Copper oxide impregnated medical textiles in the fight against nosocomial infections

The antimicrobial properties of copper have been recognized for centuries1. Peer-reviewed studies first documented copper’s antifungal, antiviral, and antibacterial properties in 1930, 1958, and 1970, respectively2. The effectiveness of copper surfaces in reducing nosocomial infections was initially published in 19833. In 2008 and 2012, the United States Environmental Protection Agency (US EPA) acknowledged copper alloys and copper oxide-impregnated surfaces, respectively, as effective antimicrobial agents capable of killing over 99.9% of bacteria within two hours. These surfaces maintain their antimicrobial efficacy even after repeated bacterial recolonization and between routine cleaning activities4.

Textiles, particularly reusable medical textiles that are in close contact with patients for extended periods of time, can significantly contribute to bacterial, fungal and viral nosocomial infections5. It has been established that indirect cross-contamination through microorganisms, including viruses that remain infectious on soft and hard surfaces, plays a role in nosocomial infections6.

The production of antimicrobial copper-impregnated textiles was first reported in 20047 , and their potential use as tools in combating hospital-acquired infections in both developed and developing countries was proposed8.

Numerous studies have demonstrated the potent biocidal efficacy of copper oxide-impregnated textiles9. Their antimicrobial effectiveness persists even after 100 commercial washes10, ensuring sustained antimicrobial activity. The high safety profile of cuprous oxide-impregnated medical and consumer products, such as adult diapers and antimicrobial wound dressings, has been validated through extensive research11. Importantly, the capacity of copper oxide-impregnated medical textiles to reduce hospital infections was demonstrated in several clinical trials12.

Cuprous oxide-impregnated woven medical textiles, including sheets, patient gowns, blankets, and towels, have been used in over 25 medical settings in the USA for more than a decade, covering over 8 million patient days without any reported adverse effects.

Cupron holds the only US EPA Registrations for copper-based root intrusion claims

Subsurface drip irrigation (SDI) systems are designed to consistently and efficiently deliver an appropriate supply of water directly to the roots of plants. This method of delivery can prevent or minimize water evaporation and runoff, thus reducing expense and water usage.

Root intrusion of SDI piping and emitter heads can have significant consequences. Root intrusion can result in clogged emitters, low pressure, leaks, altered water distribution, reduced product lifespan, and lower crop yields.

Perhaps the most significant problem caused by root intrusion is clogged emitters. Roots tend to proliferate in environments where water and nutrients are readily available. The root intrusion causes partial or total blockage of the emitters which, in some cases, can prevent water supply to several or all downstream emitters.

One way of preventing root penetration is by treating the water or the drip irrigation components with an herbicide such as trifluralin (Sheval et al. 2008; Spera et al. 2006). The addition of the herbicide may necessitate an injection pump that releases the herbicide at a prescribed dosage and rate, or alternatively the emitters may contain the herbicide. This would provide a continuous slow release of the herbicide as the water passes through it. However, herbicide use carries risks that include environmental, ecological and human health effects (Ahemad and Khan. 2009; Bernard et al. 2005; Eason et al. 2004).

Copper is known to have potent antibacterial, fungicidal and algaecidal properties (Borkow and gabbay 2005; Murray-Gulde etal. 2002). Copper compounds are widely used as algaecides and herbicides (Bishop and Rodgers 2012; Borkow and Gabbay 2005). To prevent any adverse environmental effects of soluble chemistries, Cupron uses non-leaching copper oxide-based formulations to reduce root penetration and obstruction of irrigation systems.

In this study you can read how emitter heads embedded with a Cupron copper additive prevented up to 76% of root intrusion.

As Cupron holds the only EPA registrations for copper compounds authorized to make root intrusion claims, only irrigation companies that purchase directly from Cupron can make such claims.

If your company wishes to make these root inclusion claims, or currently does so and wishes to do so legally, Contact Cupron.

Further, Cupron owns an extensive patent portfolio related, in significant part, to the use of copper compounds embedded in polymeric articles such as emitter heads and irrigation tubing. The current Cupron patent portfolio includes pending and issued patents in the United States and around the world.

It is a benefit to society that the EPA, FDA, FTC, and State Attorneys General are vigilant in enforcing false or unauthorized advertising claims to protect consumers. It is the responsibility of irrigation manufacturers and brands that sell their products in the United States to conform to all relevant legal advertising requirements.

Summary written by Dr. Gadi Borkow.

