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The Presence of Oxygen in Wound Healing
Abstract
Oxygen must be tightly governed in all phases of wound healing to produce viable granulation tissue. This idea of tight regulation has yet to be disputed; however, the role of oxygen at the cellular and molecular levels still is not fully understood as it pertains to its place in healing wounds. In an attempt to better understand the dynamics of oxygen on living tissue and its potential role as a therapy in wound healing, a substantial literature review of the role of oxygen in wound healing was performed and the following key points were extrapolated: 1) During energy metabolism, oxygen is needed for mitochondrial cytochrome oxidase as it produces high-energy phosphates that are needed for many cellular functions, 2) oxygen is also involved in the hydroxylation of proline and lysine into procollagen, which leads to collagen maturation, 3) in angiogenesis, hypoxia is required to start the process of wound healing, but it has been shown that if oxygen is administered it can accelerate and sustain vessel growth, 4) the antimicrobial action of oxygen occurs when nicotinamide adenine dinucleotide phosphate (NADPH)-linked oxygenase acts as a catalyst for the production of reactive oxygen species (ROS), a superoxide ion which kills bacteria, and 5) the level of evidence is moderate for the use of hyperbaric oxygen therapy (HBOT) for diabetic foot ulcers, crush injuries, and soft-tissue infections. The authors hypothesized that HBOT would be beneficial to arterial insufficiency wounds and other ailments, but at this time further study is needed before HBOT would be indicated.
... Among the key molecules of the wound healing process, oxygen is described to be crucial in its success, being involved in several critical steps including aerobic cell metabolism, angiogenesis, collagen maturation, and oxidative killing of bacteria [ 14 , 15 ]. Although it has been well described that despite acute hypoxia acts as an initial signal to promote wound healing, prolonged and chronic hypoxia plays a major role in non-healing chronic wounds [16] . Hence, several effort s have been made to provide oxygen to wounds either systemically or locally, including hyperbaric oxygen therapy (HBOT) or topical oxygen therapy (TOT), but larger studies are still needed, as no consistent or significant results have been obtained [16][17][18] . ...
... Although it has been well described that despite acute hypoxia acts as an initial signal to promote wound healing, prolonged and chronic hypoxia plays a major role in non-healing chronic wounds [16] . Hence, several effort s have been made to provide oxygen to wounds either systemically or locally, including hyperbaric oxygen therapy (HBOT) or topical oxygen therapy (TOT), but larger studies are still needed, as no consistent or significant results have been obtained [16][17][18] . In addition, dressings have been designed to deliver oxygen in the wound site by incorporating different chemical compounds such as hydrogen peroxide, calcium peroxide or perfluorocarbons, representing a promising approach for the local oxygenation of wounds [19] . ...
The development of biomaterials to improve wound healing is a critical clinical challenge and an active field of research. As it is well described that oxygen plays a critical role in almost each step of the wound healing process, in this work, an oxygen producing photosynthetic biomaterial was generated, characterized, and further modified to additionally release other bioactive molecules. Here, alginate hydrogels were loaded with the photosynthetic microalgae Chlamydomonas reinhardtii, showing high integration as well as immediate oxygen release upon illumination. Moreover, the photosynthetic hydrogel showed high biocompatibility in vitro and in vivo, and the capacity to sustain the metabolic oxygen requirements of zebrafish larvae and skin explants. In addition, the photosynthetic dressings were evaluated in 20 healthy human volunteers following the ISO-10993-10-2010 showing no skin irritation, mechanical stability of the dressings, and survival of the photosynthetic microalgae. Finally, hydrogels were also loaded with genetically engineered microalgae to release human VEGF, or pre-loaded with antibiotics, showing sustained release of both bioactive molecules. Overall, this work shows that photosynthetic hydrogels represent a feasible approach for the local delivery of oxygen and other bioactive molecules to promote wound healing.
Statement of significance
: As oxygen plays a key role in almost every step of the tissue regeneration process, the development of oxygen delivering therapies represents an active field of research, where photosynthetic biomaterials have risen as a promising approach for wound healing. Therefore, in this work a photosynthetic alginate hydrogel-based wound dressing containing C. reinhardtii microalgae was developed and validated in healthy skin of human volunteers. Moreover, hydrogels were modified to additionally release other bioactive molecules such as recombinant VEGF or antibiotics. The present study provides key scientific data to support the use of photosynthetic hydrogels as customizable dressings to promote wound healing.
... To determine the oxygen-release kinetics, we used an oxygensensitive luminophore, Ru(Ph 2 phen 3 )Cl 2 , whose fluorescence intensity is linearly proportional to the oxygen content (29,30). The ORMs were able to continuously release oxygen during the 2-week experimental period (Fig. 1E). ...
... In diabetic wounds, hypoxia is a major factor compromising cell survival and migration, leading to slow wound healing (6,30,32). To evaluate whether oxygen released from ORMs was able to improve cell survival under hypoxia, we incubated human keratinocytes (HaCaT cells), human dermal fibroblasts (HDFs), and human arterial endothelial cells (HAECs) with the ORMs under 1% oxygen. ...
Nonhealing diabetic wounds are common complications for diabetic patients. Because chronic hypoxia prominently delays wound healing, sustained oxygenation to alleviate hypoxia is hypothesized to promote diabetic wound healing. However, sustained oxygenation cannot be achieved by current clinical approaches, including hyperbaric oxygen therapy. Here, we present a sustained oxygenation system consisting of oxygen-release microspheres and a reactive oxygen species (ROS)–scavenging hydrogel. The hydrogel captures the naturally elevated ROS in diabetic wounds, which may be further elevated by the oxygen released from the administered microspheres. The sustained release of oxygen augmented the survival and migration of keratinocytes and dermal fibroblasts, promoted angiogenic growth factor expression and angiogenesis in diabetic wounds, and decreased the proinflammatory cytokine expression. These effects significantly increased the wound closure rate. Our findings demonstrate that sustained oxygenation alone, without using drugs, can heal diabetic wounds.
... TOT therapy can improve the blood oxygen supply to local tissues, and PRF contains growth factors that are conducive to wound regeneration and repair. In clinical practice, TOT is a new treatment method that can accelerate wound healing by injecting a high concentration of oxygen into locally confined spaces to improve the partial pressure of oxygen in wound tissues and strengthen the metabolic synthesis function of cells (18,19). Compared to tissue engineering and stem cell therapy, TOT has been increasingly applied in tissue injury repair, especially in ischemic and infectious wounds, owing to its advantages of simple operation and low equipment requirements (20,21). ...
Background:
Autologous fat transplantation has gained increasing attention in the field of cosmetic surgery. However, a series of complications can occur after fat transplantation.
Case presentation:
A 24-year-old woman presented at our Hospital with nasal skin necrosis and ulceration. She had undergone autologous fat transplantation on the nose six days ago. Physical examination showed an abnormal skin range of approximately 5 × 2 cm on the left side of the nose. The initial diagnosis was "skin necrosis after autologous fat grafting for augmentation rhinoplasty." In addition to the conventional treatment, topical oxygen therapy (TOT) and platelet-rich fibrin (PRF) injection were applied to the nasal wounds area. After 16 days, the pale and dark areas of necrosis on nose were scabby, and the local skin conditions were significantly improved.
Conclusion:
We treated a case of ischemic necrosis of the skin after autologous fat grafting for augmentation rhinoplasty. For this kind of local vascular embolism, we first proposed a comprehensive therapy of "biological + physical + drug." The therapeutic method achieved satisfactory results, providing a new strategy for the clinical treatment of vascular embolism.
... 209 During the hemostasis phase, hypoxia plays a pivotal role in initiating the wound healing process by enhancing the activity of reactive oxygen species (ROS). 210 In the inflammation phase, the elimination of bacteria occurs via phagocytosis, a process contingent upon high partial oxygen pressure. 211 Vascular endothelial growth factor, a key growth factor in angiogenesis, is upregulated by hypoxia-inducible factor 1-alpha, which is activated by both hypoxia and ROS during the proliferation phase. ...
BACKGROUND: The timely provision of load-bearing prostheses significantly reduces healthcare costs and lowers post-amputation mortality risk. However, current methods for assessing residuum health remain subjective, underscoring the need for standardized, evidence-based approaches incorporating physical biomarkers to evaluate residual limb healing and determine readiness for prosthetic rehabilitation.
OBJECTIVE(S): This review aimed to identify predictive, diagnostic, and indicative physical biomarkers of healing of the tissues and structures found in the residual limbs of adults with amputation.
METHODOLOGY: A scoping review was conducted following Joanna Briggs Institute (JBI) and PRISMA-ScR guidance. Searches using “biomarkers”, “wound healing”, and “amputation” were performed on May 6, 2023, on Web of Science, Ovid MEDLINE, Ovid Embase, Scopus, Cochrane, PubMed, and CINAHL databases. Inclusion criteria were: 1) References to physical biomarkers and healing; 2) Residuum tissue healing; 3) Clear methodology with ethical approval; 4) Published from 2017 onwards. Articles were assessed for quality (QualSyst tool) and evidence level (JBI system), and categorized by study, wound, and model type. Physical biomarkers that were repeated not just within categories, but across more than one of the study categories were reported on.
FINDINGS: The search strategy identified 3,306 sources, 157 of which met the inclusion criteria. Histology was the most frequently repeated physical biomarker used in 64 sources, offering crucial diagnostic insights into cellular healing processes. Additional repeated indicative and predictive physical biomarkers, including ankle-brachial index, oxygenation measures, perfusion, and blood pulse and pressure measurements, were reported in 25, 19, 13, and 12 sources, respectively, providing valuable data on tissue oxygenation and vascular health.
CONCLUSION: Ultimately, adopting a multifaceted approach that integrates a diverse array of physical biomarkers (accounting for physiological factors and comorbidities known to influence healing) may substantially enhance our understanding of the healing process and inform the development of effective rehabilitation strategies for individuals undergoing amputation.
... 209 During the hemostasis phase, hypoxia plays a pivotal role in initiating the wound healing process by enhancing the activity of reactive oxygen species (ROS). 210 In the inflammation phase, the elimination of bacteria occurs via phagocytosis, a process contingent upon high partial oxygen pressure. 211 Vascular endothelial growth factor, a key growth factor in angiogenesis, is upregulated by hypoxia-inducible factor 1-alpha, which is activated by both hypoxia and ROS during the proliferation phase. ...
BACKGROUND: The timely provision of load-bearing prostheses significantly reduces healthcare costs and lowers post-amputation mortality risk. However, current methods for assessing residuum health remain subjective, underscoring the need for standardized, evidence-based approaches incorporating physical biomarkers to evaluate residual limb healing and determine readiness for prosthetic rehabilitation. OBJECTIVE(S): This review aimed to identify predictive, diagnostic, and indicative physical biomarkers of healing of the tissues and structures found in the residual limbs of adults with amputation. METHODOLOGY: A scoping review was conducted following Joanna Briggs Institute (JBI) and PRISMA-ScR guidance. Searches using “biomarkers”, “wound healing”, and “amputation” were performed on May 6, 2023, on Web of Science, Ovid MEDLINE, Ovid Embase, Scopus, Cochrane, PubMed, and CINAHL databases. Inclusion criteria were: 1) References to physical biomarkers and healing; 2) Residuum tissue healing; 3) Clear methodology with ethical approval; 4) Published from 2017 onwards. Articles were assessed for quality (QualSyst tool) and evidence level (JBI system), and categorized by study, wound, and model type. Physical biomarkers that were repeated not just within categories, but across more than one of the study categories were reported on. FINDINGS: The search strategy identified 3,306 sources, 157 of which met the inclusion criteria. Histology was the most frequently repeated physical biomarker used in 64 sources, offering crucial diagnostic insights into cellular healing processes. Additional repeated indicative and predictive physical biomarkers, including ankle-brachial index, oxygenation measures, perfusion, and blood pulse and pressure measurements, were reported in 25, 19, 13, and 12 sources, respectively, providing valuable data on tissue oxygenation and vascular health. CONCLUSION: Ultimately, adopting a multifaceted approach that integrates a diverse array of physical biomarkers (accounting for physiological factors and comorbidities known to influence healing) may substantially enhance our understanding of the healing process and inform the development of effective rehabilitation strategies for individuals undergoing amputation. Layman's Abstract Providing prosthetic limbs soon after amputation reduces healthcare costs and lowers mortality risk. However, current methods for evaluating the health of the remaining limb often rely on subjective judgment, highlighting the need for a standardized, evidence-based approach using physical biomarkers to assess healing and readiness for prosthetics. This review aimed to identify physical biomarkers that can predict, diagnose, or indicate healing in amputated limbs. On May 6, 2023, a comprehensive review was conducted across multiple databases, including Web of Science, Ovid MEDLINE, Ovid Embase, Scopus, Cochrane, PubMed, and CINAHL, to find studies using search terms like “biomarkers”, “wound healing”, and “amputation”. To be included, studies had to focus on biomarkers related to healing in residual limbs, use clear research methods, have ethical approval, and be published after 2017. The quality of the studies was evaluated, and biomarkers found across multiple studies were reported. Of 3,306 sources identified, 157 focused on physical biomarkers, with histology (tissue analysis) being the most commonly reported, allowing healing progress to be diagnosed at the cellular level. Other frequently mentioned biomarkers included the ankle-brachial index and oxygenation measures, which are used to assess tissue oxygen levels and blood flow, therefore predicting or indicating healing. Using a combination of different physical markers (while considering things like overall health and existing medical conditions) can give us a much better understanding of how healing works. This approach can also help create more effective rehabilitation plans for people who have had an amputation. Article PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/43716/33400 How To Cite: Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 2 - A scoping review of physical biomarkers. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.3. https://doi.org/10.33137/cpoj.v7i2.43716 Corresponding Author: Professor Arjan Buis, PhDDepartment of Biomedical Engineering, Faculty of Engineering, University of Strathclyde, Glasgow, Scotland.E-Mail: arjan.buis@strath.ac.ukORCID ID: https://orcid.org/0000-0003-3947-293X
... These 4 stages are generally categorized into homeostasis, inflammation, proliferation, and remodeling. When this natural progression of wound healing is disrupted and the wound remains in the inflammatory stage, the wound becomes chronic, and wound closure and tissue deposition are severely limited (Bowler, 2002;Caley et al, 2015;Dreifke et al, 2015;Eming et al, 2014;Han and Ceilley, 2017;Howard et al, 2013;Kimmel et al, 2016;Koh and DiPietro, 2011;Larouche et al, 2018;Opdenakker et al, 2018;Shih et al, 2010;Tan et al, 2011). Impaired wound healing and the development of chronic wounds are a major healthcare burden, which primarily afflicts patients with diabetes and the aging population (Blakytny and Jude, 2006;Eming et al, 2010;Gary Sibbald and Woo, 2008;Han and Ceilley, 2017;Krisp et al, 2013;Lö ffler et al, 2013;Opdenakker et al, 2018;Siddiqui and Bernstein, 2010). ...
With the goal of studying skin wound healing and testing new drug treatments to enhance wound healing in rodent models, there is a clear need for improved splinting techniques to increase surgical efficiency and support routine wound monitoring. Splinted wound healing models humanize wound healing in rodents to prevent contraction and instead heal through granulation tissue deposition, increasing the relevance to human wound healing. Current technologies require suturing and heavy wrapping, leading to splint failure and cumbersome monitoring of the wound. In this study, we developed a splint with resealable cap system that provides ease of access for wound inspection, therapeutic treatment delivery, and routine wound imaging without the need to unwrap and wrap the animal. Meanwhile, to overcome the challenges associated with suturing, we also developed adherent splints that can be applied to both hairless or haired mice with minimal wrapping. Both technologies are expected to improve and encourage the adoption of splinted wound healing models.
... Additionally, chronic mechanical stress or repeated trauma can worsen wound conditions and disrupt normal healing progression. (Kimmel et al., 2016). ...
