key: cord-0725045-cxk4nelt
authors: Vigneswari, Sevakumaran; Amelia, Tan Suet May; Hazwan, Mohamad Hazari; Mouriya, Govindan Kothandaraman; Bhubalan, Kesaven; Amirul, Al-Ashraf Abdullah; Ramakrishna, Seeram
title: Transformation of Biowaste for Medical Applications: Incorporation of Biologically Derived Silver Nanoparticles as Antimicrobial Coating
date: 2021-02-24
journal: Antibiotics (Basel)
DOI: 10.3390/antibiotics10030229
sha: 3df01a5fdc4491037f1b780786f72e44e2dd24fd
doc_id: 725045
cord_uid: cxk4nelt

Nanobiotechnology has undoubtedly influenced major breakthroughs in medical sciences. Application of nanosized materials has made it possible for researchers to investigate a broad spectrum of treatments for diseases with minimally invasive procedures. Silver nanoparticles (AgNPs) have been a subject of investigation for numerous applications in agriculture, water treatment, biosensors, textiles, and the food industry as well as in the medical field, mainly due to their antimicrobial properties and nanoparticle nature. In general, AgNPs are known for their superior physical, chemical, and biological properties. The properties of AgNPs differ based on their methods of synthesis and to date, the biological method has been preferred because it is rapid, nontoxic, and can produce well-defined size and morphology under optimized conditions. Nevertheless, the common issue concerning biological or biobased production is its sustainability. Researchers have employed various strategies in addressing this shortcoming, such as recently testing agricultural biowastes such as fruit peels for the synthesis of AgNPs. The use of biowastes is definitely cost-effective and eco-friendly; moreover, it has been reported that the reduction process is simple and rapid with reasonably high yield. This review aims to address the developments in using fruit- and vegetable-based biowastes for biologically producing AgNPs to be applied as antimicrobial coatings in biomedical applications.

Silver nanoparticles (AgNPs) have received great attention for diverse applications in nanobiotechnology research [1] . Generally, silver nanoparticles are smaller than 100 nm with 20-15,000 silver atoms [2] . Owning to their chemical stability; thermal, optical, and catalytic properties; and high conductivity, silver nanoparticles have garnered increasing attention [3] . In addition, free release of silver ions from the silver nanoparticles under certain conditions induces cell death of mammalian cells or microbial cells, meaning silver nanoparticles are broad-spectrum antimicrobial agents. Therefore, AgNPs have also become the most widely used sterilizing nanomaterials in various products, including food storage bags, refrigerator surfaces, and personal care products, as well as their use in AgNP production worth noting is the advancement of AgNP composite properties using the bimetallic approach, which allows the adjustment of compositional percentage for application-specific composite properties [18] [19] [20] . Bimetallic studies have the potential to further develop nanocomposite research since this method has demonstrated enhanced outcomes, such as an improved antibacterial effectivity in Cu-AgNPs compared to sole Cuor AgNPs [19] . In addition, AgNPs have also been involved in the design of several recent patents due to their attractive characteristics ( Table 2) . Table 1 . Applications related to silver nanoparticles that have recently been investigated in multiple industries; a brief summary to illustrate the recent trends and advancements in the research of silver nanoparticle applications.

Medical Scaffold Cyto-compatible and antibacterial scaffold [21] Aerogel

Antibacterial aerogel [22] Endodontics

Antibacterial Gutta-percha [23] Dental acrylic resin Antimicrobial and biocompatible resin [24] [25] [26] Ocular therapeutics Antiangiogenic and antibacterial therapeutic nanoparticle [27] Urinary catheters Antibiofilm urinary catheter [28] Medical dressing Wound-healing cotton fabric [29] Electronics Supercapacitor and electrochemical sensing High electrochemical capacity in 3D-printed microfluidic device [30] Optoelectronic applications Enhanced optical transmittance [31] Sensing and biosensing Stable and rapid photo-optical sensor [32, 33] Packaging Table 2 . Recent patents related to silver nanoparticles.

