Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2016 Dec 15;12(12):CD011918.
doi: 10.1002/14651858.CD011918.pub2.

Protease-modulating matrix treatments for healing venous leg ulcers

Maggie J Westby  1 , Gill Norman  1 , Jo C Dumville  1 , Nikki Stubbs  2 , Nicky Cullum  1
Affiliations
Meta-Analysis

Protease-modulating matrix treatments for healing venous leg ulcers

Maggie J Westby et al. Cochrane Database Syst Rev. .

Abstract

Background: Venous leg ulcers (VLUs) are open skin wounds on the lower leg that occur because of poor blood flow in the veins of the leg; leg ulcers can last from weeks to years, and are both painful and costly. Prevalence in the UK is about 2.9 cases per 10,000 people. First-line treatment for VLUs is compression therapy, but around 60% of people have unhealed ulcers after 12 weeks' treatment and about 40% after 24 weeks; therefore, there is scope for further improvement. Limited evidence suggests non-healing leg ulcers may have persisting elevated levels of proteases, which is thought to deter the later stages of healing; thus, timely protease-modulating matrix (PMM) treatments may improve healing by physically removing proteases from the wound fluid.

Objectives: To determine the effects of protease-modulating matrix (PMM) treatments on the healing of venous leg ulcers, in people managed in any care setting.

Search methods: In September 2016 we searched: the Cochrane Wounds Specialised Register; CENTRAL; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting.

Selection criteria: We searched for published or unpublished randomised controlled trials (RCTs) that evaluated PMM treatments for VLUs. We defined PMM treatments as those with a purposeful intent of reducing proteases. Wound healing was the primary endpoint.

Data collection and analysis: Two review authors independently performed study selection, risk of bias assessment and data extraction.

Main results: We included 12 studies (784 participants) in this review; sample sizes ranged from 10 to 187 participants (median 56.5). One study had three arms that were all relevant to this review and all the other studies had two arms. One study was a within-participant comparison. All studies were industry funded. Two studies provided unpublished data for healing.Nine of the included studies compared PMM treatments with other treatments and reported results for the primary outcomes. All treatments were dressings. All studies also gave the participants compression bandaging. Seven of these studies were in participants described as having 'non-responsive' or 'hard-to-heal' ulcers. Results, reported at short, medium and long durations and as time-to-event data, are summarised for the comparison of any dressing regimen incorporating PMM versus any other dressing regimen. The majority of the evidence was of low or very low certainty, and was mainly downgraded for risk of bias and imprecision.It is uncertain whether PMM dressing regimens heal VLUs quicker than non-PMM dressing regimens (low-certainty evidence from 1 trial with 100 participants) (HR 1.21, 95% CI 0.74 to 1.97).In the short term (four to eight weeks) it is unclear whether there is a difference between PMM dressing regimens and non-PMM dressing regimens in the probability of healing (very low-certainty evidence, 2 trials involving 207 participants).In the medium term (12 weeks), it is unclear whether PMM dressing regimens increase the probability of healing compared with non-PMM dressing regimens (low-certainty evidence from 4 trials with 192 participants) (RR 1.28, 95% CI 0.95 to 1.71). Over the longer term (6 months), it is also unclear whether there is a difference between PMM dressing regimens and non-PMM dressing regimens in the probability of healing (low certainty evidence, 1 trial, 100 participants) (RR 1.06, 95% CI 0.80 to 1.41).It is uncertain whether there is a difference in adverse events between PMM dressing regimens and non-PMM dressing regimens (low-certainty evidence from 5 trials, 363 participants) (RR 1.03, 95% CI 0.75 to 1.42). It is also unclear whether resource use is lower for PMM dressing regimens (low-certainty evidence, 1 trial involving 73 participants), or whether mean total costs in a German healthcare setting are different (low-certainty evidence, 1 trial in 187 participants). One cost-effectiveness analysis was not included because effectiveness was not based on complete healing.

Authors' conclusions: The evidence is generally of low certainty, particularly because of risk of bias and imprecision of effects. Within these limitations, we are unclear whether PMM dressing regimens influence venous ulcer healing relative to dressing regimens without PMM activity. It is also unclear whether there is a difference in rates of adverse events between PMM and non-PMM treatments. It is uncertain whether either resource use (products and staff time) or total costs associated with PMM dressing regimens are different from those for non-PMM dressing regimens. More research is needed to clarify the impact of PMM treatments on venous ulcer healing.

PubMed Disclaimer

Conflict of interest statement

Maggie Westby: my employment at the University of Manchester is funded by the NIHR and focuses on high priority Cochrane reviews in the prevention and treatment of wounds.

Gill Norman: my employment at the University of Manchester is funded by the NIHR and focuses on high priority Cochrane reviews in the prevention and treatment of wounds.

Jo Dumville: I receive research funding from the NIHR for the production of systematic reviews focusing on high priority Cochrane reviews in the prevention and treatment of wounds.

Nikki Stubbs: funding from pharmaceutical companies supports training and education events in the service, and payments have been received by the author for non product related educational sessions. These have been unrelated to the subject matter of the systematic review and have never been in support or in pursuit of the promotion of products.

Nicky Cullum: I receive research funding for wounds related research and systematic reviews from the NIHR.

