Chronic Ulcers of The Foot

DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLE
Diabetes Metab Res Rev 2012; 28(Suppl 1): 119–141.

Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2246
A systematic review of interventions to enhance the

healing of chronic ulcers of the foot in diabetes
F. L. Game1,10* SUMMARY
R. J. Hinchliffe2
J. Apelqvist3 The outcome of management of diabetic foot ulcers is poor, and there is
D. G. Armstrong4 continuing uncertainty concerning optimal approaches to management. It
K. Bakker5 was for these reasons that in 2006 the International Working Group of the
Diabetic Foot (IWGDF) working group on wound healing undertook a systema-
A. Hartemann6
tic review of the evidence to inform protocols for routine care and to highlight
M. Löndahl7,8 areas which should be considered for further study. The same working group
P. E. Price9 has now updated this review by considering papers on the interventions to
W. J. Jeffcoate1 improve the healing of chronic ulcers published between December 2006
1
and June 2010. Methodological quality of selected studies was independently
Foot Ulcer Trials Unit, Nottingham assessed by two reviewers using Scottish Intercollegiate Guidelines Network
University Hospitals Trust,
criteria. Selected studies fell into the following ten categories: sharp debride-
Nottingham, UK
2
ment and wound bed preparation with larvae and hydrotherapy; wound bed
St George’s Vascular Institute, St George’s preparation using antiseptics, applications and dressing products; resection
Healthcare NHS Trust, London, UK of the chronic wound; hyperbaric oxygen therapy (HBOT); compression or
3
Department of Endocrinology, University negative pressure therapy; products designed to correct aspects of wound
Hospital of Malmö, Malmö, Sweden biochemistry and cell biology associated with impaired wound healing; appli-
4
Southern Arizona Limb Salvage cation of cells, including platelets and stem cells; bioengineered skin and skin
Alliance (SALSA), University of Arizona grafts; electrical, electromagnetic, lasers, shockwaves and ultrasound; other
College of Medicine, Tucson, AZ, USA systemic therapies which did not fit in the above categories. Heterogeneity of
5
IWGDF, Heemstede, The Netherlands studies prevented pooled analysis of results.
6
Service de diabétologie, Hôpital Pitié- Of the 1322 papers identified, 43 were selected for grading following full text
Salpêtrière, Assistance Publique des review. The present report is an update of the earlier IWGDF systematic
Hôpitaux de Paris, and Université P et review, but the conclusion is similar: that with the exception of HBOT and,
M Curie, Paris, France possibly, negative pressure wound therapy, there is little published evidence
7
Department of Endocrinology, Lund to justify the use of newer therapies. This echoes the conclusion of a recent
University Hospital, Lund, Sweden Cochrane review and the systematic review undertaken by the National Institute
8
Institution for Clinical Sciences in for Health and Clinical Excellence Guidelines Committee in the UK. Analysis
Lund, Lund, Sweden of evidence presents considerable difficulties in this field particularly as con-
9 trolled studies are few and the majority are of poor methodological quality.
School of Healthcare Studies, Cardiff
University, Cardiff, UK Copyright © 2012 John Wiley & Sons, Ltd.
10
Department of Diabetes and
Endocrinology, Derby Hospitals NHS
Keywords diabetes; diabetic foot; ulcer; wound healing; dressing
Trust, Uttoxeter Road, Derby, DE22
3NE, UK
Abbreviations ABPI – ankle : brachial pressure index
*Correspondence to: Dr F. Game,
AKA – above knee amputation
Department of Diabetes and
ATA – atmosphere absolute (pressure)
Endocrinology, Derby Hospitals NHS
bFGF – basic fibroblast growth factor
Trust, Uttoxeter Road, Derby. DE22
BKA – below knee amputation
3NE UK.
CBA – control before and after (study)
E-mail: fgame@futu.co.uk
DFU – diabetic foot ulcer
EGF – epidermal growth factor
Received: 11 October 2011
GCSF – granulocyte-colony stimulating factor
Accepted: 11 October 2011
HBOT – hyperbaric oxygen therapy
Copyright © 2012 John Wiley & Sons, Ltd.

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120 F. L. Game et al.
IQR – interquartile range systematic reviews and Cochrane reviews on the topics
ITS – interrupted time series (study) of interest were searched to determine the need for
ITT – intention to treat (analysis) an extension to the literature search. A later search
NPWT – negative pressure wound therapy was made of four clinical trials registries: http://www.
PDGF – platelet-derived growth factor
controlled-trials.com/isrct/, http://www.clinicaltrials.
RCT – randomized controlled trial
gov, http://www.anzctr.org.au/ and http://ctrl.nic.in/
rhVEGF – recombinant human vascular endothelial
growth factor Clincaltrials/index.jsp, and attempts were made to con-
SIGN – Scottish Intercollegiate Guidelines Network tact investigators if there was no evidence of any poten-
SSG – split skin graft tially relevant studies being published.
TcpO2 – transcutaneous oxygen tension Two reviewers independently assessed all identified
UT – University of Texas (wound classification system) references by title and abstract to determine possible
VAS – visual analogue scale eligibility. Full-paper copies of identified articles were
retrieved, and eligibility was confirmed by one of four pairs
of independent reviewers. Each study was scored for meth-
odological quality using scoring lists specific for each study
Introduction design and based on checklists developed by the Dutch
Cochrane Center (www.cochrane.nl/index.html). Equal
The management of foot disease in diabetes remains a
weighting was applied to each validity criterion. Findings
major therapeutic challenge throughout the world. The
on data extraction and methodological quality were dis-
International Working Group of the Diabetic Foot
cussed between co-reviewers and a final decision endorsed
(IWGDF) has issued guidelines on management since
by the entire group. Quality items were rated as ‘done’, ‘not
1999, but good evidence is still required to substantiate
done’ or ‘not reported’, and only those rated as ‘done’
the roles of particular interventions. It is for this reason
contributed to methodological quality score. This quality
that from 2005 the IWGDF established working groups
score was translated into a level of evidence according to
to undertake a series of systematic reviews into aspects
the Scottish Intercollegiate Guidelines Network instrument
of prevention and management of foot disease, including
[4]: (1) RCTs and (2) studies with case–control, cohort,
offloading [1], osteomyelitis [2] and chronic ulceration
CBA or ITS design. Studies were also rated as ++ (well
[3]. At the invitation of the IWGDF Editorial Board, the
conducted with very low risk of bias), + (well conducted
IWGDF working group on wound healing undertook a
with low risk of bias) and (low quality with higher risk
systematic review of the evidence to inform protocols for
of bias). Meta-analyses, other reviews and studies report-
routine care and to highlight areas which should be
ing non-analytic case reports and case series were not
considered for further study, considering all papers
included. Reviewers did not assess their own work because
published up to December 2006 [3]. The same working
of potential conflict of interest.
group have now updated this review by considering
Extracted data were summarized in evidence tables on
papers on the interventions to improve the healing of
a study-by-study narrative basis. Because of the heteroge-
chronic ulcers published between December 2006 and
neity of study designs, interventions, follow-up and
June 2010.
outcomes, no attempt was made to pool the results. These
evidence tables were compiled following collective discus-
sion by the working party, and conclusions were drawn
Methods and recommendations formulated. The papers selected
for scoring were divided into the same nine categories
Prospective and retrospective controlled studies, pub- used in the earlier review, except that the single article
lished in any language, that evaluated interventions for on the use of platelets has now been included in the
the treatment of chronic foot ulcers in people aged section on cell therapy (in contrast to the previous alloca-
18 years or older with either type 1 or type 2 diabetes mel- tion of platelet supernatant to the section on growth
litus were considered. Studies were included if they con- factors). A new tenth category, other systemic therapies,
cerned agents or interventions that may accelerate the was added.
healing process, and the primary outcomes used were
clinical: healing, time to healing, reduction in ulcer area
or amputation. Search strategies were defined, which
included selected search terms on study design, patient Results
group, clinical problem and interventions of interest by
using Medline (December 2006 to June 2010) and A total of 802 articles were identified from EMBASE
Embase (December 2006 to June 2010). Randomized con- and 507 from Medline. Seventy-two of these were
trolled trials (RCT), case–control studies, prospective and selected for full text review. An additional 13 articles were
retrospective cohort studies, control before-and-after identified from other sources, including other systematic
(CBA) design and interrupted time series (ITS) designs reviews. Of the total 85 articles, 43 were included
were included. Bibliography tracking of identified articles in the review. The selected papers were grouped into
was not performed. Previously performed high quality ten categories.
Copyright © 2012 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2012; 28(Suppl 1): 119–141.
DOI: 10.1002/dmrr
Interventions for Healing Diabetic Foot Ulcers 121
would not necessarily be expected

No difference in healing, but this
Sharp debridement and wound bed
Period of study unclear – ran for
characteristics of groups similar

Unclear as to whether baseline
Outcomes in DFU and venous
preparation with larvae and
Unusual definition of healing

hydrotherapy
Comments
in a study of this type

ulcers not separately
‘at least 18 months’

The earlier review concluded from three papers that the
scientific evidence to confirm the benefit of sharp
debridement was not strong. No further studies were
described.
identified on this method of wound preparation nor to
supplement the weak evidence to support the use of
hydrogels reported in the previous review. The results of
the present search are summarized in Table 1. There have
evidence
Level of
(SIGN)
been a very small number of studies undertaken of newer
2
therapies. The present search selected only one new paper
to add to the two previously reported on the use of larvae
Intervention: 10.8 min

