Hostname: page-component-cd9895bd7-p9bg8 Total loading time: 0 Render date: 2024-12-27T07:24:13.458Z Has data issue: false hasContentIssue false
  • English
  • Français

Molecular mechanisms of action of negative pressure wound therapy: a systematic review

Published online by Cambridge University Press:  19 October 2023

Bharadhwaj Ravindhran Open the ORCID record for Bharadhwaj Ravindhran [Opens in a new window] ,
Nicole Schafer ,
Annabel Howitt ,
Daniel Carradice ,
George Smith  and
Ian Chetter
Bharadhwaj Ravindhran*
Affiliation:
Academic Vascular Surgical Unit, Hull Royal Infirmary, Hull, UK Department of Health Sciences, University of York, York, UK
Nicole Schafer
Affiliation:
Academic Vascular Surgical Unit, Hull Royal Infirmary, Hull, UK
Annabel Howitt
Affiliation:
Academic Vascular Surgical Unit, Hull Royal Infirmary, Hull, UK
Daniel Carradice
Affiliation:
Academic Vascular Surgical Unit, Hull Royal Infirmary, Hull, UK
George Smith
Affiliation:
Academic Vascular Surgical Unit, Hull Royal Infirmary, Hull, UK
Ian Chetter
Affiliation:
Academic Vascular Surgical Unit, Hull Royal Infirmary, Hull, UK
*
Corresponding author: Bharadhwaj Ravindhran; Email: bharadhwaj.ravindhran@nhs.net
Rights & Permissions [Opens in a new window]

Abstract

Negative pressure wound therapy (NPWT) has significantly advanced wound care and continues to find new applications. Its effects at a molecular level however, remain a subject of debate. The aim of this systematic review is to summarize the current evidence regarding the molecular mechanisms of action of NPWT. Medline, Embase, EBSCO databases and clinical trial registries were searched from inception to January 2023. Clinical studies, animal models or in-vitro studies that quantitatively or semi-quantitatively evaluated the influence of NPWT on growth factors, cytokine or gene-expression in the circulation or wound-bed were included. Risk of Bias assessment was performed using the RoBANS tool for non-randomized studies, the COCHRANE's Risk of Bias 2(ROB-2) tool for randomized clinical studies, OHAT tool for in-vitro studies or the SYRCLE tool for animal model studies. A descriptive summary was collated and the aggregated data is presented as a narrative synthesis. This review included 19 clinical studies, 11 animal studies and 3 in-vitro studies. The effects of NPWT on 43 biomarkers and 17 gene expressions were studied across included studies. NPWT stimulates modulation of numerous local and circulating cytokines and growth factor expressions to promote an anti-inflammatory profile. This is most likely achieved by downregulation of TNFα, upregulation of VEGF, TGF-β and fibronectin.

Keywords

biomarkersmolecular mechanismsnegative-pressure wound therapywound carewound healing
Type
Review
Information
Expert Reviews in Molecular Medicine , Volume 25 , 2023 , e29
Check for updates
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
Copyright © The Author(s), 2023. Published by Cambridge University Press

Introduction

Open surgical wounds or surgical wounds healing by secondary intention are a common and complex problem. These wounds frequently take a long time to heal, require regular dressing changes and present a significant morbidity to the patient and a significant financial burden to healthcare systems. They may need many modalities of treatment, are susceptible to secondary infection, and may also require prolonged hospitalization and/or further operations (Ref. Reference Chetter1). The requirement to manage exudate and avoid repeated wound dressing changes has led to a significant increase in the use of newer modalities of wound management such as negative pressure wound therapy (NPWT) (Ref. Reference Chetter2).

NPWT is currently used widely in many aspects of wound care and has been strongly promoted for use on complex wounds (Refs Reference Armstrong and Andros3, 4). NPWT involves the application of an airtight wound dressing through which a negative pressure is applied, often with any wound and tissue fluid drawn away from the area being collected into a canister. The amount of pressure applied using the therapy can vary and there is no universally agreed protocol for its use (Ref. Reference Peinemann and Sauerland5). A number of surgical and non-surgical specialties prescribe NPWT leading to its widespread implementation in both primary/community care and in tertiary care (Refs Reference Liu6, Reference Gao7).

NPWT is postulated to facilitate wound healing via several primary and secondary mechanisms. The proposed primary mechanisms of action include macro-deformation or wound shrinkage, micro-deformation at the foam-wound interface, fluid removal whilst maintaining a moist environment and stabilization of the wound environment. The proposed secondary mechanisms include alteration of the mechanotransduction pathways and alteration of the wound healing microenvironment including cellular proliferation, differentiation, cell migration, angiogenesis and neurogenesis. Many theories have been proposed to support these primary and secondary mechanisms at a molecular level and the aim of this systematic review is to summarize the currently available evidence regarding the molecular mechanisms of action of NPWT (Refs Reference Borgquist, Ingemansson and Malmsjö8, Reference Kairinos, Solomons and Hudson9, Reference Saxena10, Reference Yang, Chang and Webb11, Reference Adámková12, Reference Kim13, Reference Gerry14, Reference Orgill15).

