Ther Adv Endocrinol
(2011) 2(6) 247 –255
© The Author(s), 2011.
Reprints and permission:
Therapeutic Advances in Endocrinology and Metabolism Original Research
The diabetic foot syndrome (DF) is a major
disabling complication with an estimated life-
time incidence of up to 25% in patients with dia-
betes mellitus [Singh et al. 2005] and peripheral
arterial disease (PAD) is one of the most com-
mon comorbidities in DF. However, despite the
frequency and importance of these pathological
conditions, clear epidemiological data with
respect to the combination of DF with critical
limb ischemia (CLI) are scarce. For example, in
the EURODIALE study [Prompers et al. 2007],
which included 1229 patients with diabetic
foot ulcers, 49% of the patients also had
PAD. However, this proportion is apparently
underestimated, as 32% of the subjects had an
ankle-brachial index (ABI) of >1.2, indicating
mediasclerosis. Therefore, we can assume a prev-
alence of >80% of PAD in DF. Moreover, in this
study, the proportion of patients with DF and
CLI with an ABI of <0.5 was 12%. In another
study from Milan [Faglia et al. 2009], data were
presented with respect to the long-term progno-
sis of patients with DF and CLI, in which 554
patients with this combination were observed
over a mean of 6 years. Peripheral angioplasty
was performed in 74% and vascular surgical
interventions in 21% of this selected group of
patients with DF and CLI. A negative option for
revascularization was given in only 5% of the
patients. These subjects were treated with pros-
tanoids (60–120 µg/day alprostadil) over 5 days
after arteriography. The initial major amputation
(MA) rate (‘early period’, within 30 days after
intervention) in this study was only 4.1%, corre-
sponding exactly to the early MA rate of our
interdisciplinary diabetic foot unit, based on 754
patients with different stages of DF [Weck et al.
2010]. During their follow up, the researchers
reported MA in 13% of all subjects, 8% in the
Noninvasive management of the diabetic foot
with critical limb ischemia: current options
and future perspectives
Mathias Weck, Torsten Slesaczeck, Hannes Rietzsch, Dirk Münch, Thomas Nanning,
Hartmut Paetzold, Hans-Joachim Florek, Andreas Barthel, Norbert Weiss and Stefan Bornstein
Abstract: Foot ulcers are a major complication in patients with diabetes mellitus and involve
dramatic restrictions to quality of life and also lead to enormous socio-economical loss due
to the high amputation rate. The poor and slow wound healing is often aggravated by the
frequent comorbidity of foot ulcers with peripheral arterial disease, making the treatment of
this condition even more complicated. While the local treatment of foot ulcers is mainly based
on mechanical relief and prevention or treatment of infection, improving perfusion of the
impaired tissue remains the major challenge in peripheral arterial disease. While focal arterial
stenosis is the domain of interventional angioplasty or vascular surgery, patients with critical
limb ischemia and lacking options for revascularization have a much worse prognosis, because
current treatment options avoiding amputation are scarce. However, based on recent research
efforts, there is rising hope for promising and more-effective therapeutic approaches for these
patients. Here, we discuss the current improvements of established therapies aimed at an
improvement of limb perfusion, as well as the development of novel cutting-edge therapies
based on stem-cell technology. The experiences of a ‘high-volume center’ for treatment of
diabetic foot syndrome with a current major amputation rate of 4% are discussed.
Keywords: autologous bone marrow transplantation, critical limb ischemia, diabetic foot,
prostaglandins, therapy, urokinase
Matthias Weck, MD
Medizinische Klinik III,
Bürgerstraße 7 01705
Torsten Slesaczeck, MD
Medizinische Klinik III,
Hannes Rietzsch, MD,
Norbert Weiss, MD,
Stefan Bornstein, MD
Medizinische Klinik und
Poliklinik III, Technische
Gustav Carus, Dresden,
Dirk Münch, MD,
Thomas Nanning, MD
Medizinische Klinik II,
Hartmut Paetzold, MD,
Hans-Joachim Florek, MD
Klinik für Gefäßchirurgie,
Andreas Barthel, MD
Medizinische Klinik und
Poliklinik III, Technische
Carl Gustav Carus,
Dresden, Germany and
427721 TAE262042018811427721M WeckTherapeutic Advances in Endocrinology and Metabolism
Therapeutic Advances in Endocrinology and Metabolism 2 (6)
group treated with angioplasty (percutaneous
transluminal angioplasty [PTA]), 21% in the
vascular surgery group and 59% in the group
without options for revascularization. In 40% of
the subjects, they found CLI of the contralateral
leg [Faglia et al. 2009]. This finding empha-
sizes the importance of a detailed angiological
examination of both legs.
