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Diabetic foot is a serious complication of diabetes which aggravates the patient's condition whilst also having significant socioeconomic impact. The aim of the present review is to summarize the causes and pathogenetic mechanisms leading to diabetic foot, and to focus on the management of this important health issue. Increasing physicians' awareness and hence their ability to identify the "foot at risk," along with proper foot care, may prevent diabetic foot ulceration and thus reduce the risk of amputation.
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Management of Diabetic Foot Ulcers
Kleopatra Alexiadou John Doupis
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Received: December 23, 2011
The Author(s) 2012. This article is published with open access at
Diabetic foot is a serious complication of
diabetes which aggravates the patient’s
condition whilst also having significant
socioeconomic impact. The aim of the present
review is to summarize the causes and
pathogenetic mechanisms leading to diabetic
foot, and to focus on the management of this
important health issue. Increasing physicians’
awareness and hence their ability to identify the
‘foot at risk,’’ along with proper foot care, may
prevent diabetic foot ulceration and thus reduce
the risk of amputation.
Keywords: Debridement; Diabetic foot;
Dressings; Neuropathy; Off-loading;
Pathogenesis; Peripheral arterial disease;
Diabetic foot is one of the most significant and
devastating complications of diabetes, and is
defined as a foot affected by ulceration that is
associated with neuropathy and/or peripheral
arterial disease of the lower limb in a patient
with diabetes. The prevalence of diabetic foot
ulceration in the diabetic population is 4–10%;
the condition is more frequent in older patients
[13]. It is estimated that about 5% of all
patients with diabetes present with a history of
foot ulceration, while the lifetime risk of
diabetic patients developing this complication
is 15% [13].
The majority (60–80%) of foot ulcers will
heal, while 10–15% of them will remain active,
and 5–24% of them will finally lead to limb
amputation within a period of 6–18 months
after the first evaluation. Neuropathic wounds
are more likely to heal over a period of 20 weeks,
while neuroischemic ulcers take longer and will
K. Alexiadou
First Department of Propaedeutic Medicine, Athens
University Medical School, Laiko General Hospital,
Athens, Greece
J. Doupis (&)
Department of Internal Medicine and Diabetes
Clinic, Salamis Naval Hospital, Salamis Naval Base,
18900 Salamis, Greece
Enhanced content for this article is
available on the journal web site:
Diabetes Ther (2012) 3:4
DOI 10.1007/s13300-012-0004-9
more often lead to limb amputation [4]. It has
been found that 40–70% of all nontraumatic
amputations of the lower limbs occur in
patients with diabetes [5]. Furthermore, many
studies have reported that foot ulcers
precede approximately 85% of all amputations
performed in diabetic patients [5].
The risk of foot ulceration and limb
amputation increases with age and the
duration of diabetes [6,7]. The prevention of
diabetic foot is crucial, considering the negative
impact on a patient’s quality of life and the
associated economic burden on the healthcare
system [8].
Diabetic foot ulceration is a major health
problem and its management involves a
multidisciplinary approach. This review aims to
provide a synopsis of the current management
strategies of diabetic foot ulcers, from prevention
to the options for treatment. The authors believe
that it may be useful to primary care physicians,
nurses, podiatrists, diabetologists, and vascular
surgeons, as well as all healthcare providers
involved in the prevention or management of
diabetic foot ulcers.
The most significant risk factors for foot
ulceration are diabetic neuropathy, peripheral
arterial disease, and consequent traumas of the
Diabetic neuropathy is the common factor in
almost 90% of diabetic foot ulcers [9,10]. Nerve
damage in diabetes affects the motor, sensory,
and autonomic fibers. Motor neuropathy causes
muscle weakness, atrophy, and paresis. Sensory
neuropathy leads to loss of the protective
sensation of pain, pressure, and heat.
Autonomic dysfunction causes vasodilation
and decreased sweating [11], resulting in a loss
of skin integrity, providing a site vulnerable to
microbial infection [12].
Peripheral arterial disease is 2–8 times more
common in patients with diabetes, starting at
an earlier age, progressing more rapidly, and
usually being more severe than in the general
population. It commonly affects the segments
between the knee and the ankle. It has been
proven to be an independent risk factor for
cardiovascular disease as well as a predictor of
the outcome of foot ulceration [13]. Even minor
injuries, especially when complicated by
infection, increase the demand for blood in
the foot, and an inadequate blood supply may
result in foot ulceration, potentially leading to
limb amputation [14]. The majority of foot
ulcers are of mixed etiology (neuroischemic),
particularly in older patients [15].
In patients with peripheral diabetic
neuropathy, loss of sensation in the feet leads
to repetitive minor injuries from internal
(calluses, nails, foot deformities) or external
causes (shoes, burns, foreign bodies) that are
undetected at the time and may consequently
lead to foot ulceration. This may be followed by
infection of the ulcer, which may ultimately
lead to foot amputation, especially in patients
with peripheral arterial disease.
Structural foot deformities and
abnormalities, such as flatfoot, hallux valgus,
claw toes, Charcot neuroarthropathy, and
hammer foot, play an important role in the
pathway of diabetic foot ulcers since they
contribute to abnormal plantar pressures and
therefore predispose to ulceration.
Other risk factors for foot ulceration include
a previous history of foot ulceration or
amputation, visual impairment, diabetic
nephropathy, poor glycemic control, and
cigarette smoking. Some studies have shown
that foot ulceration is more common in men
with diabetes than in women [14,16].
Page 2 of 15 Diabetes Ther (2012) 3:4
Social factors, such as low socioeconomic status,
poor access to healthcare services, and poor
education are also proven to be related to more
frequent foot ulceration [14,16].
Physical examination of the diabetic foot is
based on assessment of the skin and of the
vascular, neurological, and musculoskeletal
The dermatological examination includes a
visual inspection of the skin of the legs and feet,
particularly the dorsal, plantar, medial, lateral,
and posterior surfaces, as well as a close
examination of each toenail [17]. Other
observations to be noted include the presence
of peeling skin and maceration or fissuring of
the interdigital skin. The visual inspection may
discover signs of autonomic neuropathy and
sudomotor dysfunction [17].