Methods

Search strategy

Medline, Embase and Elton Bryson Stephens Company (EBSCO) databases, and Clinical trial registries were searched from inception to January 2023 using pre-specified key words (Supplementary file 1). Article screening and extraction was performed by two authors (BR and NS) using the Rayyan online screening and data tool (Ref. Reference Ouzzani16). The reference lists of the retrieved articles and similar review articles in the field were also searched to identify additional papers. Studies that examined the mechanism of action of NPWT in patients or in animal models in preclinical studies or in-vitro studies were included. We included studies that evaluated the effect of any form of NPWT on open surgical wounds including diabetic foot ulcers, pressure ulcers, surgical site infections (SSI), traumatic wounds and post-operative wounds. Studies which focussed on the effects of NPWT on primarily closed wounds or stoma creation were excluded. Case reports, non-English papers, editorials/commentaries, reviews, letters and papers with limited data on methodology were excluded. The study was registered in the PROSPERO database (CRD42022303088) and was performed according to Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines (Ref. Reference Moher17).

Data extraction

The key details regarding the method and results were recorded on a bespoke data extraction sheet. Data extraction was conducted by two independent reviewers (BR and NS). Discrepancies were resolved by discussion amongst the authors and a tie-breaking vote from the authors not involved in the screening process. Data elements extracted included study name and year of publication, country, immune cell/mediator(s) described in the study, model (clinical studies, animal wound models or in-vitro),type of wound, specific device with control intervention, duration and time points of analysis, quantitative/qualitative outcomes, duration of follow-up, publication status, funding and conflict of interest.

Assessment of risk of bias (RoB)

Risk of Bias assessment was performed using the RoBANS tool (Ref. 18) for non-randomized studies, the COCHRANE's Risk of Bias 2(ROB-2) tool (Ref. Reference Sterne19) for randomized clinical studies, Office of Health Assessment and Translation (OHAT) tool (Ref. 20) for in-vitro studies or the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool (Ref. Reference Hooijmans21) for animal model studies. The risk of bias assessment and quality assessment figures were produced with the help of the interactive online web application, ‘robvis’ (Ref. Reference McGuinness and Higgins22).

Data synthesis and analysis

Due to the diversity of the variables and immune markers being evaluated and the heterogeneity of the studies being reviewed, it was not possible to pool data and present findings as a meta-analysis. Instead, a descriptive summary was performed with aggregated data presented as a narrative synthesis. The narrative synthesis includes elements such as the immune cell or biomarker of interest, its context and the impact of NPWT on it and the relationship between the immune cell/biomarker and wound healing and the concordance between studies with respect to these findings. Also, each study's methodological and summary characteristics are presented in a separate table to include the author(s), institution, year of publication, sample size, study model, biomarkers/cell markers under review and key findings reported by authors.

Results

Out of 6397 potential studies, 33 studies were included in the systematic review. This included 19 clinical studies, 11 animal studies and 3 in-vitro studies. The exclusion of all the other studies has been outlined in Figure 1 in accordance with the PRISMA reporting guidelines. Out of the 11 animal models, 1 study was conducted in a rabbit model, 5 studies were conducted in murine models and 5 studies in porcine models. Thirteen studies had a high risk of bias and 3 studies had some concerns of bias. Ten clinical studies and 10 animal studies analysed tissue samples from wounds while 5 clinical studies analysed the wound effluent. Five clinical studies and one animal study also used serum samples to correlate the effect of NPWT on wounds. Twenty-eight studies focussed on the effect of NPWT on molecular and cellular biomarkers, while 5 focussed on the effect of NPWT on differential gene expression in wound or serum samples. Substrate analysis was carried out by a combination of quantitative and semiquantitative methods including enzyme-linked immunosorbent assay(ELISA), immunohistochemical(IHC) staining or Western blot analysis. Analysis of gene expression was predominantly carried out by RNA sequencing and/or reverse transcription-quantitative polymerase chain reaction(RT-qPCR). These findings are elaborated in Table 1.

Figure 1. Literature search and study selection.

Table 1. Characteristics of the included studies

Vascular Endothelial Growth Factor (VEGF) was the most frequently studied growth factor in relation to NPWT with 7 papers identified (Refs Reference Labler27, Reference Labler28, Reference Karam34, Reference Mu38, Reference Yang41, Reference Zhou45, Reference Erba49, Reference Jacobs50). Results from clinical studies were reported in 4 studies (Refs Reference Labler27, Reference Labler28, Reference Karam34, Reference Mu38). A significant increase in the local VEGF concentration was seen in clinical wounds treated with NPWT, and reports from animal studies concurred with these findings (Refs Reference Yang41, Reference Zhou45, Reference Erba49, Reference Jacobs50). This increase in VEGF has been postulated to contribute to the increased neovascularization and granulation tissue formation in patients treated with NPWT. VEGF was elevated in all 7 studies which studied its effects. Tumour necrosis Factor alpha(TNF α) was downregulated in 5 out of 8 studies and was the next most common biomarker that was studied (Refs Reference Stechmiller25, Reference Eisenhardt26, Reference Karam34, Reference Wang37, Reference Brownhill44, Reference Dong55). TNF α is considered as a pro-inflammatory cytokine and a potent inducing agent for the upregulation of cytokines, reactive oxygen species and apoptosis. Elevated levels of TNF α in the wound bed have been associated with chronic non healing wounds with reduced granulation tissue production. Transforming Growth Factor Beta (TGF β) was upregulated in 5 out of 7 studies that studied its effects. The data from the in vitro models included in this paper (Refs Reference Lu53, Reference McNulty54, Reference Dong55) suggest that it leads to increased granulation tissue production. NPWT induces the production of TGF-β1, which is crucial for the initiation of the proliferation phase of wound healing. The effect of NPWT on wound healing is mediated through various signals, including TGF-β-Smad, which further underscores the importance of TGF-β in this context. Fibronectin was upregulated in both studies which evaluated its effects (Refs Reference Arslan23, Reference Yang39). Equivocal results were obtained across all studies with respect to Interleukins (IL) and Matrix Metalloproteinases (MMP) including IL1β, IL 6, IL8, IL8, MMP 2, 3 and 9. The effects of NPWT on 43 other molecular biomarkers and 13 different gene expressions were analysed across included studies (Table 1).