Mesenchymal Stem Cells (MSCs) secretions, usually containing growth factors, cytokines, and chemokines, have improved wound healing via a paracrine mechanism. This makes them particularly valuable as potential cell therapeutics. Similarly, wound healing is mainly regulated via paracrine signaling of growth factors, cytokines, and chemokines. Chronic wound healing has prolonged inflammatory, proliferative, or remodeling phases, resulting in tissue fibrosis and non-healing ulcers. The growth factors, cytokines, and chemokines secreted by MSCs can be applied to wounds by transplanting cells or using the secretome/conditioned medium (CM) of MSCs, which contains these secreted bioactive molecules. For their success in increasing the wound healing rate, MSCs offer a promising option for treating chronic wounds. This review provides a concise summary of current knowledge of the biological properties of MSCs and describes the use of MSCs for wound healing. In particular, the scope of this review focuses on the role of MSCs in wound healing by increasing wound healing rate with the secretion of growth factors, cytokines, and chemokines. In addition, the function and type of MSCs also have been discussed.
... Hypoxia is one of the factors that govern reparative vs regenerative skin wound healing stimulating proliferation, migration and angiogenesis [12][13][14][15][16]. Oxygen stress initiated by injury stimulates and stabilizes the expression of the transcription factor hypoxia-inducible factor-1α (Hif-1α), which orchestrates the restoration of cellular homeostasis in the hypoxic environment. ...
Background
Foxn1−/− deficient mice are a rare model of regenerative skin wound healing among mammals. In wounded skin, the transcription factor Foxn1 interacting with hypoxia-regulated factors affects re-epithelialization, epithelial-mesenchymal transition (EMT) and dermal white adipose tissue (dWAT) reestablishment and is thus a factor regulating scar-forming/reparative healing. Here, we hypothesized that transcriptional crosstalk between Foxn1 and Hif-1α controls the switch from scarless (regenerative) to scar-present (reparative) skin wound healing. To verify this hypothesis, we examined (i) the effect of hypoxia/normoxia and Foxn1 signalling on the proteomic signature of Foxn1−/− (regenerative) dermal fibroblasts (DFs) and then (ii) explored the effect of Hif-1α or Foxn1/Hif-1α introduced by a lentiviral (LV) delivery vector to injured skin of regenerative Foxn1−/− mice with particular attention to the remodelling phase of healing.
Results
We showed that hypoxic conditions and Foxn1 stimulation modified the proteome of Foxn1−/− DFs. Hypoxic conditions upregulated DF protein profiles, particularly those related to extracellular matrix (ECM) composition: plasminogen activator inhibitor-1 (Pai-1), Sdc4, Plod2, Plod1, Lox, Loxl2, Itga2, Vldlr, Ftl1, Vegfa, Hmox1, Fth1, and F3. We found that Pai-1 was stimulated by hypoxic conditions in regenerative Foxn1−/− DFs but was released by DFs to the culture media exclusively upon hypoxia and Foxn1 stimulation. We also found higher levels of Pai-1 protein in DFs isolated from Foxn1+/+ mice (reparative/scar-forming) than in DFs isolated from Foxn1−/− (regenerative/scarless) mice and triggered by injury increase in Foxn1 and Pai-1 protein in the skin of mice with active Foxn1 (Foxn1+/+ mice). Then, we demonstrated that the introduction of Foxn1 and Hif-1α via lentiviral injection into the wounded skin of regenerative Foxn1−/− mice activates reparative/scar-forming healing by increasing the wounded skin area and decreasing hyaluronic acid deposition and the collagen type III to I ratio. We also identified a stimulatory effect of LV-Foxn1 + LV-Hif-1α injection in the wounded skin of Foxn1−/− mice on Pai-1 protein levels.
Conclusions
The present data highlight the effect of hypoxia and Foxn1 on the protein profile and functionality of regenerative Foxn1−/− DFs and demonstrate that the introduction of Foxn1 and Hif-1α into the wounded skin of regenerative Foxn1−/− mice activates reparative/scar-forming healing.
... In the wound bed, oxidative stress can augment inflammation, prolonging the inflammatory phase of wound healing. 3 Oxygen plays a vital role in collagen formation, 4,5 angiogenesis, [6][7][8] and control of infection. 9,10 1 5 Hypoxia, or reduced oxygen levels, in the wound bed arises due to disrupted blood flow and the high energy demand of regenerating tissues. ...
Wound healing represents a complex biological process crucial for tissue repair and regeneration. In recent years, biomaterial-based scaffolds loaded with bioactive compounds have emerged as promising therapeutic strategies to accelerate wound healing. In this study, we investigated the properties and wound healing effects of cryogels loaded with calcium peroxide (CP) and berberine (BB). The cryogels were synthesized through a cryogenic freezing technique and displayed pore diameters of 83 ± 39 μm, with porosity exceeding 90%. Following 20 days of degradation, the percentage of remaining weight for GPC and GPC-CP-BB cryogels was determined to be 12.42 ± 2.45% and 10.78 ± 2.08%, respectively. Moreover, the swelling ratios after 3 minutes for GPC and GPC-CP-BB were found to be 22.10 ± 0.05 and 21.00 ± 0.07, respectively. In vitro investigations demonstrated the cytocompatibility of the cryogels, with sufficient adhesion and proliferation of fibroblast (NIH-3T3) cells observed on the scaffolds, along with their hemocompatibility. Furthermore, the cryogels exhibited sustained release kinetics of both calcium peroxide and berberine, ensuring prolonged therapeutic effects at the wound site. In vivo assessment using a rat model of full-thickness skin wounds demonstrated accelerated wound closure rates in animals treated with the GPC-CP-BB scaffold compared to controls. Histological analysis revealed enhanced granulation tissue formation, re-epithelialization, and collagen deposition in the GPC-CP-BB group. Overall, our findings suggest that the scaffold loaded with CP and BB holds great promise as a therapeutic approach for promoting wound healing. Its multifaceted properties offer a multifunctional platform for localized delivery of therapeutic agents while providing mechanical support and maintaining a favorable microenvironment for tissue regeneration.
... The benefits of negative -pressure wound care are indisputable; they include accelerating angiogenesis at the damage site, effectively encouraging tissue proliferation, and reducing the healing time [12]. Nevertheless, recent research has indicated that to create pro -angiogenic hydroxylated collagen, which speeds up the healing process, hydroxylase and collagen must be mixed in an environment with enough oxygen throughout the wound -repairing process [13,14]. In our investigation, the intervention group's post -treatment push scores for wound area, type of tissues, and exudate volume within 24 hours were all lower than those of the control group. ...
... Anemia yang dialami klien menyebabkan kadar oksigen yang diedarkan dalam tubuh menjadi berkurang, sementara oksigen sangat penting untuk penyembuhan luka. Ia terlibat secara rumit dalam berbagai proses biologis termasuk proliferasi sel, angiogenesis, dan sintesis protein, yang diperlukan untuk pemulihan fungsi dan integritas jaringan (Kimmel et al., 2016). ...
Latar belakang: Buerger disease adalah penyakit inflamasi progresif, nonaterosklerotik, yang sering menyerang arteri kecil dan menengah pada ekstremitas atas dan bawah. Anemia adalah kondisi kurangnya Hb yang berfungsi mengedarkan oksigen ke seluruh tubuh. Pengobatan penyakit Buerger tujuan utamanya adalah untuk meningkatkan sirkulasi pada ekstremitas, namun pada kasus yang parah, amputasi menjadi pilihan bagi pasien. Pada dewasa, tindakan operasi sering kali memunculkan berbagai masalah, sehingga diperlukan asuhan keperawatan untuk mengatasi masalah-masalah tersebut Kasus: seorang wanita berusia 65 tahun dirawat dengan keluhan nyeri dan kehitaman pada kaki kanan dan diagnosa medis gangren pedis ec. Buerger disease dan anemia, klien direncanakan untuk menjalani tindakan amputasi. Masalah keperawatan pada klien seperti kecemasan, kurang pengetahuan, nyeri, gangguan integritas kulit. Metode: Metode penelitian yang dilakukan merupakan case study dimana studi kasus dilakukan dengan melakukan asuhan keperawatan secara komprehensif dari mulai pengkajian hingga evaluasi Rencana perawatan: rencana asuhan keperawatan menggunakan standar SDKI, SIKI dan SLKI dengan intervensi utama berupa reduksi ansietas, manajemen nyeri, edukasi kesehatan dan perawatan luka. Kesimpulan: proses pemberian asuhan keperawatan pada kasus ini berfokus pada fase pre operasi dan post operasi, dengan intervensi pre operasi berfokus pada reduksi ansietas, dan edukasi. Sementara intervensi post operasi berfokus pada perawatan luka, pencegahan infeksi dan manajemen nyeri.
... Despite their promising properties, these approaches have shown issues such as local toxicity by hyperoxia and poor stability by failing to provide oxygen in a constant and controlled manner (Ashammakhi et al., 2020;Han et al., 2023). Hyperbaric oxygen therapy has also been investigated as a mean to provide oxygen to wounds; however, clinical results remain controversial, therefore, further studies are needed to obtain conclusive data (Al-Jalodi et al., 2022;Kimmel et al., 2016;Moreira et al., 2022). ...
Oxygen is essential for tissue regeneration, playing a crucial role in several processes, including cell metabolism and immune response. Therefore, the delivery of oxygen to wounds is an active field of research, and recent studies have highlighted the potential use of photosynthetic biomaterials as alternative oxygenation approach. However, while plants have traditionally been used to enhance tissue regeneration, their potential to produce and deliver local oxygen to wounds has not yet been explored. Hence, in this work we studied the oxygen‐releasing capacity of Marchantia polymorpha explants, showing their capacity to release oxygen under different illumination settings and temperatures. Moreover, co‐culture experiments revealed that the presence of these explants had no adverse effects on the viability and morphology of fibroblasts in vitro, nor on the viability of zebrafish larvae in vivo. Furthermore, oxygraphy assays demonstrate that these explants could fulfill the oxygen metabolic requirements of zebrafish larvae and freshly isolated skin biopsies ex vivo. Finally, the biocompatibility of explants was confirmed through a human skin irritation test conducted in healthy volunteers following the ISO‐10993‐10‐2010. This proof‐of‐concept study provides valuable scientific insights, proposing the potential use of freshly isolated plants as biocompatible low‐cost oxygen delivery systems for wound healing and tissue regeneration.
... Hyperbaric oxygen (HBO) treatment can dramatically reduce the oxygen concentration in hypoperfused tissues, and elevated oxygen concentration in hypoxic tissues facilitates ischemic recovery [2,3]. Enhanced neovascularization in ischemic tissue is one of the ways HBO therapy promotes wound healing [4]. ...
This study aimed to investigate the protective effects and mechanisms of hyperbaric oxygen (HBO) preconditioning in a rat model of acute myocardial infarction (MI) established by ligation of the left anterior descending (LAD) coronary artery. Microarray, real-time PCR, and western blotting (WB) results demonstrated that the Mst1 gene was downregulated in the heart tissue of the MI rat model. HBO preconditioning significantly increased Mst1 expression in cardiac tissues of rats after MI modeling. Lentiviral infection was used to silence the Mst1 gene in rats treated with HBO to probe the effect of Mst1 on HBO cardioprotection. HBO preconditioning decreased heart infarct size and ameliorated cardiac function in MI rats, whereas Mst1 silencing reversed the effect of HBO administration, as indicated after heat infarct size determination via TTC staining, histological examination via HE staining, and measurements of cardiac function. HBO preconditioning reduced oxidative stress and inflammation in cardiac tissue of MI rat model, evidenced by alteration of malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), and protein carbonyl contents, as well as production of inflammation-associated myeloperoxidase (MPO), IL-1β, and TNF-α. These findings provide a new signaling mechanism through which HBO preconditioning can protect against acute MI injury through the Mst1-mediating Keap1/Nrf2/HO-1-dependent antioxidant defense system.
... 41 To some extent, these numbers can be improved via wound healing adjuncts, such as supplemental oxygen-a © 2023 MA Healthcare Ltd education critical element and regulator of all three stages of the wound healing process. 42 Since the development of the hyperbaric chamber by Henshaw in 1662, 43 and the first breakthrough of HBOT for the treatment of burns by Wada et al. 44 in 1965, several others have attempted to improve burn wound oxygenation via external mechanisms. Our results show that HBOT has been reported to promote the integration of fibrovascular ingrowth in porous polyethylene, inhibit the progression of necrosis and preserve active hair follicles in animal models. ...
Objective:
This review aims to evaluate the effectiveness of the two most commonly used oxygen delivery methods for the treatment of thermal burn wound healing: hyperbaric oxygen therapy (HBOT) and topical oxygen therapy (TOT).
Method:
The PubMed database was searched for articles discussing the use of HBOT or TOT in the treatment of thermal burns.
Results:
The search yielded 43,406 articles, of which 28 (23 HBOT, 5 TOT) met the inclusion criteria. Both experimental and clinical studies have demonstrated conflicting results after treating thermal burns with HBOT or TOT. Overall, 14/23 studies demonstrated positive results for HBOT on the healing of burn wounds and associated complications, such as oedema and pain. Findings from these studies showed it can reduce morbidity and mortality in certain high-risk groups such as those with diabetes or extensive burns. Although the five studies (one human and four animal trials) reviewing TOT showed promising outcomes, this therapeutic modality has not been well investigated.
Conclusion:
Therapeutic use of HBOT in thermal burns has been popular in the past but its use remains controversial due to inconsistent results, serious side-effects, lack of convenience and high costs. The use of TOT in the management of burns needs further exploration by scientists and clinicians alike, in addition to the implementation of a standardised treatment protocol.
... Oxygen is required for wound healing. 74,75 In hard-toheal wounds, there is often an imbalance between how much oxygen the tissue needs to heal and how much oxygen is available to the wound, resulting in tissue hypoxia. Importantly, the pH value in the wound influences the release of oxygen in the wound. ...
Objective
The aim of this study was to measure wound pH, wound temperature and wound size together to gain further understanding of their impact as predictors of wound healing outcomes.
Method
This study employed a quantitative non-comparative, prospective, descriptive observational design. Participants with both acute and hard-to-heal (chronic) wounds were observed weekly for four weeks. Wound pH was measured using pH indicator strips, wound temperature was measured using an infrared camera and wound size was measured using the ruler method.
Results
Most of the 97 participants (65%, n=63) were male; participant's ages ranged between 18 and 77 years (mean: 42±17.10. Most of the wounds observed were surgical 60%, (n=58) and 72% (n=70) of the wounds were classified as acute, with 28% (n=27) classified as hard-to-heal wounds. At baseline, there was no significant difference in pH between acute and hard-to-heal wounds; overall the mean pH was 8.34±0.32, mean temperature was 32.86±1.78°C) and mean wound area was 910.50±1132.30mm². In week 4, mean pH was 7.71±1.11, mean temperature was 31.90±1.76°C and mean wound area was 339.90±511.70mm². Over the study follow-up period, wound pH ranged from 5–9, from week 1 to week 4, mean pH reduced by 0.63 units from 8.34 to 7.71. Furthermore, there was a mean 3% reduction in wound temperature and a mean 62% reduction in wound size.
Conclusion
The study demonstrated that a reduction in pH and temperature was associated with increased wound healing as evidenced by a corresponding reduction in wound size. Thus, measuring pH and temperature in clinical practice may provide clinically meaningful data pertaining to wound status.
... Skin recovery may be disturbed by a number of pathological factors, which are generally classified as local and systemic [67,68]. The first group includes: oxygen level [69], infection [70,71], or foreign body. The next includes factors such as age [72], gender [73], sex hormones [74], stress [75,76], ischemia [49], diseases (diabetes, keloids, fibrosis, hereditary healing disorders, jaundice, uremia) [77], obesity [78], pharmacotherapy (steroids, nonsteroidal anti-inflammatory drugs, chemotherapeutic agents) [79,80], alcohol abuse [81], smoking [82], and conditions with reduced immunity (cancer, radiation therapy, AIDS), and nutrition habits [83,84]. ...
Alginate is a naturally derived polysaccharide widely applied in drug delivery, as well as regenerative medicine, tissue engineering and wound care. Due to its excellent biocompatibility, low toxicity, and the ability to absorb a high amount of exudate, it is widely used in modern wound dressings. Numerous studies indicate that alginate applied in wound care can be enhanced with the incorporation of nanoparticles, revealing additional properties beneficial in the healing process. Among the most extensively explored materials, composite dressings with alginate loaded with antimicrobial inorganic nanoparticles can be mentioned. However, other types of nanoparticles with antibiotics, growth factors, and other active ingredients are also investigated. This review article focuses on the most recent findings regarding novel alginate-based materials loaded with nanoparticles and their applicability as wound dressings, with special attention paid to the materials of potential use in the treatment of chronic wounds.
