WOUND HEALING AND

FACTORS AFFECTING
WOUND HEALING
PRINCIPLES OF SURGERY

OUTLINE
Wound healing as a complex cellular and biochemical
cascade

Mechanism of healing.
Factors that impede normal healing
Applications.

HISTORY OF WOUND CARE

2000 B.C. the Sumerians two modes of treatment: a
spiritual method consisting of incantations and a physical
method of applying poultice-like materials to the wound

Egyptians were the first to differentiate between infected

and diseased wounds compared to noninfected wounds

1550 B.C. the use of concoctions containing honey

(antibacterial properties), lint (absorbent properties), and
grease (barrier) for treating wounds

HISTORY OF WOUND CARE

Galen of Pergamum (120201 A.D.) emphasized the importance of
maintaining a moist environment to ensure adequate healing.

Ignaz Philipp Semmelweis, a Hungarian obstetrician (18181865),

noted that the importance of hand washing

Louis Pasteur (18221895) was instrumental in dispelling the theory

of spontaneous germ theory

In 1865, Lister began soaking his instruments in phenol and spraying

the operating rooms, reducing the mortality rates from 50 to 15%

PHASES OF WOUND HEALING

Normal wound healing follows a predictable pattern that can
be divided into overlapping phases of cellular proliferation
and biochemical activity

HEMOSTASIS AND INFLAMMATION

Disruption of tissue integrity leads to division of blood vessels and direct
exposure of extracellular matrix to platelets.

Exposure of subendo collagen to platelets results in platelet aggregation,

degranulation, and activation of the coagulation cascade.

Platelet -granules release a number of wound-active substances, such as

(PDGF), (TGF), platelet-activating factor, fibronectin, and serotonin.

The fibrin clot serves as scaffolding for the migration into the wound of
inflammatory cells such as (PMNs, neutrophils) first wave and monocytes 2 nd
wave.

CELLULAR INFILTRATION
PMNs are the first wave of cells to enter the wound site,
peaking at 24 to 48 hours.

Stimulated by
Increased vascular permeability, local prostaglandin release,
and the presence of chemotactic substances, such as
complement factors, (IL-1), (TNF-), TGF, platelet factor 4, or
bacterial products

ROLE OF NEUTROPHILS
Phagocytosis of bacteria and tissue debris.
Major source of cytokines early during
inflammation, eg TNF-,3 which influence
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.

Excessive neutrophil activity delays the epithelial

closure of wounds

THE SECOND WAVE

Consists of macrophages
Essential to successful healing
Derived from circulating monocytes, macrophages achieve
significant numbers in the wound by 48 to 96 hours
postinjury

Remain present until wound healing is complete.

THE ROLE OF MACROPHAGES

Participate in wound dbridement via phagocytosis
and contribute to microbial stasis

Activation and recruitment of other cells via

mediators such as cytokines and growth factors, as
well as directly by cellcell interaction and
intercellular adhesion molecules.

Regulate cell proliferation, matrix synthesis,

angiogenesis and matrix deposition and remodeling

T LYMPHOCYTES
Less numerous than macrophages, T-lymphocyte numbers
peak at about 1 week postinjury

Bridge the transition from the inflammatory to the

proliferative phase of healing.

T lymphocytes play an active role in the modulation of the

wound environment.

T LYMPHOCYTES
Depletion of most wound T lymphocytes decreases wound
strength and collagen content

Lymphocytes also exert a downregulating effect on fibroblast

collagen synthesis by cell-associated interferon-, TNF-, and IL1.

Extracellular matrix synthesis is regulated not only via

soluble factors but also by direct cellcell contact between
lymphocytes and fibroblasts.

PROLIFERATIVE PHASE
Second phase of wound healing and roughly spans days 4 through 12
During which tissue continuity is re-established.
Fibroblasts and endothelial cells are the last cell populations to
infiltrate the healing wound influenced by PDGF

Upon entering the wound environment, fibroblasts need to proliferate,

and then become activated, to carry out matrix synthesis remodeling.

Activation is mediated mainly by the cytokines and growth factors

released from wound macrophages.

ENDOTHELIAL CELLS
Proliferate extensively during this phase of healing.
Participate in the formation of new capillaries
(angiogenesis),essential to successful wound healing.

Migrate from intact venules close to the wound.

New capillary tubule formation are under the influence of
such cytokines and growth factors as TNF-, TGF, and VEGF.

