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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Discussion
  6. Conclusions
  7. References

The number of patients suffering from chronic wound healing disorders in Germany alone is estimated to be 2.5–4 million. Therapy related expenses reach 5–8 billion Euros annually. This number is partially caused by costly dressing changes due to non-standardized approaches and the application of non-evidence-based topical wound therapies. The purpose of this paper is to elucidate a straightforward principle for the management of chronic wounds, and to review the available evidence for the particular therapy options. The T.I.M.E.-principle (Tissue management, Inflammation and infection control, Moisture balance, Epithelial [edge] advancement) was chosen as a systematic strategy for wound bed preparation. Literature was retrieved from the PubMed and Cochrane Library databases and subjected to selective analysis.

Topical wound management should be carried out according to a standardized principle and should further be synchronized to the phases of wound healing. Despite the broad implementation of these products in clinical practice, often no benefit exists in the rate of healing, when evaluated in meta-analyses or systematic reviews. This insufficient evidence is additionally limited by varying study designs. In case of non-superiority, the results suggest to prefer relatively inexpensive wound dressings over expensive alternatives. Arbitrary endpoints to prove the effectiveness of wound dressings, contribute to the random use of such therapies. Defining rational endpoints for future studies as well as the deployment of structured therapy strategies will be essential for the economical and evidence-based management of chronic wounds.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Discussion
  6. Conclusions
  7. References

In the year 2009, the German Federal Statistical Office registered the greatest percentage rise in the costs for outpatient care facilities with 9.5 % in comparison to the previous year. Of this, 5–8 billion Euros yearly go to the treatment of chronic wounds with the associated expensive dressing changes [1]. Therapy costs may be increased unnecessarily by non-standardized management and the uncritical use of non-evidence-based treatment approaches [2, 3].

Pathophysiology of chronic wound healing

The definition of chronic wounds in the German language is still not uniform. The medical societies recommend the following definition of chronic wounds on the basis of the current S3-guideline on topical therapy of chronic wounds: “A loss of integrity of the skin and one or more deeper structures with a lack of healing within eight weeks is termed a chronic wound [4].”

Physiological wound healing is characterized by three defined healing phases: inflammatory phase (exudative phase), proliferation phase (granulation, neoangiogenesis, epithelialization) and tissue remodeling [5-8]. These phases usually do not occur strictly chronologically, but parallel in one wound. In contrast to physiologically healing wounds, chronic wounds pass through these phases incompletely. Often a persistence of the inflammatory phase is responsible for wound chronicity [9]. The imbalance between proinflammatory factors and inhibitory enzymes manifests in persistent destruction of the extracellular matrix, which prevents the formation of granulation tissue and thus compromises the phase-adapted advance of wound healing.

Insufficient wound treatment often begins with the misunderstanding of the healing wound as a disease entity. Prerequisite for proper wound healing is the identification of the pathogenetic factors. Even though the causes of chronic wounds can be diverse, most wound healing disturbances can be reduced to a few frequent etiologic and pathogenetic factors. Of these, about 80 % are of vascular genesis [10]. Disturbed venous drainage in chronic venous insufficiency (CVI) is considered the most common pathomechanism for disturbed wound healing (Figure 1). It is followed by a combination of CVI and peripheral arterial occlusive disease (PAOD) and then by purely arterial ulcers and vasculitides in decreasing frequency (Figure 1, 2) [10]. Distinctly rarer, but decisive for an accurate diagnosis, are autoimmune diseases, physical causes and malignant tumors, e.g. squamous cell carcinoma (Table 1, Figure 3, 4) [11].

Table 1. Pathogenic factors for chronic wounds
EndogenousExogenous
Local tissue hypoxia due to impaired perfusionColonization with microbes
Chronic venous insufficiency (CVI)Critical bacterial colonization
Peripheral arterial occlusive diseases (PAOD)Bacterial infection
MicroangiopathiesInfection with parasites/fungi
Disturbed lymphatic drainage 
Chronic metabolic disorderTrauma
MetabolicIatrogenic
Drug-inducedAutomutilation
Disturbances of the immune systemChemical/physical agents
SystemicChemical agents
Specific skin diseasesDrugs
NeoplasmsIonizing radiation
Primary tumorsChronic local pressure
MetastasesThermal
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Figure 1. Diagnosis: Venous ulcer presenting with yellow- brown purpura, extensive hemosiderosis and lipodermatosclerosis of the adjacent skin. Therapy: If minor eschar is present, hydrogels for tissue management and moisture balance is indicated along with compression therapy. Especially in the course of long-term treatment, sensitization to ingredients of hydrogels needs to be considered. In case of impaired epithelialization, current evidence suggests positive effects of bilayered skin substitutes.