Statistical analysis performed by Dr. Gil Harari, MediStat Ltd. (www.medistat.co.il)

The effect of Cupron’s linens gradual deployment in 11 Sentara hospitals in reducing the total rate of hospital acquired infections (HAIs) was analyzed. The HAIs included were Clostridium difficile, gram negative multidrug resistant organisms (MDROs), MRSA and VRE infections. The period of data collection of HAIs and the time of Cupron linen deployment for each hospital is detailed in Table 1 below. The data of all hospitals was gathered and referred as a whole and the effect of percent intervention in all hospitals, i.e. Cupron’s linen deployment per all hospitals (Table 2), on the rates of the total HAIs per 1000 patient days (pd) was analyzed.

The statistical methods used were:

1. Generalized Linear Model for Poisson distribution was applied for testing the statistical significance of the relation between the decrease in number of HAI/1000 patient days and the increase in percent of intervention.
2. Generalized Linear Model for Poisson distribution was applied for testing the statistical significance of the decrease in number of HAI/1000 patient days over time (in months resolution).

 

Table 1: HAI Data Collection Period and Month of Cupron Linen Integration in each hospital

Hospital Name	Data collected from – to	Cupron linens integration
SCH	January 2015 – December 2018	January 2015
SPAH	January 2013 – September 20161	October 2015
SVBGH	January 2013 – September 20162	October 2015
SNGH	January 2013 – April 20173	October 2015
SAMC	January 2013 – December 2018	May 2017
SWRMC	January 2013 – December 2018	May 2017
SOH	January 2013 – December 2018	May 2017
SRMH	January 2013 – December 2018	May 2017
SMJH	January 2015 – December 2018	May 2017
SNVMC	January 2015 – December 2018	May 2017
SHRH	January 2015 – December 2018	May 2017

1 Antimicrobial hard surfaces were included on October 2016.

2 Antimicrobial hard surfaces were included on October 2016.

3 Antimicrobial hard surfaces were included on May 2017.

 

Table 2: Percent intervention

Period	Percent Intervention
January 2013 – December 2014	0
January 2015 – September 2015	9.09
October 2015 – April 2017	49.49
May 2017 – December 2018	100

As can be seen in the Figure below, there was a decrease in the total number of HAIs/1000 patient days as the percent of intervention increased (regression red line).

As detailed in Table 3 and 4, there is a highly statistically significant relationship between the decrease in number of HAIs/1000 patient days and the increase in percent of intervention (p<0.0001), as well as the decrease in number of HAIs/1000 patient days over time (p=0.0003).

 

Table 3: Poisson regression on intervention

Analysis of Maximum Likelihood Parameter Estimates
Parameter	DF	Estimate	Standard Error	Wald 95% Confidence Limits		Wald Chi-Square	Pr > ChiSq
Intercept	1	2.0656	0.0568	1.9543	2.1770	1322.76	<.0001
Intervention	1	-0.0049	0.0012	-0.0073	-0.0025	15.61	<.0001

 

Table 4: Poisson regression on month

Analysis of Maximum Likelihood Parameter Estimates
Parameter	DF	Estimate	Standard Error	Wald 95% Confidence Limits		Wald Chi-Square	Pr > ChiSq
Intercept	1	2.1944	0.0861	2.0256	2.3632	649.31	<.0001
Month	1	-0.0082	0.0022	-0.0126	-0.0038	13.28	0.0003

 

During the whole period studied, i.e. between January 2013 and December 2018, in all Sentara Hospitals, the HAI prevention interventions were similar and constant. The main change in the anti-infective measures was the introduction of Cupron’s antimicrobial linens and in a few hospitals also the later introduction of copper oxide impregnated antimicrobial hard surfaces. In order to preclude the potential effect of the antimicrobial hard surfaces on the reduction of HAIs, no data was included in the analyses from the periods when the antimicrobial hard surfaces were already used in the hospitals (see footnotes to Table 1).

Following the full implementation of the Cupron antimicrobial linens, there was a greater than 37% reduction in the HAIs rate as compared to the HAIs rate prior to the medical textiles intervention (Table 5). Although there may be other factors that have contributed to the reduction of HAIs over time in the hospitals studied, the data presented here strongly supports the notion that that there is a good relationship between the deployment of antimicrobial Cupron linens in hospitals and the reduction in the rates of HAIs.

