wound healing tulane university division of plastic & reconstructive surgery

Wound HealingTulane University

Division of Plastic & Reconstructive Surgery

Presentation Overview

Wound HealingHistory

Phases

Factors Influencing

Adjuncts to Wound Healing

Fetal

Wound CarePrinciples

Dressings

Abnormal Scarring

Exotic Injuries

History of Wound Care

Smith papyrus (1700 B.C.)

7 of 48 case reports dealt with wound healing

Ancient Egypt, Greece, India, and Europe

Gentle wound handling

Foreign body removal

Approximating wound edges

Clean dressings

History of Wound Care

850 - Gunpowder (change in thought process)Boiling oil, hot cautery, scalding water

Worse outcomes

1500 - Ambroise PareRediscovered gentle, clean wound handling during the battle of Villaine

20th Century – Scientific Method

Phases of Wound Healing

Tissue Injury and Coagulation

InflammationRemove devitalized tissue and prevent infection

EarlyLate

FibroproliferativeBalance between scar formation and tissue regeneration

Fibroblast migrationCollagen synthesisAngiogenesisEpithelialization

Maturation/RemodelingMaximize strength and structural integrity

ContractionCollagen Remodeling

Tissue Injury and Coagulation

Tissue Injury and CoagulationINJURY (Physical, antigen-antibody reaction, or infection)

Transient (5-10 minute) vasoconstriction

Slows blood flow, aid in hemostasis

Histamine mediated vasodilation and permeability changes

Vessels become lined with leukocytes, platelets and erythrocytes

Leukocyte migration into the wound

Endothelial cells swell and pull away from each other -> allowing serum to enter the wound

Hemostatic factors from platelets, kinins, complement, and prostaglandins send signals to initiate the inflammatory phase

Fibrin, Fibronectin, and plasma help form a clot and stop bleeding

Early Inflammation

Complement Cascade Activation

PMN infiltration24-48 hours

Stimulated by:Complement components (C5a)

Formyl-methionyl peptide products from bacteria

Transforming Growth Factor (TGF)-b

Early InflammationPMNS

Predominant cell type from 24-48 hours

Phagocytosis and debridement

Removal of PMNS does not alter wound healing

Late InflammationMacrophage

Most critical cell type

Predominates after 48-72 hours

Attracted by:Growth factors (PDGF, TGF-b) ComplementClotting componentsIgGCollagen and elastin breakdown productsLeukotriene B4Platelet factor IV

Late InflammationMacrophage Functions

Phagocytosis

Primary producer of Growth Factors (PDGF, TGF-b)

Recruitment of fibroblasts (proliferative phase)Proliferation of extracellular matrix by fibroblastsProliferation of endothelial cells (angiogenesis)Proliferation of smooth muscle cells

This leads to the Fibroproliferative phase

Late InflammationLymphocyte

Appears at 72 hours

Attracted by: InterleukinsIgGComplement products

Role yet to be determined

Fibroproliferative

FibroblastsMigrate into the wound via ECM

Predominant cell type by day 7

Collagen synthesisBegins on days 5-7

Increases in linear fashion for 2 to 3 weeks

AngiogenesisPromoted by macrophages (TNF-alpha, FGF, VEGF)

EpithelializationMitosis of epithelial cells after 48-72 hours

Modulated by growth factors (EGF, FGF, KGF)

FibroproliferativeExtracellular Matrix

Forms a scaffold for cell migration and growth factor sequestration (fibronectin, proteoglycans, collagen, etc.)

Proteoglycans and GlycosaminoglycansProteoglycans are proteins covalently linked to Glycosaminoglycans

chondroitin sulfate

heparan sulfate

keratan sulfate

hyaluronic acid (1st to appear)Proteoglycans

Create a charged and hydrated environmentFacilitates cell mobility

Viscoelastic properties of normal connective tissue

Collagen

Principle building block of connective tissue

1/3 of total body protein content

3 polypeptide chains that wrap around each other to form a collagen unit (tropocollagen)

Filaments ->Fibrils -> Fibers

Collagen Types

Type 1Bones, skin, and tendons90% of total body collagen

Found in all connective tissues except hyaline cartilage and basement membranes

Type 2Hyaline cartilage, cartilage-like tissues, and eye tissue

Collagen Types

Type 3Skin, arteries, uterus, abdominal wall, fetal tissueAssociation with Type I collagen in varying ratios (remodeling phase)

