9/14/2011

Wound Healing

David G. Greenhalgh, MD
Shriners Hospitals for Children Northern
California
University of California, Davis

Wound Healing
Essential for all surgery
Wounds are created in all surgery
Failure to heal leads to
Dehiscence
Anastomotic failure
Infection
Chronic wounds

Wound Healing
Excessive healing leads to
Hypertrophic scarring
Keloids
Fibrosis
Stenosis
Cirrhosis
Contractures

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Types of Tissue Repair

Scar formation
Recreation of tissue strength
Epithelialization
Recreation of a barrier
Contraction
Shrinkage of the wound
Grafting/Flap coverage

Initiation of Tissue Repair

Local signals initiate healing
Neuron activation (S-100)
Vasoconstriction (epinephrine, NE)
Vasodilation (histamine, serotonin, bradykinin,
leukotrienes)
Increased permeability (histamine, serotonin,
bradykinin, leukotrienes)

Initiation of Tissue Repair

Vascular response
Loss of endothelium exposes type I collagen
Platelets activated by binding collagen
Alpha granules release growth factors
Clotting cascade initiated
Thrombin and fibrin initiate inflammation
Complement activated
C3a, C5a attract leukocytes

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Scar Formation
Three phases (based on incisional strength)
Inflammatory phase (lag phase)
3-5 days in an incision
No increase in strength
Proliferative phase (collagen phase)
2-3 weeks in incision
Rapid increase in strength
Maturation phase
8-12 months in incision
Mild increase in strength

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Inflammatory Phase
Vascular response
Stop hemorrhage
Vasodilation and increased permeability
Initiation of inflammation
Many signals attract inflammatory cells into the
wound
Leukocytes follow cytokine concentration
gradient

Inflammatory Phase
Neutrophil
First cell to arrive
Involved in fighting invaders
Not directly involved in tissue repair
(Simpson and Ross, 1972)
Does release some growth factors

Inflammatory Phase
Macrophage
Key orchestrator of tissue repair
Leibovich and Ross (1975) eliminated macrophage
and wounds did not heal
Releases multiple growth factors
Attracts fibroblasts to the wound

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Inflammatory Phase
Lymphocytes
Release cytokines that influence macrophages
Mainly for acquired immunity
Probably not a dominant role in wound healing

Inflammatory Phase
Stem cells
New evidence suggests that bone marrow
derived cells travel to the wound and influence
healing
Mesenchymal stem cells
Fibrocytes
Vascular progenitor cells

Proliferative Phase
Rapid increase in wound strength due to
collagen and other ECM production
Fibroblast key cell for ECM production
Creation of new vasculature needed for
ECM production

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Fibroblasts
Attracted to the wound by growth factors
PDGF, TGF-, FGF-1, FGF-2, CTGF
Create ECM
Involved in shrinkage of the wound

Growth Factors
Platelet-derived growth factor (PDGF)
A and B isoforms (forms dimers)
and receptors tyrosine kinase
Attracts inflammatory cells and fibroblasts
RegranexTM (Becaplermin, Johnson and
Johnson) proven to improve diabetic wound
healing

Growth Factors
Transforming growth factor-beta (TGF-)
Three mammalian isoforms
Attracts inflammatory cells and fibroblasts
Increases ECM production (profibrotic)
Stimulates CTGF production
Decreases collagenases
Inhibits inflammation and cell growth

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Growth Factors
Fibroblast Growth Factor Family
Multiple growth factors
FGF-1 = acidic FGF
FGF-2 = basic FGF
Stimulate angiogenesis and fibroblast growth

Growth Factors
Connective tissue growth factor (CTGF)
Induced by TGF-
Increases ECM production
Insulin-like growth factors (IGF-I, IGF-II)
Act synergistically with PDGF
Anabolic agents

Collagen Synthesis
Multiple forms of collagen
All have an triple chain alpha helix
Defect in a biologic step leads to pathology
(scurvy, Ehrlos-Danlos, Marfans, etc)
Vitamin C required for hydroxylation of proline
and lysine to form triple helix (prolyl or lysyl
hydroxylase)
Lysyl oxidase required for intermolecular bonds

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Angiogenesis
Hypoxia releases Hypoxia-inducible factor (HIF)
HIF stimulates cells to release angiogenic factors
Post-capillary venule endothelial cells release
collagenases and migrate towards signal
Migrating endothelial cells form tubes
New capillaries connect to other vessels

