft In LeadbetterWB, Buckwalter JA, Cordon SL, eds: SVons Induced lxflammatiott,Park Ridge, IL, 1990, American Associarion Orthopaedic of Surgeons. McPhersonJM, Piez KA: Collagenin dermal wound repair.In Clark RAI, HensonPM, eds:Ile Molecular aftd Cellular Biologyof \Yound Repai, New York, 1988, PlenumPress. Kosaka M, Kamrishi H: New concept of ballooncompression wear for the treaffnent of keloids and hypertrophic scars, PlastRecottstr SargOct;108(5): 1454-1,455 . , 2001 Uppal RS,Khan U, KakarS et al: The effectsof a single doseof 5-fluorouracilon keloid scars: clinicaltrial of a timed wound irrigation after extralesionalexcision, Plast Recottstt Oct;108(5):12f8-1224, Sutg 2001.. Hunt TK, Van WinlleW: Wound Healing: NormalRepair - Fundamentals \Yourd Managemettin Swgery,South of Plaintield. 1976, NJ, Chirurgecom, Inc. MaddenJ:Wound healing:the biologicalbasisof hand surgery, PlastSutg3:3-11, Clh 1976. Arem AJ, Madden IW: Iffects of stress on healing wounds: I. Intermittent nonryclica\ tensi.on, SurgRes J 20:93 02,1976. 1 Fantone JC: Basic concepts of inflammation. In Leadbetter WB, BuckwalterJA,Cordon SL,eds:Sponslnduced Inflammauon, Park fudge, IL, 1990, American Academyof Orthopaedic Surgeons. Irvin T: Collagenmetabolismin rnfectedcolonicanastomoses, urgCyxecol S Obstet 143:220-224, 6. 197 CanicoT, Mehrhof A, CohenI: Biologyofwound healng, SurgClin Nonh 64:721-733,l9B4. An Woo SL, GelbermanRM, Cobb NC et a1:The importanceof controlledpassive mobilization on flexor tendon healing: a biochemical study,Acta OnhoVScatd 52:61,5-622,1,981.

52. CelbermanRH, Woo SL,LothringerK et al: lffects of early intemittent passiveimmobilization on healing canineflexor tendons HandSurgT:170-175, 1982. ,l 53. Lau SK, Chiu KY Use of continuouspassivemohon after total knee arthroplasty, Anhtoylasty Apr;16(3): / 336-3392001 . , 54. McCar*ry M\ Yates CK, Anderson MA et al: The effcts of immediate continuous passivemotion on pain duringthe inflammatoryphaseof soft tissuehealancerior cruciare Iigament reconsuucEion, ing following (2\:96-101, 1993. IOSPT 17 55. Thomas DR: Age-relatedchangesin wound healing, -620,2001. Aging18(8):607 Drugs 56. Holm-Peterson Viidik A: Tensilepropertles P, and morphologyof healingwounds in young and old rats,Scand Reconstr 6:24-35, Surg !972. I Plast 57. van de Kerkhoff PCM, van BergenB, Spruijt K et al: Age-related changes in wound healing, Cln Lrerc 4, Dernatol1,9:369-37 1994. 58. Goodson W, Hunt T: Studies of wound healing in experimental diabetesmellitus,/ SurgRes22:22L227, 1997. 59. Peterson Barbul A, BreslinR et al: Significance M, of T-lymphocytesin wound healing, Surgery 2:300-305, 1987. 60. Cogia PP: The biology of wound healtLng, Ostomy 38(9):12-22, . 1992 61. LeadbetterWB: Corticosteroid injection therapy n sports injuries. ln Leadbetter SE, Buckwalter JA, GordonSL,eds:Spo*-lxduced l(lannation, Parkfudge, IL, 1990, AmericanAcademyof OrthopaedicSurgeons. 62. Behrens TW, Coodwin JS: Oral corticosteroids.ln \48, BuckwalterJA,Gordon SL,eds:SportsLeadbetter Ixducedlaflannation, Park fudge, IL, 1990, American Academyof Orthopaedic Surgeons. 63. EhlrichH, Hunt T: The effectof cortisoneand anabolic steroidson the tensilestrengthof healingwounds,A tl . Sutg 170:203-206 , 1969 64. BakerB, Whitaker W: Interfercnce with wound healing by the local ac on of adrenocorticalsterolds. 46.544-551, Eudoctixology 1950. 65. Howes E, Plotz C, Blunt J et al: Retardation wound of -1,81,,1,950. healingby cortisoneSurgery 28:177 , 66. Stephens Dunphy J, Hunt T; The effect of delayed F, administration of corticosteroids wound contracon ture,Ann Surg173:214-218 1. , 197 67. Abramson SB:Nonsteroidalanti-inflammatorydrugs: mechanisms action and therapeuticconsiderations. of In LeadbetterWB, Buckwalter JA, Cordon SL, eds: SVons-lxduced lnflammatlox,Park fudge, IL, 1990, AmericanAcademyof OrthopaedicSurgeons. 68. fuley CP,Cox M, HarrallRL et al: Inhibition of tendon cell proliferatronand matrix glycosaminoglycan synthesis by non-steroidal anti-inflammatory drugs in vitro,J HandSurg[Brl]rn;26(3):224-228, 2001.