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Figure 2. Diagnosis: Ischemic ulcer presenting with fibrinous and necrotic eschar, a punched-out appearance and pale adjacent skin. Therapy: Revascularization procedures in combination with maggot therapy may be applied for tissue management and pro-angiogenesis. Current evidence suggests accelerated wound healing as well as an increased rate of wound healing with maggot therapy. The patient needs to be aware of possible pain due to this therapy. Additionally, local pressure must be avoided.

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Figure 3. Diagnosis: Grade IV decubitus in the sacrum region presenting a thick layer of necrosis in a bed-ridden patient. Therapy: With the risk of infection and thick moist eschar, surgical debridement should be applied for tissue management. Subsequently, negative pressure wound therapy should be administered for moisture balance and to prepare the wound for definite plastic reconstruction. Available evidence does not provide clear proof for the endpoint of ‘complete wound healing’. Polyhexanide is indicated for infection control due to its relatively low tissue toxicity and its broad spectrum efficacy.

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Figure 4. Diagnosis: Marjolin ulcer presenting malignant transformation approximately ten years after burn trauma. Therapy: Chronic wounds that are unresponsive to therapy are symptoms of an underlying cause that needs to be clarified. Primary objectives include the certain diagnosis, screening for metastasis as well as the excision with an adequate safety margin.

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Phase-adapted wound management according to the T.I.M.E. principle

The original principle of “keeping moist wounds dry and dry wounds moist” has been abandoned with the more exact knowledge of wound pathophysiology for phase-adapted topical wound treatment. Particularly the wound exudate is of prime importance for the healing of wounds [12, 13]. An established principle of phase-adapted wound therapy is the acronym T.I.M.E., first published by Falanga et al., which illustrates the clinical implementation of the propagated phase-adapted wound treatment after Schultz et al. [5, 9, 14]. The acronym T.I.M.E. takes four fundamental principles of wound treatment together: tissue management, infection control, moisture balance and edge of wound. The individual elements of the T.I.M.E. scheme are not to be seen as strictly separated individual measures. So, for example, the use of hydrogels allows not only for keeping the wound bed moist (moisture balance), but also makes autolytic debridement (tissue management) possible [15].

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Discussion
  6. Conclusions
  7. References

A selective research was performed in the databanks PubMed and Cochrane Library on conservative topical therapy of chronic wound healing disturbances. The following keywords were used in the literature search: chronic wound in combination with the terms TIME, management, debridement, infection, topical treatment, dressing, antiseptic, topical negative pressure, silver, topical antimicrobial therapy and dermagraft. The consideration of the literature found was done in a hierarchical manner starting with systemic meta-analyses, randomized, controlled studies and controlled studies from 1999 to 2012. Case reports were not considered in the evaluation of therapies. The search served to examine the evidence base of the T.I.M.E principle with the use of common measures for topical therapy of chronic wound healing disorders.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Discussion
  6. Conclusions
  7. References

Tissue management

Tissue management includes measures to remove devitalized structures such as necrotic tissue, wound coatings or foreign bodies and can be summarized under the generic term debridement. The rationale for removal of these wound components rests on the hypothesis that devitalized and infected tissue (through colonization with microbes) favors persistence of the wound in the inflammatory phase by proinflammatory cytokines and chemokines [16]. In the following four variants of debridement are differentiated: autolytic, mechanical, enzymatic and biological (Table 2).

