534296

research-article2014

POI0010.1177/0309364614534296Prosthetics and Orthotics InternationalAndrews et al.

INTERNATIONAL
SOCIETY FOR PROSTHETICS
AND ORTHOTICS

Literature Review

Wound management of chronic diabetic

foot ulcers: From the basics to
regenerative medicine

Prosthetics and Orthotics International

2015, Vol. 39(1) 2939
The International Society for
Prosthetics and Orthotics 2014
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0309364614534296
poi.sagepub.com

Karen L Andrews1,2, Matthew T Houdek3 and Lester J Kiemele1

Abstract
Background: Hospital-based studies have shown that mortality rates in individuals with diabetic foot ulcers are about
twice those observed in individuals with diabetes without foot ulcers.
Objective: To assess the etiology and management of chronic diabetic foot ulcers.
Study design: Literature review.
Methods: Systematic review of the literature discussing management of diabetic foot ulcers. Since there were only a few
randomized controlled trials on this topic, articles were selected to attempt to be comprehensive rather than a formal
assessment of study quality.
Results: Chronic nonhealing foot ulcers occur in approximately 15% of patients with diabetes. Many factors contribute
to impaired diabetic wound healing. Risk factors include peripheral neuropathy, peripheral arterial disease, limited joint
mobility, foot deformities, abnormal foot pressures, minor trauma, a history of ulceration or amputation, and impaired
visual acuity. With the current treatment for nonhealing diabetic foot ulcers, a significant number of patients require
amputation.
Conclusion: Diabetic foot ulcers are optimally managed by a multidisciplinary integrated team. Offloading and preventative
management are important. Dressings play an adjunctive role. There is a critical need to develop novel treatments to
improve healing of diabetic foot ulcers. The goal is to have wounds heal and remain healed.
Clinical relevance
Diabetic neuropathy and peripheral arterial disease are major factors involved in a diabetic foot ulcer. Despite current
treatment modalities for nonhealing diabetic foot ulcers, there are a significant number of patients who require
amputations. No known therapy will be effective without concomitant management of ischemia, infection, and adequate
offloading.
Keywords
Diabetes, diabetic foot ulcer, neuropathy, wounds
Date received: 25 March 2014; accepted: 10 April 2014

Introduction
Chronic nonhealing neuropathic foot ulcers occur in
approximately 15% of patients with diabetes.1 In 2011,
there were an estimated 366,000,000 adults with diabetes.
Worldwide global projections indicate that this figure will
increase to 552,000,000 by 2030.2 In North America and
Europe, the number of adults with diabetes is expected to
increase by 42.4% and 20%, respectively.3,4 A major
increase is also predicted in Africa, with the number of
adults with diabetes expected to increase by 98.1% from
2010 to 2030.3,4 The main factors responsible for the

1Vascular

Ulcer/Wound Healing Clinic, Gonda Vascular Center, Mayo

Clinic, Rochester, MN, USA
2Department of Physical Medicine and Rehabilitation, Mayo Clinic,
Rochester, MN, USA
3Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
Corresponding author:
Karen L Andrews, Vascular Ulcer/Wound Healing Clinic, Gonda
Vascular Center, Mayo Clinic, 200 First St. SW, Rochester, MN 55905,
USA.
Email: andrews.karen@mayo.edu

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Prosthetics and Orthotics International 39(1)

increase in patients with diabetes are aging of the population and lifestyle changes.3,5 The dramatic increase in the
worldwide prevalence of diabetes has resulted in a rise in
diabetes-related complications.
Persons with diabetes mellitus have a 15%25% chance
of developing a diabetic foot ulcer during their lifetime
and a 50%70% recurrence rate over the ensuing 5 years.6
8 Foot lesions carry high morbidity and mortality and represent the most common cause of hospitalization in
patients with diabetes. While diabetes affects more than
8% of the US population, it has been implicated in over
60% of all nontraumatic lower extremity amputations.9
The risk of a person with diabetes undergoing a lower
extremity amputation is estimated to be 23 times that of a
person without diabetes.10 Greater than 85% of major
amputations in patients with diabetes are preceded by foot
ulceration.8,1113 Following amputation, 50% of patients
either die or lose the contralateral limb within 5 years.14
The early recognition of the high-risk foot and timely
treatment may prevent foot ulcers, save limbs, potentially
save lives, and improve patient quality of life.15 A strategy
which includes prevention, patient and staff education,
multidisciplinary treatment of foot ulcers, and close monitoring can reduce amputation rates by 49%85%. As a
result, several countries and organizations (the World
Health Organization and the International Diabetes
Federation) have set goals to reduce the rate of amputation
by up to 50%.16 Unfortunately, despite evidence to suggest
that targeted interventions resulting from multidisciplinary
care can reduce limb loss, progress to date has been slow.17