Figures

1
1
Study flow diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
1.1
1.1. Analysis
Comparison 1 PPM dressing regimen versus other dressing regimen, Outcome 1 Proportion of participants healed (short term ‐ 8 weeks).
1.2
1.2. Analysis
Comparison 1 PPM dressing regimen versus other dressing regimen, Outcome 2 Proportion of participants healed (medium term ‐ 12 weeks).
1.3
1.3. Analysis
Comparison 1 PPM dressing regimen versus other dressing regimen, Outcome 3 Proportion of participants with 1 or more adverse events at 2‐12 weeks.
1.4
1.4. Analysis
Comparison 1 PPM dressing regimen versus other dressing regimen, Outcome 4 Proportion of participants with pain at 2‐12 weeks.
1.5
1.5. Analysis
Comparison 1 PPM dressing regimen versus other dressing regimen, Outcome 5 Proportion of participants with infection at 2‐12 weeks.
1.6
1.6. Analysis
Comparison 1 PPM dressing regimen versus other dressing regimen, Outcome 6 Sensitivity analysis ‐ available case ‐ proportion of participants healed.
1.7
1.7. Analysis
Comparison 1 PPM dressing regimen versus other dressing regimen, Outcome 7 Subgroup analysis: (+/‐) silver ‐ proportion of participants healed medium term.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD011918

References

References to studies included in this review

Andriessen 2009 {published data only (unpublished sought but not used)}
    1. Andriessen A, Polignano R, Abel M. Monitoring the microcirculation to evaluate dressing performance in patients with venous leg ulcers. Journal of Wound Care 2009;18(4):145‐6, 148. - PubMed
Cullen 2012 {published and unpublished data}
    1. Cullen B, Gibson M, Nisbet L. Targeted use of collagen/ORC improves clinical outcome. woundchek.com/uploads/downloads/posters_articles/Targeted‐Use‐of‐Collage... (accessed 5 January 2016).
    1. Cullen B, Gibson M, Nisbet L. Targeted use of collagen/ORC improves clinical outcomes. Wound Repair and Regeneration 2012;20(5):A93.
Hanft 2006 {published and unpublished data}
    1. Hanft J, Serena T, Snyder R. Evaluation of the clinical effectiveness of a collagen‐ORC antimicrobial matrix in venous leg ulcers. 16th Conference of the European Wound Management Association. 2006 May 18‐20; Prague, Czech Republic. 2006:151.
    1. Hanft JR, Serena T, Snyder R. A study to evaluate the clinical effectiveness of a Collagen‐ORC Antimicrobial Matrix in venous leg ulcers. Wound Repair and Regeneration 2006;14(2):A64.
Humbert 2013 {published data only (unpublished sought but not used)}
    1. Humbert P, Faivre B, Veran Y, Debure C, Truchetet F, Becherel PA, et al. Protease‐modulating polyacrylate‐based hydrogel stimulates wound bed preparation in venous leg ulcers: a randomized controlled trial. Journal of the European Academy of Dermatology and Venereology 2013;28(12):1742‐50. - PMC - PubMed
Lanzara 2008 {published data only (unpublished sought but not used)}
    1. Lanzara S, Tacconi G, Gianesini S, Menegatti E, Federici F, Liboni A, et al. A pilot randomized trial to determine the effects of a new active dressing on wound healing of venous leg ulcers. EWMA Journal 2008;8(2 Suppl):76.
Manizate 2012 {published data only (unpublished sought but not used)}
    1. Manizate F, Fuller A, Gendics C, Lantis JC. A prospective, single‐center, nonblinded, comparative, postmarket clinical evaluation of a bovine‐derived collagen with ionic silver dressing versus a carboxymethylcellulose and ionic silver dressing for the reduction of bioburden in variable‐etiology, bilateral lower‐extremity wounds. Advances in Skin and Wound Care 2012;25(5):220‐5. - PubMed
Meaume 2012 {published and unpublished data}
    1. Augustin M, Herberger K, Kroeger K, Muenter KC, Goepel L, Rychlik R. Cost‐effectiveness of treating vascular leg ulcers with UrgoStart® and UrgoCell® Contact. International Wound Journal 2016;13:82–7. - PMC - PubMed
    1. Meaume S, Truchetet F, Cambazard F, Lok C, Debure C, Dalac S, et al. A randomized, controlled, double‐blind prospective trial with a Lipido‐Colloid Technology‐Nano‐Oligo Saccharide Factor wound dressing in the local management of venous leg ulcers. 3rd Congress of the World Union of Wound Healing Societies meeting; 2008 June 4‐8;Toronto, Canada 2012;20(4):500‐11. - PubMed
Petkov 1997 {published and unpublished data}
    1. Petkov L. A comparative study of the influence of two topical wound dressings used during healing on subsequent venous ulcer recurrence. 6th European Conference on Advances in Wound Management: Wound Healing Therapy: a critique of current practice and opportunities for improvement; 1996 October 1‐4 October; Amsterdam, Netherlands. 1997:267.
Romanelli 2015 {published data only}
    1. Romanelli M, Mulder G, Paggi B, Macchia M, Panduri S, Dini V. The use of a collagen matrix in hard‐to‐heal venous leg ulcers. Journal of Wound Care 2015;24(11):543‐7. - PubMed
Schmutz 2008 {published data only}
    1. Dompmartin A, Schmutz JL, Collier M, Smith J, Bohbot S. Management of venous leg ulcers with two active wound dressings. Protocol of a randomized clinical trial. 17th Conference of the European Wound Management Association; 2007 May 2‐4; Glasgow, Scotland. 2007:55.
    1. Meaume S, Dompmartin A, Schmutz J‐L, Ourabah Z, Thirion V. Management of venous leg ulcers with two active wound dressings. Results of a randomized clinical trial. 18th Conference of the European Wound Management Association; 2008 May 14‐16; Lisbon, Portugal. 2008; Vol. 8, issue 2 Suppl:Abstract 38.
    1. Meaume S, Schmutz J‐L, Dompmartin A, Fays S, Ourabah Z, Thirion V, et al. Management of venous leg ulcers with two active wound dressings. Results of a randomized clinical trial. 3rd Congress of the World Union of Wound Healing Societies meeting; 2008 June 4‐8; Toronto, Canada. 2008:Abstract OR047.
    1. Schmutz J‐L, Meaume S, Fays S, Ourabah Z, Guillot B, Thirion V, et al. Evaluation of the nano‐oligosaccharide factor lipido‐colloid matrix in the local management of venous leg ulcers: results of a randomised, controlled trial. International Wound Journal 2008;5(2):172‐82. - PMC - PubMed
Smeets 2008 {published data only (unpublished sought but not used)}
    1. Smeets R, Ulrich D, Unglaub F, Wöltje M, Pallua N. Effect of oxidised regenerated cellulose/collagen matrix on proteases in wound exudate of patients with chronic venous ulceration. International Wound Journal 2008;5(2):195‐203. - PMC - PubMed
Vin 2002 {published data only}
    1. Delchambre J. Venous leg ulcers trials. Journal of Wound Care 2002;12(3 Suppl):6‐7.
    1. Vin F, Teot L, Meaume S. The healing properties of Promogran in venous leg ulcers. Journal of Wound Care 2002;11(9):335‐41. - PubMed
    1. Vin F, Teot L, Meaume S. The healing properties of Promogran in venous leg ulcers. Phlebologie 2003;56(1):77‐86. - PubMed