Patients with a history of diabetic foot ulcers
alone already have high mortality rates, mainly
due to cardiovascular events but also other causes
such as cancer [Iversen et al. 2009]. However,
CLI further significantly increases the mortality
risk [Faglia et al. 2009]. On the other hand,
treatment options for this group of patients are
still very limited, demonstrating the imperative
need to develop novel therapeutic strategies.
Based on the current literature and our experi-
ence, we summarize the noninvasive treatment
options currently available for this highly morbid
group of patients with DF and CLI and draw
Therapeutic strategies in CLI without
options for revascularization
In subjects with DF, the accompanying PAD,
particularly of the lower leg arteries is apparently
the major risk factor for MA. Revascularization
appears to be possible in the large majority of
cases if these patients are referred in time to an
interdisciplinary organized center offering highly
skilled experience, not only in diabetology, but
also interventional angiology and vascular surgery
[Faglia et al. 2006, 2009; Sumpio et al. 2010]. In
these specialized units, a dramatic improvement
of healing rates and reduction of the frequency of
MA can be accomplished.
Endovascular treatment is mostly recommended
because the risk of infection is lower; subjects
with DF are older and have multiple comor-
bidities, representing additional risk factors for
vascular surgery [Zeller, 2007; Zeller et al. 2009;
Alexandrescu et al. 2009]. A clinical algorithm for
the diagnosis and treatment of DF with PAD is
illustrated in Figure 1. In patients with DF and
CLI without options for revascularization, further
therapeutic approaches must be considered in
order to avoid MA, although none of these nonin-
vasive strategies have been validated in rand-
omized clinical trials so far. This includes methods
aiming at an improvement of limb perfusion,
for example, prostaglandin treatment, low-dose
urokinase therapy and autologous bone marrow
transplantation into the affected limb.
Although the treatment of CLI with prostaglan-
dins is not a new option, this class of drugs needs
to be discussed here briefly, especially in the con-
text of other therapeutic strategies.
The impact of prostaglandins in the treatment
of PAD is still discussed in a controversial light
[Lawall et al. 2009a, 2009b; Amendt, 2005;
Norgren et al. 2007]. There is some evidence that
prostaglandin treatment improves claudication
and some evidence exists with respect to improve-
ment of walking capacity and quality of life
[Amendt, 2005]. Summarizing the literature, one
can assume an improvement of wound healing,
reduction of pain and a reduction of MAs in
~50% of subjects with CLI and lacking options
for revascularization after local infusion of prosta-
glandins. Prostaglandins are administered intra-
arterially or intra-venously for 3–4 or 7–28 days.
Prostaglandin E1 (PGE1) is commonly applied
with doses of 40 µg bid over 2–4 hours. The
majority of the current guidelines recommend
this procedure, but the intersociety consensus
for the management of PAD (TASC II) does not
[Norgren et al. 2007].
Short-term studies in subjects with CLI had no
clear results. In particular, there was no ulcer
healing or pain reduction in the majority of these
studies. In contrast to short-term studies [Belch
et al. 1983; Cronenwett et al. 1986; Schuler et al.
1984; Telles et al. 1984], the majority of long-term
studies in patients with CLI demonstrated a clear
reduction of pain and ulcer size, and some of
these studies indicate a reduced need for MA
[Norgen et al. 1990; Stiegler et al. 1992; ICAI
Study Group, 1999; UK Severe Limb Ischaemia
Study Group, 1991; Trübestein et al. 1987;
Duthois et al. 2003; Loosemore et al. 1994;
Altstaedt et al. 1993]. It should be noted that
these studies are older investigations with some
methodological problems and should be consid-
ered with caution.
A more recent meta-analysis of the administra-
tion of PGE1 for patients with PAD stage III or
IV not eligible for arterial reconstruction shows
that it not only has significant beneficial effects
over placebo on ulcer healing and pain relief, but
also increases the rate of patients surviving with
M Weck et al.
both legs after 6-months follow up [Creutzig et al.
