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Oxidative Stress in Wound Healing

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (15 February 2024) | Viewed by 20766

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Prof. Dr. Filippo Renò

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Innovative Research Laboratory for Wound Healing, Health Sciences Department, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
Interests: wound healing; innate immunity; nanomedicine; 3D bioprinting; tissue engineering

Special Issue Information

Dear Colleagues,

Wound healing is a rather complex biological process that consists of overlapping stages, including hemostasis, inflammation, cell proliferation, and tissue remodeling. Aging and medical conditions such as infections or diabetes can severely slow or impair wound healing. The generation of reactive oxygen species (ROS) is a key aspect both in the normal physiology and in the pathogenesis of many diseases, and growing evidence indicates that oxidative stress can modulate wound healing phases. Under physiological conditions, ROS production is balanced by cellular production of antioxidants that remove intermediate free radicals and inhibit oxidation, and low ROS concentrations regulate gene expression and the post-translational modifications of proteins. In wound healing, ROS exhibit a two-faced appearance of Janus, as low concentrations of generated ROS are required for antibacterial defense and cell survival signaling, whereas high ROS accumulation or impaired detoxification induce oxidative damage to the cell membrane, degradation of the extracellular matrix, and prolonged inflammation and, in turn, wounds are not healed, as demonstrated in diabetes. Additionally, elevated ROS levels can be accompanied by the production of reactive nitrogen species (RNS) such as nitric oxide (NO), a known modulator of wound healing.

This Special Issue will explore the surprising double-sided behavior of oxidative stress in wound healing through publications of original first-line research on both its basic and clinical aspects.

Prof. Dr. Filippo Renò
Guest Editor

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Keywords

wound healing
oxidative stress
chronic wound

Published Papers (9 papers)

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Research

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22 pages, 6558 KiB

Open AccessArticle

Gas Plasma Exposure Alters Microcirculation and Inflammation during Wound Healing in a Diabetic Mouse Model

by Anke Schmidt, Debora Singer, Henrike Aden, Thomas von Woedtke and Sander Bekeschus

Antioxidants 2024, 13(1), 68; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox13010068 - 02 Jan 2024

Viewed by 1142

Abstract

Diabetes can disrupt physiological wound healing, caused by decreased levels or impaired activity of angiogenic factors. This can contribute to chronic inflammation, poor formation of new blood vessels, and delayed re-epithelialization. The present study describes the preclinical application of medical gas plasma to treat a dermal, full-thickness ear wound in streptozotocin (STZ)-induced diabetic mice. Gas plasma-mediated effects occurred in both sexes but with gender-specific differences. Hyperspectral imaging demonstrated gas plasma therapy changing microcirculatory parameters, particularly oxygen saturation levels during wound healing, presumably due to the gas plasma’s tissue delivery of reactive species and other bioactive components. In addition, gas plasma treatment significantly affected cell adhesion by regulating focal adhesion kinase and vinculin, which is important in maintaining skin barrier function by regulating syndecan expression and increasing re-epithelialization. An anticipated stimulation of blood vessel formation was detected via transcriptional and translational increase of angiogenic factors in gas plasma-exposed wound tissue. Moreover, gas plasma treatment significantly affected inflammation by modulating systemic growth factors and cytokine levels. The presented findings may help explain the mode of action of successful clinical plasma therapy of wounds of diabetic patients. Full article

(This article belongs to the Special Issue Oxidative Stress in Wound Healing)

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18 pages, 3353 KiB

Open AccessArticle

Fish Skin Grafts Affect Adenosine and Methionine Metabolism during Burn Wound Healing

by Aristotelis Kotronoulas, Adrián López García de Lomana, Helga Kristín Einarsdóttir, Hilmar Kjartansson, Randolph Stone II and Óttar Rolfsson

Antioxidants 2023, 12(12), 2076; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12122076 - 05 Dec 2023

