Wound Healing

Chapter 9
Schwartz Principles of Surgery 11th ed.
Phases
of Wound Healing
• hemostasis and inflammation,
• proliferation
• maturation and remodeling.
 Hemostasis and Inflammation

Exposure of subendothelial
collagen to platelets

platelet aggregation,
degranulation, and activation of
the coagulation cascade
Hemostasis and Inflammation
• Platelet α granules
• platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β),
platelet activating factor (PAF), fibronectin, and serotonin.

• Fibrin clot serves as scaffolding for the migration into the wound of
inflammatory cells such as polymorphonuclear leukocytes (PMNs,
neutrophils) and monocytes.
Polymorphonuclear Cells
• interleukin-1 (IL-1)
• tumor necrosis factor-α (TNF-α)
• first infiltrating cells • TGF-β
• 24 to 48 hours • platelet factor 4, or bacterial
products
• Neutrophil migration:
• Increased vascular permeability
• local prostaglandin release
• the presence of chemotactic substances
Polymorphonuclear Cells
• major source of cytokines early during inflammation, especially TNF-α
which may have a significant influence on subsequent angiogenesis
and collagen synthesis
• release proteases such as collagenases, which participate in matrix
and ground substance degradation in the early phase of wound
healing
Macrophages
• TGF-β
• vascular endothelial growth factor
• second population of inflammatory cells (VEGF)
• insulin-like growth factor (IGF)
• Derived from circulating monocytes • epithelial growth factor (EGF)
• 48 to 96 hours post injury • lactate

• until wound healing is complete.

• participate in wound debridement via phagocytosis and contribute to
microbial stasis via oxygen radical and nitric oxide synthesis
• activation and recruitment of other cells
• mediators such as cytokines and growth factors
• by cell-cell interaction and intercellular adhesion molecules (ICAM)
• Regulate cell proliferation and matrix synthesis
Macrophages
T Lymphocytes
• 1 week postinjury
• truly bridge the transition from the inflammatory to the proliferative
phase of healing
• downregulating effect on fibroblast collagen synthesis by cell-
associated interferon IFN-γ, TNF-α, and IL-1
Proliferation
• days 4 through 12
• tissue continuity is re-established
• Fibroblasts and endothelial cells are the last
cell populations to infiltrate the healing
wound, and the strongest chemotactic factor
for fibroblasts is PDGF.
• Upon entering the wound environment,
recruited fibroblasts first need to proliferate,
This activation is mediated
and then become activated, to carry out their
• Cytokines
primary function of matrix synthesis • growth factors
remodeling.
Matrix Synthesis
• Collagen
• most abundant protein in the body
• deposition, maturation, and subsequent remodeling are essential to the
functional integrity of the wound.
• Type I collagen – extracellular matrix in skin.
• Type III –prominent and important during the repair process
Matrix Synthesis
• Glycosaminoglycans
• large portion of the “ground substance” that makes up granulation
tissue
• dermatan and chondroitin sulfate
• Fibroblasts synthesize these compounds, increasing their
concentration greatly during the first 3 weeks of healing.
Maturation and Remodeling
• begins during the fibroplastic phase
• characterized by a reorganization of previously synthesized collagen
• Collagen is broken down by matrix metalloproteinases (MMPs)
• the net wound collagen content is the result of a balance between collagenolysis
and collagen synthesis
• There is a net shift toward collagen synthesis and eventually the reestablishment
of extracellular matrix composed of a relatively acellular collagen-rich scar.
• Wound strength and mechanical integrity in the fresh wound are determined by
both the quantity and quality of the newly deposited collagen.
Maturation and Remodeling
• The deposition of matrix at the wound site
1. fibronectin and collagen type III – the early matrix scaffolding
2. glycosaminoglycans and proteoglycans
3. collagen type I – final matrix
Maturation and Remodeling
• By several weeks post injury, the amount of collagen in the wound
reaches a plateau, but the tensile strength continues to increase for
several more months.
• Fibril formation and fibril cross-linking
• result in decreased collagen solubility, increased strength, and increased
resistance to enzymatic degradation of the collagen matrix.
• Fibrillin
• essential for the formation of elastic fibers found in connective tissue.
• Scar remodeling continues for many (6 to 12) months post injury,
gradually resulting in a mature, avascular, and acellular scar.
• Collagenolysis is the result of collagenase activity, a class of MMPs
that require activation.
Epithelialization
• final step in establishing tissue integrity.
• proliferation and migration of epithelial cells adjacent to the wound
• Marginal basal cells – lose their firm attachment to the underlying dermis →
enlarge → begin to migrate across the surface of the provisional matrix
• Fixed basal cells in a zone near the cut edge – appear to migrate by moving over
one another in a leapfrog fashion until the defect is covered.
• Once the defect is bridged, the migrating epithelial cells lose their flattened
appearance, become more columnar in shape, and increase their mitotic activity.
• Layering of the epithelium is reestablished, and the surface layer eventually
keratinizes
• Reepithelialization – complete in less than 48 hours in the case of approximated
incised wounds
Wound Contraction
• myofibroblast
• major cell responsible for contraction
• possesses a cytoskeletal structure.
• stress fibers
• contractile capability
Heritable Diseases of Connective
Tissue
Ehler-Danlos Syndrome
• α-chains of collagen type V
• thin, friable skin with prominent veins, easy bruising, poor wound
healing, atrophic scar formation, recurrent hernias, and
hyperextensible joints.
• Gastrointestinal problems – bleeding, hiatal hernia, intestinal
diverticulae, and rectal prolapse
• Small blood vessels – fragile, making suturing difficult during surgery.
• Large vessels – aneurysms, varicosities, or arteriovenous fistulas or
may spontaneously rupture
Osteogenisis Imperfecta
• brittle bones, osteopenia, low muscle
mass, hernias, and ligament and joint
laxity
• mutation in type I collagen
Epidermolysis Bullosa
• classified into four major subtypes:
• EB simplex
determined by location in
• junctional EB
various skin layers
• dystrophic EB
• Kindler’s syndrome —multiple blisters throughout different layers of
skin.
Acrodermatitis Enteropathica
• inability to absorb sufficient zinc from breast milk or food
• affects zinc uptake in the intestine by preventing zinc from
binding to the cell surface and its translocation into the cell
• the genetic defect has been localized on chromosome 8q24.3
identified as the SLC39A4 gene, expressed in the intestinal
lumen and upregulated based on zinc stores
• impaired wound healing as well as erythematous pustular
dermatitis involving the extremities and the areas around
the bodily orifices.
HEALING IN SPECIFIC TISSUE
• GASTROINTESTINAL