Antimicrobial agent for wound healing Composition comprising amino acid polymers and a bioactive agent and method of preparing thereof US20200368176A1 [38] Scaffold Coating scaffolds AU2020250274A1 [39] Electromagnetic shielding agent Microcellular foamed HIPS electromagnetic shielding material and preparation method and application thereof CN111961305A [40] Slow-release antibacterial agent Preparation method of nano-silver slow-release antibacterial agent CN111973794A [41] Biocidal agent

Mobile device for cleaning and disinfecting room air that can be operated using a temperature difference DE202020105700U1 [42] Antioxidative agent Skin cleanser AU2020227091A1 [43] Antimicrobial agent Synthetic fiber with semi-permanent antibacterial and anti-fungal properties and uses thereof KR102163245B1 [44] Antimicrobial coating A system that provides local cooling to the brain and spinal cord JP2020171791A [45] Reducing agent in biopolymer microgel

Method of reducing an organic pollutant in contaminated water US10793684B1 [46] Slow-release bactericidal agent Medicine for treating ant bite and its medicine applying plaster CN111671844A [47] Colorimetric sensing of trypsin Trypsin detection film, preparation method and application thereof and trypsin detection kit CN111808916A [48] HIPS: high impact polystyrene.

The desirable traits of AgNPs have been reflected by the intensive and comprehensive research of the nanoparticles' potential as an antimicrobial coating. AgNPs have been recurrently credited for their biocidal (i.e., viricidal, fungicidal, bactericidal, parasiticidal, mosquitocidal), theranostic, thermoplasmonic, antiplasmodial, catalytic, electrochemical, magnetic, optical, surface-enhanced Raman scattering, large surface-area-to-volume ratio, spatial confining, surface energy, high specific surface, and chemically stable properties [14, 15, [49] [50] [51] [52] [53] [54] [55] [56] . The mentioned qualities of AgNPs have amplified their use in various applications, especially in the medical and electronic industries. For example, electrically conductive and small (1-100 nm) AgNPs can traverse nuclear and cellular membranes to trigger higher cytotoxicity with fewer implications than other drugs on the market [16] . Furthermore, AgNPs also allow versatile modification in terms of morphology and composite adjustments for desired applications [12, 50] . The efficacy, toxicity, or production costs of AgNPs can be adjusted by exploiting a variety of accessible hybrid materials (e.g., silver/biopolymer nanocomposites), as well as forming them into spherical, diamond, octagonal, or thin-sheet forms [57] [58] [59] . For example, polymers embed nanoparticles and control nucleation while AgNPs augment the nanocomposite's performance [60, 61] . In brief, the properties of AgNPs have been broadly recognised, hence driving further research and development of this material.

Although AgNP investigation is relatively focused on surfaces and medicine, the research and development of AgNPs in the sensorics field for analytical and medical equipment are comparable. AgNPs have been investigated for target biosensors of DNA or cancer, surface-enhanced Raman scattering, molecular imaging of cancer cells, enhanced X-ray contrast, photothermal ablation of tumours, colorimetric sensing of heavy metals and ammonia for water purification, signal enhancers, and biological assays [62] [63] [64] [65] [66] [67] [68] [69] . Biological assays can comprise considerable data requiring high-throughput screening technologies and AgNP compound semiconductors for biotagging. Other than their application in sensorics, the electrochemical and conductive traits of AgNPs enable their function as a power source or conductor. For example, AgNPs have been employed in power engineering, enhanced energy storage of batteries, intercalation material of electrical batteries, silver/polyaniline composites of microelectronic devices, and conductive inks [50, 61, 70, 71] .

