Wound care in venous ulcers

Abstract

Wound dressings: ulcer dressings should create and maintain a moist environment on the ulcer surface. It has been shown that in an ulcer with a hard crust and desiccated bed, the healing process is significantly slowed and sometimes completely blocked so favouring infection, inflammation and pain. In contrast a moist environment promotes autolytic debridement, angiogenesis and the more rapid formation of granulation tissue, favours keratinocytes migration and accelerates healing of wounds. Apart from these common characteristics, wound dressings are completely different in other aspects and must be used according to the ulcer stage. In necrotic ulcers, autolytic debridement by means of hydrogel and hydrocolloids or with enzymatic paste is preferred. In case of largely exuding wounds alginate or hydrofibre are indicated. When bleeding occurs alginate is indicated due to its haemostatic power. Where ulcers are covered by granulation tissue, polyurethane foams are preferred. When infection coexists antiseptics are necessary: dressing containing silver or iodine with large antibacterial spectrum have proved to be very effective. In the epithelization stage polyurethane films or membranes, thin hydrocolloids or collagen based dressings are very useful to favour advancement of the healing wound edge. Despite these considerations, a Cochrane review failed to find advantages for any dressing type compared with low-adherent dressings applied beneath compression. Surgical debridement and grafting of wounds, negative wound pressure treatment: surgical and hydrosurgical debridement are indicated in large, necrotic and infected wounds as these treatments are able to get rid of necrotic, infected tissue very quickly in a single surgical session, thereby significantly accelerating wound bed preparation and healing time. Negative wound pressure treatment creating a negative pressure on ulcer bed is able to favour granulation tissue and shorten healing time. In case of hard-to-heal leg ulcers such as large, deep, infected and long-lasting venous ulcers, sharp debridement and skin grafting may favour and shorten ulcer healing.

Keywords

venous ulcers moist dressings sharp debridement skin grafting ulcer healing

Introduction

There is no single dressing suitable for all types of wounds, and it is often necessary to use a number of dressings throughout the healing process.¹

Nevertheless all the dressings should have a common characteristic: they should be occlusive and suitable to create and maintain a moist environment at the wound/dressing interface.^2,3 In desiccated wounds covered with a hard crust, keratinocytes cannot migrate and cover the ulcer bed as they can only migrate over viable tissue. Only a moist environment promotes autolytic debridement, angiogenesis and the more rapid formation of granulation tissue, favours keratinocyte migration and accelerates healing of wounds.

A moist wound environment, reducing inflammation, infection and promoting healing also reduces wound pain and fibrosis favouring a better cosmetic outcome. In fact, it has been demonstrated that occlusive dressings are able to speed the healing process and reduce infection risk more than conventional dressings.^4–7

Other characteristics of an ideal occlusive dressing should be as follows:^8,9 •

Remove excess exudate;

•

Promote gaseous exchange;

•

Provide thermal insulation;

•

Be impermeable to bacteria;

•

Keep the wound free of particles and toxic wound contaminants;

•

Be removable without causing trauma.

The dressing should be chosen according to the wound bed characteristics:^8,9 •

Necrotic and or dry wounds should be debrided;

•

Profusely exuding wounds should be treated with exudate absorbing dressings;

•

Infected wounds should be treated with local antimicrobial therapy and, when indicated, systemic antibiotic treatment;

•

Ulcer covered with granulation tissue should be treated with absorbing and protecting dressings;

•

Ulcer in the epithelization phase should be treated with a dressing promoting epidermal advancement.

As the characteristics of the wound bed change, the dressing must also change.¹

(1) Debridement for necrotic and/or dry ulcers: Debridement can be done surgically^9,10 and hydro-surgically (sharp debridement)^11–13 or by means of dressings that produce different kinds of debridement: autolytic, enzymatic, mechanical and biological. (a)