References to studies excluded from this review

Anichini 2013 {published data only}
    1. Anichini R, Tedeschi A, Bernini A, Barbanera L, Bellis A. Detecting and treating Elevated Protease Activity (EPA) in chronic diabetic wounds. EWMA Journal 2013;13(1 Suppl):275.
Bolton 2003 {published data only}
    1. Bolton LL. Evidence corner: randomized controlled trial of collagen/oxidized regenerated cellulose dressing. Wounds 2003;15(6 Suppl):19‐20.
Brown 2014 {published data only}
    1. Brown A, Augustin M, Junger M, Zutt M, Dissemond J, Rabe E, et al. Randomized standard‐of‐care‐controlled trial of a silica gel fibre matrix in the treatment of chronic venous leg ulcers. European Journal of Dermatology 2014;24(2):210‐16. [DOI: 10.1684/ejd.2014.2344] - DOI - PubMed
Brown‐Etris 2000a {published data only}
    1. Brown‐Etris M, Shields DK, Galluzzi KE, Steinberg JS, Shalen AB, Barnes HR, et al. Preliminary clinical outcomes on the use of composite cultured skin for the healing of venous ulcers. 13th Annual Symposium on Advanced Wound Care; 2000 April 1‐4; Dallas (TX). 2000:D4.
Caprio 1995a {published data only}
    1. Caprio B, Murgiano GA, Ricci E, Siciliano G, Zurleni G. The cost effectiveness of modern dressings in leg ulcer care. 4th European Conference on Advances in Wound Management; 1994 Sept 6‐9; Copenhagen, Denmark. 1995:199.
Chaloner 1992 {published data only}
    1. Chaloner D, Fletcher M, Milward P. Clinical trials: comparing dressings. Nursing Standard 1992;7(7):9‐11. - PubMed
Curran 2002 {published data only}
    1. Curran MP, Plosker GL. Bilayered bioengineered skin substitute (Apligraf): a review of its use in the treatment of venous leg ulcers and diabetic foot ulcers. BioDrugs 2002;16(6):439‐55. [DOI: 10.2165/00063030-200216060-00005] - DOI - PubMed
Demling 2004 {published data only}
    1. Demling RH, Niezgoda JA, Haraway GD, Mostow EN. Small intestinal submucosa wound matrix and full‐thickness venous ulcers: preliminary results. Wounds 2004;16(1):18‐22.
Ebell 1998 {published data only}
    1. Ebell M. Is human skin equivalent more effective than Unna paste boots in the treatment of venous ulcers?. Evidence‐Based Practice 1998;1(6):1.
Falabella 1998 {published data only}
    1. Falabella AF, Carson P, Eaglstein WH, Falanga V. The safety and efficacy of a proteolytic ointment in the treatment of chronic ulcers of the lower extremity. Journal of the American Academy of Dermatology 1998;39(5):737‐40. - PubMed
Falanga 1998a {published data only}
    1. Falanga V, Margolis D, Alvarez O, Auletta M, Maggiacomo F, Altman M, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Archives of Dermatology 1998;134(3):293‐300. - PubMed
Falanga 1998b {published data only}
    1. Falanga V, Sabolinski M. A bilayered living skin construct (APLIGRAF(TM)) accelerates complete closure of hard‐to‐heal venous ulcers. Wound Repair and Regeneration 1999;7(4):201‐7. - PubMed
Falanga 2000 {published data only}
    1. Falanga VJ. Tissue engineering in wound repair. Advances in Skin and Wound Care 2000;13(2 Suppl):15‐19. - PubMed
Falanga 2006 {published data only}
    1. Falanga V, Saap LJ, Ozonoff A. Wound bed score and its correlation with healing of chronic wounds. Dermatologic Therapy 2006;19(6):383‐90. [DOI: 10.1111/j.1529-8019.2006.00096.x] - DOI - PubMed
Gardner 2013 {published data only}
    1. Gardner S. Using treatment pathways to improve healing of venous leg ulceration. Wounds UK 2013;9(1):67‐75.
Gilligan 2014 {published data only}
    1. Gilligan AM, Waycaster C. Cost‐effectiveness of small intestinal submucosa extracellular matrix on wound closure in patients with difficult‐to‐heal wound of mixed arterial/venous and venous etiology. Value in Health 2014;17(3):A272‐3. [DOI: 10.1016/j.jval.2014.03.1587] - DOI
Goedkoop 2010 {published data only}
    1. Goedkoop R, Juliet R, You PHK, Daroczy J, Roos K‐P, Lijnen R, et al. Wound stimulation by growth‐arrested human keratinocytes and fibroblasts: HP802‐247, a new‐generation allogeneic tissue engineering product. Dermatology 2010;220(2):114‐20. [DOI: 10.1159/000277380] - DOI - PubMed
Gravante 2013 {published data only}
    1. Gravante G, Sorge R, Giordan N, Georgescu SR, Morariu SH, Stoicescu I, et al. Multicenter clinical trial on the performance and tolerability of the Hyaluronic acid‐collagenase ointment for the treatment of chronic venous ulcers: a preliminary pilot study. European Review for Medical and Pharmacological Sciences 2013;17(20):2721‐7. - PubMed
Hodde 2006 {published data only}
    1. Hodde JP, Hiles MC, Sillings N, Metzger DW. Characterization of the local wound environment following treatment of chronic leg ulcers with SIS wound matrix: small intestinal submucosa. 19th Annual Symposium on Advanced Wound Care; 2006 April 30‐May 3; San Antonio (TX). 2006; Vol. 4:105‐6.
Karim 2006 {published data only}
    1. Karim RB, Brito BL, Dutrieux RP, Lassance FP, Hage JJ. MMP‐2 assessment as an indicator of wound healing: a feasibility study. Advances in Skin and Wound Care 2006;19(6):324‐7. - PubMed
Lantis 2013 {published data only}
    1. Lantis JC, Marston WA, Farber A, Kirsner RS, Zhang Y, Lee TD, et al. The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth‐arrested allogeneic keratinocytes and fibroblasts. Journal of Vascular Surgery 2013;58(2):433‐9. [DOI: 10.1016/j.jvs.2012.12.055] - DOI - PubMed