Furthermore, AgNPs can also function as catalysts in biochemical and chemical reactions [65, 72] . AgNPs have been reported to catalyse the oxidation of methanol to formaldehyde, ethylene to ethylene oxide, the reduction of 4-nitrophenol into 4-aminophenol, and the degradation of acridine orange and methylene blue dyes [72, 73] . Additionally, AgNPs have also shown potential applications in the agricultural field. The mentioned nanoparticles can enhance plant growth while affecting the root length, shoot length, biomass, and seedling germination [74] . Accordingly, mixed reactions were observed with different plant species, age, nanoparticle concentration, and treatment duration [74] [75] [76] [77] [78] [79] . Existing literature has upheld the attraction to AgNPs of multiple industries, especially surfaces and medicine. However, several routes regarding the biocidal mechanisms and chronic implications of AgNPs on living organisms are yet to be clarified. Consequently, thorough research is necessary to confront critical issues, such as the interaction of AgNPs with the biological system and natural environment.

Generally, there are two approaches involved in the synthesis of silver nanoparticles: either the "top-down" approach or the "bottom-up" approach ( Figure 1 ), which are commonly achieved using physical, chemical, and biological methods. In the bottom-up approach, nanoparticles can be synthesized using chemical and biological methods involving the self-assembly of atoms into new nuclei, which grow into a nanoscale particle. Conversely, in the top-down approach, suitable bulk material is broken down into fine particles by size reduction with various lithographic techniques, grinding, milling, sputtering, and thermal/laser ablations [80] . In the bottom-up approach, chemical reduction is the most common scheme for the synthesis of silver nanoparticles [81, 82] . Different organic and inorganic reducing agents, such as sodium borohydride (NaBH 4 ), sodium citrate, ascorbate, elemental hydrogen, Tollens reagent, N,N-dimethyl formamide (DMF), and poly (ethylene glycol) block copolymers are used for the reduction of silver ions (Ag+) in aqueous or nonaqueous solutions [80, [83] [84] [85] [86] [87] . The physical and chemical methods can produce well-defined AgNPs, but they have certain limitations in terms of expensive equipment usage, high energy consumption, and operation conditions, for instance, high temperature and pressure [88] . Chemical and physical methods are often costly and generate toxic byproducts; these methods involve the utilization of hazardous chemicals such as sodium borohydride (NaBH 4 ) as a reducing agent, which has an adverse effect on health due to the absorption of harmful chemicals on its surface. This has brought about the development of biological synthesis, which has been recognized as an inexpensive and eco-friendly process. Biosynthesis of nanoparticles through biological approaches offers an alternative to conventional chemical and physical methods [80] . This process includes the utilization of microorganisms, plant extracts, or agricultural biowaste, which offers a green solution with limited usage of toxic chemicals [83] . It has been noted that synthesized AgNPs can have a synergic relationship with the antibiotic levofloxacin, increasing the total antimicrobial properties against Grampositive and Gram-negative pathogens [89] , as well as exerting cytotoxic effects on different cancerous and normal cell lines. In addition, AgNPs are highly efficient due to a high surface-area-to-volume ratio, which can easily disrupt and penetrate bacterial cells when compared to silver ions alone [1] .

In the green synthesis of AgNPs, plant constituents, including proteins, enzymes, and carbohydrates, are used together with AgNO 3 to formulate nanoparticles that can easily interact with targeted biomolecules [90] . The bioactive components in plants act as reducing agents to facilitate the reduction of metallic ions to nanoparticles [91] . Several studies have reported that the biological synthesis of nanoparticles has gathered much attention due to the high-yield production of AgNPs. Furthermore, this biological approach is green, cost-effective, and biocompatible without the use of toxic chemicals. Moreover, in the biological synthesis of AgNP, it is relatively simpler to control the size, shape, and distribution of nanoparticles by optimizing several parameters, including the synthesis methods, quantity of precursors, temperature, pH, and quantity of reducing and stabilizing agents [92] . The biological synthesis of AgNPs utilises various biological systems, such as bacteria, fungi, and plant extracts, and small biomolecules such as vitamins and amino acids [6] . In this green chemistry approach, several bacteria including Pseudomonas stutzeri AG259, Lactobacillus strains, Bacillus licheniformis, Escherichia coli (E. coli), Brevibacterium casei, fungi including Fusarium oxysporum, and plant extracts including Allophylus cobbe, Artemisia princeps, and Typha angustifolia were utilized [93] .