Clinical/human studies

Nineteen clinical studies were conducted to assess the MOA of NPWT from 2003 to 2022 with study numbers varying from three to172 patients. Out of these, 12 studies compared the mechanisms of action between NPWT and standard dressings and other studies studied the MOA of NPWT alone. Eleven studies used granulation tissue samples from wound beds, 5 studies studied samples from wound effluents and 5 studies analysed peripheral blood samples. Ten studies had a high risk of bias, one study had some concerns of bias and eight studies had a low risk of bias. (Fig. 2a, 2b) The main cytokines of interest in these studies were VEGF,TNF α, Interleukin(IL)-6, IL – 8, IL 1B, and the family of matrix metalloproteinases (MMP) MMP-1, MMP-2, MMP-9, MMP-13. VEGF was upregulated in all four studies which studies it's effects TNF α was downregulated in four out of four studies, Fibronectin and TGF B1 were upregulated in both studies which studied their effects. There was no concordance regarding the impact of NPWT on the other cytokines, biomarkers and/or genes.

Figure 2. Risk of Bias Assessment of the included studies: (a) RoBANS for non-randomized studies, (b) SYRCLE tool for animal studies, (c) RoB-2 tool for randomized studies.

Animal studies

Eleven animal studies were included in this review out of which five studies used murine models, five studies used porcine models and one study used rabbit models. The sample size ranged from six to 56 animals. Three studies had a high risk of bias, two studies had some concerns and six studies had a low risk of bias. (Fig. 2c) All studies used tissue samples and two studies also used serum samples in addition for analysis. The main cytokines of interest in these studies were TNF α, FGF-2, TGFB1, PDGF and VEGF. Three out of three studies reported the upregulation of VEGF following NPWT. Two studies reported the upregulation of TNF α while one study reported its upregulation following NPWT. The results of most of the included animal studies suggest that many of the cytokines/chemokines and genes are upregulated following the upregulation of NPWT.

In vitro studies

Three studies studied the mechanisms of action of NPWT using in vitro models using murine fibroblasts (Ref. Reference Lu53), human fibroblasts in a 3D fibrin matrix (Ref. Reference McNulty56) and a combination of PMNs, HL 60 cell lines and Macrophages (Ref. Reference Dong55) respectively. Each study examined a completely different set of biomarkers (Table 1). Two studies conducted their experiments in a cell culture under negative pressure. Two studies also reported the upregulation of TGF-B under the effect of NPWT (Refs Reference Lu53, Reference McNulty56). The risk of bias assessment using the OHAT tool revealed a low risk of bias for one study, some concerns of bias and high risk of bias for the other two studies.

Gene expression changes

The effect of NPWT on 17 different gene expressions was assessed in this systematic review (Table 1). Since no two studies evaluated the effects of similar gene expressions, it was not possible to collate these findings. The results of the included studies have suggested that the genes induced by NPWT were associated with cell proliferation and inflammation, and the most down-regulated genes were linked to epidermal differentiation. NPWT has also been postulated to aid differential gene expression to influence re-epithelialization and angiogenesis (Ref. Reference Frear30). NPWT was also observed to alter multiple proteins in the granulation tissue to aid antioxidant pathways and detoxification (Ref. Reference Liu57) The gene ontology enrichment analysis performed in one of the studies was consistent with a number of previous studies showing that the wound healing process was associated with altered extracellular matrix deposition (Ref. Reference Maione58), cytoskeletal deregulation (Ref. Reference Jozic59), dyslipidemia (Ref. Reference Yazdanpanah60) and prolonged inflammation response (Ref. Reference Gouin and Kiecolt-Glaser61). They also unexpectedly found some signalling pathways that seemed weakly relevant to the curative effect of wounds in the enrichment analysis of Kyoto Encyclopaedia of Genes and Genomes (KEGG) signalling pathways, such as thyroid hormone synthesis, thyroid hormone signalling pathway, human T-cell leukaemia virus 1 infection and African trypanosomiasis (Refs Reference Capewell62, Reference McGill63, Reference Shimauchi and Piguet64).

Discussion

This systematic review summarizes the current understanding of the mechanism of action of NPWT based on studies published over the last 20 years. The effect of NPWT was assessed in 33 studies which included 19 clinical studies, 11 animal models and 3 in-vitro studies. Given that more than 43 different molecular biomarkers and 17 different gene expressions were analysed across all studies, there was some clear concordance in actions on several markers studied and variation between studies with respect to the effects on other biomarkers/genes following NPWT (Table 2).

Table 2. Variation in outcomes following NPWT on common biomarkers of interest

It has been postulated that NPWT produces hypoxia driven immunomodulation, local and/or systemic attenuation of the acute inflammatory response, angiogenesis and cell recruitment which combine to produce the clinical effects of NPWT (Refs Reference Orgill15, Reference Scherer51). However, the specific mechanisms of action by which these are achieved continue to be controversial. This is mainly because of the limited concordance among these studies to enable conclusions with regard to the specific mechanisms involved. The previous systematic review in this topic (Ref. Reference Glass65) suggested that human studies supported angiogenesis via VEGF, cell recruitment predominantly via IL-8 and reduced MMP expression, animal models suggested an anti-inflammatory response via IL-10, VEGF, FGF-2, CGRP and substance P and in vitro models suggested increased granulation tissue formation. They also reported that human studies predominantly studied cytokine and MMP data while growth factor data were predominantly derived from animal studies and in vitro models. However, the effect of NPWT on the differential gene expressions was not explored in this review. First insights into the molecular mechanisms behind NPWT suggested that NPWT also induces gene expression changes at the wound bed. These changes were postulated to range from 10-fold induction to 27-fold suppression (Refs Reference Yang41, Reference Nuutila66, Reference Liu67).

