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Wound HealingL. Coughlin
August 25, 2008
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Phases of Wound Healing Hemostasis and Inflammation
Proliferation
Matrix Synthesis
Maturation and Remodeling
Epithelialization
Contraction
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Hemostasis andInflammation Hemostasis releases
chemotactic factors
from the wound siteinitiating inflammation
Wounded tissue directly exposes the ECMto platelets ->plt aggregation, degranulation,activation of coagulation cascade
Plt granules PDGF, TGF-, PAF,fibronectin, serotonin
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Inflammation Fibrin clot- assists influx of PMNs/monocytes
PMNs-1st to arrive, peak 24-48h, vasc permeability, chemoattractants (IL-1, TNF-, TGF-)
Phagocytosis of bacteria/debris
Secrete TNF-which angiogenesis & collagen synthesis
Release proteases/collagenases which degrade matrix/groundsubstance in early wound healing
May delay epithelial closure
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Inflammation Macrophages peak 48-96h
Phagocytosis, reactive oxygen species
Wound debridement via collegenase,
elastase Regulate cell proliferation, matrix synth,
angiogenesis (via TGF-, VEGF, IGF, EGF)
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Proliferation Days 4-12
PDGF recruits fibroblasts which proliferate
Assist in matrix/collagen synthesis and remodeling
Endothelial cells proliferate
Migrate from nearby intact venules Angiogenesis of capillaries
Regulated by cytokines/GFs (VEGF, TNF-, TGF-)
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Matrix Synthesis Collagen- wound repair types I & III
Type I prominent in skin ECM
Type III skin, esp during repair
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Collagen Synthesis Glycine q3 aa 2nd position: Pro or Lys mRNA -> 1000 aa protocollagen In E.R.
hydoxylation of Pro/Lys Prolyl hydroxylase requires: O2, Fe,
ascorbic acid, -ketoglutarate
Glycosylation (Glc, Galactose) ofhydroxylysine
Steric changes cause an -helix toform
3 entwining -helices -> rt-handedsuperhelix = procollagen
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Collagen Synthesis Covalent cross-linking of Lys and after
cleavage of terminal registration peptides
Postranslational modifications requireAdequate oxygenation
Good nutritional status (aa, carbs)
Cofactors (vitamins, trace minerals) Healthy local environment (good vascularity,
no infection)
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Proteoglycans Glycosaminoglycans form the ground substance of
granulation tissue Glycosaminoglycans + proteins = proteoglycans
Dissacharide units Length varies (10 units = heparin, 2000 u = hyaluronic acid)
In wounds, fibroblasts synthesize dermatan andchondroitin sulfate Increase during the first 3 wks Lattice is used to assemble collagen fibrils/fibers Amt of proteoglycan sulfation determines collagen configuration Incorporated into collagen scar tissue\\ Amt in scar tissue decreased with maturation and remodeling
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Maturation andRemodeling Wound strength depends upon the quality/quantitiy of
deposited collagen Early matrix fibronectin and collagen type III
Fibroplastic phase reorganization of collagen Collagenolysis by collagenase a matrix metaloproteinase (MMPs) Second matrix glycosaminoglycans/proteoglycans Final matrix collagen type I
Deposited over several wks, but tensile strength increases over mos
Remodeling 6- 12 wks, Synth > lysis resulting scar is an acellular ECM Mechanical strength never reaches preinjury levels
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Epithelialization
Day 1 proliferation and migration ofepith cells adjacent to wound Stimulated by contact inhibition, ECM
exposure, cytokines
Marginal basal cells lose their dermal
attachment, enlarge, flatten, and migrateacross the matrix (leapfrog) to cover thedefect
Fixed marginal basal cells undergo rapidmitosis
Once covered, epith cells become morecolumnar, increase mitotic activity andreestablish the layered epithelium
Eventual keratinization
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Role of Growth Factors
GF and cytokinesstimulate migration,proliferation, andfunction of cells during
wound healing Act in many ways:
autocrine, paracrine,
endocrine Effected by
concentration andreceptor binding
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Wound Contraction All wounds contract
Myofibroblasts contain -smooth muscle
actin in thick bundles called stress fibers May be responsible for contraction
Increases from day 7-21, fades after 4 wks
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Connective TissueDisorders Ehlers-Danlos 10 disorders, defect in collagen formation
Thin, friable skin, prominent veins, easy bruising, poor wound healing,abnormal scar formation, recurrent hernias, hyperexensible joints,decreased coagulation, intestinal diverticulae, rectal prolapse,aneurysms, AV-fistulas
Difficult to suture vessels; recurrent hernias, thin transversalis fascia somesh may lower recurrence rate
Marfan Syndrome defect in fibrillin (assoc with elastic fibers) tall stature, arachnodactyly, lax ligaments, hyper extensible skin, myopia,
scoliosis, pectus excavatum, ascending aortic aneurysm Aortic aneurysm repair is difficult 2 to soft tissue, nl wound healing
Osteogenesis Imperfecta collagen Type I mutation, 4 subtypes Osteopenia/brittle bones, low muscle mass, hernias, lax ligaments,