Table 2. Objectives and options in therapy according to the T.I.M.E. principle
Tissue management
Antisepsis and breakthrough of chronic inflammation
AutolyticCurrent study data suggest the use of hydrogels to achieve a higher healing rate in diabetic ulcers [15, 18].
BiologicFor diabetic, venous and mixed ulcers debridement with maggots appears to be significantly more effective than with hydrogels. The rate of wound healing is not affected by maggots [15, 18].
EnzymaticCurrent data do not allow for a clear statement on the efficacy of enzymatic debridement [23, 24].
MechanicalCurrent data do not allow for a clear statement on the efficacy of mechanical debridement [18].
Infection control
Antisepsis and breakthrough of chronic inflammation
Medical honey preparations (e.g. manuka honey)Current study data demonstrate no significant difference in the healing rate or infection rate for the use of medical honey in chronic venous ulcers [72].
Antiseptic solutions (iodine solutions, octenidine, polyhexanide)In the use of antiseptic solutions, the characteristics of the individual substances, the type of wound (wound cavities, protein error) as well as the individual risk profile (allergies) of the patient should be taken into consideration [49, 51, 52].
Silver-impregnated wound dressingsCurrent study data do not allow for a clear statement on the antibacterial effects and the healing rate during the use of silver-impregnated wound dressings [64-66].
Moisture balance
Adequate moisturization of the wound bed, prevention of maceration of the wound edges
Alginates, hydrocolloids, synthetic wound dressings, foams, negative-pressure dressingsOn the whole, current study data do not allow for conclusions on a significant advantage of a certain wound dressing in the healing rate of diabetic or venous ulcers [15, 76, 78, 79, 81, 87, 88].
Edge of wound
Epithelialization possible
Allogenic keratinocytes, allogenic fibroblasts, allogenic skin constructions made of fibroblasts and keratinocytesTwo-layered artificial skin substitutes in combination with compression bandages increases the ulcer healing rate in comparison to simple wound dressings in combination with compression bandages [89].
Autolytic debridement

Autolytic debridement is found to a variable extent in all wounds. This form of debridement is characterized by parallel processes of enzymatic cleansing under sparing of granulation tissue and is highly efficient within the context of physiological (acute) wound healing. The biochemical processes are only given in a moist wound environment, which underscores the necessity of adequate moisture balance in chronic wounds [12, 13, 17]. Hydrogels appear to promote this form of autolysis demonstrably [15]. Three-dimensional networks of hydrophilic polyurethane polymers in an aqueous solution are termed hydrogels. A systematic meta-analysis by Dumville et al. in 2011 with respect to the efficacy of hydrogels in the healing rate of diabetic foot ulcers demonstrated their superiority over moist saline compresses and standard wound care (daily dressing changes, debridements, pressure relief), respectively. The authors calculated a number needed to treat (NNT) of five from the data of three studies with a total of 323 study participants. Thus, in order to heal one additional patient with a diabetic ulcer, five patients have to be treated with hydrogels instead of moist compresses or standard therapy measures alone [15]. Further meta-analyses confirmed this result for diabetic ulcers [18]. The choice of hydrogels must still be made critically due to the increased irritation and sensitization potential – particularly in patients with leg ulcers [19, 20]. In chronic wounds with extensive necrotic areas, autolytic debridement is often less efficient and must therefore be supported by other varieties of tissue management.

Mechanical debridement

An effective and inexpensive possibility for removal of devitalized tissue is mechanical debridement [21]. Mechanical “freshening” (via surgical debridement or ultrasound debridement) can transform chronic wounds in part into acute wounds that subsequently go through the physiologic wound healing phases [16, 22]. Surgical debridement is contraindicated when a pathergy phenomenon is likely, as in pyoderma gangrenosum. A disadvantage of this procedure is further a relatively unselective removal of devitalized and granulating tissue. Despite a trend to superiority, this form of debridement demonstrates no statistically significant advantage in a meta-analysis of the Cochrane Database in comparison to combination of conservative topical therapy and pressure relief at least in diabetic ulcers with respect to the wound healing rate after six months [18]. The use of surgical debridement should be oriented on the individual pain sensitivity and risk factors of the patient as well as the infrastructural requirements (inpatient vs. outpatient). Use of local anesthetic ointments, peripheral or central analgesic agents and short anesthesia can expand the spectrum of potential candidates.