Since this previous systematic review, more than 20 newer biomarkers, cytokines and genes have been studied across 19 more recent studies, the summary of which has been collated in this paper. The data summarized in this review confirms that NPWT-induced strain promotes a pro-angiogenic and pro-mitogenic phenotype in subjacent cell proliferation. NPWT induced cell deformation leads to proliferation as a consequence of cytoskeletal tension. Integrins, adhesive contacts within the cell matrix, act as strain gauges, triggering mechanoreceptor signalling pathways (Refs Reference Shyy and Chien68, Reference Wilkes69). Application of NPWT results in positive pressure at the wound bed and hence reduced blood flow in the tissue immediately adjacent to the filler material (Ref. Reference Wilkes70). NPWT enhances specific inflammatory gene expression at the acute phase associated with epithelial migration and wound healing. However, its continued use may inhibit epithelial differentiation (Ref. Reference Nuutila66). NPWT is also associated with an up-regulation of basic fibroblast growth factor (bFGF) and extracellular signal-regulated kinase (ERK) 1/2 signalling, which may be involved in promoting the NPWT-mediated wound healing response (Ref. Reference Yang41).

This systematic review has a few limitations. The inherent heterogeneity of the included studies makes the data unsuitable for meta-analysis. The clinical studies were mostly underpowered and were opportunistic as reported in the previous review. There was a significant variation in terms of the methodology, mainly concerning sample collection/storage, time interval from collection to analysis and techniques utilized to extract and study the biomarkers of interest. The data from a majority of human studies do not take into account extrinsic factors such as collection and storage of samples which do not account for degradation of biomarkers. Moreover, important clinical information including the use of antibiotics, immunosuppressants including corticosteroids or anti-biologicals was not included. Given the extensive number of biomarkers and genes analysed in the included studies, there was limited concordance to suggest a strong correlation between NPWT and regulation of many biomarkers. The time-points at which these biomarkers were studied also varied significantly among studies. It has also been suggested that the magnitude of negative pressure employed is likely to influence blood flow, which in turn influences the degree of hypoxia and reperfusion. This has been shown to alter the expression of mechanosensitive genes (Refs Reference Saxena10, Reference Glass and Nanchahal71).

There were some discrepancies between animal and human studies especially with respect to the regulation of MMP and IL-6. Although the animal studies address most of these issues, the extrapolation of this data to predict clinical biological response is not appropriate. Although in-vitro studies using human cell lines have the potential to circumvent these concerns, only three studies have been conducted over the last 10 years. Only two out of three studies studied the effects of NPWT on human derived cell lines and analysed a completely different set of biomarkers via different methodologies. Although we have a better understanding of the primary and secondary mechanisms of action of NPWT, namely: macrodeformation, cellular proliferation, differentiation, cell migration, angiogenesis and neurogenesis, a comprehensive temporal expression profile of most biomarker changes with NPWT remains elusive. However, VEGF was elevated in all 7 reports which had studied its effects. Tumour necrosis Factor alpha (TNF α) was downregulated in 5 out of 8 studies, Transforming Growth Factor Beta (TGF β) was upregulated in 4 out of 7 studies, and Fibronectin was upregulated in both studies which evaluated its effects.

In conclusion, NPWT stimulates modulation of numerous local and circulating cytokines and growth factor expressions to promote an anti-inflammatory profile. This is most likely achieved by downregulation of TNFα, upregulation of VEGF, TGF-β and fibronectin. This review has also identified many other biomarkers and gene expressions of interest with regard NPWT actions which may help to direct future research in this field.

Supplementary material

The supplementary material for this article can be found at https://doi.org/10.1017/erm.2023.24.

Acknowledgements

The authors would like to thank the Academic vascular Surgical Unit at Hull Royal Infirmary for their support with this article.

Funding statement

None.

Competing interest

None.

Data availability statement

The data that support the findings of this study are available from the corresponding author,[BR], upon reasonable request. This paper was shortlisted for the ESVS Prize poster session at the Annual Meeting of the European Society of Vascular Surgery at Rome, Italy in September 2022.

Ethical standards

None.