Marston 2012 {published data only}
    1. Marston W, Kirsner R, Snyder R, Lee T, Cargill I, Slade H. Variables affecting healing of venous leg ulcers in a randomized, vehicle‐controlled trial of topical cellular therapy. Journal of Vascular Surgery 2012;55(1):303. [DOI: 10.1016/j.jvs.2011.11.027] - DOI
Metzner 1997 {published data only}
    1. Metzner B, Vanscheidt W, Norgauer J. Influence of platelet‐derived products on mRNA expression of growth factors, inducible growth related genes, metalloproteinases and their inhibitors in ulcers of patients with chronic venous insufficiency. Australasian Journal of Dermatology 1997;38(2 Suppl):175.
Mian 1992 {published data only}
    1. Mian E, Martini P, Beconcini D, Mian M. Healing of open skin surfaces with collagen foils. International Journal of Tissue Reactions 1992;14(Suppl):27‐34. - PubMed
Moffatt 2014 {published data only}
    1. Moffatt CJ, Stanton J, Murray S, Doody V, Davis PJ, Franks PJ. A randomised trial to compare the performance of Oxyzyme and Iodozyme with standard care in the treatment of patients with venous and mixed venous/arterial ulceration. Wound Medicine 2014;6:1‐10. [DOI: 10.1016/j.wndm.2014.08.002] - DOI
Morimoto 2012 {published data only}
    1. Morimoto N, Yoshimura K, Niimi M, Ito T, Tada H, Teramukai S, et al. An exploratory clinical trial for combination wound therapy with a novel medical matrix and fibroblast growth factor in patients with chronic skin ulcers: a study protocol. American Journal of Translational Research 2012;4(1):52‐9. - PMC - PubMed
Morimoto 2013 {published data only}
    1. Morimoto N, Yoshimura K, Niimi M, Ito T, Aya R, Fujitaka J, et al. Novel collagen/gelatin scaffold with sustained release of basic fibroblast growth factor: clinical trial for chronic skin ulcers. Tissue engineering Part A 2013;19(17‐18):1931‐40. [DOI: 10.1089/ten.tea.2012.0634] - DOI - PubMed
Mostow 2005 {published data only}
    1. Mostow EN, Haraway GD, Dalsing M, Hodde JP, King D, OASIS Venus Ulcer Study Group. Effectiveness of an extracellular matrix graft (OASIS Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial. Journal of Vascular Surgery 2005;41(5):837‐43. [DOI: 10.1016/j.jvs.2005.01.042] - DOI - PubMed
Palmieri 1992 {published data only}
    1. Palmieri B. Heterologous collagen in wound healing: a clinical study. International Journal of Tissue Reactions 1992;14(Suppl):21‐5. - PubMed
Planinsek 2007 {published data only}
    1. Planinsek RT, Lunder T. Stimulation of venous leg ulcers with thrombocytic growth factors: a randomised study. 17th Conference of the European Wound Management Association; 2007 May 2‐4; Glasgow, Scotland. 2007:62.
Ramirez 1994 {published data only}
    1. Ramirez GM, Wethers DL, Koshy M, Steinberg MH, Phillips G, Siegel RS, et al. Accelerated healing of chronic sickle cell leg ulcers treated with a RGD matrix. 19th Annual Meeting of the National Sickle Cell Disease Program; 1994 March; New York. 1994:Abstract 1.
Robson 1995 {published data only}
    1. Robson MC, Phillip LG, Cooper DM, Lyle WG, Robson LE, Odom L, et al. Safety and effect of transforming growth factor‐beta(2) for treatment of venous stasis ulcers. Wound Repair and Regeneration 1995;3(2):157‐67. - PubMed
Romanelli 2006a {published data only}
    1. Romanelli M, Ellervee T, Jarve H, Kaha E. Amelogenins (Xelma) in hard‐to‐heal venous leg ulcers, an open regime investigation. 16th Conference of the European Wound Management Association; 2006 May 18‐20; Prague, Czech Republic. 2006:143.
Romanelli 2006b {published data only}
    1. Romanelli M, Dini V, Brilli C, Bertone M. Oasis wound matrix versus hyaluronic acid in the treatment of difficult‐to‐heal wounds of mixed arterial/venous aetiology. 19th Annual Symposium on Advanced Wound Care & 16th Medical Research Forum on Wound Repair; 2006 April 30‐May 3; San Antonio, Texas, USA; Ostomy Wound Manage. 2006; Vol. 52.
Romanelli 2007 {published data only}
    1. Romanelli M, Dini V, Bertone M, Barbanera S, Brilli C. OASIS wound matrix versus Hyaloskin in the treatment of difficult‐to‐heal wounds of mixed arterial/venous aetiology. International Wound Journal 2007;4(1):3‐7, 39‐40. [DOI: 10.1111/j.1742-481X.2007.00300.x] - DOI - PMC - PubMed
Romanelli 2008a {published data only}
    1. Romanelli M, Kaha E, Stege H, Wnorowski JW, Vowden P, Majamaa H, et al. Effect of amelogenin extracellular matrix protein and compression on hard‐to‐heal venous leg ulcers: follow‐up data. Journal of Wound Care 2008;17(1):17‐8, 20‐3. - PubMed
Romanelli 2008b {published data only}
    1. Romanelli M, Vowden P, Price P. An open, randomised, comparative, parallel group, multi‐centre clinical trial of amelogenin extracellular matrix therapy in the treatment of hard‐to‐heal venous leg ulcers: follow‐up data. 3rd Congress of the World Union of Wound Healing Societies; 2008 June 4‐8; Toronto, Canada 2008:Abstract OR100.
Romanelli 2010 {published data only}
    1. Romanelli M, Dini V, Bertone MS. Randomized comparison of OASIS wound matrix versus moist wound dressing in the treatment of difficult‐to‐heal wounds of mixed arterial/venous etiology. Advances in Skin and Wound Care 2010;23(1):34‐8. [DOI: 10.1097/01.ASW.0000363485.17224.26] - DOI - PubMed
Romanelli 2011 {published data only}
