The Principles of Wound Healing

Diabetes MellitusLarger arteries, rather than the arterioles, are typically affected Sorbitol accumulationIncreased dermal vascular permeability and pericapillary albumin depositionImpaired oxygen and nutrient deliveryStiffened red blood cells and increased blood viscosityAffinity of glycosylated hemoglobin for oxygen contributing to low O2 deliveryImpaired phagocytosis and bacterial killingNeuropathy

49Nutritional Supplements

Vitamin C ( Ascorbic Acid) Essential cofactor in synthesis of collagenExcessive concentrations of ascorbic acid do not promote supranormal healing

Vitamin ETherapeutic efficacy and indications remain to be definedLarge doses of vitamin E inhibit healingIncrease the breaking strength of wounds exposed to preoperative irradiation

52Nutritional SupplementsGlutamineEnhance actions of lymphocytes, macrophages and neutrophilsGlycineInhibitory effect on leukocytes, might reduce inflammation related tissue injuryZinccommon constituent of dozens of enzymesInfluences B and T cell activityepithelial and fibroblastic proliferation is impaired in patients with low serum zinc levels53

4 Another example of wounds that would require special attention This patient has gangrene of the distal extremitiesWounds

Crush injury woundIssues to consider and resolve includeviability of the remaining tissuesability to salvage the extremityfunctionality of the limb if it can be salvaged5WoundsReconstructive LadderSimple to Complex

Formal Debridement, Elevation/ABIsAppropriate IV ABX, Wound Vac, Skin Graft6Review of Wound HealingThree basic types of healingPrimaryDelayed PrimarySecondary

7PrimaryWound surfaces opposedHealing without complicationsMinimal new tissueResults optimal

8Delayed PrimaryLeft open initiallyEdges approximated 4-6 days later9This would be applicable for wounds in potentially infected fields or in situations where wound infection is very likely Perforated DiverticulitisGun shot wound to the abdomenSecondarySurfaces not approximatedDefect filled by granulationCovered with epitheliumLess functionalMore sensitive to thermal and mechanical injury10Secondary Wound Healing

11Secondary Wound Healing

12Secondary Wound Healing

13Three Phases of Wound HealingInflammatory PhaseProliferative PhaseRemodeling Phase14

15Three Phases of Wound HealingInflammatory PhaseProliferative PhaseBegins when wound is covered by epitheliumProduction of collagen is hallmark7 days to 6 weeksRemodeling Phase (Maturation Phase)16Inflammatory Phase

Hemostasis and InflammationDays 4 - 6 Exposed collagen activates clotting cascade and inflammatory phaseFibrin clot = scaffolding and concentrate cytokines and growth factors17Inflammatory: GranulocytesFirst 48 hours (Neutrophils)Attracted by inflammatory mediators Oxygen-derived free radicals Non-specific18Inflammatory: MacrophagesMonocytes attracted to area by complementActivated by:fibrinforeign body material exposure to hypoxic and acidotic environmentReached maximum after 24 hours Remain for weeks19Inflammatory: Macrophages Activated Macrophage:Essential for progression onto Proliferative PhaseMediate:Angiogenesis: FGF, PDGF, TGF- & and TNF-Fibroplasia: ILs, EGF and TNFSynthesize NO Secrete collagenases

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21

Inflammatory Phase

23Inflammatory Phase

24Inflammatory Phase

25Three Phases of Wound HealingInflammatory PhaseProliferative PhaseRemodeling Phase26Proliferative PhaseEpithelization, Angiogenesis and Provisional Matrix FormationBegins when wound is covered by epitheliumDay 4 through 14Production of collagen is hallmark7 days to 6 weeks27Type III collagen is produced first in healing woundIt is later replaced by Type I collagen as wound healing progressesEpithelializationBasal epithelial cells at the wound margin flatten (mobilize) and migrate into the open wound Basal cells at margin multiply (mitosis) in horizontal directionBasal cells behind margin undergo vertical growth (differentiation)

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Proliferative: FibroblastWork horse of wound repairProduce Granulation Tissue:Main signals are PDGF and EGFCollagen type IIIGlycosaminoglycansFibronectin Elastin fibersTissue fibroblasts become myofibroblasts induced by TGF-130Wound ContractionActual contraction with pulling of edges toward center making wounds smallerMyofibroblast: contractile propertiesSurrounding skin stretched, thinnedOriginal dermal thickness maintainedNo hair follicles, sweat glands31Epithelialization/Contraction

32Epithelialization

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Collagen HomeostasisAfter Wounding (Optimal Healing)Days 3 - 7 Collagen production beginsDays 7 42Synthesis with a net GAIN of collagenInitial increase in tensile strength due to increased amount of collagenDays 42+Remodeling with No net collagen gain

35CollagenNormal Skin collagen ratio 4 : 1 Type I/III

Hypertrophic Scarcollagen ratio 2 : 1 Type I/III36Proliferative Phase

37Three Phases of Wound HealingInflammatory PhaseProliferative PhaseRemodeling Phase38Maturation PhaseRandom to organized fibrils Day 8 through yearsType III replaced by type IWound may increase in strength for up to 2 years after injuryCollagen organizationCross linking of collagen