Diabetes and impaired healing

With the increasing prevalence of diabetes around the
world, understanding the mechanisms responsible for poor
diabetic wound healing is an important public health issue.
The increased risk of chronic ulcer formation stems from
disruption of the complex process of wound healing by the
pathophysiological abnormalities associated with diabetes.1820 Wound healing is a dynamic interactive process
involving coagulation, inflammation, granulation tissue
formation, and tissue remodeling.18,21 Analysis of human
diabetic ulcers has revealed the differential expression of
growth factors, chemokines, cytokines, and their receptors, which are critical to several phases of the normal
wound healing process.22,23 Matrix-metalloproteinases
involved in tissue remodeling are also differentially
expressed in chronic wounds, causing the dysfunctional
breakdown of the extracellular matrix.24,25 Macrophages
isolated from the wounds of diabetic mice have exhibited
a decreased ability to remove dead cells, resulting in a prolonged inflammatory response.26,27
Tumor necrosis factor- (TNF-), a potent proinflammatory cytokine, contributes to the stimulation of fibroblasts and keratinocytes, the expression of growth factors,

and upregulation of antimicrobial defenses.28 In normal

wound healing, the highest levels of TNF- are seen from
12 to 24 h after wounding.29 After completing the proliferation phase of wound healing, TNF- returns to basal
levels. During the early phase of wound repair, it is predominantly expressed in polymorphonuclear leukocytes
and later by macrophages. It is also expressed in the hyperprolific epithelium at the wound edge. In diabetic wound
healing, impaired fibroblast proliferation has been linked
to increased levels of TNF-.30 The high levels of TNF-
inhibit angiogenesis, proliferation, differentiation, migration, and increase apoptosis. TNF- inhibition attenuates
the impact of diabetes-enhanced TNF- which offers
potentially new therapeutic avenues for treatment of
chronic diabetic foot ulcers.31
Diabetes is characterized by significantly increased
cross-linking and nonenzymatic glycation of collagen and
elevated levels of advanced glycation end products
(AGEs).32,33 Blocking the receptor for advanced glycation
end products (RAGEs) restores the wound healing properties of diabetic (Db/Db) mice.34 Hyperglycemic animals
have been shown to have significantly higher concentrations of glycated collagen and higher levels of collagenase
activity.35 Furthermore, diabetic (Db/Db) mice have also
been shown to have a prolonged inflammatory phase with
sustained expression of the inflammatory cytokines.36
Diabetic skin (both murine and human cadaveric) is biomechanically inferior to nondiabetic skin.37 These results
suggest the defect in tissue integrity may be inherent to
diabetic skin at baseline.
Treatments that enhance diabetic wound healing are
often associated with reducing inflammatory cytokines in
the diabetic wound environment.38 An important yet still
unanswered question during diabetic wound healing is how
a high-glucose environment affects chemotactic activity.

Diabetic foot ulcers

Diabetic neuropathy and peripheral arterial disease (PAD)
are usually the major factors involved in diabetic foot
ulcers. These two factors may act alone, together, or in
combination with other conditions, such as microvascular
disease, biomechanical abnormalities, limited joint mobility, and increase susceptibility to infection.39,40
For every 1% increase in hemoglobin A1c, there is a
corresponding 26% risk of PAD.41
Neuropathy is a common complication of diabetes.
This is characterized by a progressive loss of peripheral
nerve fibers caused by decreased blood flow and high glycemic levels.42,43 The duration and intensity of hyperglycemia strongly influences the severity of the neuropathy.42
Neuropathy leads to an insensate and sometimes deformed
foot, often with an abnormal walking pattern. In people
with neuropathy, minor trauma (ill-fitting shoes, walking
barefoot, or an acute injury) can precipitate a chronic ulcer.

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Andrews et al.

