The management of neuropathic ulcers of the foot in diabetes by shock wave therapy.

Abstract

Diabetes is becoming one of the most common chronic diseases, and ulcers are its most serious complication. Beginning with neuropathy, the subsequent foot wounds frequently lead to lower extremity amputation, even in the absence of critical limb ischemia. In recent years, some researchers have studied external shock wave therapy (ESWT) as a new approach to soft tissue wound healing. The rationale of this study was to evaluate if ESWT is effective in the management of neuropathic diabetic foot ulcers.
We designed a randomized, prospective, controlled study in which we recruited 30 patients affected by neuropathic diabetic foot ulcers and then divided them into two groups based on different management strategies. One group was treated with standard care and shock wave therapy. The other group was treated with only standard care. The healing of the ulcers was evaluated over 20 weeks by the rate of re-epithelization.
After 20 weeks of treatment, 53.33% of the ESWT-treated patients had complete wound closure compared with 33.33% of the control patients, and the healing times were 60.8 and 82.2 days, respectively (p < 0.001). Significant differences in the index of the re-epithelization were observed between the two groups, with values of 2.97 mm2/die in the ESWT-group and 1.30 mm2/die in the control group (p < 0.001).
Therefore, ESWT may be a useful adjunct in the management of diabetic foot ulceration.

Full text

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BioMed Central
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BMC Musculoskeletal Disorders
Open Access
Research article
The management of neuropathic ulcers of the foot in diabetes by
shock wave therapy
Biagio Moretti1,3,5, Angela Notarnicola*1, Giulio Maggio2, Lorenzo Moretti1,
Michele Pascone2, Silvio Tafuri4 and Vittorio Patella1
Address: 1Department of Clinical Methodology and Surgical Techniques, Orthopedics Section, Faculty of Medicine and Surgery of University of
Bari, General Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy, 2Plastic Surgery Unit, Faculty of Medicine and Surgery of University of Bari,
General Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy, 3President of Course of Motor and Sports Sciences, Faculty of Medicine and Surgery
of University of Bari, General Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy, 4Hygiene Section, Department of Biomedical Sciences and
Human Oncology, Faculty of Medicine and Surgery of University of Bari, General Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy and 5SITOD,
Italian Society of Shock Waves Therapy, Naples, Italy
Email: Biagio Moretti - b.moretti@ortop2.uniba.it; Angela Notarnicola* - angelanotarnicola@yahoo.it; Giulio Maggio - giuliomaggio@libero.it;
Lorenzo Moretti - lorenzo.moretti@libero.it; Michele Pascone - m.pascone@dacti.uniba.it; Silvio Tafuri - silvio.tafuri@yahoo.it;
Vittorio Patella - v.patella@ortop2.uniba.it
* Corresponding author
Abstract
Background: Diabetes is becoming one of the most common chronic diseases, and ulcers are its
most serious complication. Beginning with neuropathy, the subsequent foot wounds frequently lead
to lower extremity amputation, even in the absence of critical limb ischemia. In recent years, some
researchers have studied external shock wave therapy (ESWT) as a new approach to soft tissue
wound healing. The rationale of this study was to evaluate if ESWT is effective in the management
of neuropathic diabetic foot ulcers.
Methods: We designed a randomized, prospective, controlled study in which we recruited 30
patients affected by neuropathic diabetic foot ulcers and then divided them into two groups based
on different management strategies. One group was treated with standard care and shock wave
therapy. The other group was treated with only standard care. The healing of the ulcers was
evaluated over 20 weeks by the rate of re-epithelization.
Results: After 20 weeks of treatment, 53.33% of the ESWT-treated patients had complete wound
closure compared with 33.33% of the control patients, and the healing times were 60.8 and 82.2
days, respectively (p < 0.001). Significant differences in the index of the re-epithelization were
observed between the two groups, with values of 2.97 mm2/die in the ESWT-group and 1.30 mm2/
die in the control group (p < 0.001).