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Angiogenic Factors
Direct angiogenic factors
FGF-2
Vascular-endothelial growth factor (VEGF)
Many indirect angiogenic factors
Anti-angiogenic factors being tested for
treating cancers

Vasculogenesis
Vascular stem cells released from bone
marrow
Migrate to wound to form new vessels
More important during embryogenesis

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Maturation Phase
Continued increase in wound strength
No increase in collagen content
Balance between collagen synthesis and
breakdown
Collagen lines up along lines of stress
Intercollagenous bonds form
Lasts 8-18 months

Apoptosis and Wound Healing

Healing involves rapid increases and
decreases in cell numbers
Increases due to multiple factors
Decreases due to
Loss of stimuli
Induction of apoptosis
Epithelium a key inducer of apoptosis

Epithelialization
Epithelium
Keeps water in
Keeps invading organisms out
Constantly being replaced
Needs viable bed to survive
Has little strength

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Epithelialization
Epithelial migration induced by
Loss of cell-cell contact
Epithelial growth factors
Type of ECM in contact with epithelial cell
Collagen type IV, laminin no migration
Collagen types I, III, fibronectin, migration
Need viable wound bed for migration
Digest exudate during migration

Epithelialization
Epithelial growth factors
Epidermal growth factor (EGF)
Transforming growth factor-alpha (TGF-)
Keratinocyte growth factor-1 (KGF-1, FGF-6)
Keratinocyte growth factor-2 (KGF-2, FGF-10)

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Epithelialization
Basal cells migrate
Epithelial cells maintain contact while migrating
over wound
Proliferation takes place at original wound site
Migration stops when cells contact each other
Basal cells differentiate to form multiple layers
Top layers undergo apoptosis and eventually
slough

Contraction
Open wounds contract dependent on the
resistance against the wound
Contraction occurs over a few weeks
Fibroblasts contain -actin and myosin to
allow cells to shrink
Contracting cells are called myofibroblasts

Contracture
All wounds tend to shrink over months
Shrinkage of a wound involves fibroblast
contraction and collagen remodeling
Shrinkage of a wound that interferes with
function is called a contracture

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Factors Impairing Healing

Most healing proceeds without problems
Delayed healing increases with:
Malnutrition
Infection
Diabetes mellitus
Impaired oxygenation
Other systemic diseases (uremia, malignancy)
Treatment with steroids, radiation, chemotherapy

Nutrition and Wound Healing

Chronic and acute malnutrition affect
healing
Total protein/calorie malnutrition
Protein malnutrition
Perioperative nutritional support has been
shown to improve collagen deposition

Nutrition and Wound Healing

Specific amino acids affect healing
Proline/hydroxyproline no effects
Methionine, cystine, lysine, histamine,
carnosine, histidine improved healing in
animals studies (no clinical studies)
Branched chain amino acids impaired fracture
healing

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Nutrition and Wound Healing

Specific amino acids affect healing
Arginine improves healing by augmenting
immune function
Glutamine supports rapidly proliferating cells
but no studies have demonstrated improved
wound healing

Nutrition and Wound Healing

Vitamin C
Required for hydroxylation of proline or lysine
(prolyl/lysyl hydroxylase) in collagen synthesis
Deficiency prevents collagen triple helix cross-
linkages (Scurvy)
Abnormal collagen precursors collect in cells
Wounds fail to heal
Healed wounds break down (collagenases still
function despite altered collagen production)

Nutrition and Wound Healing

Vitamin A
Induces
Inflammation
Fibroblast differentiation
Collagen deposition
Reverses altered healing caused by steroids or
radiation
Also reverses immunosuppression

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Nutrition and Wound Healing

Vitamin E
Antioxidant
No evidence of improved healing
Thiamine (vitamin B1)
Deficiency may alter healing
Vitamin B5 (panothenic acid)
Deficiency may alter healing

Nutrition and Wound Healing

Zinc
Numerous enzymes of proliferation
Lysyl oxidase requires zinc
Intermolecular collagen bonds
Collagen maturation
Zinc deficiency impairs healing
Zinc supplementation improves healing
Unna boot calamine lotion and ZnO2

Nutrition and Wound Healing

Copper
Required for lysyl oxidase
Deficiency impairs healing
Iron
Anemia must be severe to impair healing
Manganese
Galactosyl and glucosyl transferase (adds
carbohydrate side-chains to stabilize collagen)