... And increased ROS production during wound healing changed vascular permeability, accompanying with loss of vascular modulation to inhibit angiogenesis. Tissue hypoxia also limits the signal of redox, which thus disables function of several GFs while affecting antimicrobial action [47]. Some components in P.ginseng and P.notoginseng regulate oxygen levels to increase the nuclear translocalization of HIF-1a, such as 20(S)protopanaxadiol (PPD) [48]. ...
In recent years, an increasing number of reports have explored the wound healing mechanism of these two traditional Chinese herbal medicines- Panax ginseng and Panax notoginseng, but there is no systematic research on the related core functions and different mechanisms in the treatment of wound healing up to now. Based on network pharmacology and meta-analysis, the present work aimed to comprehensively review the commonality and diversity of P. ginseng and P. notoginseng in wound healing. In this study, a wound healing-related ''ingredients-targets'' network of two herbs was constructed. Thereafter, meta-analysis of the multiple target lists by Metascape showed that these two medicines significantly regulated blood vessel development, responses to cytokines and growth factors and oxygen levels, cell death, cell proliferation and differentiation, and cell adhesion. To better understand the discrepancy between these two herbs, it was found that common signaling pathways including Rap1, PI3K/AKT, MAPK, HIF-1 and Focal adhesion regulated the functions listed above. In parallel, the different pathways including renin-angiotensin system, RNA transport and circadian rhythm, autophagy, and the different metabolic pathways may also explained the discrepancies in the regulation of the above-mentioned functions, consistent with the Traditional Chinese Medicine theory about the effects of P. ginseng and P. notoginseng.
... ROS has a very important role in physiological processes and controls different intracellular signaling pathways. It has been proven that appropriate levels of ROS control various stages of wound healing, including blood coagulation, cell infiltration and proliferation, angiogenesis, and re-epithelialization. Besides, ROS increases the expression of cytokines such as EGF, KGF, and TGF-alpha and thus accelerate wound closure (36)(37)(38)(39). ...
Background and Objectives: Peptic ulcer disease is a multifactorial disease that affects up to 10% of people. The use of natural product remedies has received much attention for its treatment. In this research, the healing effect of metabiotic extracted from Bifidobacterium bifidum was investigated.
Materials and Methods: 45 male wistar rats were divided into 3 groups (Ctrl-, drug, and metabiotic), and stomach ulcers were induced by ethanol administration and treated by drug and metabiotic. The healing process was investigated on different days by histological analysis and qRT-PCR.
Results: The metabiotic increased IL-8 and PDGF expression and stimulated the recruitment of polymorphonuclear cells to the wound site. It caused a faster onset of the inflammation phase followed by the proliferation phase. The metabiotic increased the expression of SOD and GPx genes and the antioxidant capacity of the wound. The increase in EGF expression led to faster re-epithelization, which was evident in the wound closure process.
Conclusion: Metabiotic extracted from B. bifidum is a promising candidate for the treatment of PUD. It causes a faster onset of the inflammation phase. Improving the antioxidant status of the wound, causes a faster resolution of inflammation, which leads to the acceleration of the wound-healing process.
... A more recently developed strategy for wound treatment is based on the energy demand of this process. Energy supply is an essentially prerequisite for physiological wound healing [10,11]. ATP is required for the induction of angiogenesis, proliferation and differentiation of keratinocytes, cell migration, and the re-epithelialization process. ...
Amorphous calcium carbonate (ACC), precipitated in the presence of inorganic polyphosphate (polyP), has shown promise as a material for bone regeneration due to its morphogenetic and metabolic energy (ATP)-delivering properties. The latter activity of the polyP-stabilized ACC (“ACC∙PP”) particles is associated with the enzymatic degradation of polyP, resulting in the transformation of ACC into crystalline polymorphs. In a novel approach, stimulated by these results, it was examined whether “ACC∙PP” also promotes the healing of skin injuries, especially chronic wounds. In in vitro experiments, “ACC∙PP” significantly stimulated the migration of endothelial cells, both in tube formation and scratch assays (by 2- to 3-fold). Support came from ex vivo experiments showing increased cell outgrowth in human skin explants. The transformation of ACC into insoluble calcite was suppressed by protein/serum being present in wound fluid. The results were confirmed in vivo in studies on normal (C57BL/6) and diabetic (db/db) mice. Topical administration of “ACC∙PP” significantly accelerated the rate of re-epithelialization, particularly in delayed healing wounds in diabetic mice (day 7: 1.5-fold; and day 13: 1.9-fold), in parallel with increased formation/maturation of granulation tissue. The results suggest that administration of “ACC∙PP” opens a new strategy to improve ATP-dependent wound healing, particularly in chronic wounds.
... Due to the complexity, treating wounds requiresse a systemic strategy that should include counteracting and/ or preventingwith fighting and avoiding the several processes involved in the wound's progress. In this regard, the use of oxygen, for instance, has demonstrated good results against chronic and non-chronic wounds (Kimmel et al. 2016). Also, extracorporeal shock wave therapy (ESWT) has shown good results (Omar et al. 2017). ...
PurposeThe costs and complexity related to effective wound healing treatment are immense. The number of multifactorial aspects related to the treatment of wounds (inflammation, infection, and many others) implies a complex multi-therapeutic approach involving various procedures, including medication and surgery. Regarding medication, there are only a few options, especially to treat chronic wounds. Recently graphene quantum dots have been applied for their potent antimicrobial properties as well as their significant tissue remodeling properties. In this study, we developed a formulation based on graphene quantum dots in the form of as a dry powder for wound healing.Methods
Graphene quantum dots were produced by top-down technique using graphite as matrix, and fully characterized by Raman spectroscopy, atomic force microscopy, and X-ray diffractometry. The dry powder formulation was produced under aseptic conditions and evaluated in vitro and in vivo.ResultsThe results showed that the formulation improved the healing process in both: in vitro and in vivo, with good adherence, healing time and tissue reconstruction. Finally, the results demonstrated that dry powder was very effective against P. aeruginosa, S. epidermidis, C. albicans and C. tropicalis, representing an improvement
for wound healing purposes.Conclusion
The data corroborated the use of the dry powder formulation using graphene quantum dots as matrix as wound dressing, expanding the use of graphene quantum in the biomedical field.
... Moreover, an increased number of new blood vessels were detected in the ozone-treated group, which may be attributed to the direct induction of VEGF expression by H 2 O 2 and/or indirect induction of VEGF expression by HO-1. 92 Additional, ozone therapy promotes wound healing via facilitating fibroblast migration. It has demonstrated ozone oil promotes fibroblast migration and EMT process via PI3K/Akt/mTOR signalling pathway. ...
Ozone is a highly reactive oxidant molecule consisting of triatomic oxygen atoms. Ozone therapy can be achieved using ozonated hydrotherapy, ozonated oil, ozone autohemotherapy, and other innovative dosage forms of ozone products. Ozone is frequently used as a complementary therapy for various cutaneous diseases, including infectious skin diseases, wound healing, eczema, dermatitis, psoriasis, axillary osmidrosis, diabetic foot, and pressure ulcers. In addition, several studies have reported the superior potential of ozone therapy for improving skin and gut microbiomes, as well as antitumour and antiaging treatment. Ozone therapy is an emerging treatment strategy that acts via complex mechanisms, including antioxidant effects, immunomodulatory capacity, and modulation of local microcirculation. Studies assessing the mechanism of ozone have gradually expanded in recent years. This review article aims to summarise and explore the possible molecular biological mechanisms of ozone in cutaneous diseases and provide compelling theoretical evidence for the application of ozone in cutaneous diseases.
... In detail, during the inflammatory phase, oxygen is essential for the various processes that require ATP through oxidative phosphorylation in the mitochondria. After hemostasis, hypoxia activates the early stages of wound healing through HIF-mediated regulation [59]. Furthermore hypoxia causes increased ROS activity which eventually lead to the activation of platelets and monocytes to release cytokines and growth factors transforming growth factor beta one (TGF-β), VEGF-A, and tumor necrosis factor-α (TNF-α) [36]. ...
Hypoxia, a low O 2 tension, is a fundamental feature that occurs in physiological events as well as pathophysiological conditions, especially mentioned for its role in the mechanism of angiogenesis, glucose metabolism, and cell proliferation/survival. The hypoxic state through the activation of specific mechanisms is an aggravating circumstance commonly noticed in multiple sclerosis, cancer, heart disease, kidney disease, liver disease, lung disease, and in inflammatory bowel disease. On the other hand, hypoxia could play a key role in tissue regeneration and repair of damaged tissues, especially by acting on specific tissue stem cells, but their features may result as a disadvantage when it is concerned for neoplastic stem cells. Furthermore, hypoxia could also have a potential role in tissue engineering and regenerative medicine due to its capacity to improve the performance of biomaterials. The current review aims to highlight the hypoxic molecular mechanisms reported in different pathological conditions to provide an overview of hypoxia as a therapeutic agent in regenerative and molecular therapy.
Graphical abstract
... 22 Hypoxia during skin wound healing stimulates proliferation, migration, and angiogenesis. 26,27 However, it has also been shown that a hypoxic environment in the skin is associated with oxidative stress. 1 Many reports have indicated that an oxygen-reducing environment affects the stabilization of Hif-1α, especially by acting on thioredoxin 1 (Txn1) activity. 23,28,29 Thioredoxins (Txns) are the major cellular proteins that play crucial roles in the regulation of numerous biochemical processes, especially in maintaining cellular redox homeostasis and cell survival. ...
Skin exposed to environmental threats, including injuries and oxidative stress, develops an efficient but not fully recognized system of repair and antioxidant protection. Here, using mass spectrometry analysis (LC–MS/MS), followed by in vitro and in vivo experiments, we provided evidence that Foxn1 in keratinocytes regulates elements of the electron transport chain and participates in the thioredoxin system (Txn2, Txnrd3, and Srxn1) induction, particularly in a hypoxic environment. We first showed that Foxn1 in keratinocytes upregulates glutathione thioredoxin reductase 3 (Txnrd3) protein expression, and high levels of Txnrd3 mRNA were detected in injured skin of Foxn1+/+ mice. We also showed that Foxn1 strongly downregulated the Ccn2 protein expression, participating in epidermal reconstruction after injury. An in vitro assay revealed that Foxn1 controls keratinocyte migration, stimulating it under normoxia and suppressing it under hypoxia. Keratinocytes overexpressing Foxn1 and exposed to hypoxia displayed a reduced ability to promote angiogenesis by downregulating Vegfa expression. In conclusion, this study showed a new mechanism in which Foxn1, along with hypoxia, participates in the activation of antioxidant defense and controls the functional properties of keratinocytes.
... Apart from this, melatonin can also accelerate skin wound healing [74][75][76][77] and can improve the antimicrobial action of wound dressing [75]. Despite melatonin's anti-oxidative actions and the information described above, its physiological key role of a tightly controlled burst of reactive oxygen species production in tissue repair and regeneration [78,79], one of the functions of the melatoninergic system [28,80], may also be to control reactive oxygen species availability during wound healing. Thus, brand new studies [81][82][83][84][85] confirmed that melatonin may exert a beneficial role on epidermal barrier formation, indicating altogether that this indoleamine in combination with glyoxal could be considered as a safe solution, improving wound healing potential. ...
Chitosan (CTS) and collagen (Coll) are natural biomaterials that have been extensively used in tissue engineering or wound healing applications, either separately or as composite materials. Most methods to fabricate CTS/Coll matrices employ chemical crosslinking to obtain solid and stable scaffolds with the necessary porosity and mechanical properties to facilitate regeneration. In this study, we comparatively assessed the physicochemical properties of 3D scaffolds loaded with a cross-linker, glyoxal. Using a scanning electron microscope, we evaluated the microstructure of resultant matrices and their mechanistic testing by the determination of the compressive modulus (Emod), the maximum force (Fmax), thermogravimetric analysis (TG), Fourier Transform Infrared Spectroscopy–Attenuated Total Reflectance (FTIR-ATR), and proliferation rate in vitro using human epidermal keratinocytes and dermal fibroblasts cultured in presence of melatonin solution (10⁻⁵ M). We observed that enhanced content of collagen (50CTS/50Coll or 20CTS/80Coll compared to 80CTS/20Coll) significantly elevated the physicochemical capacities of resultant materials. Besides, presence of 5% glyoxal increased porosity, Emod and Fmax, compared to scaffolds without glyoxal. Finally, keratinocytes and dermal fibroblasts cultured on subjected matrices in presence of melatonin revealed a prominently enhanced growth rate. This indicates that the combination of glyoxal and melatonin make it imperative to consider these materials as a promising approach for targeting skin tissue engineering or regenerative dermatology.
... Hydrogels are commonly proposed as a favorable tool for wound repair since they may be able to provide further benefits, including a moist environment, low adhesion, and thermal insulation, to increase the probability of wound healing compared with other dressing forms, such as gauze, bandages, and/or films [6]. However, coverage provided by dressings may form another barrier to oxygen delivery over the exudates on the wound bed, as oxygen plays a crucial role in many biochemical and cellular processes related to wound healing, such as infection control [7,8], construction of the extracellular matrix [9,10], and collagen formation/remodeling [11,12]. Although hyperbaric oxygen therapy (HBOT) and topical pressurized oxygen therapy (TPOT) have been widely utilized to reduce hypoxia for DFU treatment, HBOT is costly, difficult to operate and maintain, toxic to the central nervous system, and may cause barotrauma and/or cell cycle arrest due to overexposure to a highpressure, high-oxygen environment [13,14], while TPOT is hampered by its complicated and labor-consuming procedures [15]. ...
Diabetic foot ulcers remain one of the most difficult-to-treat complications of diabetes and may seriously threaten the life of patients since it frequently results in limb loss due to amputation, suggesting that an effective therapeutic strategy is still urgently needed. In this study, a chitosan-based heterogeneous composite hydrogel encapsulating perfluorocarbon emulsions, epidermal growth factor (EGF)-loaded chitosan nanoparticles, and polyhexamethylene biguanide (PHMB) named PEENPPCH was developed for diabetic wound healing. The PEENPPCH could sustainably release EGF and PHMB in an ion-rich environment to exert antibacterial effects and promote cell growth for wound repair. In addition, the PEENPPCH can provide anti-inflammatory effects functioned by its main constituent of chitosan. Moreover, the PEENPPCH can proactively offer oxygen delivery through the incorporation of perfluorocarbon and, therefore, is able to alleviate hypoxia conditions on diabetic wounds. These functionalities enabled a markedly enhanced wound healing efficacy on diabetic rats treated with the PEENPPCHs, including thorough re-epithelization, a reduced inflammatory response, faster collagen deposition, and advanced collagen maturation resulting in a 95% of wound closure degree after 15 days that was 12.6% (p < 0.05) higher than the value of the group treated with the commercial dressing HeraDerm. Given the aforementioned advantages, together with the known merits of hydrogels, the developed PEENPPCH is anticipated to be a feasible tool for clinical diabetic wound treatment.
... The granulation tissue is a stroma composed of connective tissue containing ECM proteins, as well as the cells necessary to allow the sprouting of blood vessels and subsequent wound closure. The reduction in blood supply and the exacerbated metabolism of the cells actively working in the healing process cause hypoxia, a major angiogenesis stimulus (Semenza, 2007;Castilla et al., 2012;Kimmel et al., 2016). This hypoxic environment induces an increase in the levels of the hypoxia inducible factor 1 (Hif-1) in macrophages, endothelial cells, fibroblasts, and keratinocytes (Andrikopoulou et al., 2011). ...
Acute skin wound healing is a multistage process consisting of a plethora of tightly regulated signaling events in specialized cells. The Thy-1 (CD90) glycoprotein interacts with integrins and the heparan sulfate proteoglycan syndecan 4, generating a trimolecular complex that triggers bi-directional signaling to regulate diverse aspects of the wound healing process. These proteins can act either as ligands or receptors, and they are critical for the successful progression of wound healing. The expression of Thy-1, integrins, and syndecan 4 is controlled during the healing process, and the lack of expression of any of these proteins results in delayed wound healing. Here, we review and discuss the roles and regulatory events along the stages of wound healing that support the relevance of Thy-1, integrins, and syndecan 4 as crucial regulators of skin wound healing.
