Skin grafting and tissue replacement for treating foot ulcers in people with diabetes

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the benefits and harms of skin grafting and tissue replacement for treating foot ulcers in people with diabetes.

Background

Description of the condition

Foot ulceration is a major problem in people with diabetes, and is often caused by a combination of factors such as neuropathy (nerve damage), foot deformity, external trauma or peripheral arterial disease (Boulton 2008; Falanga 2005; Quattrini 2008; Szabo 2009). A diabetic foot ulcer has been defined as a wound of full thickness (into the subcutaneous tissue, the innermost layer of the skin) below the ankle, or as a lesion of the foot penetrating through the dermis (the inner layer of the skin), in people with type 1 or type 2 diabetes (Apelqvist 1999; Schaper 2004).

Worldwide, almost 350 million people have been diagnosed with diabetes mellitus, and this number is still increasing (Danaei 2011). The annual incidence of development of a foot ulcer in people with diabetes is 1% to 4%, and the lifetime risk is approximately 12% to 25% (Abbot 2005; Singh 2005). These ulcers are a leading cause of hospitalisation and major amputations (above the ankle joint) (Levin 1998; Pham 2000). About 85% of amputations are preceded by ulceration (Boulton 2008). After amputation there is a high risk of re-amputation at a higher level on the same limb (Izumi 2009; Skoutas 2009). It is estimated that worldwide there is an amputation due to diabetes every 30 seconds (Game 2012).

Current treatment of foot ulcers in people with diabetes usually consists of pressure off-loading (keeping weight off the area) (Lewis 2013), debridement (removal of dead tissue) (Edwards 2010), infection control, the use of wound dressings or topical agents (Bergin 2006; Dumville 2013a; Dumville 2013b; Dumville 2013c; Dumville 2013d; Jull 2013), intensive regulation of blood glucose, and - in the case of ischaemia - vascular reconstruction (Falanga 2005). Additional treatments such as hyperbaric oxygen therapy (Kranke 2012; Stoekenbroek 2014), and granulocyte-colony stimulating factor (Cruciani 2013), may also be used in these people. Despite these multidisciplinary treatments, complete healing is not accomplished in 24% to 60% of ulcers (Hinchliffe 2012; Margolis 1999).

Diabetic foot ulceration has a great impact on quality of life and poses a significant burden to the healthcare budget (Nabuurs-Franssen 2005; Valensi 2005). The direct medical costs of each ulcer can frequently exceed USD 45,000 (Jeffcoate 2003; Jeffcoate 2004; Lw; Stockl 2004). The overall long-term costs attributable to diabetic foot ulceration were analysed over a period of three years (Apelqvist 1995). This showed that the costs, including inpatient care, outpatient care, home care and social services, ranged from USD 16,100 in a person with a healed ulcer without critical ischaemia to USD 63,100 in people who underwent a major amputation.

Description of the intervention

Skin grafts and tissue replacement can be used to treat foot ulcers in people with diabetes by reconstructing the skin defect. Skin substitutes need to be placed on a prepared wound bed to ensure contact between the wound bed and the graft and they take on the functions of the missing skin layer. Before the skin substitute is applied, ulcers are usually rinsed, and debrided to remove hyperkeratinised (abnormally horny or thickened skin) or necrotic tissue. The method of clinical application of the graft/tissue replacement and the frequency of application depends on the specific product used. Some skin substitutes are designed for temporary wounds coverage and some as a permanent replacement.

Different types of skin grafts and tissue replacements are currently available. These are generally divided into the following categories: autografts (taken from the patient), allografts (taken from one person, given to another) and xenografts (taken from animals), and bioengineered tissue or artificial skin. They are used in a number of ways.

  • Autografts: skin taken from the patient and placed directly in the bed of the target ulcer (e.g. split or full-thickness skin from pinch or mesh grafts).

  • Allografts and xenografts: skin taken from other humans or animals with a similar skin structure, placed directly in the bed of the target ulcer.

  • Bio-engineered or artificial skin: skin replacement products created in a laboratory from cultures of skin components and cells (e.g. fibroblasts or keratinocytes), before being placed in the bed of the target ulcer.

Grafting and tissue replacement of allogeneic skin is associated with some risk of transmission of infections such as hepatitis or the human immunodeficiency virus (HIV). Even with screening for these diseases in donors, this risk is not eliminated entirely (Falanga 1998).