dermal thinning, increased bruising, normal scarring, blue sclera
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Connective TissueDisorders Epidermolysis Bullosa defect in tissue adhesion
3 subtypes: simplex (epidermis), junctional (basementmembrane), dystrophic (dermis)
Tissue separation and blistering
Oral erosions and esophageal obstruction cause poornutrition Esophageal dilations, G-tube, nonadhesive dressings
Acrodematitis Enteropathica inability to absorbzinc via cell surface binding and cellulartranslocation, autosomal recessive Zinc is a cofactor for DNA polymerase, RT Impaired granulation tissue formation, erythematous
pustular dermatitis Oral supplementation is curative for impaired wound
healing
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GI Tissue Healing Surgical reanastamosis with sutures or staples
Failure of healing dehiscence, leak, fistula
Excessive healing stricture, stenosis
Submucosa provides
highest tensile strength
Serosa provides a
watertight seal via afibrin seal
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GI Tissue Healing
Serosa/mucosa healswithout scarring
Decrease in strengthduring wk1 due to
collagenolysis,collagenasecolon > sm. int
Anastamosis should betension-free, good bloodsupply, adequatenutritional status,
no sepsis
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Bone Wound Healing
1. injury -> hematoma 2. liquefaction, degradation of
nonviable products,revascularization of nearby nlbone = inflammation,erythema, edema
3. 3-4d post injury soft tissuefibrocartilaginous callusbridges fractured bonesegments = internal splint
4. hard callus mineralizationof the soft callus andconversion to bone, 2-3 mos
5. remodeling/reabsorption ofhard callus, marrow cavity isrecanalized
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Cartilage Wound Healing Cartilage is an avascular ECM of proteoglycans,
collagen fibers, and water Nutrients diffuse from a hypervascular
perichondrium Injury to cartilage have poor healing
Superficial disruption of ECM, injur chondrocytesno inflammation, synth of proteoglycans/collagen,poor regeneration
Deep involve underlying bone/tissue. Hemorrhageinitiates inflammation and cellular repair. Fibroblastsmigrate across granulation tissue to fill defects wihcare eventually undergo chondrification and hyalinecartilage is formed
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Tendon Wound Healing Tendons/ligaments parallel bundles of
collagen interspersed by spindle cells
Healing: 1. hematoma
2. organization,
3. laying down ECM (collagen types I & III)
4. scar formation
Hypovascular tendons heal with less motionand more scarring
Mechanical integrity may never reach pre-
injury levels
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Nerve Wound Healing Nerve injury
neurapraxia (focal demylenation) axonotmesis (disrupted axonal continuity with
maintenance of Schwann cell basal lamina) neurotmesis (transection)
Healing 1. survival of axonal cell bodies
Wallerian degeneration phagocytosis of degenerating
axons/sheath from the distal stump 2. regeneration of axons from the proximal stump,
remyelination 3. migration/connection of regenerating ends to targets
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Fetal Wound Healing No scar formation until 3rd trimester
Environment: sterile, temperature stable, fluid
Inflammation: reduced 2 immaturity of immunesystem = ? no scarring
Growth Factors: absence of TGF-
Matrix: excessive and extended hyaluronic acidproduction by fibroblasts (stimulated by fetalurine components)
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Classification of Healing Predictable healing of incised surgical
wounds
Primary Intention Secondary
Tertiary
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Primary IntentionWound is clean and sutured closed
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Secondary Wound remains open to heal by
granulation tissue formation and scarretraction
Chosen for bacterial contamination ortissue loss
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Tertiary Delayed primary closure after a few days
of open wound healing
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Delayed Healing Normal healing continual
increase in mechanicalintegrity/strength over time
with an eventual plateau Delayed decrease in rate
with eventual achievement of normal plateau
Nutritional deficiencies, infection, severe trauma
Impaired/Chronic failure to achieve normalmechanical integrity/wound strength
Immunocompromised, diabetes, chronic steroid use,
xrt damage
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What affects wound healing? Age ?independent of
morbidities nutrition
Hypoxia,anemia,hypoperfusionlow oxygen impairs fibroplasia,
collagen syth FiO2 during/postop collagen,
infection
Steroids Inhibit inflammation,
epithelialization, wound contraction, and infection large doses/chronic use collagen and wound strength
Effects after 3-4d postinjury
Epithelialization can be stimulated with vit A
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Chemotherapy - inhibit cell proliferation/DNAand protein synthesis = repair
Effects after 2 wks postinjury Extravasation causes tissue necrosis, ulceration,
and protracted healing
Metabolic disorders DM Uncontrolled DM leads to inflammation,
angiogenesis, collagen synth, fibroblast prolif.Local hypoxemia from vessel disease.
