Continuum of care in hard-to-heal wounds by copper dressings: a case series.

OBJECTIVE: The quest for an ideal wound dressing has been a longstanding challenge due to the complex nature of wound healing, including stages of haemostasis, inflammation, maturation and remodelling, with overlapping timelines. This makes it difficult to find a single dressing that optimally supports all phases of wound healing. In addition, the ideal wound dressing should possess antibacterial properties and be capable of effectively debriding and lysing necrotic tissue. Copper is an essential trace element that participates in many of the key physiological wound healing processes. METHOD: Copper stimulates secretion of various cytokines and growth factors, thus promoting angiogenesis, granulation tissue formation, extracellular matrix proteins secretion and re-epithelialisation. Harnessing this knowledge, we have used copper oxide-impregnated wound dressings in numerous cases and observed their benefits throughout the entire wound healing process. RESULTS: This led us to postulate the 'continuum of care' hypothesis of copper dressings. In this study we describe four cases of hard-to-heal wounds of various aetiologies, in which we applied copper dressings consistently across all stages of wound healing, with rapid uneventful healing. CONCLUSION: We believe we have successfully implemented the continuum of care principle.

Stimulation of Healing of Non-Infected Stagnated Diabetic Wounds by Copper Oxide-Impregnated Wound Dressings.

Background and Objective: Copper, a wide spectrum biocide, also plays a key role in angiogenesis and wound healing. Antibacterial wound dressings impregnated with copper oxide microparticles (COD) have been recently cleared by the U.S. FDA and other regulatory bodies for the treatment of acute and chronic wounds, including diabetic wounds. Our objective was to evaluate the capacity of COD in stimulating the healing of non-infected stagnated wounds in diabetic patients initially treated with standard of care (SOC) dressings. Materials and Methods: The trial was divided into the three following phases: 1-2 weeks of screening, during which the patients were treated with SOC dressings; 4 weeks of treatment, during which the COD was applied twice weekly; and 2 weeks of follow-up, during which the patients were again treated with SOC dressings. The wound conditions and sizes were assessed by clinical evaluation and a wound imaging artificial intelligence system. Results: Following 1 month of COD treatment, there was a clear reduction in the mean wound area (53.2%; p = 0.003), an increase in granulation tissue (43.37; p < 0.001), and a reduction in fibrins (47.8%; p = 0.002). In patients with non-weight-bearing wounds, the reduction in wound size was even more dramatic (66.9%; p < 0.001). Conclusions: The results of this study, showing a statistically significant influence of COD on wound healing of hard-to-heal wounds in diabetic patients, strongly supports the notion that copper oxide-impregnated dressings enhance wound healing directly. Further larger controlled studies should be conducted to substantiate our findings.

Copper Ions Ameliorated Thermal Burn-Induced Damage in ex vivo Human Skin Organ Culture.

INTRODUCTION: The zone of stasis is formed around the coagulation zone following skin burning and is characterized by its unique potential for salvation. The cells in this zone may die or survive depending on the severity of the burn and therefore are target for the local treatments of burns. Their low survival rate is consistent with decreased tissue perfusion, hypotension, infection, and/or edema, resulting in a significant increase in the wound size following burning. Copper is an essential trace mineral needed for the normal function of almost all body tissues, including the skin. OBJECTIVE: The aim of the work was to study the effect copper ions have on skin burn pathophysiology. METHODS: Skin obtained from healthy patients undergoing abdominoplasty surgery was cut into 8 × 8 mm squares, and round 0.8-mm diameter burn wounds were inflicted on the skin explants. The burned and control intact skin samples were cultured up to 27 days after wounding. Immediately following injury and then again every 48 h, saline only or containing 0.02 or 1 µM copper ions was added onto the skin explant burn wounds. RESULTS: We found that exposing the wounded sites immediately after burn infliction to 0.02 or 1 µM copper ions reduced the deterioration of the zone of stasis and the increase in wound size. The presence of the copper ions prevented the dramatic increase of pro-inflammatory cytokines (interleukin (IL)-6 and IL-8) and transforming growth factor beta-1 that followed skin burning. We also detected re-epithelialization of the skin tissue and a greater amount of collagen fibers upon copper treatment. CONCLUSION: The deterioration of the zone of stasis and the increase in wound size following burning may be prevented or reduced by using copper ion-based therapeutic interventions.