Biowaste is also among the various biological systems that can be used to biologically synthesise AgNPs. The consumption of biowastes to produce AgNPs employs a simple, safe, eco-friendly, cost-effective, waste-to-wealth, and circular bioeconomy approach [94] [95] [96] . The prominent categories of biowastes used to biologically synthesise AgNPs are forestry, industrial, and agricultural wastes ( Figure 2 ) [95] [96] [97] [98] . Different types of biowastes, such as forest biomass, paper industry waste, sugar industry waste, spent coffee grounds, husks, as well as vegetable and fruit peels, have been broadly researched for the production of AgNPs (Table 3) . Existing literature has shown a focus of research attention on AgNP synthesis using fruit pericarp, likely due to the ease of access, relatively lower cost, and abundance of this waste type. Biowastes are sustainable renewable energy sources, hence the management and utilization of biowastes can help to alleviate the global energy consumption demand [9] . Biowaste-derived AgNPs are thus not only of low economic value but also environmentally and economically sustainable [94] . The efforts in the biological conversion of waste to a valuable product, AgNPs, not only reduce waste generation and AgNP production costs, but also help to shift the economy from a cradle-to-grave to a cradle-to-cradle concept [9] . Therefore, the biosynthesis of AgNPs from biowastes is considered to reinforce the valuable utilization of biomass for the synthesis of metal nanoparticles. Consequently, the major advantage of biological synthesis is the elimination of toxic chemicals, and the use of biological molecules for the synthesis of AgNPs is profoundly eco-friendly and pollution-free. Solanum tuberosum (potato peels) 20-40 nm -General range of AgNP-related applications [115] Oryza sativa japonica (rice husks) <47.90 nm -General range of AgNP-related applications [116] 

In the context of antibacterial purposes, silver metal has been a favoured material even 2000 years ago, and especially starting from 19th-century civilizations [117] . The studies of silver as a material that exhibits antimicrobial properties have also gained increasing attention and extensive experimentation among researchers, owing to its range of bactericidal attributes, potencies, low level of toxicity, and numerous utilisations as a sanitizer [118] . Silver nanoparticles (AgNPs) especially have prevailed in showing positive results in inhibiting the bacterial growth of a variety of Gram-negative and Gram-positive bacteria [119] . As many as 650+ microbes that are known to be affected by the antimicrobial activity of silver-based compounds have been recorded [80, 120] .

The usage of AgNPs has its own precedence of having lower reactivity compared to silver ions, making this material greatly applicable for medical and restorative purposes [121] [122] [123] . Out of the wide range of possible implementations of AgNPs in these fields, numerous research and development projects have been extensively deployed towards their auspicious utilization in wound dressings, tissue scaffolds, and protective clothing use, among others [124] [125] [126] . Furthermore, licensing bodies such as the FDA and EPA of the USA, the SIAA of Japan, the Korea Testing and Research for Chemical Indus-try, and the FITI Testing & Research Institute of Korea have granted the development of numerous products containing or associated with AgNPs [127] . This demonstrates how Ag-NPs efficacy as antimicrobial material has been taken advantage of in being implemented domestically and clinically [120] .

As a type of metal, AgNPs possess an oligodynamic effect, which is related to the biocidal effects of metals, particularly heavy metals, that may potentially take place in low concentrations of that particular material [118] . There are some important facets regarding the particular antimicrobial features of AgNPs and their innate physical and chemical attributes, which sustain their nanoscale size, enhance their rapid distribution, and avoid accruement [128] . The large surface areas of AgNPs are the important feature of their enhanced oligodynamic effect in their capability to cohere with bacterial plasma membranes, their aptitude for cell perforation, to induce synthesis of reactive oxygen species (ROS) and free radicals, and to function as signal transduction pathway modulators of microorganisms [129] . In addition, the distinctions in AgNPs' physicochemical traits, such as size [130] , morphology [131] , oxidation and dissolution states [132] , and charges and coating of surfaces [133, 134] , have great impact on their antimicrobial activity [135, 136] .