Macrophages represent a major source of VEGF in the

healing wound, and VEGF receptors are located
specifically on endothelial cells.

MATRIX SYNTHESIS
Comprises of collagen and proteoglycan
Collagen, the most abundant protein in the body
Critical role in the successful completion of adult wound
healing.

Its deposition, maturation, and subsequent remodeling are

essential to the functional integrity of the wound.

COLLAGEN
18 types of collagen described, the main ones of interest to
wound repair are types I and III.

Type I collagen is the major component of extracellular

matrix in skin.

Type III, which is also normally present in skin, becomes more

prominent and important during the repair process

COLLAGEN
SYNTHISIS

COLLAGEN
SYNTHESIS
Collagen synthesis, as well as
posttranslational modifications, is highly
dependent on systemic factors
Adequate oxygen supply, the presence
of sufficient nutrients (amino acids and
carbohydrates) and cofactors (vitamins
and trace metals), and the local wound
environment (vascular supply and lack
of infection).
Addressing these factors and reversing
nutritional deficiencies can optimize
collagen synthesis and deposition

PROTEOGLYCAN SYNTHESIS
Comprise a large portion of the "ground substance" that makes up
granulation tissue.

Couple with proteins to form proteoglycans.

The polysaccharide chain is made up of repeating disaccharide units
composed of glucuronic or iduronic acid and a hexosamine, which is usually
sulfated.

The disaccharide composition of proteoglycans varies from about 10 units in

the case of heparan sulfate to as much as 2000 units in the case of
hyaluronic acid

PROTEOGLYCAN
Major glycosaminoglycans present in wounds are dermatan and
chondroitin sulfate.

Fibroblasts synthesize these compounds, increasing their

concentration greatly during the first 3 weeks of healing.

Assembly of collagen subunits into fibrils and fibers is dependent on

the lattice provided by the sulfated proteoglycans

With scar maturation and collagen remodeling, the content of

proteoglycans gradually diminishes

MATURATION AND REMODELING PHASE

Begins during the fibroplastic phase, and is characterized by a
reorganization of previously synthesized collagen

Collagen is broken down by matrix metalloproteinases, and 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

re-establishment of extracellular matrix composed of a relatively
acellular collagen-rich scar.

MATURATION AND REMODELING PHASE

Wound strength and mechanical integrity in the fresh wound are
determined by both the quantity and quality of the newly deposited
collagen

Fibronectin and collagen type III constitute the early matrix scaffolding,
glycosaminoglycans and proteoglycans represent the next significant
matrix components, and collagen type I is the final matrix

Scar remodeling continues for many (6 to 12) months postinjury, gradually

resulting in a mature, avascular, and acellular scar. The mechanical
strength of the scar never achieves that of the uninjured tissue.

EPITHELIALIZATION
Process is characterized primarily by proliferation and
migration of epithelial cells adjacent to the wound

Begins within 1 day of injury and is seen as

thickening of the epidermis at the wound edge

Fixed basal cells in a zone near the cut edge undergo

a series of rapid mitotic divisions, and these cells
appear to migrate by moving over one another in a
leapfrog fashion until the defect is covered

EPITHELIALIZATION
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 re-established

The surface layer eventually keratinizes

EPITHELIALIZATION
Re-epithelialization is complete in less than 48 hours in the
case of approximated incised wounds, but may take
substantially longer in the case of larger wounds

If only the epithelium and superficial dermis are damaged,

such as occurs in split-thickness skin graft donor sites or in
superficial second-degree burns, then repair consists
primarily of re-epithelialization with minimal or no fibroplasia
and granulation tissue formation

WOUND CONTRACTION
All wounds undergo some degree of contraction
Surgical wounds less than that of that close by secondary intention
Myofibroblast has been postulated as being the major cell responsible
for contraction, and it differs from the normal fibroblast in that it
possesses a cytoskeletal structure containing smooth muscle actin.

Undetectable until day 6, and then is increasingly expressed for the

next 15 days of wound healing. After 4 weeks this expression fades,
and the cells are believed to undergo apoptosis

HEALING IN SPECIFIC TISSUES

Gastrointestinal Tract relatively uniform in structural layers
Within the lumen, the epithelium is supported by the lamina propria
and underlying muscularis mucosa.

The submucosa lies radially and circumferentially outside of these

layers, is comprised of abundant collagenous and elastic fibers, and
supports neural and vascular structures.

