A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes

Abstract

The outcome of management of diabetic foot ulcers is poor and there is uncertainty concerning optimal approaches to management. We have undertaken a systematic review to identify interventions for which there is evidence of effectiveness. A search was made for reports of the effectiveness of interventions assessed in terms of healing, ulcer area or amputation in controlled clinical studies published prior to December 2006. Methodological quality of selected studies was independently assessed by two reviewers using Scottish Intercollegiate Guidelines Network (SIGN) criteria. Selected studies fell into the following categories: sharp debridement and larvae; antiseptics and dressings; chronic wound resection; hyperbaric oxygen (HBO); reduction of tissue oedema; skin grafts; electrical and magnetic stimulation and ultrasound. Heterogeneity of studies prevented pooled analysis of results. Of the 2251 papers identified, 60 were selected for grading following full text review. Some evidence was found to support hydrogels as desloughing agents and to suggest that a systemic (HBO) therapy may be effective. Topical negative pressure (TNP) may promote healing of post-operative wounds, and resection of neuropathic plantar ulcers may be beneficial. More information was needed to confirm the effectiveness and cost-effectiveness of these and other interventions. No data were found to justify the use of any other topically applied product or dressing, including those with antiseptic properties. Further evidence to substantiate the effect of interventions designed to enhance the healing of chronic ulcers is urgently needed. Until such evidence is available from robust trials, there is limited justification for the use of more expensive treatments and dressings. Copyright © 2008 John Wiley & Sons, Ltd.

Introduction

Ulcers of the foot in diabetes are the source of major suffering and cost 1, 2. Only two-thirds eventually heal 3–5. Up to 28% may result in some form of amputation 6. Management is based on the simple principles of eliminating infection 7, debridement, cleansing and the use of dressings to maintain a moist wound bed 8, 9. Many different interventions have been proposed to accelerate the healing process but few have been subjected to formal evaluation. In an earlier, non-systematic review by this group, we reported little evidence to substantiate the choice of any particular agent or intervention 10. A systematic review of current evidence has now been undertaken.

Materials and methods

Prospective and retrospective controlled studies, published in any language, that evaluated interventions for the treatment of chronic foot ulcers in people aged 18 years or older with either type 1 or type 2 diabetes mellitus were considered. Studies were included if they assessed the effect of interventions on healing, time to healing, reduction in ulcer area or amputation. The following databases: Medline (1966–2006), Embase (1980–2006), the Cochrane database of systematic reviews, and the Cochrane Central Controlled Trials Register (2006) were searched using strategies that included the search term on study design, patient group, clinical problem and interventions of interest (see Appendix). There were no language restrictions. Randomized controlled trials (RCTs), case-control studies, prospective and retrospective cohort studies, control before-and-after (CBA) design and interrupted time series (ITS) designs were included. Bibliography of the identified articles was not tracked down. Previously performed high-quality systematic reviews and relevant Cochrane reviews were searched to determine the need for an extension to the literature search.

One reviewer assessed all identified references by title and abstract on the basis of patient group, intervention and outcome. Full paper copies of identified articles were then assessed for eligibility by two independent reviewers and an agreement was reached on inclusion and exclusion following discussion. Each included paper was further assessed by two reviewers, working independently, and information was extracted on study design, patient group, intervention, outcomes, duration of and loss to follow-up, using standard data extraction sheets. Each study was scored for methodological quality using design-specific scoring, based on checklists developed by the Dutch Cochrane Center (www.cochrane.nl/index.html), with equal weighting being applied to each validity criterion. Findings on data extraction and methodological quality were discussed between co-reviewers and a final decision was made. Quality items were rated as ‘done’, ‘not done’, or ‘not reported’ and only those rated as ‘done’ contributed to methodological quality score. This quality score was translated into a level of evidence according to the SIGN instrument 11: (1) RCTs and (2) studies with case-control, cohort, CBA or ITS design. Studies were also rated as: + + (high quality with low risk of bias), + (well conducted with low risk of bias) and—(low quality with higher risk of bias). Meta-analyses, other reviews and studies reporting non-analytic case reports and case series were not included.

Extracted data were summarized in evidence tables on a study-by-study narrative basis. Because of the heterogeneity of study designs, interventions, follow-up and outcomes, no attempt was made to pool the results. These evidence tables were compiled following collective discussion by the working party and conclusions were drawn and recommendations formulated.

Results

Sharp debridement and wound bed preparation with larvae

The term debridement refers to the removal of surface debris, slough and infected matter with the aim of leaving clean, viable tissue that may then heal by secondary intention. Debridement may be undertaken surgically (sharp debridement), biologically (larvae), biochemically (enzymes), or chemically (antiseptics). There were 626 relevant papers identified in which effectiveness of an intervention was compared with a contemporary control group. Only 35 of these were judged potentially eligible after screening the abstract and only 3 studies were included following full text review (Table 1).

Table 1. Wound bed preparation by sharp debridement and the use of larvae

Wound bed preparation/debridement
Reference	Study design	Study population and characteristics	Intervention and control conditions	Outcome category	Results primary outcome + statistic	Level of evidence SIGN	Comments on weaknesses
I, intervention; C, controls.
Saap 2002 15	Cohort study Study quality: 5/8	143 evaluable subjects with neuropathic superficial diabetic foot ulcers followed for 12 weeks in a parent RCT	Assessment of the extent of sharp debridement on Day 0, using a debridement index	Closure of ulcer	A wound with a debridement index of 3–6 was 2.4 times more likely to heal than one with an index of 0–2 (p = 0.03)	2+	This was a sub‒analysis of a study of the effectiveness of another intervention, (Apligraf) Veves, et al. (2001)12
Sherman 200313	Cohort study Study quality: 3/8	18 subjects with 20 chronic, non‒healing ulcers divided into three groups: 6 conventional therapy, 6 debridement therapy with larvae, 8 conventional therapy followed by larval debridement therapy Followed for 14 weeks total	Debridement therapy with larvae	Decrease in extent of necrotic tissue at 2 weeks	Decrease in necrotic tissue (4.1 versus 0 cm^2) (p = 0.02) Larvae: complete debridement at 4 weeks versus 33% at 5 weeks (p = 0.001)	2−	Complex study. Comparison between groups difficult because of the use of different times to outcome
Armstrong 200514	Case‒control study Study quality: 1/7	30 people (mean age 72 years; 26 M) with diabetes and peripheral arterial disease and confined to either bed or wheelchair, who had their foot ulcers treated with larvae, compared to 30 age‒ and sex‒matched controls who had not	History of wound debridement with larvae	Healing; time to healing; major amputations Antibiotic use (antibiotic‒free days)	Trend to difference in ulcer healing (p = 0.07); Shorter time to healing (I: 18.5 versus C: 22.4 days, p = 0.04); Fewer major amputations (I: 10% versus C: 33%, p = 0.03) and more antibiotic‒free days: (I: 127 versus C: 82, p = 0.0001)		High percentage male. Unusual population. Cases and follow‒ups selected by those in whom 6‒month follow‒up data were available. Not clear if controls matched for criteria other than age and sex

Sharp debridement

The evidence of benefit of sharp debridement is not strong and is based on a single study comprising a subgroup analysis of cases from an RCT of another intervention 15. Healing at 12 weeks was more likely following a more vigorous debridement. An earlier paper of similar design was not included because of insufficient reported detail 16.

Larvae

Two studies evaluated the effectiveness of debridement with larvae. The first was small and the structure complex, but reported a significant effect in 2 weeks 13. The second was a study of elderly, non-ambulant (bed or wheelchair bound) people with peripheral arterial disease, and reported decreased time to healing, decreased incidence of major amputation and reduced requirement for antibiotics in the intervention group 14.