... Oxygen is essential for adenosine triphosphate (ATP) synthesis, which provide biological energy for proper cellular function. 5 On the other hand, reactive oxygen species (ROS) play a vital role to prevent the wound from infection because of the oxidative killing of bacteria. 6 Oxygen is critical to the production of ROS by neutrophils and macrophages. ...
Adequate oxygen is identified as one of major factors in the processes of wound healing. Various strategies of oxygen therapy have been developed to improve wound healing, such as oxygen carriers. Herein polydopamine coated hemoglobin (Hb-PDA) nanoparticles as one of Hemoglobin-based Oxygen Carriers (HBOCs) for oxygen supply is proposed and synthesized, Hb-PDA nanoparticles accelerate the wound repair process in an excisional full-thickness mouse model. And inflammatory phased of wounds can be shortened by antioxidant properties of polydopamine (PDA) modification. Moreover, Hb-PDA nanoparticles efficiently promote the formation of blood vessel by upregulating expression of vascular endothelial growth factor (VEGF) and angiogenesis related protein. Interestingly, Hb-PDA nanoparticles improve the oxygen supply of wounds in the wound area, as well as down-regulated expression of Hypoxia-inducible factor-1α (HIF-1α). The results indicate the Hb-PDA nanoparticles might be a promising approach for efficient wound healing with the capacity to improve oxygen supply.
... In collagen synthesis, oxygen is implied within the hydroxylation of proline and lysine into procollagen which results in collagen development. Angiogenesis requires hypoxia to begin, but it has been demonstrated that if oxygen is used, vessel growth can be accelerated and sustained (Kimmel et al. 2016). ...
Background
A wound may define as an interruption within the continuity of the epithelial lining of the skin or mucosa that occurs as a result of physical or thermal damage. Wound healing is an intricate process that is highly synchronized censorious in the management of the protective means of the skin. There are a variety of systemic and local factors that influence wound healing, including oxygenation, inflammation, age, stress, diabetes, nutrition, and nicotine. Hemostasis, inflammation, proliferation or granulation, remodeling or maturation are the principle phases of wound healing.
Main body of the abstract
The authors of the current review attempt to convey that the usage of herbal drugs has extreme importance in the current era. The authors reviewed a total of 38 herbal plants with their mechanism of wound healing and the chemical constituents responsible for it. Hyperbaric oxygen therapy, negative pressure therapy, platelet-rich plasma therapy, stem cell therapy, and biosurgery are some of the most often used supporting procedures for wound healing with these herbal drugs.
Short conclusion
There are a variety of herbal plants that have wound healing properties. This evaluation covers a wide range of plants. However, a review of the literature on diverse plants reveals that diverse chemical contents are found in different plant species, but did not mention of which chemical compounds are important for wound healing.
... [5][6][7] In addition, oxygen therapy has gradually been applied to the treatment of epidermal ulcer infection in recent years. [8][9][10] Studies have found that oxygen therapy can reduce wound bleeding and promote wound healing. 11 However, there are few studies on the application of nano-silver antibacterial dressing combined with high-flow oxygen therapy in the treatment of ulcer wounds of superficial malignant tumors. ...
Background
Due to the poor healing of superficial malignant tumor ulcer wounds, patients suffer great pain and significantly reduced quality of life. Related research shows that oxygen therapy can reduce wound bleeding and promote wound healing.
Objective
This study aims to explore the therapeutic effect of nano-silver antibacterial dressing combined with high-flow oxygen therapy on surface malignant tumor ulcers.
Methods
In this retrospective analysis, 64 patients with superficial malignant tumors and ulcer infection were included and divided into the research group and the control group, with 32 cases in each group. After conventional debridement, the control group was treated with vaseline dressing, while the research group was treated with nano-silver medical antibacterial dressing combined with high-flow oxygen therapy. Both groups were treated for 7 days. The frequency of dressing change and the number of times of blood oozing between the two groups after treatment were recorded. The pain, clinical efficacy, and levels of procalcitonin (PCT) and C-reactive protein (CRP) were compared between the two groups before and after treatment.
Results
The dressing changes and blood oozing were less frequent in the research group compared with the control group. The pain score and the levels of PCT and CRP in the research group were lower than those in the control group. The overall response rate was significantly higher in the research group as compared to the control group. All the above differences were statistically significant (P<0.05).
Conclusion
Nano-silver medical antibacterial dressing combined with high-flow oxygen therapy can reduce the frequency of dressing changes in patients, relieve pain, reduce inflammation, and accelerate the healing of superficial malignant tumor ulcer wounds.
... Under hypoxia, VEGF is primarily regulated by HIF-1α [19]. VEGF is secreted at higher concentrations of O 2 [20]. We observed a decrease in hypoxia and upregulation of VEGF. ...
Introduction:
Delayed wound healing after surgery lowers the long-term quality of a patient's life and leads to discomfort and pain. However, treatments for wound healing are often difficult and have not yet been fully established. In this study, we investigated the effect of a special paste that can be administered transdermally and holds a non-gaseous carbon dioxide (CO2) source in its carrier, which can be applied to the head and neck region for wound healing in a rat skin defect model.
Methods:
Forty-eight Sprague Dawley rats were randomized into control and CO2 groups. We punched a 6.2-mm wound on the back of each rat. The control rats were left untreated, whereas rats in the CO2 group were treated with the CO2 paste every day after surgery. We evaluated wound healing 3, 7, 14, and 21 days after wounding by analyzing the diameter of the wound, gene expression of inflammatory markers vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β, hypoxia-inducible factor (HIF)-1α, interleukin (IL)-1β, and IL-6 using quantitative real-time polymerase chain reaction, hematoxylin and eosin, and immunohistochemical staining patterns.
Results:
Rats in the CO2 group showed accelerated wound healing compared to those in the control group. Furthermore, VEGF and TGF-β were overexpressed, whereas HIF-1α, IL-1β, and IL-6 were downregulated in the rats treated with CO2. Immunohistochemical analysis also revealed similar patterns of expression.
Conclusion:
Taken together, the CO2 paste promoted wound healing by regulating the hypoxic environment, reducing inflammation, and accelerating angiogenesis.
... The balance between roS formation and antioxidant enzyme activities can maintain redox homeostasis. However, this balance can easily be disrupted, resulting in oxidative stress and damage to cells, thereby prolonging the healing process (42). A previous study demonstrated that hemoglobin performs an antioxidant peroxidase function and can reduce the oxidative stress induced by hydrogen peroxide (43). ...
Label‑free quantitative mass spectrometry was used to analyze the differences in the granulation tissue protein expression profiles of patients with diabetic foot ulcers (DFUs) before and after negative‑pressure wound therapy (NPWT) to understand how NPWT promotes the healing of diabetic foot wounds. A total of three patients with DFUs hospitalized for Wagner grade 3 were enrolled. The patients received NPWT for one week. The granulation tissue samples of the patients prior to and following NPWT for one week were collected. The protein expression profiles were analyzed with label‑free quantitative mass spectrometry and the differentially expressed proteins (DEPs) in the DFU patients prior to and following NPWT for one week were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to annotate the DEPs and DEP‑associated signaling pathways. Western blotting and ELISA were performed to validate the results. By comparing the differences in the protein profiles of granulation tissue samples prior to and following NPWT for one week, 36 proteins with significant differences were identified (P<0.05); 33 of these proteins were upregulated and three proteins were downregulated. NPWT altered proteins mainly associated with antioxidation and detoxification, the cytoskeleton, regulation of the inflammatory response, complement and coagulation cascades and lipid metabolism. The functional validation of the DEPs demonstrated that the levels of cathepsin S in peripheral blood and granulation tissue were significantly lower than those prior to NPWT (P<0.05), while the levels of protein S isoform 1, inter α‑trypsin inhibitor heavy chain H4 and peroxiredoxin‑2 in peripheral blood and granulation tissue were significantly higher than those prior to NPWT (P<0.05). The present study identified multiple novel proteins altered by NPWT and laid a foundation for further studies investigating the mechanism of action of NPWT.
... It is also reported that an appropriate amount of oxygen partial pressure is essential for wound healing, which can be facilitated with TcPO 2 maintained at 50~100 mmHg [16,17]. Kimmel et al. studied the effects of different oxygen flow rates on wound healing, and found that the healing time could be greatly shortened when oxygen was given continuously at a rate of 2 to 3 L/min, with the TcPO 2 maintained at 45-80 mmHg [18]. Therefore, oxygen was given continuously at a rate of 3 L/min in our study. ...
Objective:
To evaluate the effects of topical oxygen therapy and its impacts on granulation tissue in patients with chronic traumatic wounds.
Method:
A total of 112 patients with chronic traumatic wounds were randomly divided into the control group (n=56, receiving negative-pressure wound therapy) and the intervention group (n=56, receiving negative-pressure wound therapy plus topical oxygen therapy) using a random number table and they were treated continuously for 2 weeks. Then, the scores from the Pressure Ulcer Scale for Healing (PUSH), the coverage rate of granulation tissue, the severity of pain and Transcutaneous Oxygen Partial Pressure (TcPO2) before and after treatment were compared between the two groups. Also, the bacterial culture-positive rate, the healing rate and the healing time were compared between the two groups.
Results:
The PUSH scores were significantly decreased after treatment compated to those before treatment in the two groups, and those in the intervention group were lower than those in the control group (all P<0.05). The coverage rate of granulation tissue gradually increased in the two groups from day 3 to day 14 after treatment, with that in the intervention group being higher than in the control group during the same period (all P<0.05). The bacterial culture-positive rate that was detected was significantly lower after treatment than that before treatment in the intervention group, and lower in the intervention group than in the control group after treatment (all P<0.05). The VAS scores significantly decreased and TcPO2 increased after treatment compared to those before treatment in the two groups, with changes in the intervention group being more significant than those in the control group (all P<0.05). During the 3-month follow-up, the wound healing rate was higher and the healing time shorter in the intervention group than those in the control group (all P<0.05).
Conclusion:
Negative-pressure wound therapy plus topical oxygen therapy can substantially increase the coverage rate of granulation tissue and TcPO2 at the traumatic site, thus facilitating the healing process and shortening the time for healing. So, the efficacy of negative-pressure wound therapy in combination with topical oxygen therapy is more effective in treating patients with chronic traumatic wounds than negative-pressure wound therapy alone.
... The wound healing process involves a series of overlapping stages, including inflammatory, cell proliferation and migration, tissue remodeling 44 . None of conventional therapeutic approaches to improve healing, such as therapeutic dressings, laser, hyperbaric oxygen, electrical stimulation, is completely satisfactory, also not widely used in clinical practice [45][46][47][48] . Although the underlying mechanisms of cutaneous wound healing have not been fully clarified to date, the safety and efficacy of ADSCs-Exos in skin wound repair is increasingly being elucidated through some studies in vivo and in vitro 49,50 . ...
Cutaneous wound healing has always been an intractable medical problem for both clinicians and researchers, with an urgent need for more efficacious methods to achieve optimal outcomes morphologically and functionally. Stem cells, the body's rapid response 'road repair crew,' being on standby to combat tissue injuries, are an essential part of regenerative medicine. Currently, the use of adipose-derived stem cells (ADSCs), a kind of mesenchymal stem cells with multipotent differentiation and self-renewal capacity, is surging in the field of cutaneous wound healing. ADSCs may exert influences either by releasing paracrine signalling factors or differentiating into mature adipose cells to provide the 'building blocks' for engineered tissue. As an important paracrine substance released from ADSCs, exosomes are a kind of extracellular vesicles and carrying various bioactive molecules mediating adjacent or distant intercellular communication. Previous studies have indicated that ADSCs derived exosomes (ADSCs-Exos) promoted skin wound healing by affecting all stages of wound healing, including regulating inflammatory response, promoting proliferation and migration of fibroblasts or keratinocytes, facilitating angiogenesis, and regulating remodeling of extracellular matrix, which have provided new opportunities for understanding how ADSCs-Exos mediate intercellular communication in pathological processes of the skin and therapeutic strategies for cutaneous wound repair. In this review, we focus on elucidating the role of ADSCs-Exos at various stages of cutaneous wound healing, detailing the latest developments, and presenting some challenges necessary to be addressed in this field, with the expectation of providing a new perspective on how to best utilize this powerful cell-free therapy in the future.
... Only dressings containing Ag Oxysalts were found to produce water and oxygen from hydrogen peroxide ( Figure 6). These effects may be of interest in wound healing (Kimmel et al, 2016). ...
Wounds affect large numbers of patients and produce a considerable socioeconomic burden. In 2012/2013, about 2.2 million patients were treated by the NHS in the UK for an acute or chronic wound at a cost of £4.5–5.1 billion (Guest et al, 2015). Timely healing of wounds can help to minimise impact on patients and contain costs. Wound infection or increased wound bioburden can cause or contribute to the delayed healing of wounds. The appropriate management of infection is therefore a key focus for clinicians treating wounds. A wide range of antimicrobial silver preparations and dressings are used in the management of acute and chronic wounds and have an important role in antimicrobial stewardship. The form of metallic silver or silver compound and the dressing components used in an individual product influence antimicrobial activity and clinical effectiveness. Consequently, clinicians need a clear understanding of the properties of an individual product to ensure effective use.
Ag OxysaltsTM (silver oxynitrate) is a silver compound with unique properties that produce rapid, sustained, broad-spectrum antimicrobial activity. Ag Oxysalts is currently the only silver compound used in dressings to release Ag+, Ag2+ and Ag3+ ions.
A group of experts in wound management and microbiology met in November 2017 to:
Discuss how the chemical properties of Ag Oxysalts relate to its antimicrobial activity and clinical performance
Explore the potential impact of Ag Oxysalts dressings KerraContactTM Ag and KerraCelTM Ag (Crawford Healthcare) on wound healing
Devise treatment pathways for the use of KerraContact Ag in a range of acute and chronic
wound types.
The discussions at the meeting resulted in this document, which aims to provide clinicians with understanding of the unique chemistry of Ag Oxysalts and the information they need for appropriate use of KerraContact Ag in clinical practice to improve outcomes.
Cardiovascular diseases remain the leading cause of death worldwide, underscoring the urgent need for additional therapeutic strategies to reduce their mortality rates. This review systematically outlines the historical development and recent advances of hyperbaric oxygen therapy in cardiovascular diseases, with a focus on its therapeutic mechanisms and clinical outcomes. Hyperbaric oxygen therapy enhances oxygen delivery to ischemic and reperfused tissues, promotes angiogenesis, and significantly suppresses oxidative stress, inflammatory cascades, and cardiomyocyte apoptosis, demonstrating multifaceted therapeutic potential in cardiovascular conditions. Specifically, hyperbaric oxygen therapy combined with reperfusion strategies has been shown to markedly improve left ventricular ejection fraction in acute myocardial infarction. In heart failure, it facilitates myocardial repair and enhances cardiac function. For arrhythmias, hyperbaric oxygen therapy effectively reduces the frequency and duration of premature ventricular contractions and paroxysmal tachycardia, while mitigating the risk of neurological complications following atrial fibrillation ablation. Furthermore, hyperbaric oxygen therapy preconditioning in cardiac surgery has demonstrated improvements in left ventricular stroke work, reductions in postoperative myocardial injury, and a decrease in related complications. Despite its promising applications, the widespread adoption of hyperbaric oxygen therapy remains hindered by the lack of standardized treatment protocols and high-quality evidence from rigorous clinical trials. In conclusion, this review underscores the potential value of hyperbaric oxygen therapy in the cardiovascular domain while highlighting the need for further optimization of therapeutic parameters and exploration of its synergistic effects with conventional therapies to provide clearer guidance for clinical implementation.