 

Table 5. Mean HAI/1000 patient day per intervention period

Percent Intervention	Months	HAI/1000 patient days (x10-3)	Percent Reduction from Intervention		P value (t-test) From Intervention
			Previous	0	Previous	0
0	24	7.5029	NA	NA	NA	NA
9.09	9	9.5326	-27	-27	0.02	0.02
49.49	19	6.5195	31.6	13.11	0.004	0.09
100	19	4.6708	28.36	37.75	0.03	<0.001

NA- non applicable

Baek J, Yoo M, Koh J, Borkow G.  Reduction of facial wrinkles depth by sleeping on copper oxide-containing pillowcases: a double blind, placebo controlled, parallel, randomized clinical study.  Journal of Cosmetic Dermatology 2012: 11: 193-200.

Summary

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.

 

Borkow G, del Carmen Elias A.  facial skin lifting and brightening following sleep on copper oxide containing pillowcases.  Cosmetics 2016: 3, 24.

Summary

Copper plays a key role in many of the physiological processes that occur in the skin. Previously it was found that sleeping on pillowcases impregnated with microscopic copper oxide particles results in reduction of wrinkles and fine lines.

In the current study, it was examined if sleeping on copper oxide impregnated pillowcases results also in skin lifting and skin brightness. A four week, double blind, randomized study was performed, during which 45 women, aged 37–54, slept on copper oxide containing pillowcases (test group, n = 23) or on control pillowcases without copper oxide (control group, n = 22).

Facial and eye skin surface was measured using an F-ray 3D measurement system and surface analysis was conducted using Image-pro® plus. Skin brightness was measured using a tristimulus colorimeter.

Sleeping on the test pillowcases resulted in statistically significant skin lifting on the cheek area (p = 0.039) and eye area (p = 0.001) after four weeks of use as compared to baseline. The mean skin brightness in those sleeping on the test pillowcases increased after two (p = 0.024) and four weeks (p = 0.008).

No statistically significant changes occurred during the study in the study participants using the control pillowcases. Statistically significant differences between both groups were recorded at two and four weeks for skin brightness and skin lifting, respectively.

In conclusion, sleeping on copper oxide containing pillowcases results in facial skin lifting and brightness of the skin.

 

Borkow G, Gabbay J, Lyakhovitsky A, Huszar M.  Improvement of facial skin characteristics using copper-oxide containing pillowcases: a double blind, placebo-controlled, parallel, randomized study.  International Journal of Cosmetic Science 2009:1-7.

Summary

Copper plays a key role in several processes of skin formation and regeneration. Copper has been shown to be absorbed through intact skin.

We hypothesized that sleeping on fabrics containing copper-impregnated fibers would have a positive cosmetic effect on the skin. The aim of this study was to confirm our hypothesis.

A 4-week, double blind, parallel, randomized study was carried out in which 57 volunteers aged 40–60 years used either copper oxide containing pillowcases (0.4% weight/weight) or control pillowcases not containing copper.

Photographs were taken by a professional photographer of each participant at the beginning of the study and at 2 and 4 weeks after the commencement of the study. Two expert graders (a dermatologist and a cosmetologist) evaluated the pictures for the effect on several cosmetic facial skin characteristics.

The copper-containing pillowcases had a positive effect for the following facial characteristics: reduction of wrinkles (P < 0.001) and crow’s feet/fine lines (P < 0.001) and improvement of general appearance (P < 0.001) at both 2 and 4 weeks. The differences were statistically significant (Wilcoxon scores and chi-squared tests).

Consistent sleeping for 4 weeks on copper oxide containing pillowcases caused a significant reduction in the appearance of facial wrinkles and crow’s feet/fine lines and significant improvement in the appearance of facial skin. In most trial participants, this effect was already noticeable within 2 weeks of using the copper oxide containing pillowcases.

 

Dykes, P.  Increase in skins surface elasticity in normal volunteer subjects following the use of copper oxide impregnated socks.  Skin Research and Technology 2014:  0: 1-6.

Summary

Background: Copper is an essential mineral involved in the formation and stabilization of extracellular skin proteins. As copper can be absorbed through intact skin, we reasoned that using socks containing copper-impregnated fibers may have an effect on skin elasticity.

Methods: A double blind, placebo controlled study was conducted in which one group of healthy volunteers (n = 32) wore socks with fibers containing microscopic copper oxide particles and the other group wore identical socks without copper oxide (n = 28). The socks were worn for at least 10 h a day for 4 weeks. Skin elasticity measurements were taken from three separate test sites on the side of the ankle using a Cutometer at baseline and after 2 and 4 weeks of product use.