People with diabetes are at high risk of
developing peripheral vascular disease;
therefore, the palpation of pulses bilaterally in
the dorsalis pedis, posterior tibial, popliteal, and
superficial femoral arteries is necessary for
assessment of the blood circulation in the
lower limbs. Inadequate perfusion of a limb,
due to peripheral vascular disease, may crucially
affect the progress of the healing of an ulcer,
often resulting in chronic unhealed ulcers that
are susceptible to infection [15]. A relatively
simple method to confirm the clinical suspicion
of arterial occlusive disease is to measure the
resting systolic blood pressure in the ankles and
arms. This is performed by measuring the
systolic blood pressure (using a Doppler probe)
in the brachial, posterior tibial, and dorsalis
pedis arteries [17]. The highest of the four
measurements in the ankles and feet is divided
by the higher of the two brachial
measurements. This ratio is referred to as the
ankle–brachial index (ABI). Normal ABI values
range from 1.0 to 1.3, since the pressure is
higher in the ankle than in the arm. Values over
1.3 suggest a noncompressible calcified vessel.
An ABI of less than 0.9 is indicative of
peripheral vascular disease and is associated
with 50% or more stenosis in one or more
major vessels. An ABI of 0.4–0.9 suggests a
degree of arterial obstruction associated with
claudication. An ABI of less than 0.4 or an ankle
systolic pressure of less than 50 mmHg
represents advanced ischemia [18]. The ABI
correlates with clinical measures of lower
extremity function, such as walking distance,
velocity, balance, and overall physical activity.
In addition, a low ABI has been associated with
a higher risk of coronary heart disease, stroke,
transient ischemic attack, progressive renal
insufficiency, and all-cause mortality [19]. A
potential limitation of the ABI is that calcified
vessels may not compress normally, possibly
resulting in falsely elevated Doppler signals.
Thus, an ABI of over 1.3 is suggestive of calcified
vessels. In such patients, an accurate pressure
may be obtained by measuring the blood
pressure in the toe and calculating the toe–
brachial index [19]. If ABIs are normal at rest
but symptoms strongly suggest claudication,
ABIs and segmental pressures should be
obtained before and after exercise on
a treadmill. This may unmask a
hemodynamically significant stenosis that is
subclinical at rest but significant on exertion.
The physician should also assess skin
temperature with the back of the hand.
Normal skin temperature ranges from warm at
the tibia to cool at the distal toes [20]. Foot-skin
temperature can be measured with a handheld
infrared thermometer on the plantar aspect of
the foot at the level of the first metatarsal head.
Diabetes Ther (2012) 3:4 Page 3 of 15
Elevated temperature is reported to be
associated with sudomotor dysfunction and a
higher risk for foot ulceration [21,22].
The presence of diabetic neuropathy can be
established from an abbreviated medical history
and physical examination. Symptoms such as a
burning sensation; pins and needles; shooting,
sharp, or stabbing pains; and muscle cramps,
which are distributed symmetrically in both
limbs (‘‘stocking and glove distribution’’), and
often worse at night, are usually present in
peripheral neuropathy. Diabetic peripheral
neuropathy may also be evaluated using the
Neuropathy Symptom Score (NSS), which is a
validated symptom score with a high predictive
value to screen for peripheral neuropathy in
diabetes [23,24] (Table 1).
The physical examination of the foot assesses
the perception of superficial pain (pinprick),
temperature sensation (using a two-metal rod),
light sensation (using the edge of a cotton-wool
twist), and pressure (using the Semmes–
Weinstein 5.07 monofilament). Additionally,
the physician should examine the vibration
perception using a tuning fork and/or a
biothesiometer. The examination of position
sense (proprioception) and deep tendon reflexes
(Achilles tendon, patellar) is also essential [4].
Neuropathic deficits in the feet can be
determined using the Neuropathy Disability
Score (NDS), which is derived from the
inability to detect pinprick sensation (using a
neurological examination pin), vibration (using
a 128-Hz tuning fork), or differences in
temperature sensation (using warm and cool
rods), and loss or reduction of the Achilles reflex
(using a tendon hammer) [1] (Table 1).
According to the American Diabetes
Association, a foot that has lost its protective
sensation is considered to be a ‘‘foot at risk’’
for ulceration. The diagnosis of a foot at
risk is confirmed by a positive
Table 1 Neuropathy Symptom Score (NSS) and
Neuropathy Disability Score (NDS)
Fatigue/cramping/aching 1
Burning/numbness/tingling 2
Thighs 0
Legs 1
Feet 2
Pain exacerbation:
Daytime only 0
Day and night 1
Night 2
Have the symptoms ever woken the patient from
No 0
Yes 1
Could any maneuver reduce the symptoms?
Sitting or lying 0
Standing 1
Walking 2
NSS: /9
Big toe
Normal 0
Abnormal 1
Normal 0
Abnormal 1
Vibration perception
Normal 0
Page 4 of 15 Diabetes Ther (2012) 3:4
5.07/10-g monofilament test, plus one of the
following tests: vibration test (using 128-Hz
tuning fork or a biothesiometer), pinprick
sensation, or ankle reflexes [25].
The above tests have been reported to have a
positive predictive value of 46% and a negative
predictive value of 87% for the risk of incident
neuropathy [26].
Diabetic foot ulcers are defined as:
neuropathic in the presence of peripheral
diabetic neuropathy and absence of ischemia;
ischemic if the patient presents peripheral artery
disease but no diabetic peripheral neuropathy;
and neuroischemic if neuropathy and ischemia
coexist. Apart from this rather crude
classification, many efforts have been made to
categorize foot ulcers according to extent, size
and depth, location, presence of infection, and
ischemia. The Meggitt–Wagner classification is
one of the most popular validated classifications
for the foot ulcers (Table 2). Other classification
systems for diabetic foot ulcers have also been
proposed and validated [27].
Whatever method is used for the diabetic foot
ulcer evaluation, all classification systems should
aim at facilitating the correct choice of treatment
and reliable monitoring of the healing progress
of the ulcer, while at the same time serving as a
communication tool across specialties.