40

2 . Iaflamnation and TissueRepair

69. Albina JENutrition in wound heaLng,/Parnter E4teul

80. Strickland JW: Flexor tendon injuries, Otthoy Ret

15(10):21, 1986.

-37 Nutr18(4):367 6, 1,994. 70. PollackS:Wound healing:a revtew.III. Nutritional factors affectrngwound healing,J Dernatol Sutg Onco! 1,979. 5:615-619, 7 1 . FreimanM, SerfterE, Connerton C: Vttamin A defi1'970. s:rress, Forutt21t81-82, Sutg, cienry andsurgical on influence colRL: 72. AlverezOM, Grlbreath Thramrne lagen during granulation of skin wounds, J Surg Res . 32:24-311982 , 73. GrenierJF,AprahamianM, Cenot C et al: Pantothenic acid (vitamin Br) effioency on wound healing, Acta . Vtaminol Enzymol 4:81-85 1'982 , 74. Pollack S: Systemicdrugs and nutritional aspectsof wound healing,C/laDernatol2:68-80,7984. et 75. Sandstead HenriksenLK, GreferJL al:Zinc nutri' HH, ture in the elderly rn relauonto taste acuiry immune and response, wound healng, An J Cln Natr 36(Suppl 1982. 5):1046-1059, 76. Maitra AK, Dorani B: Roleof zinc m post-injurywound 1992. rg heahtg,Arch Eme Med Jut;9(2):122-124, RJ KA, ShahAR, Hernandez et al; Basicsci' 77. Athanasrou ence of arttcular cartilage repatr, Clin Spons Med :2 Ap420(2) 23-247,2001. 7 8 . GelbermanR, GoldbergY An K-N et al: Tendon ln Woo SL-l Buckwalter JA, eds: It4ury and Repar of Soft Tssues, Park fudge, IL, 1988, Musculosheletal Surgeons. AmericanAcademyof Orthopaedic muscle. In et 79. CaplanA, CarlsonB, FaulknerJ al: Skeletal Woo SL-Y Buckwalter JA, eds ltlury and Repai of Park fudge, IL, 1988, Soft Tissues, Musculosheletal Surgeons. AmericanAcademyof Orthopaedic

8 1 .LmdsayWK: Cellularbrologyof flexor tendonhealing

LH, Mackin EJ, eds Tendon ln Hunter JM, Schnerder Mosby. Hand,St Louis, 1987, of Sutgery the brology Lrgament AkesonWH, FrankCB,Amiel D et a1: and biomechanics. In Frnnerman G, ed: Ameticax or Symyostuw Syons Surgeon's Acadenyof Onhoyaedrc M eddne SrLours,1985,Mo sby. , 83. KetchumLD: Primarytendonhealing:a revie:w, Haxd J 1977 Surg,2:428'435, . 84. Goldfarb CA, Harwood F,Silva MJ et al: The effect of vanatlons rn applied rehab rtation force on collagen concentration and maturation at t}le intrasynovial flexor tendon repair slte, J Hatd Sutg lA,:tt] 4 Sep;26(5):B I -846, 2001. 85. PeacockEE Jr: Brologicalprinciples in the healing of long tendons,Srrg Cln NonhAn 45:46L-476,1965 86. Potenza AD: Tendon healng wthin the flexor digital sheathin the dog,J Boxe lont Sutg44A:49-64, 1,962. liga87. FrankC, Woo SL-l Amiel D et al:Medial collateral rn assessment rabbits, ment healing:a multrdrscrplnary Med 1L.379'389,1983 AnJ Spons BB. FronekJ,FrankC, Amiel D et aLThe effectsof intermitmotron (lPM) in the healingof medial coltent passlve Res lateralligaments,Ir4 nsOrthoV SocS:31,1983. 89. Long M, Frank C, SchacharN et al: The effects of motion on normal and healingirgaments TMnsOfthol , Res SocT:43,1982. 90. McKibben B: The brology of fracturehealing in long 8 bones, Boneont Surg(Bk) 60:150'162197 . , I J