[5]. This study was of a low-scoring cohort design and
vs control 47.4% NS
17.7 min, p = 0.008
statistical results
Intervention 52.6%
Intervention: 14/29
Differences and
Control: 18/30 NS
Control: 11/30 NS
Intervention: 5/29
reported no significant effect on either healing or amputa-
tion following the application of larvae from the Malaysian
blowfly, Lucilia cuprina. Only one paper was identified in
vs control:
which the use of hydrotherapy using VersajetW was com-
pared with controls [6]. This was a low-scoring RCT,
however, and although wound debridement time was
complete closure by self

shorter with hydrotherapy, no benefit was observed in
healing or suitable for

‘Healing’(suitable for
Wound debridement
healing at 12 weeks.
Wounds closed at
Outcomes
Amputation
SIGN, Scottish Intercollegiate Guidelines Network; DFU, diabetic foot ulcer; ABPI, ankle : brachial pressure index.
12 weeks
grafting)
Wound bed preparation using antiseptics,
applications and dressing products time
The earlier review found evidence from a single small

standard sharp debridement
study of possible benefit from the use of zinc oxide tape.

control management
Intervention and
(Lucilia cuprina) larvae

A small RCT had also reported improved ulcer healing
hydrosurgery versus
with the use of a carboxymethylcellulose hydrofibre dres-

Malaysian blowfly
plus pulse lavage
sing (AquacelW). However, in the present search, a large,

versus standard
debridement
observer-blinded RCT of good quality was identified that
W
reported no difference between three products: Aqua-

Versajet
celW, a surface antiseptic (InadineW) and a non-adherent

product (N-AW) in terms of healing by 24 weeks, as well
Table 1. Sharp debridement and wound bed preparation with larvae
as of a variety of secondary outcome measures including

Intervention, n = 29. Control,
44% (19) had venous ulcers
41 patients: 54% had DFU,
mean healing time, incidence of major and minor amputa-

tion and the incidence of secondary infection [7]. Similarly,
ischaemia (ABPI > 0.75)
(11 with DFU); control,
n = 22 (11 with DFU)
n = 30. Patients with
another large, but non-blinded, RCT reported no difference

Population
Intervention, n = 19
between a silver impregnated carboxymethylcellulose

hydrofibre dressing (Aquacel AgW) and an alginate in the
59 with DFU
incidence of complete healing over 8 weeks, healing velo-

excluded
city, change in ulcer area and time to healing. A weak sig-

nificant effect was shown on reducing wound depth, but
depth was assessed using a relatively imprecise method,
Study quality, 2/9
and the observers were non-blinded [8]. Thus, the earlier

Study design
Study quality,
and score
data on the use of hydrofibre dressings has not been con-

Open label
firmed in these more recent, and much larger, studies. In

Cohort
the absence of supportive evidence, the additional

RCT
3/8
expense of the newer hydrofibre product is not justified.

The previous review found evidence from three con-
Caputo et al. [6]
trolled trials suggesting that hydrogels also may hasten

Paul et al. [5]
healing, but no new studies on hydrogels were identified

Reference
in this search, and the place of these products in routine

care is still not substantiated. A small study of the use of
QRB7 (oak bark extract) in Bensal HP or silver sulphadiazine
DOI: 10.1002/dmrr
for 6 weeks [9] showed a significant benefit in terms of heal- outcome, with healing in 66% versus 0% [16]. Little can
ing, but the quality of the study was difficult to assess be concluded from this non-blinded study because of the
because of missing details. The use of surface antimicrobials choice of primary outcome measure: ‘healing without sur-
(tobramycin beads) on the wound at the time of forefoot gical intervention’. The lack of blinding could have
amputation was shown in a non-randomized cohort study resulted in further surgical intervention being chosen for
to have a weak significant effect on the need for later surgi- the control group.
cal revision. Little can be drawn from this study, however, as The third new study was, however, a high quality
the apparent effect could have resulted from confounding double-blind RCT which demonstrated significantly
influences [10]. improved outcome in the intervention group [17], who
Despite its widespread use in clinical practice, it was were more likely to heal within 12 months: 25/48 (52%)
possible to identify only one study in which the effect of versus 12/42 (27%); p = 0.03. Of note, the intervention
honey was assessed in a controlled study. This study was group included patients who either had no evidence of
a small, non-blinded study of poor design and reported PAD or who were deemed unsuitable for vascular recon-
no difference between the use of honey and of povidone struction, unlike the previous RCT by Abidia et al. [14],
iodine [11]. where only patients with unreconstructable critical limb
A single non-blinded RCT on the use of superoxidized ischaemia were included. Although the limitations of this
solution (DermacynW) was identified [12], which com- study have been listed [18], its potential implications are
pared the incidence of healing at 6 months after infected far-reaching, and the study needs to be repeated with full
surgical wounds of the foot had been irrigated with either health economic analysis and with an attempt being made
the superoxidized solution or with povidone iodine. to define the population most likely to benefit.
Although the results suggested an improvement both in
healing by 6 months and in time to healing, the study was
of poor methodological quality and took no account of any Compression or negative pressure
possible adverse effect on healing of the comparator. therapy
In summary, there is little evidence to support the
choice of any one dressing or wound application in prefer- The earlier review reported a single RCT which suggested
ence to any other in attempts to promote healing of a significant benefit of compression therapy on post-
chronic ulcers of the foot in diabetes (Table 2). operative wounds. The review also identified three RCTs
on topical negative pressure wound therapy (NPWT).
Two of these were small, but the third suggested benefit,
Resection of the chronic wound again for post-operative wounds. The results of the pre-
sent search which resulted in the selection of three studies
The earlier review identified a single study which on compression and three on NPWT are given in Table 4.
reported the benefit of complete excision of plantar neu- One study of vacuum compression therapy was of poor
ropathic ulcers [13]. No recent publication on this inter- methodological quality but reported a significant reduc-
vention was identified. tion in wound area following the intervention [19], and
the conclusions that can be drawn from this study are
further limited by the fact that patients with neuropathy
Hyperbaric oxygen were excluded. Two other studies which explored the
benefit of compression therapy for (predominantly) post-
The previous review concluded that there were some data operative wounds were identified. One was a cohort study
to suggest that systemic (but not topical) hyperbaric oxy- in which the reported incidence of complete healing was
gen (HBO) reduces the rate of major amputation in peo- significantly higher and the incidence of major amputation
ple who have chronic foot ulcers complicating diabetes. significantly lower in those who received the intervention,
The strongest evidence was provided by a double-blinded, but the study was potentially biased as participants were
but rather small, RCT of patients with unreconstructable allowed to opt for or against the intervention [20]. The sec-
peripheral arterial disease (PAD) [14]. The results of the ond, randomized, study compared outcome in those with
present search resulted in three further studies being large post-operative wounds on the foot (mean area 3000
selected (see Table 3). These included ulcers of varying and 2668 mm2 in the intervention and control groups)
duration and severity and with varying severity of PAD. [21]. The results suggested a significant reduction in time
One study was a retrospective analysis of 42 people to healing in the intervention group, but the study was
who had been offered HBO, in which the outcome was non-blinded and of low methodological quality.
compared between those who had completed ten or fewer Two new studies of NPWT – one small and one large –
treatments and those that had completed more [15]. A concluded that the intervention was associated with
significant difference between groups in terms of the reduced time to 90% granulation [22], reduced time to
number of major amputations was seen, but the influence wound closure, increased incidence of healing by
of confounders cannot be excluded. In a second, poorly 16 weeks, greater reduction in cross-sectional area by
reported RCT of low methodological quality, the interven- 8 weeks and reduced incidence of minor amputation
tion group was reported to have a marked improvement in [23]. This latter study involved the randomization of
DOI: 10.1002/dmrr
Table 2. Wound bed preparation using antiseptics, applications and dressing products
Level of
Study design Intervention and Differences and evidence
Reference and score Population control management Outcomes statistical results (SIGN) Comments
W
Jeffcoate et al. [7] RCT with DFU N = 317 Three different Healing by 24 weeks Inadine 44.4% 1+ Patients and care providers
three arms randomized to dressings: InadineW, N-AW: 38.7% not blinded. Blinded
three groups: AquacelW, N-AW AquacelW: 44.7% evaluation.
Observer blinded Non-infected NS Eventual to change
ABPI > 0.7 Time to healing InadineW: 74, 1 throughout a 24-week
Study quality, Duration >6 weeks (SD 20.6) days period
6/9 Area ≥25 and ≤2500 mm2 N-AW: 75.1 (SD 18.1) No evidence to suggest
AquacelW: 72.4 that iodine-impregnated

InadineW n = 108 (SD 20.6) days dressing reduces the
AquacelW: n = 103 NS incidence of secondary
N-AW n = 106 Health economics Mean dressing cost infection
88 withdrawals per patient
InadineW: £17.48
Interventions for Healing Diabetic Foot Ulcers
N-AW: £14.85
AquacelW: £43.6
p < 0.05
Secondary infection InadineW: n = 71
AquacelW: n = 54
N-AW: n = 48
p < 0.001
Jude et al. [8] RCT DFU N = 134 Aquacel AgW versus % healing Intervention: 31% 1 Outcome assessment not
Open label Intervention, n = 67 calcium alginate dressing Control: 22% blinded
Control, n = 67 for 8 weeks NS No difference in healing
Study quality, Lost to follow-up n = 21 Healing velocity Intervention: 0.29 Poor method for assessing
4/9 (SD 0.33) cm2/week depth (cotton-tipped swab)
Control: 0.26 (SD 0.9)
cm2/week
NS
Time to healing Intervention: 52.6
(SD 1.8) days
Control: 57.7 (1.7) days
NS
% reduction in area Intervention: 58.1 (53.1)%
over 8 weeks Control: 60.5 42.7%
NS
Change in ulcer Intervention: 0.25 (0.49) cm
depth Control: 0.13 (0.37) cm
p = 0.042
Jacobs and RCT, possibly Plantar DFU N = 40 QRB7 (extract of oak bark) in Reduction in Intervention: 72.5% vs 1 Study said to be blinded
Tomczak [9] blinded Non-infected, Bensal HP versus silver diameter control: 54.7% p = 0.059 but details not given
Wagner I = II, sulphadiazine cream No details of randomization
Study quality, ABPI > 0.75 Applied daily for 6 weeks given
3/9 Duration>6 weeks
Diameter <3 cm
Baseline diameter
Intervention: 1.9
(SD 0.76) cm
DOI: 10.1002/dmrr
123
(continued)
124
Level of
Study design Intervention and Differences and evidence
Table 2. (Continues)
Reference and score Population control management Outcomes statistical results (SIGN) Comments
Control: 1.6
(SD 0.78) cm
Krause et al. [10] Cohort Following transmetatarsal Antibiotic beads (tobramycin Time to healing Intervention: 10.5 2 Retrospective study possibly