Wound bed preparation using antiseptics, applications and dressing products

Dressing products may encourage debridement by either dessicating or binding to debris such that it is removed with dressing changes. Dressings may also facilitate autologous debridement by providing a warm moist environment. Some may have antimicrobial activity. The search identified 98 papers, of which 37 were considered for selection after screening the titles and abstracts and 11 were included after full text review (Table 2).

Table 2. Wound bed preparation using antiseptics, applications and dressing products

Reference	Study design	Study population and characteristics	Intervention and control conditions	Outcome category	Results primary outcome + statistic	Level of evidence SIGN	Comments on weaknesses
RCT, randomized controlled trial.
Apelqvist 199617	RCT Study quality: 3/9	41 patients with diabetes, >40 years old, with toe/ankle pressure >30/80 mmHg, respectively, and with exudating, cavity wounds with an area of 1–25 cm^2 Intervention group 22, control group 19 Lost to follow-up 5	Lodosorb daily initially and then less often for 12 weeks or until the wound was less exudative versus saline-moistened gauze	Healing and decrease in area >50%	Healing in intervention group 5/17 versus 2/18 (NS)	1−	Primarily a health economic analysis, with limited results presented on clinical outcomes Per protocol analysis; 5 said to be lost to follow-up but results given on only 35
Apelqvist 199018	RCT Study quality: 3/9	44 patients with necrotic ulcers. Intervention group 22, control group 22 Followed for 5 weeks and lost to follow-up: 2	Adhesive zinc oxide tape versus hydrocolloid	Necrotic ulcer area reduction greater than 50%	Outcome achieved in 14/21 in the intervention group versus 6/21 controls (P < 0.025)	1−	Uncertain numbers of withdrawals
Donaghue 199819	RCT Study quality: 5/9	Patients with non-ischaemic foot ulcers, area >1 cm^2 Intervention group 50, control group 25 Followed for 8 weeks Lost to follow-up: 14	Collagen-alginate wound dressing versus saline-moistened gauze	Ulcer healing, reduction in ulcer area	48% of the intervention group healed versus 36% controls (NS). Mean reduction in ulcer area: 81% versus 61% in controls (NS)	1+	Open label study
Lalau 200220	RCT Study quality: 4/9	77 with both chronic and acute wounds, area >1 cm^2 Intervention group 39, control group 38	Calcium alginate versus vaseline gauze	>75% wound granulation plus decrease in ulcer area by >40%	Combined endpoint achieved in 42.8% intervention group versus 28.5% in controls (NS)	1−	Included acute wounds Study duration reduced from 6 weeks to 4 weeks because of high dropout rate Mean ulcer area at recruitment was very high at 8 cm^2 High percentage with type I diabetes suggests selected population
Jensen 199821	RCT Study quality: 3/9	Patients with non–ischaemic foot ulcers; area >1 cm^2 Intervention group 14, Control group17 Followed for 20 weeks Lost to follow-up: 0	Hydrogel dressing versus saline-moistened gauze	Ulcer healing	85% in the intervention group versus 46% in controls (p < 0.05)	1−	Open label study
Cangialosi 198222	Prospective cohort series Study quality: 1/8	28 diabetics with 37 lower extremity ulcers Intervention group 14, Control group 14 Dropout: unknown Follow-up: unknown	Hydrogel and sterile gauze	Ulcer healing	Healing said to be ‘about 33% more rapid in hydrogel group’	2−	No statistical analysis Duration of follow-up and number lost to follow-up not stated Stated results vague
Capasso 200323	Cohort retrospective Study quality: 2/8	50 patients (28 with diabetes) with arterial disease and foot ulcers Intervention group 25, Control group 25 Follow-up 7 weeks	Amorphous hydrogel versus wet or dry sterile gauze	Cost; Wound healing; Time to healing	No differences observed in wound healing Time to heal: p = 0.02 in favour of hydrogel	2−	Complex series of primarily health economic studies No raw data presented on either wound healing or time to healing
Piaggesi 200124	RCT Study quality: 3/9	20 patients with foot ulcers >1 cm deep Intervention group10, Control group10 Followed for 8 weeks	Hydrofibre carboxymethyl cellulose dressing versus saline-moistened gauze	Days to healing	127 (46 SD) days in the intervention group versus 23425 controls (p < 0.001)	1−
Blackman 199426	RCT Study quality: 4/9	18 patients with diabetes and Wagner grade 1 or 2 ulcers Intervention group 7 (mean age 51 years; 6 M) Control group 11 (59 years; 11 M)	Semi-permeable membrane dressing applied for 2 months versus wet-to-dry saline gauze; late cross-over for 5/7 control group	Healing by 2 months Change in ulcer area over 2 months (intervention versus control);	Intervention group 3/11 healed versus 0/7 (no statistical analysis) Intervention: reduction in area 35 ± 16% baseline at 2 months versus 105 ± 28%, p = 0.03	1−	Further reduction in area in the cross-over group
Muthukumarasamy 199127	Cohort Study quality: 4/8	100 patients with type 2 diabetes and Wagner grade 1 or 2 foot ulcers Intervention group 50 (27 M) Control group 50 (27 M)	Topical phenytoin versus saline 35 days versus an occlusive dry dressing	Decrease in ulcer area, and complete healing	Intervention group % decrease in area was 88% of baseline versus 50% (p < 0.005) 20/50 healed in the Intervention group versus 12/50	2−	No statistical analysis given for the numbers which healed
Pai 200128	RCT Study quality: 5/9	70 patients with type 2 diabetes and Wagner grade 1 or 2 ulcers Intervention group: 36 (mean age 56 years, ulcer area 11.9 cm^2; 25 M) Control group: 34 (60 years, 11.9 cm^2; 22 M) Dropouts: 13	Topical phenytoin powder for 6 weeks versus talc/silicone dioxide	% decrease in cross-sectional area	Intervention group 78.3% reduction in area versus 73.5% (NS)	1+

Antiseptics

One study demonstrated that cadexomer-iodine showed no benefit in cavity wounds 17. One RCT suggested that zinc oxide tape reduced the area of necrotic wounds within 5 weeks when compared with a hydrocolloid 18.

Alginate and collagen-alginate products

No significant effect on either wound area or rate of healing was found with a collagen-alginate dressing product, compared to a saline-moistened gauze in a non-blinded RCT 19. An alginate appeared no better than vaseline gauze in a second RCT 20.

Hydrogels

Three controlled studies of hydrogels were identified: one RCT 21 and two cohort studies 22, 23. The open label RCT reported a significant benefit in terms of healing of non-ischaemic foot ulcers when a hydrogel was compared with saline-moistened gauze. The evidence for a beneficial effect from the two cohort studies was not strong: neither reported any hard data on wound healing and one used no statistical analysis.

Carboxymethylcellulose hydrofibre dressing

A single, small RCT of subjects with deep foot ulcers reported a highly significant reduction in days to healing when a carboxymethylcellulose hydrofibre dressing was used, compared with a saline-moistened gauze 24.

Polymeric semi-permeable membrane

The use of a polymeric semi-permeable membrane dressing was reported to reduce the ulcer area better when compared with a saline-moistened gauze, over a 6-week period 26.

Resection of the chronic wound

The rationale for resecting a chronic ulcer and its bases is that a chronic wound will be replaced by one that resembles an acute one more closely and will proceed to heal more rapidly. Healing may be promoted if underlying bony prominences are also resected. The search strategy identified 879 papers and 152 of these were considered for inclusion, but only 4 were selected after full text review (Table 3).