➢Healing of full-thickness GI wounds begins with a surgical or mechanical

reapposition of the bowel ends, which is most often the initial step in the
repair process.

➢Failure of healing results in dehiscence, leaks, and fistulas, which carry

significant morbidity and mortality
• The submucosa
• Lies radially and circumferentially outside of these layers, is comprised of
abundant collagenous and elastic fibers, and supports neural and vascular
structures.

• The layer that imparts the greatest tensile strength and greatest suture-
holding capacity.
• The Serosa
• Further toward the peritoneal surface of the bowel are the inner and outer
muscle layers and ultimately a peritoneal extension

• Serosal healing is essential for quickly achieving a watertight seal from the
luminal side of the bowel.

• Significantly higher rates of anastomotic failure observed clinically in

segments of bowel that are extraperitoneal and lack serosa (i.e., the
esophagus and rectum).
BONE

Hematoma
Formation
BONE

Hematoma The liquefaction

Formation and degradation
BONE
The Soft Callus
Hematoma The liquefaction Stage
Formation and degradation
BONE
The Soft Callus
Hematoma The liquefaction Stage
Formation and degradation

The Hard Callus

Stage
BONE
The Soft Callus
Hematoma The liquefaction Stage
Formation and degradation

Remodelling The Hard Callus

phase Stage
CARTILAGE
• Cartilage consists of cells (chondrocytes) surrounded by an
extracellular matrix made up of several proteoglycans, collagen fibers,
and water.

• Cartilage is very avascular and depends on diffusion for transmittal of

nutrients across the matrix

• Therefore, injuries to cartilage may be associated with permanent

defects due to the meager and tenuous blood supply.
TENDON
• Tendons and ligaments are specialized structures that link muscle and
bone, and bone and bone.

• Tendon and ligament healing progresses in a similar fashion as in

other areas of the body.
• Through hematoma formation, organization, laying down of reparative
tissue, and scar formation

• Matrix is characterized by accumulation of type I and III collagen

along with increased water, DNA, and glycosaminoglycan content.
NERVE
• There are three types of nerve injuries:
• Neurapraxia (focal demyelination)

• Axonotmesis (interruption of axonal continuity but preservation of Schwann

cell basal lamina

• Neurotmesis (complete transection).