amputation for diabetic impregnated calcium (SD 4.5) weeks affected by selection bias
Study quality, foot disease sulphate) versus no local Control: 14.5 (SD 3.8) weeks Outcome reported in only
3/8 Intervention, n = 46 antibiotics NS 40 of 60 patients
(49 feet) Rate of surgical Intervention: 8.2%
Control, n = 14(16 feet) revision Control: 25%
p < 0.05
Transtibial amputation Intervention: 27%
at an average follow- Control: 25%
up of 28.8 months
Piaggesi et al. [12] RCT Infected surgical wounds Irrigation with superoxidized Healing at 6 months Intervention: 90% 1 Length of intervention
N = 40: solution (DermacynW) versus Control: 55% unclear
Non-blinded Intervention 20 irrigation with 50% p = 0.002 Adverse effects of povidone
Control 20 povidone iodine Time to healing Intervention: 10.5 iodine cannot be excluded
Study quality, Ulcer size: (SD 5.9) weeks
1/9 Intervention: 32.7 Control: 16.5 (SD 7.1) weeks
(SD 19.8) cm2 p = 0.007
Control: 31.3
(SD 22.4) cm2
Shukrimi et al. [11] RCT DFU N = 30 Honey plus gauze versus Time to wound Intervention: 14.4 1 Poor description of
Wagner II povidone iodine diluted with being deemed (range 7–26) days methodological detail
Non-blinded Mean TcpO239 normal saline plus gauze suitable for Control: 15.4
(36–42) mmHg (changing to saline soaked surgical closure (range 9–36) days
Study quality, gauze when wound free Follow-up 7–36 days NS
1/9 from pus)
Daily dressings
RCT, randomized controlled trial; DFU, diabetic foot ulcer; ABPI, ankle : brachial pressure index.
DOI: 10.1002/dmrr
F. L. Game et al.
Table 3. Hyperbaric oxygen therapy
Chen et al. [15] Cohort Infected DFU Group 1: received ten or Healing with preservation Group 1: 2+ Retrospective analysis
Study quality, 5/8 N = 42 less sessions of HBOT of foot at 6 months healed: 7 (33.3%); Potential for selection bias
Wagner III and IV Follow-up for mean 13.3 ‘Failure’ = amputation or failed 14 (BKA: 9, AKA: 1)
Group 1: n = 21, 10 (6–29) months follow-up persistent ulcer with no Group 2: healed:
Wagner III, 11 Group 2: received >10 significant improvement 16 (76.1%); failed:
Wagner IV sessions HBOT 5 (BKA: 2, AKA: 2)
Mean duration of Follow-up mean 14.8 p = 0.05
infection 7 (range 1–52) (6–30) months

weeks
Group 2: n = 21, 7
Wagner II, 16
Wagner IV
Mean duration of
infection 14
(range 2–52) weeks
Duzgun et al. [16] RCT DFU Intervention: HBOT plus Final healing without any Intervention: 33/50 (66%) 1 No ITT analysis
Open label N = 100 standard care form of surgical intervention Control: 0/50 (0%) No dropouts or deaths
Study quality, Wagner II–IV 2–3 ATA for 2 90 min Closure by Wagner grade: reported
2/9 II n = 18 day 1 then 1 90 min II: 6/6 (100%) Limited details on
III n = 37 following day continued III: 13/19 (68%) concomitant therapy
IV n = 45 for approximately IV: 14/25 (56%) Possible selection bias, lack of
Present for >4 weeks 20–30 days p < 0.05 clarity on baseline ulcer
50 in each group Control: standard care characteristics
Follow-up 92 12 weeks (daily wound care; No comment about vascular
debridement; status of patients
amputation when indicated; Higher number of females in
infection control) control group
Non-blinding could have led to
increased surgical
intervention in control group
Löndahl et al. [17] RCT DFU N = 94 HBOT: 2.5 ATA in multiple Healing within 12 months ITT 1++ Dropout from treatment 19/94
Double-blind HBOT: n = 49 person chamber for 85 min and maintained ‘to Intervention: 25/48 (52%) 10 patients had
Study quality, 7/9 Control, n = 45 5 days a week over 8 weeks next visit’ Control: 12/42 (27%) revascularization during
Wagner II–IV ulcers plus standard care p = 0.03 follow-up:
present for >3 months; Control: placebo 2.5 ATA air NNT = 4.2 6 in HBOT, 4 in control group
and either with adequate treatment in same chamber Per protocol (1 healed post procedure in
distal perfusion or plus standard care Intervention: 23/38 (61%) each group)
deemed not suitable Control: 10/37 (27%)
for revascularization p = 0.009
Toe systolic NNT = 3.1
pressure ≤35 mmHg: Death Intervention: 1
HBOT 33% Control: 3
Placebo 29% Amputation Intervention: 1 BKA, 2 minor
DFU, diabetic foot ulcer; HBOT, hyperbaric oxygen therapy; BKA, below knee amputation; AKA, above knee amputation; ATA, atmosphere absolute (pressure); NNT, Number needed to treat
DOI: 10.1002/dmrr
125
126
Table 4. Compression and negative pressure therapy
Akbari et al. [19] RCT DFU Intervention: Vacuum Reduction in surface area Intervention: 46.88 1 Poor description of study
Open label N = 18 Compression therapy (SD 9.24) to 35.09 Outcome not predefined
Study quality, UT Grade II 10 sessions; 1 h per day (SD 4.09) mm2(p = 0.006)
1/9 No significant loss of four times a week plus Control: 46.62 (SD 10.03)
protective sensation standard care over 3 weeks to 42.89 (SD 8.1)mm2
Control: standard care (p = 0.01)
(debridement, blood glucose Comparative reduction:
control, systemic antibiotics, p = 0.024 (intervention
saline cleansing, offloading versus control)
and daily dressing changes) Within group
improvement judged

better for Intervention
group: p = 0.03
Kavros et al. [20] Cohort Retrospective review of Intermittent pneumatic Survival at 18 months Intervention: 20/24 (83%) 2 Only 63% and 71% of the
Study quality, patients 1998–2004 compression Control: 18/24 (75%) two groups had diabetes,
3/8 Non-healing toe or 6 h/day in two 3-h NS and the results were not
amputation wounds for sessions versus standard Complete healing Intervention: 14/24 (58%) described separately from
which revascularization wound care limb intact Control: 4/24 (17%) patients without
was not possible p < 0.001 diabetes
32/48 of total population Below knee amputation Intervention: 10/24 (42%) Mixed population of chronic
had diabetes (67%) Control: 20/24 (83%) foot and post amputation
Resting ABPI p < 0.001 wounds with critical limb
Intervention: 0.55 ischaemia not defined
(IQR 0.44–0.66) Biased as patients were able
Control: 0.52 to select treatment
(IQR 0.45–0.65) No details on length of
treatment with intervention
High amputation rates
Mars et al. [21] RCT N = 60 patients with large Intervention: Compressed Time to healing Intervention: 58.1 1 No method of randomization
Open label post-op DFU (intervention: air massage at 100 kPa (by secondary intention (SD 22.3) days given
Study quality, 3000 mm2 vs control: for 15–20 min or by split skin graft Control: 82.7 No data on actual healing
3/9 2668 mm2) following extensive 5 days a week. Other (SD 30.7) days incidence
resection for infection which treatment as for controls p = 0.001 No baseline data on
required urgent surgical Control: specified Numbers receiving Intervention: 9/28 neuropathy or arteriopathy
intervention standard wound care skin grafts Control: 10/29 Results reported for
Results given for Intervention, plus antibiotics plus insulin Amputations Intervention: 14/28 only 57/60
n = 28, control, n = 29 infusion Control: 15/29
Treatment applied to the
foot and tissue around ulcer,
not to the wound bed
Sepulveda et al. [22] RCT DFU following transmetatarsal Intervention: NPWT Time to 90% granulation Intervention: 18.8 1+ Outcome assessment blinded
Single-blind amputation or removal of applied 3–5 days after (SD 6.0) days Control dressing varied by
Study quality, two or more adjacent toes surgery. Changes each Control: 32.3 extent of wound exudates
5/9 N = 22:11 in each group 2–3 days, plus standard care (SD 13.7) days Variable follow-up
Mean age Control: standard care p = 0.007 Power calculation given,
Intervention: 61.5 involving moist wound based on pilot data
(SD 10) years healing including
Control: 62.1 hydrocolloid gel or
(SD 8) years alginate
ABPI:
DOI: 10.1002/dmrr
F. L. Game et al.
Intervention: 1.05
Control: 1.16
Blume et al. [23] RCT DFU Intervention: NPWT until Healing at 16 weeks Intervention: 73/169 1+ ITT but 30.75% dropout rate
Open label Wagner II–III healing or 16 weeks (complete epithelialization (43.2%) Median baseline area of ulcers
Study quality, >2 cm2 (112 days) plus standard with no drainage) Control: 48/166 was large
5/9 Ulcer duration prior to treatment: care (28.9%) Intervention: 13.5 (18.2) cm2
NPWT: 198.3 (SD 323.5) days Control: standard care p = 0.007 Control: 11.0 (12.7) cm2
Control: 206 (SD 365.9) days (usually involving hydrogels Reduction in surface area Intervention: 4.32 cm2 Population selection:
ABPI 0.7–1.2; triphasic wave or alginates used according at day 28 (different from Control: 2.53 cm2 79% male
form and/or TcpO2 >30 mmHg to manufacturer’s guidelines) baseline) p = 0.021 Healing may not be the best
342 patients randomized Time to closure Intervention: 96 outcome measure for wounds
335 received treatment (75–114) days of this size and may not
Control: ‘unquantifiable’; be the objective
p = 0.001 of this type of therapy

