Negative pressure wound therapy in the treatment of diabetic foot ulcers may be mediated through differential gene expression

Borys, Sebastian; Ludwig-Słomczyńska, Agnieszka H.; Seweryn, Michał; Hohendorff, Jerzy; Koblik, Teresa; Machlowska, Julita; Kieć‐Wilk, Beata; Wołkow, Paweł; Małecki, Maciej

doi:10.1007/s00592-018-1223-y

Cited by 17 publications

(16 citation statements)

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“…On the molecular level, NPWT promotes proangiogenic and anti-inflammatory conditions by increasing the expression of growth factors and reducing the expression of inflammatory cytokines [26]. In our previous reports, we saw that NPWT altered the local gene expression involved with wound healing [4]. Moreover, we showed that NPWT's action is mediated through epigenetic alterations resulting mainly in the inhibition of complement system activation [5].…”

Section: Discussionmentioning

confidence: 97%

“…Negative pressure wound therapy (NPWT) has been used as an adjunct treatment for DFUs. Its potential influence on local gene expression and epigenetic methylation in the wound bed has been recently described [4, 5]. However, NPWT's novel mechanism of action may be associated with processes involving the entire organism where signals are transmitted via circulating molecules between the organism's tissues and organs.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Negative Pressure Wound Therapy on Levels of Angiopoetin-2 and Other Selected Circulating Signaling Molecules in Patients with Diabetic Foot Ulcer

Hohendorff

Drożdż

Borys

et al. 2019

Journal of Diabetes Research

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Background and Aims Diabetic foot ulcers (DFUs) are linked to amputations and premature deaths. Negative pressure wound therapy (NPWT) has been used for DFUs. The mechanism of NPWT's action may be associated with its influence on circulating molecules. We assessed NPWT's effect on the plasma levels of angiopoietin-2 (Ang2), a key regulator of angiogenesis, and its microvesicular receptors (Tie2) as well as the microvesicles (MVs) themselves in DFU patients. Materials and Methods We included 69 patients with type 2 diabetes mellitus (T2DM) and neuropathic, noninfected DFUs—49 were treated with NPWT and 20 were treated with standard therapy (ST). Assigning patients to the NPWT group was not random but based on DFU characteristics, especially wound area. Ang2 was measured by ELISA in the entire group, while in a subgroup of 19 individuals on NPWT and 10 on ST, flow cytometry was used to measure Tie2+ and the corresponding isotype control (Iso+) and annexin V (AnnV+) as well as total MVs. Measurements were performed at the beginning and after 8 ± 1 days of therapy. Results Treatment groups were similar for basic characteristics but differed by their median DFU areas (10.3 (4.2-18.9) vs. 1.3 (0.9-3.4) cm2, p = 0.0001). At day 0, no difference was observed in Ang2 levels, total MVs, MV Tie+, and MV AnnV+ between the groups. Ang2 decreased after 8 days in the NPWT group, unlike in the ST group (3.54 (2.40-5.40) vs. 3.32 (2.33-4.61), p = 0.02, and 3.19 ± 1.11 vs. 3.19 ± 1.29 ng/mL, p = 0.98, respectively). No other parameters were identified that may have been influenced by the NPWT treatment. Conclusion NPWT in T2DM patients with neuropathic, noninfected DFU seems to lead to reduction of the Ang2 level. Influencing the level of Ang2 may constitute one of NPWT-related mechanisms to accelerate wound healing.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Effects of Negative Pressure Wound Therapy on Levels of Angiopoetin-2 and Other Selected Circulating Signaling Molecules in Patients with Diabetic Foot Ulcer

Hohendorff

Drożdż

Borys

et al. 2019

Journal of Diabetes Research

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“…The patients included in this prospective clinical observation were participants of the research project on the molecular mechanisms of NPWT [ 13 ]. The total study group consisted of 75 consecutive patients with T2DM and concomitant foot ulceration(s) treated between 2014 and 2018 in the Department of Metabolic Diseases of the University Hospital in Krakow, a tertiary academic outpatient center for patients with DFS in southern Poland.…”

Section: Methodsmentioning

confidence: 99%

Negative-pressure wound therapy for management of chronic neuropathic noninfected diabetic foot ulcerations – short-term efficacy and long-term outcomes