Enzymatic debridement

The substances for the use of enzymatic debridement in Germany include streptokinase/streptodornase (Varidase® gel), desoxyribonuclease/fibrinolysin (Fibrolan® ointment) and clostridiopeptidase A (Iruxolum mono® ointment). In a systemic review, Ramundo et al. demonstrated a higher efficacy in debridement of necrotic tissue with collagenase products compared to inactive preparation in decubitus ulcers and leg ulcers of various causes in placebo-controlled studies [23]. In a placebo-controlled study on a total of 84 patients with leg ulcers Falabella et al. also observed no significant difference between the end points (reduction of pus exudation, pain, erythema and necrotic tissue). The significance of the study was limited by a lack of information on the causes of the ulcers or their distribution [24]. Enzymatic processes during wound healing are pH-dependent [25-29]. The enzymes may have limited or no activity at a given wound pH [30]. The proliferation of keratinocytes and fibroblasts appears to also be controlled by the pH value [31]. Enzymatic debridement appears suitable following mechanical debridement or in combination with an intermittent mechanical wound cleansing, particularly when coagulation disturbances or the pain situation makes necrectomy more difficult. For cleansing wounds with extensive necrotic areas and thick fibrin coats the effects are usually too little to achieve a clean wound bed in the appropriate time. Mechanical debridement is possibly superior here, but the current data does not allow a firm conclusion.

Biological debridement

Since the official approval of medical maggot therapy by the FDA in 2004, this form of biological wound cleansing is finding increasing use in the treatment of chronic wounds. Medical maggots of the common green bottle fly (Lucilia sericata) are used as free-range or contained in biobags of polyvinyl material. With respect to efficacy of free-range versus biobags the data are controversial at present [32-34]. The maggot secretions (leucine aminopeptidases, collagenases, among others) lyse necrotic tissue while sparing vital tissue. Maggot secretions also appear to have an anti-inflammatory and pro-angiogenetic effect [35]. The evidence of antibacterial efficacy is, in contrast, discussed controversially [36, 37]. In a systematic meta-analysis on 140 patients with diabetic ulcers, a significant advantage of maggot therapy for decreasing the wound size was shown as opposed to hydrogels. This does not apply, however, for the rate of complete wound healing after ten days of therapy [18]. For venous leg ulcers and mixed ulcers, a randomized, controlled study comparing maggot therapy with hydrogels showed no difference in the time to complete wound healing, but a significant shortening of the time until achieving complete debridement. The evaluation “completely debrided” was done by a blinded investigator according to purely optical criteria. No significant differences were seen in the bacterial burden and in the rate of MRSA colonization in the different study groups [34].

The selection of debridement should be made on the basis of the amount of devitalized tissue to be removed, the infection status of the wound and individual patient factors (subjective pain sensitivity, risk factors). For autolytic debridement the current data support the use of hydrogels. Surgical debridement, in contrast, is economical and efficient.

Infection control

Every chronic wound is colonized by microbes to a varying extent. Possibly, this “physiological wound flora”, which is termed wound contamination, may even have a positive impact through bacterial proteases and the stimulation of neutrophilic leukocytes [38]. Schultz et al. defined four grades of bacterial burden within wounds [5]: contamination, colonization, critical colonization and infection. The usually stated threshold for manifest infection of 1.0 × 105 colony-forming units (CFU) per gram tissue can only serve as a rough guideline [39-41]. Sibbald et al. propose the differentiation between critical colonization and the degree of infection using clinical criteria, such as healing grade, exudation, wound odor and the typical signs of infection [42]. In contrast, Serena et al. were able to demonstrate on 352 patients with chronic venous ulcers, that in 26 % of the cases (despite cultural detection of infection > 1.0 × 106 CFU per gram tissue) no clinically manifest infection could be diagnosed by an experienced investigator [43]. The Wounds At Risk Score is a purely clinical decision-making tool for the use of antiseptics that determines the probability of wound infection on the basis of risk factors [44].

Even though the absolute bacterial burden in chronic wounds has been identified as a negative predictor, new knowledge appears to show that more likely a “collective pathogenic effect” of the broad bacterial flora or the specific virulence of individual bacteria play the main role in disturbed wound healing [41, 45]. In addition, bacterial influence factors (e.g. via Toll-like receptor 3) have been identified for persistent inflammatory processes in wounds [46, 47]. Which criteria definitively detect infection in chronic wounds, still remains open for critical discussion. Antimicrobial therapy is impeded by the formation of biofilms, which are bacterial aggregates in conjunction with an extracellular polymeric protection layer against antibiotics – also termed glycocalyx – protecting them from the immune system [47, 48].

The use of wound irrigation solutions allows for the rapid wound decontamination as well as removal of adherent wound coats during dressing changes. Saline or Ringer solution and broad-band antiseptics such as polyhexanide solutions, octenidine dihydrochloride and iodine solutions in the form of povidone (e.g. Braunol®) or cadexomer compounds (e.g. Iodosorb®) are used (Table 2). The advantage of iodine solutions over other antiseptics is that no known gaps in their action spectrum exist, although a loss of effectiveness in the presence of protein components from wound exudate should be considered (termed protein error).