Amputation LEA No reported follow-up after
Intervention, n = 7 112 days
Control, n = 17
p = 0.035
Frykberg and Cohort DFU identified from two Retrospective comparison for Incidence of Significantly fewer amputations Can draw no conclusions
Williams [24] Study quality, groups of reimbursement people receiving NPWT versus amputation in NPWT group in both about clinical effectiveness
2/8 claims – payers and Medicaid people receiving other reimbursement Not completely
treatments groups (Payers/Medicaid) when contemporaneous
Data corrected for extent of adjusted either for debridement Potential source of bias:
debridement (as measure of depth (wound severity): data based on
wound severity)and for overall Payers: NPWT 26.3% vs out-patient treatment only
morbidity (as reflected in non-NPWT 52.7% p < 0.001
total reimbursement claim) Medicaid: 18.3% vs 53.3%
p < 0.001or for overall costs
(total morbidity)
Payers:
NPWT 27.3% vs
non-NPWT 45.7% p = 0.002
Medicaid 9.1% vs 44.7%
p < 0.001
DFU, diabetic foot ulcer; ABPI, ankle : brachial pressure index; IQR, interquartile range; NPWT, negative pressure wound therapy; LEA, lower extremity amputation
DOI: 10.1002/dmrr
127
342 patients and was methodologically sound. The ulcers groups and 39.6% in the control arm: p = 0.000015). It is
which were selected were >2 cm2 and had been present to be regretted that the results of later observations in this
for much longer than in other studies (mean 200 days), 8-week study were adversely affected by the insistence of the
but it was not stated how many of them had originally been ethical committee that those in the control group switch to
post-operative wounds. Further evidence is needed to an intervention arm after the first 2 weeks [27]. More studies
substantiate the place of NPWT in routine clinical practice. are needed to seek confirmation of these promising findings.
There was a single study which attempted to confirm Uchi and colleagues [28] have recently reported the
the effectiveness of NPWT through analysis of reimburse- results of a methodologically high quality, partial dose-
ment claims, but the results could potentially be ranging RCT of bFGF administered in spray form for
explained (in part) by confounding factors [24]. 8 weeks. The ulcers selected were rather small. The
authors reported a significant difference between the
higher dose used and placebo in the percentage having a
Products designed to correct aspects of reduction in area by >75%, but this was only on per pro-
wound biochemistry and cell biology tocol analysis. There was no difference in numbers healed.
associated with impaired wound healing As the difference was non-significant when intention to
treat (ITT) analysis was used, this would confirm the
In the previous review, two small RCTs reported possible earlier negative finding of Richard and colleagues [29].
benefit following the use of, firstly, lyophilized collagen A well-designed double-blind RCT assessed the effect of
and, secondly, an acellular bioproduct derived from the intramuscular injections of a plasmid containing the gene
small intestinal submucosa of pigs. There had also been for phVEGF165 [30]. In the subgroup of patients with dia-
a number of studies of specific growth factors as well as betic foot ulcers, a significantly greater percentage of the
of transretinoic acid. A single large study to suggest bene- intervention group achieved the primary outcome measure
fit of platelet-derived growth factor (becaplermin) was of >60% reduction in ulcer area than controls (33% vs 0%).
identified even though it was known that another, equally A small non-blinded RCT of 40 non-infected diabetic
large but negative, study had not been published. A single foot ulcers reported a significant benefit in the numbers
study on basic fibroblast growth factor (bFGF) had shown healed and in time to healing within 6 weeks, when a pro-
no benefit, and there had been some early, but inconclu- tease modulating dressing was compared with usual care
sive, work to suggest that there may be a role for epider- but was compromised by using per protocol analysis [31].
mal growth factor (EGF). One large RCT on a collagen/ A second study suggested that there may be an additional
oxidized regenerated cellulose dressing product (Promo- benefit to the use of a protease modulating dressing when
granW), which is believed to modify the balance between added to autologous platelet supernatant compared with
matrix metalloproteinases and their tissue inhibitors, either treatment alone [32], but the data were not fully
failed to confirm an effect on healing. presented and are therefore difficult to interpret.
Trials on granulocyte-colony stimulating factor (GCSF) A single placebo-controlled, partial dose-ranging study of
were included in the following section in the earlier review. talactoferrin, a recombinant human form of the breast milk pro-
There had been a small number of high quality trials which tein lactoferrin, was identified [33]. The study design was poor,
had been of good quality, even though they had been direc- however, and no difference was observed between groups.
ted primarily at the eradication of infection. They were Two RCTs of an acellular dermal regenerative tissue
included, however, because amputation was recorded as matrix were identified.
an end point, and an apparent trend towards limb salvage The first, a small non-blinded RCT of poor quality com-
had been noted in a separate meta-analysis [25]. No bined an acellular dermal regenerative tissue matrix with
further studies of GCSF were detected in the current a mineral oil-soaked dressing [34]. A significant differ-
search, in contrast to new studies that have examined the ence in healing and the final wound areas was shown
efficacy of EGF, bFGF, vascular endothelial growth factor when compared with the control group, but no data were
(VEGF), protease modulating dressings, talactoferrin, acel- provided on area at baseline. The second was also of poor
lular regenerative tissue matrix and chrysalin (a ligand methodological quality and compared a single application
for thrombin binding sites) (Table 5). of an acellular dermal regenerative tissue matrix com-
There are some data to suggest that EGF may hasten bined with a silver impregnated dressing, with usual
healing. A double-blind RCT examined the effect of twice wound care [35]. A significant difference in healing at
daily topical application administration of rhEGF gel to 12 weeks was found, but the study was not blinded.
non-ischaemic ulcers of 2–3 weeks’ duration [26]. The Topical Chrysalin, a ligand for thrombin binding sites,
study was weakened by the use of per protocol analysis, was studied in a double-blind placebo-controlled, partial
and although a significant benefit was reported for a sub- dose-ranging trial of 60 participants [36]. Few details were
group post hoc analysis of ulcers with an area exceeding provided, and statistical analysis was not undertaken, but
6 cm2, the overall results of the trial were essentially the incidence of wound closure at 20 weeks appeared simi-
negative. A second large, placebo-controlled and partial lar in the three groups. A double-blind controlled trial of an
dose-ranging RCT reported a highly significant difference extract of the plant Tinaspora cordifolia, applied as an
between groups in the prevalence of granulation tissue after immunomodulator to 50 patients with large foot ulcers,
just 2 weeks (73.1% and 70.8% in the two intervention reported a non-significant change in rate of healing [37].
DOI: 10.1002/dmrr
Table 5. Products designed to correct aspects of wound biochemistry and cell biology associated with impaired wound healing
Viswanathan et al. [26] RCT DFUN = 60 rhEGF 150 mcg/g Healingby 15 weeks Intervention: 25/29 1+ Actual dose given not clear
Double-blind Ulcers 2–3 weeks duration in 30 g tubes Control: 14/28 Per protocol analysis
Study quality, Area 2–50 cm2 administered topically No statistical analysis or Data in intervention group not
6/9 ABPI ≥ 0.753 dropouts as a gel twice daily comment on difference normally distributed and yet
until healing or to in the text parametric stats used
15 weeks versus placebo Post hoc analysis showed Little evidence to support
numbers healing in those statement in the Abstract that
with area >6 cm2 was ‘the study demonstrated
significantly greater the . . .efficacy of
p < 0.002 rhEGF in accelerating healing’
Time to healing Intervention:
Mean: 9.6 (SD 11.3)

Median 8.5 weeks
Control: Mean: 14.9
(SD 4.1)
Median 14.9 weeks
No statistical results given

Change in area No results given
Fernandez- RCT DFU N = 149 Intralesional injections % granulation at Group 1: 73.1% 1+ Ethics committee insisted
Montequin et al. [27] Double-blind Wagner III–IV of rhEGF 2 weeks Group 2: 70.8% that non-responders received
Study quality, 49 lost to follow-up Total intervention phase Group 3: 39.6% intervention after only
6/9 Follow-up to 12 months 8 weeks p = 0.000015 2 weeks:4 in Group 1
Group 1: 25 mcg per Partial (>50%) and Group 1: 86.8% switched to Group 2;
treatment (n = 53) complete granulation Group 2: 70.8% 5 in Group 3 switched to
Group 2: 75 mcg (n = 48) at 8 weeks Group 3: 58.3% Group 2
Group 3: placebo(n = 48) p = 0.005 No detail on % granulation
Weeks to complete Group 1:3 weeks at recruitment
response (>75% Group 2: Significance of results difficult
granulation) 3 weeks to interpret
Group 3:
5 weeks
1 vs 3 p = 0.006
2 vs 3 p = 0.031
Uchi et al. [28] RCT DFU Partial dose-ranging ≥75% ulcer area by A 27/47 (57.5%) 1++ Per protocol analysis. Small ulcers
Double-blinded Non-infected placebo-controlled 8 weeks B 34/47 (72.3%) at baseline
Study quality, Wagner grade II study C 37/45 (82.2%) Overlap between primary and
8/9 Area <900 mm2 bFGF sprayed on as C versus A p = 0.025 secondary outcome measures
ABPI > 0.9 or palpable pulses 5 puffs daily 5 cm Healing A 22/47 (46.8%)
N = 150 from target area B 27/47 (57.4%)
Three groups for 8 weeks C 30/45 (66.7%)
A Placebo n = 49 p = NS
B 0.001% bFGF n = 51 ≤ depth by 8 weeks A 26/47 (55.3%)
C 0.01% bFGF n = 50 B 29/47 (61.7%)
C 32/45 (71.1%)
p = NS
Kusumanto et al. [30] RCT 54 patients with CLI: Intramuscular injection of Improvement in ulcer Intervention: 7/21 (33%) 1++ Not clear if the subset with
Double-blinded 27 in each group. phVEGF165 gene carrying (decrease in ulcer area Control: 0/17 DFU were comparable
Study quality, Subset with DFU: plasmid 2000 mcg on days 0 by >60%) p = 0.01 between groups
7/9 Intervention: 21 and 28 versus Major amputation Intervention: 3/27 (11%) at baseline
Control: 17 saline control Control: 6/27 (22%) Data on amputation not
Follow-up over 100 days NS cited separately for the
population with DFU
Lázaro-Martínez Non-blinded DFU Protease modulating Healing Per protocol analysis only 1 Small study
et al. [31] RCT N = 40 dressing changed each Intervention: 12/19 (63%) Per protocol
DOI: 10.1002/dmrr
129
Study quality, Non-infected neuropathic day until healing Control: 3/19 (15%) analysis. Some wounds
130
3/9 TcpO2 >30 mmHg or 42 days p < 0.03 post-surgical

