The Principles of Wound Healing

Wound Healing and the Problem WoundFrederick N. Eko, MDSenior FellowDivision of Plastic SurgeryTulane University School of Medicine

1History of Wound Healing1700 BC Papyrus: Lint/animal grease/honey100 BC Egypt: Wound closure preserved soul1000 AD Gun Powder1500 AD Hot Oil20th Century Scientific Method2The Ebers Papyrus, circa 1500 BC, details the use of lint, animal grease, and honey as topical treatments for wounds.The Egyptians believed that closing a wound preserved the soul and prevented the exposure of the spirit to "infernal beings," as was noted in the Berlin papyrus.WoundsCustomize

Shotgun approach not acceptable

No two patients OR wounds are identical

58y DM, Neuropathy: unaware of R foot gangrene3 Several factors to considerThe patient and their comorbidities that may affect the development and treatment of the woundThe cause of the wound and local wound factorsThe wound healing approaches that would be appropriate for the particular wound always give diabetics and immunocompromised patients special attention.

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

Three 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

20

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)

28

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

33

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 tissue47TemperatureWound healing is accelerated at environmental temperatures of 30CTensile strength decreases by 20% in a cold (12C) wound environment

DenervationDenervation has no effect on either wound contraction or epithelialization

48Diabetes 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

49Radiation 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

51Nutritional 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 levels53Factors 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

58

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

69AcknowledgementsEdward R. Newsome, MD

Thank You

71