Further toward the peritoneal surface of the bowel are the inner and
outer muscle layers and, ultimately, a peritoneal extension, the serosa

HEALING IN SPECIFIC TISSUES

The sub mucosal layer imparts the greatest tensile strength and
greatest suture-holding capacity, a characteristic that should be kept in
mind during surgical repair of the GI tract.

Serosal healing is essential for quickly achieving a watertight seal from

the luminal side of the bowel.

Importance of the serosa is underscored by the significantly higher rates

of anastomotic failure observed clinically in segments of bowel that are
extraperitoneal and lack serosa (i.e., the esophagus and rectum).

HEALING IN SPECIFIC TISSUES

Injuries to all parts of the GI tract undergo the same sequence of healing as cutaneous
wounds.

Mesothelial (serosal) and mucosal healing can occur without scarring.

Early integrity of the anastomosis is dependent on formation of a fibrin seal on the
serosal side, which achieves watertightness, and on the suture-holding capacity of the
intestinal wall, particularly the submucosal layer.

There is a significant decrease in marginal strength during the first week due to an
early and marked collagenolysis.

Collagenase activity occurs early in the healing process, and during the first 3 to 5
days collagen breakdown far exceeds collagen synthesis

TECHNICAL CONSIDERATIONS
For an anastomosis to heal without complications it must be
Tension-free
Adequate blood supply
Receive adequate nutrition
Free of sepsis.

BONE HEALING
Similar process
Starting with hematoma formation accumulation of blood at the fracture site, which
also contains devitalized soft tissue, dead bone, and necrotic marrow.

The next stage accomplishes the liquefaction and degradation of nonviable products at
the fracture site.

Normal bone adjacent to the injury site can then undergo revascularization, with new
blood vessels growing into the fracture site similar to the formation of granulation
tissue in soft tissue.

The symptoms associated with this stage are characteristic of inflammation, with
clinical evidence of swelling and erythema

BONE
Three to 4 days after injury, soft tissue forms a bridge between the fractured
bone segments in the next stage (soft callus stage)

Soft tissue is deposited where neovascularization has taken place and serves
as an internal splint, preventing damage to the newly laid blood vessels and
achieving a fibrocartilaginous union.

Soft callus is formed externally along the bone shaft and internally within the
marrow cavity.

Clinically, this phase is characterized by the end of pain and inflammatory

signs

BONE
The next phase (hard callus stage) consists of mineralization of the soft callus
and conversion to bone.

May take up to 2 to 3 months and leads to complete bony union.

The bone is now considered strong enough to allow weightbearing and will
appear healed on radiographs.

This stage is followed by the remodeling phase, in which the excessive callus
is reabsorbed and the marrow cavity is recanalized.

This remodeling allows for the correct transmission of forces and restores the
contours of the bone

CLASSIFICATION OF
HEALING WOUNDS

THE HEALING WOUND

The healing spectrum of acute wounds is broad
Acquisition of mechanical integrity and strength
during healing is characterized by a constant and
continual increase that reaches a plateau at some
point postinjury.

Delayed healing decreased wound-breaking

strength in comparison to wounds that heal at a
normal rate

Eventually achieve the same integrity and

strength as wounds that heal normally

FACTORS AFFECTING WOUND HEALING

FACTORS AFFECTING WOUND HEALING

Age
Studies of hospitalized surgical patients show a direct
correlation between older age and poor wound healing
outcomes such as dehiscence and incisional hernia

Possibly due to multiple comorbidities

Human volunteers there was a significant delay of 1.9 days in
the epithelialization of superficial skin defects in those older
than 70 years of age when compared to younger volunteer

HYPOXIA, ANEMIA, AND

HYPOPERFUSION
Low oxygen tension has a profoundly deleterious effect on all aspects
of wound healing

Fibroplasia, although stimulated initially by the hypoxic wound

environment, is significantly impaired by local hypoxia.

Increasing subcutaneous oxygen tension levels by increasing the

fraction of inspired oxygen (FiO2) of inspired air immediately after
surgery results in enhanced collagen deposition and in decreased
rates of wound infection after elective surgery

HYPOXIA, ANEMIA, AND HYPOPERFUSION

Major factors affecting local oxygen delivery include
Hypoperfusion either for systemic reasons (low volume or cardiac failure)
Local causes (arterial insufficiency, local vasoconstriction, or excessive tension
on tissues).

