**2. Discussion**

#### *2.1. Antimicrobial Silver for Clinical and Medical Usage*

This section presents a selection of some of the most interesting and unique patented products which utilize silver for their bactericidal action in the medical field, including therapies based on silver's antimicrobial properties. The product numbers referred to in this section correspond to those listed in Table 1.

**Table 1.** List of patented medical grade products and medically related products containing silver as an antimicrobial agent.


Surface coatings incorporating silver are a common application. One new approach is a method for producing ready packed medical apparatus which sterilizes itself upon the opening of the package, by creating a vapor that activates a silver-containing hydrophilic surface coating (Product No. 1). The antimicrobial properties of silver have been highly valued in medical application where implanted devices are coated with silver nanoparticles for the antimicrobial effects, but manufacturers need to be aware that this application is claimed in a patent application (Product No. 2) with a very broad claim 1: "An article that is implantable in an animal, the article comprising a microparticulate silver-containing antimicrobial layer stably adhered upon at least one surface of the article." However, the application does not appear to have progressed towards granting. Invasive surgical tools such as medical grade needles (Product No. 3) can also be coated with silver nanoparticles as described in its related patent (Product No. 4). Medical devices that are directly introduced into the human body that contain silver include vascular catheters (Product No. 5), bone implants (Product No. 6), and biliary duct brackets (Product No. 7). Another topical application of antimicrobial silver has incorporated it into coatings applied to the interior surface of a building's exterior wall (Products No. 8a and 8b).

Another general use is for topical treatments. Numerous topical gels with different formulations of silver have been patented. Silver was first used to treat burn wounds in the form of 0.5% silver nitrate solution and silver sulfadiazine cream in 1960 [35]. However, this was impractical as the dressings required rehydration every couple of hours. To overcome this limitation silver nanoparticle-based gels and silver salt-based gels have been developed (Products No. 9a, 9b and 10), with all approaches still considered novel.

Silver based wound dressings have greatly improved in efficacy compared to standard dressings, and more complex dressings have been developed. New knowledge in burn wound managemen<sup>t</sup> led to the discovery of a method to immobilize silver nanoparticles on a gel-support matrix which is attached to a wound dressing (Product No. 11). A recently commercialized wound dressing allows a prolonged use of the dressing for up to 7 days or until saturation, without reapplication (Figure 2). It is made possible through its design, which slowly releases silver ions upon contact with wound exudates. Its highly absorbent padding is also coated with a layer of silicone which is aimed to reduce pain during removal and reapplication of the dressing. (Product No. 12). The use of silver with wound dressings is known to reduce scarring and such formulations are widely used (Product No.13). Silver-based wound dressings are available under brand names with different compositions, such as Mepilex® Ag, Acticoat ™, Aquacel®, Flaminal®, Allevyn® Ag, and Biatain® Ag, SILVERCEL ™. Other products containing a silver component, not specifically developed for wound healing, have been patented for treatment of bacterial infection (Products No. 14a and 14b).

**Figure 2. Mepilex® Ag with instructions for application**. Images used with permission of Mölnlycke Health care, Sweden.

Silver has also been applied across the dental field. Silver has been the key component in dental amalgam fillings for more than one hundred years. However, its antimicrobial properties were not patented. Silver is used in the prevention of infection during and after dental surgery (Product No. 15). Dental support fixtures made out of silver and denture materials, and other body restoration objects, having silver nanoparticles as additives can reduce bacterial infections, especially during first few months of installation (Products No. 16 and 17).

#### *2.2. Antimicrobial Silver in Personal Care Products*

This section presents grooming products and devices which utilize silver for its sanitizing effects, summarized in Table 2. Hygiene and grooming products such as shavers (Product No. 18), toothbrushes (Product No. 19) and sanitary pads (Product No. 20) are frequently employed under adverse conditions where they encounter the bacteria microbiome, but are relied upon to be sanitary. One example of such usage is by the German public company "Beiersdorf AG" which has products incorporating silver for its added antimicrobial properties. They have applied silver over a wide range of products from shower gels and deodorants to first aid bandages (Figure 3).