Figure 1. (a) Dislocation of the second toe at the MTP joint and (b) standing view showing prominence of the dislocated second
MTP joint.
MTP: metatarsal phalangeal.

Figure 2. Chronic nonhealing wound overlying prominent

second metatarsal head following debridement (patients X-rays
shown in Figure 1(a) and (b)).

Diabetes may cause stiffening of capsular structures

and ligaments. Decreased ankle, subtalar, and first metatarsal phalangeal (MTP) joint mobility results in
higher focal plantar pressures with increased risk of
ulceration. Loss of sensation, foot deformities (Figure
1(a) and (b)), and limited joint mobility can result in
abnormal biomechanical loading of the foot.16 Whatever
the primary cause, whenever patients continue walking
on the insensate foot, subsequent healing is impaired
(Figure 2).

Imaging
Plain radiographs help identify foreign bodies, bone
deformities, gas in the tissues, or evidence of osteomyelitis. Plain films lack sensitivity for detecting early osteomyelitis, especially in the presence of osteopenia associated

with neuropathy, since 30%50% of bone loss is required

to produce detectable changes.44 It is helpful if radiographic findings are positive, but if these are negative, it
does not exclude the diagnosis of osteomyelitis. Despite
the poor predictive value of a normal radiograph, it is recommended that a plain radiograph be taken in all patients
presenting with foot ulcers.45 Plain films should be
repeated in 23 weeks as radiographic changes of osteomyelitis may be delayed.
Indium plus bone scan and magnetic resonance imaging
(MRI) are used when the diagnosis is equivocal to help
gauge the extent of bone and soft tissue infection. An MRI
might be needed to better define the presence of bone or
deep soft tissue infection.46,47
MRI scans have the advantage over radionucleotide
bone scans of being able to accurately define the anatomic
location and extent of inflammatory changes or any soft
tissue infection in the foot, including sinus tracts, deep tissue necrosis, or abscesses. A meta-analysis comparing the
performance of MRI scans to bone pathology for the diagnosis of osteomyelitis showed a sensitivity of 90% and
specificity of 79%.48 The lower specificity in diabetes is
usually attributable to the difficulty of distinguishing
osteomyelitis from other causes of bone edema, in particular Charcot-neuroarthropathy.49

Antimicrobial therapy
All open wounds are colonized with microorganisms. The
generally accepted clinical definition of infection is the
presence of purulent secretions or at least two signs or
symptoms of inflammation (erythema, warmth, tenderness, pain, and induration).50 Patients with chronic ulcers
or those who have recently received antibiotic treatment
often have a polymicrobial infection with aerobic gramnegative bacilli and gram-positive cocci.51

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Prosthetics and Orthotics International 39(1)

Figure 3. (a) Chronic fracture deformities of the proximal right second through fourth metatarsals. Ununited fracture of the
proximal right fifth metatarsal with overlying wound. (b) Neuropathic wound right lateral midfoot overlying ununited fracture of the
proximal right fifth metatarsal (Figure 3(a)). Note: Periulcer callus; undermining; pale, flat tissue in the wound base; slough around
the edge of the wound. (c) Right foot 6 weeks following fifth ray amputation despite casting and instructions to offload the foot. The
patient ultimately required a transtibial amputation 7 months later.

The aim of antimicrobial therapy is to cure the infection, not to heal the wound. Extended antibiotic treatment
increases the risk of antibiotic resistance and drug-related
toxic effects. Antibiotic treatment without offloading a
plantar wound is unlikely to result in ulcer healing. There
is no role for routine suppressive antibiotics. Antibiotics
should not be used unless a wound infection is present.

It is important to review the pros and cons of each

approach with patients on an individual basis.52
Retrospective studies suggest that long-term treatment (at
least 46 weeks) with drugs that penetrate well into bone
(fluoroquinolones) can produce a remission of infection.54

