Vasculogenic ulcers (venous, arterial, and/or mixed) are the most common type of ulcers in the legs, and may last from weeks to years.1,2 They are chronic, with an ulceration period (i.e. an open wound), followed by healing and recurrence.3 Of these ulcers, 50% return within 10 years. Twenty percent of patients experience 10 or more ulceration episodes, and 9.3% develop more than one ulcer in both legs.2,4 Ulcers that do not heal within six to eight weeks have the risk of becoming infected.5 The presence of bacteria may result in increase in ulcer size and delayed healing.6
A venous leg ulcer (VLU) results from damage to superficial and/or deep vein valves, impairing venous return, causing increased venous pressure, and compromising the supply of oxygen and tissue growth factors.1,7 Arterial leg ulcers, however, are associated with the interruption or decrease of blood flow, resulting in tissue ischemia and cell death due to nutrient and oxygen deficits.4,8 Arterial ulcers are often associated with artherosclerosis.8 Mixed leg ulcers are a combination of chronic venous insufficiency and peripheral arterial occlusive disease.9,10
Of all vasculogenic ulcers, 56%–70% are of a venous origin, 10%–20% are arterial, and 9%–26% have mixed etiology.2,11,12 Approximately 1%–3% of the population is affected, starting from 14 years of age, and the prevalence grows with age.2,12-15
In the United Kingdom, the estimated prevalence of venous ulcers is 0.29 per 1000 cases, while for mixed leg ulcers, it is 0.11 per 1000.15 In England, of 221 cases, 82.8% are of venous origin, while 17.2% are mixed leg ulcers.10 The global prevalence of arterial ulcers is 0.01% in primary health care settings in the community.16
Hospitalization is frequent, due to VLU complications such as edema and infection.17 Vasculogenic ulcer treatment costs are high.13,17-19 Venous leg ulcers negatively affect the patient's quality of life, causing exudate, odor, pain, depression, social isolation, personal hygiene difficulties, limitations in physical mobility, and, in severe cases, amputation.17,20,21
Arterial and mixed leg ulcer treatment includes surgery, debridement, systemic therapies (antibiotics, analgesia), patient education and nutrition.9,22,23 For VLUs, while compression therapy is the recommended intervention based on guidelines, a high level of evidence and elevation of the lower limb are necessary.1,24 Dressings and topical agents (e.g. hydrocolloids, alginates, hydrogels, foams, antimicrobials) are applied to protect the ulcer surface, absorb the exudate, and provide comfort and a humid environment ideal for healing.1,22,25
The healing of VLUs is slow, and in some cases, they may not heal at all.26 Venous leg ulcers do not progress through the normal physiological phases of healing, but remain in the inflammatory phase.1,7 Increased levels of metalloproteinases (proteases) in the inflammatory phase destroy proteins essential for extracellular matrix (ECM) formation.27 Without these proteins, angiogenesis does not occur and cellular adhesion in the ECM is degraded, delaying healing.28,29
Healing is a dynamic process that has phases (inflammation, proliferation and maturation), involving cellular interaction, chemical mediators, growth factors and ECM to repair the damaged tissue.30 The ECM is the largest component of normal skin, comprising cells embedded in a hydrophilic polysaccharide gel.31,32 It is composed of proteins (fibronectin, collagen), glycosaminoglycans, proteoglycans and glycoproteins that confer strength, elasticity, hydration and skin resistance to external pressures.31,32
Extracellular matrix technologies are part of tissue engineering, with several products available in the market.33-36 These matrix technologies aim to stimulate matrix components or replace the damaged matrix to optimize wound healing.33-36 According to a consensus, matrix products differ by source: cellular (containing living cells) or acellular (biologically inert).34 Another difference is the composition: biological (animal, human, plant), synthetic or composite materials (biological and synthetic).34 Extracellular matrix products can be derived from human sources (allografts) (e.g. donated human skin) or animal sources (xenografts) (e.g. porcine, equine, bovine).34,35 Products derived from animal and plants sources (e.g. microalgae) can be combined with synthetic materials.35,37 Acellular matrix products (animal and human sources) are processed to remove cells resting only in the collagen matrix.34,38 Cellular matrix products combine living cells and acellular components (e.g. collagen).35,36 Some products use other ECM proteins (e.g. non-collagen ECM).33,39 These proteins stimulate production of the vascular endothelial growth factor and proteinases that regulate ECM degradation and deposition essential for wound re-epithelialization.40