Silver nanoparticles are becoming a hot topic among those in the scientific domain due to their wide range of bactericidal and fungicidal qualities. The effect of microbial inhibition can even affect both Gram-positive and Gram-negative bacteria, with high antibacterial activity. Currently, the mechanism of actions of AgNPs as antimicrobial agents consist of four main actions [118, 123] :

Adherence onto the cell membrane of microorganisms.

Perforation of cells by AgNPs, interrupting cell molecules and causing intracellular destruction.

Effecting toxicity of microbial cells through the synthesis of ROS that stimulates cell oxidative stress.

Obstruction of cell signal transduction pathways.

In a condition where AgNPs are introduced to any microorganism, the positive charge of silver ions prompted from the oxidation of AgNPs will be attracted towards the negatively charged cell membrane of microbes due to the electrostatic effect, causing the nanoparticles to fasten to the cell wall or membrane [137] . The changes in the shape of cell membrane are permanent and irreparable when AgNPs are completely attached to the plasma membrane of the microorganism, which can cause impairment of the lipid bilayer and permeability of the plasma membrane and thus ability to enclose its content of cytoplasm and nucleoplasm [138] . The modifications in the morphology of the cell can result in affecting the cell's capability to separate the cell from the surrounding interstitial fluid. As an example, formation of silver ions by the nanoparticles will reorient the movement of potassium ions (K+) from the inside and outside of the cell, which can impede the mobilization activity of essential materials of the cell [118] . Moreover, increment of membrane permeability may induce the depletion or discharge of intracellular contents including cytoplasm, ions, adenosine triphosphate (ATP), and proteins, which can engender the formation of a ghost cell of a microbe. Excretion of all essential materials out of the microorganism through membrane leakages, leaving behind an empty microbial cell envelope, is known as the ghost cell effect [139] . A study by Vazquez-Munoz et al. proved that the coherence of the plasma membrane of Gram-negative bacteria (E. coli and Salmonella typhirium) was disrupted by AgNPs' bactericidal activity through the action of membrane depolarization and destabilization, which was observed via transmission electron microscopic (TEM) images. Figure 3 shows the mechanism of AgNPs' adhesion to the cell membrane [140] . Besides the mechanism of binding onto the surface of the membrane, AgNPs can also pierce through the microbes and cause disturbance of crucial biomolecules and cellular activity [118] . There are water-filled channels known as porins located in the extracellular membrane of Gram-negative bacteria (e.g., E. coli), which can be a passageway for AgNPs to invade the intracellular environment. Following successful AgNP invasion, they will begin to cohere with biomolecules and cellular structures, including proteins, DNA, lipids, and mitochondria, that can deteriorate the inner composition of the bacteria. In addition, the free-roaming silver ions discharged from AgNPs will cohere with negatively charged proteins, resulting in modifications of protein composition and ultimately protein degeneration [118] . There is a study that demonstrated the inhibition activity of AgNPs by hindering the respiratory chain dehydrogenase through the metamorphosis of a number of enzymes, such as glycerol-3-phosphate dehydrogenase into dihydroxyacetone, in a Gram-positive bacterium (S. aureus), which concluded with the obstruction of the bacteria's normal growth and metabolic activity [141] . AgNPs can also trigger DNA denaturation and impede the cellular growth of bacteria when in contact with bacterial DNA [142] . Additionally, the stability of DNA composition can be lessened through AgNP-DNA interactions due to the occurrence of electrostatic repulsion between these two because of their similar polar charge [143] . Moreover, detachment of double-stranded DNA into single strands through a hybridization process may occur due to interfaces between silver ions and DNA, causing dissociation of H-bonds in DNA strands [144] . The simplified mechanism is illustrated in Figure 4 .