Osteomyelitis

Risk factor identification is fundamental for effective preventative management of the diabetic foot. Hospital-based
studies have shown that mortality rates in individuals with
diabetic foot ulcers are about twice those observed in individuals with diabetes without foot ulcers.57 Nearly all
patients with lower limb ulcers can benefit from evidencebased therapy aimed at reducing the risk of atherosclerotic
vascular disease. Consistently using evidence-based
wound risk assessment coupled with standardized wound
interventions may result in fewer wounds and improved
therapeutic outcomes. Unfortunately, the quality of the
evidence is low. The Cochrane reviews have attempted to
answer many treatment questions with meta-analysis and
systematic evaluation of the literature. These reviews indicate that even when combining these small studies, the
results do not provide solid conclusions regarding the efficacy of current wound treatment options. Clinicians rely
on consensus views and personal experience to guide
wound treatment options. Most randomized control trials
(RCTs) evaluate one specific intervention (often topical),
resulting in many common practices being untested or
assumed. In many wound care RCTs, the authors report
results from a small number of total subjects (often less
than 100) with limited duration of subsequent
follow-up.58,59
Adequate nutrition supports wound healing. Decreased
serum albumin is associated with poor wound healing and

Approaches to the management of osteomyelitis in diabetic foot ulcers vary widely from center to center and
country to country. At present, there are a few studies with
robust data to guide clinicians in the choice, duration, or
route of antimicrobial therapy.52,53 Osteomyelitis is probably present if the bone is visible or palpable by probing.
Other clinical clues to the presence of osteomyelitis
include general malaise, local pain, worsening diabetic
control, abnormal friable exuberant granulation tissue in
the wound, and laboratory findings of an elevated sedimentation rate or C-reactive protein.
Although there is no clear consensus as to whether
management should be primarily medical (antibiotics)
or surgical,52 when possible, bone infection is best
treated by surgical resection of the infected and necrotic
bone.54,55 A potential complication of surgical management is altered foot architecture. Careful offloading is
important in the perioperative period to avoid skin
breakdown at a new high-pressure site (Figure 3(a)(c)).
The highest risk of recurrent ulceration occurs after surgery to the first metatarsal head (28%), and the lowest
risk occurs to the fifth metatarsal head (8%).56 Surgical
management allows shorter duration of antibiotic treatment and reduces the likelihood of bacterial resistance
to antibiotics.

Risk factor modification

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Andrews et al.
poor clinical outcomes.60 Serum pre-albumin provides a
more sensitive indicator of protein status in acute stages of
malnutrition and helps evaluate the adequacy of nutritional
therapy.61 Clinically, significant malnutrition is defined as
a pre-albumin of less than 15 mg/dL or a decrease in ones
total body weight by more than 5% experienced within 1
month. If a patient develops malnutrition, they should eat
protein in the amount of 1.21.5 gm/kg of body weight
every day.62
All individuals with diabetes should have a thorough
foot examination at least once per year to identify highrisk foot conditions. This examination should assess protective sensation, foot structure and biomechanics, vascular
status, and skin integrity. Clinicians should perform a comprehensive physical examination on all patients with
ulcers, giving particular attention to the wound characteristics, vascular status, and overall health of the patient. The
wound site should be evaluated on every visit, noting
wound size and characteristics.63 Assessing the wound
margins (callous, undermining) provides clues about
offloading.
Patients at risk should understand the implications of
loss of protective sensation, the importance of foot monitoring on a daily basis, the importance of proper care of the
foot (nail and skin care), and the importance of always
wearing protective footwear. Patients with evidence of
increased plantar pressure (erythema, warmth, callus, or
measured pressure) should use footwear that provides soft
tissue supplementation and redistributes pressure. Patients
with neuropathy should be advised to break in shoes gradually to minimize the formation of blisters and ulcers.

healing for many months or years typically heal in about 6

weeks in a total contact cast.66

Debridement and biofilm disruption

Wound debridement helps to correct cellular and molecular abnormalities. The fundamental goal of basic wound
care involves keeping the wound base free of nonviable
tissue to facilitate wound healing. More recently, the treatment of diabetic foot ulcerations has focused on biofilm
reduction.67 Biofilm is defined as bacterial and/or fungal
colonies populating the surface of wounds that are highly
resistant to antibiotic treatment.68,69 Biofilm formation is a
multistage process in which microbial cells adhere to the
surface (initially reversible attachment). The subsequent
production of an extracellular matrix containing polysaccharides, proteins, and DNA results in a firmer attachment.70 Biofilm has been identified in up to 60% of chronic
wounds (greater than 30 days) versus 6% of acute
wounds.71 Biofilm reduction, eradication, and inhibition
are essential considerations in the treatment of chronic diabetic foot wounds.67
Debridement is not the only method of biofilm disruption. The use of low-frequency ultrasound has been beneficial. Ultrasound therapy is typically painless. It requires
multiple treatments (up to five times per week) for 46
weeks. Although direct measure of biofilm disruption has
not been fully elucidated utilizing ultrasound technology,
biofilm disruption may contribute to the reported increase
in healing of chronic wounds.72