Table 2 Meggitt–Wagner classification of foot ulcers
Grade Description of the ulcer
0 Pre- or postulcerative lesion completely
1 Superficial, full-thickness ulcer limited to the
dermis, not extending to the subcutis
2 Ulcer of the skin extending through the subcutis
with exposed tendon or bone and without
osteomyelitis or abscess formation
3 Deep ulcers with osteomyelitis or abscess
4 Localized gangrene of the toes or the forefoot
5 Foot with extensive gangrene
Table 1 continued
Abnormal 1
Normal 0
Abnormal 1
Dorsal foot area
Temperature sensation
Normal 0
Abnormal 1
Normal 0
Abnormal 1
Achilles reflex
Normal 0
Increased 1
Abnormal 2
Normal 0
Increased 1
Abnormal 2
NDS: /10
Peripheral neuropathy is present if there are moderate signs
(NDS[6) with or without symptoms (any NSS), or mild
signs (NDS 3–5) with moderate symptoms (NSS[5)
3–4: mild symptoms 3–5: mild neuropathic signs
5–6: moderate symptoms 6–8: moderate
7–9: severe 9–10: severe
Diabetes Ther (2012) 3:4 Page 5 of 15
The gold standard for diabetic foot ulcer
treatment includes debridement of the wound,
management of any infection, revascularization
procedures when indicated, and off-loading of
the ulcer [28]. Other methods have also been
suggested to be beneficial as add-on therapies,
such as hyperbaric oxygen therapy, use of
advanced wound care products, and negative-
pressure wound therapy (NPWT) [29]. However,
data so far have not provided adequate evidence
of the efficacy and cost-effectiveness of these
add-on treatment methods.
Debridement should be carried out in all chronic
wounds to remove surface debris and necrotic
tissues. It improves healing by promoting the
production of granulation tissue and can be
achieved surgically, enzymatically, biologically,
and through autolysis.
Surgical debridement, known also as the
‘sharp method,’’ is performed by scalpels,
and is rapid and effective in removing
hyperkeratosis and dead tissue. Particular care
should be taken to protect healthy tissue, which
has a red or deep pink (granulation tissue)
appearance [30]. Using a scalpel blade with the
tip pointed at a 45angle, all nonviable tissue
must be removed until a healthy bleeding ulcer
bed is produced with saucerization of the
wound edges. If severe ischemia is suspected,
aggressive debridement should be postponed
until a vascular examination has been carried
out and, if necessary, a revascularization
procedure performed.
Enzymatic debridement can be achieved
using a variety of enzymatic agents, including
crab-derived collagenase, collagen from krill,
papain, a combination of streptokinase and
streptodornase, and dextrans. These are able to
remove necrotic tissue without damaging the
healthy tissue. Although expensive, enzymatic
debridement is indicated for ischemic ulcers
because surgical debridement is extremely
painful in these cases [31].
Biological debridement has been applied
recently using sterile maggots. Maggots have
the ability to digest surface debris, bacteria, and
necrotic tissues only, leaving healthy tissue
intact. Recent reports suggest that this method
is also effective in the elimination of drug-
resistant pathogens, such as methicillin-
resistant Staphylococcus aureus, from wound
surfaces [32].
Autolytic debridement involves the use of
dressings that create a moist wound
environment so that host defense mechanisms
(neutrophils, macrophages) can clear
devitalized tissue using the body’s enzymes.
Autolysis is enhanced by the use of proper
dressings, such as hydrocolloids, hydrogels, and
films. Autolysis is highly selective, avoiding
damage to the surrounding skin [33].
In conclusion, debridement, especially the
‘sharp method,’’ is one of the gold standards in
wound healing management, significantly
contributing to the healing process of the
wound, including the diabetic ulcer [34,35].
Off-loading of the ulcer area is extremely
important for the healing of plantar ulcers.
Retrospective and prospective studies have
shown that elevated plantar pressures
significantly contribute to the development of
plantar ulcers in diabetic patients [3638]. In
addition, any existing foot deformities may
increase the possibility of ulceration, especially
in the presence of diabetic peripheral
neuropathy and inadequate off-loading.
Page 6 of 15 Diabetes Ther (2012) 3:4
Furthermore, inadequate off-loading of the
ulcer has been proven to be a significant
reason for the delay of ulcer healing even in
an adequately perfused limb [30]. The value of
ulcer off-loading is increasing, as it has been
reported that the risk of recurrence of a healed
foot ulcer is high if the foot is not properly off-
loaded (in the high-pressure areas), even after
closure of the ulcer [39].
The most effective method of off-loading,
which is also considered to be the gold
standard, is the nonremovable total-contact
cast (TCC). It is made of plaster or fast-setting
fiberglass cast materials, has relatively low costs,
and permits restricted activity [40].
Nonremovable TCCs are indicated for the
effective off-loading of ulcers located at the
forefoot or midfoot. Severe foot ischemia, a
deep abscess, osteomyelitis, and poor skin
quality are absolute contraindications to the
use of a nonremovable TCC. Nonremovable
TCCs work by distributing the plantar pressures
from the forefoot and midfoot to the heel. They
allow complete rest of the foot whilst also
permitting restricted activity. Nonremovable
TCCs also reduce edema, and compliance with
treatment is necessarily high [40].
There are a number of removable cast
walkers (RCW), which usually have a
lightweight, semirigid shell that helps support
the limb whilst also providing full-cell
protection (Fig. 1). The sole is of a rocker type,
offering off-loading of the forefoot during
standing and walking. The foot base is wide
and there is enough room for dressings. In some
RCWs, overlapping air cells provide
intermittent pneumatic compression for
edema reduction. In other RCWs, there are
additional layers of foam or other soft material,
offering total contact [41].
A modification of RCWs is an instant total-
contact cast (ITCC), where there is a wrapping
layer of cohesive tape or plaster bandage around
the RCW [42]. The aim of the ITCC is to
combine the efficacy of a TCC with the easy
application of a RCW.
Half shoes are another solution for patients
who cannot tolerate other methods of off-
loading, although they provide less pressure
relief than a cast boot and are difficult to walk
in. Therapeutic shoes, custom insoles, and the
use of felted foam (Fig. 2) are alternative
methods to off-load wounds located on the
forefoot, and can reduce pressure at the site of
ulceration by 4–50% [43].
