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      Angiogenesis Is Induced and Wound Size Is Reduced by Electrical Stimulation in an Acute Wound Healing Model in Human Skin

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          Abstract

          Angiogenesis is critical for wound healing. Insufficient angiogenesis can result in impaired wound healing and chronic wound formation. Electrical stimulation (ES) has been shown to enhance angiogenesis. We previously showed that ES enhanced angiogenesis in acute wounds at one time point (day 14). The aim of this study was to further evaluate the role of ES in affecting angiogenesis during the acute phase of cutaneous wound healing over multiple time points. We compared the angiogenic response to wounding in 40 healthy volunteers (divided into two groups and randomised), treated with ES (post-ES) and compared them to secondary intention wound healing (control). Biopsy time points monitored were days 0, 3, 7, 10, 14. Objective non-invasive measures and H&E analysis were performed in addition to immunohistochemistry (IHC) and Western blotting (WB). Wound volume was significantly reduced on D7, 10 and 14 post-ES (p = 0.003, p = 0.002, p<0.001 respectively), surface area was reduced on days 10 (p = 0.001) and 14 (p<0.001) and wound diameter reduced on days 10 (p = 0.009) and 14 (p = 0.002). Blood flow increased significantly post-ES on D10 (p = 0.002) and 14 (p = 0.001). Angiogenic markers were up-regulated following ES application; protein analysis by IHC showed an increase (p<0.05) in VEGF-A expression by ES treatment on days 7, 10 and 14 (39%, 27% and 35% respectively) and PLGF expression on days 3 and 7 (40% on both days), compared to normal healing. Similarly, WB demonstrated an increase (p<0.05) in PLGF on days 7 and 14 (51% and 35% respectively). WB studies showed a significant increase of 30% (p>0.05) on day 14 in VEGF-A expression post-ES compared to controls. Furthermore, organisation of granulation tissue was improved on day 14 post-ES. This randomised controlled trial has shown that ES enhanced wound healing by reduced wound dimensions and increased VEGF-A and PLGF expression in acute cutaneous wounds, which further substantiates the role of ES in up-regulating angiogenesis as observed over multiple time points. This therapeutic approach may have potential application for clinical management of delayed and chronic wounds.

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          Most cited references34

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          Pathophysiology of acute wound healing.

          Wound healing is a complex process that can be divided into at least 3 continuous and overlapping processes: an inflammatory reaction, a proliferative process leading to tissue restoration, and, eventually, tissue remodeling. Wound healing processes are strictly regulated by multiple growth factors and cytokines released at the wound site. Although the desirable final result of coordinated healing would be the formation of tissue with a similar structure and comparable functions as with intact skin, regeneration is uncommon (with notable exceptions such as early fetal healing); healing however results in a structurally and functionally satisfactory but not identical outcome. Alterations that disrupt controlled healing processes would extend tissue damage and repair. The pathobiologic states may lead to chronic or nonhealing wounds or excessive fibrosis.
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            Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells.

            Diminished production of vascular endothelial growth factor (VEGF) and decreased angiogenesis are thought to contribute to impaired tissue repair in diabetic patients. We examined whether recombinant human VEGF(165) protein would reverse the impaired wound healing phenotype in genetically diabetic mice. Paired full-thickness skin wounds on the dorsum of db/db mice received 20 microg of VEGF every other day for five doses to one wound and vehicle (phosphate-buffered saline) to the other. We demonstrate significantly accelerated repair in VEGF-treated wounds with an average time to resurfacing of 12 days versus 25 days in untreated mice. VEGF-treated wounds were characterized by an early leaky, malformed vasculature followed by abundant granulation tissue deposition. The VEGF-treated wounds demonstrated increased epithelialization, increased matrix deposition, and enhanced cellular proliferation, as assessed by uptake of 5-bromodeoxyuridine. Analysis of gene expression by real-time reverse transcriptase-polymerase chain reaction demonstrates a significant up-regulation of platelet-derived growth factor-B and fibroblast growth factor-2 in VEGF-treated wounds, which corresponds with the increased granulation tissue in these wounds. These experiments also demonstrated an increase in the rate of repair of the contralateral phosphate-buffered saline-treated wound when compared to wounds in diabetic mice never exposed to VEGF (18 days versus 25 days), suggesting that topical VEGF had a systemic effect. We observed increased numbers of circulating VEGFR2(+)/CD11b(-) cells in the VEGF-treated mice by fluorescence-activated cell sorting analysis, which likely represent an endothelial precursor population. In diabetic mice with bone marrow replaced by that of tie2/lacZ mice we demonstrate that the local recruitment of bone marrow-derived endothelial lineage lacZ+ cells was augmented by topical VEGF. We conclude that topical VEGF is able to improve wound healing by locally up-regulating growth factors important for tissue repair and by systemically mobilizing bone marrow-derived cells, including a population that contributes to blood vessel formation, and recruiting these cells to the local wound environment where they are able to accelerate repair. Thus, VEGF therapy may be useful in the treatment of diabetic complications characterized by impaired neovascularization.
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              Current understanding of molecular and cellular mechanisms in fibroplasia and angiogenesis during acute wound healing.