39Maturation Phase

40Impaired Wound Healing

41Wound HealingTo treat the wound, you have to treat the patientOptimize the patientCirculatoryPulmonaryNutritionAssociated diseases or conditions

42Oxygen

Fibroblasts are oxygen-sensitivePO2 < 40 mmHg collagen synthesis cannot take place Decreased PO2: most common cause of wound infectionHealing is Energy DependentProliferative Phase has greatly increased metabolism and protein synthesis

43Hypoxia:Endothelium responds with vasodilationCapillary leakFibrin depositionTNF-a induction and apoptosis44Edema

Increased tissue pressureCompromise perfusionCell death and tissue ulceration

45Infection

Decreased tissue PO2 and prolongs the inflammatory phaseImpaired angiogenesis and epithelializationIncreased collagenase activity

46NutritionLow protein levels prolong inflammatory phase Impaired fibroplasiaOf the essential aminoMethionine is critical

Hydration A well hydrated wound will epithelialize faster than a dry oneOcclusive wound dressings hasten epithelial repair and control the proliferation of granulation tissue47Radiation TherapyAcute radiation injury stasis and occlusion of small vesselsfibrosis and necrosis of capillariesdecrease in wound tensile strengthdirect, permanent, adverse effect on fibroblast may be progressivefibroblast defects are the central problem in the healing of chronic radiation injury

50MedicationsSteroidsStabilize lysosomes and arrest of inflammation responseInhibit both macrophages and neutrophilsInterferes with fibrogenesis, angiogenesis, and wound contractionAlso direct effect on FibroblastsMinimal endoplasmic reticulumVitamin Aoral ingestion of 25,000 IU per day pre op and 3d post op (not to pregnant women)Restores inflammatory response and promotes epithelializatonDoes not reverse detrimental effects on contraction and infection

51Factors in Wound HealingSmoking1ppd = 3x freq of flap necrosis2ppd = 6x freq of flap necrosisNicotine acts via the sympathetic systemVasoconstriction and limit distal perfusion1 cigarette = vasoconstriction > 90 minDecrease proliferation of erythrocytes, macrophages and fibroblastsSmoke contains high levels of carbon monoxide shifts the oxygen-hemoglobin curve to the left decreased tissue oxygen delivery54Syndromes Associated with Abnormal Wound HealingCutis Laxa Think defective elastin fibersCongenitalAD, recessive or X-linked recessiveAcquiredDrug, neoplasms or inflammatory skin conditionsEhlers-Danlos SyndromeThink defective collagen metabolismAD and recessive patters10 phenotypes55

Cutis Laxa56Syndromes Associated with Abnormal Wound HealingEhlers-Danlos SyndromeConnective tissue abnormalities due to defects:Inherent strengthElasticityIntegrityHealing properties57Syndromes Associated with Abnormal Wound HealingEhlers-Danlos SyndromeFour major clinical featuresSkin hyper-extensibilityJoint hyper-mobilityTissue fragilityPoor wound healing

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ElectrostimulationElectrical current applied to woundsIncreases migration of cells109% increase in collagen40% increase in tensile strength1 to 50 mA direct or pulsed based on wound60Hyperbaric OxygenDeveloped 1662 by Henshaw: DomicilliumAtmospheric pressure at sea level = 1 ATA = 1.5ml O2/dLNormal SubQ O2 tension is 30-50 mmHg.SubQ O2 tension < 30 mmHg = chronic wound61Excessive HealingHypertrophic ScarsKeloids62Wound healing gone wildHypertropic Scar

63KeloidsExtends beyond original boundsRaised and firmRarely occur distal to wrist or kneePredilection for sternum, mandible and deltoidRate of collagen synthesis increased Water content higherIncreased glycosaminoglycans64Predilection for dark- colored peopleKeloid TreatmentTriamcinolone (steroid) injections3-4 weeksCross linking modulatedInjections continued until no excess abnormal collagenExcisePrevention during healing pressure and injection65Keloid

66Keloid

67Keloid Scar

68Keloid Scar

69Marjolins UlcerJean-Nicolas Marjolin (1828)Aggressive ulcerating SCCOccurs in setting of chronic inflammationBurn woundsVenous stasis ulcersPrevious radiation therapyCharacterized by Slow growthPainless Persistent granulation

Questions72The proliferative phase of wound healing occurs how long after the injury?

1 day2 days7 days14 days

c73The proliferative phase of wound healing occurs how long after the injury?

1 day2 days7 days14 days

c74Which type of collagen is most important in wound healing?

Type IIIType VType VIIType XI

a75Which type of collagen is most important in wound healing?

Type IIIType VType VIIType XI

a76The tensile strength of a wound reaches normal (pre-injury) levels:

10 days after injury3 months after injury1 year after injurynever

d77The tensile strength of a wound reaches normal (pre-injury) levels:

10 days after injury3 months after injury1 year after injurynever

d78Which of the following is commonly seen in Ehlers-Danlos syndrome?