How the intervention might work

Despite the current variety of strategies available for the treatment of foot ulcers in people with diabetes, not all ulcers achieve complete healing. Additional treatments with skin grafts and tissue replacement products have been developed and aim to promote complete wound closure by reconstructing the skin defect. It is believed that tissue replacements promote complete closure of the ulcer through the addition of extracellular matrices that induce growth factors and cytokine expression, although the exact mechanism underlying the process remains unclear.

Why it is important to do this review

The treatment of foot ulcers in people with diabetes is complex and challenging. Foot ulceration continues to be the leading risk factor for major amputation and is a significant burden to the healthcare system. Delayed ulcer healing is an example of the impaired process of wound healing (inflammation, tissue formation and tissue remodeling) characteristic of people with diabetes. Skin grafts and tissue replacements could function as a temporary cover for ulcers and aid normal wound healing alongside usual care that includes, for example, mechanical pressure relief and - in the case of ischaemia - vascular reconstruction.

There are some reviews on the use of skin replacement therapies for treating foot ulcers in people with diabetes (Blozik 2008; Langer 2009). One review suggests that tissue-engineered artifical skin products may be cost-effective in selected patients with chronic wounds (Langer 2009), however, there is no recent review that has included a rigorous quality assessment.

This systematic review will examine current evidence for skin grafts and tissue replacement for treating foot ulcers in people with diabetes to inform current practice about effectiveness, costs and safety. The review will help clinicians to make informed decisions about the use of grafting and tissue replacement alongside usual care.

Objectives

To determine the benefits and harms of skin grafting and tissue replacement for treating foot ulcers in people with diabetes.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials (RCTs), in any setting.

Types of participants

People (18 years of age or older) with diabetes mellitus types 1 or 2, who have been diagnosed with an open foot ulcer of ischaemic, neuropathic or neuroischaemic aetiology. We will exclude trials that also include wounds of different aetiologies, such as burns, if the data for the diabetic foot ulcer subgroups are not reported separately.

Types of interventions

Skin grafts or tissue replacements applied to foot ulcers in people with diabetes. Studies will be included if they compare different types of skin grafts or tissue replacements, or compare skin grafts or tissue replacements with standard care or placebo.

Types of outcome measures

Primary outcomes
  • Incidence of complete closure of the foot ulcer.

  • Time to complete closure of the foot ulcer.

  • Total incidence of lower limb amputations (major and minor amputations with a minimum of one toe removed, defined as amputation above or below the ankle joint, respectively).

Secondary outcomes
  • Change in ulcer area (e.g. change in percentage or absolute measurements compared to baseline).

  • Recurrence rate of foot ulcers.

  • Incidence of infection.

  • Quality of life (as measured by a valid scale such as EQ-5D or SF-36).

  • Safety (treatment-related adverse events).

  • Costs of treatment.

Search methods for identification of studies

Electronic searches

We will search the following electronic databases to identify reports of relevant RCTs:

  • Cochrane Wounds Group Specialised Register;

  • The Cochrane Central Register of Controlled Trials (CENTRAL) (latest issue);

  • Ovid MEDLINE (1946 to present);

  • Ovid EMBASE (1974 to present);

  • EBSCO CINAHL (1982 to present).

We will search The Cochrane Central Register of Controlled Trials (CENTRAL) using the following search strategy:

#1 MeSH descriptor: [Foot Ulcer] explode all trees
#2 MeSH descriptor: [Diabetic Foot] explode all trees
#3 diabet* NEAR/3 ulcer*:ti,ab,kw
#4 diabet* NEAR/3 (foot or feet)*:ti,ab,kw
#5 diabet* NEAR/3 wound*:ti,ab,kw
#6 (#1 OR #2 OR #3 OR #4 OR #4 OR #5)
#7 MeSH descriptor: [Skin Transplantation] explode all trees
#8 (skin NEXT graft*) or (pinch NEXT graft*):ti,ab,kw
#9 (split NEXT thickness) or (full NEXT thickness):ti,ab,kw
#10 allograft* or autograft* or xenograft* or dermagraft* or apligraft*:ti,ab,kw
#11 tissue NEAR/3 engineer*:ti,ab,kw
#12 cultured NEAR/3 keratinocyte*:ti,ab,kw
#13 artificial NEXT skin:ti,ab,kw
#14 (#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13)
#15 (#6 AND #14)

The strategies that will be used to search Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL are detailed in Appendix 1, Appendix 2, and Appendix 3, respectively.