Conclusion: Therefore, ESWT may be a useful adjunct in the management of diabetic foot
ulceration.
Trial registration: Current Controlled Trials ISRCTN21800909
Published: 27 May 2009
BMC Musculoskeletal Disorders 2009, 10:54doi:10.1186/1471-2474-10-54
Received: 12 October 2008
Accepted: 27 May 2009
This article is available from: http://www.biomedcentral.com/1471-2474/10/54
© 2009 Moretti et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Background
The rapid rise in the incidence of diabetes is an alarming
concern to health care professionals, largely because of
the serious associated complications. Recent data from
the Centers for Disease Control and Prevention approxi-
mate that 20.8 million people, roughly 7% of the United
States' population, have diabetes [1]. In 2005 alone, 1.5
million new cases of diabetes were diagnosed in people
aged 20 years or older [1]. Diabetes mellitus is a disease
known for its multifaceted complications, and foot ulcer-
ation, which often results in lower extremity amputations,
is one of the most common complications associated with
the disease [2-5]. The prevalence of foot ulcers ranges
from 4% to 10% among persons diagnosed with diabetes
[6]. This translates to an annual population-based inci-
dence of 1.0% to 4.1% and a lifetime incidence as high as
25% [6].
At least 15% of people with diabetes will eventually
develop a lower-extremity ulcer of some sort [7]. Foot
deformities and limited joint mobility impose excessive
pressure on the plantar portion of the foot. This limitation
in joint mobility is secondary to non-enzymatic glycosyla-
tion of the periarticular soft tissues, and it reduces the
foot's ability to accommodate for ambulatory ground
reactive force to increase plantar pressure [8-13]. This
excessive pressure, combined with the repetitive or con-
stant stress from daily ambulation along with neuropathy,
will ultimately lead to failure of the protective integument
and ulceration. Although the precise pathophysiological
mechanism underlying the development of diabetic foot
ulcerations is complex [13], it is generally associated with
the presence of peripheral neuropathy and repetitive
trauma due to normal walking activities which expose the
foot to moderate or high pressure and shear forces [14-
16]. Brand [17] theorized that a local inflammatory
response, focal tissue ischemia, tissue destruction and
ulceration may occur when these types of forces are
applied to a specific area over an extended period of time.
Ulceration sites correlate with the highest plantar pressure
points [18-22]. By definition, these ulcers present within
the context of arterial perfusion adequate for wound heal-
ing [23]. The current standard treatment for foot ulcers
consists of debridement, treatment of infection, pressure
relief and arterial revascularization, if required [24].
The main objective of the present study was to evaluate
the healing rates of diabetic foot ulcers during a 20-week
period in patients treated with ESWT (plus standard ther-
apy), compared with standard therapy consisting of deb-
ridement and Silvercell dressing.
Methods
This study is a randomized, prospected, controlled, clini-
cal trial. A total of 30 patients were recruited from the Dia-
betic Ambulatory of Endocrinology Unit of the University
of Bari (Italy) between October 1, 2006 and March 31,
2007. Study subjects were evaluated for a total of 20
weeks.
Inclusion criteria were neuropathic foot plantar ulceration
below the malleoli for a period of at least 6 months with
an area wider than 1 cm2, age 30–70 years, a diameter of
the lesion between 0.5 and 5 cm and type 1 diabetes mel-
litus with insulin treatment for at least 5 years prior.
Patients also should have had peripheral neuropathy, as
defined by insensitivity to a 10-g monofilament and by a
vibration perception threshold measured at the malleolus
of at least 25 volts [25]. The vascular assessment consisted
of an ankle-brachial index > 0.7 and palpation of the dor-
salis pedis and posterior tibial arteries. If one or both arte-
rial pulses were not palpable, the subject was excluded.