**Table 2.** List of patented personal-care products containing silver as an antimicrobial agent.

**Figure 3.** Commercial utilization of silver in consumer product lines, including Elastoplast (First aid bandages) and NIVEA (Shower gels and deodorants) for enhanced antimicrobial properties. *Images used with permission of Beiersdorf AG, Germany.*

Since using silver to treat skin infections is common, researchers in dermatology frequently resort to silver for treating conditions related to bacterial colonization, such as body odors (Product No. 21), acne outbreaks (Product No. 22), eczema and rash (Product No. 23).

A range of other personal health products have also added silver to improve their hygienic capacities, including contact lenses (Product No. 24), antimicrobial fabric garments (Products No. 25a, 25b and 25c), breast pump assemblies (Product No. 26), and hair dye (Product No. 27).

Most cosmetic products come in the form of cream, aqueous lotions, or hydrogel medium. It is observed that most manufacturers favor the incorporation of silver colloids into their products as they do not precipitate and separate, with the added benefit of acting as a preservative. Colloidal silver is defined as a mixture of silver ions and silver nanoparticles suspended in an aqueous medium. They are usually synthesized by electrolysis using a set of silver cathodes [48]. Colloidal silver was first used in 1891 by a surgeon named B.C Crede to sterilize wounds [9]. The use of silver grew in popularity between 1900 to the 1940s. Subsequently, antibiotics supplanted the use of silver [9]. Today, many products are offered not only as colloidal silver solutions, but also as personal devices suitable for home use, that synthesize colloidal silver. However, the commercialization of colloidal silver has been accompanied by inconsistencies in colloidal silver production and properties, as well as cases of unexpected side effects. Therefore, the Food and Drug Administration (FDA) has excluded any commercialized colloidal silver that claims health benefits without scientific evidence [49]. Similar action has been taken by the Therapeutic Goods Administration (TGA) in Australia [49] and the European Commission (EC) [50]. The commercial sales of colloidal silver are not banned, but claims of health benefits without scientific support are not permitted.

#### *2.3. Antimicrobial Silver in Domestic Products*

The antimicrobial applications of silver started in ancient times in domestic products like silver plates and pitchers [9]. With that in mind, there continue to be domestic applications of silver, particular for surface treatments (Table 3).

Silver is widely incorporated into surface coatings of electrical goods such as automated bathtubs (Product No. 28), laundry washing machines (Product No. 29), air purifiers with silver filters (Product No. 30) and refrigerators (Product No. 31), to produce 'bacteria-free' products. Application of silver nanoparticles to other household objects with frequent handling such as keyboards (Product No. 32), bath safety aids (Product No. 33), and bathroom safety handles (Product No. 34). Special stand-alone

products such as containers for meat or water/wine/milk storage (Products No. 35a and 35b) are useful applications where bacterial contamination may present a health issue.


**Table 3.** List of patented home-use products containing silver as an antimicrobial agent.

Despite the many beneficial innovations in the use of silver as an antimicrobial agent, its application in cleaning products and disposable tools such as gloves (Product No. 36), disinfectant wipes (Product No. 37), and cleaning detergent (Product No. 38) may have negative environmental impacts. Cleaning products, once used, usually end up in sewage treatment systems, and eventually the environment. This is a concern for silver nanoparticles, as there are currently no effective methods for filtering out silver nanoparticles. The release of large amount of silver products into the environment may lead to disturbances of the microbiological ecosystem, and potentially lead to bacterial resistance to silver [63]. Consequently, alternative methods of sanitization should be considered such as the application of alcohol or bleach which are sufficient for domestic purposes, or employing 'fixed' silver containing surfaces that reduce the risk of environmental release.

