Wound Healing at the Cellular Level

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 29225

Special Issue Editor


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Guest Editor
1. Department of Plastic, Aesthetic and Hand Surgery, Interdisciplinary Center for Treatment of Chronic Wounds, Dessau Medical Center, Auenweg 38, 06847 Dessau, Germany
2. Department of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodore Fontane, Auenweg 38, 06847 Dessau, Germany
3. Institut of Applied Bio-Sciences and Process Management, University of Applied Science Anhalt, Bernburger Straße 55, 06354 Koethen, Germany
Interests: tissue engineering; growth factors; hyperspectral imaging; scaling of visual impressions

Special Issue Information

Dear Colleagues,

Wound healing is a complex pathophysiological process that is not yet fully explored and understood at the cellular level.

This applies to the diagnosis of biomarkers, physiological and pathophysiological processes, as well as targeted therapy concepts at the cellular level.

The present Special Edition is dedicated to this topic in order to shed more light on the current state of science.

Dr. Thomas Wild
Guest Editor

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Keywords

  • acute wounds
  • chronic wounds
  • wound healing

Published Papers (8 papers)

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Research

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22 pages, 4838 KiB  
Article
Composition of Challenge Substance in Standardized Antimicrobial Efficacy Testing of Wound Antimicrobials Is Essential to Correctly Simulate Efficacy in the Human Wound Micro-Environment
by Anna-Lena Severing, Mia Borkovic, Ewa K. Stuermer and Julian-Dario Rembe
Biomedicines 2022, 10(11), 2751; https://doi.org/10.3390/biomedicines10112751 - 29 Oct 2022
Cited by 8 | Viewed by 2474
Abstract
Current standards insufficiently acknowledge the influence of the wound micro-environment on the efficacy of antimicrobial agents. To address this, octenidine/phenoxyethanol, polyhexanide, povidone-iodine, and sodium-hypochloride/hypochlorous acid solutions were submitted to standard-based (DIN-EN-13727) or modified peptide-based challenges and compared to a simulated clinical reference using [...] Read more.
Current standards insufficiently acknowledge the influence of the wound micro-environment on the efficacy of antimicrobial agents. To address this, octenidine/phenoxyethanol, polyhexanide, povidone-iodine, and sodium-hypochloride/hypochlorous acid solutions were submitted to standard-based (DIN-EN-13727) or modified peptide-based challenges and compared to a simulated clinical reference using human acute or chronic wound exudate (AWF/CWF). Antimicrobial efficacy against S. aureus and P. aeruginosa was compared using a quantitative suspension method. Agreement between methods were investigated using Bland-Altman (B&A) analysis. Different substances and challenges demonstrated diverging results, depending on class and concentration of agent and challenge. Highly concentrated antiseptics maintained a high efficacy under complex challenges, while especially chlorine-based irrigation solutions showed a remarkably reduced antimicrobial effect. Composition of challenge substance proved more relevant than pure concentration. Therefore, the current standard challenge conditions did not adequately reflect the wound micro-environment with over- or under-estimating antimicrobial efficacy, whilst the modified peptide-challenge showed a higher level of agreement with simulated realistic conditions (AWF/CWF). The results emphasize that a “one-fits-all” approach is not feasible to generalize antimicrobial efficacy, as certain aspects of the complex micro-environment pose a differing influence on varying agents. Based on these results, revision and target focused adaptation of the current standards should be considered. Full article
(This article belongs to the Special Issue Wound Healing at the Cellular Level)
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22 pages, 3426 KiB  
Article
Multi-Level Analysis of Adipose Tissue Reveals the Relevance of Perivascular Subpopulations and an Increased Endothelial Permeability in Early-Stage Lipedema
by Karin Strohmeier, Martina Hofmann, Jaroslaw Jacak, Marie-Sophie Narzt, Marlene Wahlmueller, Mario Mairhofer, Barbara Schaedl, Wolfgang Holnthoner, Martin Barsch, Matthias Sandhofer, Susanne Wolbank and Eleni Priglinger
Biomedicines 2022, 10(5), 1163; https://doi.org/10.3390/biomedicines10051163 - 18 May 2022
Cited by 7 | Viewed by 3130
Abstract
Lipedema is a chronic, progressive disease of adipose tissue with unknown etiology. Based on the relevance of the stromal vascular fraction (SVF) cell population in lipedema, we performed a thorough characterization of subcutaneous adipose tissue, SVF isolated thereof and the sorted populations of [...] Read more.
Lipedema is a chronic, progressive disease of adipose tissue with unknown etiology. Based on the relevance of the stromal vascular fraction (SVF) cell population in lipedema, we performed a thorough characterization of subcutaneous adipose tissue, SVF isolated thereof and the sorted populations of endothelial cells (EC), pericytes and cultured adipose-derived stromal/stem cells (ASC) of early-stage lipedema patients. We employed histological and gene expression analysis and investigated the endothelial barrier by immunofluorescence and analysis of endothelial permeability in vitro. Although there were no significant differences in histological stainings, we found altered gene expression of factors relevant for local estrogen metabolism (aromatase), preadipocyte commitment (ZNF423) and immune cell infiltration (CD11c) in lipedema on the tissue level, as well as in distinct cellular subpopulations. Machine learning analysis of immunofluorescence images of CD31 and ZO-1 revealed a morphological difference in the cellular junctions of EC cultures derived from healthy and lipedema individuals. Furthermore, the secretome of lipedema-derived SVF cells was sufficient to significantly increase leakiness of healthy human primary EC, which was also reflected by decreased mRNA expression of VE-cadherin. Here, we showed for the first time that the secretome of SVF cells creates an environment that triggers endothelial barrier dysfunction in early-stage lipedema. Moreover, since alterations in gene expression were detected on the cellular and/or tissue level, the choice of sample material is of high importance in elucidating this complex disease. Full article
