Basic science

Basic science of
wound healing

The healing of acute wounds involves a complex, dynamic,

well-orchestrated series of events. A healed wound is one:
in which the connective tissues have been repaired and the
wound completely re-epithelialized by regeneration
that has returned to its normal anatomical structure and function without the need for continued drainage or dressing.
Some wounds fail to heal in a timely and orderly manner,
resulting in chronic, non-healing wounds that require continued
management. Also, aberrations in certain stages of the healing
process can result in excessive healing (e.g. hypertrophic scars,
keloids).
This review discusses the cellular and molecular events
involved in the various types of healing, and the mechanisms
causing abnormal healing.

Stuart Enoch
David John Leaper

Abstract
Acute wound healing involves a complex series of events including
chemotaxis, cell division, neovascularization, synthesis of new extracellular matrix, and the formation and remodelling of the scar tissue. These
events are regulated by several mediators including platelets, inflammatory cells, cytokines and growth factors, and matrix metalloproteinases
and their inhibitors. In acute wounds, these processes (which are triggered by tissue injury) involve the four overlapping (but well-defined)
phases of haemostasis, inflammation, proliferation, and remodelling; an
avascular scar is the final stage of the wound healing process. In contrast
to this, some wounds fail to heal in a timely and orderly manner, resulting in chronic non-healing wounds. Alterations in one or more of these
components could account for the impaired healing observed in chronic
wounds because cytokines, growth factors, proteases, and cellular and
extracellular elements all play important roles in different stages of the
healing process. Also, dysregulation in certain stages of the healing pro
cess could result in excessive deposition of collagen and formation of
abnormal scar, as seen in hypertrophic scars and keloids. In this review,
the cellular and molecular events involved in acute wound healing and
the mechanisms resulting in abnormal healing are discussed; the various
types of wound healing are also discussed.

Types of wound healing

Primary healing (healing by first intention) occurs when a
wound is closed within 1224 hours of its creation (e.g. clean
surgical incision, clean laceration). The wound edges are approximated directly using sutures, tissue glue, tapes or a mechanical
device.
The incision causes only focal disruption of the continuity of
the epithelial basement membrane, and the death of a relatively
few epithelial and underlying connective tissue cells. As a result,
epithelial regeneration predominates over fibrosis. Also, because
there is an appropriate balance between all phases of the healing
process (including cellular proliferation, collagen metabolism,
activity of matrix metalloproteinase, degradation of the extracellular matrix), wounds heal well and proceed rapidly towards
complete closure.
Delayed primary healing occurs in a contaminated or poorly
delineated wound that is closed after a few days having been left
open to prevent infection (e.g. bites, abdominal wounds after
peritoneal soiling). The skin and subcutaneous tissues are left
unapposed (sutures may be put in place, but not tied), and closure is performed after host defences have helped to debride the
wound.
After 34 days, local recruitment of phagocytic cells into the
wound occurs and the inflammatory cells destroy contaminating
bacteria. The wound edges may be approximated even after a
delay of several days. Collagen metabolism is usually unaffected
and the wound retains its tensile strength as if closure had been
immediate.

Keywords acute wound healing; basic science; cytokines; growth factor;

hypertrophic scars; keloids; metalloproteinases; non-healing wounds;
platelets; wound healing

A wound is a break in the epithelial integrity of the skin and may

be accompanied by disruption of the structure and function of
underlying normal tissue. A wound may result from precise disruption of tissue by the surgeons knife (incision) to widespread
damage of tissue (e.g. major trauma, burns). A wound may also
result from a contusion, haematoma, laceration or an abrasion.
The continuity of the skin must be restored expeditiously because
it plays a crucial role in maintaining homeostasis.