Healing of Chronic Wounds by Copper Oxide-Impregnated Wound Dressings-Case Series.

Novel antimicrobial wound dressings impregnated with copper oxide micro-particles have been cleared for treatment of acute and chronic wounds. Our objective is to provide preliminary data regarding the potential benefit of using these novel wound dressings including in non-infected wounds. Methods involved the treatment of wounds that responded partially or poorly to conventional wound healing treatments with copper oxide impregnated wound dressings in patients with a range of etiologies. Ten cases of patients with etiologies such as diabetes mellitus, sickle cell disease, renal failure, and necrotizing fasciitis, in which the application of copper oxide impregnated wound dressings in infected and non-infected wounds, which resulted in significant enhanced wound healing, are presented. This was exemplified by clearing of the wound infections, reduction of the fibrous and/or necrotic tissue and by intense granulation, epithelialization, and wound closure. The described 10 case reports support our hypothesis that the copper oxide-containing wound dressing not only confers protection to the wound and the dressing from microbial contamination, and in some cases may help clear the wound infections, but in addition and more importantly, stimulate skin regeneration and wound healing. Our findings are in line with previous animal and in vitro studies showing that copper plays a key role in angiogenesis and skin regeneration. These case reports support the notion that the use of copper oxide impregnated wound dressings may be an important intervention in the arsenal of wound treatment modalities, especially in hard to heal wounds.

Drastic Reduction of Bacterial, Fungal and Viral Pathogen Titers by Cuprous Oxide Impregnated Medical Textiles.

Hospital patients and personnel are at risk of nosocomial viral infections, as clearly manifested during the COVID-19 pandemic. Transmission of respiratory viral pathogens can occur through contaminated surfaces, including from medical textiles. Copper has potent biocidal properties, and cuprous oxide impregnated medical textiles (CMT) reduce hospital-acquired bacterial infections. In the current study we confirm the antimicrobial properties of CMT and determine their capacity to reduce infectious titres of human coronavirus (HCoV-229E) in an independent laboratory. The antibacterial and antiviral activities of the CMT were determined according to AATCC TM100-2019 and ISO 18184:2019 standards, respectively. The CMT reduced by 4 logs the viable titers of MRSA, Klebsiella pneumoniae, Enterococcus faecalis, and Candida auris after 2 h of incubation. Viable titers of Clostridium difficile were reduced by 2.3, 3, and 4 logs after 2, 6, and 18 h, respectively. Infectious titers of HCoV-229E exposed to CMT for 2 h were reduced by 2.8 and 4 logs (99.85% and 99.99% reductions) as compared to Time-0 control and initial inoculum, respectively. The CMT retain their antibacterial efficacy even after 100 industrial washings. Use of cuprous oxide impregnated textiles in clinical settings may reduce not only hospital acquired infections caused by bacterial and fungal pathogens, but also, and equally important, those caused by coronavirus and other viruses.

Increased pro-collagen 1, elastin, and TGF-ß1 expression by copper ions in an ex-vivo human skin model.

BACKGROUND: Clinical studies demonstrated that continued exposure to copper oxide-embedded textiles, such as pillowcases, significantly reduces depth of facial wrinkles and skin sagging and enhances skin elasticity. OBJECTIVE: Study the mechanisms by which the exposure to copper ions improve the well-being of the skin. METHODS: Human skin explants, cultured ex-vivo, were exposed topically to saline alone or saline containing 0.02 or 1 µmol/L copper ions. The skin explants viability, histology and secretion of elastin, pro-collagen 1, and TGF-ß1 to the culture medium were determined at various time intervals. RESULTS: Exposure to saline containing 0.02 or 1 µmol/L copper ions did not affect the viability or morphological profile of the explants as compared to control explants treated with saline only. Notably, exposure of the skin grafts to 0.02 or to 1 µmol/L of copper ions resulted in ~100% and ~20% increases in elastin and pro-collagen 1 concentrations, respectively, in the culture supernatants already after 1 day of incubation, which remained statistically significantly elevated also after 6 days on incubation, as compared to the control explants. In addition, ~2- and ~4-fold increases in TGF-ß1 levels in the culture supernatants of explants exposed to the copper ions were detected after 4 and 6 days of culture, as compared to the explants exposed to saline alone. CONCLUSION: This study substantiated the anti-aging effect that copper ions have on the skin and gave insights into the mechanisms by which exposure of the skin to copper ions improves the skin well-being.