Type 4Basement membranes only

Type 5Basement membranes, cornea

SkinType 1 : Type 3 ratio is 4:1Hypertrophic scars/immature scars ratio maybe as high as 2:1

Collagen Metabolism

Dynamic equilibriumSynthesis (Fibrosis) vs. Degradation (collagenases)

Collagenase activity

Stimulated: PTH, Adrenal corticosteroids, colchicine

Inhibited: Alpha 2-macroglobulin, cysteine, progesterone

Healing wound3-5 weeks equilibrium is reached between synthesis and degradation (no net change in quantity)

Angiogenesis

Formation of new blood vessels throughout inflammatory and proliferative phase of wound healing

Initiated by plateletsTGF-b and PDGF

PMN

Macrophages

TNF-alpha, FGF, VEGF

Angiogenesis

Endothelial CellForms new blood vessels

VEGF (predominant chemotactic stimulator)

Move along the ECM created by fibroblast

Epithelialization

Repithelialization begins within hours of injury

Stimulated byLoss of contact-inhibition

Growth factors

EGF (mitogenesis and chemotaxis)

KGF, FGF (proliferation)

Dissolution of hemidesmosomal links between epidermis and basement membrane allows lateral movement of epidermal cells

Expression of integrin receptors on epidermal cells allows interaction with ECM

Epithelialization

Epithelium advances across wound with leading edge cells becoming phagocytic

Collagenase (MMP)Degrades ECM proteins and collagenEnables migration between dermis and fibrin eschar

Mitosis of epithelial cells 48-72 hours after injury behind leading edge

Maturation/Remodeling

Longest phase: 3 weeks – 1 year

Least understood phase

Wound Contraction and Collagen Remodeling

Wound ContractionMyofibroblast

Fibroblasts with intracellular actin microfilaments

Uncertain if fibroblasts differentiate into, or if a separate type of cell

Maturation/Remodeling

Collagen RemodelingType 3 Collagen degraded and replaced with Type 1

Collagen degradation achieved by Matrix Metalloproteinase (MMP) activity (fibroblasts, PMNs, macrophages)Collagen reorientation

Larger bundles

Increased intermolecular crosslinks

Tensile StrengthCollagen is the main contributing factor

Load capacity per unit area(Breaking capacity- force required to break a wound regardless of its dimensions)

Rate of tensile strength increases in wounds vary greatly amongst species, tissues and individuals

All wounds begin to gain strength during the first 14-21 days (~20% strength), variable then after

Strength PEAKs @ 60 daysNEVER reaches pre-injury levels

Most optimal conditions may reach up to 80%

Predominant Cell Types

Special Characteristics of Fetal Wound Healing

Lack of inflammationAbsence of FGF and TGF-b

Regenerative process with minimal or no scar formation

Collagen deposition is more organized and rapidType 3 Collagen (No Type 1)

High in hyaluronic acid

Area of ongoing research

Factors That Influence Wound Healing

OxygenFibroblasts are oxygen-sensitive

Collagen synthesis cannot occur unless the PO2 >40mmHg

Deficiency is the most common cause for wound infection and breakdown

Hematocrit Mild to moderate anemia does not appear to have a negative influence wound healing (given sufficient oxygenation)

>50% decrease in HCT

some studies report a significant decrease in wound tensile strength

while other studies find no change


SmokingMultifactorial in limiting wound healing

Nicotine

Vasoconstrictive -> decreases proliferation of erythrocytes, macrophages, and fibroblasts

CO

Decreases the oxygen carrying capacity of Hgb

Hydrogen Cyanide

Inhibits oxidative enzymes

Increases blood viscosity, decrease collagen deposition and prostacyclin formation

A single cigarette may cause cutaneous vasoconstriction for up to 90 minutes


Mechanical StressAffects the quantity, aggregation, and orientation of collagen fibers

Abnormal tension -> blanching, necrosis, dermal rupture, and permanent stretching

Subcutaneous expansion produces stronger more organized scars

HydrationWell hydrated wounds epithelialize faster

Environmental TemperatureHealing is accelerated at temperatures of 30 C

Tensile strength decrease by 20% in 12C environment


DenervationNo direct effect on epithialization or contraction

Loss of sensation and high collagenase activities in skin -> prone to ulcerations