Apart from being a threat to beneficial environmental bacteria, another issue to be addressed is the possible longer-term reduction of the potency of silver in killing microbes. Since the discovery of antibiotics, the efficacy of antibiotics has been compromised by over-prescription and over-usage, leading to the current antibiotic crisis. The presence of low levels of antibiotics in the environment fosters the generation of multiple drug resistant strains [64]. Silver is not immune to the generation of bacterial resistance, with several reports in recent years [65,66]. This history suggests a need for a systemic reassessment of the usage of silver in domestic products, so that it is not used too extravagantly, or released haphazardly.

#### *2.4. Antimicrobial Silver in Agricultural and Industrial Products*

Silver has also been used for a variety of agricultural and industrial products. In industry, large scale water purification can be made cost effective by using colloidal silver for purification as it is needed only in small quantities and can purify large quantities of water, though potential environmental risk needs to be considered [67]. For agriculture use, silver has been incorporated in nylon ropes that are used to tie down plants, cover them with netting, and for various other applications. These ropes normally decay after time due to bacterial biofilm formation, so the silver prevents this decomposition [68]. Agricultural use of silver products must be carefully assessed to avoid any impact on the microbial flora and symbiosis. The growth of healthy crop plants relies heavily upon the formation of symbiotic microbes around the roots such as nitrifying bacteria and mycorrhiza [69]. Studies have shown that the contact of bioactive silver to nitrifying bacteria impedes the formation of symbiotic channels [70].

Table 4 presents patented industry and agricultural related products utilizing silver as an antimicrobial agent. An example of agricultural use is Product No. 39 which uses Ag (I) and Ag (II) to treat infections in plants, while Products No. 40 and 41 with coating of a single rope strand with silver to prolong resistance to biofilm formation. Silver coatings can be beneficial in industrial machines which require a completely sterile environment to manufacture food or medical grade products, employing silver in the parts that come in direct contact with the products (Product No. 42). Machinery parts are usually designed for prolonged periods and incorporating silver particles into these materials provides an effective means of isolation and retention of silver so that it is not released into the environment easily.


**Table 4.** List of patented industry and agricultural related products utilizing silver as an antimicrobial agent.

Polymers are extremely versatile and when impregnated with silver nanoparticles, they can be used for numerous applications, such as mass-produced food storage containers (Product No. 43) and industrial scale waste bins (Product No. 44). Sterility in the food and therapeutics industry is crucial, so the incorporation of silver into manufacturing equipment in contact with consumer products can be regarded as an appropriate usage. However, in the case of daily used food containers, frequent usage of silver may not be ideal as there is a risk of accumulation in the human body if the silver leaches, potentially leading to similar side effects as were observed in the middle ages when silver utensils were frequently used [9].

Products No. 45a and 45b describes a water filtration unit containing immobilized silver nanoparticles for water purification purposes. The invention and manufacture of industrial cleaning solutions containing silver (Product No. 46) is a potentially widespread application, as there is a need for instant effective sanitization to prevent bacterial transmission. However, precautions must be observed to prevent environmental release.

#### *2.5. Overview of Patent Literature from 2007–2017*

In the previous sections, applications of antibacterial silver in a variety of fields were discussed. This section presents an overview of silver-related patents on a global level for the purpose of understanding the trends, major applications as well as major contributors. Methods by which the data sets were obtained are reported in Section 3.

Tracking the number of patents disclosing antimicrobial applications of silver for each year over the past decade, as summarized in Figure 4, shows that there has been a steady upward trajectory in the number of silver patent applications in recent years. The increase may have reached a plateau in 2016/17, but it will be necessary to consider data from 2018 and onwards to confirm this hypothesis.

**Figure 4.** Trend analysis of yearly number of patent registrations involving antimicrobial silver applications over the past decade.

