WOUND HEALING
PHASES OF WOUND HEALING 3. T lymphocytes
HEMOSTASIS AND INFLAMMATION
 Hemostasis: Precedes and initiate inflammation with thee
insuing release of chemotactic factors from the wound site
 Wounding: Disrupts tissue integrity, leading to division of
blood vessels and direct exposure of ECM to platelets
- Exposure of subendothelial collagen to platelets =
Platelet aggregation, degranulation, and activation of
the coagulation cascade
- Platelet-a granules: PDGF, TGF-B, PAF, fibronectin, and
serotonin
 Cellular infiltration after injury
1. PMNs
— First infiltrating ells to enter the wound site, peaking at 24 to
48 hours
— Stimulated by increased vascular permeability, local prosta-
glandin release, and the presence of chemotactic substances
— Function: Phagocytosis of bacteria and tissue debris; Major
source of cytokines during early inflammation, esp. TNF-a for an-
giogenesis; Release proteases for matrix and ground substance
degradation in the early phase of wound healing
— Neutrophil factors have been implicated in delaying the epi-
thelial closure of wounds
2. Macrophages
— From circulating monocytes; Achieve significant numbers in
the wound by 48 to 96 hours post-injury and remain present until
wound healing is complete
— Function: Wound debridement via phagocytosis and contrib-
ute to microbial stasis via oxygen radical and nitric oxide synthe-
sis; Activation and recruitment of other cells via mediators, cell-
cell interaction, and ICAM; Regulate angiogenesis and matrix dep-
osition and remodeling
— Peak at ~1 week post-injury and truly bridge the transition
from the inflammatory to the proliferative phase of healing
— Function: Modulation of the wound environment; Downregu-
late fibroblast collagen synthesis by cell-associated IFN-γ, TNF-a,
and IL-1, which is lost if the cells are physically separated
— Depletion: Decreased wound strength and collagen contact;
Selective depletion of CD8+ suppressor T lymphocytes enhances
wound healing
PROLIFERATION
— Days 4 to 12; Tissue continuity is established
— Cell population: Fibroblasts and endothelial cells
- Strongest chemotactic factor: PDGF
- Function: Matrix synthesis remodeling
- Activation mediated mainly by the cytokines and
growth factors from wound macrophages
— Fibroblasts from wound vs. non-wound: Synthesize more col-
lagen, proliferate less, and actively carry out matrix contraction
- Mediators: Cytokines; Lactate (~10 mmol) which is a
potent regulator of collagen synthesis through ADP-
ribosylation
— Endothelial cells: Proliferate extensively for angiogenesis; Mi-
grate from intact venules close to the wound, mediated by VEGF
mainly from macrophages
MATRIX SYNTHESIS
Biochemistry of Collagen
— At least 18 types; Major types for wound healing
Type 1: Major component of skin ECM
Type III: Normally present in the skin, becomes more
prominent and important during the repair process
— Collagen chain: With glycine residue in every third posi
tion; Second position made up of proline or lysine during the
translation process
— Protocollagen
- Polypeptide chain with 1000 amino acid residues
- Release from the ER results in the hydroxylation of pro
line to hydroxyproline and lysine to hydroxylysine by
specific hydrolysis;
- Prolyl hydroxylase: Requires oxygen and iron as cofac
tors, a-ketoglurate as co-substrate, and ascorbic acid as
an electron donor
- Glycosylated in the ER by linking galactose and glucose
at specific hydroxylysine residues
- a-helical configuration: d/t hydroxylation and glycosyla
tion which alter the hydrogen bonding forces within the
chain
— Procollagen
- Right-handed super-helical structure formed by en
twined three a-helical chains
- With covalent cross-linking of lysine residues
- Registration peptides: Non-helical peptide domains at
both ends of the structure; Cleaved by procollagen pep
tidase extracellularly, and the procollagen strands under
go further polymerization and cross-linking
 WOUND HEALING
- Collagen monomer: Further polymerized and cross-
linked by the formation of intra– and intermolecular
covalent bonds
- Systemic factors for collagen synthesis and post-
translational modifications: Adequate oxygen supply;
presence of sufficient nutrients (AA and CHO) and co-
factors (vitamins and trace minerals); and the local
wound environment
Proteoglycan Synthesis
— Glycosaminoglycans: Ground substance that makes up
granulation tissue; Usually coupled with proteins, forming
proteoglycans
- Polysaccharide chain: Repeating disaccharide units
composed of glucuronic or iduronic acid, and a hex
osamine, which is usually sulfated
- Disaccharide: ~10 units in heparan sulfate, ~2000 units
in hyaluronic acid
— Major GAGs in wounds: Dermatan and chondroitin sulfate
- Synthesized by fibroblasts, increasing their concentra
tion greatly during the first 3 weeks of healing
— Assembly of collagen subunits into fibrils and fibers de
pends on the lattice provided by the sulfated proteoglycans
— Extent of sulfation: Critical in determining the configure
tion of the collagen fibrils
— With scar maturation and collagen remodeling, the proteo
glycan content gradually diminishes
MATURATION AND REMODELING
— Begins during the fibroblastic phase
— Reorganization of previously synthesized collagen broken
down by MMPs
— Net collage content: Collagenolysis = Collagen synthesis
- Net shift toward collagen synthesis and eventually the
re-establishment of ECM composed of a relatively colla
gen-rich scar
—Wound strength and mechanical integrity in fresh wound =
Quantity and quality of newly-deposited collagen
1. Fibronectin and Type III collagen
2. GAGs and proteoglycans
3. Type I collagen
— By several weeks post-injury, the amount of collagen in the
wound reaches a plateau, but the tensile strength continues to
increase for several months
— Fibril formation and fibril cross-linking: Decreased collagen
solubility, increased strength, and increased resistance to enzy-
matic degradation of the collagen
— Fibrillin: From fibroblasts; For the formation of elastic fibers
— Scar remodeling: Continues for 6-12 months post-injury; Re-
sulting in a mature, avascular, and acellular scar
— Collagenolysis: With constant turnover of collagen in the ECM;
Result of collagenase activity (an MMP), mediated by cytokines
and growth factors, such as TGF-B
EPITHELIALIZATION
— Proliferation and migration of epithelial cells adjacent to the
wound, beginning within day 1 of injury
1. Marginal basal cells at the edge of the wound lose their firm
attachment to the underlying dermis, enlarge, and begin to
migrate across the surface of the provisional matrix
2. Fixed basal cells near the cut edge undergo a series of rapid
mitotic divisions, and migrate by moving over one another in
a leapfrog fashion until the defect is covered.