(This article belongs to the Special Issue Wound Healing at the Cellular Level)
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19 pages, 5548 KiB  
Article
Combination of Glycinamide and Ascorbic Acid Synergistically Promotes Collagen Production and Wound Healing in Human Dermal Fibroblasts
by Ji Eun Lee and Yong Chool Boo
Biomedicines 2022, 10(5), 1029; https://doi.org/10.3390/biomedicines10051029 - 29 Apr 2022
Cited by 8 | Viewed by 3082
Abstract
The purpose of this study is to present a novel strategy to enhance collagen production in cells. To identify amino acid analogs with excellent collagen production-enhancing effects, human dermal fibroblasts (HDFs) were treated with 20 kinds of amidated amino acids and 20 kinds [...] Read more.
The purpose of this study is to present a novel strategy to enhance collagen production in cells. To identify amino acid analogs with excellent collagen production-enhancing effects, human dermal fibroblasts (HDFs) were treated with 20 kinds of amidated amino acids and 20 kinds of free amino acids, individually at 1 mM. The results showed that glycinamide enhanced collagen production (secreted collagen level) most effectively. Glycine also enhanced collagen production to a lesser degree. However, other glycine derivatives, such as N-acetyl glycine, N-acetyl glycinamide, glycine methyl ester, glycine ethyl ester, and glycyl glycine, did not show such effects. Glycinamide increased type I and III collagen protein levels without affecting COL1A1 and COL3A1 mRNA levels, whereas transforming growth factor-β1 (TGF-β1, 10 ng mL−1) increased both mRNA and protein levels of collagens. Ascorbic acid (AA, 1 mM) increased COL1A1 and COL3A1 mRNA and collagen I protein levels. Unlike TGF-β1, AA and glycinamide did not increase the protein level of α-smooth muscle actin, a marker of differentiation of fibroblasts into myofibroblasts. The combination of AA and glycinamide synergistically enhanced collagen production and wound closure in HDFs to a level similar to that in cells treated with TGF-β1. AA derivatives, such as magnesium ascorbyl 3-phosphate (MAP), 3-O-ethyl ascorbic acid, ascorbyl 2-O-glucoside, and ascorbyl tetraisopalmitate, enhanced collagen production, and the mRNA and protein levels of collagens at 1 mM, and their effects were further enhanced when co-treated with glycinamide. Among AA derivatives, MAP had a similar effect to AA in enhancing wound closure, and its effect was further enhanced by glycinamide. Other AA derivatives had different effects on wound closure. This study provides a new strategy to enhance cell collagen production and wound healing using glycinamide in combination with AA. Full article
(This article belongs to the Special Issue Wound Healing at the Cellular Level)
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14 pages, 3327 KiB  
Article
The Impact of Prolonged Inflammation on Wound Healing
by Judith C. J. Holzer-Geissler, Simon Schwingenschuh, Martin Zacharias, Johanna Einsiedler, Sonja Kainz, Peter Reisenegger, Christian Holecek, Elisabeth Hofmann, Barbara Wolff-Winiski, Hermann Fahrngruber, Thomas Birngruber, Lars-Peter Kamolz and Petra Kotzbeck
Biomedicines 2022, 10(4), 856; https://doi.org/10.3390/biomedicines10040856 - 6 Apr 2022
Cited by 39 | Viewed by 6098
Abstract
The treatment of chronic wounds still challenges modern medicine because of these wounds’ heterogenic pathophysiology. Processes such as inflammation, ischemia and bacterial infection play major roles in the progression of a chronic wound. In recent years, preclinical wound models have been used to [...] Read more.
The treatment of chronic wounds still challenges modern medicine because of these wounds’ heterogenic pathophysiology. Processes such as inflammation, ischemia and bacterial infection play major roles in the progression of a chronic wound. In recent years, preclinical wound models have been used to understand the underlying processes of chronic wound formation. However, the wound models used to investigate chronic wounds often lack translatability from preclinical models to patients, and often do not take exaggerated inflammation into consideration. Therefore, we aimed to investigate prolonged inflammation in a porcine wound model by using resiquimod, a TLR7 and TLR8 agonist. Pigs received full thickness excisional wounds, where resiquimod was applied daily for 6 days, and untreated wounds served as controls. Dressing change, visual documentation and wound scoring were performed daily. Biopsies were collected for histological as well as gene expression analysis. Resiquimod application on full thickness wounds induced a visible inflammation of wounds, resulting in delayed wound healing compared to non-treated control wounds. Gene expression analysis revealed high levels of IL6, MMP1 and CD68 expression after resiquimod application, and histological analysis showed increased immune cell infiltration. By using resiquimod, we were able to show that prolonged inflammation delayed wound healing, which is often observed in chronic wounds in patients. The model we used shows the importance of inflammation in wound healing and gives an insight into the progression of chronic wounds. Full article
(This article belongs to the Special Issue Wound Healing at the Cellular Level)
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34 pages, 14984 KiB  
Article
Keratinocyte and Fibroblast Wound Healing In Vitro Is Repressed by Non-Optimal Conditions but the Reparative Potential Can Be Improved by Water-Filtered Infrared A
by Cornelia Wiegand, Uta-Christina Hipler, Peter Elsner and Jörg Tittelbach
Biomedicines 2021, 9(12), 1802; https://doi.org/10.3390/biomedicines9121802 - 30 Nov 2021
Cited by 16 | Viewed by 5312
Abstract