Viewed by 841

Abstract

Burn wound healing is a complex process orchestrated through successive biochemical events that span from weeks to months depending on the depth of the wound. Here, we report an untargeted metabolomics discovery approach to capture metabolic changes during the healing of deep partial-thickness (DPT) and full-thickness (FT) burn wounds in a porcine burn wound model. The metabolic changes during healing could be described with six and seven distinct metabolic trajectories for DPT and FT wounds, respectively. Arginine and histidine metabolism were the most affected metabolic pathways during healing, irrespective of burn depth. Metabolic proxies for oxidative stress were different in the wound types, reaching maximum levels at day 14 in DPT burns but at day 7 in FT burns. We examined how acellular fish skin graft (AFSG) influences the wound metabolome compared to other standard-or-care burn wound treatments. We identified changes in metabolites within the methionine salvage pathway, specifically in DPT burn wounds that is novel to the understanding of the wound healing process. Furthermore, we found that AFSGs boost glutamate and adenosine in wounds that is of relevance given the importance of purinergic signaling in regulating oxidative stress and wound healing. Collectively, these results serve to define biomarkers of burn wound healing. These results conclusively contribute to the understanding of the multifactorial mechanism of the action of AFSG that has traditionally been attributed to its structural properties and omega-3 fatty acid content. Full article

(This article belongs to the Special Issue Oxidative Stress in Wound Healing)

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11 pages, 1319 KiB

Open AccessArticle

Laser Biostimulation Induces Wound Healing-Promoter β2-Defensin Expression in Human Keratinocytes via Oxidative Stress

by Mario Migliario, Preetham Yerra, Sarah Gino, Maurizio Sabbatini and Filippo Renò

Antioxidants 2023, 12(8), 1550; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12081550 - 03 Aug 2023

Viewed by 1168

Abstract

The innate immune system is the first line of defense of the body composed of anatomical barriers, such as skin and mucosa, as well as effector cells, antimicrobial peptides, soluble mediators, and cell receptors able to detect and destroy viruses and bacteria and to sense trauma and wounds to initiate repair. The human β-defensins belong to a family of antimicrobial small cationic peptides produced by epithelial cells, and show immunomodulatory and pro-healing activities. Laser biostimulation is a therapy widely used to contrast microbial infection and to accelerate wound healing through biological mechanisms that include the creation of oxidative stress. In this paper, we explored laser biostimulation’s ability to modulate the production of two β-defensins, hBD-1 and hBD-2, in human keratinocytes and whether this modulation was, at least in part, oxidative-stress-dependent. Human spontaneously immortalized keratinocytes (HaCaT) were stimulated using laser irradiation at a 980 nm wavelength, setting the power output to 1 W (649.35 mW/cm²) in the continuous mode. Cells were irradiated for 0 (negative control), 5, 10, 25 and 50 s, corresponding to an energy stimulation of 0, 5, 10, 25 and 50 J. Positive control cells were treated with lipopolysaccharide (LPS, 200 ng/mL). After 6 and 24 h of treatment, the cell conditioned medium was collected and analyzed via ELISA assay for the production of hBD-1 and hBD-2. In another set of experiments, HaCaT were pre-incubated for 45 min with antioxidant drugs—vitamin C (Vit. C, 100 µM), sodium azide (NaN₃, 1 mM); ω-nitro-L-arginine methyl ester (L-NAME, 10 mM) and sodium pyruvate (NaPyr, 100 µM)—and then biostimulated for 0 or 50 s. After 6 h, the conditioned medium was collected and used for the ELISA analysis. The hBD-1 and hBD-2 production by HaCaT was significantly increased by single laser biostimulation after 6 h in an energy-dependent fashion compared to basal levels, and both reached production levels induced by LPS. After 24 h, only hBD-2 production induced by laser biostimulation was further increased, while the basal and stimulated hBD-1 levels were comparable. Pre-incubation with antioxidative drugs was able to completely abrogate the laser-induced production of both hBD-1 and hBD-2 after 6 h, with the exception of hBD-1 production in samples stimulated after NaN₃ pre-incubation. A single laser biostimulation induced the oxidative-stress-dependent production of both hBD-1 and hBD-2 in human keratinocytes. In particular, the pro-healing hBD-2 level was almost three times higher than the baseline level and lasted for 24 h. These findings increase our knowledge about the positive effects of laser biostimulation on wound healing. Full article