    1. Romanelli M, Dini V, Bertone M. Histological evaluation of venous leg ulcers treated with amelogenin. EWMA Journal 2011;11(2 Suppl):224.
Ronfard 2012 {published data only}
    1. Ronfard RV, Grover GK. Allogeneic living cell spray: a new concept in the treatment of wounds. Journal of Tissue Engineering and Regenerative Medicine 2012;6(Suppl.1):91. [DOI: 10.1002/term.1586] - DOI
Serra 2013 {published data only}
    1. Serra R, Buffone G, Falcone D, Molinari V, Scaramuzzino M, Gallelli L, et al. Chronic venous leg ulcers are associated with high levels of metalloproteinases‐9 and neutrophil gelatinase‐associated lipocalin. Wound Repair and Regeneration 2013;21(3):395‐402. [DOI: 10.1111/wrr.12035] - DOI - PubMed
Serra 2014 {published data only}
    1. Serra R, Gallelli L, Conti A, Caridi G, Massara M, Spinelli F, et al. The effects of sulodexide on both clinical and molecular parameters in patients with mixed arterial and venous ulcers of lower limbs. Drug Design, Development and Therapy 2014;8:519‐27. [DOI: 10.2147/DDDT.S61770] - DOI - PMC - PubMed
Shanahan 2013 {published data only}
    1. Shanahan DR. The Explorer study: the first double‐blind RCT to assess the efficacy of TLC‐NOSF on DFUs. Journal of Wound Care 2013;22(2):78‐82. - PubMed
Sheehan 2003 {published data only}
    1. Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent change in wound area of diabetic foot ulcers over a 4‐week period is a robust predictor of complete healing in a 12‐week prospective trial. Diabetes Care 2003;26(6):1879‐82. [DOI: 10.2337/diacare.26.6.1879] - DOI - PubMed
Smith 1994 {published data only}
    1. Smith BA. The dressing makes the difference. Trial of two modern dressings on venous ulcers. Professional Nurse 1994;9(5):348, 350‐2. - PubMed
Stojadinovic 2014 {published data only}
    1. Stojadinovic O, Ramirez H, Patel S, Yin N, Bollenbach T, Golden P, et al. Genomic insight into molecular mechanisms of action of bilayered living cellular construct nonhealing venous leg ulcers. Wound Repair and Regeneration 2014;22(2):A60. [DOI: 10.1111/wrr.12155] - DOI
Thomas 1997 {published data only}
    1. Thomas S, Banks V, Fear M, Hagelstein S, Bale S, Harding K. A study to compare two film dressings used as secondary dressings. Journal of Wound Care 1997;6(7):333‐6. - PubMed
Trial 2010 {published data only}
    1. Trial C, Darbas H, Lavigne JP, Sotto A, Simoneau G, Tillet Y, et al. Assessment of the antimicrobial effectiveness of a new silver alginate wound dressing: a RCT. Journal of Wound Care 2010;19(1):20‐6. - PubMed
Varelias 2002 {published data only}
    1. Varelias A, Hughes H, Cowin A, Cowled P, Cooter R, Harries R, et al. Detection and modulation of matrix metalloproteinases in patients with chronic leg ulcers treated with whey‐derived growth factors. Fourth Australian Wound Management Association Conference; 2002 March 7‐10; Adelaide, South Australia. 2002:34.
Varelias 2006 {published data only}
    1. Varelias A, Cowin AJ, Adams D, Harries RHC, Cooter RD, Belford DA, et al. Mitogenic bovine whey extract modulates matrix metalloproteinase‐2, ‐9, and tissue inhibitor of matrix metalloproteinase‐2 levels in chronic leg ulcers. Wound Repair and Regeneration 2006;14(1):28‐37. [DOI: 10.1111/j.1743-6109.2005.00085.x] - DOI - PubMed
Veves 2001 {published data only}
    1. Veves A. Promogran, a cost‐effective new device for treating chronic ulcers. Diabetic Foot 2001;4:S4‐5.
Veves 2002 {published data only}
    1. Veves A, Sheehan P, Pham HT. A randomized controlled trial of Promogran (a collagen/oxidised regenerated cellulose dressing) vs standard treatment in the management of diabetic foot ulcers. Archives of surgery 2002;137(7):822‐7. - PubMed
Vowden 2006 {published data only}
    1. Vowden P, Romanelli M, Peter R, Boström A, Josefsson A, Stege H. The effect of amelogenins (XELMA) on hard‐to‐heal venous leg ulcers. Wound Repair and Regeneration 2006;14(3):240‐6. [DOI: 10.1111/j.1743-6109.2006.00117.x] - DOI - PubMed
Vowden 2007a {published data only}
    1. Vowden P, Romanelli M. Effect of amelogenin matrix protein solution as add‐on treatment to compression in hard‐to‐heal venous leg ulcers: a randomised controlled trial. 17th Conference of the European Wound Management Association; 2007 May 2‐4; Glasgow, Scotland. 2007:54.
Vowden 2007b {published data only}
    1. Vowden P, Romanelli M, Price P. Effect of amelogenin extracellular matrix protein and compression on hard‐to‐heal venous leg ulcers. Journal of Wound Care 2007;16(5):189‐95. - PubMed
Wethers 1994 {published data only}
    1. Wethers DL, Ramirez GM, Koshy M, Steinberg MH, Phillips G, Siegel RS, et al. Accelerated healing of chronic sickle‐cell leg ulcers treated with RGD peptide matrix. RGD Study Group. Blood 1994;84(6):1775‐9. - PubMed
Wolcott 2015 {published data only}
    1. Wolcott R. Disrupting the biofilm matrix improves wound healing outcomes. Journal of Wound Care 2015;24(8):366‐71. - PubMed
Wollina 2005 {published data only}
    1. Wollina U, Schmidt W, Kronert C, Nelskamp C, Scheibe A, Fassler D. Some effects of a topical collagen‐based matrix on the microcirculation and wound healing in patients with chronic venous leg ulcers: preliminary observations. International Journal of Lower Extremity Wounds 2005;4(4):214‐24. - PubMed