Intervention, n = 20 Time to healing Intervention: 23.3
Control, n = 20 (SD 9.9) days
One drop-out Control: 40.6 (SD 1.15)
from each group p < 0.01
Kakagia et al. [32] RCT DFU Group 1: Protease Healing at 8 weeks Group 1: n = 2 1 Description of methods
Single-blind N = 54 modulating dressing Group 2: n = 2 incomplete
Study quality, >3 months versus autologous Group 3: n = 2 Results difficult to interpret
4/9 >2.5 cm2 post debridement platelet supernatant % change in length Group 1: 18.6% because data not fully
3 lost to follow-up over 8 weeks Group 2: 14.3% presented
Not clear how many in Group 2: Group 3: 33.8% Small sample size
each group Protease modulating p < 0.01
dressing versus % change in width Group 1: 23.9%
Group 3: both Group 2: 17.4%

Group 3: 46.1%
p < 0.01
% change in depth Group 1: 35.5%
Group 2: 34.9%
Group 3: 551%
p < 0.01
Lyons et al. [33] RCT DFU N = 46 Talactoferrin alpha 75% reduction ulcer 2.5% gel: 1 Surrogate outcome measure
Single-blind 2.5% gel (n = 15) (recombinant human size at 12 weeks 7 patients (47%) but no difference
Partial dose- 8.5% gel (n = 15) lactoferrin) gel 8.5% gel:
ranging Placebo (n = 16) Topical administration 8 patients (53%)
Study quality, twice daily for 30 days Placebo:
2/9 2.5%, 8.5% versus 4 patients (25%)
placebo NS
Complete wound Intervention: 30%
healing at 90 days Control: 19%
Combined intervention p = 0.09
groups versus placebo
Brigido [34] RCT DFU N = 28 Wagner II Human acellular Healing Intervention 12/14 1 No data on baseline ulcer
Open label >6 weeks regenerative tissue (85.7%) area and yet gross
Study quality, (plus one leg ulcer) matrix (Graftjacket) Control: 4/14 (28.6%) difference between groups
2/9 Palpable/audible pulses Single application with p = 0.006 in final area
Non-infected mineral oil-soaked Final ulcer area Intervention: 1.0 Non-blinded
fluff versus wound (SD 2.57) cm2 Limited information on
gel and gauze Control: 31.14 co-morbidity
(SD 43.74) cm2
p = 0.005
Reyzelman et al. [35] RCT DFU N = 86 Single application Healing at 12 weeks Intervention: 32 (69.6%) 1 Unblinded
Open label UT grade 1 or 2 Acellular dermal Control: 18 (46.2%) Combined intervention
Study quality, Size 1–25 cm2 regenerative tissue p = 0.03 tissue matrix plus silver
3/9 TcpO2 > 30 matrix plus silver NA Time to complete Intervention: 5.7
ABPI 0.7–1.2 dressing versus healing (SD 3.5) weeks
Intervention, n = 47 standard moist wound Control: 6.8
Control, n = 39 care (SD 3.3) weeks
Fife et al. [36] RCT Patients with leg or Chrysalin (TP508): ligand Complete closure DFU: Group 1: 9/12 (75%) 1 Limited information about
Double-blind foot ulcer: N = 60 for thrombin binding within 20 weeks Group 2: 7/10 (70%) treatment application
Partial dose- DFU: n = 35 sites. Group 3: 4/13 (31%) Limited information about
ranging study Present >8 weeks Total population Group 1 versus baseline co-morbidities
Study quality, Wagner 1–III Group 1: 1 mcg n = 21, Group 3 p < 0.05 High dropout rate
3/9 TcpO2 ≥20 mmHg 12 with DFU Group 1 and Group 1: 5
Mean ulcer area Group 2: 10 mcg n = 18, Group 2 combined Group 2: 3
DOI: 10.1002/dmrr
F. L. Game et al.
(continued)
Application of cells, including platelets

25% were ulcers of lower leg and stem cells
No details on arteriopathy
Standard therapy unclear
Actual healing incidence

The previous review identified five papers reporting the use
Intervention unclear
of platelet-derived products, but all were limited by metho-
dological problems, and no firm conclusion could be drawn,
or neuropathy
although there were data to suggest possible benefit. Other
Group 3: 6
not given
work on stem cells had been restricted to uncontrolled and
observational studies. The present search revealed one
further study of the use of platelets as well as two further
studies. The details are presented in Table 6.
Intervention: 0.15 cm2/day 1
One major reason for limited adoption of platelet and

Total 87 days; DFU 71.5 days
Intervention: 0.09 mm/day
platelet-derived products is the cost of harvesting autolo-

Total 122 days; DFU 94 days
gous platelets. One group has, however, now assessed

versus Group 3 p < 0.05
Group 2 versus Group 3
Control: 0.07 cm2/day
Control: 0.07 mm/day
the use of platelets from ABO and rhesus-matched blood

Group 3: >140 days
bank samples in a single-blind RCT of good quality [38].

DFU, diabetic foot ulcer; ABPI, ankle : brachial pressure index; bFGF, basic fibroblast growth factor; NA,non-adherent; CLI, critical limb ischaemia
They reported a significant improvement in the healing

of the intervention group at 12 weeks compared with con-
p = 0.145
Group 1:
Group 2:
p = 0.09
p < 0.05
trols. The report gave no details of the inclusion criteria,

but given that 38 of the 52 in the intervention group
had exposed bone at baseline, the incidence of healing
was surprisingly high.
ulcer area (cm2/day)
perimeter (mm/day)
A retrospective comparison of fibroblast allograft recipi-

Rate of change of
ents and controls was reported by Seung-Kyu and collea-

Change of ulcer
Median time
gues [39]. A significant improvement in healing at

to closure
8 weeks in the 37 recipients who opted to have the treat-

ment when compared with 18 controls who did not was
reported. Selection bias could have influenced the results.
An observer-blind good quality RCTcomparing autologous
lipoaspirate cells or placebo was identified [40]. The inter-
Group 3: placebo (saline)
20 weeks or until healing

Twice weekly visits up to
versus standard therapy
vention group had a significantly higher incidence of healing

aqueous plant extract
n = 21, 13 with DFU
Tinospora cordifolia
at 8 weeks as well as a significantly reduced time to healing.

Topical application
and debridements
10 with DFU
Bioengineered skin and skin grafts
The earlier review noted that both dermal fibroblast cul-

ture and fibroblast/keratinocyte co-culture were asso-
Group 1: 3.59 (SD 5.31) cm2
Group 3: 4.11 (SD 5.99) cm2
ciated with improved healing of clean neuropathic ulcers

Group 2: 315 (SD 3.2) cm2
when compared with placebo, although the strength of

Ulcers >4 cm2 diameter
amputations or chronic
Digital ray or forefoot
the observation was weakened by variable rates of healing

18 month follow-up
5 lost to follow-up
non-healing ulcers
in the placebo groups. A single RCT reported the use of

Control, n = 22
Wagner I or II
keratinocytes alone, but few data were presented. The

DFU N = 50
present search identified two further papers reporting

the use of skin substitutes, as well as one on the use of
skin grafts. The details are given in Table 7.
A recently reported RCT was identified, which reported
the results of a well-designed multicentre RCT undertaken
Study quality,
Double-blind
some years earlier, in which the 12-week healing associated

with the use of fibroblast/keratinocyte co-culture (Apli-
grafW) was compared with polyamide and saline moistened
RCT
4/9
gauze [41]. The study had been stopped prematurely for

reasons unrelated to the conduct of the trial, when only
72 of 120 participants had been randomized, and data were

reported on 71 of these. Even though healing occurred in
Purandare and
51.5% of the intervention group compared with 26.3% of

Supe [37]
controls (p = 0.049), the failure to complete the study casts

doubt on the significance of the difference observed and
adds little to the available evidence.
DOI: 10.1002/dmrr
132
Table 6. Application of cells, including platelets and stem cells
Jeong et al. [38] RCT DFU N = 100 Intervention: blood bank Healing at 12 weeks Intervention: 41:52 1+ Inclusion/exclusion criteria not clear
Single-blind Intervention, n = 52 platelet concentrate (79%) versus control: 38/52 in the Intervention group had
Study quality, 6/9 Control, n = 48 (ABO and Rh compatible) 22:48 (46%) exposed bone: surprisingly high
Wagner I–II with fibrinogen (activator) p < 0.05 rate of healing
Mean area 5.7 (SD 3.6) cm2 and thrombin (sealant) Time to healing Intervention: 7.0