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Infection and Wound Healing

Local infection healing may vary
Healing improved
Mild infection (<105/gram tissue) stimulates
inflammation and healing
Healing impaired
Overwhelming infection (>105/gram tissue) impairs
healing

Infection and Wound Healing

Distant infection/sepsis
Impairs wound healing
Anorexia and malnutrition
Hypermetabolic response also involved

Diabetes Mellitus and Wound Healing

Major cause of wound-related morbidity

20% of admissions in diabetics
50% of nontraumatic lower limb amputations
25% of diabetic patients will have severe foot
problems in their lifetimes

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Diabetes Mellitus and Wound Healing

Vascular factors
Increased macrovascular disease
(atherosclerosis)
Increased microvascular disease
Capillary basement membrane thickening
Increased permeability (edema leads to ischemia)
Impaired leukocyte migration
Uremia also contributes to altered healing

Diabetes Mellitus and Wound Healing

Neuropathy
Sensory nerve loss
Do not detect injuries or pressure
Motor/sympathetic nerve loss
Lose normal muscular control of arch
Pressure develops on metatarsal heads (classic
wound of diabetes)
Inability to sweat leads to cracking and increased
risk of infection

Diabetes Mellitus and Wound Healing

Increased risk of infection

Loss of sweating
Cracks allow for bacterial entry
Flora is altered
Hyperglycemia increases infection risk
Altered leukocyte/immune function
Simple wounds often lead to larger infections
High amputation rate

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Diabetes Mellitus and Wound Healing

Cellular reasons for impaired healing

Decreased growth factor production
Increased proteolytic (MMP) activity

Diabetes Mellitus and Wound Healing

Cellular Na+/K+ ATPase activity

Increased polyol pathway activity
Aldose reductase activity increases (glucose to
sorbitol)
Sorbitol increases in tissues
Sorbitol inhibits myo-inositol uptake
Decreased myo-inositol inhibits Na+/K+ ATPase
Decreased NADPH and increased oxidative stress
Inhibitors of aldose reductase may improve
complications of diabetes

Diabetes Mellitus and Wound Healing

Increased protein kinase C (PKC) activity

Related to decreased diacylglyceride activity
(DAG)
Increased PKC leads to alterations in
proliferation and other cellular activities

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Diabetes Mellitus and Wound Healing

Advanced glycosylation end products (AGEs)

Result from hyperglycemia
Large aggregates of aldoses covalently bound to
reactive amino acids
Increase oxidative stress
Activate NF-B to increase cytokines
Cross-link collagen to inhibit breakdown
Aminoguanidine may inhibit AGEs effects

Diabetes Mellitus and Wound Healing

Prevention
Improve glucose control
Frequent checks of feet
Proper fitting shoes
Check for ischemia
Ulcer develops
Routine treatment 31% healing by 20 weeks

Diabetes Mellitus and Wound Healing

Treatment
Off-loading feet
Keep pressure off of wound
Total contact casts are effective
Debride wound (improves healing)
Growth factors (PDGF)
Skin subsitutes (Dermagraft, Apligraft)

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Ischemia and Wound Healing

Hypoxia significantly impairs healing
Check pulses and ABI
Doppler studies
Transcutaneous oxygen (>40 mmHg) for
healing
Revascularization improves healing

Drugs and Wound Healing

Inhibitors of proliferation impair healing
Steroids are also anti-inflammatory
Amount of inhibition varies with steroid type
Chemotherapy agents designed to kill rapidly
proliferating cells also impair healing
Radiation (local or systemic) inhibits
proliferation and healing

Pressure Sores
Pressure >30 mmHg can lead to tissue
ischemia
Normally, people move to allow for
perfusion
Pressure manifested by pain
Any postoperative pain should be assessed
for pressure

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Pressure Sores
Pathophysiology
Tissue atrophy with bony prominences
Impaired mobility
Loss of sensation (no stimulus to move)
Moisture increases chances for shear
Repetitive injury (scar less tolerant)
Age, nutritional status, underlying diseases are
important

Pressure Sores
Treatment
Remove pressure (increase mobility)
Frequent inspection
Remove moisture (clean rapidly after soiling)
Prevent drying of skin (eliminate cracking)
Prevent shear
Aggressive wound care (debridement, growth
factors, flaps)