Results: There was an increase in the mean net skin elasticity (R5) of 6.4% (P = 0.6) and 31.4% (P = 0.004) after 2 and 4 weeks respectively, in the group of individuals that used the copper oxide containing socks, but no increase in the group of individuals that used the control socks. Similarly, there was an increase in the mean biological elasticity (R7 values) of 3% (P = 0.55) and 20.7% (0.014) after 2 and 4 weeks, respectively, only in the group of individuals that used the copper oxide containing socks. The differences between treatments (i.e. socks used) were statistically significant at 4 weeks (P = 0.0058 and P = 0.0327 for R5 and R7, respectively).

Conclusion: Using copper oxide containing socks results in an increase in skin elasticity of the feet.

Copper has a long history of use for disinfection and treating infections, dating back to ancient civilizations. As early as 2600 B.C., ancient Egyptians used copper for sterilizing wounds and drinking water. In Egyptian hieroglyphics, copper was denoted by the ankh symbol, representing endless life. One of the oldest known medical records, the Smith Papyrus, attributed to an Egyptian physician around 1700 B.C. but based on information dating back to 3200 B.C., documents the use of copper as an anti-infection agent.

The Chinese used copper coins as medicine to cure bladder problems and aches as early as 1600 B.C. Hindus have been storing holy water from the Ganges River (Gangajal) in copper utensils for centuries before drinking it. The water remained clean due to copper’s anti-fouling and bactericidal properties, protecting them from diarrhea. The ancient Greeks during the time of Hippocrates (400 B.C.) independently discovered the sanitizing power of copper. They used copper to treat pulmonary diseases and to purify drinking water. Early Phoenician sailors treated their battle wounds with shavings from their bronze swords and placed copper strips in their ships’ hulls to inhibit fouling. The Romans used copper for treating eye infections and cleaning wounds.

During the Middle Ages, copper was used less prominently in Europe due to a decline in medical knowledge. However, it continued to be used in other parts of the world, such as in traditional Chinese and Indian (Ayurvedic) medicine. During the Renaissance, with the revival of scientific inquiry, copper’s medicinal properties were rediscovered. Alchemists and early chemists experimented with copper compounds for treating diseases and infections. Copper sulfate was used to treat agricultural diseases and as an antiseptic in medical treatments. The advent of antibiotics reduced the reliance on copper for medical purposes. However, it remained in use in various forms, such as copper-based fungicides in agriculture and copper-lined vessels for water purification. In recent decades, the rise of antibiotic-resistant bacteria has renewed interest in copper as an antimicrobial agent.

Early civilizations did not understand the mechanisms by which copper had such a beneficial effect on their lives. Today, with the development of modern microbiology, the potent antimicrobial properties of copper have been scientifically validated and the biocidal mechanisms elucidated (Borkow, G. (2012) Using copper to fight microorganisms. Current Chemical Biology 6(2): 93-103.). Heavy metals, including gold and silver, also possess antibacterial properties, but copper’s specific atomic configuration, featuring a free electron in its outer orbital shell that readily participates in oxidation-reduction reactions, makes copper an extremely reactive and highly effective biocide. Copper ions disrupt microbial cell membranes, generate reactive oxygen species, and interfere with vital enzymes, leading to the death of bacteria, viruses, and fungi. Importantly, copper’s antimicrobial effect is not reduced over time. For example, the old railings of the Grand Central Terminal in New York remain highly biocidal even though they were installed more than a hundred years ago, demonstrating that the antimicrobial properties of copper do not diminish over time (https://www.smithsonianmag.com/science-nature/copper-virus-kill-180974655/).

Today, copper surfaces and copper impregnated products are used in hospitals to reduce the spread of infections (Borkow, G. and Monk, A.B. (2012) Fighting nosocomial infections with biocidal non-intrusive hard and soft surfaces. World Journal of Clinical Infectious Diseases 2(4): 77-90; Marcus et al (2017) Reduction of healthcare-associated infection indicators by copper oxide impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients. American Journal of Infection Control 45(4): 401–403); and to heal wounds (e.g. Melamed et al. (2021) Stimulation of Healing of Non-Infected Stagnated Diabetic Wounds by Copper Oxide-Impregnated Wound Dressings. Medicina 57(10):1129).

Both copper and silver antimicrobial efficacy can be affected by temperature and humidity. In general, higher temperatures can accelerate ion release from both copper and silver surfaces, thus enhancing their antimicrobial activity. Humidity can also play a role, as moisture on the surface can facilitate ion release and enhance antimicrobial efficacy.

But what happens at room environmental conditions? “Room environmental conditions” typically refer to the ambient conditions within an indoor space such as a room or building, and it is under these ambient conditions that you need to achieve the potent antimicrobial effect of the silver or copper containing products. The temperature of the room, measured in degrees Celsius (°C) or Fahrenheit (°F), can vary depending on factors such as climate control systems, outdoor temperature, and building insulation.