Ulcers heal more quickly and are often less
complicated by infection when in a moist
environment. The only exception is
Fig. 1 Removable cast walker
Diabetes Ther (2012) 3:4 Page 7 of 15
dry gangrene, where the necrotic area should be
kept dry in order to avoid infection and
conversion to wet gangrene. A wound’s
exudate is rich in cytokines, platelets, white
blood cells, growth factors, matrix
metalloproteinases (MMPs), and other
enzymes. Most of these factors promote
healing via fibroblast and keratinocyte
proliferation and angiogenesis, while others,
such as leukocytes and toxins produced by
bacteria, inhibit the healing process. Moreover,
it has been reported that local concentrations of
growth factors [platelet-derived growth factor-
beta (PDGF-beta), transforming growth factor-
beta] are low in patients with chronic ulcers
[44]. The ideal dressing should be free from
contaminants, be able to remove excess
exudates and toxic components, maintain a
moist environment at the wound-dressing
interface, be impermeable to microorganisms,
allow gaseous exchange, and, finally, should be
easily removed and cost-effective [45]. Various
dressings are available that are intended to
prevent infection and enhance wound healing,
and several studies support their effectiveness
for this purpose [46,47]. However, most of
these studies were performed in wounds and
not in diabetic ulcers [44,46,47]. Available data
on their use in diabetes are scarce [35], and
therefore further randomized clinical trials are
needed to support the existing evidence for
their benefit in diabetic ulcers.
Growth Factors
PDGF-beta (becaplermin; available as
; Ortho-McNeil Pharmaceutical, Inc.,
Titusville, NJ, USA; and Janssen-Cilag
International NV, Beerse, Belgium) has been
developed as a topical therapy for the treatment
of noninfected diabetic foot ulcers. It is applied
in the form of a once-daily gel along with
debridement on a weekly basis [48]. Initial
studies have indicated a significant positive
effect of becaplermin [49,50] on ulcer healing;
however, more recent studies have reported an
increased incidence of cancer in patients treated
with becaplermin, especially at high doses [48].
Consequently, the US Food and Drug
Administration has published a warning of an
increased risk of cancer if more than three tubes
of becaplermin are used [51]. Further studies are
necessary in order to explore the benefit-to-risk
ratio, as well as the cost effectiveness of this
Platelet-rich plasma (PRP) is an autologous
product, extracted from the patient’s plasma,
which includes a high platelet concentration in
Fig. 2 Off-loading of a diabetic foot ulcer with felted
Page 8 of 15 Diabetes Ther (2012) 3:4
a fibrin clot that can be easily applied to the
ulcer area. The fibrin clot is absorbed during
wound healing within days to weeks following
its application [52]. There are a few studies
reporting a shorter closure time and higher
healing percentage in patients using PRP and
platelet-derived products [53,54]. However,
further studies are required to support the
possible beneficial effect of this method in
ulcer healing.
The results of the subcutaneous
administration of granulocyte colony-
stimulating factor (GCFS) in patients with
infected foot ulcers vary, with some studies
indicating faster resolution of the infection and
faster healing [55,56], while others did not
report any significant difference [57,58]. Basic
fibroblast growth factor (bFGF) is known to be
beneficial in the formation of granulation tissue
and normal healing [59]; however, one small
study failed to prove any significant difference
between the intervention and the control group
[60]. Epidermal growth factor (EGF) acts on
epithelial cells, fibroblasts, and smooth muscle
cells to promote healing [61]. Evidence for the
use of EGF in diabetic ulcers is limited, with
only a small amount of data reporting a
significantly higher rate of ulcer healing with
EGF use compared with placebo [62].
Bioengineered Skin Substitutes
Tissue-engineered skin substitutes are classified
into allogenic cell-containing (Apligraf
Graftskin, Organogenesis Inc., Canton, MA,
USA; Dermagraft
, Advanced Biohealing
Westport, CT, USA; OrCell
, Ortec
International Inc., New York, NY, USA),
autologous cell-containing (Hyalograft
Fidia Advanced BioPolymers, Abano Terme,
Italy; Laserskin
, Fidia Advanced BioPolymers,
Abano Terme, Italy; TranCell
, CellTran Ltd.,
Sheffield, UK), and acellular (OASIS
, Cook
Biotech, West Lafayette, IN, USA;
, Wright Medical Group Inc.,
Arlington, TN, USA; AlloDerm
, LifeCell
Corporation, Branchburg, NJ, USA) matrices.
The first two types of matrix contain living cells,
such as keratinocytes or fibroblasts, in a matrix,
while acellular matrices are free of cells and act
by releasing growth factors to stimulate
neovascularization and wound healing.
Accumulating evidence shows that
bioengineered skin substitutes may be a
promising therapeutic adjunct therapy to the
standard wound care for the management of
noninfected diabetic foot ulcers. Nevertheless,
more studies need to be conducted in the future
in order to confirm these results [6369].
Extracellular Matrix Proteins
(Fidia Farmaceutici, Abano Terme, Italy)
is a semisynthetic ester of hyaluronic acid
which facilitates the growth and movement of
fibroblasts, and controls hydration [70].
Other available products contain lyophilized
collagen from various sources (bovine, porcine),
alone or in combination with alginates,
cellulose (Promogran
, Johnson & Johnson,
New Brunswick, NJ, USA), or antibiotics.
Collagen seems to induce the production of
endogenous collagen and to promote platelet
adhesion and aggregation. It has been reported
to be safe and effective as an adjunctive therapy
in the management of foot ulceration; however,
evidence is still limited [71].
MMP Modulators
Matrix metalloproteinases regulate the
extracellular matrix components. During
normal wound healing, there is a balance
between the construction and the destruction
Diabetes Ther (2012) 3:4 Page 9 of 15
of the extracellular matrix. In chronic wounds,
a high expression of MMP-2 in fibroblasts and
the endothelium is detected and is believed to
favor destruction. Thus, downregulation of
MMP-2 expression may enhance the healing
process [72].
(Tyco Healthcare Group Lp, North
Haven, CT, USA) is a dressing containing metal
ions and citric acid, and its topical application is
associated with a lower expression of MMP-2 by
fibroblasts and endothelial cells. Metal ions
inhibit the production of reactive oxygen
species by polymorphonuclear cells, and citric
acid acts as a scavenger of superoxide anions
[72]. One pilot study provided encouraging
results [73]. Certainly, randomized trials are
necessary in order to establish the role of
DerMax in the treatment of diabetic ulcers.