Reactive oxygen species (ROS), a type of cellular oxidative stress of microorganisms, is another course of action affected by AgNPs' inhibiting activity [145] . AgNPs can cause an increment of cell oxidative stress due to the nanoparticles' capability of generating ROS and free radicals [118] . The potential of nanoparticles to prompt lipid destruction, perforation of biomolecules, and also programmed cell death are things to look into as it suggests the occurrence and generation of intercellular ROS inside the cells is one of the biggest factors to determine the toxicity of AgNPs [146] . Su et al. reported that treatment with clay and AgNPs could enhance the bactericidal properties towards S. aureus, P. aeruginosa, and Streptococcus pyrogens, causing a declination of membrane integrity in response to the formation of ROS, followed by cell death [147] . There is another study that proposed that the antibacterial activity due to ROS generation is dependent on the size of AgNPs, where nanoparticles with a concentration of 10 mg/L resulted in higher levels of ROS production in Azotobacter vinelandii and Nitrosomonas europaea compared to 50 mg/L of AgNPs [148] . The method of ROS formation in bacterial cells induced by AgNPs is shown in Figure 5 . The mechanism of action involving pathway signaling is influenced by the phosphorylation and dephosphorylation cascade of important enzymes or protein contents that is required for growth of bacteria and cellular activity [118] . The distinctive physicochemical traits of AgNPs may bring about the potential for another mechanism of bacterial inhibition through functionality of these nanoparticles as modulators of cell signal transduction [149] . A study had experimented on the capability of gold-silver nanoparticles to effectuate bacterial cell apoptosis through destruction of the bacterial actin cytoskeletal network [126] . The study also discovered that the cytoskeletal actin MreB (an actin homologue), which has a crucial responsibility in the modulation of local cell shapes and survivability, was experiencing changes in morphology, causing an increase of membrane liquidity and thus mediating cell destruction. Figure 6 shows the mechanism of action of bacterial inhibition through pathway signaling modification. Different strains will experience different mechanisms of action of nanoparticles' antibacterial activities. Table 4 lists the microbial inhibition studies of AgNPs, including their mechanism of action. Table 4 . The antimicrobial activities of AgNPs [118, 123] .

Gram-positive Staphylococcus aureus <100 nm Oxidative stress caused by modification of kynurenine protein [152] Bacillus subtilis <100 nm

Modification of kynurenine protein-mediated kynurenine pathways that inhibited growth [152] Listeria monocytogenes 23 ± 2 nm Increase in ROS levels [153] Clostridium diphteria 28.42 nm Cell wall hostility, denaturation of proteins [154] Gram-negative Escherichia coli <100 nm Oxidative stress caused by modification of kynurenine protein [155] Escherichia coli AB1157 8.3 ± 1.9 nm Destruction of DNA [156] Escherichia coli ATCC25922 3.91 nm/2.29 nm/1.59 nm Obstruction of membrane due to increased ROS formation [151] Pseudomonas aeruginosa 45 nm Binding of AgNPs to cell wall and synthesis of ROS [157] Klebsiella pneumoniae <100 nm

Modification of kynurenine protein-mediated kynurenine pathways that inhibited growth [152] Proteus sp. 38 nm Estrangement of cell membrane and hindered DNA replication [155] Vibrio cholera <50 nm Impeded metabolic pathways [158] Salmonella thyphii 2-23 nm Cell wall rupture [159] 