et al. 2018

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PurposeNegative pressure wound therapy (NPWT) is an adjunct method used in the treatment of diabetic foot ulceration (DFU). Real world data on its effectiveness and safety is scarce. In this prospective observational study, we assessed the short-term efficacy, safety, and long-term outcomes of NPWT in patients with type 2 diabetes (T2DM) and neuropathic, noninfected DFUs.MethodsBased on wound characteristics, mainly area (>1 vs. ≤1 cm2), 75 patients with DFUs treated in an outpatient clinic were assigned to NPWT (n = 53) or standard therapy (n = 22). Wound area reduction was evaluated after 8 ± 1 days. Long-term outcomes assessed included complete ulceration closure and recurrence rate.ResultsPatients assigned to NPWT were characterized by greater wound area (15.7 vs. 2.9 cm2). Reduction in wound area was found in both the NPWT (−1.1 cm2, −10.2%, p = 0.0001) and comparator group (−0.3 cm2, −18.0%, p = 0.0038). No serious adverse events related to NPWT were noted. Within 1 year, 55.1% (27/49) of DFUs were closed in the NPWT group and 73.7% (14/19) in the comparator group (p = 0.15). In the logistic regression, wound duration and smaller initial area, but not treatment mode, were associated with closure. One-year follow-up after DFU resolution revealed an ~30.0% recurrence rate in both groups (p = 0.88).ConclusionsNPWT is a safe treatment for neuropathic, nonischemic, and noninfected DFU in patients with T2DM, although this observational study did not prove its effectiveness over standard therapy. Additionally, we report a high rate of both closure and recurrence of ulcers, the latter irrespective of initial ulcer area.

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“…We have recently reported our results on the effect of NPWT on gene expression as assessed by microarray technology in patients with type 2 diabetes and DFU in comparison with standard therapy. We identified four genes that were differentially expressed—GFRA2 (GDNF family receptor alpha‐2), C1QBP (complement C1q binding protein), RAB35 (member of RAS oncogene family) and SYNJ1 (synaptic inositol 1,4,5‐trisphosphate 5‐phosphatase 1) . Interestingly, all four genes seemed to be functionally involved in wound healing by influencing re‐epithelialization and angiogenesis.…”

Section: Negative Pressure Wound Therapy Molecular Mechanismsmentioning

confidence: 99%

“…We identified four genes that were differentially expressed-GFRA2 (GDNF family receptor alpha-2), C1QBP (complement C1q binding protein), RAB35 (member of RAS oncogene family) and SYNJ1 (synaptic inositol 1,4,5-trisphosphate 5-phosphatase 1). 58 Interestingly, all four genes seemed to be functionally involved in wound healing by influencing re-epithelialization and angiogenesis. They were not reported earlier as genes potentially related to NPWT action.…”

Section: Therapy Molecular Mechanismsmentioning

confidence: 99%

Negative pressure wound therapy use in diabetic foot syndrome—from mechanisms of action to clinical practice

Borys

Hohendorff

Frankfurter

et al. 2019

Eur J Clin Investigation

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Background Diabetes and its complications constitute a rising medical challenge. Special attention should be given to diabetic foot syndrome (DFS) due to its high rate of associated amputation and mortality. Negative pressure wound therapy (NPWT) is a frequently used supportive modality in a diabetic foot with ulcerations (DFUs). Design Here, we reviewed the current knowledge concerning the tissue and molecular mechanisms of NPWT action with an emphasis on diabetes research followed by a summary of clinical DFU studies and practice guidelines. Results Negative pressure wound therapy action results in two types of tissue deformations—macrodeformation, such as wound contraction, and microdeformation occurring at microscopic level. Both of them stimulate a wound healing cascade including tissue granulation promotion, vessel proliferation, neoangiogenesis, epithelialization and excess extracellular fluid removal. On the molecular level, NPWT results in an alteration towards more pro‐angiogenic and anti‐inflammatory conditions. It increases expression of several key growth factors, including vascular endothelial growth factor and fibroblast growth factor 2, while expression of inflammatory cytokinesis reduced. The NPWT application also alters the presence and function of matrix metalloproteinases. Clinical studies in DFU patients showed a superiority of NPWT over standard therapy in terms of efficacy outcomes, primarily wound healing and amputation rate, without a rise in adverse events. International guidelines point to NPWT as an important adjuvant therapy in DFU whose use is expected to increase. Conclusions This current knowledge improves our understanding of NPWT action and its tailoring for application in diabetic patients. It may inform the development of new treatments for DFU.

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Negative pressure wound therapy in the treatment of diabetic foot ulcers may be mediated through differential gene expression

Abstract: We found initial evidence that the NPWT effect on DFUs may be mediated through differential gene expression. A discovery of the specific molecular mechanisms of NPWT is potentially valuable for its clinical application and development of new therapies.

Cited by 17 publications

References 19 publications

Effects of Negative Pressure Wound Therapy on Levels of Angiopoetin-2 and Other Selected Circulating Signaling Molecules in Patients with Diabetic Foot Ulcer

Effects of Negative Pressure Wound Therapy on Levels of Angiopoetin-2 and Other Selected Circulating Signaling Molecules in Patients with Diabetic Foot Ulcer

Negative-pressure wound therapy for management of chronic neuropathic noninfected diabetic foot ulcerations – short-term efficacy and long-term outcomes

Negative pressure wound therapy use in diabetic foot syndrome—from mechanisms of action to clinical practice

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