Foreign Bodies (including necrotic tissue)Delay healing and prolong the inflammatory phase

NutritionDelays increases in tensile strengthProlonged inflammatory phase and impaired fibroplasia

EdemaMay compromise tissue perfusion


LathyrogensInhibit the cross linking of collagen bundles

Ex. D-penacillamine

Oxygen Derived Free RadicalsDegrade Hyaluronic acid and collagen

Destroy cell and organelle membranes

Interfere with enzymatic functions

AgeTensile strength and wound closure rates decrease with age


InfectionProlongs inflammatory phase, impairs epithiliazation and angiogenesisIncreased collagenolytic activity -> decreased wound strength and contractureBacterial counts > 105, b-hemolytic strep

ChemotherapyDecreases fibroblast production and wound contractionIf started 10-14 days after injury, no significant long term problems, but short term decreased tensile strength

RadiationStasis and occlusion of small blood vesselsDecreased tensile strength and collagen deposition

Systemic DiseasesDM

Glycosylated RBCs Stiffened RBCs & Increased blood viscosityGlycosylated WBCs impaired immune function

Renal Dz


SteroidsInhibit wound macrophages

Interfere with fibrogenesis, angiogenesis, and wound contraction

Vitamin A and Anabolic steroids can reverse the effects

Vitamin AStimulates collagen deposition and increase wound breaking strength

Topical Vitamin A has been found to accelerate wound reepithealization


Vitamin CEssential cofactor in the synthesis of collagen

Deficiency is associated with immune dysfunction and failed wound healing (Scurvy)

Immature fibroblasts and extracellular material

Decreased Alkaline phosphatase

Defective capillary formation -> local hemorrhages

High concentrations do not accelerate healing


Vitamin ELarge doses inhibit wound healing

Decreased tensile strength

Less collagen accumulation

HOWEVERAntioxidant that neutralizes lipid peroxidation caused by radiation Decreasing levels of free radicals and peroxidases increases the breaking strength of wounds exposed to preoperative radiation


ZincDeficiency:

Impairs epithelial and fibroblast proliferation

Decreases B and T cell activity

Only accelerates healing when there is a preexisting deficiency


NSAIDsDecrease collagen synthesis an average of 45% (ordinary therapeutic doses)

Dose-dependent effect mediated through prostaglandins


Fibrin-based tissue adhesivesIncrease breaking strength, energy absorption, and elasticity in healing wounds


HydrotherapyWhirlpool

Pulsed LavageStimulates formation of granulation tissue

Clean non draining wounds with healthy granulation tissue should NEVER be subjected to hydrotherapy

Water agitation damages fragile cells

ElectrostimulationImitates the natural electrical current that occurs when skin is injured

Increases migration of neutrophils and macrophages

Promotes fibroblastsIncreased collagen production and tensile strength


Ultrasound TherapyElectrical energy converted to sound waves

Thermal component -> improves scar outcome

Nonthermal component -> cavitation

In animal models

Changes in cell membrane permeability, increase cellular recruitment, collagen synthesis, tensile strength, angiogenesis, wound contraction, fibrinolysis, and stimulates fibroblast and macrophage production

Clinically results are equivocal

LED (Light-emitting diode)Produces light at multiple wave lengths

Larger area than lasers

Studied by NASA in weightless environments (space station, submarines)

Improved wound healing alone or in combination with hyperbaric oxygen


Hyperbaric OxygenIncreases levels of O2 and NO to the wound

Benefit: Amputations, osteoradionecrosis, surgical flaps, skin grafts

None to minimal benefit with necrotizing soft-tissue infections

Wounds require adequate perfusion

Many off-label uses (Benefit? Financial?)Acne, Migraines, Lupus, Stroke, MS, and many more

Medicare Coverage14 Covered Areas (next slide)

~1/3 of claims are for problems not covered

Medicare Coverage of HBO

(1) Acute carbon monoxide intoxication

(2) Decompression illness

(3) Gas embolism

(4) Gas gangrene

(5) Acute traumatic peripheral ischemia

(6) Crush injuries

(7) Progressive necrotizing infections

(8) Acute peripheral arterial insufficiency

(9) Preparation and preservation of compromised skin grafts

(10) Chronic refractory osteomyelitis

(11) Osteoradionecrosis (ORN)

(12) Soft tissue radionecrosis (STRN)