References to studies awaiting assessment

Braumann 2008 {published data only}
    1. Braumann C, Pirlich M, Menenakos C, Lochs H, Mueller JM. Implementation of the clean and close concept for treatment of surgical and chronic wounds in three university centres in Berlin, Germany. EWMA Journal 2008;8(2 Suppl):41.

References to ongoing studies

NCT 01537003 {published data only (unpublished sought but not used)}
    1. NCT01537003. WOUNDCHEK™ protease status point of care (POC) diagnostic test. clinicaltrials.gov/ct2/show/NCT01537003 (accessed 08 July 2016).

Additional references

Altman 2000
    1. Altman DG, Machin D, Bryant TN, Gardner MJ. Statistics with confidence. 2nd Edition. London: BMJ, 2000.
Ashby 2014
    1. Ashby RL, Gabe R, Ali S, Adderley U, Bland JM, Cullum NA, et al. Clinical and cost‐effectiveness of compression hosiery versus compression bandages in treatment of venous leg ulcers (Venous leg Ulcer Study IV, VenUS IV): a randomised controlled trial. Lancet 2014;383(9920):871‐9. - PubMed
Augustin 2012
    1. Augustin M, Brocatti LK, Rustenbach SJ, Schäfer I, Herberger K. Cost‐of‐illness of leg ulcers in the community. International Wound Journal 2012;11(3):283‐92. - PMC - PubMed
Balshem 2011
    1. Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011;64:401‐6. - PubMed
Beidler 2008
    1. Beidler SK, Douillet CD, Berndt DF, Keagy BA, Rich PB, Marston WA. Multiplexed analysis of matrix metalloproteinases in leg ulcer tissue of patients with chronic venous insufficiency before and after compression therapy. Wound Repair and Regeneration 2008;16(5):642‐8. - PubMed
BNF 2016
    1. Joint Formulary Committee. British National Formulary (BNF). www.evidence.nhs.uk/formulary/bnf/current/a5‐wound‐management‐products‐a... (accessed 14 December 2016).
Callam 1987
    1. Callam MJ, Harper DR, Dale JJ, Ruckley CV. Chronic ulcer of the leg: clinical history. British Medical Journal 1987;294(6584):1389‐91. - PMC - PubMed
Coleridge 1988
    1. Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis. British Medical Journal 1988;296(6638):1726‐7. - PMC - PubMed
Cullen 2002
    1. Cullen B, Smith R, McCulloch E, Silcock D, Morrisson L. Mechanism of action of PROMOGRAN, a protease modulating matrix, for the treatment of diabetic foot ulcers. Wound Repair and Regeneration 2002;10(1):16‐25. - PubMed
Deeks 2011
    1. Deeks JJ, Higgins JP, Altman DG, on behalf of the Cochrane Statistical Methods Group. Chapter 9: Analysing data and undertaking meta‐analyses. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Dumville 2009
    1. Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, et al. VenUS II: a randomised controlled trial of larval therapy in the management of leg ulcers. Health Technology Assessment 2009;13(55):1‐182. - PubMed
Elbourne 2002
    1. Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta‐analyses involving cross‐over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140‐9. - PubMed
Euroqol 2015
    1. Reenen M, Janssen B. EQ‐5D‐5L User Guide. www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ‐5... (accessed 30 March 2015).
Fletcher 2013
    1. Fletcher J, Moffatt C, Partsch H, Vowden K, Vowden P. Principles of compression in venous disease: a practitioner’s guide to treatment and prevention of venous leg ulcers. Wounds International 2013; available from www.woundsinternational.com (accessed 15 July 2016).
Galea 2015
    1. Galea E. Managing chronic/stalled arterial, venous and pressure ulcers with collagen and oxidised regenerated cellulose dressings. 2015. www.worldwidewounds.com/2015/August/Galea/wounds‐galea.html (accessed 05 May 2016).
Ghauri 2010
    1. Ghauri AS, Nyamekye IK. Leg ulceration: the importance of treating the underlying pathophysiology. Phlebology/Venous Forum of the Royal Society of Medicine 2010;25(Suppl 1):42‐51. - PubMed
Graham 2003
    1. Graham ID, Harrison MB, Nelson EA, Lorimer K, Fisher A. Prevalence of lower‐limb ulceration: a systematic review of prevalence studies. Advances in Skin and Wound Care 2003;16(6):305‐16. - PubMed
Graves 2014
    1. Graves N, Finlayson K, Gibb M, O’Reilly M, Edwards H. Modelling the economic benefits of gold standard care for chronic wounds in a community setting. Wound Practice and Research 2014;22(3):163‐8.
Hall 2014
    1. Hall J, Buckley HL, Lamb KA, Stubbs N, Saramago P, Dumville JC, et al. Point prevalence of complex wounds in a defined United Kingdom population. Wound Repair and Regeneration 2014;22(6):694–700. - PubMed
Harding 2011
    1. Harding K, Armstrong DG, Barrett S, Kaufman H, Lázaro‐Martínez J L, Mayer D, et al. International consensus. The role of proteases in wound diagnostics. An expert working group review. 2011. woundchek.com/uploads/downloads/consensus_documents/Role‐of‐proteases‐in.... London, (accessed 15 July 2016).
Hart 2002
    1. Hart J, Silcock D, Gunnigle S, Cullen B, Light ND, Watt PW. The role of oxidised regenerated cellulose/collagen in wound repair: effects in vitro on fibroblast biology and in vivo in a model of compromised healing. The International Journal of Biochemistry & Cell Biology 2002;34(12):1557–70. - PubMed
Herber 2007
    1. Herber OR, Schnepp W, Rieger MA. A systematic review on the impact of leg ulceration on patients' quality of life. Health and Quality of Life Outcomes 2007;5:44‐55. - PMC - PubMed