Topical therapies

Thermography
The use of temperature is a quantifiable, reproducible
measurement of inflammation. One study evaluated the
effectiveness of at-home infrared temperature monitoring
as a preventative tool in patients with diabetes at high risk
of lower extremity ulceration or amputation. The study
group patients had temperatures measured in the morning
and evening, were instructed to reduce their activity, and
contact the study nurse when temperatures increased. This
group had significantly fewer foot complications owing to
their early warning of inflammation and tissue injury.64

Offloading
The treatment of diabetic foot ulcers includes pressure
relief (offloading) by limiting walking, wearing special
footwear, or both.
Patients should be counseled never to walk in shoes that
contributed to a foot ulcer.65 The most compelling evidence that offloading accelerates ulcer healing comes from
studies using total contact casting for healing of noninfected neuropathic ulcers. Neuropathic ulcers that resisted

Dressings play an adjunctive role in the treatment of diabetic wounds; however, this role can be limited, and dressings should never be considered the sole treatment
modality. Clinicians typically use three types of dressings:
hydrating; debriding; and antimicrobial (Table 1).
Clinicians should always consider cost when choosing
wound care products. Wound characteristics such as location, size, depth, and presence of drainage may influence
the topical agent chosen.
Topical antimicrobials (ointments, creams, and gels)
have long been utilized for the treatment of wounds.
Despite their widespread use, there is a paucity of evidence
to support the use of topical therapies for diabetic foot
ulcers.73 Topical antiseptics can impair wound healing.
Dressings containing silver or iodine appear to be safe and
possibly useful.74

Cellular and/or tissue-based products

Cellular and/or tissue-based products (CTP) include a
number of products derived from human, animal, and
synthetic tissues that have been manufactured, cleaned,

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Protection from friction

Transparent films

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Cellular and/or
tissue-based products

Inhibit or kill microbes in

chronic wounds without the
use of antibiotics

Antimicrobial
dressings
Worsening infection;
hypersensitivity/reaction to
the antimicrobial product

Cellulitis; systemic infection;

photophobia

Poor skin integrity; infected

ulcers; deep/tunneling
wounds

Dry, minimally draining, or

superficial wounds

Exudative wounds; bacterial

or fungal skin infections

Can be costly

If cut, fibers can be retained

in wound bed

Disadvantages

Expensive; best applied

by a skilled clinician; may
not be covered by certain
commercial insurance
carriers; most products must
be applied every 12 weeks

Will not eradicate a wound

infection; alternative
treatment may need to be
used

Requires secondary dressing;

not occlusive; macerates
periwound margins; not
efficacious in highly exudative
or infected wounds
Better able to visualize the
Can cause further skin
wound; stays in place
damage if removed
incorrectly; nonpermeable
Maintains moist wound
Can dehydrate a drier wound;
environment; nonadherent; can needs a secondary dressing;
be used on infected wounds
ineffective for dry eschar
Malleable; insulates
Cannot be used on highly
wound; provides moist
exudative wounds, over
wound environment;
sinus tracks, exposed bone/
autolytically debrides; surface tendon, fragile periwound
impermeable to bacteria; no
tissue or on infected wounds;
secondary dressing required; macerates healthy skin
less frequent dressing changes
Has antibacterial, antifungal,
May cause silver staining on
and antiviral properties;
the skin
improves wound hygiene

Low cost; readily available;

fills dead space; retains
moisture; absorbs exudate;
mechanically debrides
Maintains wound moisture;
absorbs some wound
exudate; insulates wounds
Improves wound hydration;
easily removed; facilitates
debridement; fills dead space

Advantages

Easy to use; readily

available; less costly than
antibiotics; available without
a prescription; less risk
of resistance; effective at
reducing wound bioburden
Provide a temporary biologic Infected wounds; significant
Provide wound coverage to
barrier to augment wound
drainage; osteomyelitis;
complete wound closure;
healing by stimulating the
cellulitis; tunneling, or eschar reduce healing time and pain;
recipients own skin cells;
that prevents graft adherence improve appearance and
Wounds that do not respond
functional abilities; improve
to previous conservative
overall quality of life; less
wound treatment
invasive than skin grafting