Secondary healing (healing by second intention) occurs in

a wound with extensive loss of soft tissue, as seen in major
trauma, severe burns and after some surgical procedures (e.g.
laparostomy).
Regeneration of epithelial cells alone cannot restore the original
architecture, so there is ingrowth of granulation tissue from the
wound margin, followed by accumulation of extracellular matrix
with the laying down of collagen. These open, full-thickness
wounds thus close by subsequent wound contraction and
epithelialization. For example, large defects of skin may reduce to
510% of their original size within six weeks, largely by contraction. Myofibroblasts, having structural properties between those
of a fibroblast and a smooth muscle cell, are thought to play a

Stuart Enoch MB PhD MRCS is a Specialist Registrar in Plastic Surgery at

the University Hospitals of Manchester, UK. Conflicts of interest: none
declared.
David John Leaper FRCSEng FRCSEd is Emeritus Professor of Surgery at
Newcastle upon Tyne University, Newcastle, UK, and Visiting Professor
of Surgery, Wound Healing Research Unit, Department of Surgery,
Cardiff University, UK. Conflicts of interest: none declared.

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key role in this type of healing. They appear in the wound about
three days after wounding and increase in number to a maximal
level between the tenth and twenty-first days. Healing by secondary intention is slower, may lead to contractures (particularly over
joints) and may lead to functional restriction.

Cells involved in wound healing

Healing of superficial (partial-thickness) wounds is seen in

injuries such as superficial burns, split-thickness donor graft
sites, and abrasions where the injury involves the epithelium and
the superficial (papillary) part of the dermis. The basal layer of
cells remains uninjured and the epithelial cells within the dermal appendages, hair follicles, and sebaceous glands replicate to
cover the exposed dermis; the cells migrate towards each other
from the basal layer to surround the wound. Healing occurs
purely by epithelialization, and anatomical and physiological
restoration is virtually complete.

Cell type

Function related to wound healing

Platelets

Involved in thrombus formation

 granules are a rich source of inflammatory
mediators including cytokines (e.g. TGF-,
PDGF, -thromboglobulin, platelet factor-4)
Major initial stimulus for inflammation
First cells to infiltrate site of injury
Phagocytosis and intracellular killing of
invading bacteria
Phagocytose and destroy invading bacteria
Clear debris and necrotic tissue
Rich source of inflammatory mediators
including cytokines
Stimulate fibroblast division, collagen
synthesis and angiogenesis
Not clearly defined
May produce cytokines in certain types of
wound
Produce various components of the ECM,
including collagen, fibronectin, hyaluronic
acid, proteoglycans
Synthesize granulation tissue
Help to reorganize the provisional ECM

Neutrophils

Monocytes
(macrophages)

Healing of acute wounds

Lymphocytes

Healing of acute wounds (as seen in primary healing) occurs as

a carefully regulated, systemic cascade of overlapping processes
that require the coordinated completion of a variety of cellular
activities, including phagocytosis, chemotaxis, mitogenesis, and
synthesis of components of the extracellular matrix. These activities occur in a cascade that correlates with the appearance of
different cell types in the wound during various stages of the
healing process (Figure 1). These processes (triggered by tissue
injury) involve four overlapping (but well-defined) phases of
haemostasis, inflammation, proliferation, and remodelling and
scar maturation. Some of the important cells and growth factors
(cytokines) involved during various stages of the healing process
are summarized in Tables 1 and 2. The regulation of these events
is multifactorial.

Fibroblasts

TGF: Transforming growth factor; PDGF: Platelet-derived growth factor;

ECM: Extracellular matrix.

Table 1

Coagulation
Platelet activation

III Proliferative phase

II Inflammatory phase

IV Remodelling and scar formation

I Haemostasis

Ea

Macrophages

0.1

Lymphocytes

Cytokines and growth factors

ECM formation: fibroplasia,

synthesis of collagen, adhesive
glycoproteins and proteoglycans
Angiogenesis and granulation
tissue formation
Re-epithelialization

Phagocytosis
Neutrophilis
0.3

Abnormalities in these phases result

in hypertrophic scars and keloids

10

Further synthesis
of ECM, degradation
and remodelling
MMP and TIMP activity
Tensile strength
Fibroblast density
Capillary growth
30

100

V Scar maturation

rly

Alterations in one or more of these phases

could result in chronic wounds
te
La

Maximum response

Phases of wound healing

300

Days after wounding (log scale)

ECM: Extracellular matrix; MMP: Metalloproteinases; TIMP: Tissue inhibitors of metalloproteinases.
Adapted from: Clark RA. In: Goldsmith LA, ed. Physiology, biochemistry, and molecular biology of the skin, 2nd edn, Vol. I. New York:
Oxford University press, 1991, p 577.