In large and infected ulcers or in the diabetic foot or when tendons and bone involvement coexists, surgical debridement is the fastest and most effective way to get rid of debris and necrotic tissue, decrease bacterial burden and remove old and senescent cells. With scalpel, scissors and curette a bleeding base can be achieved transforming a chronic into an acute wound that can heal following the physiological healing process. Hydrosurgical debridement (Versajet^® Hydro-surgery System) is based on fluidjet technology: water, forced through a suitable hose to the tip of a procedure-specific hand piece, at high pressure and velocity (103–827 bar and 426–1078 km/h), form jets able to debride ulcer bed. This is made possible by means of the Venturi effect, the waterjet can hold, cut and remove the damaged tissue and the contaminants centred in the operating window and take them at the collection point. This operating method allows good visibility, prevents vaporization and eliminates the risk of the operators inhaling contaminated particles. Surgical and hydrosurgical treatment can be very painful, cause bleeding and have to be performed in the operating theatre under general anaesthesia by experienced clinicians. These techniques should not be used for ischaemic ulcers.

(b)

Autolytic debridement can be performed by means of moist dressings, such as hydrogels¹⁴ and hydrocolloids.^15–17 Hydrogels consist of hydrophilic polymers, which are commonly hydrated almost to saturation. They increase the moisture within the wound, which makes the gel effective in enhancing debridement by activating the de-sloughing process and removing devitalized tissue in dry necrotic wounds. Hydrocolloids are occlusive or semi-occlusive dressings composed of gelatine, pectin and carboxymethylcellulose; they are self-adherent, impermeable to bacteria and other contaminants and slightly to moderately exudate absorbing. They should not be used on heavily exudative wounds. Together with hydrogel, they enhance spontaneous autolysis and create the proper environment for debridement by phagocytic cells. Through such mechanisms they liquefy debris and slough and favour the formation of granulation tissue.

(c)

Enzymatic debridement^18–21 can be achieved with topical application of exogenous enzymes, which can work synergistically with endogenous enzymes to debride the surface. Fibrinolysin/DNase, collagenase and papain/urea are the most frequently used enzymes.

(d)

Mechanical debridement^22–26 can be performed with several systems: wet to dry dressings, wound irrigation and ultrasound-based devices are the most used mechanical methods for debridement.

(e)

Biological debridement^27,28 can be achieved with sterile larvae of the Lucilia sericata fly, which produce powerful enzymes, which digest dead tissue without damaging the healthy granulation tissue. It is especially used in the UK.

(2) Hyperexudating wounds need highly absorbing dressings, such as alginates^29,31 and hydrofibres.^32,35 Alginates are derived from brown seaweed and are composed of soft, non-woven fibres, which are able to absorb up to 20 times their weight. Calcium alginates, absorbing exudate tend to gel. In fact, they can donate calcium, promoting haemostasis, and accept sodium, transforming into a sodium alginate hydrogel able to create a moist environment on the ulcer bed and to trap bacteria. They are indicated for exudative, infected and bleeding wounds. Hydro fibres, sterile, non-woven sheets of sodium carboxymethylcellulose are 30% more absorbant than alginates as they can retain fluid and bacteria not only in the inter-fibre space but also within the fibre. They are indicated in exuding and infected ulcers and specifically under compression therapy as their absorbing capability does not decrease significantly under compression. Both dressings make the formation of crust impossible and the wound can progress from the inflammatory to the proliferative stage. Biocellulose^36–38 is a particular kind of dressing. For its unique mode of action it is classified as a Hydrobalance dressing: it is able to release water to a desiccated wound and absorb fluids from a moderately exuding wound. This is the only dressing, which may release or absorb water depending on the wound's clinical condition.

(3) Infected wounds must be treated by local antiseptics containing dressings:^9–49 silver, iodine, polihexanide. Silver is found in conjunction with many products: hydrocolloids, alginate, hydro fibres, foam, adding its antiseptic action to the individual properties of every dressing. The spectrum of bacteria, which can be killed by antiseptic agents, is very broad, including highly resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and Pseudomonas aeruginosa. Absence of toxicity and resistance to silver are claimed while they have not been shown for polihexanide. All dressings containing antiseptics should be strictly limited to infected wounds and discontinued when infection has been eliminated. Systemic antibiotics therapy should always be considered in adjunction with local treatment.

