Abstract


Oxygen is an undisputed key factor in wound healing. Adequate oxygen pressure in tissues allows for cell growth and proliferation, necessary for wound healing. In the case of peripheral arterial disease leading to hypoxemia, oxygen supplementation is beneficial. The roles and validity of topical and systemic oxygen therapy in wound healing is debated. Topical oxygen therapy (TOT) is delivered at 100% oxygen saturation and has been demonstrated to increase the pO2 levels within the wound base center, decrease the size of the wound, and decrease the time to wound healing compared to patients that did not undergo topical oxygen therapy. Alternatives to topical oxygen therapy are systemic oxygen therapy including hyperbaric oxygen therapy and inspired oxygen therapy. Systemic oxygen therapy carries the risk of oxygen organ toxicity as the result of an oxidative stress and genotoxicity state. Topical O2 therapy is a viable option for chronic wounds, with its demonstrated effects on decrease in wound size and time to healing. Adjunctive clinical wound debridement’s decrease the necrotic debris and therefore the topical oxygen diffusion distance optimizing the therapy effect.

Abstract


We report our experience in patients who were treated with cold plasma wound therapy from 2016 to 2020. Thirty-six patients with a median age of 71 years (23 males, 13 females) were registered in a prospective database. The median follow up was six months.
In 15 patients, their wounds were associated with peripheral arterial disease, and they received peripheral interventional or open revascularisation prior to cold plasma therapy. Seven patients had a chronic venous insufficiency and 3 diabetic patients had chronic wounds caused by polyneuropathy. One patient suffered from chronic lymphoid disease. The cause of the wound could not be identified in the remaining patients. Wound treatment was conducted in an outpatient setting, if possible.
Four patients were lost during follow-up. Surgical debridement of the wound before cold plasma therapy began was necessary in 14 cases. Each patient received 1 to 3 cold plasma treatments a week; 2 patients were treated for 1 year and the remaining patients were treated for 4 to 11 weeks.
There were no major amputations in the long-term follow-up. In 25 patients, the progress of the wound stopped and in 11 patients the wounds were closed at the end of the therapy. In conclusion, our results support the use of cold plasma in complex wounds. Causal therapy is mandatory. Further studies are necessary to evaluate the impact of supplemental modern wound treatment with cold plasma therapy.

Abstract


Treatment of chronic wounds that are at risk of infection, or that are infected, require the use of antimicrobial dressings, most often those that contain silver. Silver exerts its antimicrobial effects by binding to multiple cellular components and, as such, bacterial resistance to it is low; however, molecular silver resistance has been documented and is attributed to the presence of the sil operon or changes in genes encoding porin and efflux pump expression. The aim of this study was to evaluate spontaneous silver resistance development in common opportunistic pathogens, Staphylococcus, Pseudomonas and Enterococcus cloacae, as well as resistance development when exposed to subtherapeutic concentrations over a prolonged period. Furthermore, following silver resistance development, cross-resistance to several classes of antibiotics was evaluated. Following exposure of the strains to silver sulfadiazine (SSD) at two times and four times minimum inhibitory concentration (MIC), the mutation rate was <1010 colony forming unit (CFU)/mL. Serial passage of S. aureus and P. aeruginosa in subinhibitory concentrations of SSD selected for no resistant mutants. The SSD MIC of E. cloacae increased past the solubility limit of SSD at serial passage 17. MIC testing of this isolate showed a >2048-fold increase in MIC to silver in comparison to the parent strain. MIC testing of the serial passage isolates demonstrated no cross-resistance to antibiotics from six different classes. Overall, the results of this study show resistance development to silver is low and, if it does occur, it does not confer resistance to several antibiotic classes. However, as this study was carried out with a small number of strains, a study with a larger panel of strains and sequencing of the strains to determine the exact mechanism of resistance would be needed to investigate the threat of silver resistance further.

Abstract


We treated a small cohort of venous ulcers that were very unresponsive to standard and advanced therapies with autologous cultured bone marrow-derived mesenchymal stem cells (MSCs). This pilot clinical trial was randomized, controlled, and double-blinded. Subjects were treated with either normal saline (Group A), fibrin spray alone (Group B), or MSCs in fibrin (1 million cells/cm2 of wound bed surface) (Group C). The control and test materials were applied to the wound using a double-barreled syringe with thrombin and fibrinogen (with or without MSCs) in each barrel, or saline alone in both barrels. The MSCs were separated, cultured in vitro, and expanded in a dedicated Good Manufacturing Practice (GMP) facility from 30-50 ml of bone marrow aspirate obtained from the iliac crest in Group C subjects. To ensure that the study remained controlled and blinded, subjects who were randomized to one of the two control arms (saline or fibrin) underwent sham bone marrow aspiration performed by a hematologist who anesthetized the iliac crest area down to and pushing against the periosteum, but without penetrating the bone marrow. Therefore, both the clinician who evaluated wound progress and the study subjects had no knowledge of whether bone aspiration was actually performed and what treatment had been applied to the wound. The study was performed after full FDA investigational new drug (IND) approval. The primary endpoint was the rate of healing (wound closure as linear healing from the wound margins in cm/week), as measured by the Gilman equation. One-way ANOVA was used to calculate the statistical significance of differences between the mean healing rates of each of the 3 treatment groups every 4 weeks and over the 24 weeks of treatment. Overall, treatment with MSCs accelerated the healing rate by about 10-fold compared to those in the saline and fibrin control groups. Although the total number of patients in this pilot study was small (n=11), the statistical significance was surprisingly promising: p<0.01 and f-ratio of 15.9358. No serious adverse events were noted. This small but carefully performed prospective, controlled, randomized, and double-blinded pilot study in a rare population of totally unresponsive patients adds to previous reports showing the promise of MSCs in the treatment of chronic wounds and provides proof of principle for how to approach this type of very demanding clinical and translational research.

Abstract


Chronic, non-healing wounds, such as diabetic foot ulcers and venous leg ulcers, have a significant economic impact on healthcare and are associated with elevated patient morbidity. Among the toolset of treatment options available to clinicians, skin grafts from other species (xenografts) are often used to promote wound closure. While porcine xenografts have been the most used skin xenograft over the years, acellular fish skin grafts from Atlantic cod (Gadus morhua) have steadily gained traction in usage. Unlike other skin grafts, acellular fish skin grafts have a substantial lipid profile primarily composed of omega-3 fatty acids, notably eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish oil supplementation has been shown to result in faster rates of wound epithelialization, and omega 3 fatty acids provide barrier protection against bacteria and alter the inflammatory profile of wounds. EPA and DHA have been shown to have modulatory effects on the progression of wound healing. These characteristic omega-3 fatty acids and their metabolites alter skin physiology at a cellular and molecular level. Clinically, fish skin grafts continually demonstrate increased efficacy in treatment of wounds. When applied to non-responsive diabetic foot ulcers, acellular fish skin grafts have resulted in accelerated healing rates and significantly more fully healed wounds when compared to standard options. Here, we explore the role of omega-3 fatty acids in wound regeneration and repair, with particular focus on EPA and DHA. Then, we review clinical research outcomes to address notable clinical research studies and highlight the therapeutic potential of fish skin grafts with omega-3 as a treatment for chronic, non-healing wounds.