3. Once the defect is bridged, the migrating epithelial cells lose
their flattened appearance, become more columnar and
increase their mitotic activity
— Re-epithelialization
- Complete in <48 hours for approximated incised wounds
- Damaged epithelium and superficial dermis: Minimal or no
fibroplasia and granulation tissue formation
- Mediated by loss of contact inhibition; exposure to constit
uents of the ECM, particularly fibronectin; and cytokines
from immune mononuclear cells: EGF, TGF-B, bFGF, PDGF,
and IGF-1
ROLES OF GROWTH FACTORS IN NORMAL HEALING
— Action: Autocrine, paracrine, endocrine manner
— Timing of release may be as important as concentration in de-
termining the effectiveness of growth factors
— Exert effects through cell-surface receptor binding, eliciting
phosphorylation or de-phosphorylation of second-messenger
molecules through the action of phosphatases or kinases, re-
sulting in activation or deactivation of proteins in the cytosol or
nucleus of the target cell
— Phosphorylation: Followed by initiation of transcript
tion of target genes
— Signal is stopped by internalization of the receptor-
ligand complex
WOUND CONTRACTION
— Contracture: Shortening of the scar
— Healing by secondary intention: For wounds that do not have
surgically approximated edges
— Myofibroblasts: Responsible for wound contraction; With a
cytoskeletal structure and contains stress fibers or a-smooth mus-
cle actin in thick bundles
- a-smooth muscle actin: Undetectable until day 6; In
creasingly expressed for the next 15 days of wound heal
ing; Expression fades after 4 weeks, and the cells are
believed to undergo apoptosis
 WOUND HEALING
HEALING IN SPECIFIC TISSUES
GASTROINTESTINAL TRACT
— Healing of full-thickness wounds begins with a surgical or me-
chanical reapposition of the bowel ends
- Sutures or stapples; Buttons, plastic tubes, and various
wrappings
— Failure of healing: Dehiscence, leaks, and fistulas
— Excessive healing: Stricture formation and stenosis of the lu-
men
— Gross anatomic features of the GI tract
- Submucosa: Imparts greatest tensile strength and
greatest suture-holding capacity
- Serosal healing: Essential for quickly achieving a water
tight seal from the luminal side of the bowel
— Mesothelial (serosal) and mucosal healing can occur without
scarring
- Early integrity of the anastomosis = Formation of a fi
brin seal on the serosal side and on the suture-holding
capacity of the intestinal wall
— Significant decrease in marginal strength during the first week
d/t an early and marked collagenolysis
- Collagenase from neutrophils, macrophages, and in
traluminal bacteria
- Strains of P. aeruginosa undergo phenotypic shifts:
Higher collagenase secretion in an injured/anastomosed
bowel environment
- Collagenase activity occurs early in the healing process
- First 3 to 5 days, collagenolysis >>> collagen synthesis
- Collagenase expression: Colon > Small bowel
— Collagen synthesis via fibroblasts and smooth muscle cells
- Colon fibroblasts > Skin fibroblasts
— Ultimate anastomotic strength is not always related to the
absolute amount of collagen, and the structure and arrangement
of the collagen may be more important.
Technical Considerations
— Anastomotic healing without complications
- Tension-free, with adequate blood supply and nutri
tion, and free of sepsis
— No convincing evidence that a given suturing technique has
any advantage over another
- Hand-sutured vs. stapled, continuous vs. interrupted
sutures, absorbable vs. non-absorbable, or single– vs.
two-layered closure
— Amount of IV fluid administered perioperatively affects many
aspects of recovery from colonic surgery
- Anastomotic healing may be adversely affected by
overzealous fluid administration, which results in fluid a
accumulation in the third space, increased abdominal
pressure, and tissue edema, which can compromise
blood flow in the small vessels at the healing edge
BONE
1. Hematoma formation
— Accumulation of blood at the fracture site which contains the
devitalized tissue, dead bone, and necrotic marrow
2. Liquefaction and degradation of non-viable products at the
fracture site
3. Revascularization
— New vessels grow into the fracture site; Similar in the for-
mation of granulation tissue in soft tissue
— Sx: Inflammation, e.g. swelling and erythema
4. Soft callus stage
— 3 to 4 days post-injury
— Soft tissue forms a bridge between the fractured bone seg-
ments, where neovascularization has taken place
— Serves as an internal splint, preventing damage to the newly
laid blood vessels and achieving a fibrocartilaginous union
— Formed externally along the bone shaft and internally within
the marrow cavity
— Sx: End of pain and inflammatory signs
5. Hard callus stage
— ~2 to 3 months
— Mineralization of the soft callus and conversion to bone
— Bone is now considered strong enough to allow weight-bearing
and will appear healed on radiographs
6. Remodeling phase
— Excessive callus is reabsorbed and the margin is now re-
canalized
— Allows for the correct transmission of forces and restores the
contours of the bone
— Mostly mediated by BMP from the TGF-B superfamily
- Stimulate the differentiation of mesenchymal cells into
chondroblasts and osteoblasts
CARTILAGE
— Very avascular and depends on the diffusion for transmittal of
nutrients across the matrix and on the hypervascular perichondri-
um
— Healing response depends o the depth of injury
1. Superficial injury
- Disruption of the proteoglycan matrix and injury to the
chondrocytes
- No inflammatory response
- With increased synthesis of proteoglycan and collagen
dependent entirely on chondrocytes
- Inadequate healing power and incomplete overall re
generation
- Slow to heal and often result in persistent structural
defects
2. Deep injury
- Involve underlying bones and soft tissues
- With exposed vascular channels of the surrounding
damaged tissue that may help in the formation of granu
lation tissue
 WOUND HEALING
— Hemorrhage: Allows initiation of the inflammatory response
and the subsequent mediator activation of cellular function for
repair
— Hyaline cartilage: Restores the structural and functional integ-
rity of the injured site
TENDON
— Consists of parallel bundles of collagen interspersed with spin-