Venous Stasis Ulcers

Classic medial malleolus ulcer
Pathophysiology
Venous hypertension
Increased permeability leads to edema
Fibrin deposition (impairs nutrient and cell delivery)
Increased collagen deposition
Extravasation of RBCs (hemosiderin pigment)
Ischemia

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Venous Stasis Ulcers

Treatment
Eliminate venous hypertension
Elevation
Stay off feet
Compression
Growth factors
High recurrence rate
Attempt to fix venous hypertension

Mortality after Injury

Immediate causes of death
Head injury
Hemorrhage
Long-term causes of death
Sepsis
Multiple Organ Dysfunction Syndrome
(MODS)

Sepsis
The major cause of mortality in ICUs
Understanding of pathophysiology
improved
Treatment options still limited
Treatment recommendations published
Surviving Sepsis Campaign

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The Visual
We are a fortress
The wall is our skin
The wall protects the citizens (the cells)
The citizens have different jobs that are concentrated
in organs
Sentinels (tissue-resident macrophages) monitor the
state of the fortress
Soldiers (inflammatory cells) fight invaders
Construction workers (fibroblasts) repair damage

Creation of a Barrier
Barrier created to stop invasion of micro-
organisms (the wall of the fortress)
First line of defense
Epithelium true barrier
Keeps invaders out
Keeps water in
Recreation of epithelium needed to stop
inflammation
Dermis gives the wall strength

Inflammation
Inflammation is the second line of defense
Inflammatory cells (soldiers behind the
wall)
Release weapons that destroy invaders
Release proteins (cytokines) that attract more
troops to the wound
Leukocytes have rank
Macrophage sergeant
Neutrophil private (sacrificed early)

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Sentinels
Cells exist that monitor the state of the
tissues
Tissue-resident macrophages
10-15% of cells in most tissues
Mast cells
Release danger signals

Creation of an Alternative Barrier

Create a poor alternative to epithelium
Fibroblasts attempt to replace the dermis
Granulation tissue
Collagen scaffolding produced by fibroblasts
High density of capillaries to feed the fibroblasts
Patrol of inflammatory cells
Less effective than a new epithelium
(Epithelium must heal itself)
Inflammatory mediators persist as long as exposed
Eventually, fibroblasts maintain the poor alternative
despite a new epithelium hypertrophic scarring

Creation of a Barrier
Reducing the wound size (shrink the wall)
Fibroblasts produce collagen scaffolding
Myofibroblasts have myosin/actin
Myofibroblasts grasp collagen matrix and
contract to shrink the wound
Walls actually move
Force created is tremendous
Contraction persists for months

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The Concept
Best description: Origin and physiologic
roles of inflammation. Ruslan Medzhitov,
Nature 2008;454:428-35
Inflammation involves the similar responses
but in various forms

Inflammation
An adaptive response for restoring homeostasis
in response to some form of stress
Purpose of inflammation
Remove or sequester the source of a disturbance
Allow the host to adapt to abnormal conditions
Restore functionality and homeostasis to the tissue

(Medzhitov, Nature 2008;454:428-35)

Degrees of the Inflammatory

Response
Severe insult systemic response
Trauma (burns the ultimate)
Infection
Mild insult local response (local recruitment)
Small injury
Hypoxia
Hyperglycemia
Very mild handled by resident cells

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Degrees of the Inflammatory

Response
Severe insult systemic response
Trauma (burns the ultimate)
Infection
Mild insult local response (local recruitment)
Small injury
Hypoxia
Hyperglycemia
Very mild handled by resident cells

Outcome of Inflammation
Success
Elimination of infection
Tissue repair
Return to homeostasis
Stalemate or compromise
Chronic inflammation (diabetes, obesity, granulomas,
foreign body response, cancer)
Scar formation
Failure
Death

Categories of the Inflammatory

Pathway
Inducers signals that initiate the
inflammatory response
Sensors detect inducers and then elicit the
production of mediators
Mediators alter the functional state of
tissues and organs which allows them to
adapt
Effectors cells, tissues and organs

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Host Defense
Two systems
Innate immune response
Exists in all animals from single cell organisms to
man
Immediate response to invading organisms
Adaptive immune response
In higher vertebrates
Antibody-antigen mediated response

