WoundHealing Coughlin 8-25-08

7/27/2019 WoundHealing Coughlin 8-25-08

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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.

WoundHealing Coughlin 8-25-08

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