Negative-Pressure Wound Therapy
Negative-pressure wound therapy (NPWT) has
emerged as a new treatment for diabetic foot
ulcers. It involves the use of intermittent or
continuous subatmospheric pressure through a
special pump (vacuum-assisted closure)
connected to a resilient open-celled foam
surface dressing covered with an adhesive
drape to maintain a closed environment. The
pump is connected to a canister to collect
wound discharge and exudate. Experimental
data suggest that NPWT optimizes blood flow,
decreases tissue edema, and removes exudate,
proinflammatory cytokines, and bacteria from
the wound area [74]. It should be performed
after debridement and continued until the
formation of healthy granulation tissue at the
surface of the ulcer. Currently, NPWT is
indicated for complex diabetic foot wounds
[74]; however, it is contraindicated for patients
with an active bleeding ulcer. Two small studies
[75,76] and one larger study [77] provide some
encouraging data concerning the possible
benefit of NPWT in the healing rate and time
of diabetic foot ulcers. However, more
randomized trials are needed in order to
confirm these results.
Hyperbaric Oxygen
There is strong evidence that fibroblasts,
endothelial cells, and keratinocytes are
replicated at higher rates in an oxygen-rich
environment [78,79]. Moreover, leukocytes kill
bacteria more effectively when supplied by
oxygen. It is also known that fibroblasts from
diabetic individuals show diminished cell
turnover in comparison with those from
nondiabetic persons. Based on these data, the
idea was that the administration of oxygen at
high concentrations might accelerate wound
healing in diabetes [78]. Treatment with
hyperbaric oxygen therapy involves the
intermittent administration of 100% oxygen at
a pressure greater than that at sea level. It is
performed in a chamber with the patient
breathing 100% oxygen intermittently while
the atmospheric pressure is increased to
2–3 atmospheres for a duration of 1–2 h. A full
course involves 30–40 sessions. A small amount
of data suggests significant reduction of the
ulcer area [79] as well as reduction of the risk for
major amputation [80]. Hyperbaric oxygen can
be applied as an adjunctive therapy for patients
with severe soft-tissue foot infections and
osteomyelitis who have not responded to
conventional treatment. Adverse effects
include barotrauma to the ears and sinuses,
pneumothorax, transient changes in visual
acuity, and seizures [81]. Furthermore, a recent
systematic review by the National Institute for
Health and Clinical Excellence (NICE)
Guidelines Development Group in the UK
concluded that the available data are
Page 10 of 15 Diabetes Ther (2012) 3:4
insufficient to demonstrate that hyperbaric
oxygen therapy is cost-effective [82].
The management of diabetic foot ulcers remains
a major therapeutic challenge which implies an
urgent need to review strategies and treatments
in order to achieve the goals and reduce the
burden of care in an efficient and cost-effective
way. Questions remain as to which types of
intervention, technology, and dressing are
suitable to promote healing, and whether all
therapies are necessary and cost-effective as
adjunctive therapies. The International
Working Group on the Diabetic Foot has
conducted two systematic reviews [35,83]of
the evidence and effectiveness of interventions
to enhance the healing of chronic diabetic foot
ulcers. The preliminary results are promising,
but large randomized controlled trials are
necessary in order to establish the cost-
effectiveness of the new therapies.
Prevention of diabetic foot ulceration is
critical in order to reduce the associated high
morbidity and mortality rates, and the danger
of amputation. It is essential to identify the
‘foot at risk,’’ through careful inspection and
physical examination of the foot followed by
neuropathy and vascular tests.
Regular foot examination, patient education,
simple hygienic practices, provision of
appropriate footwear, and prompt treatment of
minor injuries can decrease ulcer occurrence by
50% and eliminate the need for major
amputation in nonischemic limbs [84,85].
Diabetic foot ulcers should be carefully
evaluated and the gold-standard treatments
should be strictly applied in order to prevent
amputation. Further clinical studies are needed
to support the existing evidence regarding the
clinical benefit of new approaches for the
treatment of diabetic ulcers, and these
approaches should be used only as add-on
therapies to the gold-standard wound care.
Dr. Doupis is the guarantor for this article, and
takes full responsibility for the integrity of the
work as a whole.
Conflict of interest. The authors declare that
they have no conflicts of interest.
Open Access. This article is distributed under
the terms of the Creative Commons Attribution
Noncommercial License which permits
any noncommercial use, distribution, and
reproduction in any medium, provided the
original author(s) and source are credited.
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... Chronic diabetic wounds are characterized by a prolonged inflammation stage, impaired proliferation stage and long-lasting remodeling stage. During the impaired proliferation stage, VEGF protein expression, angiogenesis and re-epithelialization (RE) are impaired due to prolonged inflammation and hyperglycemia-induced excessive oxidative stress (1). Therefore, the resolution of prolonged inflammation is a key point in the transition to the impaired proliferation stage that may improve wound healing (1)(2)(3). ...
... During the impaired proliferation stage, VEGF protein expression, angiogenesis and re-epithelialization (RE) are impaired due to prolonged inflammation and hyperglycemia-induced excessive oxidative stress (1). Therefore, the resolution of prolonged inflammation is a key point in the transition to the impaired proliferation stage that may improve wound healing (1)(2)(3). Notably, promoting angiogenesis is one of the gold standard treatments for diabetic foot ulcers (1-3). Bitto et al (4) demonstrated that topical application of simvastatin (SIM) enhanced wound healing in diabetic mice. ...
... One of the most catastrophic complications of diabetes is diabetic foot ulcers (1). The prevalence of diabetic foot ulceration among diabetic population is 4-10%. ...
... Among diabetes population, the lifetime risk of diabetic foot ulcers is 15% (2). The management of diabetic foot ulcers is challenging and need further review of strategies and treatments, so we can reduce cost effectively (1). ...