dle cells
— Damaged ends usually separate d/t the mobility of the under-
lying bones and muscles
— Healing: Through hematoma formation, organization, laying
down of reparative tissue, and scar formation
— Matrix: Accumulated type I and III collagen along with in-
creased water, DNA, and GAG content
— Restoration of the mechanical integrity may never be equal to
that of the undamaged tendon
— Tendon vasculature
- Hypovascular tendons tend to heal with less motion
and more scar formation than tendons with better blood
supply
— Tenocytes: Metabolically very active and retain a large regen-
erative potential, even in the absence of vascularity
NERVE
— Nerve injuries
- Neurapraxia: Focal demyelination
- Axonotmesis: Interruption of axonal continuity, but
preservation of Schwann cell basal lamina
- Neurotmesis: Complete transection
— Predictable pattern of changes
a) Survival of axonal cell bodies
b) Regeneration of axons that grows across the transected
nerve to reach the distal stump; and
c) Migration and connection of the regenerating nerve ends to
appropriate nerve ends or organ targets
— Wallerian degeneration: Phagocytes remove the degenerating
axons and myelin sheath from the distal stump
— Regenerating axonal sprouts extend from the proximal stump
and probe the distal stump and the surrounding tissue
— Nerve healing factors: Growth factors, cell adhesion mole-
cules, and non-neuronal cells and receptors
- Growth factors: Nerve growth factor, brain-derived
neurotrophic factor, basic and acidic FGF, and neu
roleukin
- Cell adhesion molecules: Nerve adhesion molecule,
neuron-glia adhesion molecule, myelin adhesion glycol
protein, and N-cadherin
FETAL WOUND HEALING
— Early fetal healing: Absence of scarring and resembles tissue
regeneration
— Transition wound
- Phase of transition during gestational life when a more
adult-like healing pattern emerges
- Occurs at the beginning of the third trimester
- With scarless healing, but with a loss of the ability to
regenerate skin appendages
— Overall healing continues to be faster than in adults
Wound Environment
— Sterile, temperature-stable environment
— Experiments: Scarless healing may occur outside the amniotic
fluid environment, and scars can form in utero
Inflammation
— Extent and robustness of response = Amount of scar for-
mation
— Reduced fetal inflammation: D/t immaturity of the fetal im-
mune system, neutropenic, wounds with low numbers of PMNs
and macrophages
Growth Factors
— (-) TGF-B
- Blocking TGF-B1 or TGFB2 using neutralizing antibodies
considerably reduces scar formation in adult wounds
- Exogenous application of TGF-B3 downregulates TGF-
B1 and TGF-B2 levels at the wound site with a resultant
reduction in scarring
Wound Matrix
— (+) Excessive and extended hyaluronic acid production
- Hyaluronic acid: HMW GAG from fibroblasts
- Sustained synthesis in fetal wound, which may be stim
ulated by the components of amniotic fluid, most specifi
cally fetal urine
- Used topically to enhance healing and to inhibit post-
operative adhesion formation
— Collagen production: Fetal fibroblasts > Adult fibroblasts
- Increased level of hyaluronic acid may aid in the orderly
organization of collagen
- Pattern in fetal wounds: Reticular and resembles sur
rounding tissues
- Pattern in adult wounds: Large bundles of parallel colla
gen fibrils oriented perpendicular to the surface
 WOUND HEALING
CLASSIFICATION OF WOUNDS
— Healing processes
1. Primary intention: Incised wound that is clean and closed by synthesis and wound strength
sutures
2. Secondary intention: Wound left open because of bacterial
contamination or tissue loss heal by granulation tissue for-
mation and contraction
3. Tertiary intention: Delayed primary closure; Combination of
the first two, consisting of placement of sutures, allowing the
wound to stay open for a few days, and the subsequent clo-
sure of sutures
— Delayed healing
- Decreased wound-breaking strength in comparison to
wounds that heal at the normal rate
- Eventually achieve the same integrity and strength as
wounds that heal normally
- Factors: Nutritional deficiencies, infections, or severe
trauma
— Impaired healing
- Failure to achieve mechanical strength equivalent to
normally healed wounds in patients with compromised
immune systems
FACTORS AFFECTING WOUND HEALING
— Systemic: Age, nutrition, trauma, metabolic diseases, immuno- Metabolic Disorders
suppression, connective tissue disorders, smoking
—Local: Mechanical injury, infection, edema, ischemic/necrotic
tissue, topical agents, ionizing radiation, low oxygen tension, for-
eign bodies
Advanced Age
— Direct correlation between older age and poor wound healing
outcomes, such as dehiscence and incisional hernia
— D/t increased incidence of CVD, metabolic diseases, and can-
cer, and the widespread use of drugs that impair wound healing
— Major operative interventions can be accomplished safely in
the elderly
— Although wound collagen synthesis does not seem to be im-
paired with advanced age, non-collagenous protein accumulation
at wounded sites is decreased with aging, which may impair the
mechanical properties of scarring in elderly patients
Hypoxia, Anemia, and Hypoperfusion
— Fibroplasia: Stimulated initially by the hypoxic wound environ-
ment; Significantly impaired by local hypoxia
— Optimal collagen synthesis: Requires oxygen as a cofactor,
particularly for the hydroxylation steps
— Major factors affecting local oxygen delivery
- Hypoperfusion, either for systemic or local causes
— Level of vasoconstriction of the subcutaneous capillary bed is
exquisitely responsive to fluid status, temperature, and hyperac-
tive sympathetic tone as is often induced by post-operative pain
— Mild to moderate normovolemic anemia does not appear to
adversely affect wound oxygen tension and collagen synthesis,
unless the hematocrit falls below 15%
Steroids and Chemotherapeutic Drugs
— Large doses or chronic use of glucocorticoids reduce collagen
- D/t inhibition of the inflammatory phase of wound
healing (angiogenesis, neutrophil and macrophage mi
gration, and fibroblast proliferation) and the release of
lysosomal enymes
— Stronger anti-inflammatory effect of the steroid com
pound = Greater inhibitory effect on wound healing