Figure 1

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Growth factors involved in wound healing

Growth factor

Major source

Function related to wound healing

VEGF

Platelets, neutrophils

FGFs

Fibroblasts, endothelial cells, smooth muscle cells,

macrophages; also brain, pituitary

KGFs
EGF

Fibroblasts
Platelets, macrophages, keratinocytes; also saliva,
urine, milk, plasma

PDGF

Platelets, fibroblasts, macrophages, endothelial cells

G-CSF

Monocytes, fibroblasts, lymphocytes

GM-CSF
TGF-

Keratinocytes, macrophages, lymphocytes, fibroblasts

Activated macrophages, platelets, epithelial cells

TGF-

Platelets, macrophages, fibroblasts, neutrophils,

keratinocytes

IL-1

Macrophages, lymphocytes, many other tissues and

cells
Macrophages, mast cells, T-lymphocytes
Fibroblasts, plasma, liver

Stimulates angiogenesis in granulation tissue

Stimulates formation of collateral blood vessels in peripheral
vascular disease
Proliferation of fibroblasts and epithelial cells; matrix
deposition; wound contraction; angiogenesis
Accelerates formation of granulation tissue
Proliferation and migration of keratinocytes
Differentiation, proliferation, migration and adhesion of
keratinocytes
Formation of granulation tissue
Mitogenic for smooth muscle cells, endothelial cells and
fibroblasts
Chemoattractant for neutrophils and fibroblasts
Fibroblast proliferation and collagen metabolism
Stimulates production of neutrophils
Enhances function of neutrophils and monocytes
Promotes proliferation of keratinocytes
Mediates proliferation of epidermal cells
Stimulates proliferation of epithelial cells and fibroblast
Formation of granulation tissue
Mitogenic for fibroblasts and smooth muscle cells
Chemotactic for macrophages
Stimulates angiogenesis (indirect) and collagen metabolism
Neutrophil chemotaxis
Fibroblast proliferation
Fibroblast proliferation
Fibroblast proliferation
Stimulates synthesis of sulphated proteoglycans and collagen
Re-epithelialization
Neovascularization
Formation of granulation tissue

TNF
IGF-1
HGF

Fibroblasts, keratinocytes, endothelial cells, tumour

cells

VEGF: Vascular endothelial growth factor; FGFs: Fibroblast growth factors; EGF: Epidermal growth factor; KGFs: Keratinocyte growth factors;
TGF-: Transforming growth factor-; TGF-: Transforming growth factor-; IL-1: Interleukin-1; TNF: Tumour necrosis factor; HGF: Hepatocyte growth factor; IGF-1:
Insulin-like growth factor-1; G-CSF: Granulocyte-colony stimulating factor; GM-CSF: Granulocyte macrophage-colony stimulating factor; PDGF: Platelet-derived
growth factor.

Table 2

These proteins initiate the wound healing cascade by attracting

and activating fibroblasts, endothelial cells and macrophages.
These events also activate four major amplification systems
(complement cascade, clotting mechanism, kinin cascade, plasmin generation), which contribute to haemostasis and the sub
sequent stages of the healing process. However, healing can
occur in wounds where there is no haemorrhage (and therefore
no platelets).
The clot (comprising fibrin, fibronectin, vitronectin, von Willibrand factor, thrombospondin) provides the provisional matrix
for cellular migration. The platelets also contain dense bodies that store vasoactive amines (e.g. serotonin) that increase
microvascular permeability, leading to exudation of fluid into the
extravascular space.

Haemostasis (immediate)
Tissue injury is characterized by microvascular injury and
extravasation of blood into the wound. Loss of structural integrity initiates the coagulation cascade and constriction of vessel
walls; the resulting clot formation and platelet aggregation limits
further blood loss. The platelets trapped in the clot are essential
for haemostasis and a normal inflammatory response.
The platelets degranulate and release their alpha granules,
which secrete several growth factors, including:
platelet-derived growth factor
insulin-like growth factor-1
epidermal growth factor
transforming growth factor-
platelet factor-IV.