Duration >4 weeks: Applied following (SD 1.9) weeks vs 9.2
mean 12.4 (SD 5.6) weeks debridement on 2 (SD 2.2)
occasions, 3–4 days apart p < 0.05
Control: fibrinogen plus % reduction in area Intervention: 96.3
thrombin (SD 7.8) vs control:
81.6 (SD 19.7)
p < 0.05
Satisfaction (VAS) Intervention: 7.6 1.6
vs control: 5.3 (SD 1.4)
p < 0.05
Seung-Kyu et al. [39] Case–control Non-infected DFU N = 55 Intervention: fresh human Healing at 8 weeks Intervention: 83% (n = 37) 2 Retrospective analysis
Study quality, 2/7 Without severe arteriopathy fibroblast allograft with Control: 50% (n = 18) Selection bias as intervention group
Intervention, n = 37 fibrinogen and local (p < 0.05) comprised those accepting fibroblast
Control, n = 18 thrombin Time to healing in Intervention: 31 days treatment, whereas controls did not
TcpO2 >30 mmHg Control: fibrinogen and those who healed Control: 42 days accept this treatment
ABPI > 0.5 thrombin without (p < 0.05) No details on arterial status
fibroblasts
Seung-Kyu et al. [40] RCT DFU N = 54 Intervention: single Healing at 8 weeks Intervention: 26/26 1+ Patient groups very similar at
Single-blind Non-ischaemic treatment human Control: 16/26 baseline
Study quality, 6/9 non-infected lipoaspirate cells p < 0.05 Outcome assessments
Wagner I or II autograft, tegaderm Time to healing Intervention: 33.8 (but not patients) blinded
At least 6 weeks duration as dressing. Control: the (SD 11.6) days to group allocation
Intervention, n = 28 same cell carrier without Control: 42.1
Control, n = 26 lipoaspirate cells (SD 9.5) days
Mean duration: p < 0.05
Intervention: 12.5
(SD 5.6) weeks
Control: 12.5
(SD 5.5) weeks
Area:
Intervention: 4.3 cm2
Control: 4.0 cm2
DFU, diabetic foot ulcer; ABPI, ankle : brachial pressure index; VAS, visual analogue scale
DOI: 10.1002/dmrr
F. L. Game et al.
Table 7. Bioengineered skin and skin grafts

Edmonds [41] RCT DFU N = 72 Intervention: ApligrafTM Healing at 12 weeks Intervention: 17/33 1+ Prematurely stopped by sponsor
Open label from 20 centres (living keratinocytes (51.5%) for non-safety reasons (original
Study quality, 5/9 Neuropathic non- Control: 10/38 aim 120 patients per arm)
and fibroblasts)
infected ulcers Control: polyamide and (26.3%) Low healing rate in the control
Intervention, n = 33 saline moistened gauze p = 0.049 group but median ulcer duration
Control, n = 39 prior to recruitment was long:
Intervention: 1.1
Control: 1.2 years
Moustafa et al. [42] RCT DFU N = 12 Intervention: dressing with Healing Intervention: 4/7 1 Weak design. Very small sample
Open label Wagner I autologous keratinocytes Control: 1/5 size, inconclusive result
Study quality, 3/9 once a week during 12 weeks
Control: dressing without
cells during 6 weeks then
one treatment once a week
during 6 or 12 weeks
Mahmoud et al. [43] Case–control DFU N = 100 Intervention: skin graft Median healing time Intervention: 34 days 2 Biased as patients allowed to
Study quality, 3/7 Intervention, n = 50 Control: paraffin gauze Control: 145 days choose treatment group
Control, n = 50 p = 0.03 Few data on baseline
ABPI ≥ 0.4 Mean hospital stay Intervention: 6 days characteristics of groups
DFU ≥ 2 cm2 Control: 18 days All patients eventually healed,
Ulcer area and duration p < 0.05 but no data on how healing
equivalent in the Ulcer recurrence Intervention: 8% confirmed
two groups Control: no result given
DFU, diabetic foot ulcer; ABPI, ankle : brachial pressure index.
DOI: 10.1002/dmrr
133
Equally, the very small RCT that reported the use a A double-blind RCT of up to 3 months treatment with a
novel keratinocyte delivery system was of very poor meth- low molecular weight heparin, bemiparin, reported a sta-
odological quality, and the result was inconclusive [42]. tistically significant difference in the size or Wagner grade
Mahmoud and colleagues reported a case–control study of uncomplicated foot ulcers, although there was no dif-
with 50 having their foot ulcer managed by split skin graft ference in the percentage healing in the intervention
and 50 having paraffin gauze dressings [43]. The authors and control groups (35.1% vs 33.3%, respectively) [48].
reported a significant difference in median healing time A small poor quality RCT of iloprost infusion was con-
between groups, but the study was of poor methodological ducted with the main aim of investigating changes in
quality and susceptible to bias because the patients had the endothelial function in patients with severe peripheral
option to select their treatment group. ischaemia and Wagner grade III–IV foot ulcers, but the inci-
dence of amputation at 30 days was also reported [49]. The
intervention group received treatment for ten consecutive
Electrical, electromagnetic, lasers, days, whereas controls had no treatment; the study was
shockwaves and ultrasound unblinded. There was no apparent difference in the inci-
dence of major and minor amputations between the inter-
The previous review described reports on the use of elec- vention groups.
trical stimulation, ultrasound, normothermic therapy, In a study of a Chinese herbal preparation, 80 partici-
magnets and laser therapy but found no convincing evi- pants with necrotic/gangrenous ulcers who had pre-
dence of clear benefit of any. The present search resulted viously been deemed to require amputation of the digit
in the selection of four further papers on physical meth- were randomized to receive either the herbal formulation
ods, and the details are given in Table 8. or placebo in a patient-blinded RCT [50]. There was no
A cohort study investigated reduction in ulcer area fol- difference between groups in the primary end point,
lowing rhythmical electrical stimulation of the edge of the which was time to ulcer granulation sufficient to enable
ulcer on alternate days over 1 month [44]. The study was skin grafting. There was similarly no difference in the
methodologically weak, however, and the means of alloca- incidence of amputation.
tion to groups was not clear. Although there was an appar- In another study of a herbal extract ANGIPARS™, 21
ently greater reduction in ulcer area at 45 days, this was not participants were randomized in a three-way trial compar-
maintained at 60 days. ing the reduction in wound surface area at 6 weeks fol-
A second study [45] compared the use of electrical sti- lowing treatment with (1) twice daily oral administration
mulation with a placebo comprising local warming of of the herbal extract, (2) oral administration plus topical
the skin. Although a significant reduction in ulcer area application of the extract to the wound surface and (3)
in the intervention group was seen at 4 weeks, the study standard care [51]. Significant reductions in surface area
was very small and methodologically weak, and the lack were reported within group for the two treatment groups
of blinding throws doubt on the significance of the differ- but not for the control. No between-group comparisons
ence described. were reported. The quality of the trial methodology was
No studies on shockwave therapy were included in the low scoring.
earlier review, but the present search yielded two trials. The same preparation which was reported above is also
The first randomized 30 patients to receive either shock- available for intravenous administration and was the basis
wave therapy to the perimeter of the ulcer each 72 h or of another small and methodologically weak RCT [52].
a sham intervention [46]. There was no difference in Intravenous herbal extract was administered daily for
healing by 20 weeks, although the time to healing in the 28 days, and the primary outcome measure was change
small number who were healed was reported to be signif- in ulcer area over the same period. A highly significant
icantly shorter. The strength of the statistical significance change in area was reported in the intervention group,
is surprising for such small numbers and may relate to the but the change in the (smaller number of) controls was
inappropriate use of parametric statistics. not significant. There also appeared to be a difference
The second compared extracorporeal shockwave treat- between the groups in terms of the ulcer area at baseline
ment with hyperbaric oxygen [47]. Again methodologically (intervention 479.9 vs 766 mm2).
weak, the reporting of a significant difference between the
two groups was based on a curious composite end point of
the proportion of ulcers healed, or ‘greater than 50% im-
proved’. Our reworking of the statistics based on the raw Discussion
data given in the paper casts doubt on even these results.
The response to treatment of many diabetic foot ulcers is
poor, and this tempts clinicians to try any therapy which
Other systemic therapies may hasten healing. It is, however, important that the ef-
fectiveness of different treatments is rigorously assessed,
Five trials were identified, which did not fit into any of the and treatments that lack evidence of effectiveness should
categories used in the earlier review. The details are given not be used. The present report is an update of an earlier
in Table 9. IWGDF systematic review in 2007[3], and the conclusion
DOI: 10.1002/dmrr
Table 8. Electrical, electromagnetic, lasers, shockwaves and ultrasound
Margara et al. [44] Cohort DFUs N = 30 Frequency rhythmic Reduction in ulcer area 30 days 2 Means of allocation not clear
Study quality, 3/8 Intervention, n = 16 electrical modulation at 30, 45 and 60 days Intervention: 33 (SD 22)% Not randomized
Control, n = 14 applied to edge of ulcer as % baseline Control: 14 (SD 10)% Possible less than adequate
Not infected for 30-min sessions p < 0.05 management of control group
Baseline ulcer area: alternate days for 45 days No difference in long-term
Intervention: 8.08 1 month Intervention: 65 (SD 14)% outcome
(SD 2.36) cm2 Control: dressing at Control: 51 (SD 14)%
Control: 8.01 least weekly p < 0.05