Matrices provide a tissue scaffold for the cellular base, allowing cellular interaction for migration, proliferation and differentiation, thus promoting re-epithelialization, revascularization and closure of the VLU.31,33 Application of Porcine's Matrix, derived from small intestinal submucosa associated with compression therapy, has shown healing in 55% of venous ulcers in 12 weeks compared to 34% with standard care (p = 0.0196).41 Acellular matrix poly-N-acetyl glucosamine has demonstrated healing in 86.4% of VLUs, compared to 45.0% with standard care alone.37 A multicenter study with amelogenin proteins and compression therapy identified a VLU wound size reduction of 33.8% in 12 weeks, compared to 25.6% for propylene glycol alginate.42 Application of biological ECM on VLUs and mixed arterial/venous ulcers, together with standard care, resulted in 80% healing, compared to 65% with standard care alone (p < 0.05).43
Application of acellular matrix on mixed leg ulcers has resulted in a better life quality by providing comfort, pain reduction and lowering time-to-dressing change.44 The cost-effectiveness of ECM application as a complement to standard care may be higher when compared with standard care alone.45 A recent cost-effectiveness study comparing matrices applied on VLUs and mixed leg ulcers against standard care alone identified slightly lower direct costs (US$2527 versus US$2540).46 Extracellular matrix annual average costs, including additional physician visits, compression dressings, home health visits, management of adverse events and hospitalizations amounted to US$20,041, compared to US$27,493 with Unna's Boot.47 These studies41-47 have demonstrated that ECM products are good options for hard-to-heal vasculogenic ulcers.
A prior systematic review investigated collagen-based ECM efficacy in diabetic foot management.48 However, this systematic review will focus on the evaluation of ECM effects on vasculogenic ulcers, investigating the effectiveness of ECM products, including not only collagen-based products but also non-collagen ECM, biosynthetic composite scaffolds and processed native skin products, in different application forms (e.g. dressing, topical). An up-to-date and transparent evidence review is required on the use of ECM products for the treatment of vasculogenic ulcers.
This review will consider studies that include adult participants over 18 years with venous, arterial or mixed leg ulcers in any setting: hospital, clinic, outpatient clinic, long stay institution or home care.
This review will consider studies that evaluate the effect of ECM products applied as dressings or in topical form on venous, arterial or mixed leg ulcers. We will consider dressings and topical agents that simulate the ECM, whether associated with cell culture or not. We will also consider acellular matrix products, which can be collagen-based ECM, non-collagen ECM, biosynthetic composite scaffolds, processed native skin products, and cellular matrix products that combine living cells and acellular components. Likewise, we will consider matrices of any composition, such as biological, including allografts (e.g. donated human skin), xenografts (e.g. porcine, equine, bovine), and plants (e.g. microalgae); synthetic; and biosynthetic (combination of biologica and synthetic materials). We will include all studies wherein the only systematic difference between treatment groups is the presence or absence of ECM agents.
The comparator will be compression therapy alone, any type of dressing, topical agents and placebos.
This review will consider studies that include the following outcome measures:
i. Complete healing (re-epithelization of the skin), as measured by proportion and number of completely closed ulcers during follow-up.
ii. Time to complete healing of ulcers, based on survival approach, event time, adjusted for relevant covariates, such as baseline size, according to days, weeks or months required for complete closure of the wound.
iii. Adverse events, indicated by infection rate, according to evaluation of clinical signs and symptoms (exudate, odor, necrotic tissue and the need for amputation).
i. Reduction of area (rate of change of wound area – length, width and depth) absolute changes (area change in cm2, based on the first wound measurement) and relative changes (variation of area percentage related to initial measurement of the wound), as measured with planimetry, digital photography, transparent diagrams with grid scale in mm2, and infrared camera with specific thermal sensitivity for the human skin.
ii. Pain control (assessed during treatment period and dressing change, as measured with quantitative pain evaluation scales, questionnaires and other validated tools).
iii. Quality of life measured with generic (SF-36, EQ, SF-12, SF-6) or specific standard questionnaires (Charing Cross Venous Ulcer Questionnaire [CCVUQ]).
Types of studies
The review will consider experimental study designs, including randomized controlled trials. In the absence of randomized controlled trials, we will consider other designs including quasi-experimental studies like non-randomized controlled trials. Also, observational studies such as prospective and retrospective cohort studies, case-control studies and case series studies will be included.
Studies published between 1960 and the present date will be considered for inclusion in this review. The delimitation of the search time is justified, since the results of the first research on the effects of the ECM on wounds were initially published in the 1960s.49,50 Studies published in English, Portuguese and Spanish will be considered for inclusion in this review.