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inadequate angiogenesis, and poor fibrosis. Additional growth

factors (e.g. transforming growth factor-, heparin-binding epidermal growth factor, basic fibroblast growth factor) are secreted
by polymorphonuclear leukocytes and macrophages, which further stimulate the inflammatory response.
During the late inflammatory phase, collagen fibres are evident
at the incision margins of the wound, but these are vertically oriented and do not bridge the incision. Epithelial cell proliferation
continues, yielding a thickened epidermal covering layer.

Inflammation
Inflammation can be divided into early and late phases depending on the time and duration of response and the type of inflammatory cell involved.
Early inflammatory phase (days 12): inflammation begins
with the activation of the classical and alternative pathways of
the complement cascade. This leads to infiltration of the wound
with neutrophil granulocytes (polymorphonuclear leukocytes)
that are attracted to the wound site within 2448 hours of injury
by a number of chemoattractants such as:
fragments of extracellular matrix protein
transforming growth factor-
complement components (e.g. C3a, C5a)
formyl-methionyl peptide products from bacteria.
Within a short time, the polymorphonuclear leukocytes begin
to adhere to the endothelial cells in the adjacent blood vessels (margination) and start to actively move through the vessel wall (diapedesis). Once in the wound environment, they
phagocytose bacteria and other foreign particles, and kill them
by releasing degrading enzymes and free radicals derived from
oxygen.
During this period, basal cells at the cut edge of the epidermis
begin to exhibit increased mitotic activity. Within 2448 hours,
epithelial cells from both edges begin to migrate and proliferate
along the dermis, depositing components of basement membrane
as they progress.
The activity of polymorphonuclear leukocytes usually stops
within a few days of wounding (after the contaminating bacteria
have been cleared). Redundant cells are cleared from the wound
by extrusion to the wound surface as slough or by phagocytosis by macrophages. The main function of polymorphonuclear
leukocytes is to minimize bacterial contamination of the wound,
thus preventing infection, and they add little to the normal process of wound healing beyond this stage.

Proliferation (day 3 to week 2)

The proliferative phase starts at about day 3 and lasts for 24
weeks after wounding and is characterized by fibroblast migration, deposition of the extracellular matrix and formation of
granulation tissue. With progression of the proliferative phase,
the provisional fibrin/fibronectin matrix is replaced by the newly
formed granulation tissue. Epithelialization of the wound rep
resents the final stage of the proliferative phase.
Fibroblast migration: fibroblasts appear in the wound 24 days
after wounding and endothelial cells follow about one day later.
Following injury, fibroblasts are attracted to the wound by a
number of factors, including platelet-derived growth factor and
transforming growth factor-.
Once within the wound, fibroblasts proliferate and produce
the matrix proteins fibronectin, hyaluronan and, later, collagen
and proteoglycans. These components help to construct the new
extracellular matrix, which supports further ingrowth of cells
and is essential for the repair process. Crucial interaction exists
between the fibroblasts and the extracellular matrix which helps
to regulate further synthesis of the extracellular matrix and subsequent remodelling.
Formation of the extracellular matrix: besides providing turgor to soft tissues and rigidity to bone, extracellular matrix supplies a substratum for cell adhesion and critically regulates the
growth, movement and differentiation of the cells within it. The
extracellular matrix consists of fibrous structural proteins (collagens, elastin) and an interstitial matrix composed of adhesive
glycoproteins embedded in a proteoglycan and glycosaminoglycan gel. The seemingly random array of interstitial matrix in
connective tissues soon becomes highly organized around epithelial cells, endothelial cells and smooth muscle cells, forming the specialized basement membrane (which directs cell
polarity and is required for the orderly renewal of the epithelial
tissue).
Collagens are synthesized by fibroblasts and are the most
abundant family of proteins in the body. They provide strength
and integrity to all tissues and so play a vital role in wound
repair. Platelet-derived growth factor, basic fibroblast growth
factor, transforming growth factor-, interleukin-1, tumour
necrosis factor induce collagen synthesis during the proliferative
and remodelling phases.
Collagens are composed of three protein -chains braided into
a rope-like triple helix; the individual chains are able to intertwine tightly because each polypeptide has one glycine mo
lecule at every third position. More that 30 distinct -chains form
about 18 different collagen types (some of which may be unique
to specific cells and tissues). Some collagen types (e.g. I, III, V)