It is a general goal to improve wound healing, especially of chronic wounds. As light therapy has gained increasing attention, the positive influence on healing progression of water-filtered infrared A (wIRA), a special form of thermal radiation, has been investigated and compared to [...] Read more.
It is a general goal to improve wound healing, especially of chronic wounds. As light therapy has gained increasing attention, the positive influence on healing progression of water-filtered infrared A (wIRA), a special form of thermal radiation, has been investigated and compared to the detrimental effects of UV-B irradiation on wound closure in vitro. Models of keratinocyte and fibroblast scratches help to elucidate effects on epithelial and dermal healing. This study further used the simulation of non-optimal settings such as S. aureus infection, chronic inflammation, and anti-inflammatory conditions to determine how these affect scratch wound progression and whether wIRA treatment can improve healing. Gene expression analysis for cytokines (IL1A, IL6, CXCL8), growth (TGFB1, PDGFC) and transcription factors (NFKB1, TP53), heat shock proteins (HSP90AA1, HSPA1A, HSPD1), keratinocyte desmogleins (DSG1, DSG3), and fibroblast collagen (COL1A1, COL3A1) was performed. Keratinocyte and fibroblast wound healing under non-optimal conditions was found to be distinctly reduced in vitro. wIRA treatment could counteract the inflammatory response in infected keratinocytes as well as under chronic inflammatory conditions by decreasing pro-inflammatory cytokine gene expression and improve wound healing. In contrast, in the anti-inflammatory setting, wIRA radiation could re-initiate the acute inflammatory response necessary after injury to stimulate the regenerative processes and advance scratch closure. Full article
(This article belongs to the Special Issue Wound Healing at the Cellular Level)
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16 pages, 6088 KiB  
Article
Recovery of Altered Diabetic Myofibroblast Heterogeneity and Gene Expression Are Associated with CD301b+ Macrophages
by MaryEllen R. Haas, Darlene V. Nguyen and Brett A. Shook
Biomedicines 2021, 9(12), 1752; https://doi.org/10.3390/biomedicines9121752 - 24 Nov 2021
Cited by 4 | Viewed by 2391
Abstract
Diabetic wound healing is associated with impaired function and reduced numbers of myofibroblasts, a heterogeneous cell population with varying capacities to promote repair. To determine how diabetes alters myofibroblast composition, we performed flow cytometry and spatial tissue analysis of myofibroblast subsets throughout the [...] Read more.
Diabetic wound healing is associated with impaired function and reduced numbers of myofibroblasts, a heterogeneous cell population with varying capacities to promote repair. To determine how diabetes alters myofibroblast composition, we performed flow cytometry and spatial tissue analysis of myofibroblast subsets throughout the healing process in diabetic (db/db) and control (db/+) mouse skin. We observed reduced numbers of profibrotic SCA1+; CD34+; CD26+ myofibroblasts in diabetic wounds five days after injury, with decreased expression of fibrosis-associated genes compared to myofibroblasts from db/+ mouse wounds. While the abundance of myofibroblasts remained reduced in db/db mouse wounds compared to controls, the altered myofibroblast heterogeneity and gene expression in diabetic mice was improved seven days after injury. The natural correction of myofibroblast composition and gene expression in db/db wound beds temporally corresponds with a macrophage phenotypic switch. Correlation analysis from individual wound beds revealed that wound healing in control mice is associated with CD206+ macrophages, while the rescued myofibroblast phenotypes in diabetic wounds are correlated with increased CD301b+ macrophage numbers. These data demonstrate how diabetes impacts specific subsets of myofibroblasts and indicate that signaling capable of rescuing impaired diabetic wound healing could be different from signals that regulate wound healing under nonpathological conditions. Full article
(This article belongs to the Special Issue Wound Healing at the Cellular Level)
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18 pages, 4730 KiB  
Article
A 3D In Vitro Model for Burn Wounds: Monitoring of Regeneration on the Epidermal Level
by Verena Schneider, Daniel Kruse, Ives Bernardelli de Mattos, Saskia Zöphel, Kendra-Kathrin Tiltmann, Amelie Reigl, Sarah Khan, Martin Funk, Karl Bodenschatz and Florian Groeber-Becker
Biomedicines 2021, 9(9), 1153; https://doi.org/10.3390/biomedicines9091153 - 3 Sep 2021
Cited by 7 | Viewed by 2885
Abstract
Burns affect millions every year and a model to mimic the pathophysiology of such injuries in detail is required to better understand regeneration. The current gold standard for studying burn wounds are animal models, which are under criticism due to ethical considerations and [...] Read more.
Burns affect millions every year and a model to mimic the pathophysiology of such injuries in detail is required to better understand regeneration. The current gold standard for studying burn wounds are animal models, which are under criticism due to ethical considerations and a limited predictiveness. Here, we present a three-dimensional burn model, based on an open-source model, to monitor wound healing on the epidermal level. Skin equivalents were burned, using a preheated metal cylinder. The healing process was monitored regarding histomorphology, metabolic changes, inflammatory response and reepithelialization for 14 days. During this time, the wound size decreased from 25% to 5% of the model area and the inflammatory response (IL-1β, IL-6 and IL-8) showed a comparable course to wounding and healing in vivo. Additionally, the topical application of 5% dexpanthenol enhanced tissue morphology and the number of proliferative keratinocytes in the newly formed epidermis, but did not influence the overall reepithelialization rate. In summary, the model showed a comparable healing process to in vivo, and thus, offers the opportunity to better understand the physiology of thermal burn wound healing on the keratinocyte level. Full article
(This article belongs to the Special Issue Wound Healing at the Cellular Level)
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Review