— Adverse effects of steroids: Used during immediate
post-operative period >>> Used after the first 3 to 4 days
post-injury
— If possible, use should be delayed or alternative forms
with lesser anti-inflammatory effects should be adminis
tered
— Steroids inhibit epithelialization and contraction and
contribute to increased rated of wound infection, re
gardless of the time of administration
— Stimulate by topical application of Vitamin A
— Chemotherapeutic anti-metabolite drugs
— Inhibit early cell proliferation and wound DNA and
protein synthesis
—Delay use for ~2 weeks post-injury
— Extravasation = Tissue necrosis, marked ulceration,
and protracted healing at the affected site
— Diabetes mellitus
— Uncontrolled: Reduced inflammation, angiogenesis,
and collagen synthesis
— Large– and small-vessel disease: Hallmark of ad
vanced diabetes and contributed to local hypoxemia
— With defects in granulocytes function, capillary in
growth, and fibroblast proliferation
— Insulin restores collagen synthesis and granulation
tissue formation to normal levels if given during the ear
ly phases of healing
— Type I DM: Decreased wound collagen accumulation,
independent of glycemic control
— Type II DM: No effect on collagen accretion when
compared to healthy, age-matched controls
— Diabetic wound appears to be lacking in sufficient
growth factor levels, which signal normal healing
— Careful preoperative correction of blood sugar levels
improve the outcome of wounds in diabetic patients
— Uremia
— Clinical use of dialysis to correct the metabolite ab
normalities and nutritional restoration
— Obesity
— Uncomplicated obesity: (-) comorbid conditions
— Visceral adiposity: Active metabolically and immune
logically, through generation of pro-inflammatory cyto
kines and adipokines; Leads to the development of the
metabolic syndrome
— With high rates of perioperative complications:
Wound dehiscence (30%), surgical site infections (17%),
incisional hernias (39%), seromas (19%), hematomas
(13%), and fat necrosis (10%)
 WOUND HEALING
— Surgery-related complications: Anastomotic leaks,
abdominal collection, and wound infections
— Constant and major risk factor for hernia formation
and recurrence after repair
Nutrition
— Nutritional status of patients with wounds
— PEM: With diminished hydroxyproline accumulation (index of
collagen deposition) into subcutaneously implanted polytetraflu-
oroethylene tubes when compared to normally nourished pa-
tients
— Malnutrition correlates clinically with enhanced rates of
wound complications and increased wound failure
— Impaired healing response and reduced cell-mediated immuni-
ty, phagocytosis, and intracellular killing of bacteria by macro-
phages and neutrophils
— Degree of nutritional impairment need not be long-standing
— Impaired fibroplasias: Patients with brief periopera
tive illnesses or reduced nutrient intake in the period
immediately preceding the injury or operative intervene
tion
— Brief and not necessarily intensive nutritional intervention,
either via the parenteral or enteral route, can reverse or prevent
the decreased collagen deposition noted with malnutrition or
with post-operative starvation
— Arginine
— Study: Deficiency = Decreased wound-breaking
strength and wound-collagen accumulation
— Supplementation has no enhanced DNA synthesis;
Had no effect on the rate of epithelialization of a superfi
cial skin defect
— Main effect maybe enhancing wound collagen deposi
tion
— B-hydroxyl-B-methyl butarate and glutamine: Signifi
cantly and specifically enhance collagen deposition in
Elderly
— Vitamins C
— Scurvy: Defect in wound healing, particularly in colla
gen synthesis and cross-linking; Increased incidence of
infection, and if wound infection does occur, it tends to
be more severe
— Effects associated with impaired neutrophil function,
decreased complement activity, and decreased walling-
off of bacteria, secondary to insufficient collagen deposi
tion
— RDA for healthy, non-smokers: 60 mg
— RDA for severely injured or extensively burned: 2 g
— Vitamin A
—Increases inflammatory response in wound healing d/t
increased liability of lysosomal membranes
— Increased influx of macrophages, with an increase in
their activation and increased collagen synthesis
— Directly increases collagen production and EGF recep
tors in fibroblasts
— Reverse the inhibitory effects of corticosteroids
— Restore wound healing impaired by diabetes, tumor
formation, cyclophosphamide, and radiation
— Increased requirements in serious injury or stress
— RDA: 25,000 to 100,000 IU per day
— Zinc
— Most well-known element in wound healing
— Cofactor for ~150 enzymes
— Deficiency: Decreased fibroblast proliferation, de
creased collagen synthesis, impaired overall wound
strength, and delayed epithelializaion
Infections
— Occurrence while using implants may lead to removal of the
prosthetic material
— Can weaken an abdominal closure or hernia repair and result
in wound dehiscence or recurrence of hernia
— Antibiotic
— Prophylaxis: Most effective when adequate concen
trations are present in the tissues at the time of incision
— Addition after operative contamination: Ineffective
— Repeat dosing essential in decreasing post-operative
wound infections in operations with durations exceeding
the biochemical half-life of the antibiotic or in which
there is large-volume blood loss and fluid replacement
— Selection for prophylaxis = Type of surgery, operative
contaminants that might be encountered, and the pro
file of resistant organisms present at the institution
where the surgery is performed
- Patients with prosthetic heart valves or any
implanted vascular or orthopedic prostheses
- Dental procedures: Broad-spectrum penicillins
or amoxicillin
- Urologic instrumentation: 2nd generation
cephalosporin
- Patients with prostheses and GI surgery: An
aerobic coverage with a cephalosporin
- Nasal screening and decolonization of S. aure
us carries: For cardiac, orthopedic neurosurgi
cal procedures with implants
— Increased risk of infection if the wound is contaminated with
>10^5 microorganisms
— Pathogens from the endogenous flora of the patient’s
skin, mucous membranes, or from hollow organs
— Staphylococcus sp., Streptococcus, enterococci, and E.