Malodorous, highly
exudative, slow-healing
wounds; increased wound
bioburden

Silver dressings

Hydrocolloids

Absorb excessive drainage;

fill dead space; autolytic
debridement
Semi-permeable dressing for
low to moderate exudate;
autolytic debridement

Wound hydration

Hydrogels

Alginates

Low- to moderately
exudative wounds

Foam

Excessive wound drainage;

dry wound base; eschar;
deep or tunneling wound
Wound maceration;
excessive drainage

Deep wounds, especially with Can traumatize certain

tunneling and undermining
wounds

Gauze

Contraindications

Indications

Dressing

Table 1. Common wound dressings.

Used for diabetic foot or

venous stasis ulcers that have
failed to heal after 6 weeks
of standard wound care;
documentation must confirm
Type I or Type II diabetes
mellitus

Less frequent dressing

changes; variety of
formulations makes it
a versatile dressing for
different wound situations
Antimicrobial dressings
should be continued until the
wound improves

Keep dressing within wound

borders; requires secondary
dressing
Can be used to frame a
wound to secure dressing;
can apply over alginate to
control drainage

May use skin prep to protect

skin from adhesive

Stays moist longer than

saline; reduces adherence of
gauze to wound bed; must
control for maceration

Needs to be remoistened
often to maintain a moist
wound environment

Comments

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Andrews et al.
or otherwise altered. CTP products are typically indicated when split thickness skin graft, local or free tissue
flaps, or primary closures are not feasible options. These
products work to awaken and activate senescent cells in
the chronic diabetic wound. Some CTP products contain
viable cells including fibroblast and keratinocytes which
are delivered to the nonhealing wound site (Apligraf
and Dermagraft (Organogenesis, Canton, MA, USA)).
In contrast, other CTP products provide an organized
scaffold to facilitate cell migration (Integra (Integra
Life Sciences, Plainsboro, NJ, USA) and MatriStem
(ACell, Columbia, MD, USA)). These products provide
the durable dermal layer necessary for granulation tissue
formation.
Prior to applying a CTP product, it is important that the
wound bed and local perfusion are optimized. Although
CTP products can be applied repeatedly until complete
epithelialization occurs, complete epithelialization is not
always the goal of this therapy. The relatively high cost of
these products may prohibit this approach. Close monitoring of wound quality and size is essential.

Regenerative medicine
With an estimated annual cost of over US$20 billion, there
is a critical need to develop novel treatments to improve
healing of chronic nonhealing cutaneous wound, in particular diabetic foot ulcers.75 There have been encouraging
results in preclinical models of diabetic wound healing.
The plasticity of bone marrow-derived mesenchymal stem
cells (MSCs) is well established, differentiating various
cells including skin cells, specifically keratinocytes.7678
The addition and incorporation of stem cells into wounds,
particularly if they are capable of differentiating into a
number of cell types, is promising. Similarly, MSCs have
been shown to suppress the local immune response, reduce
inflammation, and stimulate the differentiation and proliferation of local progenitor cells through the secretion of
growth factors and their ability to modulate the immune
system of the local soft-tissue.75,7981 Stem cells are thought
to modulate all the phases of wound healing, allowing for
a wound to progress from the initial inflammatory state,
and preventing them from becoming a chronic wound.
MSCs have been shown to reduce inflammation by
decreasing the amount of TNF- and interferon-, both
proinflammatory cytokines, helping to regulate the bodys
response to injury.82 Along with reducing inflammation,
MSCs have also been shown to have an antimicrobial
effect.83,84 They are able to do this through the secretion of
antimicrobial factors and by upregulating the phagocytosis
and bacteriocidal effect of immune cells.83,84
It is thought that one of the greatest actions of MSCs in
ameliorating chronic wounds is through their paracrine
effects. Although studies have shown MSCs are capable
of differentiating into keratinocytes, the secretion of