(13) Cyanide poisoning

(14) Actinomycosis


Lasers “Biostimulation”Excites physiologic processes and increases cellular activity in wounded skin

Accelerates healing of hypoxic and infected wounds when combined with hyperbaric oxygen

Low energy -> promote epithelialization

Different wave-lengths (multiple treatments)

VAC

Bioengineered Matrices

Wound Care General Principles

Cleaning and IrrigationNeed at least 7psi to flush bacteria out of a wound

High pressure can damage wounds and should be reserved only for heavily contaminated wounds

DebridementMost critical step to produce a wound that will heal rapidly without infection

Non-selective: WTD, DTD, WTW, Hydrogen Peroxide, etc.

Useful in wounds with heavy contamination

When starts to granulate, start selective

Selective: sharp, enzymatic, autolytic, or biologic

Selective Debridement

EnzymaticNaturally occurring enzymes that selectively digest devitalized tissue

Collagenase (Santyl), Papain-Urea (Accuzyme), etc.

AutolyticUses the body’s own enzymes and moisture to breakdown necrotic tissue

7-10 days under semi occlusive and occlusive dressings

Ineffective in malnourished patients

BiologicMaggots

Calcium salts and bactericidal peptides

Separate necrotic from living tissue making surgical debridement easier

Wound Care General Principles

Fundamentals of Surgical Wound ClosureIncision should follow tension lines and natural folds in the skin

Gentle tissue handling

Complete hemostasis

Eliminate tension

Fine sutures and early removal

Evert wound edges

Allow scars to mature before repeat intervention (2 weeks to 2 months scar appearance is the worst)

Scar appearance depends more on type of injury than method of closure

Technical factors of suture placement and removal are more critical than type of suture used

Immobilization of wounds to prevent disruptions and excessive scarring (Adhesive strips after suture removal)

Wound Dressings

Over 2,000 commercially available

Red-Yellow-Black ClassificationCreated to help choose appropriate dressings in wounds healing by secondary intention

Treat worse colors first Black -> Yellow -> Red

Dressing Types

AlginatesWounds with heavy exudates (dry the wound)

Converts in a sodium salt -> hydrophilic gel occlusive environment

Change when begins to weep exudate

CreamsOpaque, soft solid or thick liquids with a slight drying effect

Wounds with moist weeping lesions

OintmentsSemisolids that melt at body temperature

Aid in rehydration and topical application of drugs

Dressing Types

FoamsHydrophobic polyurethane sheets with a non absorbent adhesive occlusive cover (very absorbent and nonadherent)

Absorb environmental water and slow epitheliaztion

FilmsTransparent polyurethane membranes with water-resistant adhesives

Conform well, semipermeable to moisture and oxygen, impermeable to bacteria

Promote autolytic debridement

Good for wound monitoring

Can lead to maceration in wounds with a heavy exudate and can tear skin

Dressing Types

GauzeHighly permeable to air and allow rapid moisture evaporation

Stick to granulation tissue and damage the wound with removal

Painful removal

Lint can harbor bacteria

HydrocolloidsCompletely impermeable

Avoid in anaerobic infections

Comfortable and adhere well (good for high-friction areas)

Good at absorbing exudate

HydrogelsStarch and water polymers in gels, sheets, or impregnated gauze

Rehydrate wounds (poor for absorbing exudate)

Dressing Types

VAC DressingSub atmospheric pressure dressing to convert an open wound to a controlled closed wound

Decreases interstitial fluid/edema

Improves tissue oxygenation

Removes inflammatory mediators

Increase speed of granulation tissue formation

Reduces bacterial counts

Silver-impregnated (Acticoat, Arglaes, Silveron)Antibacterial (effective against MRSA, VRE, yeast, and fungi)

Moist environment

Wound Matrix (Alloderm, Oasis, Apligraft, Dermagraft, Integra)

Alloderm

Acellular dermal matrix derived from donated human skin

Epidermis and all dermal cellular components are removed

Oasis

Thin (0.15mm), translucent layer of porcine small intestinal submucosa (SIS)

Primarily made of a collagen-based ECM

Biologically important components of the ECM remain active

Glycosaminoglycans (hyaluronic acid), proteoglycans, fibronectin, and growth factors such as FGF and TGF

Application:

Clean wound base

Cut to size slightly larger than wound, apply directly, moisten with saline

Dress with standard dressings: moist, compressive, etc.