In hospitals in the USA, indoor temperatures and humidity levels are typically regulated to ensure patient comfort, staff productivity, and the optimal functioning of medical equipment. While exact ranges may vary depending on specific hospital policies, local climate conditions, and the needs of patients, the recommended temperature range in hospital environments is typically between 20°C (68°F) and 24°C (75°F). This range is chosen to provide a comfortable environment for patients, visitors, and staff while also minimizing the risk of infections and ensuring the proper functioning of medical equipment. And the recommended relative humidity (RH) level in hospitals usually falls between 30% and 60%. This range helps maintain a comfortable indoor environment while also minimizing the growth of mold, bacteria, and other pathogens. Additionally, proper humidity levels can help prevent discomfort associated with dry air, such as irritated respiratory passages and skin.

Thus, the question is – are there any differential antimicrobial efficacies between copper and silver containing products at typical hospital indoor room temperatures and humidity conditions?

In order to address this question, Michels HT and colleagues tested the antimicrobial efficacy of two silver-containing products, one incorporating ‘silver ions in a zeolite carrier’ and the second ‘silver ions as the active ingredient, in an organic matrix’ in comparison to 5 different copper alloys containing between 65% to 99.9 copper, under typical indoor environmental conditions (Michels HT, Noyce JO, & Keevil CW (2009) Effects of temperature and humidity on the efficacy of methicillin-resistant Staphylococcus aureus challenged antimicrobial materials containing silver and copper. Lett Appl Microbiol 49(2):191-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779462/).

Triplicate coupon sample from each material were inoculated with very high titres (2×107 Colony Forming Units (CFU)/coupon) of methicillin resistant Staphylococcus aureus (MRSA). The inoculated samples were exposed to different temperatures and RH conditions for varying times ranging from 15 minutes to 6 hours. The bacteria were then recovered and their viability determined.

While the copper alloys showed a 7-log reduction (99.99999%) of the MRSA viable titres in 75 minutes at 22°C and 50% RH, no meaningful reductions were seen at 360 minutes in the silver coupons. Even at longer incubation times (24 hours) both silver products showed less than 0.3 log reduction at 90% RH at 20°C and 35°C, and no reduction at all at 22% RH and 35°C. In contrast, the copper allows demonstrated > 5 log reduction under all test conditions.

The high efficacy levels displayed by the copper alloys, at temperature and humidity levels typical of indoor environments, compared to the low efficacy of the silver ion-containing material under the same conditions, favours the use of copper alloys as antimicrobial materials in indoor environments such as hospitals. Indeed, copper alloys and polymeric surfaces containing copper oxide microparticles have received EPA approval to make public health claims (EPA registrations 85012, 1-6 and 84542-7, respectively) and thus in many hospitals metallic copper and polymeric surfaces containing copper oxide microparticles were installed in frequently touched surfaces [Coppin JD, et al. (2017) Self-sanitizing copper impregnated surfaces for bioburden reduction in patient rooms. Am J Infect Control 45(6): 692-694.]. In addition, many hospitals surround the patients with antimicrobial copper oxide containing medical textiles (Borkow G (2014) Biocidal hard and soft surfaces containing copper oxide particles for the reduction of healthcare-acquired pathogens. Use of Biocidal Surfaces for Reduction of Healthcare Acquired Infections 1(5): 85-101.https://link.springer.com/chapter/10.1007/978-3-319-08057-4_5).

In summary, copper containing materials are more appropriate for applications in room environmental conditions and accordingly, several studies have shown the efficacy of copper containing materials in reducing bioburden in hospital environments and reducing hospital acquired infections (e.g. Lazary A, et al. (2014) Reduction of healthcare-associated infections in a long-term care brain injury ward by replacing regular linens with biocidal copper oxide impregnated linens. Int J Infect Dis 24: 23-29; Harold TM et al. (2015) From Laboratory Research to a Clinical Trial: Copper Alloy Surfaces Kill Bacteria and Reduce Hospital-Acquired Infections. HERD. 9(1): 64–79; Marcus et al. (2017) Reduction of healthcare-associated infection indicators by copper oxide impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients. American Journal of Infection Control 45(4): 401–403; Arendsen LP et al., (2019) The Use of Copper as an Antimicrobial Agent in Health Care, Including Obstetrics and Gynecology. Clin Microbiol Rev. 32(4): e00125-18).