Exclusion criteria included patients with any of the fol-
lowing around the time of ESWT applications: peripheral
vascular disease, coronary bypass, pregnancy, coagulation
diseases or history of neoplasia or other conditions, based
on the principal investigator's clinical judgment.
The population was randomized into two groups that
received standard care consisting of therapeutic footwear,
debridement and dressing. In addition to the standard
therapy, the ESWT group also received three applications
of shock wave therapy.
The study protocol and informed consent were approved
by the Ethics Committee of the University of Medicine in
Bari (Italy). Usual clinical management for neuropathic
ulcers was used, that is a regular debridement to remove
surrounding callus and local would care by Silvercell
dressing for an average of 48–72 hours. Then, in the ESWT
group, the shock wave applicator head was placed over the
wound, utilizing ultrasonic gel and plastic draping to pre-
vent any cross-contamination of the device.
The treatment lasted just one or two minutes. The proto-
col consisted of a course of three sessions (every 72
hours), with 100 pulses per 1 cm2 of wound delivered at
each session at a flux density of 0.03 mJ/mm2 using a elec-
tromagnetic lithotripter (MINILITH SL1 by STORZ MED-
ICAL) with a cylindrical coil, parabolic focus and
ultrasound scanning. We aimed the device directly around
the perimeter of the ulcer. The most the patient may have
noticed was the sound of the ESWT machine as it gener-
ates the shock wave, so no local anesthetic was used dur-
ing treatment.
Patients in the control group were treated with the essen-
tials of foot ulcer care, namely debridement, adequate

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pressure relief and treatment of infection, as required by
current international guidelines [24].
Patients were permitted to ambulate as tolerated, and
each patient was provided with an orthopedic device to
remove mechanical stress and pressure at the site of the
ulcer during walking.
The ulcers were photographed by digital camera using the
macro function. The wound area and its following reduc-
tions were measured with the Rhinoceros program run-
ning on a personal computer.
If clinical signs of infection were evident, a swab for bac-
teriological analysis was taken, and the microbiological
results were recorded. Wound infection was treated by
appropriate systemic antibiotics.
All data elements recorded during the study period were
entered and validated in Microsoft Excel. The time to com-
plete ulcer healing was measured as the number of days
from the start of treatment to the date in which each
patient achieved complete wound healing. If the healing
did not occur within the 20 weeks of the study, the patient
was considered to be non-healing and the time was not
registered. The comparison between the two treatment
groups was made as the proportion of patients (%) who
reached target healing of their ulcers at the end of the
study. The time to complete healing and the index of re-
epithelization of the wound area were compared between
the two groups. All data were expressed as mean ± SD and
analyzed by Student's t-test. P value less than 0.05 was
regarded as significant.
Results
There were no significant differences between the two
groups in terms of demographics and clinical data, as
reported in tables 1 and 2. Group A (treated with ESWT)
was composed of fifteen patients: nine males and six
females. The age of these patients was 56.2 +/- 4.9 (mean
+/- DS). Group B (treated with standard management)
was composed of fifteen patients: seven males and eight
females. The age of all the patients was 56.8 +/- 7.5 (mean
+/- DS). The median size of the lesion in group A was
297.8 +/- 129.4 mm2 (mean +/- DS) and in group B was
245 +/- 100.9 mm2 (mean +/- DS).
All patients of both groups completed the study and
attended all control visits. No significant differences
emerged between the two groups with regard to treatment
complications.
The proportions of ulcers that healed in 20 weeks in the A
and B groups were 53.33% and 33.33%, respectively.
For the ulcers that healed during the 20-week period, the
healing times were 60.8 +/- 4.7 days (mean +/- DS) in
group A and 82.2 +/- 4.7 days (mean +/- DS) in group B
patients (p < 0.001).
A significant difference was observed in the index of the
re-epithelization between the two groups, with values of
2.97 +/- 0.34 mm2/die (mean +/- DS) in the ESWT group
[fig. 1 and 2] and 1.30 +/- 0.26 mm2/die (mean +/- DS) in
the control-group (fig. 3 and 4) (p < 0.001). Both the heal-
ing rate and the healing time were increased in the ESWT
group, and the differences were statistically significant.