AgNPs have been investigated for a multitude of applications due to their qualities. The existing commercial products that employ the use of AgNPs include surfaces, textiles, food containers, nutrient supplements, cosmetics, packaging materials, electronics, domestic appliances, water and air disinfectants, as well as medical and laboratory instruments [11, 160] (Figure 7) . Furthermore, AgNP research and development has also contributed to the surfaces, medical, electronic, remediation, sanitation, catalyst, and agricultural industries, as well as analytical and medical equipment. Existing literature has shown relatively abundant publications of AgNPs in the industrial fields of surfaces and medicine. The properties of AgNPs (e.g., biocidal, superhydrophobic, thermal conductive) have advocated its use as a sheet or layer to improve apparel, footwear, paint, wound dressings, cosmetics, appliances, packaging, and plastics applications [161] . For example, biocidal AgNPs allow the production of antimicrobial paints and sterile wound dressings for accelerated wound healing, which incites the option of future AgNP deployment in odourless fabrics for sensitive skin [44] . In addition, silver/polymer composites allow applications that require high thermal conductivity, such as electronic packaging, encapsulations, light-based sensors, and satellite devices [50] . The prospects of AgNPs as an accommodating surface have also promoted its application as a coating in the field of medicine. The previously mentioned qualities of AgNPs have fostered its application as antimicrobial medical coatings in scaffolds, skin recipient and donor sites, wound dressings, clinical fabrics, cancer therapy, protein detection, antibiofilm catheters, hydro-or aerogels, and gene or drug delivery. The diverse applications of AgNPs in medical coatings demonstrate the prominence of the AgNPs' superior antimicrobial trait. For example, biocidal fabrics are essential clinical accessories since microbial pathogens can survive on laundered clothes for up to 3 months, posing infection risks to surgical wounds, bedding, or patient clothing. Moreover, infections contracted post-injury or surgery can be fatal. Besides that, AgNPs have also shown to inhibit cancer cell lines, multidrug-resistant bacterial strains, plus the herpes simplex virus type 1 (HSV-1) and influenza A virus subtype H1N1 [162] [163] [164] [165] . In addition, therapeutic gel comprising AgNPs has shown potential to accelerate wound healing without scarring. Also, AgNP-based antimicrobial coatings have been applied in the sanitation sector for various public and domestic-use surfaces including wood, glass, and polystyrene. In conclusion, AgNPs possess immense potential as a coating enhancer for various industries, although they are remarkably valuable in the medical field due to their biocidal feature.

The properties of AgNPs have been widely acknowledged, thus propelling the research and development of this material. The main advantages of biomediated AgNPs are their nontoxic and eco-friendly production route and properties, which reduce undesirable negative implications on human health [90] . The biologically mediated AgNP synthesis is thus safer for medical applications and essential antimicrobial coatings that are required in clinical settings. The biological synthesis of AgNPs has also been reported to be rapid and of high yield. Moreover, unlike physical and chemical methods, the biomediated synthesis of AgNPs does not require expensive equipment, high pressure, high temperature, or chemical additives (e.g., stabilizers) [80] [81] [82] [83] [84] [85] [86] [87] . However, although the chemical synthesis of AgNP generates relatively uniform structures, the capability to produce homogenous surfaces and crystallographic structures is a current and major challenge for the biological synthesis of AgNPs. The inconsistent composition of biowaste in each batch can cause yield fluctuations and problems with standardized quality demands of the AgNP-based final product [91] . Furthermore, the availability of biowaste for large-scale continuous manufacturing and the feasibility (e.g., costs) of biowaste refining remains questionable.