Copper dressings, as opposed to silver dressings, enhance wound healing

Copper, in addition to being a potent biocide (1), is one of the 11 essential trace minerals needed by human body as it is involved in many physiological processes in all human tissues (2). Copper is indispensable for many wound healing-related processes (3;4). It stimulates a) angiogenesis (5) by upregulating Hypoxia Induced Factor 1alpha (HIF-1α) (6), vascular endothelial growth factor (VEGF) (7), and Cu-dependent transcription factor Atox1 (8); b) expression of integrin (9); c) stimulation of secretion of fibrinogen, elastin and collagen by dermal fibroblasts (10;11) and their stabilization (12;13); d) upregulation of copper-dependent enzymes and polysaccharides, such as lysyl oxidase, metalloproteinases, glycosaminoglycans and small proteoglycans, important for matrix remodeling, cell proliferation and re-epithelization (14-17) and e) migration of skin and stem cells (18;19).

MedCu wound dressing, which are based on Cupron’s platform technology under licence, in addition of having potent antimicrobial properties as described below and in (20), serve as a reservoir of copper ions that are slowly liberated into the wounds, where they readily stimulate wound healing. This was demonstrated in diabetic mice (6) and the substantiated mechanism of enhanced wound healing by the dressings was described (6). Already in 2010, we demonstrated that the upregulation of HIF-1α played a central role in the mechanism of the observed enhanced wound healing by the copper wound dressings. Interestingly, the scientist who discovered HIF-1α received the Nobel Prize for Medicine in 2019.

In contrast, silver, which is not metabolized by the human body, has been found to downregulate HIF-1α (21), explaining at least in part the several reports of toxicity of silver wound dressings, especially to keratinocytes and fibroblasts (22). As such, in a comprehensive review conducted on the effect of silver dressings on wound healing, it was concluded that there is some evidence, although poor, that short-term use silver dressings may be helpful in infected wounds, silver dressings are not appropriate for non-infected wounds and surgical incisions (22).

The different effects of copper and silver on the very important wound healing related factor HIF-1α are depicted in Figure 1.

Figure 1. Copper upregulates HIF-1α (6;23;24). The upregulation of HIF-1α induces generation of new blood capillaries (angiogenesis), extracellular matrix production and epithelialization, leading to improved wound healing (25). Silver, in contrast, inhibits the upregulation of HIF-1α (21), impeding wound healing.

The capacity of copper-oxide containing wound dressings to enhance wound closure in non-infected wounds, in contrast to silver wound dressings, is depicted in Figure 2.

Figure 2. Following circular full-thickness single skin wounds surgically inflicted in the dorsum of diabetic mice, the wounds were directly and continuously covered with control or copper oxide-containing wound dressings or silver-containing wound dressings. The mean wound area ± standard error (SE) at several time points following wounding, the number of the mice examined, and the p values (t-test) between the mean wound areas in the control dressing or copper dressing-treated groups, are depicted (6).

The enhanced wound healing of chronic and hard to heal wounds infected and non-infected wounds, including in wounds that responded poorly to management with silver wound dressings (26), of diabetic patients and other patients, was also demonstrated in the clinic (27-32).

The following Table briefly compares copper and silver in terms of its effect on wound healing and skin related effect.

Feature / Type	Silver	Copper
Wound Healing in General	No direct role in wound healing or any other body physiological function	Essential mineral involved in many of the physiological processes of wound healing
Production of Extracellular Matrix (ECM) Skin Proteins	None	Copper stimulates production by dermal fibroblasts of collagen, elastin and other ECM skin proteins
Production of blood capillaries (angiogenesis)	None	Copper is involved in the production of growth factors needed for formation of blood capillaries
Stabilization of Extracellular Matrix (ECM) Skin Proteins	No	Copper stabilizes the ECM once formed
Reduction of Inflammation	No	Copper has anti-inflammatory properties
Essential element for the human body	No	Yes. Copper is one of the 11 essential elements the body needs
Does the body need these elements to survive	No	Yes
Adverse effects due to skin contact	Rare	Extremely rare
Toxicity	Rare	Extremely rare
Effect of intact skin	Potential argyria (black coloration of the skin)	Improves skin elasticity and improves healthy skin appearance
Does the element play a role in our daily diet	No	Official Recommended Dietary Allowance is 0.9 mg/day in the USA

Antimicrobial activity

As depicted in Figures 3 and 4, and as published (32, 33), copper oxide impregnated wound dressings demonstrated a significant superior antimicrobial efficacy in comparison to most tested silver containing wound dressings against gram positive, gram negative, antibiotic resistant bacteria and fungi.