AIM: using immunohistochemical reaction to antibodies to fW, to identify the dynamics of the number and size of skin vessels at different stages of regenerative histogenesis after mechanical injury. METHODS. An experimental single-center continuous controlled randomized unblinded study was conducted. The objects of the study were skin fragments of Wistar rats taken from the middle third of the thigh at different stages of healing after a deep cut wound. The animals were divided into 9 groups: 1st - intact individuals (control group, n = 3), the remaining groups correspond to the periods of withdrawal from the experiment (3 animals per group) at 12 hours, 24 hours, 2nd, 3rd, 6th, 10th, 15th and 25th days after mechanical injury. Histological preparations were prepared from skin biopsies for immunohistochemical studies using antibodies to the von Willebrand factor and subsequent morphometric processing of the obtained digital images. RESULTS. Blood vessels were visualized in the dermis and hypodermis of the rat skin and divided into 4 groups depending on their caliber (visible cross-sectional area). The most striking dynamics are demonstrated by the group of vessels with a cross-sectional area ≤100 μm2. Starting from the 2nd to the 10th day of the experiment, their number increases. The preparations of the 15th and 25th days of the experiment show a gradual decrease in the number of such vessels. Similar dynamics were found in the groups of medium (S = 100-500 μm2) and large (S = 500-1000 μm2) caliber vessels. Vessels with a cross-sectional area ≥ 1000 μm2 are single and it is not possible to talk about a correlation between the number of such vessels and the phase of the wound process. CONCLUSION. The immunohistochemical reaction using antibodies to fW on rat skin preparations is characterized by good reproducibility and allows obtaining high-quality preparations. In the experimental wound process, the method showed high selectivity for detecting blood vessels. As a result of morphometric processing of histological preparations, data were obtained confirming the relationship between the number of vessels and successive phases of the wound process.
Diabetic foot ulcers (DFUs) present a formidable threat to individuals grappling with diabetes mellitus (DM), often culminating in severe complications like infection, gangrene, and the prospect of amputation. This study investigates the potential of cold atmospheric plasma (CAP) as an innovative therapeutic intervention to augment the recovery process in chronic DFUs. Examining a 67-year-old diabetic patient with a grade 3 DFU, the efficacy of CAP is inspected through an inventive treatment protocol. The research reveals a noteworthy decrease in both wound depth and bacterial load by the application of the remote CAP treatment, showcasing promising outcomes. The paper involvedly explores the diverse effects of remote CAP treatment, encompassing the generation of reactive species, electromagnetic fields, and ultraviolet (UV) light, which collectively initiate processes such as tissue regeneration, angiogenesis, and the inactivation of bacteria. While underscoring the safety and precision of the experimental procedure, the study underscores CAP's potential as a cost-effective and efficacious solution for DFU management, addressing a critical necessity in the global healthcare landscape. The findings provide valuable insights into the evolving realm of DFU treatment, emphasizing CAP's synergistic role in fostering healing and combatting infections.
The hypoxic environment is among the most important factors that complicates the healing of chronic wounds, such as venous leg ulcers, pressure injuries and diabetic foot ulcers, which seriously affects the quality of life of patients. Various oxygen supply treatments are used in clinical practice to improve the hypoxic environment at the wound site. However, problems still occur, such as insufficient oxygen supply, short oxygen infusion time and potential biosafety risks. In recent years, artificial photosynthetic systems have become a research hotspot in the fields of materials and energy. Photosynthesis is expected to improve the oxygen level at wound sites and promote wound healing because the method provides a continuous oxygen supply and has good biosafety. In this paper, oxygen treatment methods for wounds are reviewed, and the oxygen supply principle and construction of artificial photosynthesis systems are described. Finally, research progress on the photosynthetic oxygen production system to promote wound healing is summarized.
Chronic wounds take longer to heal and, if left untreated, can result in severe repercussions such as sepsis, gangrene, and amputation. The current treatment procedures followed are wound cleaning and debridement, specialized dressings, antibiotics and antiseptics, hyperbaric oxygen therapy, and vacuum-assisted wound closure. Some of the limitations of these treatment options are multi-drug resistance and tissue toxicity. Cold plasma is an emerging technology that has opened a new frontier in biomedical applications and is found to have great utility in wound healing. Cold plasma comprises of Reactive Oxygen and Nitrogen Species (RONS) that can be targeted against bacterial inactivation and improve wound healing. The amount of RONS produced can be controlled by several parameters such as gas composition, flow rate, power, frequency, voltage, distance and exposure time. The reactive species causes damage to the cell membrane as well as the intracellular components which ultimately lead to bacterial cell death. It can also accelerate wound healing by activating neutrophils, macrophages, endothelial cells, keratinocytes and fibroblasts. These help in maintaining tissue oxygenation, initiating angiogenesis, collagen synthesis which aids in rapid wound closure. In this review, we summarize the various characteristics of cold plasma that can be optimized to produce an effective antimicrobial effect. The different mechanisms of bacterial inactivation and the stimulation of wound healing processes by the reactive species are discussed. Furthermore, numerous pieces of evidence from in vitro and in vivo experiments and clinical trials that prove that cold plasma is an effective approach are presented.
Objective:
To compare the operation times, graft survival and success rates, audiometric outcomes, and complications of patients who underwent transperforation myringoplasty with and without packing but without perforation rimming.
Study design:
A prospective, randomized controlled trial.
Setting:
A university-affiliated teaching hospital.
Methods:
We conducted a randomized controlled trial that enrolled patients who underwent underlay myringoplasty. No patient underwent perforation rimming. Patients underwent myringoplasty with or without graft lateral packing. The operation times, graft survival and success rates, audiometric outcomes, and complications were compared between the 2 groups.
Results:
Sixty patients with unilateral perforations were included. The mean neovascularization score at postoperative week 2 was significantly higher in the no-packing group than in the packing group (p < .01) but did not differ significantly at postoperative weeks 3 and 4, or postoperative month 3. Neither the graft healing rate (p = .313) nor the perforation closure rate (p = .640) significantly differed between the 2 groups. The mean air-bone gap improved by 8.91 ± 5.45 dB in the packing group and 8.17 ± 1.19 dB in the no-packing group (p = .758).
Conclusion:
The long-term graft success and hearing improvements in transperforation myringoplasty with no rimming of the perforation and no-graft lateral packing were comparable to those in the graft lateral packing group with no rimming of the perforation, with a low incidence of complications. These results may change the traditional practice of packing the external auditory canal and rimming the perforation in underlay myringoplasty, even for all myringoplasty surgery.
Cutaneous wound healing is a complex process, while modulating the wound microenvironment has become an essential therapeutic goal. In clinics, advanced dressings or dermal templates can promote wound healing but their ability in mediating wound microenvironment is limited. In the last decade, microneedle (MN) array patches have emerged as a new class of wound dressings. These dressings enable non-invasive transdermal and precise medication delivery. Combined with smart materials, MN additionally allows real-time monitoring of wound site markers such as inflammatory factors, oxygen levels, vascularization, pH and temperature, etc., while releasing therapeutic molecules responsively to the wound site. In this review, the MN-based strategies were reviewed for modulating wound microenvironment via introducing the main characteristics of the wound microenvironment and various types of MN-based delivery systems. Additionally, the progress and future trends in the application of MNs in mediating wound microenvironments are also discussed.
Knee injury negatively impacts routine activities and quality of life of millions of people every year. Disruption of tendons, ligaments, and articular cartilage are major causes of knee lesions, leading to social and economic losses. Besides the attempts for an optimal recovery of knee function after surgery, the joint healing process is not always adequate given the nature of intra-articular environment. Based on that, different therapeutic methods attempt to improve healing capacity. Hyperbaric oxygen therapy (HBOT) is an innovative biophysical approach that can be used as an adjuvant treatment post-knee surgery, to potentially prevent chronic disorders that commonly follows knee injuries. Given the well-recognized role of HBOT in improving wound healing, further research is necessary to clarify the benefits of HBOT in damaged musculoskeletal tissues, especially knee disorders. Here, we review important mechanisms of action for HBOT-induced healing including the induction of angiogenesis, modulation of inflammation and extracellular matrix components, and activation of parenchyma cells-key events to restore knee function after injury. This review discusses the basic science of the healing process in knee injuries, the role of oxygen during cicatrization, and shed light on the promising actions of HBOT in treating knee disorders, such as tendon, ligament, and cartilage injuries.
Background. Wounds, despite the diversified development of modern medicine,
remain one of the main problems in surgery due to their frequent occurrence, as well as due
to the high costs of working time and material resources for their treatment. The wound
process is a complex set of body responses to damage and is characterized by a certain
phase of its course. Materials and methods. Despite the variety of existing means and methods of treatment, generally accepted recommendations for the management of patients
with wounds have not yet been developed. However, one should take into account the diversity
of types of wounds, which necessitates an individual approach to the choice of therapy
for each patient. Thanks to a more detailed study of the pathophysiology and pathogenesis
of the wound process, it became possible not only to prescribe more effective and
pathogenetically substantiated treatment to patients, but also to search, develop and implement
new modern highly effective methods in the process of wound treatment. Results and
conclusions. The review discusses in detail the issues of classifications of wounds, the
pathogenesis of the wound process, as well as an analytical study regarding the treatment of
wounds, depending on the phase of the wound process, based on modern literature data.
This retrospective study aimed to explore the clinical efficacy of chitosan‐based hydrocolloid dressing in treating chronic refractory wounds. A total of 80 patients with chronic refractory wounds were randomly divided into the control group (n = 40) and the study group (n = 40). The control group was given inert saline gauze, while the study group was given chitosan‐based hydrocolloid dressing. After 3 weeks of treatment, the wound healing efficiency, itching pain score, changes in the wound area, dressing change frequency, and cost were measured. There was a significant difference in the wound healing effect (t = 2.738), and degree of pain (t = 4.76) between the study and control groups, after 3 weeks of treatment. Similarly, a prominent reduction in the itching frequency (t = 8.62), and wound area (t = 6.379) was observed in the study group compared to the control group (P < .05). Moreover, the frequency and total cost of dressing change in the study group were also lower than the control group and the difference was statistically significant (P < .05). To summarise, the application of chitosan‐based hydrocolloid dressing in treating chronic refractory can effectively alleviate pain, accelerate wound healing, relieve itching pain, and reduce the overall cost and frequency of dressing change.
Anaemia is a common and multifactorial blood disorder in elderly individuals. This condition may be a significant barrier to pressure ulcers healing as it is associated with a decreased level of oxygen being supplied to body tissues. Some nutritional deficiencies such as iron, vitamin B12 and folate may also cause anaemia and have a negative impact on pressure ulcer healing. An increased iron demand in hard-to-heal pressure ulcers is a significant factor associated with the risk of anaemia of chronic disease in elderly patients. Anaemia screening and correction may need to be considered as well as iron supplementation if required in pressure ulcer prevention and management.
Background:
Despite the success of anatomic total shoulder arthroplasty (TSA) and reverse shoulder arthroplasty (RSA), the clinical course of some patients necessitates operative intervention in the acute postoperative period. In this study, we evaluate the risk of subsequent prosthetic joint infection (PJI) in patients who undergo an aseptic reoperation within 90 days of primary shoulder arthroplasty.
Method:
A retrospective review of patients with primary TSA and RSA was performed using a commercially available national database (PearlDiver Inc., Fort Wayne, IN, USA). Queries were performed with use of International Classification of Diseases, Ninth Revision and Tenth Revision and Current Procedural Technology codes. Patients were divided into cohorts based on undergoing aseptic reoperation, reoperation for PJI, or no reoperations within 90 days of index procedure. Primary outcome was subsequent PJI within 1 year of index procedure. Observed PJI rates were compared using chi-square analysis. Risk factors for PJI were compared using logistic regression.
Results:
From 2010 to 2018, a total of 96,648 patients underwent primary shoulder arthroplasty: 46,810 underwent TSA and 49,838 underwent RSA. The rate of aseptic reoperation within 90 days was 0.72% and 1.5% in the TSA and RSA cohorts, respectively. At 1 year postoperatively, patients who underwent an aseptic reoperation within 90 days had an elevated risk of subsequent PJI compared with the overall rate of PJI in the TSA (3.54% vs. 0.75%; P < .001) and RSA (3.08% vs. 0.73%; P < .001) cohorts. On multivariate logistic regression analysis, aseptic reoperation within 90 days was identified as a significant risk factor for subsequent PJI in the TSA cohort (odds ratio, 14.19; P < .001) and RSA cohort (odds ratio, 8.38; P < .001). The most common indication for aseptic reoperation was postoperative prosthetic joint instability in both the TSA (31%) and RSA (49%) cohorts.
Conclusion:
Aseptic reoperation within 90 days of primary TSA or primary RSA was associated with a notably increased risk of subsequent PJI.
Objective:
Hyperbaric oxygen therapy (HBOT) is used for the treatment of chronic diabetic foot ulcers (DFUs). The controlled evidence for the efficacy of this treatment is limited. The goal of this study was to assess the efficacy of HBOT in reducing the need for major amputation and improving wound healing in patients with diabetes and chronic DFUs.
Research design and methods:
Patients with diabetes and foot lesions (Wagner grade 2-4) of at least 4 weeks duration participated in this study. In addition to comprehensive wound care, participants were randomly assigned to receive 30 daily sessions of 90 min of HBOT (breathing oxygen at 244 kPa) or sham (breathing air at 125 kPa). Patients, physicians, and researchers were blinded to group assignment. At 12 weeks postrandomization, the primary outcome was freedom from meeting the criteria for amputation as assessed by a vascular surgeon. Secondary outcomes were measures of wound healing.
Results:
One hundred fifty-seven patients were assessed for eligibility, with 107 randomly assigned and 103 available for end point adjudication. Criteria for major amputation were met in 13 of 54 patients in the sham group and 11 of 49 in the HBOT group (odds ratio 0.91 [95% CI 0.37, 2.28], P = 0.846). Twelve (22%) patients in the sham group and 10 (20%) in the HBOT group were healed (0.90 [0.35, 2.31], P = 0.823). All other indices of wound healing were also not statistically significantly different between groups.
Conclusions:
HBOT does not offer an additional advantage to comprehensive wound care in reducing the indication for amputation or facilitating wound healing in patients with chronic DFUs.
In patients with chronic wounds, autologous tissue repair is often not sufficient to heal the wound. These patients might benefit from regenerative medicine or the implantation of a tissue-engineered scaffold. Both wound healing and tissue engineering is dependent on the formation of a microvascular network. This process is highly regulated by hypoxia and the transcription factors hypoxia-inducible factors-1α (HIF-1α) and -2α (HIF-2α). Even though much is known about the function of HIF-1α in wound healing, knowledge about the function of HIF-2α in wound healing is lacking. This review focuses on the function of HIF-1α and HIF-2α in microvascular network formation, wound healing, and therapy strategies.
Barrier structures (e.g. epithelia around tissues, plasma membranes around cells) are required for internal homeostasis and protection from pathogens. Wound detection and healing represent a dormant morphogenetic program that can be rapidly executed to restore barrier integrity and tissue homeostasis. In animals, initial steps include recruitment of leukocytes to the site of injury across distances of hundreds of micrometers within minutes of wounding. The spatial signals that direct this immediate tissue response are unknown.
Due to their fast diffusion and versatile biological activities, reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are interesting candidates for wound-to-leukocyte signalling. We probed the role of H2O2 during the early events of wound responses in zebrafish larvae expressing a genetically encoded H2O2 sensor1. This reporter revealed a sustained rise in H2O2 concentration at the wound margin, starting ∼3 min after wounding and peaking at ∼20 min, which extended ∼100−200 μm into the tail fin epithelium as a decreasing concentration gradient. Using pharmacological and genetic inhibition, we show that this gradient is created by Dual oxidase (Duox), and that it is required for rapid recruitment of leukocytes to the wound. This is the first observation of a tissue-scale H2O2 pattern, and the first evidence that H2O2 signals to leukocytes in tissues, in addition to its known antiseptic role.
Re-epithelialization of skin wounds depends upon the migration of keratinocytes from the cut margins of the wound and is enhanced when human keratinocytes are covered with occlusive dressings that induce hypoxia. In this study, two independent migration assays were used to compare cellular motility on connective tissue components under normoxic or hypoxic conditions. Human keratinocytes apposed to collagens or fibronectin exhibited increased motility when subjected to hypoxic (0.2 or 2% oxygen) conditions compared with normoxic (9 or 20% oxygen) conditions. When compared with normoxic cells, hypoxic keratinocytes exhibited increased expression and redistribution of the lamellipodia-associated proteins (ezrin, radixin, and moesin). Furthermore, hypoxic keratinocytes demonstrated decreased secretion of laminin-5, a laminin isoform known to inhibit keratinocyte motility. Hypoxia did not alter the number of integrin receptors on the cell surface, but did induce enhanced secretion of the 92-kD type IV collagenase. These data demonstrate that hypoxia promotes human keratinocyte motility on connective tissue. Hypoxia-driven motility is associated with increased expression of lamellipodia proteins, increased expression of collagenase and decreased expression of laminin-5, the locomotion brake for keratinocytes.