coli
— Incidence of wound infection = Degree of contamination
a) Class I—Clean
b) Class II—Clean contaminated
c) Class III—Contaminated
d) Class IV—Dirty
— Most surgical infections appear 7 to 10 days post-operatively
— Wound infection
— Wounds that drain purulent material with bacteria
identified on culture
— All wounds draining pus, whether or not bacteriologic
studies are positive; wounds that are opened by the sur
geon; and wounds that the surgeon considers infected
— Anatomical classification of wounds
— Superficial incisional: Skin and subcutaneous (3/4);
Looks edematous and erythematous, and is tender
— Deep incisional: Immediately adjacent the fascia;
Often with an abdominal component
— Organ/space wound infections: Fascia, muscle, or the
abdominal cavity
 WOUND HEALING
— Inspection of the wound is most useful in detecting subtle
edema around the suture and staple line
— Early phase of infection: Waxy appearance of the skin
— (+) Pus: Further opening of the subcutaneous and skin
layers to the full extent of the infected pockets for clean
ing and sample-taking
— System antibiotics: For immunosuppressed patients with evi-
dence of tissue penetration or systemic toxicity, or who have had
prosthetic devices inserted
— Deep wound infections
— Most intra-abdominal infections do not communi
cate with the wound; (+) Fever and leukocytosis
— Necrotizing fasciitis
— Most dangerous, particularly in the elderly
— Septic thrombosis of the vessels b/w the
skin and the deep layers
— Skin: (+) Hemorrhagic bullae and subsequent
frank necrosis, with surrounding areas of in
flammation and edema
— Usually wider than the skin involvement
— Toxic patient, with high fever, tachycardia,
and marked hypovolemia which may lead to CV
collapse
— Mixed infections: High dose penicillin (20-40
million U/d IV) for C. perfringens and others
— CV resuscitation with electrolyte solutions,
blood, and/or plasma prior to induction of anes
thesia
— Aim of surgery: Remove all necrosed skin
and fascia
— If viable skin overlies necrotic fascia = Multi
ple longitudinal skin incisions for excision of
devitalized fascia
— Careful inspection every 12 to 24 hours will
reveal any new necrotic areas for debridement
and excision
— (+) Bacteria
— Contamination: Presence without multiplication
— Colonization: Multiplication without host response
— Infection: (+) Host response from deposition and mul
tiplication of bacteria
— Cellulitis, abnormal discharge, delayed heal
Ing, change in pain, abnormal granulation tis
sue, bridging, and abnormal color and odor
— Chronic Granulomatous Disease (CGD)
— Genetically heterogeneous group of diseases with
deficiency in reduced NADPH-dependent oxide enzyme
— With impaired killing of microorganisms causing re
current infections and form granulomas, which can lead
to obstruction of the gastric antrum and GUT and poor
wound healing
— Dx: Nitroblue tetrazolium (NBT) reduction test
— Reduced by normal neutrophils via a colori
metric test
— Agents: S. aureus, Aspergillus, Klebsiella, Serratia, or
Candida
— Require pre-operative pulmonary function test d/t
predisposition to obstructive and restrictive lung disease
— Sutures should be removed as late as possible since
the wounds heal slowly; Abscess drains left
— Hyperglycemia in post-operative infections
—Moderate control (120-180 mg/dL) > Too tight glyce
mic control (80-100 mg/dL)
— State of subcutaneous capillary bed
— Sensitive to hypovolemia, hypothermia, and stress,
leading to rapid vasoconstriction with secondary im
paired oxygen delivery and increased rates of infection
— Management: Maintain euvolemia, core temperature
>36-36.5, and pain control; Increase inspired FIO2 to 0.8
CHRONIC WOUNDS
— Wounds that have failed to proceed through the orderly pro-
cess that produces satisfactorily anatomic and functional integrity
or that have proceeded through the repair process without pro-
ducing an adequate anatomic and functional result
— Wounds >3 months
— Skin ulcers: In traumatized or vascular compromised soft tissue
— Causes: Repeated trauma, poor perfusion or oxygenation,
and/or excessive inflammation
— Unresponsiveness to normal regulatory signals
— Fibroblasts with decreased proliferative potential
— Malignant transformation (Marjolin’s ulcer)
— With overturned wound edges
— Biopsy of wound edges
— Usually squamous and basal cell carcinomas
Ischemic Arterial Ulcers
— D/t lack of blood supply; Painful at presentation
— Associated with intermittent claudication, rest pain, night pain,
and color or trophic changes
— Usually at the most distal portions of extremities
— Signs: Diminished or absent pulses with decreased ankle-
branchial index, and poor formation of granulation tissue; dry-
ness of skin, hair loss, scaling, and pallor
— Wound: Shallow with smooth margins, pale base and sur-
rounding skin
— Management: Revascularization and wound care
— Non-healing of these wounds is the norm, unless suc
cessful revascularization is done
— Removal of restrictive stocking, frequent reposition
ing, and surveillance
Venous Stasis Ulcers
— Ulcer that fails to re-epithelialize despite adequate granulation
tissue
— D/t venous stasis and hydrostatic back pressure
— Possible mechanisms
— With alteration and distention of the dermal capillary
ies with leakage of fibrinogen into the tissues; polymeri
zation of fibrinogen into fibrin cuffs leads to perivascular
cuffing that can impede oxygen exchange
— Neutrophils adhere to the capillary endothelium and
cause plugging with diminished dermal blood flow
— Venous HPN and capillary damage lead to extravasa
tion of hemoglobin
— Lipidermatosclerosis: Resulting brownish pigmentation with
loss of subcutaneous fat
 WOUND HEALING
— D/t incompetence of either superficial or deep venous systems
— Deep venous system: Painless
— Tend to occur at the sites of incompetent perforators
— Most common: Above medial malleolus, over Cock
ett’s perforator
— Dx: Location + Hx of venous incompetence and other skin
changes
— Wound: Shallow with irregular margins and pigmented sur-
rounding skin
— Tx: Compression therapy, via rigid or flexible means
— Most common: Rigid, zinc oxide-impregnated, non-
elastic bandage
— Wound care: Maintaining a moist wound environ
ment, with hydrocolloids
— Use of vasoactive substances and growth factor appli
cation, and skin substitutes; Sprayed allogeneic keratino
cytes and fibroblasts plus four-layer bandages
— Recurrences d/t patients’ lack of compliance
Diabetic Wounds
— Major contributors
— Neuropathy (60-70%)
— Ischemia (15-20%)
— Combination (15-20%)
— Foot deformity
— Neuropathy: Motor and sensory
— Allows unrecognized injury
— Motor neuropathy or Charcot’s foot: Collapse or dislo
cation of the IP or MTP joints, causing pressure on areas
with little protection
— Once ulceration occurs, the chances of healing are poor
— Treatment