The biocompatibility index (BI) describes the ratio between the antimicrobial effectiveness and tissue tolerance and is often stated as a parameter for the quality of topical antiseptics. For example, for iodine solutions, due to their in vitro cytotoxicity, a relatively low BI of 0.68 is reported, while in contrast a cytotoxic effect of cadexomer iodine according to recent studies could not be confirmed in vivo [49]. For povidone iodine, histologically detectable tissue toxicity could not be demonstrated in a controlled study [50]. The reverse is true for octenidine solutions that have relatively high BI values of 1.73–2.11; unwanted drug side effects with edema and tissue necrosis when used under pressure or by residues in wound cavities have been reported repeatedly in “red hand letters” (letters to bring side effects to the attention of physicians) [49, 51]. Polyhexanide solutions are considered to possess only low risks with respect to their tissue toxicity or contact sensitization [44, 52, 53].

In a randomized study, povidone iodine solution in combination with paraffin gauze showed no significant difference with respect to the wound healing rate in comparison to hydrocolloid dressings in the treatment of venous ulcers. With respect to antibacterial efficacy, the results were, however, controversial [54]. Despite several case reports of anti-proliferative, cytotoxic, irritative and allergenic potency of povidone iodine preparations up to anaphylactic reactions, Vermeulen et al. concluded in a meta-analysis of 29 randomized, controlled studies that the side effect profile of iodine preparations – at least with respect to its anti-proliferative and cytotoxic effects – is acceptable [55-58].

Particularly in the outpatient setting, wound irrigation with tap water (such as through showering) is an established method for wound cleansing. In a randomized, controlled study, Griffiths et al. found no significant difference in using tap water in contrast to saline solution with respect to the end points healing rate and infection rate. The impact of this study is limited by the small sample size of 49 wounds [59]. Showering of wounds in the sense of wound irrigation with simultaneous mild debridement is a cost-effective alternative to irrigation solutions containing active ingredients [60]. The unsecured quality of tap water, particularly at home (due to lack of sterile filter systems) as well as return spray exposure from the drain and inadequate water temperature is problematic.

Ionic silver has a long history of medical use in ointments in the therapy of burns. The basis of the use of silver as antimicrobial therapy is the property of ionic silver to bind to protein disulfate bridges and arrest microbial metabolic processes. It is effective against a broad spectrum of microbes (yeast, viruses, anaerobes, aerobes) and extends to gram-positive and gram-negative bacteria [61]. In recent years, wound dressings impregnated with silver have become increasingly available. In a systematic review of the Cochrane Library, Vermeulen et al. found on the basis of three randomized, controlled studies on a total of 847 patients with predominantly infected diabetic, venous and decubitus ulcers, that with silver-containing wound dressings no significantly higher healing rate could be achieved within the study duration of four weeks. No valid conclusions could be drawn from the study data with respect to reduction of wound infections. Significant results were seen with respect to reduction of ulcer surface as opposed to the comparative groups. It is notable, that each of the three studies was financed by the same manufacturer. Overall, the data are unsatisfactory in terms of short study duration and lack of results with respect to effects on wound infection [54, 62]. A further meta-analysis from 2010 confirmed these observations [63]. Bergin et al. also concluded in 2010 after a systematic literature review that due to the inadequate study quality no conclusion could be made with respect to efficacy of silver-impregnated wound dressings with respect to healing and infection for the use in diabetic foot ulcers [64]. Current review articles are contradictory in their conclusions on the effects of silver-impregnated wound dressings in chronic wounds [65, 66]. In addition, there are indications of tissue toxicity or cytotoxicity in vivo and in vitro [67]. On the whole, the benefits of silver-impregnated wound dressings must be viewed as questionable because of the lack of quality of the studies.

In vitro studies demonstrate the antimicrobial efficacy of diverse honey types [68, 69]. Newer studies suggest that methylglyoxal is responsible for the bactericidal properties of some honey types [70]. New Zealand manuka honey appears to possess the highest concentration of methylglyoxal. In various in-vitro studies, medical honey was shown to be bactericidal towards Pseudomonas aeruginosa, Enterococcus faecium and even MRSA [68, 71]. In a systematic review published in 2009, no significant differences in the healing rate or in the infection rate were found for honey wound dressings for chronic venous ulcers of the lower extremity [72].