Figure 3. The antimicrobial efficacy of silver wound dressings and copper oxide impregnated wound dressing against Methicillin Resistant Staphylococcus aureus) MRSA( was tested according to the AATCC Test Method 100.

Figure 4. The antimicrobial efficacy of two additional commercially available silver wound dressings and copper oxide impregnated wound dressing was tested according to the AATCC Test Method 100. MedCu wound dressings reduced to a greater degree the initial amounts (titers) of the microorganisms added to the dressings as compared to the tested silver dressings.

In conclusion, copper oxide-containing wound dressing not only confer protection to the wound and the dressing from microbial contamination, and silver dressings do to a lesser degree, but very importantly the copper dressings stimulate skin regeneration and wound healing. This is achieved via the constant release in situ of ppm of copper ions, which in the wound itself stimulate angiogenesis and formation of intense granulation tissue. Thus, copper wound dressings can be used not only on infected wounds (as silver dressings do for a limited time), but can be used in non-infected wounds for very prolonged periods of time until wound closure.

References

(1) Borkow G, Gabbay J. Copper as a biocidal tool. Curr Med Chem 2005; 12(18): 2163-2175.

(2) Uauy R, et al. Essentiality of copper in humans. Am J Clin Nutr 1998; 67(5 Suppl): 952S-959S.

(3) Borkow G, et al. Could chronic wounds not heal due to too low local copper levels? Med Hypotheses 2008; 70(3): 610-613.

(4) Kornblatt AP, et al. The neglected role of copper ions in wound healing. J Inorg Biochem 2016; 161: 1-8.

(5) Parke A, et al. Characterization and quantification of copper sulfate-induced vascularization of the rabbit cornea. Am J Pathol 1988; 130(1): 173-178.

(6) Borkow G, et al. Molecular mechanisms of enhanced wound healing by copper oxide-impregnated dressings. Wound Repair Regen 2010; 18(2): 266-275.

(7) Sen CK, et al. Copper-induced vascular endothelial growth factor expression and wound healing. Am J Physiol Heart Circ Physiol 2002; 282(5): H1821-H1827.

(8) Das A, et al. Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo. Sci Rep 2016; 6: 33783.

(9) Tenaud I, et al. In vitro modulation of keratinocyte wound healing integrins by zinc, copper and manganese. Br J Dermatol 1999; 140(1): 26-34.

(10) Harris ED, et al. Copper and the synthesis of elastin and collagen. Ciba Found Symp 1980; 79: 163-182.

(11) Philips N, et al. Beneficial regulation of fibrillar collagens, heat shock protein-47, elastin fiber components, transforming growth factor-beta1, vascular endothelial growth factor and oxidative stress effects by copper in dermal fibroblasts. Connect Tissue Res 2012; 53(5): 373-378.

(12) Ahmed Z, et al. Stabilization of fibronectin mats with micromolar concentrations of copper. Biomaterials 1999; 20(3): 201-209.

(13) Ahmed Z, et al. Stabilisation of cables of fibronectin with micromolar concentrations of copper: in vitro cell substrate properties. Biomaterials 2004; 25(5): 803-812.

(14) Lansdown AB. Metallothioneins: potential therapeutic aids for wound healing in the skin. Wound Repair Regen 2002; 10(3): 130-132.

(15) Rucker RB, et al. Copper, lysyl oxidase, and extracellular matrix protein cross-linking. Am J Clin Nutr 1998; 67(5 Suppl): 996S-1002S.

(16) Simeon A, et al. Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+). J Invest Dermatol 2000; 115(6): 962-968.

(17) Simeon A, et al. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sci 2000; 67(18): 2257-2265.

(18) Chen M, et al. Copper promotes migration of adipose-derived stem cells by enhancing vimentin-Ser39 phosphorylation. Exp Cell Res 2020; 388(2): 111859.

(19) Alizadeh S, et al. Copper nanoparticles promote rapid wound healing in acute full thickness defect via acceleration of skin cell migration, proliferation, and neovascularization. Biochem Biophys Res Commun 2019; 517(4): 684-690.

(20) Borkow G, et al. Copper oxide impregnated wound dressings: biocidal and safety studies. Wounds 2010; 22: 310-316.

(21) Yang T, et al. Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis. Int J Nanomedicine 2016; 11: 6679-6692.

(22) Khansa I, et al. Silver in Wound Care-Friend or Foe?: A Comprehensive Review. Plast Reconstr Surg Glob Open 2019; 7(8): e2390.