(4) Ulcers in the proliferative stage (granulation tissue). Ulcers in this stage should be dressed as infrequently as possible to allow keratinocytes to advance from the edges to cover the ulcer. When possible weekly dressings are highly advisable. Therefore foam dressings^50–53 providing thermal insulation, high absorbency, a moist environment and gas permeability are recommended. They are constructed from a conformable polyurethane foam pad with a transparent adhesive film on top, which acts as a barrier to outside contamination, including bacteria and viruses but is gas and vapour permeable. Foams can have adhesive or non-adhesive edges. The non-adhesive dressing can be cut and shaped to cover the ulcer. Some foam contains additional elements (silicone) to avoid adherence to the healing ulcer bed allowing for an atraumatic and painless removal.

(5) Ulcers in the epithelization phase should be dressed as infrequently as possible, 7, 10 or 14 days can be the right time interval between dressing change according to the ulcer size, amount of exudate and used dressing which will favour epidermal advancement.

Foams, thin hydrocolloids, transparent films and polyurethane membrane dressings that are waterproof and impermeable to bacteria and contaminants, but are vapour permeable and allow for observation of the wound bed are the most used dressings.

Absorbable collagen sponge,^54,55 even if not creating a moist environment, is also particularly recommended in this ulcer stage. Collagen absorbs wound fluid and factors that inhibit wound healing such as proteases, radicals and cytokines and has also haemostatic properties. Collagen actively promotes wound healing also accelerating re-epithelialization.

Wound dressings and evidence-based medicine

Despite these theoretical positive effects on ulcer healing, wound dressings failed to show any clinical benefit on ulcer healing rate as stated by a Cochrane review.⁵⁶ In contrast, the Cochrane review conclusions are quite negative as can be seen in the summary of the report:

Main results: 42 randomised controlled studies meeting the inclusion criteria and evaluating hydrocolloids (n = 23), foams (n = 6), alginates (n = 4), hydrogel dressings (n = 6) and a group of miscellaneous dressings (n = 3) were analysed. In none of the comparisons was there evidence that any one dressing type was better than others in terms of number of ulcers healed. Current evidence suggests that hydrocolloids are no more effective than simple low adherent dressings. For other comparisons there was insufficient evidence.

Authors' conclusions: the type of dressing applied beneath compression has not been shown to affect ulcer healing. For the majority of dressing types there were insufficient data to allow us to draw strong conclusions except for hydrocolloid compared with a low adherent dressing. The results of the meta-analysis indicate no significant difference in healing rates between hydrocolloid dressings and simple, low-adherent dressings when used beneath compression.

Despite these restricting conclusions it must be underlined that in all the studies included in the Cochrane review the ulcer size is usually smaller than 10 cm² and often smaller than 5 cm²; only in three studies ulcer size was about 20 cm². It is conceivable that these very small venous ulcers, all submitted to compression therapy, did not show any significant difference in wound healing as regards local dressings.

The Cochrane conclusion should be modified as follows:

The type of dressing applied beneath compression has not been shown to affect very small ulcer healing. For ulcers with a size greater than 20 cm² there are no data to allow us to draw any conclusion. Further studies are necessary to evaluate the effectiveness of occlusive dressings in larger size ulcers.

Negative pressure wound therapy

In large and infected wounds, not responding to moist dressings, negative pressure wound therapy (NPWT)^57–71 assists drainage (serous fluid and/or blood) from the treated wound. The technique is very simple. A foam, with an open-cell structure is shaped to cover the wound and topped with a transparent adhesive membrane fixed to peri-wound skin and connected, through a drain tube, to a vacuum source that can exert a continuous or intermittent subatmospheric pressure ranging from 25 to 200 mmHg.

Independent from brand name, two types of units are usually available depending on their size: a large one with large canister volume for patients with large and exuding ulcers and limited mobility who stay lying in bed or sit on an arm-chair or a lightweight, battery-powered unit with a canister volume of 50 mL that can deliver therapy to the ambulatory patient with minimal to moderate levels of exudate.