(This article belongs to the Special Issue Oxidative Stress in Wound Healing)

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18 pages, 3538 KiB

Open AccessArticle

Role of Enzymic Antioxidants in Mediating Oxidative Stress and Contrasting Wound Healing Capabilities in Oral Mucosal/Skin Fibroblasts and Tissues

by Parkash Lohana, Albert Suryaprawira, Emma L. Woods, Jordanna Dally, Edward Gait-Carr, Nadia Y. A. Alaidaroos, Charles M. Heard, Kwok Y. Lee, Fiona Ruge, Jeremy N. Farrier, Stuart Enoch, Matthew P. Caley, Matthew A. Peake, Lindsay C. Davies, Peter J. Giles, David W. Thomas, Phil Stephens and Ryan Moseley

Antioxidants 2023, 12(7), 1374; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12071374 - 30 Jun 2023

Cited by 2 | Viewed by 1796

Abstract

Unlike skin, oral mucosal wounds are characterized by rapid healing and minimal scarring, attributable to the “enhanced” healing properties of oral mucosal fibroblasts (OMFs). As oxidative stress is increasingly implicated in regulating wound healing outcomes, this study compared oxidative stress biomarker and enzymic antioxidant profiles between patient-matched oral mucosal/skin tissues and OMFs/skin fibroblasts (SFs) to determine whether superior oral mucosal antioxidant capabilities and reduced oxidative stress contributed to these preferential healing properties. Oral mucosa and skin exhibited similar patterns of oxidative protein damage and lipid peroxidation, localized within the lamina propria/dermis and oral/skin epithelia, respectively. SOD1, SOD2, SOD3 and catalase were primarily localized within epithelial tissues overall. However, SOD3 was also widespread within the lamina propria localized to OMFs, vasculature and the extracellular matrix. OMFs were further identified as being more resistant to reactive oxygen species (ROS) generation and oxidative DNA/protein damage than SFs. Despite histological evaluation suggesting that oral mucosa possessed higher SOD3 expression, this was not fully substantiated for all OMFs examined due to inter-patient donor variability. Such findings suggest that enzymic antioxidants have limited roles in mediating privileged wound healing responses in OMFs, implying that other non-enzymic antioxidants could be involved in protecting OMFs from oxidative stress overall. Full article

(This article belongs to the Special Issue Oxidative Stress in Wound Healing)

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16 pages, 20658 KiB

Open AccessArticle

ARAG, an Antioxidant-Rich Gel, Shows Superiority to Mepilex Ag in the Treatment of Deep Partial Thickness Burns without Sacrificing Antimicrobial Efficiency

by Brian Michael Cartwright, Sean James Fox, Mary Jane Underdown, William Andrew Clark and Joseph Andrew Molnar

Antioxidants 2023, 12(6), 1176; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12061176 - 30 May 2023

Viewed by 2094

Abstract

Current treatments for deep tissue burns are limited, and most serve only to enhance hydration or prevent bacterial growth. This leaves burn healing dependent on slow natural processes to debride the wound and reestablish the epidermal and dermal layers of the skin. Infections are well known to destabilize this process through a variety of mechanisms, most notably through increased inflammation and the resulting oxidative stress. In this study, we show that ARAG (an antioxidant-rich antimicrobial gel) can suppress the growth of multiple bacteria commonly found to infect burns (Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa, and Staphylococcus aureus). This inhibition is comparable to that conferred by silver ion release from burn dressings such as Mepilex-Ag. We further show, using a porcine model for deep partial-thickness burns, that ARAG allows for enhanced wound healing over Mepilex-Ag, the current standard of care. Histological findings indicate this is likely due to increased wound debridement and dampening of late inflammatory processes, leading to more balanced physiologic healing. Taken together, these findings show promise for ARAG as a superior alternative to the current standard of care. Full article