Obesity, insulin resistance, hyperglycemia, anddiabetic kidney dz independently impair healing
Preoperative correction of blood glc, FiO2, abx
use improve outcomes
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Nurtition malnutrition wound complications/failure
Affects healing and immune response Particularly protein-deficient diets show impaired collagen deposition,
skin/fascial strength, infection Brief preoperative malnourishment demonstrates decreased healing
Arginine aa deficiency impairs fibroplasia Supplementation enhances collagen/protein deposition but not the rate of
epithelialization
Vitamin Cdeficiency (scurvy) wound healing via collagensyth/crosslinking/pro and lys hydroxylation, infection/severity
Vitamin A - wound healing, supplementation is beneficial, reverses theeffects of corticosteroids/DM, tumors, xrt
Zinc - deficiency impairs fibroplasia, collagen syth, wound strength andrate of epithelialization
Supplementation is useful if deficient
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Chronic Wounds Fail to achieve adequate wound integrity
Repeated trauma, excessive inflammation,
poor perfusion/oxygenation Ischemic arterial ulcers
Venous stasis ulcers
Diabetic ulcers Decubitus/pressure ulcers
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Ischemic arterial ulcers Poor blood supply
Painful, usually distal
Shallow wound, smooth margins, pale
S/Sx of PVD: intermittent claudication,
rest pain, color changes, pulses, ABI
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Venous stasis ulcers
Incompetence of the deepvein perforators
capillary leakage-polymerization of fibrin
impairs oxygenation Painless, shallow ulcer with
irregular margins, possibleskin pigmentation
(hemoglobin extravasationand breakdown)
Tx: compression therapy(rigid or flexible)
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Diabetic ulcers 10-15% of DM pts develop ulcers
Causes: ischemia, neuropathy(unrecognized injury,Charcot foot)
Poor healing
Tx: Tight blood glc control, abx,wide debridement of necrotic/
infected tissue, relief ofpressure via orthotics/casts,
potentially: topical PDGF and
GM-CSF, skin grafts
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Decubitus/pressure ulcers
Localized tissue necrosis fromcompression over a bony prominence, nutrients/O2
by friction, moisture 3-9% acute care, 2.4-23% in long-term
care facilities
Cost of management $50-60,000/ulcer Tx: debridement of all necrotic tissue,
relief of pressure, wound care (moistenviron), surgical flap repair, nutrition
4 stages: I. Non blanchable erythema, intact skin
II. Partial thickness skin loss ofepidermis/dermis
III. Full thickness skin loss, above fascia IV. Full thickness, involves muscle or
bone
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Excess Dermal Scarring Occur after trauma, may burn or be pruritic
Xs of collagen/glycoprotein deposition
Hypertropic scars Usu develop within 4 wks of trauma Collagen bundles are wavy pattern Stay within the original wound, elevated < 4mm Occur across areas of tension/flexing Often regress Tx: excision + corticosteroids
Keloids 15x more common in pts with darker skin pigmentation
Develop 3mos-years after trauma Collagen fibers are larger, random/ not bundled Expand beyond wound edges, can become large Rarely regress Excision alone (45-100% recurrence). Corticosteroids
then Excision + corticosteroid injections, topicalsilicone, external compression, xrt, IFN-, 5-FU,bleomycin
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Peritoneal Adhesions Fibrous bands of tissue between normally
separated organs Usually result from prior surgery, or intra-
abdominal infection Most common cause (65-75%) of small bowel
obstruction Prevention: careful surgical
handling/instrumentation, barrier membranesand gels modified oxidized regenerated cellulose gel hyaluronic acid membranes
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Local wound care Exam: depth, configuration, extent of
necrosis, foreign bodies, infection
Irrigation with NS (iodine, H2O2, andorganic antibacterial preps healing)