Reduction of health care-associated infection indicators by copper oxide-impregnated textiles: Crossover, double-blind controlled study in chronic ventilator-dependent patients.

BACKGROUND: Copper oxide has potent wide-spectrum biocidal properties. The purpose of this study is to determine if replacing hospital textiles with copper oxide-impregnated textiles reduces the following health care-associated infection (HAI) indicators: antibiotic treatment initiation events (ATIEs), fever days, and antibiotic usage in hospitalized chronic ventilator-dependent patients. METHODS: A 7-month, crossover, double-blind controlled trial including all patients in 2 ventilator-dependent wards in a long-term care hospital. For 3 months (period 1), one ward received copper oxide-impregnated textiles and the other received untreated textiles. After a 1-month washout period of using regular textiles, for 3 months (period 2) the ward that received the treated textiles received the control textiles and vice versa. The personnel were blinded to which were treated or control textiles. There were no differences in infection control measures during the study. RESULTS: There were reductions of 29.3% (P = .002), 55.5% (P < .0001), 23.0% (P < .0001), and 27.5% (P < .0001) in the ATIEs, fever days (>37.6°C), days of antibiotic treatment, and antibiotic defined daily dose per 1,000 hospitalization days, respectively, when using the copper oxide-impregnated textiles. CONCLUSIONS: Use of copper oxide-impregnated biocidal textiles in a long-term care ward of ventilator-dependent patients was associated with a significant reduction of HAI indicators and antibiotic utilization. Using copper oxide-impregnated biocidal textiles may be an important measure aimed at reducing HAIs in long-term care medical settings.

Potent bactericidal efficacy of copper oxide impregnated non-porous solid surfaces.

BACKGROUND: The role of fomites and the environment in nosocomial infections is becoming widely recognized. In this paper we discuss the use of Cupron copper oxide impregnated non-porous solid surface in the hospital setting and present in vitro testing data via USA Environmental Protection Agency (EPA) approved testing protocols that demonstrate the efficacy of these products to assist in reduction in environmental contamination and potentially nosocomial infections. RESULTS: The two countertops tested passed all the acceptance criteria by the EPA (>99.9% kill within 2 hours of exposure) killing a range of bacterial pathogens on the surface of the countertops even after repeated exposure of the countertops to the pathogen, and multiple wet and dry abrasion cycles. CONCLUSIONS: Cupron enhanced EOS countertops thus may be an important adjunct to be used in hospital settings to reduce environmental bioburden and potentially nosocomial infections.

Using Copper to Improve the Well-Being of the Skin.

Copper has two key properties that are being exploited in consumer and medical device products in the last decade. On the one hand, copper has potent biocidal properties. On the other hand, copper is involved in numerous physiological and metabolic processes critical for the appropriate functioning of almost all tissues in the human body. In the skin, copper is involved in the synthesis and stabilization of extracellular matrix skin proteins and angiogenesis. This manuscript reviews clinical studies that show that the use of textile consumer and medical device products, embedded with microscopic copper oxide particles, improve the well-being of the skin. These include studies showing a) cure of athlete's foot infections and improvement in skin elasticity, especially important for individuals suffering from diabetes; b) reduction of facial fine line and wrinkles; and c) enhancement of wound healing; by copper oxide embedded socks, pillowcases and wound dressings, respectively. The manuscript also reviews and discusses the mechanisms by which the presence of copper in these products improves skin well-being.

Reduction of facial wrinkles depth by sleeping on copper oxide-containing pillowcases: a double blind, placebo controlled, parallel, randomized clinical study.