Table 3. Resection of the chronic wound

Reference	Study design	Study population and characteristics	Intervention and control conditions	Outcome category	Results primary outcome + statistic	Level of evidence SIGN	Comments on weaknesses
RCT, randomized controlled trial; MT, medical treatment.
Piaggesi 199829	RCT Study quality: 5/9	Patients with plantar diabetic forefoot ulcers: intervention group 21, control group 20 Followed for at least 6 months None lost to follow-up	Ulcer excision with removal of bone and closure of wound versus conservative treatment	Healing and time to healing	21/22 ulcers treated with surgery healed compared with 19/24 controls (NS) Time to healing (days) shorter in the intervention group (46 versus 128 in controls (p < 0.001)	1+	Also recorded incidence of secondary infection per ulcer (not per patient): 3/24 intervention group versus 1/22 (p = 0.72)
Armstrong 200530	Retrospective cohort study Study quality: 3/8	40 patients with a chronic ulcer under 5th metatarsal head Intervention group 22, control group 18 Followed for 6 months	5th MT head resection versus medical treatment only	Time to ulcer healing	5.8 (2.9) weeks in cases versus 8.7 (4.3) in controls (p < 0.05)	2−
Armstrong 200331	Cohort study Study quality: 2/8	Uninfected, non-ischaemic ulcers under the interphalangeal joint of the hallux or the 1st metatarsophalangeal joint Intervention group 21, control group 20 Followed for 6 months	1st MTP joint arthroplasty, and resection head of 1st metatarsal versus non-surgical management	Time to ulcer healing and ulcer recurrence	24.2 days in the intervention group versus 67.1 in controls (p = 0.0001) Ulcer recurrence in intervention group 4.8% versus 35% controls (p = 0.02)	2−
Tan 199632	Cohort study Study quality: 3/8	112 patients hospitalized with 164 diabetic foot infections 77 patients had surgery within 3 days 87 had no surgery within 3 days	Surgery within 3 days of hospital admission versus no surgery within 3 days	Amputation and resolution of infection	Those operated early had 77 episodes of infection and 10 major amputations versus 87 infection episodes and 35 major amputations in the non-surgical group (p < 0.01)	2−	Description of outcomes and lesion types is incomplete. The incidence of amputation in the control group was high.

Excision of plantar ulcers with/without removal of underlying bone

Wide excision of chronic plantar ulcers—combined when indicated with removal of underlying bone—reduced time to healing but had no effect on eventual healing rate 29. A retrospective cohort study of the effect of excising the 5th metatarsal head underlying a chronic ulcer revealed a weak effect when compared to non-surgical management 30. A similar study involving excision of wounds under the interphalangeal joint of the hallux or first metatarsophalangeal joint, combined with arthroplasty of the metatarsophalangeal joint, reported healing of more ulcers by 6 months as well as reduced recurrence 31.

Early excision of infected soft tissue

A cohort study compared outcomes in patients admitted to hospital with extensive infection and who either underwent surgical excision of infected tissue within 3 days of admission, or not 32. The incidence of major amputation was significantly lower in the group treated surgically (13% versus 41%).

Hyperbaric oxygen

The search strategy identified 114 studies, of which 6 were selected on the basis of title and abstract. All the six fulfilled the inclusion criteria and were selected (Table 4). Topical treatment involves inclusion of the affected foot into a sealed chamber containing hyperbaric oxygen (HBO) Systemic HBO involves the patient spending prolonged periods of time in a large HBO chamber.

Table 4. Hyperbaric oxygen therapy—both topical and systemic

Reference	Study design	Study population and characteristics	Intervention and control conditions	Outcome category	Results primary outcome + statistic	Level of evidence SIGN	Comments on weaknesses
RCT, randomized controlled trial; HBO, hyperbaric oxygen.
Leslie 199833	RCT Study quality: 6/9	28 with diabetic foot ulcers (16 Hispanic, 7 black, 7 white) Intervention group 12, Control group 16	Topical HBO versus standard care	Change in cross-sectional area at day 7 and 14	Day 7: Area reduced to 67.1% in the intervention group versus 69.6% controls (NS) Day 14: 45.6% versus 35.6% (NS)	1+
Heng 200034	RCT Study quality: 3/9	Intervention group 13, Controls 13 (plus an additional 14 controls who were not randomized) Follow for 4 weeks Lost to follow-up: not clear	Topical HBO versus standard care	Ulcer healing	90% healing in the intervention group versus 28% controls	1−	Partial randomization: the control group was larger because of lack of treatment spaces Complicated data presentation. No statistical analysis presented. Not all patients had diabetes
Faglia 199635	RCT Study quality: 5/9	68 diabetic patients with ulcers Wagner grade 2–4 Intervention group 35, Control group 33	Systemic HBO (2.5 ATA, 90 min daily) continued until healing or amputation versus standard care	Amputation	30% fewer major amputations in Wagner grade 4 patients (p < 0.016)	1+	Randomization process unclear. Not blinded. Time to healing not reported. High frequency of vascular surgery after randomization. Mean age in the Intervention group 61.7 years versus 65.6 years in the control group.
Kessler 200336	RCT Study quality: 6/9	28 patients with neuropathic ulcers Wagner grade 1–3 and Duration >3 months Intervention group 15, Control group 13 Followed for 4 weeks Lost to follow-up: 1	HBOT (2,5 ATA, 90 min bd 5 days a week for 2 weeks) versus standard care	Reduction in ulcer area at 2 weeks and at 4 weeks	Wound area reduction at 2 weeks: 42% in the intervention group versus 21% (p = 0.037) and at 4 weeks: 62% versus 55% (NS)	1+	One patient excluded from evaluation due to barotraumatic otitis
Doctor 199237	RCT Study quality: 3/9	30 patients: 23 with gangrene and 5 neuropathic ulcers Intervention group 15, Control group 15	Systemic HBO (3 ATA, 45 min, 4 sessions—mean 34 treatments) versus standard care	Amputation	Major amputation: 2 in the intervention group versus 7 controls (p < 0.05)	1−	Wound size and depth are not reported No differences in number of healed ulcers Less positive bacterial cultures in HBOT group
Abidia38 2003	RCT Study quality: 9/9	18 patients with diabetic ulcers area 1–10 cm^2 and duration >6 weeks Intervention group 9, Control group 9 Lost to follow-up: 2	Systemic HBO (2,4 ATA, 90 min, 30 sessions) versus hyperbaric air (2,4 ATA, 90 min, 30 sessions)	Healing; Reduction in ulcer area Number healed at 12 months	5/8 healed in the intervention group versus 1/8 controls Median area reduction 100% in the intervention group versus 52% controls (p = 0.02) Healed at 12 months I5/8 in the intervention group versus 0/8 controls (p = 0.026)	1+ +

Topical HBO

Two studies evaluated topical HBO. One was randomized and reported no apparent reduction in the cross-sectional area of ulcers at either 7 or 14 days 33. The other was only partially randomized but reported an apparent benefit at 4 weeks 34.

Systemic HBO

The four RCTs 35–38 provided some evidence to suggest that systemic HBO may reduce the rate of major amputation, although all were limited by aspects of trial design and/or small numbers. A fifth study 39 reported a significant reduction in the ulcer area, but was not randomized.

Reduction of tissue oedema

Reduction of tissue oedema may promote healing. In addition, topical negative pressure (TNP) may also reduce accumulation of surface debris. The search identified 66 studies and 40 were considered for inclusion on the basis of title and abstract. Four (three on TNP; one on compression) were selected after full text review (Table 5). All studies were undertaken in populations who had previously undergone surgery.