References

Chetter, IC et al. (2017). A survey of patients with surgical wounds healing by secondary intention; an assessment of prevalence, aetiology, duration and management. Journal of Tissue Viability [Internet]. [cited 2022 Aug 27]; 26, 103–107. Available at https://pubmed.ncbi.nlm.nih.gov/28049612/CrossRefGoogle ScholarPubMed
Chetter, I et al. (2019) Surgical wounds healing by secondary intention: characterising and quantifying the problem, identifying effective treatments, and assessing the feasibility of conducting a randomised controlled trial of negative pressure wound therapy versus usual care.Google Scholar
Armstrong, DG and Andros, G (2012) Use of negative pressure wound therapy to help facilitate limb preservation. International Wound Journal [Internet]. [cited 2022 Aug 27];9(suppl. 1), 1–7. Available at https://onlinelibrary.wiley.com/doi/full/10.1111/j.1742-481X.2012.01015.xCrossRefGoogle ScholarPubMed
Using negative pressure therapy in wound healing |Nursing Times [Internet]. [cited 2022 Aug 27]. Available at https://www.nursingtimes.net/clinical-archive/tissue-viability/using-negative-pressure-therapy-in-wound-healing-31-08-2012/Google Scholar
Peinemann, F and Sauerland, S (2011) Negative-pressure wound therapy: systematic review of randomized controlled trials. Deutsches Arzteblatt International [Internet]. [cited 2022 Aug 27];108, 381–389. Available at https://pubmed.ncbi.nlm.nih.gov/21712971/Google ScholarPubMed
Liu, Z et al. (2018) Negative pressure wound therapy for treating foot wounds in people with diabetes mellitus. The Cochrane Database of Systematic Reviews [Internet]. [cited 2022 Aug 27];10. Available at https://pubmed.ncbi.nlm.nih.gov/30328611/Google ScholarPubMed
Gao, J et al. (2021) Negative pressure wound therapy for surgical site infections: a systematic review and meta-analysis. Journal of Advanced Nursing [Internet]. [cited 2022 Aug 27];77, 3980–3990. Available at https://pubmed.ncbi.nlm.nih.gov/33905552/CrossRefGoogle ScholarPubMed
Borgquist, O, Ingemansson, R and Malmsjö, M (2011). The influence of low and high pressure levels during negative-pressure wound therapy on wound contraction and fluid evacuation. Plastic and Reconstructive Surgery 127, 551–559.CrossRefGoogle ScholarPubMed
Kairinos, N, Solomons, M and Hudson, DA (2010) The paradox of negative pressure wound therapy--in vitro studies. Journal of Plastic, Reconstructive & Aesthetic Surgery: JPRAS [Internet]. [cited 2021 Oct 28];63, 174–179. Available at https://pubmed.ncbi.nlm.nih.gov/19036656/CrossRefGoogle ScholarPubMed
Saxena, V et al. (2004) Vacuum-assisted closure: microdeformations of wounds and cell proliferation. Plastic and Reconstructive Surgery [Internet]. [cited 2021 Oct 28];114, 1086–1096. Available at https://pubmed.ncbi.nlm.nih.gov/15457017/CrossRefGoogle ScholarPubMed
Yang, CC, Chang, DS and Webb, LX (2006) Vacuum-assisted closure for fasciotomy wounds following compartment syndrome of the leg. Journal of Surgical Orthopaedic Advances 15, 19–23.Google ScholarPubMed
Adámková, M et al. (2005) First experience with the use of vacuum assisted closure in the treatment of skin defects at the burn center. Acta Chirurgiae Plasticae 47 24–27.Google ScholarPubMed
Kim, PJ et al. (2013) Negative-pressure wound therapy with instillation: international consensus guidelines. Plastic and Reconstructive Surgery 132, 1569–1579.CrossRefGoogle ScholarPubMed
Gerry, R et al. (2007) Silver-impregnated vacuum-assisted closure in the treatment of recalcitrant venous stasis ulcers. Annals of Plastic Surgery 59, 58–62.CrossRefGoogle ScholarPubMed
Orgill, DP et al. (2009) The mechanisms of action of vacuum assisted closure: more to learn. Surgery 146, 40–51.CrossRefGoogle ScholarPubMed
Ouzzani, M et al. 2016). Rayyan – a web and mobile app for systematic reviews. Systematic Reviews [Internet]. [cited 2022 Apr 30];5, 210. Available at https://link.springer.com/epdf/10.1186/s13643-016-0384-4.CrossRefGoogle Scholar
Moher, D et al. (2016) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Revista Espanola de Nutricion Humana y Dietetica [Internet]. [cited 2022 Apr 30];20, 148–160. Available at https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/2046-4053-4-1Google Scholar
Risk of Bias Assessment tool for Non-randomized Studies (RoBANS): Development and validation of a new instrument | Colloquium Abstracts [Internet]. [cited 2022 Apr 30]. Available at https://abstracts.cochrane.org/2011-madrid/risk-bias-assessment-tool-non-randomized-studies-robans-development-and-validation-newGoogle Scholar
Sterne, JAC et al. (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ [Internet]. [cited 2022 Apr 30];366, I4898. Available at https://pubmed.ncbi.nlm.nih.gov/31462531/.CrossRefGoogle ScholarPubMed
Office of Health Assessment and Translation (OHAT) (2019) Handbook for conducting a literature-based health assessment using OHAT approach for systematic review and evidence integration: National Institute of Environmental Health Sciences; Available at https://ntp.niehs.nih.gov/ntp/ohat/pubs/handbookmarch2019_508.pdfGoogle Scholar