Late inflammatory phase (days 23): on arriving at the wound

site, blood monocytes undergo a phenotypic change to become
tissue macrophages. Monocytes are attracted to the wound by a
variety of chemoattractants, including:
complement
clotting components
fragments of immunoglobulin G
breakdown products of collagen and elastin
cytokines (e.g. leukotrine B4, platelet factor IV, plateletderived growth factor, transforming growth factor-).
Macrophages are the most important cells present in the later
(4872 hours) stages of the inflammatory process and appear
to act as the key regulatory cells for repair. They function as
phagocytic cells as well as being the primary producer of growth
factors responsible for the proliferation:
and production of the extracellular matrix by fibroblasts
of smooth muscle cells
of endothelial cells resulting in angiogenesis.
Also, macrophages release proteolytic enzymes (e.g. collagenase)
that help to debride the wound.
If depleted, circulating monocytes and tissue macrophages
cause severe alterations in wound healing, leading to poor
debridement of the wound, delayed proliferation of fibroblasts,

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form fibrils due to lateral crosslinking of the triple helices, and

form most of the connective tissue in healing wounds; other collagens (e.g. type IV) are non-fibrillar and become components of
the basement membrane.
Adhesive glycoproteins are structurally diverse proteins that
link the components of the extracellular matrix to one another and
to cells, and include fibronectin, laminin, and thrombospodin.
Fibronectin, a large (400-kD) disulphide-linked heterodimer,
is associated with cell surfaces, basement membranes and the
pericellular matrix. It has specific domains that bind to a wide
spectrum of components of the extracellular matrix (e.g. collagen, fibrin, proteoglycans) and can also attach to cell integrins.
Adhesive matrix proteins such as fibronectin can directly mediate the attachment, spreading, and migration of cells. Fibronectin
also enhances the sensitivity of certain cells (e.g. endothelial)
to the proliferative effect of growth factors by activating intra
cellular signalling pathways.
Integrins are a family of / heterodimeric glycoproteins that
mediate cellcell and cellmatrix adhesion. They are important
in the integration of function between the extracellular matrix
and the cytoskeleton.
Proteoglycans consist of glycosaminoglycans (e.g. dermatan
sulphate, heparan sulphate) linked to a protein backbone; they
help to regulate the structure and permeability of the extracellular matrix. Proteoglycans can modulate the growth and differentiation of cells (e.g. syndecan binds extracellular matrix collagen,
fibronectin, thrombospondin and basic fibroblast growth factor,
and associates with the intracellular actin cytoskeleton to maintain the normal morphology of epithelial sheets). Glycosaminoglycans without a protein core (e.g. hyaluronan) are important
constituents of the extracellular matrix.

Granulation tissue bleeds easily if traumatized. The appearance of the granulation tissue may indicate wound status:
healing wounds have a moist and shiny, hyperaemic, and
reddish appearance
excessive, soft, friable wounds with a beefy-red colour indicate poor healing.
Epithelialization: within a few hours of wounding, a single layer
of epidermal cells migrates from the wound edges to form a delicate covering over the exposed raw area, a process known as
epiboly.
From about 12 hours, there is a marked increase in mitotic
activity within the basal epithelial cells of the wound edges. These
cells migrate as a sheet, extending lamellipodia along the advancement edge. Later, they loosen their normally firm attachments to
the underlying dermis, allowing them to migrate in a leapfrog
fashion across the provisional matrix. When advancing epithelial cells meet, further movement is halted by contact inhibition
and a new basement membrane regenerates; further growth and
differentiation of epithelial cell re-establishes the stratified epithelium. Epithelialization requires a moist environment, adequate
nutrition and bacteriological control, and is modulated by several
growth factors, including keratinocyte growth factor, epidermal
growth factor, and basic fibroblast growth factor.
Remodelling and scar maturation (week 1 to several weeks)
The synthesis and remodelling of the extracellular matrix is
initiated concurrently with the development of granulation tissue and continues over prolonged periods. There is continuous
synthesis and breakdown of collagen as the extracellular matrix
is constantly remodelled, equilibrating to a steady state about
21 days after wounding. Wound contraction occurs through the
interactions between fibroblasts and the surrounding extracellular matrix and is influenced by a number of cytokines including
transforming growth factor-, platelet-derived growth factor and
basic fibroblast growth factor.