— Achievement of adequate blood sugar levels
— Address possible presence of osteomyelitis: Antibi
otics and debridement
— Off-loading of the ulcerated are with specialized or
thotic shoes or casts for ambulation with protection
— Topical application of PDGF and GM-CSF
— Application of engineered skin allograft substitutes
Decubitus / Pressure Ulcers
— Localized area of tissue necrosis that develops when soft tissue
is compressed between a bony prominence and an external sur-
face
— Excessive pressure = Capillary collapse
— Formation accelerated in the presence of friction, shear forces,
and moisture; Immobility, altered activity levels, altered mental
status, chronic conditions, and altered nutritional status
— Stages of ulcer formation
Stage 1: Non-blanching erythema of the intact skin
Stage 2: Partial-thickness skin loss (epidermis/dermis/both)
Stage 3: Full-thickness skin loss, but not through the fascia
Stage 4: Full-thickness skin loss, extensive involvement of mus-
cles and bone
— Management
— Debridement of all necrotic tissue, maintenance of a
favorable moist wound environment, relied of pressure,
and addressing host issues
— Debridement: Surgical; Enzymatic proteolytic prepara
tions and hydrotherapy
— Moist wound bed: Dressings that absorb secretions
but do not dessicate the wound
— Operative repair: Flap rotation
— Extremely high recurrence rates
EXCESS HEALING
— Manifestations
Skin: Mutilating / debilitating scars, burn contractions
Tendons: Frozen repairs
GIT: Strictures and stenosis
Solid organs: Cirrhosis, pulmonary fibrosis
Peritoneal cavity: Adhesive disease
— Overabundance of fibroplasia in the dermal healing process
1. Hypertrophic scars (HTSs)
— Rise above the skin level, but stay within the con
fines of the original wound and often regress over time
— Usually develops 4 weeks after trauma
— Risk increases if epithelialization >21 days, independ
ent of site, age, and race
— Rarely elevated >4 mm above the skin level, usually
across the areas of tension and flexor surfaces, which
tend to be at right angles to joint or skin creases
— Collagen bundles: Flatter and more random; Wavy
pattern of fibers
— Higher TGF-B and IGF-1, which reduces collagenase
mRNA activity and increases mRNA for type I and III col
lagen
— With higher T lymphocyte and Langerhans cell con
tents
2. Keloids
— Rise above the skin, but extend beyond the border
of the original wound, and rarely regress spontaneously
— 15x more common in dark pigmented ethnicities
— Men = Women
— Predilection: Autosomal dominant with incomplete
penetration and variable expression
— Occur 3 months to years after the initial insult
— Rarely extends into the underlying subcutaneous tis
Sue
— Higher incidence of formation on the skin of the ear
lobe, deltoid, pre-sternal, and upper back regions
— Rarely occurs on eyelids, genitalia, pals, soles, or
across joints
— Collagen bundles: Virtually non-existent; Fibers hap
hazardly in loose sheets with random orientation to the
epithelium
— Collagen fibers: Larger and thicker
— Myofibroblasts: Absent
— Fibroblasts: With normal proliferation parameters;
Synthesize collagen 20x greater than in normal epider
mis, and 3x greater than in HTS; With enhanced expres
sion of TGF-B1 and B2, VEGF, and PAI-1, and PDGF re
ceptors
— Abnormal ECM: Fibronectin, elastin, proteoglycans
d/t altered growth factor expression
— Increased deposition of IgG, IgA, and IgM
— (+) Antinuclear antibodies against fibroblasts, epitheli
al and endothelial cells
 WOUND HEALING
— With increased thickness of the epidermis with an absence of
rete ridges
— With abundance of collagen and glycoprotein deposition
— Express HLA-2 and ICAM-1 which are absent in normal
keratinocytes
— With large number of mast cells
— Fibrinocytes
— Leukocyte subpopulation from peripheral mononucle
ar cells, which stimulate fibroblast numbers and collagen
synthesis
— Generate large number of cytokines, growth factors,
and ECM proteins
— Abnormal scarring mechanisms
— Mechanical tension and prolonged irritation and/or
inflammation
— Treatment: Restoration of function to the area, relief of symp-
toms, and prevention of recurrence
— Excision: High recurrence rate (45-100%)
— Inclusion of dermal advancing edge, use of
incisions in skin tension lines, and tension-free
closure: Decreased recurrence rates
— Surgery
- For debulking large lesions or as a second-line
therapy when other modalities have failed
- Combined with intralesional corticosteroid
injection, topical application of silicon sheets, or
use of radiation or pressure
— Silicone application
- Relatively painless; Maintained for 24 hours/
day/3 months to prevent rebound hypertrophy
- Mechanism: Increased hydration which de
creases capillary activity, inflammation, hypere
mia, and collagen deposition
- More effective especially for children and oth
ers who cannot tolerate the pain from other
modalities
— Intralesional corticosteroid injection
- Decrease fibroblast proliferation, collagen and
GAG synthesis, inflammatory process, and TGF-
B levels
- First-line treatment for keloids and second-
line treatment for HTSs, if topical therapies
have failed
- May soften, flatten, and give symptomatic
relief to keloids, but does not make the lesions
disappear or narrow wide HTSs
- Serial injections: Every 2-3 weeks
- Complications: Skin atrophy, hypopigmenta
tion, telangiectasias, necrosis, and ulceration
— Radiation
- Variable results; 10-100% recurrence
- More effective when combined with surgical
excision
- 1500 to 2000 rads
- Risks: Hyperpigmentation, pruritus, erythema,
paresthesias, pain, and possible secondary ma
lignancies
- Reserved for adults with scars resistant to oth
er modalities
— Pressure
— Aids collagen maturation, flattens scars, and
improves thinning and pliability
— Reduces number of cells in an area, possibly
d/t ischemia, which decreases tissue metabo
lism and increases collagenase activity
— External compression for HTSs after burns:
24-30 mmHg to exceed capillary pressure, yet
preserve peripheral blood circulation
— Garments should be worn 23-24 hours/day/
1 or more years to avoid rebound hypertrophy
— Topical retinoids
— 50-100% responses
— Intralesional injection of IFN-γ
— Reduce collagen types I, II, and III by de
creasing mRNA and possibly by reducing TGF-B
levels
— Imiquimod
— Immunomodulator inducing IFN-γ and other
cytokines at the site of application, following
excision
—Intralesional injection of chemotherapeutic agents
— 5-fluorouracil, bleomycin, neomycin
Peritoneal Scarring / Adhesions
— Fibrous bands of tissues formed between organs that are nor-
mally separated and/or between organs and the internal body
wall
— Result of peritoneal injury
— Prior surgical procedures (67%)
— With hx of intraabdominal infection (28%)
— Most common (65-75%) cause of small bowel obstruction,
especially in the ileum