BACKGROUND: Copper up-regulates the secretion of extracellular skin proteins and stabilizes the extracellular matrix once formed. As copper can be absorbed through intact skin, we reasoned that sleeping on pillowcases containing copper-impregnated fibers would reduce skin wrinkles. OBJECTIVE: Demonstrate that sleeping on pillowcases containing copper-impregnated fibers reduce facial skin wrinkles. PATIENTS/METHODS: An 8-week, double blind, parallel, randomized study was carried out, in which healthy volunteers, aged 30-60, used either copper oxide-containing pillowcases (1% weight/weight) (test group, n = 30) or control pillowcases without copper (control group, n = 31). Skin conditions of the subjects were evaluated by visual grading by two expert graders and by 3D Image Analysis GFM PRIMOS(®) at baseline (before treatment) and following 4 and 8 weeks of sleeping on the pillowcases. RESULTS: The use of the copper oxide-containing pillowcase resulted in significant decrease of crow's feet after 4 (P = 0.01) and 8 (P = 0.002) weeks, but none was observed in the control group, as determined by the expert graders. On the basis of the 3D measurements, three roughness (R) parameters were improved after 4 and 8 weeks (P < 0.02) and the Rmax parameter at 8 weeks (P = 0.016) in the test group, but there were no changes in the R-parameters during the course of the study in the control group. The average reduction per month in the R-parameters was approximately 9%. No adverse reactions were observed or reported during the 8 weeks study. CONCLUSIONS: Sleeping on copper oxide-containing pillowcases results in reduction of wrinkles depth and overall improvement of skin appearance.

Beneficial regulation of fibrillar collagens, heat shock protein-47, elastin fiber components, transforming growth factor-ß1, vascular endothelial growth factor and oxidative stress effects by copper in dermal fibroblasts.

Skin aging is associated with the loss of the structural collagens and the elastin fiber components that form the extracellular matrix (ECM). It is associated with reduced transforming growth factor-ß (TGF-ß), angiogenesis and increased oxidative stress. Copper has been incorporated into cosmetics for anti-skin aging. This research investigated the mechanism for the anti-skin aging effect copper ions, from cuprous oxide powders. Dermal fibroblasts were exposed to copper and examined for expression (protein and/or promoter levels) of types I, III, V collagen, heat shock protein-47 (HSP-47), elastin, fibrillin-1, and fibrillin-2, TGF-ß1, vascular endothelial growth factor (VEGF), and in addition for membrane damage and lipid peroxidation. The direct antioxidant activity of copper was also determined. The research indicates that copper's anti-skin aging and skin regeneration potential is through its stimulation of ECM proteins, TGF-ß1, VEGF, and inhibition of oxidative stress effects at physiological concentrations; and supports its use in cosmetics.

Prevention of human immunodeficiency virus breastmilk transmission with copper oxide: proof-of-concept study.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) transmission through breastmilk is the chief modality through which HIV-1 is transmitted from HIV-1-infected mothers to their babies in developing countries, where alternative feeding options lack practical feasibility. The development of an approach to inactivate the HIV-1 virions ingested by an infant on a daily basis through breastmilk is thus of critical importance. METHODS: Copper has potent virucidal properties. Stoichiometric concentrations of copper ions inactivate the HIV-1 protease, which is essential for viral replication. Cell-free and cell-associated HIV-1 infectivity is inhibited when the virus is exposed to copper oxide in a dose-dependent manner. Passage of high titers of a wide range of HIV-1 isolates, spiked in culture medium, through filters containing copper oxide powder resulted in their deactivation. RESULTS: In the current study, we demonstrate that the infectivity of three different HIV-1 isolates, spiked in breastmilk obtained from HIV-1-seronegative donors, or of wild-type isolates found in breastmilk obtained from HIV-1-seropositive donors, is drastically reduced (>98%) when exposed to copper oxide. CONCLUSIONS: This study is proof of concept that copper oxide is efficacious against HIV-1 found in breastmilk and serves as the basis for further research aimed at determining the possible effects that copper may have on the nutritional and anti-infective properties of breastmilk. Furthermore, this supports the continuing study of the feasibility of developing a filtering device, such as an "at-the-breast" disposable shield that can be used discreetly and safely by HIV-1-infected mothers during breastfeeding.

