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Clinical practice
practice
Clinical
Why don’t wounds heal?
T
Author:
Dr Michael Stacey
he healing of a wound is achieved by way
of the integrated phases of haemostasis,
inflammation, proliferation, and
remodelling [Table 1], which must occur in the
proper sequencing and time period, without
interference and at an optimal intensity, in
order for a wound to heal normally[1].
Normal stages of wound healing
Rapid haemostasis
Haemostasis begins as soon as the wound
occurs, with constriction of the blood
vessels and fibrin clot formation. The
blood clot and surrounding tissues release
pro-inflammatory cytokines and growth factors,
such as platelet-derived growth factor (PDGF)
[1]
. These growth factors stimulate epithelial
cells, recruit fibroblasts, and recruit neutrophils
and monocytes, resulting in initiation of the
inflammatory phase of wound healing[2].
Appropriate inflammation
Once bleeding is controlled, the inflammatory
cells migrate into the wound. This stage involves
the sequential infiltration of neutrophils,
macrophages and lymphocytes into the
wound site[3-5]. Neutrophils are responsible for
phagocytosing cell debris and microorganisms,
ensuring defense against infection. As they
die, neutrophils release intracellular enzymes
(e.g. elastase), which further digest tissue.
Macrophages also phagocytose bacteria
and provide a second line of defence, as well
as secreting extracellular enzymes (matrix
metalloproteases [MMPs]) to degrade necrotic
tissue at the wound site. Macrophages also
secrete various cytokines and growth factors
— such as fibroblast growth factor, epidermal
growth factor, transforming growth factor-beta
and interleukin-1 — which are important in the
next stage of healing[6].
The role of T-lymphocytes — which migrate
into the wound following inflammatory cells and
macrophages — is not completely understood,
although several studies suggest that delayed
infiltration and decreased concentration of
T-cells at the wound site may be associated
with impaired healing. Other studies report
that subsets of T-lymphocytes have differential
effects on wound healing, suggesting a positive
role for CD 4+ cells in wound healing and an
inhibitory role for CD 8+ cells[7-8].
Proliferation and re-growth of the epithelial
tissue surface
The proliferative phase, which usually overlaps
with the inflammatory phase, is characterised
by re-epitheliasation, whereby epithelial cells
Table 1: The phases of normal wound healing[1-2].
Phase
Time frame
Cells involved Function of
activity
Cellular and bio-physiologic
events
Haemostatis
Immediate
Platelets
Vascular constriction
Clotting
Platelet aggregation, degranulation,
and fibrin formation (thrombus)
Inflammation
Day 1 – 4
Neutrophils
Macrophages
Phagocytosis
Neutrophil infiltration,
Macrophages
Lymphocytes
Angiocytes
Neurocytes
Fibroblasts
Keratinocytes
Fill defect
Re-epithelialisation
Re-establish
skin function
Angiogenesis
Fibrocytes
Develop
tensile
strength
Monocyte infiltration, and
differentiation to macrophages
Lymphocyte infiltration
Proliferation
Days 4 – 21
Acknowledgement
This article was sponsored by Acelity
Dr Michael Stacey is Surgeon in
Chief, Hamilton General Hospital,
Hamilton, Canada
16
Remodelling
Day 21 – 2 years
Closure
Collagen synthesis
Collagen remodelling
Vascular maturation and
regression
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Clinical practice
proliferate and migrate over a provisional
matrix within the wound[1].
In the reparative dermis, fibroblasts and
endothelial cells are the most prominent
cell types. These cells have a number of
functions including supporting capillary
growth, as well as formation of collagen
and granulation tissue at the wound site.
Endothelial cells are important during the
process of angiogenesis, where they support
regeneration of the capillary linings[2]. In the
wound bed, fibroblasts produce collagen,
glycosaminoglycans and proteoglycans, all
of which are important components of the
extracellular matrix[1].