Mode of action:

NPWT is reported effective in: •

Increasing blood flow in the ulcer bed and peri-wound skin up to four times the baseline value with negative pressure values not higher than 125 mmHg;

•

Increasing granulation tissue production rate by means of negative pressure applied both continuously and intermittently although intermittent pressure seems to be more effective;

•

Increasing skin graft take and flap survival by 21% compared with control values;

•

Decreasing the number of microorganisms in the ulcer bed and exudate within four days.

Multiple mechanisms might be responsible for these observed effects. It was suggested that removal of interstitial fluid decreases localized oedema and bacterial levels and increases blood flow, protein and matrix molecule synthesis and angiogenesis. Other authors report an enhanced epithelialization.

Independently from experimental studies NPWT has been reported effective in favouring healing of: •

Chronic and difficult to heal wounds;

•

Degloving injuries;

•

Infected sternotomy wounds;

•

Various soft tissue injuries prior to surgical closure;

•

Surgical dehiscence;

•

Grafting take or reconstructive surgery;

•

Donor sites.

Skin grafting for hard-to-heal venous ulcers

Reconstructive surgery^72–79 for hard-to-heal leg ulcers can be performed using skin substitutes when ulcers are large and deep and a deep layer must be reconstructed or with the skin of the patient in superficial ulcers when only the epidermal layer is missing. Engineered acellular skin substitutes, consisting of a collagen matrix, have proved to be effective in reforming the deep skin layers by integrating in wound and preparing the ulcer bed for a subsequent autograft in 3–4 weeks time.

Allograft (preserved cadaver skin) can be used in the same way as a skin substitute and have been proved to be very effective both in burns and in chronic leg wounds by accelerating healing and minimizing scarring.

Another skin substitute, as an acellular allograft made of cryopreserved cadaver skin (AlloDerm^® Lifecell Corporation, NJ, USA) consisting of a decellularized dermal matrix with a structurally intact dermis and basement membrane can be placed on the wound bed and immediately covered with a thin autograft. It seems to be effective although it was studied in a single trial.

Also cellular skin substitutes where a bovine collagen matrix has been seeded with fibroblast and epidermal keratinocytes (Apligraf^® Organogenesis, MA, USA) or where a polyglycolic mesh was infiltrated by dermal fibroblasts (Dermagraft^® Shire Regenerative Medicine, CA, USA) have been used successfully.

Funding

This research received no specific grant from any funding agency in the public, commercial or not for-profit sectors.

Footnotes

Conflict of interest

None.

References

Turner

. Semipermeable films as wound dressings. Schweiz Rundsch Med Prax 1984; 73: 950–2

Winter

. formation of the scab and rate of epithelialization of superficial wounds in the skin of the young domestic pig. Nature 1962; 193: 293–4

Hinman

, Mailbach

. Effect of air exposure and occlusion on experimental human skin wounds. Nature 1963; 200: 377–8

Geronemus

, Robins

. The effect of two new dressings on epidermal wound healing. J Dermatol Surg Oncol 1982; 8: 850–2

Alvarez

, Hefton

, Eaglstein

. Healing wounds: occlusion or exposure. Infect Surg 1984; 3: 173–181

Alvarez

, Mertz

, Eaglstein

. The effect of occlusive dressings on collagen synthesis and re-epithelialization. Superficial wounds. J Surg Res 1983; 35: 142

Hutchinson

, Lawrence

. Wound infection under occlusive dressings. J Hosp Infect 1991; 17: 83–94

Attinger

, Janis

, Steinberg

, Schwartz

, Al-Attar

, Couch

. Clinical approach to wounds: debridement and wound bed preparation including the use of dressings and wound-healing adjuvants. Plast Reconstr Surg 2006; 117 (Suppl. 7): 72S–109S

Schultz

, Sibbald

, Falanga

. Wound bed preparation: a systematic approach to wound management. Wound Repair Regen 2003; 11 (Suppl. 1): S1–S28

10.

Williams

, Enoch

, Miller

, Harris

, Price

, Harding

. Effect of sharp debridement using curette on recalcitrant nonhealing venous leg ulcers: a concurrently controlled, prospective cohort study. Wound Repair Regen 2005; 13: 131–7

11.

Mosti

, Mattaliano

. The debridement of chronic vascular leg ulcers. In: Granick

, Gamelli

, eds. Surgical Wound Healing and Management. New York: Informa Healthcare, 2007: 117–30

12.