Antiviral propierties of 5,5'-dithiobis-2-nitrobenzoic acid and bacitracin against T-tropic human immunodeficiency virus type 1.

Bacitracin and the membrane-impermeant thiol reagent 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) are agents known to inhibit protein disulfide isomerase (PDI), a cell-surface protein critical in HIV-1 entry therefore they are fusion inhibitors (FI). Here we investigated the possibility that Bacitracin and or DTNB might have other antiviral activities besides FI. By means of residual activity assays, we found that both compounds showed antiviral activity only to viruses T-tropic HIV-1 strain. Cell-based fusion assays showed inhibition on HeLa-CD4-LTR-ß-gal (CD4) and HL2/3 cells treated with Bacitracin, and DTNB with the latest compound we observed fusion inhibition on both cells but strikingly in HL2/3 cells (expressing Env) indicating a possible activity on both, the cell membrane and the viral envelope. A time-of-addition experiment showed that both compounds act on HIV entry inhibition but DTNB also acts at late stages of the viral cycle. Lastly, we also found evidence of long-lasting host cell protection in vitro by DTNB, an important pharmacodynamic parameter for a topical microbicide against virus infection, hours after the extracellular drug was removed; this protection was not rendered by Bacitracin. These drugs proved to be leading compounds for further studies against HIV showing antiviral characteristics of interest.

A novel anti-influenza copper oxide containing respiratory face mask.

BACKGROUND: Protective respiratory face masks protect the nose and mouth of the wearer from vapor drops carrying viruses or other infectious pathogens. However, incorrect use and disposal may actually increase the risk of pathogen transmission, rather than reduce it, especially when masks are used by non-professionals such as the lay public. Copper oxide displays potent antiviral properties. A platform technology has been developed that permanently introduces copper oxide into polymeric materials, conferring them with potent biocidal properties. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that impregnation of copper oxide into respiratory protective face masks endows them with potent biocidal properties in addition to their inherent filtration properties. Both control and copper oxide impregnated masks filtered above 99.85% of aerosolized viruses when challenged with 5.66+/-0.51 and 6.17+/-0.37 log(10)TCID(50) of human influenza A virus (H1N1) and avian influenza virus (H9N2), respectively, under simulated breathing conditions (28.3 L/min). Importantly, no infectious human influenza A viral titers were recovered from the copper oxide containing masks within 30 minutes (< or = 0.88 log(10)TCID(50)), while 4.67+/-1.35 log(10)TCID(50) were recovered from the control masks. Similarly, the infectious avian influenza titers recovered from the copper oxide containing masks were < or = 0.97+/-0.01 log(10)TCID(50) and from the control masks 5.03+/-0.54 log(10)TCID(50). The copper oxide containing masks successfully passed Bacterial Filtration Efficacy, Differential Pressure, Latex Particle Challenge, and Resistance to Penetration by Synthetic Blood tests designed to test the filtration properties of face masks in accordance with the European EN 14683:2005 and NIOSH N95 standards. CONCLUSIONS/SIGNIFICANCE: Impregnation of copper oxide into respiratory protective face masks endows them with potent anti-influenza biocidal properties without altering their physical barrier properties. The use of biocidal masks may significantly reduce the risk of hand or environmental contamination, and thereby subsequent infection, due to improper handling and disposal of the masks.

Molecular mechanisms of enhanced wound healing by copper oxide-impregnated dressings.

ABSTRACT Copper plays a key role in angiogenesis and in the synthesis and stabilization of extracellular matrix skin proteins, which are critical processes of skin formation. We hypothesized that introducing copper into wound dressings would enhance wound repair. Application of wound dressings containing copper oxide to wounds inflicted in genetically engineered diabetic mice (C57BL/KsOlaHsd-Lepr(db)) resulted in increased gene and in situ up-regulation of proangiogenic factors (e.g., placental growth factor, hypoxia-inducible factor-1 alpha, and vascular endothelial growth factor), increased blood vessel formation (p<0.05), and enhanced wound closure (p<0.01) as compared with control dressings (without copper) or commercial wound dressings containing silver. This study proves the capacity of copper oxide-containing wound dressings to enhance wound healing and sheds light onto the molecular mechanisms by which copper oxide-impregnated dressings stimulate wound healing.