Small bowel obstructionsSpontaneous thrombosisDirect hernia in childrenAbnormal scarring of the hands with contractures.

d79Which of the following is commonly seen in Ehlers-Danlos syndrome?

Small bowel obstructionsSpontaneous thrombosisDirect hernia in childrenAbnormal scarring of the hands with contractures.

d80Steroids impair wound healing by:

Decreasing angiogenesis and macrophage migrationDecreasing platelet plug integrityIncreasing release of lysosomal enzymesIncreasing fibrinolysis

a81Steroids impair wound healing by:

Decreasing angiogenesis and macrophage migrationDecreasing platelet plug integrityIncreasing release of lysosomal enzymesIncreasing fibrinolysis

a82Supplementation of which of the following micronutrients improves wound healing in patients without micronutrient deficiency?

Vitamin CVitamin ASeleniumZinc

a83Supplementation of which of the following micronutrients improves wound healing in patients without micronutrient deficiency?

Vitamin CVitamin ASeleniumZinc

a84Signs of malignant transformation in a chronic wound include:

Persistent granulation tissue with bleedingOverturned wound edgesNon-healing after 2 weeks of therapyDistal edema

A marjolin ulcer85Signs of malignant transformation in a chronic wound include:

Persistent granulation tissue with bleedingOverturned wound edgesNon-healing after 2 weeks of therapyDistal edema

A marjolin ulcer86The treatment of choice for keloids is:

Excision aloneExcision with adjuvant therapy (e.g. radiation)Pressure treatmentIntralesional injection of steroids

d87The treatment of choice for keloids is:

Excision aloneExcision with adjuvant therapy (e.g. radiation)Pressure treatmentIntralesional injection of steroids

d88The major cause of impaired wound healing is:

AnemiaDiabetes mellitusLocal tissue infectionMalnutrition

c89The major cause of impaired wound healing is:

AnemiaDiabetes mellitusLocal tissue infectionMalnutrition

c90Bradykinin, serotonin, and histamine in wounds are released from:

LymphocytesMast cellsPolymorphonuclear leukocytesPlatelets

b91Bradykinin, serotonin, and histamine in wounds are released from:

LymphocytesMast cellsPolymorphonuclear leukocytesPlatelets

b92Platelets in the wound form a hemostatic clot and release clotting factors to produce:

FibrinFibrinogenThrombinThromboplastin

c93Platelets in the wound form a hemostatic clot and release clotting factors to produce:

FibrinFibrinogenThrombinThromboplastin

c94In a healing wound, metalloproteinases are responsible for:

Establishing collagen cross-linkGlycosylation of collagen moleculesIncorporation of hydroxyproline into the collagen chainInitiating collagen degradation

d95In a healing wound, metalloproteinases are responsible for:

Establishing collagen cross-linkGlycosylation of collagen moleculesIncorporation of hydroxyproline into the collagen chainInitiating collagen degradation

d96Severe cases of hidradenitis suppurativa in the groin area are best managed by excision of the involved area and?

Closure by secondary intensionDelayed primary closurePrimary closureSplit thickness skin grafting

d97Severe cases of hidradenitis suppurativa in the groin area are best managed by excision of the involved area and?

Closure by secondary intensionDelayed primary closurePrimary closureSplit thickness skin grafting

d98All of the following statements about keloids are true except?

Keloids do not regress spontaneouslyKeloids extend beyond the boundaries of the original woundKeloids or hypertrophic scars are best managed by excision and careful reapproximation of the woundKeloid tissue contains an abnormally large amount of collagen.

c99All of the following statements about keloids are true except?

Keloids do not regress spontaneouslyKeloids extend beyond the boundaries of the original woundKeloids or hypertrophic scars are best managed by excision and careful reapproximation of the woundKeloid tissue contains an abnormally large amount of collagen.

c100

The following photograph most accurately demonstrates:Hypertropic Scar Auricular Lymphedema Keloid Scar Cauliflower ear

The following photograph most accurately demonstrates:Hypertropic Scar Auricular Lymphedema Keloid Scar Cauliflower ear The Proliferative Phase of wound healing is classically described as beginning:Immediately after injuryWhen the wound is covered with epitheliumWhen the collagen content has reached equilibriumWhen the macrophage enters the wound

b103The Proliferate Phase of wound healing is classically described as beginning:Immediately after injuryWhen the wound is covered with epitheliumWhen the collagen content has reached equilibriumWhen the macrophage enters the wound

b104Under ideal circumstances the tensile strength of the wounded area reaches what % of strength compared to normal skin?10-20%20-40%60-70%70-90%

Under ideal circumstances the tensile strength of the wounded area reaches what % of strength compared to normal skin?10-20%20-40%60-70%70-90%

d106Which of the following does NOT affect wound healingInfectionHydrationNutritionDenervation

Which of the following does NOT affect wound healingInfectionHydrationNutritionDenervation

d108AcknowledgementsEdward R. Newsome, MD

Thank You

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