Mosti

, Mattaliano

. The debridement of chronic leg ulcers by means of a new, Fluidjet-based device. Wounds 2006; 8: 227–37

13.

Mosti

, Iabichella

, Picerni

, Magliaro

, Mattaliano

. The debridement of hard to heal leg ulcers by means of a new device based on Fluidjet technology Int Wound J 2005; 2: 307–14

14.

Agren

. An amorphous hydrogel enhances epithelialisation of wounds. Acta Dermatol Venereol (Stockh) 1998; 78: 119–22

15.

Falanga

. Occlusive wound dressings: why, when, which? Arch Dermatol 1988; 124: 872

16.

Freidman

, Su

WPD

. Management of leg ulcers with hydrocolloid occlusive dressings. Arch Dermatol 1984; 120: 1329

17.

Kannon

, Garret

. Moist wound healing with occlusive dressing: a clinical review. Dermatol Surg 1995; 21: 583

18.

Drager

, Winter

. Surgical debridement versus enzymatic debridement. In: Baharestani

, Gottrup

, Holstein

, Vanscheidt

, eds. The Clinical Relevance of Debridement. Berlin, Heidelberg, New York: Springer-Verlag, 1999:59–71

19.

Jung

, Winter

. Considerations for the use of Clostridial collagenase in clinical practice. Clin Drug Invest 1998; 15: 245–52

20.

Marazzi

, Stefani

, Chiaratti

, Ordanini

, Falcone

, Rapisarda

. Effect of enzymatic debridement with collagenase on acute and chronic hard-to-heal wounds. J Wound Care 2006; 15: 222–7

21.

Ramundo

, Gray

. Enzymatic wound debridement. J Wound Ostomy Continence Nurs 2008; 35: 273–80

22.

Ovington

. Hanging wet-to-dry dressing out to dry. Adv Skin Wound Care 2002; 15: 79

23.

Cullum

, Nelson

, Flemming

. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy. Health Technol assess 2001; 5: 1

24.

Brölmann

, Ubbink

, Nelson

, Munte

, van der Horst

, Vermeulen

. Evidence-based decisions for local and systemic wound care. Br J Surg 2012; 99: 1172–83

25.

Herberger

, Franzke

, Blome

, Kirsten

, Augustin

. Efficacy, tolerability and patient benefit of ultrasound-assisted wound treatment versus surgical debridement: a randomized clinical study. Dermatology 2011; 222: 244–9

26.

Rodeheaver

, Smith

, Thacker

, Edgerton

, Edlich

. Mechanical cleansing of contaminated wounds with a surfactant. Am J Surg 1975; 129: 241–5

27.

Thomas

, Andrews

, Jones

. The use of larval therapy in wound management. J Wound Care 1998; 7: 521–4

28.

Courtney

. The use of larval therapy in wound management in the UK. J Wound Care 1999; 8: 177–9

29.

Blair

, Jarvis

, Salmon

, McCollum

. Clinical trial of calcium alginate haemostatic swabs. Br J Surg 1990; 77: 568–70

30.

Barnett

, Varley

. The effects of calcium alginate on wound healing. Ann R Coll Surg Engl 1987; 69: 153–5

31.

Thomas

, Tucker

. Sorbsan in the management of leg ulcers. The Pharmaceut J 1989; 243: 706–9

32.

Williams

. An investigation of the benefits of Aquacel Hydrofibre wound dressing. Br J Nurs 1999; 8: 676–80

33.

Lydon

. The development of Aquacel hydrofibre dressings. In: Kreig

, Harding

, eds. Proceedings of Satellite Symposium European Academy of Dermatology and Venerology London: Churchill Communications, 1998

34.

Robinson

. The use of a hydrofibre dressing in wound management. J Wound Care 2000; 9: 32–4

35.

Harding

, Price

, Robinson

, Thomas

, Hofman

. Cost and dressing evaluation of hydrofiber and alginate dressings in the management of community-based patients with chronic leg ulceration. Wounds 2001; 13: 229–36

36.