Formation of granulation tissue: by 35 days, granulation tissue (indicative of optimal healing) is well established. Granulation tissue has a pink, soft, granular gross appearance (such
as that seen beneath the scab of a skin wound). Histologically,
it is denoted by proliferating fibroblasts and loops of capillaries
in a loose extracellular matrix. This phase is characterized by
angiogenesis or formation of new blood vessels from pre-existing
vessels at the site of injury (neovascularization). Four steps are
recognized during this process:
proteolytic degradation of the basement membrane of the
parent vessel, allowing formation of a capillary sprout
migration of endothelial cells towards the angiogenic stimulus
proliferation of endothelial cells behind the leading front of
migrating cells
maturation of endothelial cells with organization into capillary tubes.
These new vessels are oedematous due to incompletely formed
interendothelial junctions and increased transcytosis. Several
factors (including vascular endothelial growth factor, plateletderived growth factor, basic fibroblast growth factor and
transforming growth factor-) induce angiogenesis. Angiogenic
capillary sprouts invade the fibrin/fibronectin-rich wound clot
and within a few days organize into a microvascular network
throughout the granulation tissue. The density of blood vessels
diminishes because collagen accumulates in the granulation tissue to produce scar; disturbance of this dynamic process may
influence the development of chronic wounds.

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Collagen degradation is achieved by specific metalloproteinases

that are produced by fibroblasts, neutrophils and macrophages
at the wound site.
Metalloproteinases the synthesis and secretion of metalloproteinases is regulated by growth factors, cytokines, and phagocytic stimuli. Metalloproteinases include:
interstitial collagenases, which cleave the fibrillar collagen
types I, II, and III
gelatinases (or type-IV collagenases), which degrade amorphous collagen and fibronectin
stromelysins, which catabolize a variety of constituents of the
extracellular matrix, including proteoglycans, laminin, fibronectin and amorphous collagen.
Metalloproteinases are dependent on zinc ions for their activity
and should be distinguished from neutrophil elastase, cathepsin
G, plasmin, and other serine proteases that can also degrade the
extracellular matrix, but are not metalloenzymes.
The activity of metalloproteinases is tightly regulated because
they have the potential to degrade essential collagen and thereby
cause impaired healing. They are typically elaborated as inactive
(zymogen) precursors that must be first activated; this is accomplished by certain proteases (e.g. plasmin) likely to be present
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only at injury sites. Also, activated collagenases can be rapidly

inhibited by specific tissue inhibitors of metalloproteinases, produced by most mesenchymal cells.

components may account for impaired healing. Also condition-specific factors (e.g. neuropathy in diabetes; ischaemia in
peripheral vascular disease) may lead to non-healing (Table 3
and Figure 2).
The following have been implicated in predisposing to chronic
wounds:
changes in the profile and activity of cells
alterations in the composition of the extracellular matrix
failure of epithelialization
presence of free radicals and micro-organisms.

Further remodelling of the wound causes a:

decrease in the activity of metalloproteinases and an increase
in activity of tissue inhibitors of metalloproteinase
reduction in the density of macrophages and fibroblasts
halt in the outgrowth of capillaries
reduction in the blood flow and metabolic activity
decrease in size of the underlying contractile connective tissue
(which brings the wound margins closer together).
Ultimately, the granulation tissue scaffolding evolves into an
avascular scar which is composed of largely inactive fibroblasts,
dense collagen, fragments of elastic tissue and other components
of the extracellular matrix.

Proteases: the production and activity of proteases (which are

tightly regulated in the healing of acute wounds) are disrupted in
chronic wounds. Several types of metalloproteinases have been
identified within the fluid of chronic wounds, including type-2
and type-9, both of which are absent in the fluid of acute wounds.
Other proteases (e.g. neutrophil elastase) are also significantly
higher in chronic wounds. Similarly, the activity of tissue inhibitors of metalloproteinases is decreased in chronic wounds.