Higgins 2003
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327:557‐60. - PMC - PubMed
Higgins 2011a
    1. Higgins JP, Altman DG, Sterne JAC editor(s). Chapter 8: Assessing risk of bias in included studies. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Higgins 2011b
    1. Higgins JP, Deeks JJ, Altman DG editor(s). Chapter 16: Special topics in statistics. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Iglesias 2004
    1. Iglesias C, Nelson EA, Cullum NA, Torgerson DJ. VenUS 1: a randomised controlled trial of two types of bandage for treating venous leg ulcers. Health Technology Assessment 2004;8(29). - PubMed
Johnson 1995
    1. Johnson M. The prevalence of leg ulcers in older people: implications for community nursing. Public Health Nursing 1995;12(4):269‐75. - PubMed
Jull 2012
    1. Jull AB, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/14651858.CD001733.pub3] - DOI - PMC - PubMed
Kontopantelis 2012
    1. Kontopantelis E, Springate DA, Reeves D. A re‐analysis of the Cochrane Library data: the dangers of unobserved heterogeneity in meta‐analyses. PLoS One 2013;26:e69930. - PMC - PubMed
Ladwig 2002
    1. Ladwig GP, Robson MC, Liu R, Kuhn MA, Muir DF, Schultz GS. Ratios of activated matrix metalloproteinase‐9 to tissue inhibitor of matrix metalloproteinase‐1 in wound fluids are inversely correlated with healing of pressure ulcers. Wound Repair and Regeneration 2002;10(1):26‐37. - PubMed
Lefebvre 2011
    1. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Liberati 2009
    1. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA Statement for reporting systematic reviews and meta‐analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Medicine 2009;6(7):e1000100. doi:10.1371/journal.pmed.1000100. - PMC - PubMed
Liu 2009
    1. Liu Y, Min D, Bolton T, Nube V, Twigg SM, Yue DK, et al. Increased matrix metalloproteinase‐9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care 2009;32(1):117‐9. - PMC - PubMed
Lobmann 2006
    1. Lobmann R, Zemlin C, Motzkau M, Rescke K, Lehnert H. Expression of matrix metalloproteinases and growth factors in diabetic foot wounds treated with a protease absorbent dressing.. Journal of Diabetes and its Complications 2006;20(5):329‐35. - PubMed
Madden 2014
    1. Madden M. Is research in chronic wound care focusing on the outcomes that matter most to patients?. BSA Annual Conference 2014: Changing Society; 23‐25 April 2014, University of Leeds, UK. 2014:232.
Margolis 2004
    1. Margolis DJ, Allen‐Taylor L, Hoffstad O, Berlin JA. The accuracy of venous leg ulcer prognostic models in a wound care system. Wound Repair and Regeneration 2004;12(2):163‐8. - PubMed
McCarty 2012
    1. McCarty SM, Cochrane CA, Clegg PD, Percival SL. The role of endogenous and exogenous enzymes in chronic wounds: A focus on the implications of aberrant levels of both host and bacterial proteases in wound healing. Wound Repair and Regeneration 2012;20(2):125–36. - PubMed
MeReC 2010
    1. MeReC publications. Evidence‐based prescribing of advanced wound dressings for chronic wounds in primary care. MeReC Bulletin 2010;21(1).
Moffatt 2004
    1. Moffatt CJ, Franks PJ, Doherty DC, Martin R, Blewett R, Ross F. Prevalence of leg ulceration in a London population. QJM: Monthly journal of the Association of Physicians 2004;97(7):431‐7. - PubMed
Mwaura 2006
    1. Mwaura B, Mahendran B, Hynes N, Defreitas D, Avalos G, Adegbola T, et al. The impact of differential expression of extracellular matrix metalloproteinase inducer, matrix metalloproteinase‐2, tissue inhibitor of matrix metalloproteinase‐2 and PDGF‐AA on the chronicity of venous leg ulcers. European Journal of Vascular and Endovascular Surgery 2006;31(3):306‐10. - PubMed
Nelson 2016
    1. Nelson EA, Adderley U. Venous leg ulcers. Systematic review 1902. January 2016. clinicalevidence.bmj.com/x/systematic‐review/1902/overview.html (accessed 8 July 2016).
Nelzén 1994
    1. Nelzén O, Berqvist D, Lindhagen A. Venous and non‐venous leg ulcers: clinical history and appearance in a population study. British Journal of Surgery 1994;81(2):182‐7. - PubMed
Nelzén 2008
    1. Nelzén O. Prevalence of venous leg ulcer: the importance of the data collection method. Phlebolymphology 2008;15(4):143‐50.
Norman 2016
    1. Norman G, Westby MJ, Stubbs N, Dumville JC, Cullum N. A 'test and treat' strategy for elevated wound protease activity for healing in venous leg ulcers. Cochrane Database of Systematic Reviews 2016, Issue 1. [DOI: 10.1002/14651858.CD011753] - DOI - PMC - PubMed
Nwomeh 1998
    1. Nwomeh BC, Liang HX, Diegelmann RF, Cohen IK, Yager DR. Dynamics of the matrix metalloproteinases MMP‐1 and MMP‐8 in acute open human dermal wounds. Wound Repair and Regeneration 1998;6(2):127‐34. - PubMed
Nwomeh 1999
    1. Nwomeh BC, Liang HX, Cohen IK, Yager DR. MMP‐8 is the predominant collagenase in healing wounds and nonhealing ulcers. Journal of Surgical Research 1999;81(2):189‐95. - PubMed
O'Meara 2012
    1. O'Meara S, Cullum N, Nelson EA, Dumville JC. Compression for venous leg ulcers. Cochrane Database of Systematic Reviews 2012, Issue 11. [DOI: 10.1002/14651858.CD000265.pub3] - DOI - PMC - PubMed