2004]. Despite this positive statement, the com-
bined endpoint ‘MA and death after 6-month
follow up’ seems to be very high, at 22.6%.
However, in TASC II it is concluded that the cur-
rent data do not provide evidence for a significant
benefit of prostaglandins in CLI with respect to
amputation-free survival, whereas all other scien-
tific associations recommend the use of prosta-
glandins in CLI if revascularization is not possible
[Lawall et al. 2009a; Hirsch et al. 2006; Ryden
et al. 2007]. In the guidelines for the diagnosis
and treatment of PAD from the German Society
of Angiology and Vascular Surgery, the follow-
ing recommendation is given: ‘In consideration of
the meta-analysis about clinical efficiency of pros-
tanoides, the recommendation of administration
of prostanoids is given with level of evidence A.
This conclusion is based, (apart from the out-
come of the meta-analysis), on the assessment of
predominantly older studies and concordant
experiences of the authors (of this guideline)’
[Lawall et al. 2009b]. Special recommendations
of administration of prostaglandins on patients
with DF and CLI do not exist.
Hyperfibrinogenemia with the resulting increase
in plasma viscosity and erythrocyte aggregation
has been demonstrated in patients with coronary
heart disease and PAD [Leschke et al. 1986, 1997;
Peters et al. 1999; Partsch and Jochmann, 1993;
Weck et al. 2008; Rietzsch et al. 2008]. The increase
in plasma viscosity, in particular, can be a flow-
limiting factor and a critical determinant of oxy-
gen supply in the poststenotic microcirculation of
myocardium and diabetic foot. It has been shown
that urokinase is effective in improving the micro-
circulation in patients with coronary heart disease
[Peters et al. 1999; Leschke et al. 1996, 2003;
Figure 1. Clinical algorithm illustrating the currently available treatment options for patients with the diabetic
foot syndrome in combination with peripheral artery disease. PTA, percutaneous transluminal angioplasty,
diabetic osteoarthropathy (DOAP) [Weck et al. 2006, reproduced with permission from UNI MED].
Therapeutic Advances in Endocrinology and Metabolism 2 (6)
Leschke, 2008]. Plasma fibrinogen, plasma vis-
cosity and red blood cell aggregation were reduced
significantly in these studies. In another study,
low-dose urokinase was used to treat subjects
with nonhealing leg ulcers. The authors reported
a significant improvement of microcirculation
measured by an increase of laser-Doppler indices,
increase of tcpO2 and a significant decrease of
plasma viscosity and plasma fibrinogen [Partsch
and Jochmann, 1993].
In addition, it has been shown that urokinase is
effective in improving the microcirculation in dia-
betic patients with PAD stages III and IV accord-
ing to Fontaine (CLI) or Rutherford stages 4–6
[Leschke et al. 1997; Weck et al. 2001, 2008;
Hicken et al. 1995]. These preliminary data pro-
vide some evidence that diabetic patients appar-
ently benefit more from rheologic treatment of
PAD than nondiabetic patients. However, studies
on the effect of intravenous urokinase treatment
in patients with CLI and diabetic foot lesions are
mostly retrospective in small patient cohorts.
Therefore, we performed an open, prospective,
noncontrolled, multicenter cohort study in 77
type 2 diabetic patients with CLI and diabetic
foot ulceration [Weck et al. 2008]. Patients had no
surgical or endovascular treatment option based
on interdisciplinary consensus. Urokinase (1 IU if
plasma fibrinogen ≥2.5 g/l; 0.5 IU if fibrinogen
<2.5 g/l) was administered for 21 days as an intra-
venous infusion over 30 minutes. After 12 months,
33% of the surviving patients showed completely
healed ulcers without having MA (Figure 2). The
total survival rate was 85%, amputation-free sur-
vival 69% and the rate of MA was 21%. Within
the course of the study, 82% of patients experi-
enced ulcer healing at least once. It should be
noted that the mortality rate and also the rate of
MA in this study was surprisingly low as com-
pared with the literature and 33% of the patients
in this study even met the ultimate treatment
goal of freedom from amputation and residual
ulcers for at least 1 year. Although this study was
not controlled, randomized or blinded, it estab-
lishes a solid basis for the use of urokinase in this
special patient population. The specific reasons
for the low event rates in this study can be specu-
lated upon. For example, high levels of fibrinogen
have been associated with an increased cardio-
vascular risk and fibrinogen is known to rise as
an acute-phase protein in the acutely infected
diabetic foot. Alternatively, the effect of uroki-
nase therapy has been attributed to a decrease
in fibrinogen concentration with a subsequent
improvement of microcirculation [Leschke et al.