The search strategy aims to find both published and unpublished studies. An initial limited search of MEDLINE and CINAHL has been undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe the articles. This informed the development of a search strategy which will be tailored for each information source. A full search strategy in a relevant database is detailed in Appendix I. The reference lists of all studies selected for critical appraisal will be screened for additional studies.
The databases and sources to be searched will include: PubMed, CINAHL, Embase, Web of Science, LILACS (Latin American and Caribbean Health Sciences Literature).
The search for unpublished studies will include: ProQuest Dissertations and Theses, EThOS - Beta - Electronic Thesis Online, Open Grey System Capes Portal.
The trial registers to be searched will include: Cochrane Central Register of Controlled trials, Clinical trial records platforms: ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/Default.aspx), European Union (EU) Clinical Trials Register (https://www.clinicaltrialsregister.eu/), Brazilian Registry of Clinical Trials (ReBEC) (http://www.ensaiosclinicos.gov.br/).
Following the search, all identified citations will be collated and uploaded into Mendeley (Mendeley Ltd., Elsevier, Netherlands)51 and duplicates removed. Titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion criteria for the review. Studies that meet and could potentially meet the inclusion criteria will be retrieved in full and their details imported into Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI).52 The full text of selected studies will be retrieved and assessed in detail against the inclusion criteria. Full text studies that do not meet the inclusion criteria will be excluded and reasons for exclusion will be provided in an appendix in the final systematic review report. Included studies will undergo a process of critical appraisal. The results of the search will be reported in full in the final report and presented in a PRISMA flow diagram. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer.
Assessment of methodological quality
Selected studies will be critically appraised by two independent reviewers at the study level for methodological quality in the review using standardized critical appraisal instruments from the JBI SUMARI52 for the following study types: randomized controlled trials, quasi-experimental studies (non-randomized experimental studies), cohort studies, case-control studies and case series. Any disagreements that arise will be resolved through discussion or with a third reviewer. All studies, regardless of their methodological quality, will undergo data extraction and synthesis (where possible).
Data will be extracted from papers included in the review using the standardized data extraction tool available in JBI SUMARI52 by two independent reviewers. The data extracted will include specific details about the interventions, populations, intervention comparators, study methods and outcomes of significance to the review question and specific objectives. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. If data are missing or unclear, the authors will contact the investigators to clarify the study findings.
Papers will, where possible, be pooled in statistical meta-analysis using JBI SUMARI. All results will be subjected to double data entry by two separate reviewers, and, where discrepancies occur, a third reviewer will be called to arbitrate. Effect sizes will be expressed as odds ratio (for dichotomous data and weighted (or standardized) mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and I squared tests (i2).The choice of model (random or fixed effects) and method for meta-analysis will be based on the guidance by Tufunaru et al.53 Heterogeneity will also be explored using subgroup analysis based on the different study designs included in this review. If data are available and can be pooled, a subgroup analysis will be explored based on the grouping of studies that will test the intervention by type of participant(s) according to age. A sensitivity analyses will be conducted to test decisions made regarding each comparison that has a meta-analysis. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation, where appropriate.
A funnel plot will be generated to assess publication bias if there are 10 or more studies included in the meta-analysis. Statistical tests for funnel plot asymmetry (Egger test, Begg test, Harbord test) will be performed, where appropriate.
Assessing certainty in the findings
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for grading the quality of evidence will be followed. A Summary of Findings will be created using GRADEPro GDT software. The table will present the following information where appropriate: absolute risks for treatment and control, estimates of relative risk, and a ranking of the quality of the evidence based on study limitations (risk of bias), indirectness, inconsistency, imprecision and publication bias.
The following outcomes will be included in the summary of findings: complete healing of ulcers, time to complete healing of ulcers, and adverse events (infection). If data are available, these other outcomes will be included: reduction of area of ulcers, pain and quality of life.
Appendix I: Search strategy for PubMed
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39. Fogh K, Nielsen CB, Dam W. Effect of amelogenin ECM protein on the healing of chronic leg ulcers with atrophie blanche. J Wound Care
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40. Mirastschijski U, Konrad D, Lundberg E, Lyngstadaas SP, Jorgensen LN, Agren MS. Effects of a topical enamel matrix derivative on skin wound healing
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48. Holmes C, Wrobel JS, Maceachern MP, Boles BR. Collagen-based wound dressings for the treatment of diabetes-related foot ulcers: a systematic review. Diabetes Metab Syndr Obes
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