Table 5. Reduction of tissue oedema

Reference	Study design	Study population and characteristics	Intervention and control conditions	Outcome category	Results primary outcome + statistics	Level of evidence SIGN	Comments on weaknesses
RCT, randomized controlled trial.
McCallon 200040	RCT Study quality: 4/9	Non-healing ulcers of duration >1 month Intervention group 5, Control group 5 Followed until healing Lost to follow-up: 0	Negative pressure therapy (NPT) versus saline-moistened gauze	Time to ulcer healing	22.8 days in the intervention group versus 42.8 days controls (NS)	1−	Small numbers
Eginton 200341	RCT Study quality: 4/9	10 patients with non-ischaemic foot ulcers Followed for 4 weeks Lost to follow-up: 4	Cross-over design Randomly allocated to start with either NPT therapy for 2 weeks or with saline-moistened gauze for 2 weeks	Reduction in ulcer volume	59% reduction with NPT therapy compared with 0.1% for saline-moistened gauze (p < 0.05)	1−	Small numbers and with 40% dropout rate
Armstrong 200542	RCT Study quality: 5/9	162 patients with residual wounds of mean duration 1.5 months after foot surgery Intervention group 77, Control group 85 Followed for 16 weeks and lost to follow-up: 38	NPT therapy versus standard dressings	Healing (but including those unhealed and rendered suitable for surgical closure	56% in the intervention group versus 39% controls (p = 0.04)	1+	This study was of wounds after diabetic foot amputation, rather than chronic foot ulcers. It was also marred by a high rate of dropouts The strength of the observation is weakened by the definition of healing used
Armstrong 200043	RCT Study quality: 6/9	115 patients with post-operative infected diabetic neuropathic foot ulcers Intervention group 52, control group 45 Followed for 12 weeks Lost to follow-up: 18	Pneumatic foot compression device versus placebo non-functioning device	Wound healing	39/52 healed in the intervention group versus 23/45 (p < 0.02) Odds ratio 2.9 (1.2–6.8)	1+	In addition there was a difference in the intervention group between those who were and were not compliant

TNP

Two of the three RCTs of TNP were very small but reported significant benefits in both healing rate and healing time 40, 41. A third, much larger study reported a significant benefit of TNP in both time to and proportion of persons healing in those who had recently undergone pedal surgery 42, even though the definition of healing used included those who healed after repeat surgery and this weakens the conclusions to be drawn from the results.

Compression

The single RCT on post-operative wounds suggested a significant benefit of compression therapy 43.

Application of products designed to correct aspects of wound biochemistry and cell biology associated with impaired wound healing

Knowledge of the factors which inhibit the healing of chronic wounds is rudimentary, although the importance of different growth factors is accepted 44. Moreover, abnormalities in growth factor expression 45 and other aspects of cell biology have been defined in chronic wounds in diabetes, including changes in the relative concentrations of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) 46. Neutrophils and macrophages are also known to have impaired function in hyperglycaemia and this could have an adverse impact on healing 47, 48. A number of attempts have therefore been made to evaluate interventions that might influence such alterations in wound biology. Of the 107 studies identified, 15 were suitable for inclusion (Table 6).

Table 6. Application of products designed to correct aspects of wound biochemistry and cell biology associated with impaired wound healing

Reference	Study design	Study population and characteristics	Intervention and control conditions	Outcome category	Results: primary outcome + statistic	Level of evidence SIGN	Comments on weaknesses
EGF, epidermal growth factor; bFGF, fibroblast growth factor; PDGF, derived growth factor; PDWHF, platelet-derived wound healing fluid; RCT, randomized controlled study.
Di Mauro 199149	RCT Study quality: 3/9	20 patients (6 with ischaemic, 4 with neuropathic and 9 with neuro-ischaemic ulcers) Followed until healing Lost to follow-up: 0	Lyophilized collagen versus hyaluronic acid-medicated gauze	Time to healing	32 days in the intervention group versus 49 days controls (p < 0.001)	1−	One ulcer was a wrist ulcer
Krupski 199150	RCT Study quality: 8/9	18 non-healing ulcers of both leg and foot (14 had diabetes) Followed for 12 weeks Lost to follow-up: Nil	Autologous platelet factor versus saline	Healing and reduction in area	24% healed in the intervention group versus 33% controls; 4.3 cm^2 reduction in area per week in intervention group versus 1.9 cm^2 controls (NS)	1+ +	Both diabetic and non-diabetic patients Outcomes were for wounds and per patient
Steed 199251	RCT Study quality: 6/9	13 subjects with neuropathic diabetic foot ulcers Intervention group 7, control group 6 Followed for 20 weeks	PDWHF (CT-102) versus normal saline	Proportion of healing and area reduction	5/7 healed in the intervention group versus 1/6 control (p < 0.05) Reduction in ulcer area 6.2 mm^2/day in the intervention group versus 1.8 mm^2/day controls (p < 0.05)	1+	Definition of healing unclear (3 subjects still needed dressings in one treatment arm)
Margolis 200152	Retrospective Cohort Study quality: 5/8	20 347 patients with neuropathic ulcers identified from the database of the Citizen Health System Followed for 20 weeks	Platelet factor given to 6252 patients within 12 weeks	Proportion healed	50% healed in intervention group versus 41% in controls Relative risk (RR): 1.38 (1.33–1.42)	2+	Retrospective analysis of treatment given in practice: Inconsistent dose and duration of treatment Selected population
Feng 199953	Cohort Study quality: 2/8	78 cases with diabetes and ulcers of the leg, foot (and elsewhere); 62 on the foot Mean ulcer area 10.7 cm^2; mean ulcer duration 8.9 days	EGF or PDWHF or saline control administered daily	Wound closure index at 6 weeks % healed at 2, 4, 6 and 8 weeks	Closure index higher in both the EGF and PDWHF groups when compared with placebo (p < 0.01) % healed higher in EGF and PDWHF groups (p < 0.01)	2−	Incomplete reporting of results Mean duration of the ulcers was short at 8.9 days
Driver 200654	RCT Study quality: 7/9	72 (out of 129 screened) people with diabetes (type 1 or 2) and uninfected ulcers (UT 1A) of more than 4 weeks duration Intervention: mean age 56 years; 32 M; mean ulcer area 3.2 cm^2 Control: 58 years; 27 M; mean ulcer area 4.0 cm^2	Platelet autogel for 12 weeks versus placebo gel, with 11 weeks follow-up	Proportion healed (confirmed at 1 week) and time to healing	Healing in 13/16 in the intervention group versus 8/19 in controls Time to healing significantly shorter in the Intervention group (p = 0.018)	1+	Very high exclusion rate necessitated per protocol analysis High percentage of heel ulcers
Niezgoda 200555	RCT Study quality: 3/9	98 with diabetic foot ulcers Intervention group 37 Control group 36 Followed for 12 weeks Lost to follow-up: 25 patients (25%)	Acellular wound care product versus becaplermin (PDGF)	Healing at 12 weeks, time to healing	49% healed in the intervention group versus 28% controls (NS) Time to healing 67 days in the intervention group versus 73 days controls (NS)	1−	Unexplained high dropout rate
Steed 199556	RCT Study quality: 2/9	118 subjects with diabetic foot ulcers Intervention group 61, control group 57 Followed for 20 weeks Lost to follow-up: 3	Recombinant PDGF versus placebo gel	Proportion of patients healed at 20 weeks	29 (48%) of 61 PDGF versus 14 (25%) of 57 patients randomized to the placebo group (p = 0.01)	1−	Details of treatment in the two arms unclear Although only 3 were lost to follow-up, total withdrawals were high, with only 86/118 completing the study
Wieman 199857	RCT Study quality: 6/9	Uninfected non-ischaemic ulcers present for 8 weeks or more Intervention groups: (30 mcg/g) 132 (100 mcg/g) 123 Placebo gel 127 Followed up to 20 weeks Lost to follow-up: 73/382	Dose-ranging becaplermin gel applied daily versus placebo gel	Proportion healed at 20 weeks, time to healing, reduction in ulcer area	100 mcg/g associated with 50% versus 35% placebo (p = 0.007) Time to healing 100 mcg/g 86 days versus 127 placebo (p = 0.013) No differences between 30 mcg/g and placebo	1+	Details of randomization not specified, nor the blinding of the assessor
Robson 200558	RCT Study quality: 4/9	146 neuropathic plantar foot ulcers, duration >4 weeks Intervention group 74, control group 72 Lost to follow-up: 3	0.01% becaplermin (PDGF) versus an adaptive dressing	Healing at 20 weeks, time to healing	Healing in 42% in the intervention group versus 35% in controls (NS) Time to healing NS (no data reported)	1−	Only 146 enrolled of target of 340
Richard 199559	RCT Study quality: 6/9	17 patients with diabetic foot ulcers Intervention group 9, control group 8 Followed for 12 weeks	Fibroblast growth factor (bFGF) versus placebo vehicle	Ulcer healing and reduction in ulcer area	5 healed in the intervention group versus 3 controls (NS) 47.2% had reduction in area in intervention group 35.8% controls (NS)	1+	Small sample size
Tsang 200360	RCT Study quality: 7/9	61 patients with neuropathic diabetic foot ulcers Intervention groups 0.02% 21 0.04% 21 Control group 19 Followed for 12 weeks	Dose-ranging study of EGF 0.02% versus EGF 0.04% versus placebo	Proportion of healing	12/21 receiving 0.02% EGF healed, compared with 20/21 0.04% EGF, and 8/19 controls (p = 0.0003) at 12 weeks for 0.04% gel	1+	Small sample size
Afshari 200561	RCT Study quality: 4/9	50 patients, including 25% with a leg ulcer Intervention group 30, control group 20 Followed for 4 weeks Lost to follow-up: 0	Topical epidermal growth factor versus placebo	Proportion healed by 4 weeks; >70% reduction in ulcer area	No difference in proportion of ulcers healed. 70% reduction in area in 50% of the intervention group versus 15% in controls (p = 0.05)	1−	Reduction in ulcer area adopted as an endpoint retrospectively after no difference found in primary end point
Veves 200262	RCT Study quality: 2/9	276 diabetic foot ulcers Intervention group 138 Control group 138 Followed for 12 weeks Loss to follow-up: 27%	Hydrofibre (cellulose/collagen dressing) versus saline-moistened gauze	Healing by 12 weeks	No significant difference in healing (37.0% versus 28.3% p > 0.05)	1−	High dropout rate Suboptimal off-loading strategy
Tom 200525	RCT Study quality: 7/9	24 subjects with neuropathic diabetic foot ulcers Intervention group13 Control group 11 Followed for 16 weeks. Lost to follow-up: 2	Solution of topical Tretinoin (retinoin A-) versus placebo saline solution applied for 4 weeks	Proportion healed by 16 weeks Reduction in ulcer area and depth	6/13 healed in the intervention group versus 1/11 in controls (p = 0.03) Reduction in area (p < 0.02), and depth (p < 0.01) greater in intervention group	1+	Details of the analysis are not clear