We will combine the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision) (Lefebvre 2011). We will combine the Ovid EMBASE search with the Ovid EMBASE filter developed by the UK Cochrane Centre (Lefebvre 2011). We will combine the EBSCO CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2014). There will be no restrictions with respect to language, date of publication or study setting.

We will search the following clinical trials registries in an effort to identify published, unpublished and ongoing trials:

Searching other resources

We will handsearch the bibliographies of all relevant articles for further relevant studies.

Data collection and analysis

We will summarise data using standard Cochrane Collaboration methodologies (Higgins 2011a).

Selection of studies

Independently, two review authors will assess titles and abstracts of the studies identified by the search strategy. We will retrieve the full text of all potentially relevant abstracts and citations. Independently, two review authors will check all full text papers for eligibility. Disagreements will be resolved by discussion between the review authors, with the third review author acting as an arbitrator, if necessary.

Data extraction and management

Details of eligible studies will be extracted independently and summarised by two review authors using a standardised data extraction sheet. Discrepancies between review authors will be resolved by discussion to achieve a final consensus, with the third author acting as an arbitrator if necessary. Where data are missing from reports, we will attempt to obtain the missing information by contacting the study author. One review author will enter the data into Review Manager (RevMan 2012), and another author will check the data entered.

We plan to extract the following data:

  • country of origin;

  • patient inclusion and exclusion criteria;

  • type of ulcer;

  • study setting;

  • a priori sample size calculation;

  • unit of allocation and number of participants randomised to each intervention;

  • baseline participant data;

  • description of intervention and comparison;

  • details of any co-interventions;

  • types of primary and secondary outcome measures (with definitions);

  • primary and secondary outcome data;

  • duration of follow-up;

  • number of withdrawals and reasons for withdrawal (by group);

  • adverse events (including amputations);

  • source of funding of the trial.

Assessment of risk of bias in included studies

Independently, two review authors will assess the risk of bias for each included study using the Cochrane Collaboration tool for assessing risk of bias (Higgins 2011b). This tool addresses six specific domains, namely: sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other issues (e.g. extreme baseline imbalance or bias related to the specific study design). See Appendix 4 for the criteria on which the judgement will be based.

The authors will assess blinding and completeness of outcome data separately for each outcome. We will complete a risk of bias table for each eligible study. We will discuss any disagreement amongst all review authors to achieve a consensus. We will present assessment of risk of bias using a 'Risk of bias' summary figure, which presents all of the judgements in a cross-tabulation of study by entry. This display of internal validity indicates the weight the reader may give the results of each study.

Measures of treatment effect

We plan to calculate risk ratios (RR) with 95% CI for dichotomous outcomes, such as incidence of complete closure of the ulcer and incidence of amputation. For time to complete wound healing we will extract or calculate hazard ratios (HR) with 95% CI. We will use the methods of Tierney 2007 for these calculations. For continuous outcomes, such as quality of life and cost, we plan to calculate the difference in means (MD) with 95% confidence intervals (CI) as recommended by Higgins 2011a.

Unit of analysis issues

We will deal with unit of analysis issues according to guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will report whether studies measured outcomes per person or per ulcer, and whether multiple ulcers on the same person were studied. Since the healing of multiple ulcers on an individual person cannot be considered to be independent events, we will report outcomes per person whenever possible.

Dealing with missing data

We will contact the study authors when data are incomplete or missing. Where trials report outcomes only for participants who completed the follow-up period, we will treat the participants who were not included in the analysis as if their wound did not heal (e.g. withdrawals, participants lost-to follow up or otherwise excluded from analysis).

We will evaluate whether an intention-to-treat (ITT) analysis was performed or could have been performed. An ITT analysis includes all participants randomised into a trial irrespective of what happened subsequently (Higgins 2011a).

Assessment of heterogeneity

We will evaluate clinical and methodological heterogeneity by comparing population, methods, interventions, and outcomes of studies.

We will assess statistical heterogeneity by visual inspection of the forest plots (overlap of CIs) and by using the Chi2 test and the I² statistic. If the P value of the Chi2 test is greater than 0.1, there will be no significant statistical heterogeneity present. The I² statistic will be interpreted as suggested by Higgins: 0% to 40% might not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% may represent substantial heterogeneity and 75% to 100% may represent considerable heterogeneity (Higgins 2003).

Assessment of reporting biases

If a sufficient number of trials are available (10 or more), we will use a funnel plot of primary outcomes to illustrate variability between trials visually and to assess whether the review is subject to publication bias. If there are fewer than 10 trials available, we will discuss the potential for publication and reporting bias.