Despite theoretical advantages of topical antibiotics (such as high local agent concentrations, reduced systemic side effects, outpatient use), topical use of antibiotics is contraindicated on the basis of frequent antibiotic resistances, pathogen selection, contact dermatitis and lack of evidence [73-75].

The detection of microbes in a chronic wound does not necessarily require antiseptic therapy. When the grade of critical colonization is exceeded, antiseptics should be employed taking into consideration their individual positive and negative features.

Moisture balance

The moisture balance in the wound bed decisively impacts the formation of granulation tissue, epithelialization, the degree of maceration, the susceptibility for bacterial colonization as well as patient comfort [12, 13]. Against this background manufacturers of medicinal products have flooded the market with immense numbers of “interactive” wound dressings, where the following generic classes of dressing materials can be differentiated: hydrocolloids, alginates, hydrogels, foam and negative-pressure dressings (Table 2). Common to all is the impact on the moisture level in the wound, with the individual products differing decisively in their absorption properties.

Hydrocolloids

Hydrocolloid wound dressing usually consist of sodium carboxymethyl cellulose in association with a secondary dressing. In the moist environment of the wound, the sodium carboxymethyl cellulose takes on a gel- like consistency. The gel binds wound exudate and simultaneously keeps the wound moist. Prerequisite is an adequate exudate amount or moisture from irrigation solutions. In a systematic Cochrane meta-analysis taking four studies with a total of 511 participants into consideration, no significant differences were found in the healing rate in the therapy of diabetic ulcers of the legs with hydrocolloid wound dressings as opposed to gauze compresses moistened with saline, foam dressings or silver-impregnated wound dressings [76].

Alginates

Alginate dressings are in principle similar to the hydrocolloid class. In analogy to hydrocolloids, fluid exposure leads to gel formation in calcium alginate with deposition of calcium ions in the alginate structure. Considering six studies with a total 375 participants, a systematic Cochrane library analysis came to the result that alginate dressings had no clear advantage as opposed to alternative wound dressings (foam dressings, hydrocolloid, paraffin compresses) in the treatment of diabetic ulcers of the legs [77]. For the use of alginates for venous ulcers, no increase in the healing rate could be achieved after six weeks in comparison to hydrocolloid wound dressings [78].

Hydrogels

Hydrogels are polymer structures out of hydrophilic components that primarily ensure moistening of a dry wound bed. In a systematic meta-analysis of the Cochrane Library including three studies with a total of 198 participants, a significantly higher healing rate in diabetic ulcers was seen during therapy with hydrogels in comparison to gauze compresses moistened with saline or dry compresses [15]. Edwards et al. confirmed this observation for diabetic ulcers [18]. In a further meta-analysis of 42 randomized clinical studies with a comparison of hydrocolloid, foam, alginate and hydrogel dressings in combination with compression for the therapy of venous ulcers, none of the products displayed a significantly higher healing rate [79]. Especially innovative hydrogels that react to wound conditions (for example, pH-dependent release of wound healing factors) may play an increasing role in the topical therapy of chronic wounds [19].

Foams

Foam dressings have become increasingly established in recent years due to their easy use in comparison to the gel-forming dressings. Employed as dressing or wound tamponade, the polyurethane foams enable the ingrowth of granulation tissue through their pores and due to their relative permeability allow for undisturbed gas exchange. The relatively low absorption ability can be increased by acrylates or other superabsorbers. The removal of the granulation tissue which has infiltrated the foam is supposed to affect a freshening of the wound bed. Wound dressings should not be changed too often; the changing intervals are determined by the pore size of the foam used, the granulation tendency and the infection status of the wound, and can be extended to once weekly [80]. In a systematic meta-analysis published in 2011 with six studies on a total of 157 participants, no advantage of foam dressings in comparison to saline- moistened gauze compresses, alginates and hydrocolloids was seen with respect to the healing rate of diabetic ulcers of the legs [81].