Lyophilized collagen

A small RCT reported a highly significant reduction in time to healing for lyophilized collagen when compared with hyaluronic acid-medicated gauze 49.

Platelets and platelet-derived products

A small RCT (of both leg and foot ulcers, in patients both with and without diabetes mellitus) revealed no apparent benefit and, indeed, the intervention group appeared to do rather worse than the control group 50. A very small study (in which the definition of healing was not clear) reported an apparent benefit of the product in neuropathic ulcers 51. A large cohort study of neuropathic ulcers reported significant benefit but was weakened by being a retrospective analysis of a database of the outcome of patients treated with different doses and for different periods with a platelet-derived product, and compared with those who did not receive it but were otherwise managed but in no specified way 52. A significant reduction in ulcer area was reported in a non-randomized study, undertaken in diabetics with chronic ulcers which were mainly, but not exclusively, on the feet 53. A more recent study 54 was a well-designed RCT but was marred by a very high exclusion rate which necessitated a per protocol analysis.

An acellular wound care product

An acellular product derived from the pig intestine was evaluated in a single study. When compared with platelet-derived growth factor (PGDF), no benefit was observed 55.

Platelet-derived growth factor (PDGF, becaplermin)

The initial RCT of becaplermin in non-infected neuropathic ulcers 56 indicated a significant effect, and this was confirmed in the later definitive phase III study 57. A further study failed to recruit sufficient numbers and no differences were observed 58.

Basic fibroblast growth factor (bFGF)

One small RCT of bFGF suggested an increase in healing by 12 weeks but the difference from controls was insignificant 59.

Epidermal growth factor (EGF)

EGF has been shown to accelerate epidermal growth in experimental wounds. Two studies reported a significantly higher rate of healing of ulcers (mainly of the foot) when compared to placebo 58, 60. Another study 61 was less robust and included patients with leg ulcers. Although ulcer area and depth were reduced in the intervention group, there was no difference in the numbers healing by 16 weeks.

Hydrofibre dressing

A hydrofibre dressing which may modulate expression of MMPs and TIMPs in healing wounds was found to have no demonstrable effect on healing by 12 weeks in a single large RCT 62.

Trans-retinoic acid

One RCT has reported an increase in healing of neuropathic ulcers by 16 weeks, as well as a reduction in ulcer area 25.

Stem cell therapy (including G-CSF)

The search identified 51 papers and 22 of these were considered for inclusion on the basis of the title and abstract. Although there have been small uncontrolled observational studies of administering autologous bone marrow, the only studies suitable for inclusion in this section were of granulocyte-colony stimulating factor (G-CSF). Published studies on G-CSF were designed to determine its effect of infection, but five RCTs also assessed wound healing and reduction of amputation as secondary endpoints 63–67. The sixth 68 was not considered. Only one of the five 67 was associated with any apparent benefit (Table 7).

Table 7. Stem cell therapy (including G-CSF)

Reference	Study design	Study population and characteristics	Intervention and control conditions	Outcome category	Results: primary outcome + statistics	Level of evidence SIGN	Comments on weaknesses
G-CSF, granulocyte-colony stimulating factor; RCT, randomized controlled trial.
Gough 199763	RCT Study quality: 9/9	Patients with foot ulcers complicated by soft tissue infection Intervention group 20 Control group 20 Followed for 7 days Lost to follow-up: 0	G-CSF administered sc daily for 7 days versus saline injections sc	Ulcer healing	4 healed in the intervention group versus 0 controls (p = 0.09)	1+ +	This was primarily a study of the eradication of infection and not powered for ulcer healing Short duration of intervention
de Lalla 200164	RCT Study quality: 4/9	Patients all with osteomyelitis Intervention group 20 Control group 20 Followed for 6 months Lost to follow-up: 4	G-CSF sc and conventional treatment versus conventional treatment alone	Cure, improvement of infection, failure, amputation	No significant differences were reported	1−	All dropouts were in the intervention group The use of composite endpoints makes interpretation difficult
Yonem 200165	RCT Study quality: 3/9	Patients with ulcers Wagner grade 2 complicated by soft tissue infection (inflammation >2 cm) Intervention group 15 Control group 15 Lost to follow-up: nil	G-CSF given sc versus standard treatment for 10 days	Duration of hospital admission, time to infection resolution and proportion of amputation	Duration of hospital admission 26.9 days in the intervention group versus 28.3 controls (NS) Amputation 13.3% in the intervention group versus 20% controls (NS) Time to resolution 23.6 days in the intervention group versus 22.3 controls (NS)	1−	No data regarding healing rate No information given on blinding
Kastenbauer 200366	RCT Study quality: 7/9	Patient with foot ulcers complicated by cellulitis Intervention group 20 Control group 17 Followed for 10 days Lost to follow-up: 0	G-CSF sc daily for 10 days versus saline sc	Ulcer volume reduction	Reduction in ulcer volume in 59% in the intervention group versus 35% controls (NS)	1+	Primary endpoint was eradication of infection (study not powered for volume reduction)
Huang 200567	RCT Study quality: 4/9	Patients with ischaemic ulcers Intervention group 14 Control group 14 Followed for 3 months Lost to follow-up: 0	IM administration of autologous monocytes following G-CSF sc for 5 days versus IV administration of prostaglandin E2	Ulcer healing	14/18 healed in the Intervention group versus 7/18 controls (p = 0.016)	1−	The primary endpoint was improvement of limb ischaemia Ulcers were analysed instead of patients

Bioengineered skin and skin grafts

Of 72 papers identified in the search, 51 were considered but only six met the inclusion criteria (Table 8). Three concerned the use of a dermal fibroblast culture, and one each was of a fibroblast/keratinocyte co-culture, keratinocytes and the effectiveness of different split-skin grafts.