— Leading cause of secondary infertility in women and can cause
substantial abdominal and pelvic pain
— Development of adhesion
— Injury disrupts the protective mesothelial cell layer
lining the peritoneal cavity and the underlying connec
tive tissue
— Injury elicits an inflammatory response
— Fibrin deposition occurs between the damage but
opposed serosal surfaces
— Often transient and degraded by proteases of the
fibrinolytic system, with restoration of the normal peri
toneal surface
— Insufficient fibrinolytic activity = Permanent adhesions
will form by collagen deposition within 1 week of the
injury
— During normal repair, fibrin is principally degraded by
the fibrinolytic protease plasmin from inactive plasmino
gen via tissue plasminogen activator (tPA) and urokinase
-type plasminogen activator (uPA)
— Fibrinolytic activity in peritoneal fluid is reduced after
abdominal surgery
— D/t initial decreases in tPA levels, increases
in PAI-1 via TNF-a, IL-1, and IL-6
 WOUND HEALING
— Prevention / reduction
— Laparoscopic techniques
— Surgical trauma is minimized within the peri
toneum by careful tissue handling, avoiding
dessication and ischemia, and spare use of cau
tery, laser, and retractors
— Introduciton of barrier membrane and gels
— Separate and create barriers between dam
aged mesothelial surfaces, allowing for adhe
sion-free healing
— FDA-approved: Interceed, Seprafilm, Adept
— Contraindication: Use directly over bowel
anastomoses d/t an elevated risk of leak
TREATMENT OF WOUNDS
LOCAL CARE
— Examination of the wound
— Depth and configuration of the wound, the extent of
nonviable tissue, and the presence of foreign bodies and
other contaminants
— May require irrigation and debridement of the edges
of the wound, facilitated by local anesthesia
— Antibiotic and tetanus prophylaxis
— Planning the type and timing of wound repair
— Meticulously anesthesizing the wound
— Lidocaine (0.5-1.0%) or bupivacaine (0.25-0.5%) com
bined with a 1:100,000 to 1:200,000 dilution of epineph
rine
— Epinephrine: Should not be used in wounds of the
fingers, toes, ears, nose, or penis d/t risk of tissue necro
sis secondary to terminal arteriole vasospasm in these
structures
— May cause significant initial patient discomfort
— Minimized by slow injection, infiltration of
the subcutaneous tissues, and buffering the
solution with sodium bicarbonate
— Irrigation
— Best accomplished with normal saline (without addi
tives)
— High-pressure wound irrigation: For complete deb
ridement of foreign material and non-viable tissues
— Iodine, povidone-iodine, hydrogen peroxide, and or
ganically based antibacterial preparations: Impair
wound healing d/t injury to wound neutrophils and mac
rophages
— All hematomas within the wounds should be careful
ly evacuated and any remaining bleeding sources con
trolled with ligature or cautery
— Area surrounding the wound should be cleaned, inspected,
and the surrounding hair clipped
— Povidone iodine, chlorhexidine, or similar bacterio
static solutions and draped with sterile towels
— Irregular, macerated, or beveled wound edges should
be debrided in order to provide a fresh edge for reap
proximation
— Re-approximation
— Realign wound edges properly, particularly for
wounds that cross the vermilion border, eyebrow, and
hairline
—Smallest suture to hold the various layers of the
wound in approximation should be selected to minimize
suture-related inflammation
— Non-absorbable or slowly absorbing monofilament
sutures: For approximating deep fascial layers, particu
larly in the abdominal wall
— Braided absorbable sutures: For subcutaneous tissue;
Avoid placement of sutures in fat d/t increased risk of
infection
— In areas of significant tissue loss: Rotation of adja
cent musculocutaneous flaps to provide sufficient tissue
mass for closure
— Split-thickness skin grafting
— Ensure hemostasis of underlying tissue bed
— Hematoma below the graft will prevent the
graft from taking, resulting in sloughing of the
graft
— Acute contaminated wounds with skin loss:
Porcine skin xenografts or skin cadaveric allo
grafts
— Re-approximation: Stainless steel staples or non-
absorbable monofilament sutures
— Failure to remove the sutures or staples prior
to 7 to 10 days after repair will result in a cos
metically inferior wound
— Wound cosmesis: Placement of buried der
mal sutures using absorbable braided sutures to
allow for reapproximation of wound edges and
may be enhanced by application of wound clo
sure tapes to the surface of the wound
— Intradermal absorbable sutures do not re
quire removal
— Skin tapes: For closure of the smallest super
ficial wounds
— Octyl-cyanoacrylate tissue glues: Less prone
to brittleness, with superior burst-strength
characteristics; Suitable for contaminated
wound without significant risk of infection
 WOUND HEALING
ANTIBIOTICS
— Should only be used when there is an obvious wound infec-
tion: Erythema, cellulitis, swelling, and purulent discharge
— Acute wounds: Antibiotics based on organisms suspected to
be found within the infected wound and the patient’s overall im-
mune status
— Single specific organism suspected: Commence using a single
antibiotic
— Multiple organisms suspected: Commence with a broad-
spectrum antibiotic or several agents in combination
— Location of the wound and the quality of tissue perforation to
the region = Wound performance post-injury
— Can be delivered as part of irrigations or dressings
DRESSINGS
— Provide the ideal environment for wound healing
— Control level of hydration and oxygen tension within
the wound
— Allows transfer of gases and water vapor from the
wound surface to the atmosphere
— Other functions: Barrier; application of compression provides
hemostasis and limits edema
— Occlusion affects epidermis and dermis: Exposed wounds are
more inflamed and develop more necrosis than covered wounds
— Helps in dermal collagen synthesis and epithelial cell migration
and limits tissue dessication
— May enhance bacterial growth: Contraindicated in infected
and/or highly exudative wounds
— Classification
Primary dressing — Placed directly on the wound and
may provide absorption of fluids and prevent dessica
tion, infection, and adhesion of a secondary dressing
Secondary dressing — Placed on the primary dressing
for further protection, absorption, compression, and
occlusion
Absorbent Dressings
— Absorb without getting soaked through, as this would permit
bacteria from the outside to enter the wound
— Must be designed to match the exudative properties of the
wound and may include cotton, wool, sponge
Non-adherent Dressings
— Impregnated with paraffin, petroleum jelly, or water-soluble
jelly as non-adherent coverage
— Secondary dressing must be placed on top to seal the edges
and prevent dessication and infection
Occlusive and Semiocclusive Dressings