The data obtained from Figure 4 can be further dissected to reveal patents registered under each language, as shown in Figure 5. This can be linked to a deduction of the country of origin of these patents. This analysis demonstrates that patents claiming antimicrobial silver products are predominantly contributed by Asian countries, with China (55%), Korea (7%), and Japan (8%) comprising 70% of the chart. Patents registered in English compose 25% while another 5% are various European language patent registrations. It has been speculated that since the FDA and EMA have

reduced influence in the Asian countries [49], this opens up opportunities in Asia for innovations with antimicrobial silver. Indeed, there is some basis for this speculation given the large number of silver related patents being registered in Asian languages, but additional research will be needed to establish the causes of this phenomenon. One of the potential reasons explaining the more substantial contribution of Asian countries in patented silver related innovations and consumer products is the fast-track approval pathway for new drugs in China, supported by consumer trials that are significantly cheaper than in other countries, which can be performed on higher number of participants. There is also a Chinese governmen<sup>t</sup> strategy to commercialize non-Chinese ideas in China and financially support innovators who are willing to patent their ideas in China, with a preference to procure products whose IP is owned or registered in China. Finally, the database search may produce multiple results for a single patent that are particularly difficult to detect for Chinese applications because Chinese individuals' names typically have only three or two characters [79].

**Figure 5.** Analysis of language of patent registrations involving antimicrobial silver over the past decade with major contribution of Chinese (55%), English (25%), Korean (7%), Japanese (8%), and others (5%).

We have also assessed the application of silver according to its field of use. Based on the analysis from Figure 6, only about 20% of the patents in each year claimed medical uses of silver. This could mean that approximately about 80% of the patented silver applications are for other usages, such as domestic, agricultural and industrial usage. If this trend continues, there is potential for damage to the ecosystem if the non-medical uses result in release to the environment. This could lead to a worrisome situation where bacteria evolve resistance to silver, one of few promising alternatives to current classes of antibiotics.

**Figure 6.** Total patents registered globally for silver used in the medical field compared to all other applications.

#### **3. Materials and Methods**

The patent analysis data and trend chart were generated through search results obtained from the scientific publication database, SciFinder® by the American Chemical Society. It was accessed through the University of Queensland Library portal. Results generated were accurate as of 15 June 2018.

#### *3.1. Dataset 1—Application of Antibacterial Silver from the Global Perspective*

The keywords used to generate this search were "antibacterial + silver" and "silver + medical" that narrowed down the number of silver related patents to those presenting the word "silver" in the title and describing only silver components. Therefore, patents with the general terms such as "metal nanoparticles" covering all nanomaterials with potential antibacterial applications like silver, platinum, gold, palladium, copper, zinc, and other metals, are not included here. Result limiters used were publication years (2007–2017) and document type (Patent). Search results yielded 5054 hits of exact words and concepts related to its words. No duplicates were found throughout the result set. The full result was analyzed by publication year and was sorted out by natural order to reflect results in yearly order. Obtained results were used to generate a bar chart as Figure 5 by using Microsoft Word chart sketching function.

#### *3.2. Dataset 2—Application of Antibacterial Silver from a Regional Perspective*

The keywords used to generate this search were as for Dataset 1, "antibacterial + silver". Result limiters used were publication years (2007–2017) and document type (Patent). Search results yielded 5054 hits of exact words and concepts related to its words. No duplicates were found throughout the result set. The full result was analyzed by language and was sorted out by frequency of region. Results obtained were used to generate the pie chart (Figure 6) by using the Microsoft Word chart sketching function.

#### *3.3. Dataset 3—Application of Antibacterial Silver in the Medical Field*

The keywords used to generate this search were "silver + medical". Result limiters used were publication years (2007–2017) and document type (Patent). Search results yielded 1310 hits of exact words and concept related to its words. No duplicates were found throughout the result set. The full result was analyzed by publication year and was sorted out by natural order to reflect results in yearly order. Results obtained were tabulated against dataset 1 to in order to obtain a 100% stacked bar chart presented at Figure 6 by using Microsoft Word chart sketching function.