NERVE
• Predictable pattern of changes involving three crucial steps:

• 1. Survival of axonal cell bodies

• 2. Regeneration of axons that grow across the transected nerve to reach the
distal stump

• 3. migration and connection of the regenerating nerve ends to the

appropriate nerve ends or organ targets.
 Fetal wound healing
46

 apparent lack of scar formation.

 scarring of wounds begins at approximately 24 weeks
of gestation.
 At the beginning of the third trimester, and during this
period there is scarless healing; however, there is a loss
of the ability to regenerate skin appendages.
 Cont…
47

 There are a number of characteristics that may influence

the differences between fetal and adult wounds.
Wound environment: sterile and stable temprature
Inflammatory responses: immature immune system
Growth factors: absence of TGF beta
Wound matrix: high hyalurinic acid
 Wound classification
49

 acute or chronic.
 Acute wounds heal in a predictable manner and time
frame.
 Surgical wounds can heal in several ways.
Cont…
 Cont….
51
 Factor affecting wound healing
 Normal
52 healing is affected by both systemic
and local factors.
 Age
53

 The increased incidence of comorbidity may

contribute to impaired wound healing
 Noncollagenous protein accumulation at
wounded sites is decreased with aging which
may impair the mechanical properties of
scarring in elderly patients.
Hypoxia,Anemia, Hypoperfusion
54

 Low oxygen tension has a profoundly

deleterious effect on all aspects of wound
healing.
 Optimal collagen synthesis requires oxygen as
a cofactor, particularly for the hydroxylation
steps.
 Increasing FiO2 of inspired air for brief periods
during and immediately after surgery results in
enhanced collagen deposition and in
decreased rates of wound infection after
elective surgery.
Drug
55

Steroid
 Steroids inhibit the inflammatory phase of wound
healing (angiogenesis, neutrophil and macrophage
migration, and fibroblast proliferation) and the release of
lysosomal enzymes.
 Steroids used after the first 3 to 4 days postinjury do
not affect wound healing as severely as when they
are used in the immediate postoperative period.
 inhibit epithelialization and contraction
chemotherapeutic
56

 inhibiting early cell proliferation and wound

DNA and protein synthesis.
 Delay in the use of such drugs for about 2
weeks postinjury appears to lessen the wound
healing impairment.
 Metabolic disorder
57

 Uncontrolled diabetes results in reduced

inflammation, angiogenesis, and collagen
synthesis
 The large- and small-vessel disease that is the
hallmark of advanced diabetes contributes to
local hypoxemia.
 Defects in granulocyte function, capillary
ingrowth, and fibroblast proliferation all have
been described in diabetes.
 Uremia also has been associated with
disordered wound healing.
 Nutrition
58

Protein and energy

 Malnutrition correlates clinically with enhanced

rates of wound complications and increased

wound failure.
 During protein-calorie malnutrition

◼ impaired healing response and

◼ reduced cell-mediated immunity, and
◼ phagocytosis, and intracellular killing of bacteria by
macrophages and neutrophils
 Arginine appears most active in terms of
enhancing wound fibroplasia.
 Cont..
59

Vitamins
 The vitamins most closely involved with wound

healing are vitamin C and vitamin A.

 Vitamin C deficiency leads to a defect in

wound healing, particularly via a failure in

collagen synthesis and cross-linking.
 Vitamin A increases the inflammatory response
in wound healing, probably by increasing the
lability of lysosomal membranes.
60

Minerals
 There are over 150 known enzymes for which
zinc is either an integral part or an essential
cofactor, and many of these enzymes are
critical to wound healing.
 Zinc deficiency:
◼ decreased fibroblast proliferation,
◼ decreased collagen synthesis,
◼ impaired overall wound strength, and
◼ delayed epithelialization.
Excess wound healing
61

Hypertrophic scars
 Represent an overabundance of fibroplasia in

the dermal healing process.

 Rise above the skin level but stay within the
confines of the original wound and often
regress over time.
 Occur after trauma to the skin and may be

tender, pruritic, and cause a burning sensation

 Cont…
62

 Usually develops within 4 weeks after trauma.

 Risk increases if epithelialization takes longer
than 21 days.
 Rarely elevated more than 4 mm above the
skin level and stay within the boundaries of the
wound.
 Usually occur across areas of tension and
flexor surfaces -- right angles to joints or
skin creases.
63
Keloid 64

 Can result from surgery, burns, any

infectious skin lesion, sometimes
spontaneously
 It tend to occur 3 months to years
after the initial insult.
 Rise above the skin level and extend
beyond the border of the original wound
and rarely regress spontaneously.
 earlobe and the deltoid, presternal, and
upper back regions have higher
incidance of keloid

67The underlying mechanisms that cause HTSs and
keloids are not known.
 Proposed causes are:
The immune system
Mechanical tension
Prolonged irritation and/or inflammation
 Mgt principles:
surgery
intralesional corticosteroid injection,
topical application of silicone sheets,
the use of radiation or pressure
Topical retinoids
Treatment of wounds
Antibiotics
• Antibiotics should be used only when there is an obvious wound
infection.