Change dressings with standard frequency

Apligraf

Living bilayered skin substitute (epidermis and dermis)

Dermis is devoid of Langerhans cells, melanocytes, macrophages, lymphocytes, hair or blood vessels

Includes: PDGF, TNF, VEGF, FGF

Has shown improved healing in Diabetic and Venous stasis ulcers

Dermagraft

Derived from newborn foreskin tissue

Cryopreserved human fibroblast-derived dermal substitute

Composed of fibroblasts, ECM, and a bioabsorbable scaffold

Fibroblast are seeded into the scaffold and secrete collagen, matrix proteins, growth factors and cytokines to create a human dermal substitute containing living cells

Multiple studies showing higher percentage of healed diabetic foot ulcers versus controls

Integra

Outer layer of a semi-permeable silicone membrane

Inner layer is a porous matrix of fibers of cross-linked bovine tendon and glycosaminoglycans, that allows dermal ingrowth

After dermal ingrowth the silicone film is removed and a STSG is placed (~3 weeks)

Abnormal Scarring

Hypertrophic Scars

Keloids

Widespread Scar

Comparison of Abnormal Scars

Keloid Hypertrophic Scar

Widespread Scar

Borders Outgrows wound borders Remains within wound borders

Wide, flat, depressed

Natural History

Appears months after injury, rarely regresses

Appears soon after injury, regresses with time

Appears within 6 months of injury

Location Mostly face, earlobes, chest(Never eyelids or mucosa)

Flexor surfaces Arms, legs, abdomen

Etiologic Factors

Possible autoimmune, endocrine (puberty, pregnancy)

Tension Tension and mobility of wound edges

Treatment Intralesional steroids, compression therapy, silicone gel sheeting, radiation therapyOften worse after surgery alone

Same as Keloids but outcome usually more successful

Scar excision/layered closure

Comparison of Abnormal Scars

Keloid Hypertrophic Scar Widespread Scar

Genetics

Significant familial predilection

Low familial incidence

No inheritance pattern

Race African > Caucasian

Low racial incidence Not related to race

Sex Females > Males(Equal)

Equal Unknown

Age Most commonly 10-30 years

Any age, mostly less than 20 years

Any Age

Hypertrophic Scar

Keloids

Keloid: Treatments

No universally effective treatment, usually a combination of treatment types

Case by Case basis

Prevention (the best therapy)Avoid non essential surgery, minimal tension, use cuticular monofilament synthetic sutures, avoid wound-lengthening techniques, and avoid incisions across joints

Keloids: Treatments

Surgery: Alone 50-80% reoccurrence rateExcision with early postoperative radiation (~25% reoccurrence rate)

Excision with corticosteroids (50-70% reoccurrence rate)

Pressure- increase collagenase activity24-30mm Hg, 18-24h/day for 4-6 months

Silicone gel sheeting- mechanism unclear (decrease movement/tension)80-100% -improvement in hypertrophic scars

35%- improvement in keloids

Corticosteroids- intralesionalDecreases collagen synthesis- unclear mechanism

Maybe used in conjunction with surgical excision

Complications- hypopigmentation, skin atrophy, telangiectasias

Lack of randomized control trials to determine site specific dosages

CryotherapyFound to be helpful in early vascularized lesions

Keloid TreatmentRadiation

Most effective when given post operativelyNo advantage if given preoperatively

~25% reoccurrence rate when combined with excision

15-20 Gy administered over several doses (5-6)

Guix et al: Bracytherapy is more effective than externally supplied

Keloid TreatmentsAntitumor/Immunosuppressive Agents

5-FUReports of effectiveness

Uppal et al.: 50% improvement in Keloid Score

Haurani et al.: 19% reoccurrence rate after intralesion injection after surgery at 1 year

Literature still in debate over appropriate dosage

BleomycinLimited studies to date suggesting effectiveness

InterferonSome reports showing effectiveness others showing none

Ongoing study needed

Exotic Wounds

Radiation Injury

Chemical burns

Aquatic animal wounds

Bites (snakes, spiders)

Radiation Injury

Damage caused by energy transferenceFree radicals form causing intracellular and molecular damage