TGF-beta1 is a pleiotropic cytokine that plays a key role in wound healing and organ fibrosis. We have recently demonstrated that, in part, some fibrogenic actions of TGF-beta1 are mediated via formation of H(2)O(2). We have also demonstrated that TGF-beta1 plays a key role in the accelerated healing response induced by a peptidoglycan derived from some strains of Staphylococcus aureus (SaPG).
To investigate further the role of H(2)O(2) in healing responses, we implemented and improved a method to measure this reactive oxygen species. Using this method, we quantified the production of H(2)O(2) by cultured hepatic stellate cells-the main cells involved in type I collagen production in the liver-and by saline- and SaPG-inoculated polyvinyl alcohol sponges that had been surgically subcutaneously implanted in the dorsum of rats.
We show that cultured hepatic stellate cells produce significant amounts of H(2)O(2). We show also that H(2)O(2) formation by saline- and SAPG-inoculated sponges is more intense during the early inflammatory phase of the healing response and precedes collagen deposition. Moreover, the production of H(2)O(2) is much higher in SaPG-inoculated sponges than in those inoculated with saline solution.
Based on these findings, and on the fact that H(2)O(2) is produced during TGF-beta-induced upregulation of the alpha1(I) procollagen gene, we conclude that H(2)O(2) is one of the mediators of healing responses.
Vascular injury after balloon angioplasty results in the rapid activation of platelets leading to the release of growth factors and vasoactive substances. In addition, up-regulation of tissue factor (TF) and an increased production of reactive oxygen species (ROS) have been detected at sites of vascular injury. We investigated whether platelet-derived products (PDP) released from activated human platelets increase ROS production, resulting in the induction of TF expression in vascular smooth muscle cells (SMC). PDP induced a time- and concentration-dependent increase in ROS generation in cultured SMC that was mediated mainly by PDGF-AB and TGF-beta1 and impaired by the flavin inhibitor diphenylene iodonium. Increased ROS formation was associated with enhanced mRNA levels of the small NAD(P)H oxidase subunit p22phox or its smooth muscle isoform. Transient transfection with a p22phox antisense vector decreased PDP-induced ROS generation. PDP up-regulated TF mRNA expression, which was redox sensitive and reduced by transfection of the p22phox antisense vector. In addition, PDP-stimulated reporter gene activity of two TF promoter constructs was decreased by coexpression of the p22phox antisense vector. These results indicate that activated platelets up-regulate TF expression and that this response involves ROS generation and a p22phox-containing NAD(P)H oxidase in SMC.
During the past 20 years, it has become generally accepted that the modulation of fibroblastic cells towards the myofibroblastic phenotype, with acquisition of specialized contractile features, is essential for connective-tissue remodelling during normal and pathological wound healing. Yet the myofibroblast still remains one of the most enigmatic of cells, not least owing to its transient appearance in association with connective-tissue injury and to the difficulties in establishing its role in the production of tissue contracture. It is clear that our understanding of the myofibroblast its origins, functions and molecular regulation will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally.
Neutrophils and macrophages, recruited to the wound site, release reactive oxygen species by respiratory burst. It is commonly understood that oxidants serve mainly to kill bacteria and prevent wound infection. We tested the hypothesis that oxidants generated at the wound site promote dermal wound repair. We observed that H(2)O(2) potently induces vascular endothelial growth factor (VEGF) expression in human keratinocytes. Deletion mutant studies with a VEGF promoter construct revealed that a GC-rich sequence from bp -194 to -50 of the VEGF promoter is responsible for the H(2)O(2) response. It was established that at microm concentrations oxidant induces VEGF expression and that oxidant-induced VEGF expression is independent of hypoxia-inducible factor (HIF)-1 and dependent on Sp1 activation. To test the effect of NADPH oxidase-generated reactive oxygen species on wound healing in vivo, Rac1 gene transfer was performed to dermal excisional wounds left to heal by secondary intention. Rac1 gene transfer accelerated wound contraction and closure. Rac1 overexpression was associated with higher VEGF expression both in vivo as well in human keratinocytes. Interestingly, Rac1 gene therapy was associated with a more well defined hyperproliferative epithelial region, higher cell density, enhanced deposition of connective tissue, and improved histological architecture. Overall, the histological data indicated that Rac1 might be an important stimulator of various aspects of the repair process, eventually enhancing the wound-healing process as a whole. Taken together, the results of this study indicate that wound healing is subject to redox control.
This article provides an overview of the role of oxygen in wound healing. The understanding of this role has undergone a major evolution from its long-recognized importance as an essential factor for oxidative metabolism, to its recognition as an important cell signal interacting with growth factors and other signals to regulate signal transduction pathways. Our laboratory has been engaged in the study of animal models of skin ischemia to explore in vivo the impact of hypoxia as well as the use of oxygen as a therapeutic agent either alone or in combination with other agents such as growth factors. We have demonstrated a synergistic effect of systemic hyperbaric oxygen and growth factors that has been substantiated by Hunt's group. Within the past 10 years research in the field of wound healing has given new insight into the mechanism of action of hypoxia and hyperoxia as modifiers of the normal time-course of wound healing. The article concludes with a discussion of why hypoxia and hyperoxia intercurrently play an important role in wound healing. Hypoxia-inducible factor 1 is crucial in that interplay.
Hypoxia limits wound healing. Both normobaric (1 atm) and hyperbaric oxygen (HBO) approaches have been used clinically to oxygenate wound tissue. Recently, we reported that HBO ameliorates stress-induced impairment of dermal healing. We examined the effect of pressure on oxygen-induced vascular endothelial growth factor (VEGF) expression by human HaCaT keratinocytes. Next, we investigated the effect of HBO on whole-body redox and on the ratio of oxidized to reduced glutathione (GSSG/GSH) in the liver, heart, lung, and brain of rats. Superoxygenation (90% O2) of keratinocytes partially arrested cell growth. G2-M growth arrest was substantially augmented by HBO. HBO also caused apoptosis in a small subpopulation. Normobaric oxygen, but not HBO (2 atm), potently induced the expression of VEGF165 and 189. In vivo electron paramagnetic resonance spectroscopy imaging revealed a clear shift of the whole-body redox status toward oxidation in response to HBO. The standard diet of laboratory rats contains excessive (17x human recommended dietary allowance) alpha-tocopherol (E++), which confers exceptional resistance to oxidant insults. People with chronic wounds commonly suffer from under- or malnutrition. We generated vitamin E-deficient (E-) rats by long-term dietary vitamin E restriction. HBO did not raise GSSG/GSH in E++ rats, but post-HBO GSSG/GSH was significantly higher in E- compared with E++. Thus, rats on antioxidant-enriched diet were well protected against HBO. The risk of oxidative stress may negatively impact the net benefits of HBO. This is of special concern for people with inadequate intake of dietary antioxidants. Nutritional antioxidant supplementation may offset HBO-induced oxidative stress.
Previously we have reported in vitro evidence suggesting that that H2O2 may support wound healing by inducing VEGF expression in human keratinocytes (C. K. Sen et al., 2002, J. Biol. Chem.277, 33284-33290). Here, we test the significance of H2O2 in regulating wound healing in vivo. Using the Hunt-Schilling cylinder approach we present the first evidence that the wound site contains micromolar concentrations of H2O2. At the wound site, low concentrations of H2O2 supported the healing process, especially in p47(phox)- and MCP-1-deficient mice in which endogenous H2O2 generation is impaired. Higher doses of H2O2 adversely influenced healing. At low concentrations, H2O2 facilitated wound angiogenesis in vivo. H2O2 induced FAK phosphorylation both in wound-edge tissue in vivo and in human dermal microvascular endothelial cells. H2O2 induced site-specific (Tyr-925 and Tyr-861) phosphorylation of FAK. Other sites, including the Tyr-397 autophosphorylation site, were insensitive to H2O2. Adenoviral gene delivery of catalase impaired wound angiogenesis and closure. Catalase overexpression slowed tissue remodeling as evidenced by a more incomplete narrowing of the hyperproliferative epithelium region and incomplete eschar formation. Taken together, this work presents the first in vivo evidence indicating that strategies to influence the redox environment of the wound site may have a bearing on healing outcomes.
Supplemental perioperative oxygen has been variously reported to halve or double the risk of surgical wound infection.
To test the hypothesis that supplemental oxygen reduces infection risk in patients following colorectal surgery.
A double-blind, randomized controlled trial of 300 patients aged 18 to 80 years who underwent elective colorectal surgery in 14 Spanish hospitals from March 1, 2003, to October 31, 2004. Wound infections were diagnosed by blinded investigators using Centers for Disease Control and Prevention criteria. Baseline patient characteristics, anesthetic treatment, and potential confounding factors were recorded.
Patients were randomly assigned to either 30% or 80% fraction of inspired oxygen (FIO2) intraoperatively and for 6 hours after surgery. Anesthetic treatment and antibiotic administration were standardized.
Any surgical site infection (SSI); secondary outcomes included return of bowel function and ability to tolerate solid food, ambulation, suture removal, and duration of hospitalization.
A total of 143 patients received 30% perioperative oxygen and 148 received 80% perioperative oxygen. Surgical site infection occurred in 35 patients (24.4%) administered 30% FIO2 and in 22 patients (14.9%) administered 80% FIO2 (P=.04). The risk of SSI was 39% lower in the 80% FIO2 group (relative risk [RR], 0.61; 95% confidence interval [CI], 0.38-0.98) vs the 30% FIO2 group. After adjustment for important covariates, the RR of infection in patients administered supplemental oxygen was 0.46 (95% CI, 0.22-0.95; P = .04). None of the secondary outcomes varied significantly between the 2 treatment groups.
Patients receiving supplemental inspired oxygen had a significant reduction in the risk of wound infection. Supplemental oxygen appears to be an effective intervention to reduce SSI in patients undergoing colon or rectal surgery. Trial Registration ClinicalTrials.gov Identifier: NCT00235456.
M-CSF induces PI 3-kinase activation, resulting in reactive oxygen species (ROS) production. Previously, we reported that ROS mediate macrophage colony-stimulating factor (M-CSF)-induced extracellular regulated kinase (Erk) activation and monocyte survival. In this work, we hypothesized that M-CSF-stimulated ROS products modulated Akt1 and p38 activation. Furthermore, we sought to clarify the source of these ROS and the role of ROS and Akt in monocyte/macrophage survival. Macrophages from p47(phox-/-) mice, lacking a key component of the NADPH oxidase complex required for ROS generation, had reduced cell survival and Akt1 and p38 mitogen-activated protein kinase (MAPK) phosphorylation compared with wild-type macrophages in response to M-CSF stimulation, but had no difference in M-CSF-stimulated Erk. To understand how ROS affected monocyte survival and signaling, we observed that NAC and DPI decreased cell survival and Akt1 and p38 MAPK phosphorylation. Using bone marrow-derived macrophages from mice expressing constitutively activated Akt1 (Myr-Akt1) or transfecting Myr-Akt1 constructs into human peripheral monocytes, we concluded that Akt is a positive regulator of monocyte survival. Moreover, the p38 MAPK inhibitor, SB203580, inhibited p38 activity and M-CSF-induced monocyte survival. These findings demonstrate that ROS generated from the NADPH oxidase complex contribute to monocyte/macrophage survival induced by M-CSF via regulation of Akt and p38 MAPK.
We have shown previously that wounding of human corneal epithelial (HCE) cells resulted in epidermal growth factor receptor (EGFR) transactivation through ectodomain shedding of heparin-binding EGF-like growth factor (HB-EGF). However, the initial signal to trigger these signaling events in response to cell injury remains elusive. In the present study, we investigated the role of ATP released from the injured cells in EGFR transactivation in HCE cells as well as in BEAS 2B cells, a bronchial epithelial cell line. Wounding of epithelial monolayer resulted in the release of ATP into the culture medium. The wound-induced rapid activation of phosphatidylinositol-3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) pathways in HCE cells was attenuated by eliminating extracellular ATP, ADP and adenosine. The nonhydrolyzable ATP analog ATP-gamma-S induced rapid and sustained EGFR activation that depended on HB-EGF shedding and ADAM (a disintegrin and metalloproteinase). Targeting pathways leading to HB-EGF shedding and EGFR activation attenuated ATP-gamma-S-enhanced closure of small scratch wounds. The purinoceptor antagonist reactive blue 2 decreased wound closure and attenuated ATP-gamma-S induced HB-EGF shedding. Taken together, our data suggest that ATP, released upon epithelial injury, acts as an early signal to trigger cell responses including an increase in HB-EGF shedding, subsequent EGFR transactivation and its downstream signaling, resulting in wound healing.
Chronic wounds have traditionally been treated by conservative means. It was Winter's moist wound healing research, in 1962, that stimulated a proliferation of a moist interactive dressing technologies. Even considering this advancement in thinking, chronic wounds continue to be a problem for many clinicians. An increasing delineation of the science of healing in the past 20 years has redefined the way in which we both evaluate and treat wounds. This scientific understanding has raised wound care from the clinical problem arena to that of clinical specialty, where many now cross refer patients to specialists in this field. Wound bed preparation (WBP) has played a significant role in this change in practice. The concept has changed an 'art' of switching at random from one dressing to another, into a clinical science. WBP has come to the forefront as a major educational aid to help others develop appropriate treatment of the underlying disease causing the wound and patient requirements. The concept of WBP evolved over the recent years, becoming more and more sophisticated with time. Recent adaptations have brought together many of the current components. This article proposes yet another element of WBP, that of 'oxygen balance'.
Injury to stratified epithelia causes a strong induction of keratins 6 (K6) and 16 (K16) in post-mitotic keratinocytes located at the wound edge. We show that induction of K6 and K16 occurs within 6 h after injury to human epidermis. Their subsequent accumulation in keratinocytes correlates with the profound reorganization of keratin filaments from a pan-cytoplasmic distribution to one in which filaments are aggregated in a juxtanuclear location, opposite to the direction of cell migration. This filament reorganization coincides with additional cytoarchitectural changes and the onset of re-epithelialization after 18 h post-injury. By following the assembly of K6 and K16 in vitro and in cultured cells, we find that relative to K5 and K14, a well-characterized keratin pair that is constitutively expressed in epidermis, K6 and K16 polymerize into short 10-nm filaments that accumulate near the nucleus, a property arising from K16. Forced expression of human K16 in skin keratinocytes of transgenic mice causes a retraction of keratin filaments from the cell periphery, often in a polarized fashion. These results imply that K16 may not have a primary structural function akin to epidermal keratins. Rather, they suggest that in the context of epidermal wound healing, the function of K16 could be to promote a reorganization of the cytoplasmic array of keratin filaments, an event that precedes the onset of keratinocyte migration into the wound site.
Hypothesis Hyperbaric oxygen (HBO) therapy increases vascular endothelial growth factor (VEGF) levels in wounds. Design Wounds were monitored for oxygen delivery during HBO treatment, and wound fluids were analyzed for VEGF and lactate on days 2, 5, and 10 following wounding. Setting Experimental animal model. Interventions Rats were randomized to HBO therapy and control groups. The HBO therapy was administered for 90 minutes, twice daily with 100% oxygen at 2.1 atmospheres absolute. Treatment was administered for 7 days following wounding. Main Outcome Measures Vascular endothelial growth factor, PO 2 , and lactate levels in wound fluid were measured on days 2, 5, and 10. Results Wound oxygen rises with HBO from nearly 0 mm Hg to as high as 600 mm Hg. The peak level occurs at the end of the 90-minute treatment, and hyperoxia of lessening degree persists for approximately 1 hour. The VEGF levels significantly increase with HBO by approximately 40% 5 days following wounding and decrease to control levels 3 days after exposures are stopped. Wound lactate levels remain unchanged with HBO treatment (range, 2.0-10.5 mmol/L). Conclusions Increased VEGF production seems to explain in part the angiogenic action of HBO. This supports other data that hypoxia is not necessarily a requirement for wound VEGF production.