Full-text available
Background: Honey known as wound healer, but the use of honey for diabetes population is lack. Scientific studies needed to provide enough evidence to justify the benefits of honey for the treatment of diabetic foot ulcers. Aims: To identify the benefit of honey as healing diabetic foot ulcer. Methods: The author was used PICO question as the first step of this study, then the second step was searching the articles from several databases. The inclusion and exclusion criterias were using only honey as a diabetic foot treatment on human, randomized control trial study or quasy experimental study, published less than 10 years ago (2009 – 2019), available in English and provide full text. Meanwhile, for the exclusion criteria were literature review, systematic review or meta-analysis study, using honey as a treatment to animal such as rat and rabbit, combine honey with another treatment. By using PRISMA guideline, researchers were systematically review several articles from 4 databases. Results: After conducted search strategy by using Boolean search strategy, 4 articles were included. The articles used different types of honey and the population ranged from 8 to 63 peoples. According to the results, majority of study showed honey is effective as wound healer and safe Conclusion: Honey wound dressing is an option for managing diabetic foot Recommendation: As a nurse, we can offer the honey as an effective treatment or intervention tools for targeted patients or populations
... Diabetic foot is defined as a foot with ulceration that is caused by peripheral artery disease and sensory neuropathy of the feet. 1 Diabetic foot syndrome refers to a group of conditions that include infection, diabetic foot ulcers, and neuropathy. 2 Lifetime incidence of foot ulcers in diabetics is around 15%, and it is expected to rise to 25% in the future. 3 Diabetes is becoming more common and its complications are becoming more common. ...
... The importance of early diagnosis and intervention, as well as routine foot care, cannot be underrated. 1 Recognizing risk factors like poor health literacy, physical inactivity and poor glycaemic control allows clinicians to create strategies for detecting them early in order to prevent other related complications. ...
Full-text available
Objective: To determine the risk factors associated with the development of diabetic foot. Methodology: The case control study was conducted from 15 th March to 15 th June 2021 at Riphah College of Rehabilitation & Allied Health Sciences in collaboration with District Headquarters Hospital, Rawalpindi. Using purposive sampling, diabetic patients with and without diabetic foot were enrolled. A total of 196 patients responded to the questionnaire, which had 26 closed ended questions and comprised of different domains regarding risk factors associated with diabetic foot. Data were analysed using SPSS 20. Results: Poor health literacy was seen in 167 (85.2%) patients (OR: 3.512 and p = 0.002). 157 (80.1%) patients were physically inactive (OR: 3.431 and p = 0.001), poor glycaemic control was detected in 177 (90.3%) patients (OR: 2.465 p = 0.058), 144 (73.5%) did not have comfortable foot wear (OR: 1.696 and p = 0.145), junk food consumptions were seen in 78 (39.8%) OR: 1.198 and p = 0.563). Conclusion: Diabetic foot was observed in the patients of diabetes who had poor health literacy, were physically inactive, had poor glycemic control and did not have comfortable footwear.
... [1] DFU is defined as foot ulcers in people with DM that are accompanied by neuropathy or peripheral artery disease (PAD). [2] In particular, PAD is known as the major risk factor in patients with DM, and 10% to 15% of foot ulcers remain unhealed, while 5% to 24% of patients undergo lower-limb amputation, including foot or symes, within 6 to 18 months after the initial diagnosis of DFU. [3][4][5] Diabetic foot complications are often caused by dysfunction of microcirculation, which is frequently accompanied by peripheral neuropathy and PAD. ...
Full-text available
Extracorporeal shockwave therapy (ESWT) can induce wound healing by increasing tissue microcirculation. However, studies on the effect of ESWT on enhancing tissue microcirculation in diabetic foot ulcer (DFU), particularly on when the microcirculation increases after ESWT application, are still lacking. Therefore, we aimed to examine the effectiveness of ESWT in promoting microcirculation in DFU patients in a time-dependent manner. We included 50 feet of 25 patients with type 2 diabetes mellitus and Wagner grade I to II DFU in this study. The affected feet were used as the ESWT group and the unaffected contralateral feet were used as the control group. ESWT was performed in 3 sessions per week for a total of 3 weeks. Transcutaneous partial oxygen pressure (TcPO2) was used to evaluate the tissue microcirculation. The TcPO2 level (>43 mm Hg) in the ESWT group was recovered by the 2nd week of treatment, and statistical significance (P < .05) was demonstrated at the same time. From the 2nd week of ESWT, a significant increase in TcPO2 was observed in Wagner grade I and II DFU. These findings imply that the ESWT may improve microcirculation in patients with Wagner grades I to II DFU. However, this impact requires at least 2 weeks or more than 6 sessions. For better comparison, further studies with larger clinical groups and extended period are needed.
... A chronic wound can be broadly classified as any wound that is subject to poor wound healing; this is typically associated with recalcitrant infection, ischaemia of the tissue and a prolonged or arrested inflammatory phase . Diabetic foot ulcers (DFU) are a severe complication observed in 15% of neuropathic diabetic patients, making DFUs one of the most prevalent examples of a chronic wound worldwide (Alexiadou and Doupis, 2012). One of the hallmarks of a chronic wound is high microbial burden and diversity, which is typically attributed to the formation of poly-microbial drug-resistant biofilms in the wound bed (Banu et al., 2015). ...