(SD 2.23) cm2 Follow-up 2 months 60 days
Intervention: 93 (SD 1)%
Control: 83 (SD 15)%
NS
Petrofsky et al. [45] RCT DFU N = 20 Electrical stimulation Reduction in wound Intervention: 68.4 (SD 28.6)% 1 Assessment difficult because
Open label Wagner II and local heat area at 4 weeks Control: 30.1 (SD 6.7)% p < 0.05 of much missing data
Study quality, 3/9 Baseline area (infrared lamp) determined by length Small sample size
Intervention: 30 min 3 times a and width multiplied; Rate of healing surprisingly
(n = 10) 24.1 week for 4 weeks digital images high considering the baseline
(SD 6.2) cm2 versus infrared Wound volume at Intervention: 69.3 (SD 27.1)% wound area
Control: (n = 10) lamp alone 4 weeks Control: 22.3 (SD 5.3)%
28.2 (SD 5.7) cm2 p < 0.05
Moretti et al. [46] RCT DFU N = 30 Extracorporeal Healing at 20 weeks Intervention: 8/15 1+ Non-blinded. No detail on index
Open label Intervention, n = 15 shockwave therapy Control: 5/15 of epithelialization
Study quality, 5/9 Control, n = 15 3 sessions each 72 h NS No detail on frequency of
Neuropathic with 100 pulses per cm2 Time to healing Intervention: 60.8 (SD 4.7) days follow-up
ABPI > 0.7 to perimeter of ulcer Control: 82.2 (SD 4.7) days Very small numbers
Baseline mean versus standard care p < 0.001 Possible inappropriate use of
wound area: Index of epithelialization Intervention: 2.97 mm2/day parametric statistics
Intervention: 297.8 Control: 1.3 mm2/day
(SD 129.4) mm2 p < 0.001
Control: 245
(SD 100.9) mm2
Wang et al. [47] RCT DFU N = 74 Extracorporeal Composite end point: p = 0.001 for composite: 1 Unusual choice of composite
Non-blinded present for >3 months shockwave treatment Complete healing/more Healing end point
Study quality, 3/9 4 lost to follow-up each 2 weeks for three than 50% improved or Intervention: 11/36 ulcers The stated level of significance
35 in each group treatments, repeated if unchanged Control: 8/36 seems high, given the apparent
Mean ABPI: necessary Improved small difference in outcome
Intervention: 1.22 Controls received HBO daily Intervention: 21/36 between groups
Control: 1.26 for 20 treatments Control: 18/36
Mean follow-up Unchanged
Intervention: 11.64 Intervention: 4/36
(6–14) months Control: 10/36
Control: 12.14
(6–14) months
DFU, diabetic foot ulcer; ABPI, ankle : brachial pressure index; HBO, hyperbaric oxygen.
DOI: 10.1002/dmrr
135
136
Table 9. Other systemic therapies
Rullan et al. [48] RCT Patients N = 70 Bemiparin 3500 IU/day Composite primary Intervention: 70.3% 1+ Sample size powered to
Double-blind with leg for 10 days followed by outcome: vs control: 45.5% detect a difference of 30%
Study quality, 6/9 (n = 18) and DFU 2500 IU/day for up to Decrease in ulcer area by (p = 0.035) (65% vs 35%)
(n = 52) 3 months versus saline ≥50% or reduction in Post hoc analysis of DFU Composite end point
DFU: Wagner grade I–II control Wagner grade at 3 months group 72.4% vs 47.8% DFU subgroup subjected to
Intervention, n = 37 (CI 1.5–50.7) post hoc analysis with
Control, n = 33 Secondary outcome: Intervention: 35.1% no significant
healing by 3 months vs control:33.3% difference between groups
(p = 0.874) but no details given

Sert et al. [49] RCT DFU N = 60 Intervention: iloprost Amputation rate at Intervention: 25/30 1 Study was primarily designed
Open label Wagner III–IV (prostacyclin) 0.5 to 30 days amputations (12 minor to investigate endothelial
Study quality, 3/9 Severe peripheral 2 ng/kg/min over 6 h for and 13 major) function
ischaemia without 10 consecutive days Control: 29 /30 Results regarding healing
possibility for vascular Control: no iloprost amputations (12 minor are inconclusive
intervention and 17 major) (NS)
Control, n = 30
Leung et al. [50] RCT DFU N = 80 Intervention: Chinese Time to ulcer granulation Intervention: 5.9 weeks 1 Patient blind but probably
Single-blind Necrotic and/or infected oral herbal to enable skin grafting Control: 9.2 weeks not investigator or observer
Study quality, 4/9 ulcers 47% gangrenous formulation NS blind only
toes deemed requiring Control: oral placebo Amputation first Intervention: 3 Time to total amputations
amputation 4 weeks Control: 3 not known
Unhealed ulcers for Eventual amputations Intervention: 3 Amputation is not defined
up to 25 weeks Control: 9 as major/minor
Intervention, p = 0.057 Study was for 4 weeks, but
n = 40 all patients received study
Control, n = 40 drug at 4 weeks if no
healing or improvement
Bahrami et al. [51] RCT DFU N = 21 Intervention: ANGIPARS™ % wound surface change G1: 375 (SD 118) mm2 1 Large difference in baseline
Single-blind No improvement in herbal extract plus at 6 weeks to 41.7 (SD 33.7) mm2 area between G2 and G3
Study quality, 4/9 2 weeks standard care (88% reduction) ? inappropriate use of
Wagner grade I–II 1 oral 100 mg bd for p = 0.04 parametric statistics
Total 21: 6 weeks G2: 916.7 (SD 228.6) No between-group
G1: 6 2 oral as above plus to 137.5 (SD 41.7)mm2 comparisons
G2: 6 3% gel to wound (84%reduction)
G3: 9I Control: standard p = 0.01
wound care (specified G3: 766.3 (SD 320.2 to 689.1
in general terms) (SD 329.1) mm2
(25% reduction)
p = 0.076
‘Improvement’ Complete improvement:
on 4-point scale Group 1: 5
‘Complete’ = >70% Group 2: 6
improved Group 3: 2
Relative improvement Group 1: 1
= 10–70% Group 2: 0
Group 3: 1
DOI: 10.1002/dmrr
F. L. Game et al.
(continued)
is similar: that with the exception of hyperbaric oxygen
Control group have larger

Primary outcome healing
therapy (HBOT) and, possibly, negative pressure wound
at 4 weeks but no data

therapy, there is little published evidence to justify the
Unequal distribution
wounds at baseline
Blinding uncertain
use of more recent therapies. This echoes the conclusion
Small sample size
between groups
of a recent Cochrane review [53] and the systematic review
undertaken by the National Institute for Health and Clinical
Excellence Guidelines Committee in the UK [54].
given
Analysis of evidence presents considerable difficulties in
this field. The number of controlled studies is small, and
the majority are of poor methodological quality. Moreover,
1
the complexity of the clinical condition and its frequently

slow response to intervention pose particular problems in
trial design. Of these, the most important relates to the
(SD 379.8) mm2 to 198.9
(SD 960.5) mm2 to 689.1
selection of the primary outcome measure. The most clini-

64% vs 25% reduction
cally relevant measures are healing, time to healing,

Intervention: 479.9
avoidance of amputation and survival, but these may not

(64% reduction)
(25% reduction)
(SD 143.8) mm2
(SD 846.7) mm2
necessarily reflect the effect of a chosen intervention. Thus,

Control: 766
a therapy or dressing may have a significant stimulatory

p = 0.000
p = 0.076
p = 0.015
effect for only a finite period during the course of the life
span of the ulcer being treated. Antibiotics may have a clear
benefit in the management of any ulcer that is infected but
may not influence the overall rate of healing if this is criti-
cally affected by other factors, such as poor peripheral circu-
Change in ulcer area
lation. Nevertheless, these problems do not mean that stu-

dies of effectiveness should not be undertaken: they just
need to be designed with great care.
at 4 weeks
New evidence of effectiveness of tested

interventions
Intervention: ANGIPARS™
saline daily for 28 days
When the results of this updated review are taken

IV 4 mL in 50–100 mL
Control: placebo plus

plus standard wound
standard wound care
together with those of the earlier report, they provide lim-

ited evidence to justify a change in routine clinical prac-
tice. With the exception of a new RCT on HBO and a further
study reporting a weakly significant benefit of negative
pressure therapy, all either showed lack of effect and/or
care
were of questionable methodological quality.
Scoring of published articles

>2 weeks without
Intervention: 16
improvement
The chosen scoring system is primarily based on aspects of

Control: 9
trial design, whereas the concern of clinicians is with both

DFU 25
study design and conduct. This can lead to some anoma-

lies, with relatively poor studies scoring highly on the
basis of stated design.
Blinding uncertain
Study quality, 3/9
Aspects of trial design and choice of

end points
RCT
DFU, diabetic foot ulcer
Trial design is very difficult in this field because the popu-

lation (of both people and ulcers) is heterogeneous, with

Larijani et al. [52]
multiple factors contributing to both ulcer onset and fail-

ure to heal. As an intervention is likely to be directed at
only one of these factors, it is poss xible that an agent
can have an effect, but this may be hidden. As ulcers also
typically take many weeks to heal, it is likely that the factor
DOI: 10.1002/dmrr
most responsible for healing delay may be different at dif- Debridement

ferent stages of the process, and this means that an agent
may be effective at one stage but not necessarily all the ((“Debridement”[MeSH]) OR (debrid* OR larv* OR
time. This leads to uncertainty concerning the choice of enzym* OR surgic* OR topical OR silver* OR iodin* OR
end points. Clinically relevant end points (such as ulcer mechanic* OR biologic* OR autol*))
healing or amputation) may mean more in practice but
may be only partially dependent on any effect of the chosen
intervention. On the other hand, surrogate end points (such
as change in wound bed appearance or in ulcer area) may Bioengineered skin and skin grafts
be more closely related to the effect of the product being
tested but have little relevance to clinical outcome. ((“Skin Transplantation”[MeSH]) OR (skin graft OR bio
engineered skin OR bioengineered skin OR bio-
engineered skin OR dermagraft OR apligraf OR tendra))
Ulcer characterization
One surprising feature of selected articles is the widespread Electromagnetic, laser and ultrasound
reliance on the Wagner classification of wound type. This
method is widely regarded as being relatively imprecise
therapy
and has been to a large extent rejected by many experts in
((“Electromagnetics”[MeSH] OR “Lasers”[MeSH] OR
the field. More recent options (such as University of Texas,
“Ultrasonic Therapy”[MeSH]) OR (Electromagnetic* OR
“PEDIS” and “SINBAD” [55]) should be used in future
Laser* OR Ultrasonic Therap* OR ultrasonic OR
studies.
magnetic))
Appendix A Stem cell therapy
Search strings for each ((“Stem Cells”[MeSH] OR “Stem Cell Transplantation”