various growth factors, including vascular endothelial

growth factor (VEGF), stromal cell-derived factors
(SDF), platelet-derived growth factor (PDGF), fibroblast
growth factor (FGF), and keratinocyte growth factor
(KGF), allows MSCs to modulate the local tissue environment to increase the survival and proliferation of
local repair cells.8587 The addition of MSCs to fibroblasts has been shown to accelerate wound closure and
increase the proliferation of keratinocytes, endothelial
cells, and dermal fibroblasts.85,87,88
Preclinical models of diabetic wound healing MSCs
have resulted in new granulation tissue formation,
increased blood vessel formation and cellularity,8992 and
increased wound closure. In the treatment of chronic
wounds, including diabetic foot ulcers, MSCs have been
shown to be beneficial.93 Animal studies have shown that
when MSCs are injected into the wounds of chronic
wound model mice, there is an increased rate of wound
closure, reepithelialization, and angiogenesis.94 Small
clinical studies have also shown the effectiveness of
using MSCs in the treatment of chronic wounds.9597 In
one of the largest clinical studies examining the use of
MSCs for the treatment of chronic wounds, MSCs were
added to a dermal replacement in 20 patients and the
authors noted a 90% healing rate, with regeneration of
the native tissue.97
There is accumulating evidence to confirm the efficacy
of stem cells in the treatment of critical limb ischemia.98
Stimulation of angiogenesis and arteriogenesis represents
attractive approaches to the diabetic foot ulcer.
Angiogenesis is essential for wound healing, and multiple
studies have demonstrated the proangiogenic nature of
MSCs and their ability to secrete PDGF, VEGF, and
EGF.90,99,100 A large level I RCT using bone marrowderived MSCs in wounds of the limbs was published by
Dash et al.101 This trial showed that MSC therapy significantly reduced wound size and increased several clinical
parameters when compared with controls. A study in China
demonstrated improved ulcer healing rates with bone marrow mesenchymal stem cells (BMMSC).102
An interdisciplinary approach involving scientists,
biologists, and wound care providers will be important to
develop novel therapies for tissue regeneration and treatment of complex wounds. Hopefully cell-based therapy
will augment angiogenesis, optimize healing, and avoid
amputation.

Hyperbaric oxygen
Hyperbaric oxygenation (HBO) has been proposed as an
adjunctive treatment for diabetic foot ulcers.103105 A recent
review provides evidence that HBO therapy in patients
with diabetic ulcers decreases the overall risk of amputation, especially major amputation, when compared to therapy without HBO (13.63% vs 30.07%).103

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Prosthetics and Orthotics International 39(1)

Reported benefits of hyperbaric oxygen therapy

(HBOT) include detrimental effect on bacteria via the production of oxygen free radicals and enhanced leukocyte
activity.106 Chen et al.107 reported increased limb salvage
rates (78.3%) for infected diabetic wounds with greater
than 10 HBOT treatments. A meta-analysis found no statistically significant difference in major amputation rate
with adjunctive HBOT (pooled data of five trials with 312
patients).108

Prevention of ulcer recurrence

An adequate care plan must ensure offloading and sufficient arterial blood flow as prerequisites for healing. After
the ulcer heals, the patient and their caregivers must incorporate preventative measures in care plans to reduce the
risk of wound reoccurrence. Prevention of ulcer recurrence
is a major clinical challenge, with recurrence rates ranging
from 28% at 12 months to 100% at 40 months.109
A newly healed ulcer is covered with fragile skin; after
complete healing, there is an area of higher density tissue
(scar), and sheering between the different tissue densities
often contributes to new ulcers. The highest incident of
reulceration is in the site of a previous ulceration.
A major goal of preventative treatment is the removal
and prevention of calluses. Removal of plantar calluses
can reduce peak plantar pressure by 26%.110 In addition,
removal of callus can help decrease forces at the site of the
wound.

Conclusion
Advances in treating chronic diabetic wounds are promising; however, the intrinsic pathophysiologic abnormalities that lead to ulcers in the first place cannot be ignored.
No known therapy will be effective without concomitant
management of ischemia, infection, and adequate
offloading.
Not all diabetic foot complications can be prevented,
but it is possible to dramatically reduce their incidence
through appropriate management and prevention programs. The multidisciplinary team approach to diabetic
foot disorders has been demonstrated as the optimal
method to achieve favorable rates of limb salvage in the
high-risk diabetic patient.
Author contribution
All authors contributed equally in the preparation of this
manuscript.

Conflict of interest
No disclosures of funding were received for this work from NIH,
Wellcome Trust, or HHMI. No conflicts of interest are declared
by any author on this study.

Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.

References
1. Brem H and Tomic-Canic M. Cellular and molecular basis
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