Main targets: Cellular and Nuclear Membranes, DNA

Rapidly dividing cells are the most sensitiveSkin, bone marrow, GI

MorbidityDose received

Time

Volume of tissue

Type of radiation

Cellular changesLow dose -> apoptosis

High dose-> direct cellular necrosis

Radiation Injury

Injury with Time1st week: faint erythema, hair loss, dryness

3rd/4th week: localized erythema, edema, warmth, tenderness

5th week:30G: dry desquamation, pruritus, scaling, increase pigmentation -> brown pigmentation at 2 months

>40G: moist desquamation, bullous formation, may rupture -> ulcers (tendency to heal and recur)

1 year: thin semi translucent skin, dry, easily seen vessels, lack of hair follicles and sebaceous glands -> fibrosis, induration

Radiation Injury

Delayed:

Eccentric vessel proliferation -> thrombosis -> ischemic changes within the skin -> ulceration

Hard to heal, painful, easily traumatized and infected

Radiation Injury

Surgical PrinciplesEstablish a diagnosis

Rule out malignancy

Determine extent of injuryOften boundaries exceed what is seen grossly

Debride all nonviable tissue and foreign material (in stages if needed)

Transfer as much tissue as possible to permit resection of additional tissue in the periphery of questionable wounds

Replace with well vascularized tissue (all neurovascular bundles, bone tendon, prosthetic material, etc. – need coverage)

Better to base pedicle flaps on non irradiated pedicle

Free flaps should utilize non irradiated recipient vessels

Plan for complications and other reconstructive options

Specific Chemical Burns

Black LiquorWarm alkaline solution used to convert wood chips to pulp

Tx:

Water irrigation

Silvadene and normal saline occlusive dressings BID

May require debridement and skin grafting


CementInjuries related to alkaline nature or heat related

Initial contact is initially painless and allows progression

Redness ->Purple-Blue -> Blistering and Ulceration

Tx:Removal of the cement and copious irrigation

White PhosphorusInsecticides and Fertilizers

Yellow burn with a garlic-like scent

Tx:Copious irrigation and neutralization with a dilute Copper Sulfate solution


Chromic AcidUsed in alloy and dye production

Coagulative necrosisPossible systemic toxicity (require dialysis, exchange transfusion)

GI hemorrhage, n/v, diarrhea, renal, hepatic, CNS, coagulopathies

Tx:

Burns <2% calcium EDTA dressings

Burns >2% immediate excision and STSG


Formic AcidRubber, Textile Tanning, Descaling Agent

Causes a systemic acidosis- IV hydration, HCO3, dialysis

Burns treated with irrigation

Hydrofluoric AcidIndustrial and cleaning industries

Initial injury may be subtle, deep penetration of fluoride ion leads to liquefactive necrosis of soft tissue and decalcification and corrosion of bone

Cardiac and Respiratory complications

Irrigation and treatment with calcium gluconate gel

Wounds by Aquatic Animals

Easily become infected, should allow to heal by secondary intention

Snake Bites

45,000 snakebites per year8,000 are venomous

Majority from Pit Vipers

~15 deaths annually

General TreatmentIncision and drainage through a linear incision through skin across the fang marks and slightly beyond

Only works in the first 45 minutes

Loose tourniquet if over an hour from the time of the bite and a delay in transport is anticipated can decrease venom dissemination by 50%

Antibiotics and Tetanus

Debridement of necrotic tissue

Fashiotomy if evidence of compartment syndrome

Antivenin if indicated

Spider Bites

Black Widow Females only carry enough venom

Neurotoxin20-30 minutes -> cramps, abdominal pain, restlessness, perspiration, possible convulsions and shock

TreatmentCalcium gluconate 10ml of 10% solution over 20 minutes for pain control

Muscle relaxants- robaxin, valium

Black widow antivenin- 2.5 ml vial (Lyovac) in severe cases

Spider Bites

Brown Recluse

Proteolytic enzymes

Several hours- erythema, blistering (pale halo)

Progressing to ulceration, extensive tissue destruction, occasional limb loss

System symptoms include hemolytic anemia, thrombocytopenia, and DIC

Treatment- (Controversial)

Dapsone 100-200 mg po qd x 10-25 days

Surgical excision

Thank You

wound healing tulane university division of plastic & reconstructive surgery

Documents

wound healing slide

kgf slide

bleeding slide

wound endothelial cells

wound hemostatic factors

fibroproliferative phase

clean wound handling

europe gentle wound