Czaja

, Krystynow icz

, Bielecki

, Brown

Jr . Microbial cellulose-the natural power to heal wounds. Biomaterials 2006; 27: 145–51

37.

Solway

, Clark

, Levinson

. A parallel open-label trial to evaluate microbial cellulose wound dressing in the treatment of diabetic foot ulcers. Int Wound J 2011; 8: 69–73

38.

Alvarez

, Patel

, Booker

, Markowitz

. Effectiveness of a biocellulose wound dressing for the treatment of chronic venous leg ulcers: results of a single center randomized study involving 24 patients. Wounds 2004; 16: 224–33

39.

O'Meara

, Cullum

, Majid

, Sheldon

. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration. Health Technol assess 2000; 4: 21

40.

Cazzaniga

, Serralta

, Davis

, Orr

, Eaglestein

, Mertz

. The effect of an antimicrobial gauze dressing impregnated with 0.2% polyhexamethylene biguanide (PHMB) as a barrier to prevent Pseudomonas aeruginosa wound invasion. Wounds 2000; 14: 169–76

41.

Mulder

, Cavorsi

, Lee

. Polyhexamethylene biguanide (PHMB): an addendum to current topical antimicrobials. Wounds 2007; 19: 173–82

42.

Sibbald

, Browne

, Coutts

, Queen

. Screening evaluation of an ionized nanocrystalline silver dressing in chronic wound care. Ost Wound Manage 2001; 47: 38–43

43.

Bowler

, Duerden

, Armstrong

. Wound microbiology and associated approaches to wound management. Clin Microbiol Rev 2001; 14: 244

44.

Vilijanto

. Disinfection of surgical wounds without inhibition of normal wound healing. Arch Surg 1980; 115: 253

45.

Falanga

. Iodine Containing Pharmaceuticals: A Reappraisal. 91. Proceedings of the Sixth European Conference on Advances in Wound Management, vol. 191, 1-4 October 1996, Amsterdam: MacMillan, 1997: 4

46.

Viljanto

. Disinfection of surgical wounds without inhibition of normal wound healing. Arch Surg 1980; 115: 253–6

47.

Gruber

, Vistnes

, Pardue

. The effect of commonly used antiseptics on wound healing. Plast Reconstr Surg 1975; 55: 472–6

48.

Moberg

, Hoffman

, Grennert

, Hoist

. A randomized trial of cadexomer iodine in decubitus ulcers. J Am Geriatr Soc 1983; 31: 462–5

49.

Boyce

, Holder

. Selection of topical antimicrobials agents for cultured skin for burns: combined assessment of cellular cytotoxicity and antimicrobial activity. Plast Reconstr Surg 1993; 92: 493–500

50.

Woo

, Coutts

, Price

, Harding

, Sibbald

. A randomized crossover investigation of pain at dressing change comparing 2 foam dressings. Adv Skin Wound Care 2009; 22: 304–10

51.

Payne

, Posnett

, Alvarez

. A prospective, randomized clinical trial to assess the cost-effectiveness of a modern foam dressing versus a traditional saline gauze dressing in the treatment of stage II pressure ulcers. Ostomy Wound Manage 2009; 55: 50–5

52.

Zoellner

, Kapp

, Smola

. A prospective, open-label study to assess the clinical performance of a foam dressing in the management of chronic wounds. Ostomy Wound Manage 2006; 52: 34–6

53.

Banks

, Bale

, Harding

. Evaluation of a new polyurethane foam dressing. J Wound Care 1997; 6: 266–9

54.

King

. Catrix: an easy-to-use collagen treatment for wound healing. Br J Community Nurs 2005; 10: S31–4

55.

Andriessen

, Polignano

, Abel

. Monitoring the microcirculation to evaluate dressing performance in patients with venous leg ulcers. J Wound Care 2009; 18: 145–50

56.

Palfreyman

, Nelson

, Lochiel

, Michaels

. Dressings for healing venous leg ulcers. Cochrane Database of Syst Rev 2006; Issue 3. Art. No.: CD001103

57.

Guy

, Grothier

. Using negative pressure therapy in wound healing. Nurs Times 2012; 108: 16–20

58.