              Cutaneous wound healing ultimately functions to facilitate barrier restoration following injury-induced loss of skin integrity. It is an evolutionarily conserved, multi-cellular, multi-molecular process involving co-ordinated inter-play between complex signalling networks. Cellular proliferation is recognised as the third stage of this sequence. Within this phase, fibroplasia and angiogenesis are co-dependent processes which must be successfully completed in order to form an evolving extracellular matrix and granulation tissue. The resultant structures guide cellular infiltration, differentiation and secretory profile within the wound environment and consequently have major influence on the success or failure of wound healing. This review integrates in vitro, animal and human in vivo studies, to provide up to date descriptions of molecular and cellular interactions involved in fibroplasia and angiogenesis. Significant molecular networks include adhesion molecules, proteinases, cytokines and chemokines as well as a plethora of growth factors. These signals are produced by, and affect behaviour of, cells including fibroblasts, fibrocytes, keratinocytes, endothelial cells and inflammatory cells resulting in significant cellular phenotypic and functional plasticity, as well as controlling composition and remodelling of structural proteins including collagen and fibronectin. The interdependent relationship between angiogenesis and fibroplasia relies on dynamic reciprocity between cellular components, matrix proteins and bioactive molecules. Unbalanced regulation of any one component can have significant consequences resulting in delayed healing, chronic wounds or abnormal scar formation. Greater understanding of angiogenic and fibroplastic mechanisms underlying chronic wound pathogenesis has identified novel therapeutic targets and enabled development of improved treatment strategies including topical growth factors and skin substitutes. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                30 April 2015
                2015
                : 10
                : 4
                : e0124502
                Affiliations
                [1 ]Plastic & Reconstructive Surgery Research, Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom
                [2 ]University Hospital of South Manchester NHS Foundation Trust, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
                [3 ]Oxford Bioelectronics, Innovation Centre, Abingdon, United Kingdom
                [4 ]Medical Statistics, University Hospital South Manchester, Manchester, United Kingdom
                [5 ]BioElectroMed Corporation, Burlingame, CA, United States of America
                [6 ]Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom
                [7 ]Centre for Dermatology Research, Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom
                University of New Mexico HSC, UNITED STATES
                Author notes

                Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Partial funding was provided by Fenzian Ltd. Only authors P. Giddings and J. Colthurst are paid as employees of Fenzian Ltd. Dr. Richard Nuccitelli is employed by BioElectroMed Corporation. No funding was provided by this company. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The remaining funding was a philanthropic donation which was funded by a generous donation from William Henry Smith of Hambleden. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: AB JC PG MB. Performed the experiments: SU AS. Analyzed the data: SU AB SW JM AS. Contributed reagents/materials/analysis tools: JC PG RN CP. Wrote the paper: SU AB AS.

                Article
                PONE-D-14-56250
                10.1371/journal.pone.0124502
                4415761
                25928356
                deeaa14b-34a8-41cd-b7ad-ee426bf9395c
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 31 December 2014
                : 3 March 2015
                Page count
                Figures: 8, Tables: 1, Pages: 22
                Funding
                Partial funding was provided by Fenzian Ltd. Only authors P. Giddings and J. Colthurst are paid as employees of Fenzian Ltd. (URL - www.fenzian.com). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The remaining funding was a philanthropic donation which was funded by a generous donation from William Henry Smith of Hambleden.
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