(This article belongs to the Special Issue Oxidative Stress in Wound Healing)

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17 pages, 6128 KiB

Open AccessArticle

Wound Healing and Antioxidant Properties of Launaea procumbens Supported by Metabolomic Profiling and Molecular Docking

by Shaimaa R. Ahmed, Ehab M. Mostafa, Arafa Musa, Enas Ezzat Rateb, Mohammad M. Al-Sanea, Dalia H. Abu-Baih, Mahmoud A. Elrehany, Entesar Ali Saber, Mostafa E. Rateb and Usama Ramadan Abdelmohsen

Antioxidants 2022, 11(11), 2258; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11112258 - 16 Nov 2022

Cited by 6 | Viewed by 2545

Abstract

Wounds adversely affect people’s quality of life and have psychological, social, and economic impacts. Herbal remedies of Launaea procumbens (LP) are used to treat wounds. In an excision wound model, topical application of LP significantly promoted wound closure (on day 14, LP-treated animals had the highest percentages of wound closure in comparison with the other groups, as the wound was entirely closed with a closure percentage of 100%, p < 0.05). Histological analysis revealed a considerable rise in the number of fibroblasts, the amount of collagen, and its cross-linking in LP-treated wounds. Gene expression patterns showed significant elevation of TGF-β levels (2.1-fold change after 7 days treatment and 2.7-fold change in 14 days treatment) and downregulation of the inflammatory TNF-α and IL-1β levels in LP-treated wounds. Regarding in vitro antioxidant activity, LP extract significantly diminished the formation of H₂O₂ radical (IC₅₀ = 171.6 μg/mL) and scavenged the superoxide radical (IC₅₀ of 286.7 µg/mL), indicating antioxidant potential in a dose-dependent manner. Dereplication of the secondary metabolites using LC-HRMS resulted in the annotation of 16 metabolites. The identified compounds were docked against important wound-healing targets, including vascular endothelial growth factor (VEGF), collagen α-1, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and transforming growth factor-β (TGF-β). Among dereplicated compounds, luteolin 8-C-glucoside (orientin) demonstrated binding potential to four investigated targets (VEGF, interleukin 1β, TNF-α, and collagen α-1). To conclude, Launaea procumbens extract could be regarded as a promising topical therapy to promote wound healing in excisional wounds, and luteolin 8-C-glucoside (orientin), one of its constituents, is a potential wound-healing drug lead. Full article

(This article belongs to the Special Issue Oxidative Stress in Wound Healing)

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Review

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14 pages, 1102 KiB

Open AccessReview

Influence of Reactive Oxygen Species on Wound Healing and Tissue Regeneration in Periodontal and Peri-Implant Tissues in Diabetic Patients

by Prima Buranasin, Hiromi Kominato, Koji Mizutani, Risako Mikami, Natsumi Saito, Kohei Takeda and Takanori Iwata

Antioxidants 2023, 12(9), 1787; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12091787 - 21 Sep 2023