Bacterial biofilms are an ever growing concern for public health; featuring both inherited genetic resistance and a conferred innate tolerance to traditional antibiotic therapies. Consequently, there is a growing interest in novel methods of drug delivery, in order to increase the efficacy of antimicrobial agents. One such method is the use of acoustically activated microbubbles, which undergo volumetric oscillations and collapse upon exposure to an ultrasound field. This facilitates physical perturbation of the biofilm, and provides the means to control drug delivery both temporally and spatially. In line with current literature in this area, this report offers a rounded argument and research evidence to outline why ultrasound-responsive agents could be an integral part of advancing wound care. The fabrication of a stable ultrasound-responsive carrier of nitric oxide was an important first step in this research, this was achieved by exploring two primary lipid microbubble shell constituents: 1,2-distearoylphosphatidylcholine (DSPC) and 1,2-dibehenoyl-sn-glycero-3-phosphocholine (DBPC). It was successfully demonstrated that DBPC shelled microbubbles exhibited the greatest stability in ambient temperature over 60 minutes. Targeting biofilms to increase the efficacy of antimicrobial delivery and optimised local concentrations has proved challenging, due to the complex and heterogeneous nature of the biofilm extracellular matrix. This research assessed the utility of cationic microbubbles, as a means of non-selective electrostatic targeting of the anionic biofilm structure. Cationic microbubbles demonstrated the ability enhance microbubble-biofilm contact by up to 37%, with a binding strength comparable to that seen in specific ligand-receptor targeting of biofilm extracellular matrix constituents. The anti-biofilm and bactericidal efficacy of neutral and cationic airand nitric oxide-loaded microbubbles, were assessed both in terms of their passive nitric oxidemediated action and active response to ultrasound stimulation. To facilitate growth of biofilms with morphological and phenotypic characteristics of biofilms found in chronic wounds, a wound constituent media that featured key pathophysiological components of the in vivo wound environment was developed. It was successfully demonstrated that insonified DBPC nitric oxide microbubbles could elicit a clinically significant 99.9% (3-log reduction) in viable cells recovered from treated biofilms, by enhancing the efficacy of sub-inhibitory (4 µg/mL) concentrations of the antibiotic gentamicin. Moreover, the combination of the nitric oxide and the ultrasound mediated physical perturbation of biofilms by microbubbles, was also shown to elicit a significant 99.9% reduction in surface area covered by P. aeruginosa biofilms.
... Page 2 of 9 Dai et al. BMC Musculoskeletal Disorders (2023) 24:135 Current treatment guidelines for DFU recommend foot wound debridement, glycemic control, infection management, revascularization, and decompression to promote healing [3]. Wound infection is a predictor of poor wound healing and amputation [4]. ...
Full-text available
Background In this study, we try to investigate the effect of antibiotic bone cement in patients with infected diabetic foot ulcer (DFU). Methods This is a retrospective study, including fifty-two patients with infected DFU who had undergone treated between June 2019 and May 2021. Patients were divided into Polymethylmethacrylate (PMMA) group and control group. 22 patients in PMMA group received antibiotic bone cement and regular wound debridement, and 30 patients in control group received regular wound debridement. Clinical outcomes include the rate of wound healing, duration of healing, duration of wound preparation, rate of amputation, and frequency of debridement procedures. Results In PMMA group, twenty-two patients (100%) had complete wound healing. In control group, twenty-eight patients (93.3%) had wound healing. Compared with control group, PMMA group had fewer frequencies of debridement procedures and shorter duration of wound healing (35.32 ± 3.77 days vs 44.37 ± 7.44 days, P < 0.001). PMMA group had five minor amputation, while control group had eight minor amputation and two major amputation. Regarding the rate of limb salvage, there was no limb lose in PMMA group and two limb losses in control group. Conclusion The application of antibiotic bone cement is an effective solution for infected DFU treatment. It can effectively decreased the frequency of debridement procedures and shorten the healing duration in patients with infected DFU.
... Often, chronic diseases, such as diabetes mellitus, chronic venous insufficiency, or age-associated diseases, are underlying issues behind dysfunctional healing. The healthcare costs of non-healing wounds are high since there are no highly effective therapies currently available (Alexiadou and Doupis, 2012). For example, over the past fifteen years, the success rate for therapeutic trials in wound healing has been zero percent, resulting in no approved therapeutics for wound healing in that time frame (Thomas et al., 2016). ...
While wound healing in humans occurs primarily through re-epithelization, in rodents it also occurs through contraction of the panniculus carnosus, an underlying muscle layer that humans do not possess. Murine experimental models are by far the most convenient and inexpensive research model to study wound healing, as they offer great variability in genetic alterations and disease models. To overcome the obstacle of contraction biasing wound healing kinetics, our group invented the splinted excisional wound model. While other rodent wound healing models have been used in the past, the splinted excisional wound model has persisted as the most used model in the field of wound healing. Here, we present a detailed protocol of updated and refined techniques necessary to utilize this model, generate results with high validity, and accurately analyze the collected data. This model is simple to conduct and provides an easy, standardizable, and replicable model of human-like wound healing.
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Objectives The objective of the present study is to discuss the use of nanomaterials like nanosensors for diagnosing Diabetes and highlight their applications in the treatment of Diabetes.Methods Diabetes mellitus (D.M.) is a group of metabolic diseases characterized by hyperglycemia. Orally administered antidiabetic drugs like glibenclamide, glipalamide, and metformin can partially lower blood sugar levels, but long-term use causes kidney and liver damage. Recent breakthroughs in nanotheranostics have emerged as a powerful tool for diabetes treatment and diagnosis.ResultsNanotheranostics is a rapidly developing area that can revolutionize diabetes diagnosis and treatment by combining therapy and imaging in a single probe, allowing for pancreas-specific drug and insulin delivery. Nanotheranostic in Diabetes research has facilitated the development of improved glucose monitoring and insulin administration modalities, which promise to improve the quality of life for people with Diabetes drastically. Further, nanomaterials like nanocarriers and unique functional nanomaterials used as nano theranostics tools for treating Diabetes will also be highlighted.Conclusion The nanosensors discussed in this review article will encourage researchers to develop innovative nanomaterials with novel functionalities and properties for diabetes detection and treatment.