1996, 1997, 2003; Leschke, 2008]. In another
observational study, the heparin-induced extra-
corporeal LDL-precipitation (HELP) was used
as an alternative therapeutic approach in subjects
with diabetic foot, CLI and sepsis [Rietzsch et al.
2008]. The risk of limb loss in these patients was
extreme. HELP reduced the fibrinogen levels by
68%. Only 3 of 17 patients underwent MA, thus,
the HELP approach seems to be a proof of prin-
ciple for fibrinogen-lowering therapy.
Urokinase treatment in diabetic patients with
chronic foot lesions and CLI appears to be feasi-
ble, safe and effective. Based on our promising
clinical experience with low-dose urokinase in
the treatment of DF with chronic, nonhealing
ulcers and CLI without options for revasculariza-
tion, we have extended the application of uroki-
nase to the perioperative treatment of borderline
amputations in some cases. With this strategy,
we have seen an improvement in wound healing
in some subjects with fatal distal vascularization.
It should be noted that these are observational
data. Nevertheless, urokinase treatment in these
patients appears a reasonable option in order to
avoid MA. The data and theoretical considera-
tions on low-dose urokinase treatment in subjects
with diabetic foot presented here should be
treated with caution and considered as a strong
endorsement for the implementation of a pro-
spective randomized controlled study, which is
3 month6 month9 month12 month
Percentage of’ patients (95%CI)
Figure 2. Ulcer healing rates in patients with diabetic
foot ulcers and critical limb injury after short time
urokinase treatment. The patients were monitored up
to 12 months after treatment. Data were obtained in an
open, prospective, noncontrolled multicenter cohort
study in 77 patients with type 2 diabetes [Weck et al. 2008,
reproduced with permission from Thromb Haemost].
M Weck et al.
Autologous bone marrow transplantation
A large body of experimental evidence in mice,
rats and larger animals has demonstrated the
feasibility and efficacy of stem cell therapies
in restoring blood flow to the critical ischemic
limb. These studies demonstrated that the
number of circulating endothelial precursor cells
(EPCs) increases in response to ischemia
[Shintani et al. 2001; Takahashi et al. 1999] and
that EPCs can be found incorporated into capil-
laries and interstitial arteries [Shintani et al.
2001]. It is assumed that EPCs may act in a par-
acrine manner by secreting vascular growth fac-
tors and cytokines [Asahara et al. 1999; Kamihata
et al. 2001]. In 2000, Kalka and colleagues
demonstrated that intracardial application of
human EPCs in nude mice improved the periph-
eral circulation [Kalka et al. 2000]. Recently,
Turan and colleagues demonstrated that intrac-
oronary transplantation of autologous freshly iso-
lated bone marrow cells (BMCs) improved global
ejection fraction and infarct size significantly in
patients with ischemic heart disease after 3 and
12 months of transplantation [Turan et al. 2011].
These results formed the basis for the rapid
growth in studies with stem cells in patients with
PAD. The Therapeutic Angiogenesis using Cell
Transplantation (TACT) study in 2002 was the
first report on application of bone-marrow
derived mononuclear cells (BMMNCs) in the
treatment of patients with CLI [Tateishi-Yuyama
et al. 2002]. After 24 weeks, the ABI was improved
by 31% and the pain-free walking distance was
increased by 80% following intramuscular injec-
tion of BMMNCs. Of course, the early TACT
study has been criticized for its lack of credibil-
ity, in particular with regard to all vascular infor-
mation (angiogram, ABI, walking distance).
Nevertheless, these studies raised considerable
interest in stem cell and/or BMMNC therapy
in PAD [Fadini et al. 2010; Lawall et al. 2010].
It can be argued that the data were based on a
wide variety of different experimental approaches.