Data synthesis

We will generate a 'Summary of findings' table for the key outcomes along with the GRADE score (Guyatt 2008). We plan to include the following key outcomes in the 'Summary of findings' tables:

  • incidence of complete closure of the ulcer;

  • time to complete closure of the ulcer;

  • total incidence of lower limb amputations (major and minor amputations (as previously described)).

Subgroup analysis and investigation of heterogeneity

Where trials are similar in terms of population, methods, interventions and outcomes, we will consider pooling them using a random-effects model to summarize their results. If the I2 is less than 50%, we will also present the results of a fixed-effect model and discuss which measure we believe to be the most appropriate. If I2 is substantial (over 75%) we will not pool studies.

If the data allow, we plan to carry out subgroup analyses to examine the treatment effects of the different types of skin grafts or skin replacements. Even if subgroup analyses are not possible due to a lack of data, we will report the results narratively, according to the types of skin graft or replacement.

Sensitivity analysis

We plan to conduct sensitivity analysis to assess the impact of excluding trials assessed as being at high, or unclear, risk of bias. We will exclude trials from this sensitivity analysis if they are at high risk or unclear risk of bias in at least two of the following three domains, namely: generation of the allocation sequence, concealment of allocation and blinding of outcome assessor.

Furthermore we plan to test the results by excluding trials that cause significant clinical or statistical heterogeneity in the data.

Acknowledgements

The authors would like to thank Sally Bell-Syer, Ruth Foxlee and Denise Mitchell for suggestions that have enhanced the quality of this protocol. In addition we acknowledge the comments made by the peer referees Joan Webster, Amanda Briant, Debra Fayter, Gill Worthy, Joyce Black, Sharon Van Wicklin and DeviPrashad Mohapatra and the copy editor Elizabeth Royle.

Appendices

Appendix 1. Search strategy for Ovid MEDLINE

1 exp Foot Ulcer/
2 exp Diabetic Foot
3 (diabet*adj3 ulcer*).tw.
4 (diabet*adj3 (foot or feet)).tw.
5 or/1-4
6 exp Skin Transplantation/
7 (skin graft$ or pinch graft$).ti,ab.
8 (split thickness or full thickness).ti,ab.
9 (allograft$ or dermagraft$ or apligraf$).ti,ab.
10 (tissue adj2 engineer$).ti,ab.
11 (cultured adj2 keratinocyte$).ti,ab.
12 artificial skin.ti,ab.
13 or/6-12
13 5 and 13

Appendix 2. Search strategy for Ovid EMBASE

1 exp Diabetic Foot/
2 exp Foot Ulcer/
3 (diabet* adj3 ulcer*).tw.
4 (diabet* adj3 (foot or feet)).tw.
5 (diabet* adj3 wound*).tw.
6 (diabet* adj3 defect*).tw.
7 or/1-6
8 exp Skin Transplantation/
9 (skin graft* or pinch graft*).tw.
10 (split thickness or full thickness).tw.
11 (allograft* or dermagraft* or apligraf*).tw.
12 exp Tissue Engineering/
13 exp Biocompatible Materials/
14 exp Tissue Scaffolds/
15 (tissue adj5 (engineer* or scaffold* or replacement*)).tw.
16 exp Keratinocytes/
17 exp Cells, Cultured/
18 (cultured adj2 keratinocyte*).tw.
19 (artificial adj2 skin).tw.
20 or/8-19
21 7 and 20
22 randomized controlled trial.pt.
23 controlled clinical trial.pt.
24 randomi?ed.ab.
25 placebo.ab.
26 clinical trials as topic.sh.
27 randomly.ab.
28 trial.ti.
29 or/22-28
30 exp animals/ not humans.sh.
31 29 not 30
32 21 and 31

Appendix 3. Search strategy for EBSCO CINAHL

S15 S6 and S14
S14 S7 or S8 or S9 or S10 or S11 or S12 or S13
S13 TI artificial skin or AB artificial skin
S12 TI cultured N2 keratinocyte* or AB cultured N2 keratinocyte*
S11 TI tissue N2 engineer* or AB tissue N2 engineer*
S10 TI ( allograft* or dermagraft* or apligraf* ) or AB ( allograft* or dermagraft* or apligraf* )
S9 TI ( split thickness or full thickness ) or AB ( split thickness or full thickness )
S8 TI ( skin graft* or pinch graft* ) or AB ( skin graft* or pinch graft* )
S7 (MH “Skin Transplantation”)
S6 S1 or S2 or S3 or S4 or S5
S5 TI diabet* N3 wound* or AB diabet* N3 wound*
S4 (diabet* N3 foot OR diabet* N3 feet) or AB (diabet* N3 foot OR diabet* N3 feet)
S3 TI diabet* N3 ulcer* or AB diabet* N3 ulcer*
S2 (MH “Diabetic Foot’’)
S1 (MH “Diabetic Ulcer+’’)

Appendix 4. Risk of bias

1. Was the allocation sequence randomly generated?

Low risk of bias

The investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random-number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots.