Synthesis, cross-linking and alignment
of collagen
Once fibroblast cells have secreted the
collagen framework upon which further dermal
regeneration can occur, the remodelling phase
of the wound healing process can begin. The
remodelling phase involves the realignment of
this collagen tissue to develop tensile strength,
and can take up to 2 years[2]. During this phase,
the vascular density of the wound also returns
to normal[1].
When is a wound defined as nonhealing?
When these precise processes occur normally,
a wound should reach re-epithelialisation
within 4 weeks. However, the normal wound
healing process is complex, involving multiple
interlinked phases that must occur in a timely
fashion, but are each vulnerable to interruption
by external and internal inhibitory factors[9]. As
such, some wounds fail to progress through
this orderly and timely repair sequence,
leading to delayed healing, also known as
wound ‘stalling’. Where healing is delayed,
wounds can become chronic, posing a
number of difficulties to both the patient and
healthcare system, including increased costs[9].
What factors may contribute to
delayed healing?
Wound healing can stall for numerous
reasons, related to the individual patient,
their specific wound, and to a variety of biophysiological factors. In order to recognise that
a wound is non-healing, the wound itself, the
surrounding area, and the systems of care in
place must be carefully assessed so that any
precipitating factors acting as a barrier within
the healing process can be quickly identified
and resolved[9].
18
Patient-related factors
Patients with underlying pathologies and
comorbidities, such as coronary artery
disease or diabetes mellitus, may experience
compromised healing. Studies have shown
that vascular insufficiency is a common cause
of arterial, diabetic, pressure or venous ulcers,
affecting the lower extremities of the body[10].
Patients with diabetes mellitus are well
documented to exhibit poor wound healing,
and are prone to developing chronic diabetic
foot ulcers (these are estimated to occur in
15% of all patients with diabetes). Multiple
mechanisms, including decreased cell growth
and local angiogenesis, contribute to this poor
healing. In addition, people with diabetes
have a number of additional risk factors, such
as neuropathy and an impaired ability to fight
infection, and are largely unable to mount an
adequate inflammatory response to wounding.
All of these factors increase the risk of delayed
healing and can lead to sepsis and limb
amputation. Indeed, there are over 100 known
physiologic factors that contribute to wound
healing deficiency in diabetic patients[11].
Patients undergoing treatments or taking
certain medication for other conditions, such
as radiotherapy, may also be at risk of delayed
wound healing. In the case of radiation therapy,
the immune system is suppressed, which can
cause ulceration either during treatment or
once the treatment is completed[10]. Many
medications, particularly those that affect
blood clot formation or platelet function, also
disturb healing; commonly, glucocorticoid
steroids, non-steroidal anti-inflammatories, and
chemotherapeutic drugs interfere with normal
wound healing[1].
Healing may also be impeded by a number
of systemic factors that appear to bare no
relation to the wound itself, such as age, body
type, alcohol consumption, and nutritional
status [Figure 1][10].
The age of a patient can affect the healing
trajectory of a wound. Older patients
may have a number of comorbidities that
increase the risk of skin breakdown and
delay healing, such as poor nutrition, altered
hormonal response and problems with the
immune, circulatory, or respiratory systems[10].
Differences in healing capacity of older
patients compared with younger patients can
be seen at each stage of the process, including
enhanced platelet aggregation, delayed
macrophage and lymphocyte infiltration,
delayed re-epithelialisation and reduced
collagen remodelling[3].
Wounds International 2016 | Vol 7 Issue 1 | ©Wounds International 2016 | www.woundsinternational.com
hypoxia, and hydrogen cyanide impairs cellular
oxygen metabolism[16–18].
Chronic
illness
Age
Immune
status
Smoking
PATIENT
Oxygenation/
Medications
Circulation
Stress
Nutritional
status
Local wound environment
Figure 1. Patient factors that affect
wound healing.
Lifestyle choices also play a role in wound
healing success, with nutrition, smoking and
alcohol consumption all affecting outcomes.