Enzyme fractions which catalyze the hydroxylation of peptidyl-proline to form peptidyl-hydroxyproline have been prepared from chick embryo, guinea-pig granuloma and fetal rat skin. In all preparations ferrous ion, ascorbic acid, α-ketoglutarate and molecular oxygen are required for activity. No compounds have been found which can replace ferrous ion and α-ketoglutarate. Reduced pteridines can partially replace ascorbic acid, but reduced pyridine nucleotides are inactive. The enzyme has been called collagen proline hydroxylase and has been tentatively classified as a mixed-function oxidase. A formulation of the reaction catalyzed by this enzyme has been proposed in which ascorbate functions as a reducing agent and α-ketoglutarate as a modifier of the enzyme.
The repair of wounds is one of the most complex biological processes that occur during human life. After an injury, multiple biological pathways immediately become activated and are synchronized to respond. In human adults, the wound repair process commonly leads to a non-functioning mass of fibrotic tissue known as a scar. By contrast, early in gestation, injured fetal tissues can be completely recreated, without fibrosis, in a process resembling regeneration. Some organisms, however, retain the ability to regenerate tissue throughout adult life. Knowledge gained from studying such organisms might help to unlock latent regenerative pathways in humans, which would change medical practice as much as the introduction of antibiotics did in the twentieth century.
BACKGROUND: Disrupted vasculature and high energy-demand to support processing and regeneration of wounded tissue are typical characteristics of a wound site. Oxygen delivery is a critical element for the healing of wounds. Clinical experience with adjunctive hyperbaric oxygen therapy in the treatment of chronic wounds have shown that wound hyperoxia increases wound granulation tissue formation and accelerates wound contraction and secondary closure. Nevertheless, the physiologic basis for this modality remains largely unknown. Also, systemic hyperbaric oxygen therapy is associated with risks related to oxygen toxicity. Topical oxygen therapy represents a less explored modality in wound care. The advantages of topical oxygen therapy include low cost, lack of systemic oxygen toxicity, and the ability to receive treatment at home, making the benefits of oxygen therapy available to a much larger population of patients. MATERIALS AND METHODS: Over 9 months, seven surgeons treated 58 wounds in 32 patients with topical oxygen with follow-up ranging from 1 to 8 months. The data presented herein is a retrospective analysis of the results we have achieved using topical oxygen on complex wounds. RESULTS: Thirty-eight wounds in 15 patients healed while on topical oxygen. An additional five wounds in five patients had preoperative oxygen therapy; all wounds initially healed postoperatively. In two patients, wounds recurred post-healing. In ten wounds, topical oxygen had no effect; and two of those patients went on to require limb amputation. There were no complications attributable to topical oxygen. Three patients died during therapy and one died in the first postoperative month from underlying medical problems. Two patients were lost to follow-up. CONCLUSIONS: In this case series, topical oxygen had no detrimental effects on wounds and showed beneficial indications in promoting wound healing.
The co-substrate requirements of prolyl hydroxylase were studied with pure enzyme from chick embryos. No hydroxylation occurred without added Fe2+, indicating that the enzyme does not retain iron sufficiently to catalyze any reaction. Zn2+ was an effective competitive inhibitor with respect to Fe2+, but was noncompetitive with respect to the polypeptide substrate and 2-oxoglutarate, suggesting that it replaced iron in the active site of the enzyme.
The enzyme catalyzed the uncoupled decarboxylation of 2-oxoglutarate at a rate of about 4 mol CO2 formed (mol enzyme)−1 min−1 in the presence of Fe2+, O2, and ascorbate but in the absence of the polypeptide substrate. This rate was about 1/80 of that observed in the presence of the substrate. Several compounds inhibited the enzyme competitively with respect to 2-oxoglutarate but non-competitively with respect to Fe2+. It seems that these two co-substrates become bound at separate sites on the enzyme, and additional data suggested that these are distinct from the binding site of the polypeptide substrate.
The reaction was completely dependent on O2. Nitroblue tetrazolium was a competitive inhibitor with respect to O2, but noncompetitive with respect to the polypeptide substrate and all other co-substrates. Epinehrine also inhibited the enzyme, but this inhibition was competitive with respect to Fe2+. The results suggest that nitroblue tetrazolium consumed an activated form of oxygen, whereas epinephrine acted primarily by binding Fe2+.
The reaction was completely dependent on ascorbate, and in contrast to previous data, this could not be significantly replaced by tetrahydrofolic acid or dithiothreitol. Dehydroascorbate replaced ascorbate in the presence of dithiothreitol but not in its absence. The results also indicate that ascorbate is not stoichiometrically consumed during the reaction.
Oxygen is a prerequisite for successful wound healing due to the increased demand for reparative processes such as cell proliferation, bacterial defence, angiogenesis and collagen synthesis. Even though the role of oxygen in wound healing is not yet completely understood, many experimental and clinical observations have shown wound healing to be impaired under hypoxia. This article provides an overview on the role of oxygen in wound healing and chronic wound pathogenesis, a brief insight into systemic and topical oxygen treatment, and a discussion of the role of wound tissue oximetry. Thus, the aim is to improve the understanding of the role of oxygen in wound healing and to advance our management of wound patients.
NADPH oxidase isoforms with different gp91phox subunits as well as an unusual cytochrome aa3 with a heme a/a3 relationship of 9:91 are discussed as putative oxygen sensor proteins influencing gene expression and ion channel conductivity. Reactive oxygen species (ROS) are important second messengers of the oxygen sensing signal cascade determining the stability of transcription factors or the gating of ion channels. The formation of ROS by a perinuclear Fenton reaction is imaged by 1 and 2 photon confocal microscopy revealing mitochondrial and non-mitochondrial generation. (C) 2001 Elsevier Science B.V. All rights reserved.
The state of wound oxygenation is a key determinant of healing outcomes. From a diagnostic standpoint, measurements of wound oxygenation are commonly used to guide treatment planning such as amputation decision. In preventive applications, optimizing wound perfusion and providing supplemental O(2) in the perioperative period reduces the incidence of postoperative infections. Correction of wound pO(2) may, by itself, trigger some healing responses. Importantly, approaches to correct wound pO(2) favorably influence outcomes of other therapies such as responsiveness to growth factors and acceptance of grafts. Chronic ischemic wounds are essentially hypoxic. Primarily based on the tumor literature, hypoxia is generally viewed as being angiogenic. This is true with the condition that hypoxia be acute and mild to modest in magnitude. Extreme near-anoxic hypoxia, as commonly noted in problem wounds, is not compatible with tissue repair. Adequate wound tissue oxygenation is required but may not be sufficient to favorably influence healing outcomes. Success in wound care may be improved by a personalized health care approach. The key lies in our ability to specifically identify the key limitations of a given wound and in developing a multifaceted strategy to specifically address those limitations. In considering approaches to oxygenate the wound tissue it is important to recognize that both too little as well as too much may impede the healing process. Oxygen dosing based on the specific need of a wound therefore seems prudent. Therapeutic approaches targeting the oxygen sensing and redox signaling pathways are promising.
Studies over the past 15 years have disclosed a number of inherited conditions in which there is a deficiency in one or another of the enzymes involved in the oxidative killing mechanisms of phagocytes. Some of these conditions are characterized by a marked impairment in host defense against bacterial infection, whereas others are clinically benign.
Stimulation of rat vascular smooth muscle cells (VSMCs) by platelet-derived growth factor (PDGF) transiently increased the intracellular concentration of hydrogen peroxide (H2O2). This increase could be blunted by increasing the intracellular concentration of the scavenging enzyme catalase or by the chemical antioxidant N-acetylcysteine. The response of VSMCs to PDGF, which includes tyrosine phosphorylation, mitogen-activated protein kinase stimulation, DNA synthesis, and chemotaxis, was inhibited when the growth factor-stimulated rise in H2O2 concentration was blocked. These results suggest that H2O2 may act as a signal-transducing molecule, and they suggest a potential mechanism for the cardioprotective effects of antioxidants.
The function of keratinocyte growth factor (KGF) in normal and wounded skin was assessed by expression of a dominant-negative KGF receptor transgene in basal keratinocytes. The skin of transgenic mice was characterized by epidermal atrophy, abnormalities in the hair follicles, and dermal hyperthickening. Upon skin injury, inhibition of KGF receptor signaling reduced the proliferation rate of epidermal keratinocytes at the wound edge, resulting in substantially delayed reepithelialization of the wound.
Oxidation-reduction (redox) based regulation of signal transduction and gene expression is emerging as a fundamental regulatory mechanism in cell biology. Electron flow through side chain functional CH2-SH groups of conserved cysteinyl residues in proteins account for their redox-sensing properties. Because in most intracellular proteins thiol groups are strongly "buffered" against oxidation by the highly reduced environment inside the cell, only accessible protein thiol groups with high thiol-disulfide oxidation potentials are likely to be redox sensitive. The list of redox-sensitive signal transduction pathways is steadily growing, and current information suggests that manipulation of the cell redox state may prove to be an important strategy for the management of AIDS and some forms of cancer. The endogenous thioredoxin and glutathione systems are of central importance in redox signaling. Among the thiol agents tested for their efficacy to modulate cellular redox status, N-acetyl-L-cysteine (NAC) and alpha-lipoic acid hold promise for clinical use. A unique advantage of lipoate is that it is able to utilize cellular reducing equivalents, and thus it harnesses the metabolic power of the cell to continuously regenerate its reductive vicinal dithiol form. Because lipoate can be readily recycled in the cell, it has an advantage over N-acetyl-L-cysteine on a concentration:effect basis. Our current knowledge of redox regulated signal transduction has led to the unfolding of the remarkable therapeutic potential of cellular thiol modulating agents.
Chronic wound healing conditions are often observed in elderly patients with poor tissue oxygenation. Impaired re-epithelialization is a hallmark of these wounds, which is seen in both clinical studies and in our animal models of impaired healing. To investigate the pathogenic mechanism of chronic wounds, we studied the effect of hypoxia on migration of keratinocytes isolated from human donors of increasing age. Keratinocytes from elderly donors had depressed migratory activity when exposed to hypoxia, as opposed to an increase in migration in young cells. Analysis of underlying biochemical changes demonstrated a differential activation of matrix metalloproteinases by hypoxia in keratinocytes isolated from the young and the old. Matrix metalloproteinases-1 and -9 and tissue inhibitor of matrix metalloproteinase-1 were strongly upregulated by hypoxia in young cells, whereas no induction was observed in aged cells. Furthermore, transforming growth factor-beta 1 signaling appears to be involved in the keratinocyte differential response to hypoxia, as transforming growth factor-beta type I receptor was upregulated by hypoxia in young cells, while there was no induction in aged cells. Transforming growth factor-beta neutralizing reagents blocked hypoxia-induced matrix metalloproteinase-1, matrix metalloproteinase-9 expression, and hypoxia-induced cell migration as well. Our results suggest that an age-related decrease in response to hypoxia plays a crucial part in the pathogenesis of retarded re-epithelialization in wound.
Wound healing is critically affected by age, ischemia, and growth factors such as TGFbeta1. The combined effect of these factors on fibroblast migration, an essential component of wound healing, is poorly understood. To address this deficiency, we examined expression of TGFbeta receptor type I and II (TGFbetaRI and RII) under normoxia or hypoxia (1% O(2)) in cultured human dermal fibroblasts (HDFs) from young (ages 24-33) and aged (ages 61-73) adults. TGFbetaRI and RII expression was similar in both groups under normoxia. Hypoxia did not alter receptor levels in young HDFs but significantly decreased TGFbetaRI in aged cells (12 and 43%, respectively). Additionally, young cells displayed a 50% increase in activation of p42/p44 mitogen-activated kinase by TGFbeta1 (2-200 pg/ml) under hypoxia while aged cell levels of active p42/p44 decreased up to 24%. To determine functional outcomes of these findings, we measured the migratory capacity of the cells on type I collagen using a gold salt migration assay. Hypoxia increased the migratory index (MI) of young HDFs over normoxia by 30% but had no effect on aged cells. Under normoxia, TGFbeta1 (1-1000 pg/ml) increased young HDF migration in a concentration-dependent manner up to 109% over controls but minimally increased aged HDF migration (37%). Under hypoxia, TGFbeta1 significantly increased young cell MI at all concentrations but was without effect on the aged HDF response. These data demonstrate that aged fibroblasts have an impaired migratory capacity with complete loss of responsiveness to hypoxia and deficits in the migratory and signal transduction responsiveness to TGFbeta1 that may partly explain diminished healing capabilities often observed in aged patients.
Human dermal myofibroblasts, characterised by the expression of alpha-smooth muscle actin, are part of the granulation tissue and implicated in the generation of contractile forces during normal wound healing and pathological contractures. We have compared the contractile properties of single human dermal fibroblasts and human dermal myofibroblasts by culturing them on flexible silicone elastomers. The flexibility of the silicone substratum permits the contractile forces exerted by the cells to be measured [Fray et al., 1998: Tissue Eng. 4:273-283], without changing their expression of alpha-smooth muscle actin. The mean contractile force produced by myofibroblasts (2.2 microN per cell) was not significantly different from that generated by fibroblasts (2.0 microN per cell) when cultured on a substrata with a low elastomer stiffness. Forces produced by fibroblasts were unaffected by increases in elastomer stiffness, but forces measured for myofibroblasts increased to a mean value of 4.1 microN/cell. This was associated with a higher proportion of myofibroblasts being able to produce wrinkles on elastomers of high stiffness compared to fibroblasts. We discuss the force measurements at the single cell level, for both fibroblast and myofibroblasts, in relation to the proposed role of myofibroblasts in wound healing and pathological contractures.
Genetic defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme system result in chronic granulomatous disease (CGD). In addition to recurrent, life-threatening infections, patients with CGD frequently present with sterile inflammatory complications, suggesting that NADPH-oxidase deficiency predisposes to these responses in the absence of persistent microbial infection. The mechanisms involved in the aberrant, inflammatory process are unknown. In this study, we have shown that neutrophils isolated from CGD patients, which are more resistant to spontaneous apoptosis in vitro, also produce significantly less of the anti-inflammatory mediator cyclopentenone prostaglandin D(2) (PGD(2)). In addition, during phagocytosis of opsonized and nonopsonized apoptotic targets, CGD macrophages are severely compromised in their ability to produce PGD(2) and transforming growth factor-beta (TGF-beta). We suggest that delayed apoptosis of inflammatory cells, such as neutrophils and deficient production of the anti-inflammatory mediators PGD(2) and TGF-beta during macrophage clearance of apoptotic debris and invading pathogens, contributes to persistence of inflammation in CGD.
It is a fundamental clinical observation that wounds do not heal in tissue that does not bleed, and they almost always heal in tissue that bleeds extensively. Continuous supply of oxygen to the tissue through microcirculation is vital for the healing process and for resistance to infection. Evaluation of tissue perfusion and oxygenation is important in all types of wound patients. Monitoring systems should measure the hemodynamic situation and the ability of the cardiovascular system to deliver an adequate volume of oxygen to meet the metabolic demands of the peripheral tissue. Oxygen therapy is important in relation to both healing and resistance to infections. External factors have been shown to significantly decrease the peripheral oxygen supply, and supplementary perioperative oxygen to reduce the surgical wound infection rate by one- half in patients undergoing colorectal resection. Hyperbaric oxygen therapy may be beneficial in situations where the nutritive flow and oxygen supply to the healing tissue are compromised by local injury, and particularly if anaerobic infection is present. However, the definitive proof for the effect and indications of this therapy in wound healing still has to be established. It can be concluded that adequate delivery of oxygen to the wound tissue is vital for optimal healing and resistance to infection. Assessment of perfusion and oxygenation is essential for the wound patient, as well as the treating personnel. The indication for hyperbaric oxygen treatment still needs to be defined. During wound healing the continuity and function of the damaged tissue are re-established. This is only possible through a restoration of the microcirculation and thereby the nutrition to the tissue. The main component of the nutrition is oxygen, which is critically important for healing a wound by production of granulation tissue and for ensuring resistance against infection. This has been shown experimentally, but recently a short period of supplementary oxygen has been shown to decrease wound complications in clinical practice as well.