Negative-pressure dressings

Since the 1990s sealed negative-pressure systems have been used broadly in wound treatment [82]. Although often termed vacuum-assisted wound closure, no vacuum is produced, but only continuous or intermittent negative pressure between about 60 and 180 mmHg in the wound cavity (sealed with foil in an airtight fashion). Hydrophobic or hydrophilic polyurethane sponges are employed as wound fillers. According to the manufacturers the negative pressure should ensure adequate drainage of wound secretion, reduce tissue edema and simultaneously increase tissue perfusion. These claims are only in part supported by evidence. Contradictory data exist on the increase of local tissue perfusion [[84], 84]. An advantage in edema reduction rests on weak evidence [85]. There are contradictory indications with overall weak evidence for selective drainage of destructive proteases with the relative predominance of healing-promoting cytokines in the wound bed [85, 86]. Independent of the involved mechanisms of action, however, the success in healing of negative-pressure therapy must be evaluated. In their systematic meta-analysis published in 2011 with consideration of seven studies, Ubbink et al. found that negative-pressure therapy of chronic wounds is not superior in comparison to gauze compresses moistened with saline, hydrocolloids, hydrogels, alginates and foam dressings. Peinemann et al. concluded after a meta-analysis of 21 randomized, controlled studies, that despite possible positive effects on wound healing no definitive advantages or disadvantages as opposed to conventional wound treatment exist [88]. The differentiated view of these results concludes that not every negative-pressure therapy pursues the aim of definitively healing the wound with this technique. Negative- pressure therapy often serves to prepare the wound bed for other procedures. The cited studies define the complete wound closure as the primary endpoint of their analysis. The possible benefits of this therapy as a temporary measure until final wound closure through a surgical technique has not been adequately addressed.

Despite undisputed advantages due to the physical properties of modern wound dressings, current data show no clear advantage of a certain type of wound dressing. Wound dressings should therefore be selected based on the principles of moist wound treatment, patient comfort and economic aspects.

Edge of wound

The epithelialization is a component of the proliferation phase. Reepithelialization from the wound edges or skin appendages requires a wound bed with granulation tissue as the base for migration. To make this process possible, an adequate moist environment is crucial, since wound secretion continually decreases during the granulation phase and must be compensated by moistened wound dressings [6]. Frequently, chronic wounds fail to epithelialize despite adequate moistening. To overcome this problem, several manufacturers have introduced products for biologically active skin replacement as a conservative therapy alternative to autologous split-skin covering (Table 2). Skin substitutes consisting of cryoconserved allogenic keratinocytes (CryoCeal®), cultured allogenic fibroblasts (Dermagraft®) or full-thickness constructions consisting of keratinocytes and fibroblasts on a collagen matrix (Apligraf®, Orcel®) are used. A systematic meta-analysis of the Cochrane Library confirmed an advantage of two-layer skin substitutes versus placebo in combination with compression therapy in venous ulcers with an NNT of five. For all other replacement materials, no statistically significant advantage in comparison among each other or in comparison to non-adherent wound dressings could be detected [60, 89]. Overall, the data are of limited impact due to the small sample sizes.

Epithelialization usually occurs as soon as sufficient granulation tissue has formed. Particularly in venous ulcers epithelialization is often insufficient due to dystrophic wound edges and can be supported with two-layered skin substitutes.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Discussion
  6. Conclusions
  7. References

Prior to the therapy of chronic wounds, diagnostics to reveal the cause should be performed. The T.I.M.E principle promotes focused therapy according to the predominant pathophysiology in the wound and thus contributes to systematic and phase-adapted therapy of chronic wounds. Even if no comparative studies exist, a systematic approach has proven itself in the clinical routine in many areas of medicine.

Some cost-intensive measures for phase-adapted wound treatment can be waived in lack of evidence and thus possibly contribute to unnecessarily high expenses in the treatment of chronic wounds. The selection of a wound therapy should be based on available evidence on its efficacy, patient comfort and economic aspects [2].

There are still no objective evaluation criteria for the measurement of the healing process in chronic wounds. Here modern measuring methods for important surrogate parameters of wound healing (such as local pH level and local oxygen partial pressure) can be of great benefit [26, 28, 29, 90]. These biological parameters affect multiple processes within the context of wound healing (including proliferation and migration of cells, activity of matrix metalloproteinases) and wound therapy (e.g. therapeutic enzymes for wound healing) [27, 29, 31]. The definition of rational end points for the evaluation of the efficacy of wound therapy products as well as the use of structured therapy concepts are essential for the future economic and evidence-based therapy of chronic wounds.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Discussion
  6. Conclusions
  7. References