Good nutritional status is essential for wound
healing to take place. Ignoring nutritional status
may compromise the patient’s ability to heal
and subsequently prolong the stages of wound
healing. For example, an obese patient may
experience compromised wound healing due
to inadequate blood supply to adipose tissue or
protein malnutrition, whereas patients who are
emaciated may lack the oxygen and nutritional
stores required for normal wound healing.
These studies highlight the importance of
assessing a patient’s nutritional status to ensure
that, regardless of visual appearance, they are
not malnourished[10].
Studies have also shown that alcohol exposure
impairs wound healing and increases infection
incidence[12-13], with intoxication at the time of
wounding a risk factor for infection susceptibility[14].
A review of the effect of alcohol on host defense
showed that short-term alcohol exposure leads
to suppressed pro-inflammatory cytokine
release[15]. Moreover, the higher rate of infection
in patients with acute alcohol exposure correlates
with decreased neutrophil recruitment and
phagocytic action[15].
The association between cigarette smoking
and delayed wound healing is also well
recognised. Nicotine is a vasoconstrictor that
reduces nutritional blood flow to the skin,
resulting in tissue ischaemia and impaired
healing of injured tissue[16]. Proliferation of red
blood cells, fibroblasts, and macrophages are
also reduced by nicotine. Additionally, carbon
monoxide in cigarette smoke leads to tissue
Wound-related factors
There is evidence to suggest that a number
of wound-specific factors play an important
role in healing processes. In a study of 30,000
patients with diabetic foot ulcers, the three
most important wound-related factors that
affected healing outcome were size, depth,
and duration of the wound. A study by
Margolis and colleagues indicated patients
with wounds larger than 2cm2, of more than
2 months’ duration and with penetration
through to exposed tendon, ligament, bone
or joint, had only a 22% chance of healing by
20 weeks[19].
Wound duration is a recognised indicator
for non-healing across a variety of wound
types, relating perhaps to the development of
senescent cells that are unable to replicate. An
accumulation of greater than 15% senescent
fibroblast cells has been described as a
threshold beyond which wounds become
difficult to heal[20]. In addition, it is expected
that large wounds will take longer to heal
than small wounds, and the longer a wound
is open, the greater the risk of complications,
such as infection[21]. If infection is present — as
evidenced by signs such as pain, heat, swelling,
erythema, and loss of function — it is important
to treat appropriately to accelerate healing[10].
Delayed or non-healing may also be due
to a number of other local factors, including
desiccation, maceration, necrosis, pressure, or
oedema[10]. A moist environment is essential
to healing, with moisture first appearing
during the inflammatory phase when the
fibrin clot is degraded and capillaries dilate
and become permeable[22]. Indeed, the process
of epithelialisation — whereby new skin
cells form over the wound — is dependent
on the presence of moisture[23]. However,
excessive wound exudate can be detrimental
to wound healing, particularly in chronic
wounds, where exudate can contain cellular
debris and enzymes that harm the wound bed
and periwound skin[23]. Conversely, in a dry
environment, a wound can become desiccated
and cells will typically dehydrate and die; such
wounds heal more slowly and painfully than
moist wounds[10].
Necrotic tissue results from the
accumulation of dead cells and debris
following haemorrhage. Necrotic tissue can
impair assessment attempts and will act as
a focal point for infection. As such, dead or
Wounds International 2016 | Vol 7 Issue 1 | ©Wounds International 2016 | www.woundsinternational.com19
Clinical practice
Positive factors
Growth fa
ctors
Cell proli
fe
ration
Figure 2. The inflammatory
environment.
Negative factors
Bacterial
bioburde
n
Protease
activity
Inflamma
to
cytokine ry
devitalised tissue should be removed before
repair and healing can occur. If pressure at the
wound site is excessive or sustained, this can
also impair healing since the blood supply to
the area may be disrupted. Additionally, any
wound that is deprived of an adequate blood
supply as a result of trauma or oedema may
also be at risk of non-healing[10].