Webster

, Scuffham

, Sherriff

, Stankiewicz

, Chaboyer

. Negative pressure wound therapy for skin grafts and surgical wounds healing by primary intention. Cochrane Database Syst Rev 2012; (4):CD009261

59.

Kanakaris

, Thanasas

, Keramaris

, Kontakis

, Granick

, Giannoudis

. The efficacy of negative pressure wound therapy in the management of lower extremity trauma: review of clinical evidence. Injury 2007; 38 (Suppl. 5): S9–S18

60.

Ubbink

, Westerbos

, Evans

, Land

, Vermeulen

. Topical negative pressure for treating chronic wounds. Cochrane Database Syst Rev 2008; 16: CD001898

61.

Moues

, Heule

, Hovius

. A review of topical negative pressure therapy in wound healing: sufficient evidence? Am J Surg 2011; 201: 544–56

62.

Birke-Sorensen

, Malmsjo

, Rome

. Evidence-based recommendations for negative pressure wound therapy: treatment variables (pressure levels, wound filler and contact layer) – steps towards an international consensus. J Plast Reconstr Aesthet Surg 2011; (Suppl): S1–16

63.

Weston

. The science behind topical negative pressure therapy. Acta Chir Belg 2010; 110: 19–27

64.

Evans

, Land

. Topical negative pressure for treating chronic wounds. Cochrane Database Syst Rev 2001; (1): CD001898. Review. Update in: Cochrane Database Syst Rev 2008;(3):CD001898

65.

Thompson

, Marks

. Negative pressure wound therapy. Clin Plast Surg 2007; 34: 673–84

66.

Damiani

, Pinnarelli

, Sommella

. Vacuum-assisted closure therapy for patients with infected sternal wounds: a meta-analysis of current evidence. J Plast Reconstr Aesthet Surg 2011; 64: 1119–23

67.

Jones

, Banwell

, Shakespeare

. Advances in wound healing: topical negative pressure therapy. Postgrad Med J 2005; 81: 353–7

68.

Xie

, McGregor

, Dendukuri

. The clinical effectiveness of negative pressure wound therapy: a systematic review. J Wound Care 2010; 19: 490–5

69.

Shirakawa

, Isseroff

. Topical negative pressure devices: use for enhancement of healing chronic wounds. Arch Dermatol 2005; 141: 1449–53

70.

Banwell

, Musgrave

. Topical negative pressure therapy: mechanisms and indications. Int Wound J 2004; 1: 95–106

71.

Peinemann

, Sauerland

. Negative-pressure wound therapy: systematic review of randomized controlled trials. Dtsch Arztebl Int 2011; 108: 381–9

72.

Canonico

, Campitiello

, Delia Corte

, Fattopace

. The use of a dermal substitute and thin skin grafts in the cure of ‘complex’ leg ulcers. Dermatol Surg 2009; 35: 195–200

73.

Jeschke

, Rose

, Angele

. Development of new reconstructive techniques: use of Integra in combination with fibrin glue and negative pressure therapy for reconstruction of acute and chronic wounds. Plast Reconstr Surg 2004; 113: 525

74.

Heimbach

, Warden

, Luterman

. Multi-center post approval clinical trial of Integra dermal regeneration template for burn treatment. J Burn Care Rehabil 2003; 24: 42

75.

Wainright

, Madden

, Luterman

. Clinical evaluation of an acellular allograft dermal matrix in full thickness burns. J Burn Care Rehab 1996; 17: 124

76.

Butler

, Langstein

, Kronowitz

. Pelvic, abdominal, and chest wall reconstruction with AlloDerm in patients at increased risk for mesh-related complications. Plast Reconstr Surg 2005; 116: 1263

77.

Falanga

, Margolis

, Alvarez

. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Arch Dermatol. 1998; 134: 293

78.

Omarr

, Mavor

, Jones

. Treatment of venous leg ulcers with Dermagraft. Eur J Endovasc Surg 2004; 27: 666

79.

Bello

, Falabella

, Eaglstein

. Tissue-engineered skin: current status in wound healing. Am J Clin Dermatol 2001; 2: 305