Hooijmans, CR et al. (2014) SYRCLE's risk of bias tool for animal studies. BMC Medical Research Methodology 14, 43.CrossRefGoogle ScholarPubMed
McGuinness, LA and Higgins, JPT (2021) Risk-of-bias VISualization (robvis): an R package and shiny web app for visualizing risk-of-bias assessments. Research Synthesis Methods [Internet]. [cited 2022 May 8];12, 55–61. Available at https://onlinelibrary.wiley.com/doi/full/10.1002/jrsm.1411CrossRefGoogle Scholar
Arslan, E et al. (2011) Vacuum-assisted closure therapy leads to an increase in plasma fibronectin level. International Wound Journal [Internet].[cited 2023 Feb 18];8, 224–228. Available at https://pubmed.ncbi.nlm.nih.gov/21401882/CrossRefGoogle Scholar
Borys, S et al. (2018) Negative-pressure wound therapy for management of chronic neuropathic noninfected diabetic foot ulcerations – short-term efficacy and long-term outcomes. Endocrine [Internet]. [cited 2023 Feb 18];62, 611–616. Available at https://pubmed.ncbi.nlm.nih.gov/30099674/CrossRefGoogle ScholarPubMed
Stechmiller, JK et al. (2006) Effect of vacuum-assisted closure therapy on the expression of cytokines and proteases in wound fluid of adults with pressure ulcers. Wound Repair and Regeneration [Internet]. 2006 [cited 2021 Nov 16];14, 371–373. Available at https://pubmed.ncbi.nlm.nih.gov/16808818/CrossRefGoogle Scholar
Eisenhardt, SU et al. (2012) Negative pressure wound therapy reduces the ischaemia/reperfusion-associated inflammatory response in free muscle flaps. Journal of Plastic, Reconstructive & Aesthetic Surgery: JPRAS [Internet]. [cited 2021 Nov 16];65, 640–649. Available at https://pubmed.ncbi.nlm.nih.gov/22137686/CrossRefGoogle ScholarPubMed
Labler, L et al. (2006). Wound conditioning by vacuum assisted closure (V.A.C.) in postoperative infections after dorsal spine surgery. European Spine Journal: Official Publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society [Internet]. [cited 2022 Sep 7];15, 1388–1396. Available at https://pubmed.ncbi.nlm.nih.gov/16835734/CrossRefGoogle ScholarPubMed
Labler, L et al. (2009) Vacuum-assisted closure therapy increases local interleukin-8 and vascular endothelial growth factor levels in traumatic wounds. The Journal of Trauma [Internet]. [cited 2021 Nov 16];66, 749–757. Available at https://pubmed.ncbi.nlm.nih.gov/19276749/Google ScholarPubMed
Greene, AK et al. (2006) Microdeformational wound therapy: effects on angiogenesis and matrix metalloproteinases in chronic wounds of 3 debilitated patients. Annals of Plastic Surgery [Internet][cited 2021 Nov 16];56,418–422. Available at https://pubmed.ncbi.nlm.nih.gov/16557076/CrossRefGoogle ScholarPubMed
Frear, CC et al. (2020) The modulation of the burn wound environment by negative pressure wound therapy: insights from the proteome. Wound Repair and Regeneration [Internet]. [cited 2022 Aug 27];29, 288–297. Available at https://pubmed.ncbi.nlm.nih.gov/33374033/CrossRefGoogle ScholarPubMed
Hohendorff, J et al. (2019) Effects of negative pressure wound therapy on levels of angiopoetin-2 and other selected circulating signaling molecules in patients with diabetic foot ulcer. Journal of Diabetes Research 2019, 1756798.CrossRefGoogle ScholarPubMed
Jia, Z et al. (2021) Proteomics changes after negative pressure wound therapy in diabetic foot ulcers. Molecular Medicine Reports [Internet]. [cited 2022 Aug 27];24, 834. Available at https://pubmed.ncbi.nlm.nih.gov/34608502/.CrossRefGoogle ScholarPubMed
Kapusta, P et al. (2020) Negative pressure wound therapy affects circulating plasma microRNAs in patients with diabetic foot ulceration. Diabetes Research and Clinical Practice [Internet]. [cited 2023 Feb 19];165, 108251. Available at http://www.diabetesresearchclinicalpractice.com/article/S0168822720305015/fulltext.CrossRefGoogle ScholarPubMed
Karam, RA et al. (2018) Effect of negative pressure wound therapy on molecular markers in diabetic foot ulcers. Gene 667, 56–61.CrossRefGoogle ScholarPubMed
Ludwig-Slomczynska, AH et al. (2019) DNA Methylation analysis of negative pressure therapy effect in diabetic foot ulcers. Endocrine Connections [Internet]. [cited 2023 Feb 19];8, 1474–1482. Available at https://pubmed.ncbi.nlm.nih.gov/31634866/CrossRefGoogle ScholarPubMed
Mouës, CM et al. (2008) The role of topical negative pressure in wound repair: expression of biochemical markers in wound fluid during wound healing. Wound Repair and Regeneration [Internet]. [cited 2023 Feb 22];16, 488–494. Available at https://pubmed.ncbi.nlm.nih.gov/18638266/CrossRefGoogle ScholarPubMed
Wang, T et al. (2019) Negative pressure wound therapy promoted wound healing by suppressing inflammation via down-regulating MAPK-JNK signaling pathway in diabetic foot patients. Diabetes Research and Clinical Practice [Internet]. [cited 2022 Sep 28];150, 81–89. Available at http://www.diabetesresearchclinicalpractice.com/article/S0168822718312919/fulltextCrossRefGoogle ScholarPubMed