"Diabetic foot is one of the main long-term complications of diabetes, having a significant impact on a patient’s quality of life. However, prevention by daily checking of the limbs and observance of the rules of care remains particularly important to avoid total or partial amputation. This paper aims to highlight the main challenges and progress in the treatment of the diabetic foot. To achieve this, we analyzed a database consisting of more than 100 articles published in recent years, approaching the treatment of the diabetic foot. The main problems that occur with the diabetic foot are peripheral vascular disease and diabetic neuropathy. These can lead to blisters and skin lesions that can eventually lead to ulcers in the lower limbs and even amputation. In conclusion, prevention is the main method of treatment for diabetic foot, followed by the treatment of each complication depending on when it is identified and its severity. "
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Aims To provide one of the diagnostic categories for distal diabetic polyneuro-pathy,several symptom scoring systems are available, which are often extensive andlack in validation. We validated a new four-item Diabetic Neuropathy Symptom (DNS) scorefor diagnosing distal diabetic polyneuropathy. Methods We compared score characteristics of the generally accepted NeuropathySymptom Score (NSS) with the DNS score, and tested construct validity,predictive value and reproducibility with the Diabetic Neuropathy Examinationscore, Semmes–Weinstein monofilaments and Vibration Perception Threshold(clinical standards) in 73 patients with diabetes (24 Type 1, 49 Type 2;43 male/30 female; mean age 57 years (19–90);mean diabetes duration 15 years (1–43)). Results Correlation between NSS and DNS score was high (Spearman r= 0.88). Patient scoreswere more differentiated on the DNS score. The relation of the NSS andDNS scores, respectively, with clinical standards was good (Spearman r= 0.21–0.60). Reproducibility ofthe DNS score was high (Cohen weighted κ 0.78–0.95). The DNSscore was easier to perform in clinical practice. Conclusions The DNS is validated, fast and easy to perform, with a high predictive valuewhen screening for diabetic polyneuropathy. Diabet. Med. 19, 962–965 (2002)
Nonhealing diabetic foot ulcers are a common cause of amputation. Emerging cellular therapies such as platelet-rich plasma gel provide ulcer management options to avoid loss of limb. The purpose of this prospective, randomized, controlled, blinded, multicenter clinical study was to evaluate the safety and efficacy of autologous platelet-rich plasma gel for the treatment of nonhealing diabetic foot ulcers. One hundred, twenty-nine (129) patients were screened; 72 completed a 7-day screening period and met the study inclusion criteria. Patients were randomized into two groups - the standard care with platelet-rich plasma gel or control (saline gel) dressing group - and evaluated biweekly for 12 weeks or until healing. Healing was confirmed 1 week following closure and monitored for another 11 weeks. An independent audit led to the exclusion of 32 patients from the final per-protocol analysis because of protocol violations and failure to complete treatment. In the 40 wounds per-protocol group, 13 out of 19 (68.4%) of the platelet-rich plasma gel and nine out of 21 (42.9%) of the control wounds healed. After adjusting for wound size outliers (n = 5), significantly more platelet-rich plasma gel (13 out of 16, 81.3%) than control gel (eight out of 19, 42.1%) treated wounds healed (P = 0.036, Fishers exact test). Kaplan-Meier time-to-healing also was significantly different between groups (log-rank, P 0.0177). No treatment-related serious adverse events were reported and bovine thrombin used in the preparation of PRP did not cause Factor V inhibition. When used with good standards of care, the majority of nonhealing diabetic foot ulcers treated with autologous platelet-rich plasma gel can he expected to heal.
Retrospective and prospective studies have shown that elevated plantar pressure is a causative factor in the development of many plantar ulcers in diabetic patients and that ulceration is often a precursor of lower-extremity amputation. Herein, we review the evidence that relieving areas of elevated plantar pressure (off-loading) can prevent and heal plantar ulceration. There is no consensus in the literature concerning the role of off-loading through footwear in the primary or secondary prevention of ulcers. This is likely due to the diversity of intervention and control conditions tested, the lack of information about off-loading efficacy of the footwear used, and the absence of a target pressure threshold for off-loading. Uncomplicated plantar ulcers should heal in 6 to 8 weeks with adequate off-loading. Total-contact casts and other nonremovable devices are most effective because they eliminate the problem of nonadherence to recommendations for using a removable device. Conventional or standard therapeutic footwear is not effective in ulcer healing. Recent US and European surveys show that there is a large discrepancy between guidelines and clinical practice in off-loading diabetic foot ulcers. Many clinics continue to use methods that are known to be ineffective or that have not been proved to be effective while ignoring methods that have demonstrated efficacy. A variety of strategies are proposed to address this situation, notably the adoption and implementation of recently established international guidelines, which are evidence based and specific, by professional societies in the United States and Europe. Such an approach would improve the often poor current expectations for healing diabetic plantar ulcers. (J Am Podiatr Med Assoc 100(5): 360–368, 2010)
The diabetic foot is one of the most significant complications of diabetes and is considered to be a major medical, social, and economic problem worldwide. The risk for foot ulceration in patients with diabetes is close to 25% and is also closely related to risk of limb amputation. Diabetic neuropathy, limited joint mobility, micro- and macroangiopathy, and high plantar pressures have been described as the main risk factors for diabetic foot ulceration. Proper diagnosis and adequate therapeutic treatment are considered the cornerstones to prevention of limb amputation and preservation of quality of life in patients with diabetes. The following review focuses on the classification, diagnosis, and current trends in the treatment of diabetic foot ulceration.
Hypothesis Promogran, a wound dressing consisting of collagen and oxidized regenerated cellulose, is more effective that standard care in treating chronic diabetic plantar ulcers.Design Randomized, prospective, controlled multicenter trial.Setting University teaching hospitals and primary care centers.Patients A total of 276 patients from 11 centers were enrolled in the study. The mean age of the patients was 58.3 years (range, 23-85 years). All patients had at least 1 diabetic foot ulcer.Interventions Patients were randomized to receive Promogran (n = 138) or moistened gauze (control group; n = 138) and a secondary dressing. Dressings were changed when clinically required. The maximum follow-up for each patient was 12 weeks.Main Outcome Measure Complete healing of the study ulcer (wound).Results After 12 weeks of treatment, 51 (37.0%) Promogran-treated patients had complete wound closure compared with 39 (28.3%) control patientss, but this difference was not statistically significant (P = .12). The difference in healing between treatment groups achieved borderline significance in the subgroup of patients with wounds of less than 6 months' duration. In patients with ulcers of less than 6 months' duration, 43 (45%) of 95 Promogran-treated patients healed compared with 29 (33%) of 89 controls (P = .056). In the group with wounds of at least 6 months' duration, similar numbers of patients healed in the control (10/49 [20%]) and the Promogran (8/43 [19%]; P = .83) groups. No differences were seen in the safety measurements between groups. Patients and investigators expressed a strong preference for Promogran compared with moistened gauze.Conclusions Promogran was comparable to moistened gauze in promoting wound healing in diabetic foot ulcers. It showed an additional efficacy for ulcers of less than 6 months' duration that was of marginal statistical significance. Furthermore, Promogran had a safety profile that was similar to that of moistened gauze, with greater user satisfaction. Therefore, Promogran may be a useful adjunct in the management of diabetic foot ulceration, especially in ulcers of less than 6 months' duration.