Cited by 3 | Viewed by 1546

Abstract

Diabetes mellitus (DM) is associated with periodontal disease. Clinically, periodontal treatment is less effective for patients with DM. Oxidative stress is one of the mechanisms that link DM to periodontitis. The production of reactive oxygen species (ROS) is increased in the periodontal tissues of patients with DM and is involved in the development of insulin resistance in periodontal tissues. Insulin resistance decreases Akt activation and inhibits cell proliferation and angiogenesis. This results in the deterioration of wound healing and tissue repair in periodontal tissues. Antioxidants and insulin resistance ameliorants may inhibit ROS production and improve wound healing, which is worsened by DM. This manuscript provides a comprehensive review of the most recent basic and clinical evidence regarding the generation of ROS in periodontal tissues resulting from microbial challenge and DM. This study also delves into the impact of oxidative stress on wound healing in the context of periodontal and dental implant therapies. Furthermore, it discusses the potential benefits of administering antioxidants and anti-insulin resistance medications, which have been shown to counteract ROS production and inflammation. This approach may potentially enhance wound healing, especially in cases exacerbated by hyperglycemic conditions. Full article

(This article belongs to the Special Issue Oxidative Stress in Wound Healing)

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28 pages, 1817 KiB

Open AccessReview

Antioxidant Activities of Natural Compounds from Caribbean Plants to Enhance Diabetic Wound Healing

by Laura Accipe, Alisson Abadie, Remi Neviere and Sylvie Bercion

Antioxidants 2023, 12(5), 1079; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12051079 - 11 May 2023

Cited by 5 | Viewed by 3008

Abstract

Diabetic wound healing is a global medical challenge. Several studies showed that delayed healing in diabetic patients is multifactorial. Nevertheless, there is evidence that excessive production of ROS and impaired ROS detoxification in diabetes are the main cause of chronic wounds. Indeed, increased ROS promotes the expression and activity of metalloproteinase, resulting in a high proteolytic state in the wound with significant destruction of the extracellular matrix, which leads to a stop in the repair process. In addition, ROS accumulation increases NLRP3 inflammasome activation and macrophage hyperpolarization in the M1 pro-inflammatory phenotype. Oxidative stress increases the activation of NETosis. This leads to an elevated pro-inflammatory state in the wound and prevents the resolution of inflammation, an essential step for wound healing. The use of medicinal plants and natural compounds can improve diabetic wound healing by directly targeting oxidative stress and the transcription factor Nrf2 involved in the antioxidant response or the mechanisms impacted by the elevation of ROS such as NLRP3 inflammasome, the polarization of macrophages, and expression or activation of metalloproteinases. This study of the diabetic pro-healing activity of nine plants found in the Caribbean highlights, more particularly, the role of five polyphenolic compounds. At the end of this review, research perspectives are presented. Full article

(This article belongs to the Special Issue Oxidative Stress in Wound Healing)

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35 pages, 2534 KiB

Open AccessReview

Antioxidant Biomaterials in Cutaneous Wound Healing and Tissue Regeneration: A Critical Review

by Nur Izzah Md Fadilah, Shou Jin Phang, Nurkhuzaiah Kamaruzaman, Atiqah Salleh, Mazlan Zawani, Arka Sanyal, Manira Maarof and Mh Busra Fauzi

Antioxidants 2023, 12(4), 787; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12040787 - 23 Mar 2023

Cited by 18 | Viewed by 4548

Abstract

Natural-based biomaterials play an important role in developing new products for medical applications, primarily in cutaneous injuries. A large panel of biomaterials with antioxidant properties has revealed an advancement in supporting and expediting tissue regeneration. However, their low bioavailability in preventing cellular oxidative stress through the delivery system limits their therapeutic activity at the injury site. The integration of antioxidant compounds in the implanted biomaterial should be able to maintain their antioxidant activity while facilitating skin tissue recovery. This review summarises the recent literature that reported the role of natural antioxidant-incorporated biomaterials in promoting skin wound healing and tissue regeneration, which is supported by evidence from in vitro, in vivo, and clinical studies. Antioxidant-based therapies for wound healing have shown promising evidence in numerous animal studies, even though clinical studies remain very limited. We also described the underlying mechanism of reactive oxygen species (ROS) generation and provided a comprehensive review of ROS-scavenging biomaterials found in the literature in the last six years. Full article

(This article belongs to the Special Issue Oxidative Stress in Wound Healing)

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