Mu, S et al. (2019) Effect of negative-pressure wound therapy on the circulating number of peripheral endothelial progenitor cells in diabetic patients with mild to moderate degrees of ischaemic foot ulcer. Vascular 27, 381–389 doi: 10.1177/1708538119836360.CrossRefGoogle ScholarPubMed
Yang, SL et al. (2017) Effect of negative pressure wound therapy on cellular fibronectin and transforming growth factor-β1 expression in diabetic foot wounds. Foot & Ankle International [Internet]. [cited 2023 Feb 22];38, 893–900. Available at https://pubmed.ncbi.nlm.nih.gov/28459181/CrossRefGoogle ScholarPubMed
Liu, L et al. (2022) Downregulation of hsa-miR-203 in peripheral blood and wound margin tissue by negative pressure wound therapy contributes to wound healing of diabetic foot ulcers. Microvascular Research 139, 104275.CrossRefGoogle ScholarPubMed
Yang, SL et al. (2014) Negative pressure wound therapy is associated with up-regulation of bFGF and ERK1/2 in human diabetic foot wounds. Wound Repair and Regeneration [Internet]. [cited 2022 Aug 27];22, 548–554. Available at https://pubmed.ncbi.nlm.nih.gov/24809625/CrossRefGoogle ScholarPubMed
Kilpadi, DV et al. (2006) Effect of vacuum assisted closure therapy on early systemic cytokine levels in a swine model. Wound Repair and Regeneration [Internet]. [cited 2023 Feb 22];14, 210–215. Available at https://pubmed.ncbi.nlm.nih.gov/16630111/CrossRefGoogle Scholar
Norbury, K and Kieswetter, K (2007) Vacuum-assisted Closure Therapy Attenuates the Inflammatory Response in a Porcine Acute Wound Healing Model – PubMed [Internet]. [cited 2023 Mar 14]. Available at https://pubmed.ncbi.nlm.nih.gov/26110258/Google Scholar
Brownhill, VR et al. (2021) Pre-clinical assessment of single-use negative pressure wound therapy during in vivo porcine wound healing. Advances in Wound Care [Internet]. [cited 2022 Sep 28];10, 345–356. Available at https://pubmed.ncbi.nlm.nih.gov/32633639/CrossRefGoogle ScholarPubMed
Zhou, M et al. (2013) Role of different negative pressure values in the process of infected wounds treated by vacuum-assisted closure: an experimental study. International Wound Journal [Internet]. [cited 2022 Sep 28];10, 508–515. Available at https://pubmed.ncbi.nlm.nih.gov/22640026/CrossRefGoogle ScholarPubMed
Li, J et al. (2013) Treatment of infected soft tissue blast injury in swine by regulated negative pressure wound therapy. Annals of Surgery [Internet]. [cited 2023 Mar 14];257, 335–344. Available at https://pubmed.ncbi.nlm.nih.gov/23108116/CrossRefGoogle ScholarPubMed
Aydin, OE et al. (2019) A novel method for flap delay vacuum assisted flap delay: an experimental study in rabbits. Journal of Plastic Surgery and Hand Surgery [Internet]. [cited 2023 Feb 22];53, 208–215. Available at https://pubmed.ncbi.nlm.nih.gov/30929553/CrossRefGoogle ScholarPubMed
Younan, G et al. (2010) Analysis of nerve and neuropeptide patterns in vacuum-assisted closure-treated diabetic murine wounds. Plastic and Reconstructive Surgery [Internet]. [cited 2021 Nov 16];126, 87–96. Available at https://pubmed.ncbi.nlm.nih.gov/20595860/CrossRefGoogle ScholarPubMed
Erba, P et al. (2011) Angiogenesis in wounds treated by microdeformational wound therapy. Annals of Surgery [Internet]. 2011 Feb [cited 2021 Nov 16];253, 402–409. Available at https://pubmed.ncbi.nlm.nih.gov/21217515/CrossRefGoogle ScholarPubMed
Jacobs, S et al. (2009) Efficacy and mechanisms of vacuum-assisted closure (VAC) therapy in promoting wound healing: a rodent model. Journal of Plastic, Reconstructive & Aesthetic Surgery: JPRAS [Internet]. [cited 2022 Sep 28];62, 1331–1338. Available at https://pubmed.ncbi.nlm.nih.gov/18617451/CrossRefGoogle ScholarPubMed
Scherer, SS et al. (2008) The mechanism of action of the vacuum-assisted closure device. Plastic and Reconstructive Surgery [Internet]. [cited 2021 Nov 16];122, 786–797. Available at https://pubmed.ncbi.nlm.nih.gov/18766042/CrossRefGoogle ScholarPubMed
Qiu, X et al. (2021) Roles of oxidative stress and raftlin in wound healing under negative-pressure wound therapy. Clinical, Cosmetic and Investigational Dermatology [Internet]. [cited 2023 Feb 22];14, 1745. Available at /pmc/articles/PMC8612843/CrossRefGoogle ScholarPubMed
Lu, F et al. (2011) Microdeformation of three-dimensional cultured fibroblasts induces gene expression and morphological changes. Annals of Plastic Surgery [Internet]. [cited 2022 Sep 28];66, 296–300. Available at https://pubmed.ncbi.nlm.nih.gov/21233699/CrossRefGoogle ScholarPubMed
McNulty, AK et al. (2009) Effects of negative pressure wound therapy on cellular energetics in fibroblasts grown in a provisional wound (fibrin) matrix. Wound Repair and Regeneration [Internet]. [cited 2021 Nov 16];17, 192–199. Available at https://pubmed.ncbi.nlm.nih.gov/19320887/CrossRefGoogle Scholar
Dong, J et al. (2020) Potential molecular mechanisms of negative pressure in promoting wound healing. International Wound Journal [Internet]. [cited 2022 Sep 28];17, 1428–1438. Available at https://onlinelibrary.wiley.com/doi/full/10.1111/iwj.13423CrossRefGoogle ScholarPubMed