Table 8. Bioengineered skin and skin grafts

Reference	Study design	Study population and characteristics	Intervention and Pcontrol conditions	Outcome category	Results: primary outcome + statistic	Level of evidence SIGN	Comments on weaknesses
RCT, randomized controlled trial.
Gentzkow 199669	RCT Study quality: 6/9	Patients with non-ischaemic plantar foot ulcers Intervention groups: 12,14,11 Control group 13 Followed for 12 weeks Lost to follow-up: 0	Group 1: application of 1 piece of dermal fibroblast culture weekly Group 2: 2 pieces every 2 weeks Group 3: 1 piece every 2 weeks Controls: saline-moistened gauze	Proportion with ulcer healing	Group 1: 50% Group 2: 21% Group 3: 18% Controls: 8% (Group 1 versus controls, p < 0.05)	1+	The percentage of controls healing at 12 weeks was very low
Naughton 199770	RCT Study quality: 3/9	281 Patients with non-ischaemic plantar neuropathic ulcers of duration >2 weeks and area >1 cm^2 Intervention group 139 Control group 142 Followed for 12 weeks Lost to follow-up: 46 (17.4%)	Dermal fibroblast culture weekly for 8 weeks versus standard care	Healing at 12 weeks	38.5 healed in the intervention group versus 31.7% controls (NS)	1−	Per protocol analysis. The data were also reanalysed on the basis of perceived metabolic inactivity of some batches of dermal fibroblast culture Short ulcer duration before study
Marston 200371	RCT Study quality: 5/9	245 patients with non-ischaemic plantar neuropathic ulcers of duration >2 weeks and area >1 cm^2 Intervention group 130 Control group 115 Lost to follow-up : 46 (19%)	Dermal fibroblast culture weekly for up to eight treatments versus conventional therapy	Healing at 12 weeks, time to healing	30% healed in the intervention group versus 18% controls (p = 0.023) RR = 1.6 Time to healing: p = 0.04 in favour of the intervention group	1+	90% of the patients were male, suggesting selection bias No raw data on time to healing Short ulcer duration before study
Veves 200112	RCT Study quality: 5/9	277 patients with non-ischaemic plantar neuropathic ulcers of duration >2 weeks and area >1 cm^2 Intervention group 112 Control group 96 69 were excluded and ITT analysis performed on remaining 208 44 withdrawals (21%)	Tissue engineered sheet of fibroblast/keratinocyte co-culture once a week for 12 weeks versus saline-moistened gauze	Numbers healed at 12 weeks, days to healing	56% healed in the intervention group versus 38% controls (p = 0.004) OR = 2.14 (95% CI 2.3–3.74) Median time to healing 65 days in the intervention group versus 90 controls (p = 0.003)	1+	Suboptimal off-loading strategy Open study (difficult to blind) Large number of exclusions and withdrawals
Bayram 200572	RCT Study quality: 0/9	40 patients with Wagner grade 2 and 3 foot ulcers Intervention group 20 Control group 20 Followed for 1 year Lost to follow-up: unknown	Keratinocyte loaded microcarrier versus microcarrier placebo	Ulcer healing, reduction of ulcer area and wound condition	Reduction in ulcer area: 92% in the intervention group versus 32% in controls Wound condition: intervention group 5.86 versus 2.85 controls (p < 0.001)	1−	Ulcer healing: no data given Missing data make interpretation difficult
Puttirutvong 200473	RCT Study quality: 3/9	80 patients with infected ulcers of both legs and feet Intervention group 36 Control group 44	Meshed skin graft versus split thickness graft	Time to healing	19.8 days in the intervention group versus 20.4 days controls (NS)	1−	Inconsistency between patient numbers in the abstract and the text

Dermal fibroblast culture

One dose-ranging study 69 reported that weekly applications of dermal fibroblast culture improved healing of plantar non-ischaemic ulcers by 12 weeks, when the highest dose was compared with saline-moistened gauze. It should be noted that the healing proportion in the control was only 8% in this study. Another study 70 found no difference between intervention and placebo. Although the definitive RCT of fibroblast culture 71 reported that healing by 12 weeks was significantly greater in the intervention arm than in controls, the percentage healing in the intervention group was only 30%, and in controls was only 18%. A report by Hanft et al.74 was a single centre subgroup analysis of the parent study 71.

Fibroblast/keratinocyte co-culture

The 12 week healing rate in both intervention and control groups were higher in the study of fibroblast/keratinocyte co-culture (56% and 38%, respectively) 12 than those reported for dermal fibroblast culture 69–71. The difference between intervention and control groups was significant.

Keratinocytes

The single published RCT did not report full results 72, but a reduction was claimed in wound area, as well as improvement in the wound bed in the intervention group.

Skin grafts

The study by Puttirutvong et al.73 reported no difference between meshed autologous and conventional split-skin grafts. The study included leg ulcers and there were some discrepancies between data in the text and in the abstract.

Electrical, electromagnetic, lasers and ultrasound

Of 142 identified studies, 14 were considered for selection on the basis of title and abstract and 6 were included after full text review (Table 9).

Table 9. Electrical, electromagnetic, lasers and ultrasound

Reference	Study design	Study population and characteristics	Intervention and Pcontrol conditions	Outcome category	Results: primary outcome + statistic	Level of evidence SIGN	Comments on weaknesses
RCT, randomized controlled trial.
Baker 199775	RCT Study quality: 3/9	80 people with 114 chronic ulcers randomized to one of four groups: three with different amounts of stimulation and one control	Electrical stimulation for 4 weeks and then follow-up for an unspecified period	Ulcer healing Compliance with treatment	No difference between intervention and control groups	1−	Post hoc analysis with stratification by compliance, and combination of one of the treatment groups into the controls suggested a statistically significant difference of uncertain meaning
Peters 200176	RCT Study quality: 9/9	40 people with uninfected ulcers (UT Grade 1A–2A) and TcpO2 >30 mmHg Intervention: 21 (mean age 54 years; 19 M) Controls: 20 (59.4 years; 16 M) Lost to follow-up: 5	Electrical stimulation	Healing Time to healing	Intervention: 13/21 (65%) healed versus 7/20 (35%) of controls; p = 0058 No difference in time to healing	1+ +	The difference between groups was significant when adjusted post hoc for compliance
Ennis 200577	RCT Study quality: 6/9	133 neuropathic DFU (Wagner 1), duration >30 days Follow-up 12 weeks Lost to follow-up:24 (+ 12 study violations) leaving only 97; then a further 42 had study violation (leaving only 55 assessed)	Ultrasound versus sham therapy	Ulcer healing	Analysis of 133 patients: no data (p = 0.69) Per protocol: intervention 41% versus 14% in controls (p = 0.04)	1+	Data only given on the 55 patients who did not violate the protocol or dropout in some way. Number of patients randomized to each arm not given
Alvarez 200378	RCT Study quality: 5/9	20 patients with neuropathic DFU Intervention group 10 Control group 10 12-week follow-up Lost to follow-up: 0	Non-contact thermal wound care system versus saline dressing	Ulcer healing	Intervention group 70% healing versus 40% in controls at 12 weeks (p = 0.069)	1+	Interim analysis
Szor 200279	RCT Study quality: 4/9	56 subjects of whom 37 completed the study: Intervention group 19 Control group18	Magnetic stimulation: magnets implanted into insoles held on by stockinette for 12 h (overnight), for a total of 8 weeks	Wound healing	None reported	1−	Sample required was 70. Insufficient evaluable patients for results to be analysed
Chiglashvili 200480	Cohort Study quality: 1/8	46 people with diabetes Intervention group 28 Control group 18 Lost to follow-up: 0	Complex intervention involving the administration of antioxidant and immunomodulatory agents, combined with laser therapy	Time to elimination of debris and fibrin Time to wound healing	12.6 ± 2,1 days versus 16,3 ± 2,6 days and wound healing duration 27,3 ± 2.8 versus 36,4 ± 3,9 days (versus control)	2−	No clear description of the patient groups, the intervention or trial design. No statistical analysis