Debridement, hematoma evacuation
Sterilize area/field, edge approximationvs split thickness skin/allografts vsrotation/free flaps
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Antibiotics Utilize for obvious wound infections
Erythema, cellulitis, swelling, purulence
Tailor usage to suspected microbes forthe wound location and pts immune
function
IV, po, topically as irrigations/dressings
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Growth Factor Therapy PDGF-BB is FDA approved for treatment
of diabetic foot ulcers
Recombinant human GF in a gel suspension
Increases healing, decreases healing time
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Dressings Mimics epithelial barrier, protection of site
Compression provides hemostasis, decreasesedema
Occlusion controls hydration and allows foroxygenation/gaseous diffusion
Occlusion stimulates collagen synth and epithcell migration
Primary- directly on wound
Secondary- placed on a primary dressing
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Dressings Absorbent- absorbs wound fluid which could lead to maceration and bacterial
overgrowth Nonadherent- impregnated with paraffin, petroleum jelly or water-soluble jelly.
Requires a secondary dressing to seal edges and prevent desiccation/infection (semi)occlusive- Film dressing good for minimally exudative wounds.
Waterproof, impervious to microbes, permeable to water vapor and O2. Hydrophillic- Aid in absorption
Hydrophobic- Waterproof, prevents absorption. Hydrocolloid/hydrogel- absorbent + occlusive. Absorption of exudates leaves a
gelatinous mass after dressing removal (atraumatic, can be washed off).Hydrogels are useful for burns because they allow for a high rate of evaporationwithout decreasing wound hydration.
Alginates- derived from brown algae. Polysaccharide polymers have a highabsorbency. Good for skin loss, open surgical wounds with medium exudation,
and full-thickness chronic wounds Absorbablewithin wounds as hemostatic agent. Collagen, gelatin, cellulose. Medicated- benzoyl peroxide, zinc oxide, noemycin, bacitracin-zinc. Increase
epithelialization. Mechanical- wound v.a.c. applies negative pressure to the sur and surface and
margins of the wound via a foam dressing.,Exudate absorption, odor control.
Effective for chronic ulcers, trauma, flaps/grafts, dehiscent incisions.
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Skin Grafts
Split/partial thickness graft = epidermis +partial dermis Require less vascular supply
Full thickness = entire epidermis and dermis Greater mechanical strength, increased resistance to wound
contraction, improved cosmesis
Autograft transplant from another site Allograft transplant from a living nonidentical donor or
cadaver Subject to rejection, may contain pathogens
Xenograft from another species Subject to rejection, may contain pathogens
Preparation of wound bed debridement ofnecrotic/fibrinous tissue, control of edema, minimizingexudate, revascularization of wound bed, bacterial load
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Skin Substitutes
Good for extensive wounds with limited availability ofautografts Now may be used a wound dressing Tissue engineered with living cells Does not require tissue harvesting, readily available, may
be sutured or applied topically Promote healing Disadvantages: limited survival, high cost, requires multiple
applications Cultured Epithelial Autografts expanded from a biopsy of
the pts skin and grown into sheets. Not rejected, stimulateepithelialization Disadvantages- fragile, difficult to manipulate, susceptible to
infection, contract poorly with poor cosmesis Can also be obtained from cadavers, donors and cryopreserved
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ReferencesThe material in this presentation was directly
adapted from:
Adrian Barbul. Chapter 8. Wound Healing. InSchwartz's Principles of Surgery, 8th ed. F. C.Brunicardi, D. K. Andersen , T. R. Billiar, D. L.
Dunn, J. G. Hunter, R. E. Pollock, eds.McGraw-Hill Professional, 2004.