(23) Martin F, et al. Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation. Blood 2005; 105(12): 4613-4619.

(24) Wu Z, et al. Copper affects the binding of HIF-1alpha to the critical motifs of its target genes. Metallomics 2019; 11(2): 429-438.

(25) Ruthenborg RJ, et al. Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor-1. Mol Cells 2014; 37(9): 637-643.

(26) Gorel, O., Hamuda, M., Feldman, I., Kucyn-Gabovich, I. (2024) Enhanced healing of wounds that responded poorly to silver dressing by copper wound dressings: prospective single arm treatment study. Health Science Reports 14;7(1):e1816.

(27) Melamed, E., Kiambi, P., Okoth, D., Honigber, I., Tamir, E., Borkow, G. (2021) Healing of Chronic Wounds by Copper Oxide-Impregnated Wound Dressings – Case Series. Medicina 57, 296. https://doi.org/10.3390/

(28) Melamed E., Rovitsky, A., Roth, T., Assa, L., Borkow, G. (2021) Stimulation of Healing of Non-Infected Stagnated Diabetic Wounds by Copper Oxide-Impregnated Wound Dressings. Medicina 57(10):1129. doi: 10.3390/medicina57101129.

(29) Weitman, C.C., Roth, T., Borkow, G. (2022) Copper to the wound rescue after everything else failed: Case Report. Archives of Clinical and Medical Case Reports 6 (3): 459-466.

(30) Melamed, E., Rovitsky, A., Roth, T., Borkow, G. (2022) Anterior Ankle Full Thickness Skin Necrosis Treated with Copper Oxide Dressings without Debridement and Skin Graft – A Case Report. Archives of Clinical and Medical Case Reports 6: 501-510.

(31) Melamed E., Borkow G. (2023) Continuum of care in hard-to-heal wounds by copper dressings: a case series. J Wound Care 32(12):788-796. doi: 10.12968/jowc.2023.32.12.788.

(32) Borkow, G., Melamed, E. (2021) Copper, an abandoned player returning to the wound healing battle. In: Recent Advances in Wound Healing. Ed: Shahin Aghaei; IntechOpen London: 5 Princes Gate Court, London, SW7 2QJ, UK. Chapter 9, pp. 165-184. ISBN: 978-1-83968-572-9

(33) Borkow, G., Roth, T., Kalinkovich, A. (2022) Wide Spectrum Potent Antimicrobial Efficacy of Wound Dressings Impregnated with Cuprous Oxide Microparticles. Microbiol. Res. 13(3), 366-376. https://doi.org/10.3390/microbiolres13030029

Enhanced Healing of Wounds that Responded Poorly to Silver Dressing by Copper Wound Dressings: Prospective Single Arm Treatment Study

Dr. Oxana Gorel and her colleagues in wound management at the Loewenstein Rehabilitation Center in Ra’anana, Israel embarked on a study to investigate the efficacy of copper dressings in non-infected wounds that were unresponsive to conventional silver-based treatments. Despite the widespread use of silver dressings as the standard of care in their facility, they encountered numerous cases where wounds showed little to no improvement or progressed at a sluggish pace.

The study enrolled 20 patients, ranging from 18 to 85 years old, with non-infected wounds spanning 2 to 30 cm². These patients had been previously treated with silver wound dressings for a duration of 17 to 41 days, failing to achieve a reduction in wound size greater than 50%. Subsequently, they were switched to copper dressings. Among the participants, ten had diabetes, ten had hypertension, and six suffered from Peripheral Vascular Disease, with two patients exhibiting multiple wounds, predominantly located below the knee due to amputation.

Over a period of 25 days, the mean reduction in wound area during treatment with copper dressings was approximately 2.4 times higher compared to silver dressings, with reductions of 87.35% ± 22.4% and 37.02% ± 25.11% respectively (mean ± SD; p < 0.001; paired t-test).

The notable acceleration in wound healing observed with copper dressings is attributed to the essential role copper plays in all phases of physiological skin repair. In contrast, silver lacks a physiological role in the human body and emerging evidence suggests it may even impede wound healing processes. These findings align with previous clinical reports demonstrating the superior wound healing efficacy of copper dressings, applicable to both infected and non-infected wounds.

Published in the peer-reviewed journal Health Science Reports (2024;7:e1816, https://doi.org/10.1002/hsr2.1816), this study provides strong evidence supporting the hypothesis that the application of copper dressings stimulates wound healing processes in non-infected wounds, offering a promising alternative to silver dressings.