LPS Binding
Several components to LPS binding
LPS bound by LBP (LPS binding protein)
LPS/LBP bound by CD14
CD14 has no cytoplasmic portion, so no
signaling
LPS/LBP/CD14 bind TLR4
MyD88 and M2 also part of receptor complex

TLR4 Intracellular Signaling

TLR4 leads to complex intracellular
signaling
Several pathways can be used
Most described pathway involves NF-B
Most described result TNF- production

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Monitoring the State of Cells

Health of cells/tissues monitored by
resident macrophages
10-15% of cells in tissues
Maintain homeostasis in basal states
Send signals during times of stress
Increase signals during major stress (call for
additional help)
If stress too high and adaptation no longer
possible apoptosis or necrosis

Friendly Fire
Inflammatory mediators (weapons against
invaders) damage local tissues
Large burn (> threshold size)
Residua from weapons (oxidants, free radicals,
cytokines) diffuse throughout Fortress
leading to distant organ damage

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Inflammation and Sepsis

Excessive inflammation spills into the
systemic system
Requires larger volume of inflammatory
response (larger burn, peritonitis, etc.)
Involves leukocyte response
Initiated through cytokines

Systemic Response to Burns

Excessive injury signal sent to command
center (brain) that the entire Fortress must
respond
Signal - excessive cytokine release from inflammatory
cells spills into systemic circulation
Hypothalamus detects danger signal
Hypermetabolic response initiated
Hypothalamic-Pituitary-Adrenal system activated
Release of catecholamines
Release of corticosteroids
Acute phase proteins produced

Controlling the Response to Injury

Eliminate the inflammatory source

Cover the wound
Autografts replace dermis and epidermis
Allografts replace dermis, temporary epidermis
Integra replaces dermis, silicone is temporary
epidermis
Rapid closure reduces inflammatory response
Not proven but accepted

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Wound Closure
Depends on size and type of wound
Small wounds
Primary closure
Within 6 hours
Face within 24 hours
Secondary closure if concerns with infection
Delayed primary closure
Wait for infection risk to be reduced
Wound strength as good as primary closure

Wound Closure
Larger wounds
Contraction for less vital areas
Skin grafting for larger areas
Flaps if wound bed does not allow for graft
Massive wounds require special strategies

Philosophy
Doing it right the first time
leads to excellent functional and cosmetic
outcomes
Minimizes need for reconstructive surgery
Shortens hospitalization
Earlier return to work/school

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Principle of burn wound healing

Heals within 2 weeks: minimal scarring
Open after 2 weeks:
Scarring is often excessive
Grafting improves result

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Superficial burns
Optimize re-epithelialization
Moist wound environment
Prevent infection
Biologic dressings (balance cost with benefit)
Wait 2 weeks if indeterminant depth

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Skin Grafts
Three phases of skin graft take
Phase of Imbibition (1-3 days)
Diffusion of nutrients from wound bed
Graft lost if seroma, hematoma, infection,
inadequate excision or bed
Phase of Vascularization (day 2-5)
Involves inosculation, angiogenesis, vasculogenesis
Shear leads to hematoma and loss
Phase of Maturation (lasts 8-18 months)

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Principles of grafting
Thicker grafts contract less
Thickest grafts for more important areas
(hands and face)
Balance graft thickness with potential for
donor site scarring
No need to allograft prior to autografting
Sheet grafts eliminate mesh pattern

Principles of grafting
Donor site harvest
Use SQ epinephrine solution
reduces bleeding
produces firm, wide surface
Choose best site
Thickest skin (back) allows for thick graft with
reduced risk for donor scarring
Hide donors
Consider color match

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Principles of grafting
Preparation of graft recipient site
Ensure adequate excision
Excise to bleeding
Tourniquet reduces blood loss but surgeon must
know viable tissue
Grafting on fat is OK
Removal of dermis reduces inclusion cysts
Bleeding must be controlled for sheet grafts

Skin Grafts
Expansion of grafts
Full-thickness limited availability
Split-thickness
Donor sites can be reharvested (re-epithelialization)
Meshing proportional to type of mesh (1:1, 2:1, 4:1)
Sheet grafts superior

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Principles of grafting
Sheet grafts
Cosmetically superior
Functionally superior
Require more work
Check early for hematomas
Require more skin
Alignment of seams to reduce scarring
Use for functionally important areas