Copper oxide impregnated wound dressing: biocidal and safety studies.

 Copper plays a key role in angiogenesis and in the expression and stabilization of extracellular skin proteins. Copper also exhibits broad biocidal properties. The authors hypothesized that introducing copper into a wound dressing would not only reduce the risk of wound and dressing contamination, but would also stimulate wound repair. To test this hypothesis, non-stick dressings composed of a highly absorbent internal mesh fabric and an external non-woven fabric were fabricated, and each was impregnated with ~2.65% (weight/weight) copper oxide particles. The application to wounds inflicted in genetically engineered diabetic mice resulted in increased gene and in-situ upregulation of proangiogenic factors, increased blood vessel formation, and enhanced wound closure. The present study reports both the potent broad spectrum antimicrobial and antifungal properties of these wound dressings and the lack of adverse reactions as determined in rabbits and a porcine wound model. The prolonged efficacy of the wound dressing is demonstrated by its capacity to reduce the microbial challenge by more than 99.9% even when spiked 5 consecutive times with a high bacterial titer. The dressing's antimicrobial efficacy is exerted within minutes. The dressing did not cause any skin irritation or sensitization to closed skin. Furthermore, no histological differences were found between open wounds exposed to copper oxide containing wound dressings or control dressings. Therefore, copper containing wound dressings hold significant promise in wound healing and their clinical use should be explored .

Reducing the risk of skin pathologies in diabetics by using copper impregnated socks.

Diabetic individuals frequently suffer from skin pathologies, especially in their feet. Co-existing peripheral vascular disease and neuropathy exacerbate the capacity of these individuals to cope with infections, minor cuts and wounds, often leading to hard to treat and chronic ulcers. Copper has potent anti-fungal and antibacterial properties. Copper is also an essential trace element vital for the normal function of many tissues and indispensable for the generation of new capillaries and skin. Human skin is not sensitive to copper and the risk of adverse reactions due to dermal exposure to copper is extremely low. We hypothesize that part of the increased risk of developing foot skin pathologies in diabetic patients with compromised blood circulation to the foot is due to low local copper levels. We further hypothesize that copper ions released from copper impregnated socks and absorbed through the skin would improve the well-being of the skin of diabetic patients by inducing angiogenesis and expression and stabilization of extracellular skin proteins, in addition to their biocidal effect of reducing the risk of fungal and bacterial infection of the diabetic foot. Thus, the use of copper impregnated socks may be used as a preventive modality. Furthermore, we hypothesize that the copper released from the socks may even be beneficial in the healing of cuts, wounds and even hard to treat skin pathologies.

Insight into the mechanisms of aminoglycoside derivatives interaction with HIV-1 entry steps and viral gene transcription.

In recent years, based on peptide models of HIV-1 RNA binding, NMR structures of Tat-responsive element-ligand complexes and aminoglycoside-RNA interactions, and HIV-1 Tat structure, we have designed and synthesized aminoglycoside-arginine conjugates (AACs) and aminoglycoside poly-arginine conjugates (APACs), to serve as Tat mimetics. These novel molecules inhibit HIV-1 infectivity with 50% effective concentration values in the low micromolar range, the most potent compounds being the hexa-arginine-neomycin B and nona-D-arginine-neomycin conjugates. Importantly, these compounds, in addition to acting as Tat antagonists, inhibit HIV-1 infectivity by blocking several steps in HIV-1 cell entry. The AACs and APACs inhibit HIV-1 cell entry by interacting with gp120 at the CD4-binding site, by interacting with CXCR4 at the binding site of the CXCR4 mAb 12G5, and apparently by interacting with transient structures of the ectodomain of gp41. In the current review, we discuss the mechanisms of anti-HIV-1 activities of these AACs, APACs and other aminoglycoside derivatives in detail. Targeting several key processes in the viral life cycle by the same compound not only may increase its antiviral efficacy, but more importantly, may reduce the capacity of the virus to develop resistance to the compound. AACs and APACs may thus serve as leading compounds for the development of multitargeting novel HIV-1 inhibitors.