[MeSH]) OR (Stem Cell* OR Stem Cell therapy OR
of the sections marrow OR GCSF OR granulocyte colony stimulating

factor*))
(((“Growth Substances”[MeSH] OR “Endothelial Growth
Factors”[MeSH] OR “Fibroblast Growth Factors”[MeSH]
Medline search ‘Wound Healing OR “Hematopoietic Cell Growth Factors”[MeSH] OR “Vas-
cular Endothelial Growth Factors”[MeSH] OR “Epidermal
Guidelines’ Growth Factor”[MeSH] OR (“Fibroblast Growth Factor
2”[MeSH] OR “Fibroblast Growth Factor 1”[MeSH] OR
Dec 2006 to June 2010
“Granulocyte-Macrophage Colony-Stimulating Factor”
Basic search was combined with searches for specific
[MeSH]) OR “Platelet-Derived Growth Factor”[MeSH])
interventions of interest by adding the search term AND
OR (Growth Substance* OR Endothelial Growth Factor*
OR Fibroblast Growth Factor* OR Hematopoietic Cell
Growth Factor* OR Vascular Endothelial Growth Factor*
Basic search OR Epidermal Growth Factor* OR Fibroblast Growth
Factor 2 OR Fibroblast Growth Factor 1 OR Granulocyte-
(((“Diabetes Mellitus”[MeSH]) OR (Diabetes Mellitus) Macrophage Colony-Stimulating Factor OR Platelet-
OR (Diabetes)) AND ((“Clinical Trials”[MeSH]) or (“com- Derived Growth Factor) OR (Growth Factor OR Growth))
parative study”[Mesh]) OR (“epidemiologic study charac- OR (matrix replacement OR hyalofil* OR collagen* OR
teristics”[Mesh]) OR (Clinical Trial*) OR (case-control emdogain OR hyaluronic acid OR metalloproteinase
stud*) OR (case control stud*) OR (cohort stud*) OR inhibitor*) OR (tissue enzym* OR timp* OR promogran*
(Comparative stud*)) AND ((“Foot Ulcer”[MeSH]) OR OR tissue inhibitor* OR metalloproteinase*) OR (angio-
(Foot Ulcer) OR (Ulcer) OR (diabetic foot))) genesis OR gene therap* OR vascular endothelial growth
factor* OR VEGF))
Dressings
Tissue oedema
((“Biological Dressings”[MeSH] OR “Occlusive Dressings”
[MeSH] OR “Bandages, Hydrocolloid”[MeSH]) OR (film* ((vac OR vacuum assisted closure OR vacuum* OR kerra-
OR foam* OR hydrogel* OR hydrocolloid* OR alginat* boot OR compress*) OR (“Bandages”[MeSH]) OR (stock-
OR hydrofib* OR dressing*)) ing* OR elastic OR bandage*))
DOI: 10.1002/dmrr
Hyperbaric oxygen Electromagnetic, laser and ultrasound

((“Hyperbaric Oxygenation”[MeSH]) OR (hyperbar* OR ((‘electromagnetic radiation’/exp OR ‘electromagnetic
oxygen*)) radiation’) AND [embase]/lim) or ((‘ultrasound therapy’/
exp OR ‘ultrasound therapy’) AND [embase]/lim) or (elec-
tromagnetic* OR laser* OR ‘ultrasonic therap’ OR (‘ultraso-
Resection of the chronic wound/ nic’/exp OR ‘ultrasonic’) OR magnetic AND [embase]/lim)
surgical procedures
((surgic* OR resect* OR remov* OR excisi*) OR (“Surgical Stem cell therapy
Procedures, Operative”[MeSH]) OR (“surgery”[Subheading]))
((‘stem cell’/exp OR ‘stem cell’) AND [embase]/lim) or
((‘stem cell transplantation’/exp OR ‘stem cell transplan-
Embase search ‘Wound Healing tation’) AND [embase]/lim) or ((‘stem cell therapy’/exp
Guidelines’ OR ‘stem cell therapy’) OR ‘stem cell’ OR (‘marrow’/exp
OR ‘marrow’) OR gcsf OR ‘granulocyte colony stimulating
Dec 2006 to June 2010 factor’ AND [embase]/lim)
Basic search was combined with searches for specific
interventions of interest by adding the search term AND
Abnormalities of wound biology and
Basic search gene therapy
((((‘observational study’/exp OR ‘observational study’) ((‘growth factor’/exp OR ‘growth factor’) AND [embase]/
AND [embase]/lim) or ((‘experimental study’/exp OR lim) or (‘matrix replacement’ OR hyalofil* OR collagen*
‘experimental study’) AND [embase]/lim) or ((‘controlled OR emdogain OR (‘hyaluronic acid’/exp OR ‘hyaluronic
study’/exp OR ‘controlled study’) AND [embase]/lim) or acid’) OR (‘metalloproteinase inhibitor’/exp OR ‘metallo-
((‘comparative study’/exp OR ‘comparative study’) AND proteinase inhibitor’) OR ‘tissue enzym’ OR timp* OR pro-
[embase]/lim)) and ((‘diabetes mellitus’/exp/mj OR ‘dia- mogran* OR ‘tissue inhibitor’ OR metalloproteinase* OR
betes mellitus’) AND [embase]/lim)) and (((‘foot ulcer’/ (‘angiogenesis’/exp OR ‘angiogenesis’) OR ‘gene therap’
exp/mj OR ‘foot ulcer’) AND [embase]/lim) or ((‘diabetic OR (‘vegf’/exp OR ‘vegf’) AND [embase]/lim)
foot’/exp OR ‘diabetic foot’) AND [embase]/lim))
Tissue oedema
Dressings
((‘compression therapy’/exp OR ‘compression therapy’)
((‘bandages and dressings’/exp OR ‘bandages and dres- AND [embase]/lim) or ((‘vacuum assisted closure’/exp
sings’) AND [embase]/lim) or (film* OR foam* OR hydro- OR ‘vacuum assisted closure’) OR vacuum* OR kerraboot
gel* OR hydrocolloid* OR alginat* OR hydrofib* AND OR compress* OR stocking* OR elastic OR bandage* AND
[embase]/lim) [embase]/lim)
Debridement Hyperbaric oxygen

((‘debridement’/exp OR ‘debridement’) AND [embase]/
((‘hyperbaric oxygen’/exp OR ‘hyperbaric oxygen’) AND
lim) or (debrid* OR larv* OR enzym* OR surgic* OR
[embase]/lim) or (hyperbar* OR oxygen* AND
(‘topical’/exp OR ‘topical’) OR silver* OR iodin* OR
[embase]/lim)
mechanic* OR biologic* OR autol* AND [embase]/lim)
Bioengineered skin and skin grafts

Resection of the chronic wound/
((‘skin transplantation’/exp OR ‘skin transplantation’) surgical procedures
AND [embase]/lim) or ((‘skin graft’/exp OR ‘skin graft’)
OR ‘bioengineered skin’ OR ‘bio engineered skin’ OR ((‘orthopedic surgery’/exp OR ‘orthopedic surgery’) AND
‘bio-engineered skin’ OR dermagraft OR apligraf OR [embase]/lim) or (resect* OR surgic* OR remov* OR
tendra AND [embase]/lim) excisi* AND [embase]/lim)
DOI: 10.1002/dmrr
Acknowledgements Conflict of Interest

We thank Irina Gurieva, Kate Shu Shan and Edwin Soar for their
help in assessing papers written in Russian, Chinese and Spanish. None declared.
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DOI: 10.1002/dmrr

Chronic Ulcers of The Foot

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Chronic Ulcers of The Foot

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DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLE

Diabetes Metab Res Rev 2012; 28(Suppl 1): 119–141.

A systematic review of interventions to enhance the

Copyright © 2012 John Wiley & Sons, Ltd.

would not necessarily be expected

Period of study unclear – ran for

characteristics of groups similar

Unusual deﬁnition of healing

in a study of this type

‘at least 18 months’

Intervention: 10.8 min

complete closure by self

healing or suitable for

The earlier review found evidence from a single small

study of possible beneﬁt from the use of zinc oxide tape.

(Lucilia cuprina) larvae

with the use of a carboxymethylcellulose hydroﬁbre dres-

sing (AquacelW). However, in the present search, a large,

reported no difference between three products: Aqua-

celW, a surface antiseptic (InadineW) and a non-adherent

as of a variety of secondary outcome measures including

mean healing time, incidence of major and minor amputa-

n = 30. Patients with

another large, but non-blinded, RCT reported no difference

between a silver impregnated carboxymethylcellulose

incidence of complete healing over 8 weeks, healing velo-

city, change in ulcer area and time to healing. A weak sig-

and the observers were non-blinded [8]. Thus, the earlier

data on the use of hydroﬁbre dressings has not been con-

ﬁrmed in these more recent, and much larger, studies. In

the absence of supportive evidence, the additional

expense of the newer hydroﬁbre product is not justiﬁed.

trolled trials suggesting that hydrogels also may hasten

healing, but no new studies on hydrogels were identiﬁed

in this search, and the place of these products in routine

Copyright © 2012 John Wiley & Sons, Ltd.

Copyright © 2012 John Wiley & Sons, Ltd.

Copyright © 2012 John Wiley & Sons, Ltd.

Table 4. Compression and negative pressure therapy

Copyright © 2012 John Wiley & Sons, Ltd.

Copyright © 2012 John Wiley & Sons, Ltd.

Copyright © 2012 John Wiley & Sons, Ltd.

No statistical results given

3/9 TcpO2 >30 mmHg or 42 days p < 0.03 post-surgical

Copyright © 2012 John Wiley & Sons, Ltd.

Application of cells, including platelets

Actual healing incidence

One major reason for limited adoption of platelet and

Intervention: 0.09 mm/day

platelet-derived products is the cost of harvesting autolo-

gous platelets. One group has, however, now assessed

Group 2 versus Group 3

Control: 0.07 cm2/day

Control: 0.07 mm/day

the use of platelets from ABO and rhesus-matched blood

bank samples in a single-blind RCT of good quality [38].

They reported a signiﬁcant improvement in the healing

trols. The report gave no details of the inclusion criteria,

A retrospective comparison of ﬁbroblast allograft recipi-

ents and controls was reported by Seung-Kyu and collea-

gues [39]. A signiﬁcant improvement in healing at

8 weeks in the 37 recipients who opted to have the treat-

20 weeks or until healing