McNulty, AK et al. (2007) Effects of negative pressure wound therapy on fibroblast viability, chemotactic signaling, and proliferation in a provisional wound (fibrin) matrix. Wound Repair and Regeneration [Internet]. Nov [cited 2022 Sep 28];15, 838–846. Available at https://pubmed.ncbi.nlm.nih.gov/18028132/CrossRefGoogle Scholar
Liu, X et al. (2014) Thyroid hormone induced angiogenesis through the integrin αvβ3/protein kinase D/histone deacetylase 5 signaling pathway. Journal of Molecular Endocrinology [Internet]. [cited 2022 Aug 27];52, 245–254. Available at https://pubmed.ncbi.nlm.nih.gov/24532656/CrossRefGoogle ScholarPubMed
Maione, AG et al. (2016) Altered ECM deposition by diabetic foot ulcer-derived fibroblasts implicates fibronectin in chronic wound repair. Wound Repair and Regeneration [Internet]. [cited 2022 Aug 27];24, 630–643. Available at https://pubmed.ncbi.nlm.nih.gov/27102877/CrossRefGoogle ScholarPubMed
Jozic, I et al. (2016) Stress signals, mediated by membranous glucocorticoid receptor, activate PLC/PKC/GSK-3β/β-catenin pathway to inhibit wound closure. Journal of Investigative Dermatology [Internet].[cited 2022 Aug 27];137, 1144–1154. Available at https://europepmc.org/articles/PMC7540219CrossRefGoogle ScholarPubMed
Yazdanpanah, L et al. (2018) Risk factors associated with diabetic foot ulcer-free survival in patients with diabetes. Diabetes & Metabolic Syndrome [Internet]. [cited 2022 Aug 27];12, 1039–1043. Available at https://pubmed.ncbi.nlm.nih.gov/30168426/CrossRefGoogle ScholarPubMed
Gouin, JP and Kiecolt-Glaser, JK (2011) The impact of psychological stress on wound healing: methods and mechanisms. Immunology and Allergy Clinics of North America [Internet]. [cited 2022 Aug 27];31, 81. Available at /pmc/articles/PMC3052954/CrossRefGoogle ScholarPubMed
Capewell, P et al. (2016) The skin is a significant but overlooked anatomical reservoir for vector-borne African trypanosomes. Elife 2016 Sep 22;5, e17716. doi: 10.7554/eLife.CrossRefGoogle ScholarPubMed
McGill, NK et al. (2012) HTLV-1-associated infective dermatitis: updates on the pathogenesis. Experimental Dermatology [Internet]. [cited 2022 Aug 27];21, 815–821. Available at https://pubmed.ncbi.nlm.nih.gov/23163646/CrossRefGoogle ScholarPubMed
Shimauchi, T and Piguet, V (2015) DC-T cell virological synapses and the skin: novel perspectives in dermatology. Experimental Dermatology [Internet]. Jan 1 [cited 2022 Aug 27];24, 1–4. Available at https://pubmed.ncbi.nlm.nih.gov/25039899/CrossRefGoogle ScholarPubMed
Glass, GE et al. (2014) Systematic review of molecular mechanism of action of negative-pressure wound therapy. British Journal of Surgery [Internet]. [cited 2022 Aug 27];101(13), 1627–1636. Available at https://pubmed.ncbi.nlm.nih.gov/25294112/CrossRefGoogle ScholarPubMed
Nuutila, K et al. (2013) Gene expression profiling of negative-pressure-treated skin graft donor site wounds. Burns: Journal of the International Society for Burn Injuries [Internet]. [cited 2022 Aug 27];39, 687–693. Available at https://pubmed.ncbi.nlm.nih.gov/23141686/CrossRefGoogle ScholarPubMed
Liu, D et al. (2014) Negative-pressure wound therapy enhances local inflammatory responses in acute infected soft-tissue wound. Cell Biochemistry and Biophysics [Internet]. [cited 2022 Aug 27];70, 539–547. Available at https://pubmed.ncbi.nlm.nih.gov/24748178/CrossRefGoogle ScholarPubMed
Shyy, JYJ and Chien, S (1997) Role of integrins in cellular responses to mechanical stress and adhesion. Current Opinion in Cell Biology [Internet]. [cited 2022 Aug 27];9, 707–713. Available at https://pubmed.ncbi.nlm.nih.gov/9330875/CrossRefGoogle ScholarPubMed
Wilkes, R et al. (2009) Effects of dressing type on 3D tissue microdeformations during negative pressure wound therapy: a computational study. Journal of Biomechanical Engineering [Internet]. [cited 2022 Aug 27];131, 031012. Available at https://pubmed.ncbi.nlm.nih.gov/19154071/.CrossRefGoogle ScholarPubMed
Wilkes, R et al. (2009) 3D strain measurement in soft tissue: demonstration of a novel inverse finite element model algorithm on MicroCT images of a tissue phantom exposed to negative pressure wound therapy. Journal of the Mechanical Behavior of Biomedical Materials [Internet]. [cited 2021 Nov 16];2, 272–287. Available at https://pubmed.ncbi.nlm.nih.gov/19627832/CrossRefGoogle ScholarPubMed
Glass, GE and Nanchahal, J (2012) The methodology of negative pressure wound therapy: separating fact from fiction. Journal of Plastic, Reconstructive & Aesthetic Surgery: JPRAS [Internet]. [cited 2022 Sep 7];65, 989–1001. Available at https://pubmed.ncbi.nlm.nih.gov/22236476/CrossRefGoogle ScholarPubMed
Figure 0

Figure 1. Literature search and study selection.

Figure 1

Table 1. Characteristics of the included studies

Figure 2

Figure 2. Risk of Bias Assessment of the included studies: (a) RoBANS for non-randomized studies, (b) SYRCLE tool for animal studies, (c) RoB-2 tool for randomized studies.

Figure 3

Table 2. Variation in outcomes following NPWT on common biomarkers of interest

Supplementary material: File

Ravindhran et al. supplementary material

Ravindhran et al. supplementary material

Download Ravindhran et al. supplementary material(File)
File 17 KB