— Provide a good environment for clean, minimally exudative
wounds
— Water-proof and impervious to microbes but permeable to
water vapor and oxygen
Hydrophilic and Hydrophobic Dressings
— Components of a composite dressing
— Hydrophilic dressing: Absorption
— Hydrophobic dressing: Water-proof and prevents absorption
Hydrocolloid and Hydrogel Dressings
— Attempt to combine the benefits of occlusion and absorbency
— Form complex structures with water, and fluid absorption oc-
curs with particle swelling, which aids in atraumatic removal of
the dressing
— Hydrocolloid dressing
— For absorption of exudates
— Leaves yellowish-brown gelatinous mass after dress
ing removal that can be washed-off
— Hydrogel
— Allow a high rate of evaporation without compromise
ing wound hydration, which makes them useful in burn
wound treatment
Alginates
— From brown algae and contain long chains ofpolysaccharides
containing mannuronic and glucuronic acid
— Processed as the calcium form, alginates turn into soluble sodi-
um alginate through ion exchange in the presence of wound exu-
dates
— Used when there is skin loss, in open surgical wounds with
medium exudation, and on full-thickness chronic wounds
Absorbable Materials
— Mainly used within wounds as hemostats
— Include collagen, gelatin, oxidized cellulose, and oxidized re-
generated cellulose
Medicated Dressings
— Drug-delivery system: Benzoyl peroxide, zinc oxide, neomycin,
and bacitracin-zinc, which increase epithelialization by 28%
— Type of dressing = Amount of wound drainage
— Non-draining wound: Semiocclusive dressing
— Draining wound (<1-2 ml/day): Semiocclusive or ab
sorbent non-adherent dressing
— Moderate draining wounds (3-5 ml/day): Non-
adherent primary layer plus an absorbent secondary
layer plus an occlusive dressing to protect normal tissue
— Heavily draining wounds (>5 ml/day): Similar dressing
as moderately draining wounds, but with the addition of
a highly absorbent secondary layer
Mechanical Devices
— For absorption of exudates and control of odor
— Vacuum-assisted closure (VAC) system
— Applying localized negative pressure to the surface
and margins of the wound
— Negative-pressure therapy: Applied to a special foam
dressing cut to the dimensions of the wound and posi
tioned in the wound cavity or over a flap or graft
 WOUND HEALING
— Effective for chronic wounds (diabetic ulcers, stages III — Cultured epithelial autografts (CEA)
and IV pressure ulcers), acute and traumatic wounds,
flaps and grafts, and subacute wounds (dehisced inci
sions)
SKIN REPLACEMENTS
Conventional Skin Grafts
— Split/partial-thickness grafts: Epidermis plus part of dermis;
Require less blood supply to restore skin function
— Full-thickness grafts: Entire epidermis and dermis; Dermal
component lends mechanical strength and resists wound contrac-
tion better
— Autologous grafts / autografts: Transplants from one site on
the body to another
— Allogeneic grafts / allografts / homografts: Transplants from a
living non-identical donor or cadaver to the host
— Xenogeneic graft / heterografts: Taken from another species,
e.g. porcine
— Allogeneic and xenogeneic grafts require the availabil
ity if tissue, subject to rejection, and may contain patho
gens
— Use cannot be effective unless the wound bed is adequately
prepared
— Debridement to remove necrotic or fibrinous tissue,
control of edema, revascularization of the wound bed,
decreasing the bacterial burden, and minimizing or eli
minating exudate
— Temporary placement of allografts or xenografts
Skin Substitutes
— Provide coverage of extensive wounds with limited availability
of autografts
— Can be used as natural dressings
— Manufactured by tissue engineering: Combine novel materials
with living cells to provide functional skin substitutes, providing a
bridge between dressings and skin grafts
— Theoretical advantages
— Readily available and not requiring painful harvest,
and they may be applied freely or with surgical suturing
— Promote healing, either by stimulating host cytokine
generation or by providing cells that may also produce
growth factors locally
— Disadvantages
— Limited survival, high cost, and need for multiple ap
plications
— Allografting for complete coverage
— Components
— Acellular: E.g. Native collagen or synthetic material;
Acts as a scaffold, promoted cell migration and growth,
and activates tissue regeneration and remodeling
— Cellular: Re-establish lost tissue and associated func
tion, synthesize ECM, produce essential mediators, and
promote proliferation and migration
— Expanded autologous or homologous keratinocytes
— Expanded from a biopsy of the patient’s own skin,
will not be rejected, and can stimulate re-
epithelialization and growth of the underlying connec
tive tissue
— Harvested as little as postage stamp and cultured
with fibroblasts and growth factors
— Until epithelial sheets are sufficiently expanded, the
wound must be covered with a occlusive dressing or a
temporary allograft or xenograft
— Available from cadavers, unrelated adult donors, or
neonatal foreskins
— Can be left in place long enough to be superseded by
multiplying endogenous skin cells because they do not
contain MHC antigens
— Cryopreserved CEAs: Readily available “off the shelf”
and provide growth factors that may aid healing
— Lack the strength provided by a dermal component
and pose a risk of disease transmission
— Viable fibroblasts can be grown on bioabsorbable or non-
bioabsorbable meshes to yield living dermal tissue that can act as
a scaffold for epidermal growth
— Type I collagen and GAGs, adhesive ligands
— Indicated for use with standard compression therapy in the
treatment of venous insufficiency ulcers and for the treatment of
neuropathic diabetic foot ulcers
Growth Factor Therapy
— Analogous growth factors
— Harvested from the patient’s own platelets, yielding
an unpredictable combination and concentration of fac
tors, which are then applied to the wound
— Allows treatment with patient-specific factors at an
apparently physiologic ratio of growth factor concentra
tions
— Recombinant molecular biologic
— Permit purificationof high concentrations of individu
al growth factors
— PDGF-BB: FDA-approved for treatment of diabetic
foot ulcers; Gel suspension
Gene or Cell Therapy
— Direct access to the open wound bed, which characterizes
almost all chronic wounds
— Traditional approaches: Viral vectors and plasmid delivery;
Electroporation and microseeding
— Delivering extra genes into the wound presents the challeng-
es of expression of the necessary signals to turn the genes on and
off at the appropriate times so that the dysregulated, hyper-
trophic, and abnormal healing does not occur
— Deliver multiple genes coding for proteins that can act syner-
gistically and even in a timed sequence, as would occur during
normal healing
— Use of mesenchymal cellls