Electrical stimulation

Two RCTs examined electrical stimulation of the feet. The first was methodologically weaker and no benefit was observed 75. In contrast, Peters et al.76 reported a trend towards a greater proportion healing at 12 weeks.

Ultrasound

The single selected study was flawed methodologically but reported no significant difference between groups when analysed on an intention to treat basis 77.

Normothermic therapy

A single published study was described as an interim analysis of a non-blinded RCT of wound (‘normothermic’) warming (under an occlusive dressing), but did not describe the intended primary endpoint 78. No significant benefit was observed.

Magnet therapy

A single RCT 79 was well designed but failed to recruit sufficient numbers and also had a high dropout rate. It was underpowered and no data were presented.

Complex intervention including laser therapy

Chiglashvili and Istomin 80 compared improvement in wound surface and healing in a non-blinded study of two, non-randomized groups and reported that outcome was improved by a complex intervention involving the administration of antioxidant and immunomodulatory agents, combined with laser therapy. No statistical analysis was presented.

Discussion

The causes of diabetic foot ulcers are complex and the factors that delay their healing are poorly understood. Management is generally supportive and requires the input of different health care professionals, using different interventions—often over a prolonged period. It follows that the main aim of management (ulcer healing) is unlikely to be responsive to any single treatment and it may therefore be difficult to demonstrate the effectiveness of an intervention in studies that use measures of ulcer healing as the primary endpoint. Moreover, the complex pathogenesis of chronic foot ulcers means that different causative factors may be dominant in different individuals and if the benefit of an intervention is limited to one particular type of ulcer, limb or person, it may be masked in a study of the relatively large numbers needed for an RCT. Assessment of surgical interventions poses particular difficulties in that they are generally adopted when other therapies have failed, and thus in a selected population. It may also be ethically difficult to undertake a study which involves randomization of patients to surgical and non-surgical groups. Trial design therefore poses considerable problems in this field, and the absence of evidence of effectiveness from robust studies does not necessarily mean that an intervention will not be effective in some people. Nevertheless, the reports selected for review here should be sufficient to indicate whether or the interventions studied are likely to be effective in relatively unselected populations, and hence, whether they should be considered for adoption in routine clinical practice.

RCTs and other controlled studies were included. Of the 2251 papers identified in the search, 462 were considered potentially eligible after review of the title and abstract, but only 60 were selected for full text review. One of the most constant findings from this work is the poverty of the evidence available for most interventions and the generally poor methodological quality of reported studies. The quality scores were often low simply because of the omission of important information from the reports. The overall conclusions to be drawn from this review are that few interventions have robust evidence to support their use. Clinicians should view some of those that report positive results with caution.

The evidence to underpin the use of sharp debridement and debriding agents is not strong, and robust prospective controlled studies are needed if the benefit of either is to be established more formally. Further evidence is, however, urgently needed to substantiate the role of larvae, topical antiseptics and all dressing products. No data were available at the time of this review to support the current widespread use of silver-containing dressings, confirming another recent review 81. Although a single study had compared the use of a silver-containing dressing with usual care in a mixed population of chronic wounds, it was not included in this review because of lack of clear presentation of the subpopulation (8%) with diabetic foot ulcers, even though it was reported that there was no apparent effect on healing in this small group 82. The group of agents for which there exists some evidence of effectiveness is the hydrogels, as has been noted previously 83, 84, but further studies are required.

In contrast, there is evidence that a complete excision of plantar neuropathic ulcers—including resection of the entire wound bed, together with any underlying bony prominences—is associated with faster wound healing with fewer recurrences 29. This is especially true of ulcers beneath the hallux 31, rather than the 5th metatarsophalangeal joint 30. Although there is limited information on long-term outcome, it is possible that early extended resection might be considered more often in the management of these types of ulcer.

Systemic HBO may reduce the incidence of major amputation. While further evidence of effectiveness and cost-effectiveness, is required from larger, more robust and blinded studies, there are sufficient data to justify its use where the necessary facilities are available, especially when revascularization is not possible. The benefit of topically administered HBO is not established. Attempts to reduce oedema with either compression or TNP therapy have been shown to improve the rate of healing after foot surgery, although the conclusions to be drawn from the large study by Armstrong et al.42 on the use of TNP therapy were weakened by the definition of healing used. Further evidence is required to substantiate the benefit and cost–benefit of TNP therapy after surgery, as well as in the non-operated chronic wound.

Despite the relatively large number of studies of growth factors and other agents modulating aspects of wound biology, there is currently little evidence to suggest that any of the reported interventions should be adopted in routine practice. The trial of PDGF (becaplermin) undertaken in the US 57 reported apparent benefit in neuropathic foot ulcers, although this was not confirmed in the subsequent study by Robson et al.58, which failed to recruit sufficient numbers. In addition, it is known that an equivalent large randomized trial of becaplermin was undertaken in Europe but the results have not been published, suggesting that its benefit was not confirmed. Moreover, the findings of Wieman et al.57 cannot necessarily be extrapolated to routine care because many of the ulcers included in this study might well have responded to simpler and cheaper interventions. As becaplermin is likely to be reserved in practice for those whose ulcers have proved resistant to simpler interventions, its effect needs to be evaluated in that group.

There is early evidence to suggest that EGF may hasten healing and further randomized trials are urgently needed. In contrast, the effect of G-CSF was studied primarily to determine whether its use may help eradicate infection, and published trials were of either too small or too short a term to demonstrate an effect on healing when it was included as a secondary endpoint. Nevertheless, a small meta-analysis suggested that G-CSF may lead to a reduced incidence of major amputation in limb-threatening infection 85.

Bioengineered skin products and skin grafts are widely used in some areas, but their benefit has not been clearly established. The significance of the single large RCT of dermal fibroblast culture reported by Marston et al.71 was marred by the poor healing rate in the control group, and it should be noted that the rate of healing with dermal fibroblast culture in this study was worse than that in the control group in the study of fibroblast/keratinocyte co-culture 12. Moreover (and as mentioned regarding becaplermin, see above), many clinicians will reserve the use of these relatively expensive treatments for ulcers that fail to respond to simpler approaches and yet bioengineered skin products have not been evaluated in such populations.