Furthermore, the degree of ischemia was hetero-
geneous in these studies and CLI was not gener-
ally present. However, despite these limitations a
meta-analysis demonstrated a consistent improve-
ment of perfusion (based on quantitation of ABI,
wound healing, walking capacity, tcpO2) through-
out most of the studies [Fadini et al. 2010].
In the majority of studies in humans, the intra-
muscular injection of BMMNCs into the gastroc-
nemius muscle along a symmetric grid with fixed
number of injections (20–60) was the preferred
mode of application [Miyamoto et al. 2004;
Prochaska et al. 2009; Van Tongeren et al. 2008].
The density of preformed capillaries and collater-
als is highest in close proximity to the axial arteries
and collateral growth preferably occurs in these
regions. Therefore, it is rational to place injections
along the occluded vessels of the lower leg, as per-
formed in the studies by Amann and colleagues
[Amann et al. 2008, 2009]. A schematic display of
the injections is shown in Figure 3. Formation and
extension of small collateral vessels appears to be
the most important physiological repair mecha-
nism in PAD [Unthank et al. 2004], presumably
due to the local production of growth factors
by BMMNCs. These collaterals can form direct
connections between the axial main vessels.
Nevertheless, the growth capacity of these col-
laterals is reduced in atherosclerosis and espe-
cially in diabetic macroangiopathy [Helisch and
Schaper, 2003]. In contrast to intramuscular
injection, intra-arterial application guides the
injected BMMNCs to the border zone of maxi-
mum ischemia [Yoshida et al. 2003]. In order to
optimize the therapeutic procedure, Bartsch and
colleagues conducted an ischemic precondi-
tioning of the affected leg by means of exercise
and combined this procedure with intra-arterial
and intramuscular administration of BMMNCs
[Bartsch et al. 2007]. Recently, Kolvenbach
and colleagues applied BMMNCs as adjuvant
treatment in patients with PAD and CLI during
bypass surgery and/or endovascular interventions
[Kolvenbach et al. 2010]. In addition, BMMNCs
have also been locally applied to restore angio-
genesis and promote wound healing in type 2
diabetic patients with neuro-ischemic wounds
[Humpert et al. 2005].
In the majority of studies, bone marrow is the pri-
mary source of stem cell material and enrichment
of mononuclear cells from the crude aspirate can
be accomplished with different techniques such as
density gradient centrifugation (Ficoll™) [Boyum
et al. 2002] or other commercially available
blood-centrifugation and plasmapheresis systems
[Tateishi-Yuyama et al. 2002]. However, these are
laborious and require the background of a special-
ized and certified hematological or immunological
unit. In contrast, bedside centrifugation systems
have been developed (e.g. Smart Prep®, Harvest
Technol ogies, USA) that can be easily used on the
ward. These systems yield sufficient amounts of
purified BMMNCs in a short time (~1 hour) and
are considerably cheaper than the other tech-
niques mentioned [Amann et al. 2008].
Therapeutic Advances in Endocrinology and Metabolism 2 (6)
Relating to the clinical outcome of BMMNC
therapy in PAD, two major studies with regard to
the number of treated patients and duration of
follow up should be mentioned. In the TACT fol-
low-up study, mortality and amputation-free sur-
vival were analyzed as primary endpoints [Matoba
et al. 2008]. The 3-year overall mortality was only
20% and after 3 years 60% of the patients were
free of amputation. The BONMOT pilot study
included 51 subjects with CLI and impending
risk for amputation. During 3.2 years of follow
up, limb salvage was 53%. The improvement of
the mean Rutherford category from 4.9 at base-
line to 3.3 after 6 months appears to be clinically
important [Amann et al. 2009].
Based on the combined efforts in basic together
with clinical research, the therapeutic arsenal for
the treatment of patients with diabetic foot ulcers
and CLI is growing constantly. The current devel-
opment of novel techniques and clinical protocols
including stem cell-based approaches gives realis-
tic hope for the future to substantially improve
the prognosis of this multi-morbid and critically
ill group of patients.
This work was supported by the BMBF (grant
number FKZ01GI0924 to the Paul Langerhans
Institute Dresden - DZD e.V.), DFG SFB 655
‘from cells to tissues’ and by the Centre for
Regenerative Therapy Dresden (CRTD) to SRB.
Conflict of interest statement
The authors declare no conflicts of interest in
preparing this article.
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