Scar maturation: as the scar matures, fibronectin and hyaluro

nan are broken down and collagen bundles increase in dia
meter, corresponding with increasing tensile strength of the
wound. However, these collagen fibres never regain the original
strength of unwounded skin, and a maximum of 80% strength of
unwounded skin can be achieved.

Inflammatory response: the normal inflammatory response seen

in healing of acute wounds is significantly altered in chronic
wounds. Wound fluid derived from chronic venous ulcers is rich
in pro-inflammatory cytokines such as tumour necrosis factor-,
interleukin-1 and transforming growth factor-1. Also, the
levels of these cytokines decreases as the chronic wound begins
to heal, indicating a correlation between non-healing wounds
and increased levels of pro-inflammatory cytokines.

Abnormal wound healing

Non-healing (chronic) wounds
A chronic wound is one in which the normal process of healing
is disrupted at one or more points in the phases of haemostasis,
inflammation, proliferation or remodelling, resulting in a delay in
healing beyond the anticipated time.

Excessive wound healing

Hypertrophic scars and keloids are forms of excessive healing
resulting from overproduction of all components of the healing
process, including fibroblasts, collagen, elastin and proteoglycans.
They are unique to humans and occur in 515% of wounds, with
a higher incidence in the non-white population.

Cause: growth factors, cytokines, proteases, and cellular and

extracellular elements play important roles in different stages of
the healing process, hence alterations in one or more of these

Local and systemic factors that impede wound healing

Local

Systemic

Inadequate blood supply

Increased skin tension
Poor venous drainage
Presence of foreign body and foreign body reactions
Presence of slough and/or non-viable tissue
Continued presence of micro-organisms
Infection
Excess local mobility
Underlying osteomyelitis
Malignant transformation (Marjolins ulcer)

Advancing age and general immobility

Obesity
Malnutrition
Deficiency of proteins, vitamins (particularly A and C) and/or trace elements
(e.g. zinc)
Systemic malignancy and terminal illness
Shock of any cause (e.g. haemorrhage, sepsis)
Chemotherapy and radiotherapy
Immunosuppressant drugs, corticosteroids, anticoagulants
Peripheral vascular disease and vasculitis
Venous oedema or lymphoedema
Systemic diseases (e.g. diabetes mellitus, rheumatoid arthritis, connective
tissue diseases, metabolic diseases)
Neuropathy secondary to congenital or acquired spinal cord pathology, leprosy
Inherited neutrophil disorders (e.g. leukocyte adhesion deficiency)
Impaired macrophage activity (malacoplakia)

Table 3

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Also, factors causing local inflammation (e.g. persistent irritation, haematoma, infection, wound dehiscence, foreign bodies)
predispose to a hypertrophic scar.
Keloids do not have a specific cause, although genetic predis
position is heavily implicated. Frequently the injury is trivial and
no direct correlation appears to exist between the magnitude of
the skin injury and the size of the resultant scar.
Biochemical differences exist between normal skin, mature
scars, hypertrophic scars and keloids. Collagen synthesis is three
times higher in keloids than in hypertrophic scars, and 20 times
higher in keloids than in normal skin. The absolute amount of
collagen is increased in keloids, indicative of increased collagen
synthesis or decreased crosslinking; mature scars have a higher
content of crosslinked collagen than exists in keloids. Colla
genase activity is 14 times greater in keloids than in normal scar,
while hypertrophic scars show a four-fold increase compared to
normal skin.

Figure 2 Bilateral chronic ulcers of the leg. These ulcers are due to
mixed (arteriovenous) aetiology. Note the extensive slough and nonviable tissue covering the wound beds and the absence of healthy
granulation tissue.

Hypertrophic scars: the incidence is highest in:

wounds crossing tension lines
areas of increased tension and movement in skin
deep dermal burns
wounds left to heal by secondary intention (>3 weeks).

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Further reading
Leaper DJ, Harding KG. Wounds: biology and management. Oxford:
Oxford University Press, 1998.

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