High risk of bias

The investigators describe a non-random component in the sequence generation process. Usually, the description would involve some systematic, non-random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number.

Unclear

Insufficient information about the sequence generation process provided to permit a judgement of low or high risk of bias.

2. Was the treatment allocation adequately concealed?

Low risk of bias

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based and pharmacy-controlled randomisation); sequentially-numbered drug containers of identical appearance; sequentially-numbered, opaque, sealed envelopes.

High risk of bias

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non opaque or not sequentially-numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear

Insufficient information provided to permit a judgement of low or high risk of bias. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially-numbered, opaque and sealed.

3. Blinding - was knowledge of the allocated interventions adequately prevented during the study?

Low risk of bias

Any one of the following.

  • No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding.

  • Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.

  • Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of others was unlikely to introduce bias.

High risk of bias

Any one of the following.

  • No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding.

  • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken.

  • Either participants or some key study personnel were not blinded, and the non-blinding of others was likely to introduce bias.

Unclear

Either of the following.

  • Insufficient information provided to permit a judgement of low or high risk of bias.

  • The study did not address this outcome.

4. Were incomplete outcome data adequately addressed?

Low risk of bias

Any one of the following.

  • No missing outcome data.

  • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).

  • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate.

  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes was not enough to have a clinically relevant impact on observed effect size.

  • Missing data have been imputed using appropriate methods.

High risk of bias

Any one of the following.

  • Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups.

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was enough to induce clinically relevant bias in intervention effect estimate.

  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes was enough to induce clinically relevant bias in observed effect size.

  • ‘As-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation.

  • Potentially inappropriate application of simple imputation.

Unclear

Either of the following.

  • Insufficient reporting of attrition/exclusions to permit a judgement of low or high risk of bias (e.g. number randomised not stated, no reasons for missing data provided).

  • The study did not address this outcome.

5. Are reports of the study free of suggestion of selective outcome reporting?

Low risk of bias

Either of the following.

  • The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way.

  • The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).

High risk of bias

Any one of the following.

  • Not all of the study’s pre-specified primary outcomes have been reported.

  • One or more primary outcomes are reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified.

  • One or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).

  • One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis.

  • The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Unclear

Insufficient information provided to permit judgement of low or high risk of bias. It is likely that the majority of studies will fall into this category.

6. Other sources of potential bias

Low risk of bias

The study appears to be free of other sources of bias.

High risk of bias

There is at least one important risk of bias. For example, the study:

  • had a potential source of bias related to the specific study design used; or

  • has been claimed to have been fraudulent; or

  • had some other problem.

Unclear

There may be a risk of bias, but there is either:

  • insufficient information to assess whether an important risk of bias exists; or

  • insufficient rationale or evidence that an identified problem will introduce bias.

Contributions of authors

TB (Katrien) Santema: conceived the review question, developed and co-ordinated the protocol, completed the first draft of the protocol, approved the final version of the protocol prior to submission and is guarantor for the protocol.
PPC (Paul) Poyck: made an intellectual contribution to the protocol and approved the final version of the protocol.
DT (Dirk) Ubbink: edited the protocol, made an intellectual contribution to the protocol and approved the final version of the protocol.

Contributions of editorial base:

Joan Webster: Approved the final protocol prior to submission.
Sally Bell-Syer: coordinated the editorial process. Advised on methodology, interpretation and content. Edited the protocol.
Amanda Briant: designed the search strategy and edited the search methods section.

Declarations of interest

TB (Katrien) Santema: none known
PPC (Paul) Poyck: none known
DT (Dirk) Ubbink: none known

Sources of support

Internal sources

  • Academic Medical Centre at the University of Amsterdam, Amsterdam, Netherlands.

    Salary

External sources

  • The National Institute for Health Research (NIHR) is the sole funder of the Cochrane Wounds Review Group, UK.

Ancillary