O'Meara 2013
    1. O'Meara S, Martyn‐St James M. Foam dressings for venous leg ulcers. Cochrane Database of Systematic Reviews 2013, Issue 5. [DOI: 10.1002/14651858.CD009907.pub2] - DOI - PMC - PubMed
O'Meara 2014
    1. O'Meara S, Al‐Kurdi D, Ologun Y, Ovington LG, Martyn St‐James M, Richardson R. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database of Systematic Reviews 2014, Issue 1. [DOI: 10.1002/14651858.CD003557.pub5] - DOI - PMC - PubMed
Palolahti 1993
    1. Palolahti M, Lauharanta J, Stephens RW, Kuusela P, Vaheri A. Proteolytic activity in leg ulcer exudate. Experimental Dermatology 1993;2(1):29‐37. - PubMed
Parmar 1998
    1. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta‐analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17(30):2815‐34. - PubMed
Persoon 2004
    1. Persoon A, Heinen MM, Vleuten CJM, Rooji MJ, et al. Leg ulcers: a review of their impact on daily life. Journal of Clinical Nursing 2004;13(3):341‐54. - PubMed
Ragnarson Tennvall 2005
    1. Ragnarson Tennvall G, Hjelmgren J. Annual costs of treatment for venous leg ulcers in Sweden and the United Kingdom. Wound Repair and Regeneration 2005;13(1):13‐18. - PubMed
RevMan 2014 [Computer program]
    1. Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Schünemann 2011a
    1. Schünemann HJ, Oxman AD, Higgins JPT Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and 'Summary of findings' tables. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Schünemann 2011b
    1. Schünemann HJ, Oxman AD, Higgins JP, Deeks JJ, Glasziou P, Guyatt GH. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
SIGN 2010
    1. Scottish Intercollegiate Guidelines Network (SIGN). Management of chronic venous leg ulcers. National clinical guideline 120. August 2010. www.sign.ac.uk/pdf/sign120.pdf (accessed 05 September 2016).
SIGN 2015
    1. Scottish Intercollegiate Guidelines Network (SIGN). Search filters. www.sign.ac.uk/methodology/filters.html (accessed 8 July 2016).
Srinivasaiah 2007
    1. Srinivasaiah N, Dugdall H, Barrett S, Drew PJ. A point prevalence survey of wounds in north‐east England. Journal of Wound Care 2007;16(10):413‐9. - PubMed
Sterne 2011
    1. Sterne JA, Egger M, Moher D. Chapter 10: Addressing reporting biases. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Systagenix Portugal 2016
    1. Systagenix Portugal. How does it work? [Como funciona?]. www.systagenix.com.br/our‐products/lets‐promote/fibracol‐plus‐307/how‐do... (accessed 19 April 2016).
Thompson 1999
    1. Thompson SG, Sharp SJ. Explaining heterogeneity in meta‐analysis: a comparison of methods. Statistics in Medicine 1999;18(20):2693‐708. - PubMed
Thompson 2002
    1. Thompson SG, Higgins JP. How should meta‐regression analyses be undertaken and interpreted?. Statistics in Medicine 2002;21(11):1559‐73. - PubMed
Tierney 2007
    1. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time‐to‐event data into meta‐analysis. Trials 2007;8(16). [DOI: 10.1186/1745-6215-8-16] - DOI - PMC - PubMed
Trengove 1999
    1. Trengove NJ, Stacey MC, MacAuley S, Bennett N, Gibson J, Burslem F, et al. Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound Repair and Regeneration 1999;7(6):442‐52. - PubMed
Valencia 2001
    1. Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. Journal of the American Academy of Dermatology 2001;44(3):401‐21. - PubMed
Velnar 2009
    1. Velnar T, Bailey T, Smrkolj V. The wound healing process: an overview of the cellular and molecular mechanisms. Journal of International Medical Research 2009;37(5):1528‐42. - PubMed
Vlajinac 2014
    1. Vlajinac H, Marinkovic J, Maksimovic M, Radak D. Factors related to venous ulceration: a cross‐sectional study. Angiology 2014;65(9):824‐30. - PubMed
Vowden 2009
    1. Vowden KR, Vowden P. The prevalence, management and outcome for acute wounds identified in a wound care survey within one English health care district. Journal of Tissue Viability 2009;18(1):7‐12. - PubMed
Walker 2002
    1. Walker N, Rodgers A, Birchall N, Norton R, MacMahon S. The occurrence of leg ulcers in Auckland: results of a population based study. New Zealand Medical Journal 2002;115(1151):159‐62. - PubMed
Wang 2013
    1. Wang Y, Zeng T. Response to: Practical methods for incorporating summary time‐to‐event data into meta‐analysis [addendum to Tierney 2007]. Trials 2013;14(391). [DOI: 10.1186/1745-6215-14-391] - DOI - PMC - PubMed
Wlaschek 1997
    1. Wlaschek M, Peus D, Achterberg V, Meyer‐Ingold W, Scharffetter‐Kochanek K. Protease inhibitors protect growth factor activity in chronic wounds. British Journal of Dermatology 1997;137(4):646‐66. - PubMed
Wound Care Handbook 2016
    1. MA Healthcare. Wound Care Handbook. www.woundcarehandbook.com/ (accessed 10 October 2016).
Yager 1997
    1. Yager DR, Chen SM, Ward SI, Olutoye OO, Diegelmann RF, Cohen IK. Ability of chronic wound fluids to degrade peptide growth factors is associated with increased levels of elastase activity and diminished levels of proteinase inhibitors. Wound Repair and Regeneration 1997;5(1):23‐32. - PubMed
Young 2012
    1. Young T. Using a protease test to inform wound care treatment decisions. Wounds UK 2012;8(4):74‐80.

Publication types

LinkOut - more resources