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Medium size grafts

Sheet grafts still better
may require second harvest
excellent cosmetic results
Mesh for less cosmetically important areas
still use sheet for hands and faces

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Principles of grafting
Large burns
Remove burn within 1-2 weeks
Cover wounds with skin
autograft as much as possible
use allograft or substitute to close wound
Replace allograft/substitute when donors
available
Optimize donor site healing (growth hormone)

Principles of grafting
Large burns
Sheet or minimal mesh for hands and face
Larger mesh for less essential areas
Stages
extremities
trunk (back often has a chance of healing)
face (face also may heal)

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Principles of grafting
Skin substitutes
Work well with small burns
not as good as autografts
Do not use when adequate donor site available
sheet autografts superior
autografts quicker
Good option when lack of reasonable donor site
Do not ignore important areas while waiting

Cultured Epithelial Autograft

Effective for covering large areas
Problems
No dermis
Persistent fragility
Placed on fascia
Significant scarring

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Dermal Substitutes
Integra
Dermal matrix with silicone epithelium
Needs 3-4 weeks to vascularize
Excellent for rapid closure of wounds
Eliminates scarring

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Composite Skin Substitutes

Autogenous dermal and epidermal
components
Produced by Steven Boyce, PhD in
Cincinnati, Ohio

Preparation of CSS

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Flaps
Required for areas of inadequate wound bed
Random flap blood supply through dermis
Axial flap blood supply through central vessel
Myocutaneous flap blood supply through
muscle group beneath skin
Free flap myocutaneous flap that has
vasculature separated and re-anastomosed to
new site

Excessive Scar Formation

A greater problem than impaired healing
Treatments are limited and relatively
ineffectual
Hypertrophic scar -within original wound
Keloid beyond original wound

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Dogmas to Overcome
Scar milieu
Wounds must mature prior to reconstructive
surgery
Scar environment prevents optimal outcomes

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Dogmas to Overcome
Timing of contracture release
Must wait for scar maturation prior to release
Auto-release requires operative intervention
Early scar release is effective
Release of tension turns off TGF- expression

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Hurdles to Overcome
Understanding the controls of scarring
Why is there a genetic predisposition?
Learning why wounds that remain open
after 2 weeks scar more (why is control of
scarring lost?)
Funding
Treatment
Research

Factors that Increase Scar

Well-known
Persistent inflammation
Growth factors increase growth
TGF- is key factor
Scarless to scarring in fetal healing
Increased serum levels in patients with
tendencies to hypertrophic scarring

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Factors that Increase Scar

Tension increases scar formation
Body resists tension by increasing scar
Collagen is deposited to counteract stress
Collagen is reduced with decreased stress
Role of TGF-
Increases with tension
Releasing tension decreases TGF- and decreases
scarring

Factors that Decrease Scar

Traditional factors
Mechanisms unknown
Stretching and massage
Pressure (does it work?)
Silicone
Some understanding of mechanisms
Steroids
Radiation

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Factors that Decrease Scar

Eliminate exposure (inflammation)
Apoptosis
Epithelium a source of apoptosis
Thicker grafts/flaps increase apoptosis
Interferons (decrease TGF-)
Blockers of TGF-

The Scar Control Switch

Wounds open >2 weeks scar more
Why is scar regulation tied to exposure?
What is the switch?
Can we influence the switch?

The Scar Control Switch

TGF- hypothesis:
TGF- has dual roles
Immune regulation (immunosuppression)
Fibrosis
Prolonged inflammatory stimulus leads to
prolonged TGF- stimulation and loss of the
ability to turn off TGF- activity

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Conclusion
Three phases of healing
Healing proceeds normally if no
abnormalities
Several factors impair healing
Multiple strategies for closing wounds

1. Wilmore, 1984, Exposed at 25oC

140 Y = 15.78 + 1.09X, R = 0.7322, P <.001
2. Caldwell, 1981, Exposed at 28oC
1.
Y = 12.89 + 1.12X, R =0.7826, P <.001
120
% Metabolic Rate Above Normal

3. Arthurson, 1978, Infrared heat (self-control) 2.

Y = 7.89 + 0.55X, R = 0.561, P < .05
4. Caldwell, 1981, Occlusive bandages
100 Y = 7.88 + 0.46X, R = 0.4425, P < .05

80
60
3.
40
4.
20
0
20 40 60 80 100
% Body Surface Burned

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