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15 pages, 333 KiB  
Review
Stem Cell-Based Therapeutic Strategies in Diabetic Wound Healing
by Meng-Chien Willie Hsieh, Wei-Ting Wang, Chuang-Yu Lin, Yur-Ren Kuo, Su-Shin Lee, Ming-Feng Hou and Yi-Chia Wu
Biomedicines 2022, 10(9), 2085; https://doi.org/10.3390/biomedicines10092085 - 25 Aug 2022
Cited by 6 | Viewed by 2323
Abstract
Impaired wound healing and especially the “all-too-common” occurrence of associated diabetic foot ulcers (DFU) are becoming an increasingly urgent and deteriorating healthcare issue, which drastically impact the quality of life and further heighten the risks of infection and amputation in patients with diabetes [...] Read more.
Impaired wound healing and especially the “all-too-common” occurrence of associated diabetic foot ulcers (DFU) are becoming an increasingly urgent and deteriorating healthcare issue, which drastically impact the quality of life and further heighten the risks of infection and amputation in patients with diabetes mellitus. Amongst the multifactorial wound healing determinants, glycemic dysregulation has been identified to be the primary casual factor of poor wound healing. Unfortunately, current therapeutic modalities merely serve as moderate symptomatic relieves but often fail to completely restore the wound site to its pre-injury state and prevent further recurrence. Stem cell-based therapeutics have been employed for its promising potential to address the root of the problem as they not only exhibit the capacity for self-renewal and differentiation towards multiple lineages, but also have been disclosed to participate in mediating variant growth factors and cytokines. Herein we review the current literatures on the therapeutic benefits of using various kinds of stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and adipose-derived stem cells (ASCs) in diabetic wound healing by searching on the PubMed® Database for publications. This study shall serve as an overview of the current body of research with particular focus on autologous ASCs and the laboratory expandable iPSCs in hope of shedding more light on this attractive therapy so as to elevate the efficacy of wound healing that is almost always compromised in diabetic patients. Full article
(This article belongs to the Special Issue Wound Healing at the Cellular Level)
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