One patient in each group developed local signs of infec-
tion (peri-lesional erythema and edema), which led to the
administration of oral antibiotics (1 g b.i.d. amoxicillin-
clavulanate) for 10 days. The signs of infection were
resolved in five days in the one patient in the ESWT group
and in one week in the patient in the control group, and
both patients remained in the study.
Table 1: Characteristics of patients in the ESWT group (group A)
PatientAgeInitial area (mm2) Complete healing (mm2) Re-epithelization index (mm2/die)
1. woman
2. man
3. man
4. woman
5. man
6. man
7. man
8. woman
9. woman
10. woman
11. man
12. man
13. man
14. man
15. woman
47
50
66
55
61
50
58
62
53
56
55
56
58
57
60
185
390
440
180
205
400
145
450
175
180
460
215
375
187
480
60
-
-
62
66
-
60
-
52
66
-
57
-
64
-
3.1
2.7
3
2.9
3.1
2.7
2.4
2.9
3.4
2.7
3.2
3.8
2.6
2.9
3.2

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Discussion
Neuropathic foot ulcers generally do not respond well to
treatment, and several novel treatment modalities have
been proposed over the past few years [26-29], including
the development of new dressings, growth factors, bioen-
gineered skin and tissue substitutes, hyperbaric oxygen,
negative pressure wound therapy and other novel
approaches to stimulate wound healing [30,29,31-33].
Limbs with non-healing neuropathic ulcers may eventu-
ally require amputation. Individuals with lower-limb
amputations are at risk for developing concomitant med-
ical ailments, report a diminished quality of life and are
more likely to die than other individuals with diabetes
[34]. In a meta-analysis of standard ulcer treatment, only
30% of individuals with a neuropathic diabetic foot ulcer
will heal within 20 weeks of commencing good care [35].
For the past 20 years, ESWT has been used in the treat-
ment of a number of musculoskeletal conditions, includ-
ing plantar fasciitis, tendinosis calcarea of the shoulder,
tennis elbow, pseudoarthrosis and algodystrophy. A
shock wave (SW) is a longitudinal acoustic wave, travel-
ling with ultrasonic speed in the water of the body tissue,
which is a single pressure pulse with a short needle-like
positive spike of less than 1 microsecond with a lower
amplitude [36]. SWs are known to exert "cavitation
effects" (a micrometer sized violent collapse of bubbles
inside the cells) and have recently been demonstrated to
induce localized impulses on cell membranes that resem-
ble shear stress [36,37]. The rational of this treatment is
the stimulation of tissue healing, reduction of calcifica-
tion and inhibition of pain receptors or denervation to
achieve pain relief [38-40].
Table 2: Characteristics of patients in the control group (group B).
Patient AgeInitial area (mm2) Complete healing (mm2) Re-epithelization index (mm2/die)
1. man
2. man
3. man
4. woman
5. woman
6. man
7. woman
8. woman
9. man
10. woman
11. woman
12. man
13. woman
14. man
15. woman
45
55
43
58
63
59
57
68
52
63
65
59
52
48
65
440
145
300
145
250
275
290
350
100
300
105
310
250
116
300
-
80
-
90
-
-
-
-
83
-
80
-
-
78
-
1.3
1.8
1.5
1.6
1.3
1.2
1.1
0.7
1.2
1.4
1.3
1
1.4
1.5
1.2
The ulcer of case 9 in group A
Figure 1
The ulcer of case 9 in group A. The lesion was localized
to the plantar surface of the 3rd intermetatarsal space and
was 175 mm2 before ESWT.
Ulcer of case 9 in group A
Figure 2
Ulcer of case 9 in group A. The lesion healed after 52
days with a re-epithelization index of 3.4 mm2/die.