Bio-physiological factors
The biochemistry of a non-healing wound is
stuck in a state of perpetual inflammation;
it is necessary to break this cycle in order
for a wound to heal. The elevated levels of
inflammatory cytokines, free radicals, and
proteases found in chronic wounds create
an environment not conducive to healing,
and while a wound remains in a stalled state,
this hostile environment is sustained and
non-healing continues to be perpetuated[24].
Although inflammation is a normal part of
the wound healing process, where elevation
of pro-inflammatory cytokines continues and
elongates the inflammation phase, healing
can be delayed. Prolonged inflammation leads
to increased levels of serine proteases, such
as elastase and plasmin, and MMPs, a group
of proteases that break down the extracellular
matrix, and a decrease in naturally occurring
protease inhibitors. This shift may cause
degradation in growth factors, which are
important in the proliferation stage of healing
[Figure 2][24-25]. In addition, the presence of
bacteria may increase the inflammatory
response and intensify an already hostile
healing environment[24].
Clinical competency and service delivery
Although factors affecting wound healing
have often only been described from a
patient perspective, there are also numerous
20
factors relating to clinical competency and
environment of care that may influence
wound healing. The healthcare professional’s
knowledge and attitude can have a great
impact on clinical outcome; for example,
quality of assessment, their ability to control
a patient’s symptoms and management
of underlying comorbidities. Healthcare
professionals providing patient-centred care
will take into consideration the patient’s
individual needs, discuss potential barriers
to healing, and provide support while calling
on other professionals and agencies where
needed, aiming to ensure the care they
provide is holistic[21].
How does non-healing manifest itself
in clinical signs and symptoms?
The longer a non-healing wound is left
without appropriate treatment, the worse it is
likely to become[9]. Therefore, it is important
to recognise a number of symptoms and
clinical signs that may be manifest when a
wound is failing to heal within the proper
sequence and time. Table 2 lists a number of
signs and symptoms that may indicate that a
wound is failing to progress along a normal
healing trajectory.
These symptoms and signs of non-healing
indicate a need to re-evaluate the underlying
cause of the wound and look for factors that
could be contributing to non-healing. Indeed,
they may provide the stimulus needed to
properly treat an underlying condition or
address inadequacies in service delivery,
thereby enabling the healing process to
proceed in an orderly fashion.
Conclusion
The normal sequence of wound healing,
which comprises four interlinked phases,
can often be compromised and prolonged.
If the intricate building blocks of normal
wound healing are disrupted, complete
healing may never be achieved. Some
barriers to healing may be obvious, such as
identifiable comorbidities and concomitant
treatments, but other factors may not be
immediately apparent. As such, effective
wound assessment must look at a wound’s
complexity, ability to heal and potential
barriers to healing, as well as taking into
account clinical signs and symptoms of nonhealing, so that problems within the healing
cycle can be quickly resolved. Treating early
and appropriately is vital, considering use
of advanced therapies if standard of care
Wounds International 2016 | Vol 7 Issue 1 | ©Wounds International 2016 | www.woundsinternational.com
Table 2: How does non-healing manifest in clinical signs and symptoms?
The wound is large in size; expanding or there is a failure to decrease in size over time
The wound bed is in poor condition with little healthy granulation tissue and little improvement is seen over time
There are higher than expected levels of exudate, which itself can lead to the healthy surrounding skin becoming
macerated or ulcerated
There is evidence of critical colonisation or local infection, with signs such as pain, swelling, redness or loss of function
There is abnormal or persistent inflammation, which clinically can be difficult to differentiate from infection in a chronic wound
is not enough to heal a wound, since the
longer a compromised wound is left without
appropriate treatment, the higher the risk of
Wint
delayed or non-healing.
13.Szabo G, Mandrekar P. A recent perspective on
alcohol, immunity, and host defense. Alcohol Clin
Exp Res 2009; 33:220-232
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