"Wound Healing: Oxygen & Emerging Therapeutics" Columbus, Ohio, September 12-15, 2002. Sponsored by the National Institutes of Health (R13 AR 049171), International Union of Biochemistry & Molecular Biology and UNESCO-Global Network of Molecular & Cell Biology. Conference co-chairs: Chandan K. Sen, the Ohio State University Medical Center and Thomas K. Hunt, University of California-San Francisco. This congress was conceived for two reasons: to consolidate what is known about oxygen in the repair process and to stimulate discussion about new developments of control of healing by redox regulated signaling processes. A historical and evolutionary perspective on the role of oxygen in wound healing--from the classical physiology of oxygen in the wound to the refined concept of redox signaling--is presented.
The skin cells chiefly depend on carbohydrate metabolism for their energy requirement during cutaneous wound healing. Since the glucose metabolism is greatly hampered in diabetes and this might affect wound repair process. This prompted us to investigate the intermediate steps of energy metabolism by measuring enzyme activities in the wound tissues of normal and streptozotocin-induced diabetic rats following excision-type of cutaneous injury. The activities of key regulatory enzymes namely hexokinase (HK), phosphofructokinase (PFK), lactate dehydrogenase (LDH), citrate synthase (CS) and glucose-6 phosphate dehydrogenase (G6PD) have been monitored in the granulation tissues of normal and diabetic rats at different time points (2, 7, 14 and 21 days) of postwounding. Interestingly, a significant alteration in all these enzyme activities was observed in diabetic rats. The activity of PFK was increased but HK, LDH and CS showed a decreased activity in the wound tissue of diabetics as compared to normal rats. However G6PD exhibited an elevated activity only at early stage of healing in diabetic rats. Thus, the results suggest that significant alterations in the activities of energy metabolizing enzymes in the wound tissue of diabetic rats may affect the energy availability for cellular activity needed for repair process and this may perhaps be one of the factor responsible for impaired healing in these subjects.
There is a need for a noninvasive method that measures wound angiogenesis. Hyperoxia is known to increase the appearance of new blood vessels in wounds, yet no study has confirmed increases in wound bed perfusion with periodic hyperbaric oxygen (HBO) exposure. This study investigates whether laser Doppler imaging is able to detect and quantify the enhancement of wound angiogenesis that is known to occur with intermittent HBO treatments. Full-thickness dorsal dermal wounds were created on mice randomized to hyperoxic (n = 14) and control (n = 15) groups. Hyperbaric oxygen was administered twice daily for 90 minutes each at 2.1 atmospheres for 7 days. Wound bed perfusion was measured by laser Doppler imaging on days 0, 7, and 10 postwounding. Wound blood flow increased significantly over baseline on day 7 and 10 in the hyperoxic group, but only on day 10 in the control group. Comparison between groups showed a 20% statistically significant increase in wound perfusion in HBO-treated animals compared to control on day 10 (p = 0.05). Laser Doppler imaging was able to detect and quantify the increase in wound bed perfusion resulting from intermittent HBO treatments and shows promise as a noninvasive measure of angiogenesis and wound healing.
Hypoxia, caused by disrupted vasculature and peripheral vasculopathies, is a key factor that limits dermal wound healing. Factors that can increase oxygen delivery to the regional tissue, such as supplemental oxygen, warmth, and sympathetic blockade, can accelerate healing. Clinical experience with adjunctive hyperbaric oxygen therapy (HBOT) in the treatment of chronic wounds have shown that wound hyperoxia may increase granulation tissue formation and accelerate wound contraction and secondary closure. However, HBOT is not applicable to all wound patients and may pose the risk of oxygen toxicity. Thus, the efficacy of topical oxygen treatment in an experimental setting using the pre-clinical model involving excisional dermal wound in pigs was assessed. Exposure of open dermal wounds to topical oxygen treatment increased tissue pO2 of superficial wound tissue. Repeated treatment accelerated wound closure. Histological studies revealed that the wounds benefited from the treatment. The oxygen treated wounds showed signs of improved angiogenesis and tissue oxygenation. Topically applied pure oxygen has the potential of benefiting some wound types. Further studies testing the potential of topical oxygen in pre-clinical and clinical settings are warranted.
We hypothesized that tissue hyperoxia would enhance and hypoxia inhibit neovascularization in a wound model. Therefore, we used female Swiss-Webster mice to examine the influence of differential oxygen treatment on angiogenesis. One milliliter plugs of Matrigel, a mixture of matrix proteins that supports but does not itself elicit angiogenesis, were injected subcutaneously into the mice. Matrigel was used without additive or with added vascular endothelial growth factor (VEGF) or anti-VEGF antibody. Animals were maintained in hypoxic, normoxic, or one of four hyperoxic environments: hypoxia -- 13 percent oxygen at 1 atmosphere absolute (ATA); normoxia -- 21 percent oxygen at 1 ATA; hyperoxia -- (groups a-d) 100 percent oxygen for 90 minutes twice daily at the following pressures: Group a, 1 ATA; Group b, 2 ATA; Group c, 2.5 ATA; Group d, 3.0 ATA. Subcutaneous oxygen tension was measured in all groups. The Matrigel was removed 7 days after implantation. Sections were graded microscopically for the extent of neovascularization. Angiogenesis was significantly greater in all hyperoxic groups and significantly less in the hypoxic group compared with room air-exposed controls. Anti-VEGF antibody abrogated the angiogenic effect of both VEGF and increased oxygen tension. We conclude that angiogenesis is proportional to ambient pO(2) over a wide range. This confirms the clinical impression that angiogenesis requires oxygen. Intermittent oxygen exposure can satisfy the need for oxygen in ischemic tissue.
Cellular O(2) sensing enables physiological adjustments to variations in tissue pO(2). Under basal conditions, cells are adjusted to an O(2) environment biologically read as normoxia. Any sharp departure from that state of normoxia triggers O(2)-sensitive biological responses. The stabilization of hypoxia-inducible factor (HIF) signifies a robust biological readout of hypoxia. In the presence of sufficient O(2), HIF is hydroxylated and degraded. HIF prolyl hydroxylation is catalyzed by prolyl hydroxylase isoenzymes PHD1, 2, and 3. Using HT22 neurons stably transfected with a HIF reporter construct, we tested a novel hypothesis postulating that biological cells are capable of resetting their normoxic set point by O(2)-sensitive changes in PHD expression. Results of this study show that the pO(2) of the mouse brain cortex was 35 mm Hg or 5% O(2). Exposure of HT22, adjusted to growing in 20% O(2), to 5% O(2) resulted in HIF-driven transcription. However, cells adjusted to growing in 5% O(2) did not report hypoxia. Cells adjusted to growing in 30% O(2) reported hypoxia when acutely exposed to room air culture conditions. When grown under high O(2) conditions, cells reset their normoxic set point upward by down-regulating the expression of PHD1-3. When grown under low O(2) conditions, cells reset their normoxic set point downward by inducing the expression of PHD1-3. Exposure of mice in vivo to a hypoxic 10% O(2) environment lowered blood as well as brain pO(2). Such hypoxic exposure induced PHD1-3. Exposure of mice to a hyperoxic 50% O(2) ambience repressed the expression of PHD1-3, indicating that O(2)-sensitive regulation of PHD expression is effective in the brain in vivo. siRNA dependent knockdown of PHD expression revealed that O(2)-sensitive regulation of PHD may contribute to tuning the normoxic set point in biological cells.
Human health is under constant threat of a wide variety of dangers, both self and nonself. The immune system is occupied with protecting the host against such dangers in order to preserve human health. For that purpose, the immune system is equipped with a diverse array of both cellular and non-cellular effectors that are in continuous communication with each other. The naturally occurring nucleotide adenosine 5'-triphosphate (ATP) and its metabolite adenosine (Ado) probably constitute an intrinsic part of this extensive immunological network through purinergic signaling by their cognate receptors, which are widely expressed throughout the body. This review provides a thorough overview of the effects of ATP and Ado on major immune cell types. The overwhelming evidence indicates that ATP and Ado are important endogenous signaling molecules in immunity and inflammation. Although the role of ATP and Ado during the course of inflammatory and immune responses in vivo appears to be extremely complex, we propose that their immunological role is both interdependent and multifaceted, meaning that the nature of their effects may shift from immunostimulatory to immunoregulatory or vice versa depending on extracellular concentrations as well as on expression patterns of purinergic receptors and ecto-enzymes. Purinergic signaling thus contributes to the fine-tuning of inflammatory and immune responses in such a way that the danger to the host is eliminated efficiently with minimal damage to healthy tissues.
The observation that many chronic wounds are ischemic has spurred a series of studies evaluating the response of cells exposed to hypoxia. To date, these studies have shown largely beneficial effects from hypoxia, such as increased cellular replication and procollagen synthesis. These findings are counter-intuitive from a clinical standpoint because cellular growth and synthetic function are known to be retarded in chronic ischemic wounds. We have established an in vitro system in which human dermal fibroblasts grown chronically at 5 +/- 3 mm Hg will proliferate at a rate three times slower than those fibroblasts grown under standard culture conditions (namely an oxygen partial pressure of 150 mm Hg). No phenotypic changes are noted in chronically hypoxic cells, and the growth-retarding effects are reversible when the cells are returned to standard oxygen conditions. Competitive reverse transcription-polymerase chain reaction showed that acute exposure to hypoxia (up to 1 week) results in a 6.3-fold increase in the relative expression of transforming growth factor-beta1 messenger RNA, whereas chronic exposure to hypoxia leads to a 3.1-fold decrease in this message. Collagen production measured at both the mRNA and protein level is also decreased in the setting of chronic hypoxia. We propose that this system may be the most appropriate setting for studying the role of oxygen on dermal fibroblasts in ischemic, nonhealing wounds.
The crucial role of oxygen during the complex process of wound healing has been extensively described. In chronic or nonhealing wounds, much evidence has been reported indicating that a lack of oxygen is a major contributing factor. Although still controversial, the therapeutic application of hyperbaric oxygen (HBO) therapy can aid the healing of chronic wounds. However, how HBO affects reepithelization, involving processes such as keratinocyte proliferation and differentiation, remains unclear. We therefore used a three-dimensional human skin-equivalent (HSE) model to investigate the effects of daily 90-minute HBO treatments on the reconstruction of an epidermis. Epidermal markers of proliferation, differentiation, and basement membrane components associated with a developing epidermis, including p63, collagen type IV, and cytokeratins 6, 10, and 14, were evaluated. Morphometric analysis of hematoxylin and eosin-stained cross sections revealed that HBO treatments significantly accelerated cornification of the stratum corneum compared with controls. Protein expression as determined by immunohistochemical analysis confirmed the accelerated epidermal maturation. In addition, early keratinocyte migration was enhanced by HBO. Thus, HBO treatments stimulate epidermal reconstruction in an HSE. These results further support the importance of oxygen during the process of wound healing and the potential role of HBO therapy in cutaneous wound healing.
High oxygen tension (hyperoxia) causes pulmonary cell death, involving apoptosis, necrosis, or mixed death phenotypes, though the underlying mechanisms remain unclear. In mouse lung endothelial cells (MLEC) hyperoxia activates both extrinsic (Fas-dependent) and intrinsic (mitochondria-dependent) apoptotic pathways. We examined the hypothesis that FLIP, an inhibitor of caspase-8, can protect endothelial cells against the lethal effects of hyperoxia. Hyperoxia caused the time-dependent downregulation of FLIP in MLEC. Overexpression of FLIP attenuated intracellular reactive oxygen species generation during hyperoxia exposure, by downregulating extracellular-regulated kinase-1/2 activation and p47(phox) expression. FLIP prevented hyperoxia-induced trafficking of the death-inducing signal complex from the Golgi apparatus to the plasma membrane. Furthermore, FLIP blocked the activations of caspase-8/Bid, caspases -3/-9, and inhibited the mitochondrial translocation and activation of Bax, resulting in protection against hyperoxia-induced cell death. Under normoxic conditions, FLIP expression increased the phosphorylation of p38 mitogen-activated protein kinase leading to increased phosphorylation of Bax during hyperoxic stress. Furthermore, FLIP expression markedly inhibited protein kinase C activation and expression of distinct protein kinase C isoforms (alpha, eta, and zeta), and stabilized an interaction of PKC with Bax. In conclusion, FLIP exerted novel inhibitory effects on extrinsic and intrinsic apoptotic pathways, which significantly protected endothelial cells from the lethal effects of hyperoxia.
This brief review first touches on the origins of the earth's oxygen. It then identifies and locates the principal oxygen sensor in vertebrates, the carotid body (CB). The CB is unique in that in human subjects, it is the only sensor of lower than normal levels in the partial pressure of oxygen (hypoxia, HH). Another oxygen sensor, the aortic bodies, are mostly vestigial in higher vertebrates. At least they play a much smaller role than the CB. In such an important role, the many reflexes in response to CB stimulation by HH are presented. After briefly reviewing what CB stimulation does, the next topic is to describe how the CB chemotransduces HH into neural signals to the brain. Several mechanisms are known, but critical steps in the mechanisms of chemosensation and chemotransduction are still under investigation. Finally, a brief glance at the operation of the CB in chronic heart failure patients is presented. Specifically, the role of nitric oxide, NO, is discussed.
We sought to review the role of oxygen in wound healing, with an emphasis on the role tissue oximetry has played in clinical advances in the care of patients with wounds. Oxygen is required for wound healing. Hypoxia sufficient to impair healing is common in wounds, frequently resulting from sympathetically induced vasoconstriction. Correction or prevention of vasoconstriction, as well as provision of increased inspired oxygen in well-perfused patients, has been shown in randomized, controlled clinical trials to improve wound outcomes. Our understanding of the role of oxygen in wound healing has been fueled by tissue oximetry. Advances in technology will lead to further advances in the management of patients with wounds.
In recent years, it has become clear that reactive oxygen species (ROS, which include superoxide, hydrogen peroxide, and other metabolites) are produced in biological systems. Rather than being simply a by-product of aerobic metabolism, it is now recognized that specific enzymes--the Nox (NADPH oxidase) and Duox (Dual oxidase) enzymes--seem to have the sole function of generating ROS in a carefully regulated manner, and key roles in signal transduction, immune function, hormone biosynthesis, and other normal biological functions are being uncovered. The prototypical Nox is the respiratory burst oxidase or phagocyte oxidase, which generates large amounts of superoxide and other reactive species in the phagosomes of neutrophils and macrophages, playing a central role in innate immunity by killing microbes. This enzyme system has been extensively studied over the past two decades, and provides a basis for comparison with the more recently described Nox and Duox enzymes, which generate ROS in a variety of cells and tissues. This review first considers the structure and regulation of the respiratory burst oxidase, and then reviews recent studies relating to the regulation of the activity of the novel Nox/Duox enzymes. The regulation of Nox and Duox expression in tissues and by specific stimuli is also considered here. An accompanying review considers biological and pathological roles of the Nox family of enzymes.
high oxygen concentrations can damage cells. Whereas the detrimental effects of oxygen have been well-reported ([1][1]), respiratory diseases such as pneumonia and neonatal surfactant deficiency often cause hypoxemia and necessitate the use of supplemental oxygen as part of their management.
Vascularization, under physiological or pathophysiological conditions, typically takes place by one or more of the following processes: angiogenesis, vasculogenesis, arteriogenesis, and lymphangiogenesis. Although all of these mechanisms of vascularization have sufficient contrasting features to warrant consideration under separate cover, one common feature shared by all is their sensitivity to the VEGF signaling pathway. Conditions such as wound healing and physical exercise result in increased production of reactive oxygen species such as H(2)O(2), and both are associated with increased tissue vascularization. Understanding these two scenarios of adult tissue vascularization in tandem offers the potential to unlock the significance of redox regulation of the VEGF signaling pathway. Does H(2)O(2) support tissue vascularization? H(2)O(2) induces the expression of the most angiogenic form of VEGF, VEGF-A, by a HIF-independent and Sp1-dependent mechanism. Ligation of VEGF-A to VEGFR2 results in signal transduction leading to tissue vascularization. Such ligation generates H(2)O(2) via an NADPH oxidase-dependent mechanism. Disruption of VEGF-VEGFR2 ligation-dependent H(2)O(2) production or decomposition of such H(2)O(2) stalls VEGFR2 signaling. Numerous antioxidants exhibit antiangiogenic properties. Current evidence lends firm credence to the hypothesis that low-level endogenous H(2)O(2) supports vascular growth.