• Signs of infection to look for include

• erythema
• cellulitis
• swelling
• purulent discharge.
Antibiotics
• Antibiotic treatment of acute wounds must be based on organisms
suspected to be found within the infected wound and the patient’s
overall immune status.

• When multiple organisms are suspected, as with enteric

contamination or when a patient’s immune function is impaired by
diabetes, chronic disease, or medication, treatment should
commence with a broad-spectrum antibiotic or several agents in
combination
Dressing
• provide the ideal environment for wound healing.

• The dressing should facilitate the major changes taking place during
healing to produce an optimally healed wound.

• Occlusion of a wound with dressing material helps healing by

controlling the level of hydration and oxygen tension within the
wound.
Absorbent Dressings
• Accumulation of wound fluid can lead to maceration and bacterial
overgrowth.
• should absorb without getting soaked through, as this would permit bacteria
from the outside to enter the wound.
Nonadherent Dressings
• Nonadherent dressings are impregnated with paraffin, petroleum jelly, or
water-soluble jelly for use as nonadherent coverage. A secondary dressing
must be placed on top to seal the edges and prevent desiccation and
infection.
Occlusive and Semiocclusive Dressings
• Occlusive and semiocclusive dressings provide a good environment for clean,
minimally exudative wounds. These film dressings are waterproof and
impervious to microbes but permeable to water vapor and oxygen.
Hydrophilic and Hydrophobic Dressings
• attempt to combine the benefits of occlusion and absorbency.
• form complex structures with water, and fluid absorption occurs with particle
swelling, which aids in atraumatic removal of the dressing
Alginates
• Alginates are derived from brown algae and contain long chains of
polysaccharides containing mannuronic and glucuronic acid. The ratios of
these sugars vary with the species of algae used, as well as the season of
harvest.
Absorbable Materials
• Absorbable materials are mainly used within wounds as hemostats
and include collagen, gelatin, oxidized cellulose, and oxidized
regenerated cellulose.
Medicated Dressings
• Medicated dressings have long been used as a drug-delivery system. Agents
delivered in the dressings include benzoyl peroxide, zinc oxide, neomycin, and
bacitracin-zinc. These agents have been shown to increase epithelialization by
28%.
Mechanical Devices
• Mechanical therapy augments and improves on certain functions of
dressings, in particular the absorption of exudates and control of
odor.

• The vacuum-assisted closure (VAC) system assists in wound closure by

applying localized negative pressure to the surface and margins of the
wound.
Skin Replacements
Conventional Skin Grafts
• Skin grafts have long been used to treat both acute and chronic
wounds.
• Split- (partial-) thickness grafts consist of the epidermis plus part of the
dermis
• Full-thickness grafts retain the entire epidermis and dermis.
• Autologous grafts (autografts) are transplants from one site on the body to
another
• Allogeneic grafts (allografts, homografts) are transplants from a living
nonidentical donor or cadaver to the host
• Xenogeneic grafts (heterografts) are taken from another species (e.g.,
porcine).
• Split-thickness grafts require less blood supply to restore skin function.
Skin Substitutes
• Desired features of tissue-engineered skin
Growth Factor Therapy
• Growth factors for clinical use may be either recombinant or
homologous/autologous.

• Autologous growth factors are harvested from the patient’s own

platelets, yielding an unpredictable combination and concentration of
factors, which are then applied to the wound.

• This approach allows treatment with patient-specific factors at an

apparently physiologic ratio of growth factor concentrations.
Growth Factor Therapy
• At present, only platelet-derived growth factor BB (PDGF-BB) is
currently approved by the FDA for treatment of diabetic foot ulcers.
Gene or Cell Therapy
• Gene delivery to wounds includes traditional approaches such as viral
vectors and plasmid delivery or, more recently, electroporation and
microseeding.

• Although a variety of genes expressing interleukin-8, PDGF, IGF-1,

keratinocyte growth factor, and laminin-5 have been successfully delivered
to wounds in both animal and human models, the effects have been
modest and specific to unique wound situations.

• Another approach is to deliver multiple genes coding for proteins that can
act synergistically and even in a timed sequence, as would occur during
normal healing.