Appendix

A search strings for each of the sections

Medline search ‘wound healing guidelines’

Basic search was combined with searches for specific interventions by adding the search term AND

Basic search

(((‘Diabetes Mellitus’[MeSH]) OR (Diabetes Mellitus) OR (Diabetes)) AND ((‘Clinical Trials’[MeSH]) or (‘comparative study’[Mesh]) OR (‘epidemiologic study characteristics’[Mesh]) OR (Clinical Trial*) OR (case-control stud*) OR (case-control stud*) OR (cohort stud*) OR (Comparative stud*)) AND ((‘Foot Ulcer’[MeSH]) OR (Foot Ulcer) OR (Ulcer) OR (diabetic foot)))

Dressings

((‘Biological Dressings’[MeSH] OR ‘Occlusive Dressings’[MeSH] OR ‘Bandages, Hydrocolloid’ [MeSH]) OR (film* OR foam* OR hydrogel* OR hydrocolloid* OR alginat* OR hydrofib* OR dressing*))

Debridement

((‘Debridement’[MeSH]) OR (debrid* OR larv* OR enzym* OR surgic* OR topical OR silver* OR iodin* OR mechanic* OR biologic* OR autol*))

Bioengineered skin and skin grafts

((‘Skin Transplantation’[MeSH]) OR (skin graft OR bioengineered skin OR bioengineered skin OR bioengineered skin OR dermagraft OR apligraf OR tendra))

Electromagnetic, laser and ultrasound therapy

((‘Electromagnetics’[MeSH] OR ‘Lasers’[MeSH] OR ‘Ultrasonic Therapy’[MeSH]) OR (Electromagnetic* OR Laser* OR Ultrasonic Therap* OR ultrasonic OR magnetic))

Stem cell therapy

((‘Stem Cells’[MeSH] OR ‘Stem Cell Transplantation’[MeSH]) OR (Stem Cell* OR Stem Cell therapy OR marrow OR G-CSF OR granulocyte-colony stimulating factor*))

Abnormalities of wound biology and gene therapy

(((‘Growth Substances’[MeSH] OR ‘Endothelial Growth Factors’[MeSH] OR ‘Fibroblast Growth Factors’[MeSH] OR ‘Hematopoietic Cell Growth Factors’[MeSH] OR ‘Vascular Endothelial Growth Factors’[MeSH] OR ‘Epidermal Growth Factor’[MeSH] OR (‘Fibroblast Growth Factor 2’[MeSH] OR ‘Fibroblast Growth Factor 1’[MeSH] OR ‘Granulocyte-Macrophage Colony-Stimulating Factor’[MeSH]) OR ‘Platelet-Derived Growth Factor’[MeSH]) OR (Growth Substance* OR Endothelial Growth Factor* OR Fibroblast Growth Factor* OR Hematopoietic Cell Growth Factor* OR Vascular Endothelial Growth Factor* OR Epidermal Growth Factor* OR Fibroblast Growth Factor 2 OR Fibroblast Growth Factor 1 OR Granulocyte-Macrophage Colony-Stimulating Factor OR Platelet-Derived Growth Factor) OR (Growth Factor OR Growth)) OR (matrix replacement OR hyalofil* OR collagen* OR emdogain OR hyaluronic acid OR metalloproteinase inhibitor*) OR (tissue enzym* OR timp* OR promogran* OR tissue inhibitor* OR metalloproteinase*) OR (angiogenesis OR gene therap* OR vascular endothelial growth factor* OR VEGF))

Tissue oedema

((vac OR vacuum assisted closure OR vacuum* OR kerraboot OR compress*) OR (‘Bandages’[MeSH]) OR (stocking* OR elastic OR bandage*))

Hyperbaric oxygen

((‘Hyperbaric Oxygenation’[MeSH]) OR (hyperbar* OR oxygen*))

Resection of the chronic wound/surgical procedures

((surgic* OR resect* OR remov* OR excisi*) OR (‘Surgical Procedures, Operative’[MeSH]) OR (‘surgery’ [Subheading]))

Embase search ‘wound healing guideline’

A basic search was combined with searches for interventions of interest by adding the search term AND

Basic search

((((‘observational study’/exp OR ‘observational study’) AND [embase]/lim) or ((‘experimental study’/exp OR ‘experimental study’) AND [embase]/lim) or ((‘controlled study’/exp OR ‘controlled study’) AND [embase]/lim) or ((‘comparative study’/exp OR ‘comparative study’) AND [embase]/lim)) and ((‘diabetes mellitus’/exp/mj OR ‘diabetes mellitus’) AND [embase]/lim)) and (((‘foot ulcer’/exp/mj OR ‘foot ulcer’) AND [embase]/lim) or ((‘diabetic foot’/exp OR ‘diabetic foot’) AND [embase]/lim))

Dressings

((‘bandages and dressings’/exp OR ‘bandages and dressings’) AND [embase]/lim) or (film* OR foam* OR hydrogel* OR hydrocolloid* OR alginat* OR hydrofib* AND [embase]/lim)

Debridement

((‘debridement’/exp OR ‘debridement’) AND [embase]/ lim) or (debrid* OR larv* OR enzym* OR surgic* OR (‘topical’/exp OR ‘topical’) OR silver* OR iodin* OR mechanic* OR biologic* OR autol* AND [embase]/lim)

Bioengineered skin and skin grafts

((‘skin transplantation’/exp OR ‘skin transplantation’) AND [embase]/lim) or ((‘skin graft’/exp OR ‘skin graft’) OR ‘bioengineered skin’ OR ‘bioengineered skin’ OR ‘bioengineered skin’ OR dermagraft OR apligraf OR tendra AND [embase]/lim)

Electromagnetic, laser and ultrasound

((‘electromagnetic radiation’/exp OR ‘electromagnetic radiation’) AND [embase]/lim) or ((‘ultrasound therapy’/exp OR ‘ultrasound therapy’) AND [embase]/lim) or (electromagnetic* OR laser* OR ‘ultrasonic therap’ OR (‘ultrasonic’/exp OR ‘ultrasonic’) OR magnetic AND [embase]/lim)

Stem cell therapy

((‘stem cell’/exp OR ‘stem cell’) AND [embase]/lim) or ((‘stem cell transplantation’/exp OR ‘stem cell transplantation’) AND [embase]/lim) or ((‘stem cell therapy’/exp OR ‘stem cell therapy’) OR ‘stem cell’ OR (‘marrow’/exp OR ‘marrow’) OR G-CSF OR ‘granulocyte-colony stimulating factor’ AND [embase]/lim)

Abnormalities of wound biology and gene therapy

((‘growth factor’/exp OR ‘growth factor’) AND [embase]/ lim) or (‘matrix replacement’ OR hyalofil* OR collagen* OR emdogain OR (‘hyaluronic acid’/exp OR ‘hyaluronic acid’) OR (‘metalloproteinase inhibitor’/exp OR ‘metalloproteinase inhibitor’) OR ‘tissue enzym’ OR timp* OR promogran* OR ‘tissue inhibitor’ OR metalloproteinase* OR (‘angiogenesis’/exp OR ‘angiogenesis’) OR ‘gene therap’ OR (‘vegf’/exp OR ‘vegf’) AND [embase]/lim)

Tissue oedema

((‘compression therapy’/exp OR ‘compression therapy’) AND [embase]/lim) or ((‘vacuum assisted closure’/exp OR ‘vacuum assisted closure’) OR vacuum* OR kerraboot OR compress* OR stocking* OR elastic OR bandage* AND [embase]/lim)

Hyperbaric oxygen

((‘hyperbaric oxygen’/exp OR ‘hyperbaric oxygen’) AND [embase]/lim) or (hyperbar* OR oxygen* AND [embase]/lim)

Resection of the chronic wound/surgical procedures

((‘orthopedic surgery’/exp OR ‘orthopedic surgery’) AND [embase]/lim) or (resect* OR surgic* OR remov* OR excisi* AND [embase]/lim)

Acknowledgements

We thank Drs Irina Gurieva, Sabine Kleinert, Kong Yun Cheung, Shigeo Kono and Xavier Lopez for their considerable help in translating and helping us assess papers published in languages other than English. We are also most indebted to Catherine Griffis for her help in obtaining copies of original articles.

Conflict of interest

The authors have no conflicts of interest.