Vasoconstriction of the subcutaneous capillary bed responsive to fluid status,

temperature, and hyperactive sympathetic tone induced by postoperative
pain.

Correction of these factors can have a remarkable influence on wound

outcome, particularly on decreasing wound infection rates.

STEROIDS AND CHEMOTHERAPEUTIC

DRUGS
Large doses or chronic usage of glucocorticoids reduce collagen
synthesis and wound strength

Major effect of steroids is to inhibit the inflammatory phase of

wound healing (angiogenesis, neutrophil and macrophage
migration, and fibroblast proliferation)

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

STEROIDS AND CHEMOTHERAPEUTIC

DRUGS
Inhibit epithelialization and contraction and contribute to
increased rates of wound infection, regardless of the time of
administration

Steroid-delayed healing of cutaneous wounds can be

stimulated to epithelialize by topical application of vitamin

Collagen synthesis of steroid-treated wounds also can be

stimulated by vitamin A.

METABOLIC DISORDERS
Uncontrolled diabetes results in reduced inflammation,
angiogenesis, and collagen synthesis

Additionally, 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

METABOLIC DISORDERS
Insulin restores collagen synthesis and granulation tissue formation
to normal levels if given during the early phases of healing.

In clean, noninfected, and well-perfused experimental wounds in

human diabetic volunteers, type I diabetes mellitus was noted to
decrease wound collagen accumulation in the wound, independent
of the degree of glycemic control.

Type II diabetic patients showed no effect on collagen accretion

when compared to healthy, age-matched controls

NUTRITION
Poor nutritional intake or lack of individual nutrients
significantly alters many aspects of wound healing

Vitamin C and vitamin A

VITAMIN C
Required for the conversion of proline and lysine to
hydroxyproline and hydroxylysine, respectively.

Vitamin C deficiency has also been associated with an

increased incidence of wound infection, and if wound
infection does occur, it tends to be more severe

Due to an associated impairment in neutrophil

function, decreased complement activity, and
decreased walling-off of bacteria secondary to
insufficient collagen deposition

VITAMIN A
Vitamin A deficiency impairs wound healing, whereas supplemental
vitamin A benefits wound healing in nondeficient humans and
animals

Increases the inflammatory response in wound healing. There is an

Increased influx of macrophages, with an increase in their activation
and increased collagen synthesis.

Directly increases collagen production and epidermal growth factor

receptors when it is added in vitro to cultured fibroblasts

INFECTIONS
Effect of infections
impact on the length of hospital stay and medical.
The occurrence of infections is of major concern when implants are
used

Weaken an abdominal closure or hernia repair and result in wound

dehiscence or recurrence of the hernia.

Cosmetically, infections can lead to disfiguring, unsightly, or delayed

closures.

WOUND INFECTION
Bacterial contaminants normally present on skin are
prevented from entry into deep tissues by intact epithelium.

Surgery breaches the intact epithelium, allowing bacteria

access to these tissues and the bloodstream

Treated with appropriate prophylactic antibiotics have only

one third the wound infection rate

WOUND INFECTION
Source of pathogens for the infection is usually the endogenous flora of the
patient's skin, mucous membranes, or from hollow organs.

Most common organisms responsible for wound infections, in order of

frequency, are Staphylococcus species, coagulase-negative Streptococcus,
enterococci, and Escherichia coli

Incidence of wound infection bears a direct relationship to the degree of

contamination that occurs during the operation from the disease process
itself (cleanclass I, clean contaminatedclass II, contaminatedclass III,
and dirtyclass IV).

WOUND INFECTION
Clean surgery

No viscus opened (e.g. hernia repair)

Infection rate typically 1-2%
Clean-contaminated

Viscus opened but no spillage of gut contents (e.g. right

hemicolectomy)

Infection rate usually <10%

WOUND INFECTION
Contaminated

Viscus opened with inflammation or spillage of contents (e.g.

colectomy for obstruction)

Infection rate 15-20%

Dirty

Intraperitoneal abscess formation or visceral perforation

Infection rate 40%

WOUND INFECTION
Contamination, colonization, and infection should be
differentiated. Contamination is the presence of bacteria
without multiplication

Colonization is multiplication without host response

Infection is the presence of host response in reaction to
deposition and multiplication of bacteria. The presence of a
host response helps to differentiate between infection and
colonization as seen in chronic wounds.

END
Questions