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Researchers have shown that the local delivery of shock
wave therapy stimulates the early expression of angiogen-
esis-related growth factors, including endothelial nitric
oxide synthase, vascular endothelial growth factor and
proliferating cell nuclear antigen. As such, it results in new
vessel in-growth that improves blood supply, increases
cell proliferation and accelerates tissue regeneration and
healing [41,42]. A study of ESWT application on the por-
cine heart indicates that low-energy ameliorates myocar-
dial perfusion and cardiac function in a model of chronic
myocardial ischemia, and clinical trials started in patients
with severe chronic artery disease and no adverse effects
were found [43,44]. Recently, this treatment has also been
applied to skin lesions. In a previous study [45], treatment
with ESW was demonstrated to enhance epigastric skin
flap survival in rats, as confirmed by the significant reduc-
tion in necrotic flap zones. Additionally, in tissue samples
adjacent to the necrosis areas, increased vascular endothe-
lial growth factor expression was observed in the ESW-
treated skin flap [46]. Histological staining indicated that
ESW treatment substantially increased vascular endothe-
lial growth factor and proliferating cell nuclear antigen
expression, reduced leukocyte infiltration and suppressed
tumor necrosis factor alpha expression in flap tissue
ischemic zones compared with controls. It was postulated
that ESW treatment has a positive effect in rescuing the
ischemic zone of flaps by increasing tissue perfusion, and
it is associated with a suppression of the inflammatory
response [47]. After experimental studies in animal mod-
els, the clinical application of shock waves for the therapy
of acute and chronic soft tissue wounds is becoming more
popular. Two hundred and eight patients were prospec-
tively enrolled into a trial, and the treatment consisted of
debridement and ESWT at 100 to 1,000 shocks/cm2 at 0.1
mJ/mm2. Since surface defects are often involved,
researchers modified the shock wave head so that the
shock wave would no longer be focused in a small plane
of the treatment area. It was found that 75% of treated
patients had 100% wound epithelization during a 3 to 12
week period of monitoring [48].
Here we have completed a clinical trial to evaluate the
possibility of utilizing this treatment for wounds that have
a difficult recovery. We used an electromagnetic generator,
which we apply in the treatment of the orthopedic dis-
eases (fig. 5). We selected patients affected by diabetic
neuropathic foot ulcers. In a detailed analysis by Margolis
et al [35], of the factors that may contribute to healing, the
only ones that emerged from logistic regression were ulcer
area, ulcer duration and the race of the patient. This study
revealed that those patients with a diabetic neuropathic
foot ulcer that healed within 20 weeks using standard care
were more likely to have a smaller wound that existed for
a shorter period and to be non-whites, compared with
patients whose wounds did not heal within 20 weeks. The
neuropathic ulcers we studies were present for a longer
time prior to treatment, became larger and took more
time to heal. The patient's age, serum level of glycosylated
hemoglobin at the start and sex were not associated with
the probability of wound healing. Nevertheless, no differ-
ence was observed in the rate of healing of plantar and
non-plantar ulcers. In the meta-analysis, only 30.9% of
the diabetic neuropathic ulcers healed after 20 weeks of
good treatment [35].
During our previous preliminary experience in the appli-
cation of the shock waves for the treatment of ulcers, we
found that the rate of re-epithelization was higher in big
ulcers. To avoid any selection bias, we chose a homogene-
ous type of ulcer that was smaller than 5 cm in diameter
and of non-recent arising, both plantar and dorsal and in
Caucasian patients. In according with Ethic Committee's
Ulcer of case 4 in group B
Figure 3
Ulcer of case 4 in group B. The lesion was localized to the
plantar surface of the tarsus and was 145 mm2 before stand-
ard management.
Ulcer of case 4 in group B
Figure 4
Ulcer of case 4 in group B. The lesion healed after 90
days with a re-epithelization index of 1.6 mm2/die.