Nevertheless, the existing and projected gaps of AgNP research should be identified concurrently to better protect public health in the direction of the third Sustainable Development Goal (Figure 8 ). The potential harm of loosely attached or detached nanoparticles' entry into the biological system is still being validated. The main target organs (e.g., liver, spleen, gastrointestinal tract, lung) likely to be exposed to nanoparticles after intravenous administration should be monitored, as the mononuclear phagocytic system may also recognise these nanoparticles as foreign agents and then remove them from the circulation system [166] . Additionally, past research has been focused on the fine manipulation of the crystallinity, shape, size, and stability of AgNPs to achieve various physicochemical characteristics. Although green biological synthesis methods at present are mostly preferred over chemical and physical techniques (e.g., photochemical, electrochemical, thermal, radiation, lithographic, and laser ablation processes) to tailor nanoparticle qualities toward specific applications, any inevitable use of hazardous materials during the synthesis or structuring of AgNPs should not be overlooked in terms of usage and environmental safety [167] [168] [169] [170] . Other gaps in AgNP research should also be pinpointed to attain more comprehensive insight in this field. Currently, limited information is available on the possible risks of AgNP exposure or lack thereof. Other knowledge gaps within AgNP research include the genotoxicity, carcinogenicity, and toxicokinetics of AgNPs as individual compounds and composites in a wide range of forms and intensities [11, 171, 172] . Nevertheless, as a final point, AgNP advancements continue to move forward despite the limitations and gaps confronted in this field, thus emphasising the prospective outlook of AgNP-related applications. In conclusion, AgNP nanocomposite research has been extensively reported on and developed over the past decade. The present review reports the industrial use of AgNPs, especially in the field of medicine, chiefly due to their antimicrobial properties. Along with other attractive properties of AgNPs, research and development involving the utilisation of this material have been increasing, particularly in 2019 and 2020. Our review reveals the diverse applications of AgNP that include but are not limited to medical antimicrobial coatings. The possibility of composition and chemical modifications to achieve desirable properties and functionalities has been and is still being explored as a high-potential research area. Moreover, several studies have accentuated the need to better understand the environmental and biological impacts of AgNPs. Substantial reductions in environmental implications can be obtained with the appropriate waste management strategies of AgNP development prior to further commercialization. Furthermore, future research is also expected to focus on cost-effective processes and more sustainable materials. In addition, efforts are also observed in AgNP development for the large industrial scale of the material sciences and manufacturing fields. 

The data presented in this study are openly available.

The authors declare no conflict of interest.

Food Shelf Life Stability

Biosynthesis of nanoparticles and silver nanoparticles

Synthesis and characterization of silver nanoparticles and their application as an antibacterial agent

Biosynthesis of silver nanoparticles and its applications

Green synthesis of gold and silver nanoparticles from plant extracts and their possible applications as antimicrobial agents in the agricultural area

Silver nanoparticles: Synthesis, characterization, properties, applications, and therapeutic approaches

Preparation and characterization of biocompatible silver nanoparticles using pomegranate peel extract

Bio-based synthesis of silver nanoparticles from orange waste: Effects of distinct biomolecule coatings on size, morphology, and antimicrobial activity

Bioconversion of agro-industry sourced biowaste into biomaterials via microbial factories-A viable domain of circular economy

Potent antiviral effect of silver nanoparticles on SARS-CoV-2

Change in functional state of bone marrow-derived mesenchymal stem cells after incubation with silver nanoparticles

Nanocomposite hydrogels containing silver nanoparticles as materials for wound dressings

Tryptophan-stabilized plasmonic Fe 3 O 4 /Ag nanoparticles

Encapsulation of amphotericin B into quercetin based silver nanoparticles: Preparation, characterization and preliminary investigation of antiparasitic activity

Green synthesis of silver nanoparticles from de-oiled rhizomes of Curcuma longa L. and its biomedical potential

Phytosynthesis of silver nanoparticles using Rhynchosia heynei wight & arn leaf extract: Characterization and in vitro assessment of antimicrobial, antioxidant and anticancer activities

Green synthesis of silver nanoparticles using Ledebouria revoluta bulb extract and its biological activity

A simple robust method of synthesis of copper-silver core shell nano-particle: Evaluation of its structural and chemical properties with anticancer potency

Copper-based nanoparticles, their chemistry and antibacterial properties: A review

Synthesis of phenolic precursor-based porous carbon beads in situ dispersed with copper-silver bimetal nanoparticles for antibacterial applications

Biocompatible silver nanoparticles incorporated in acrylic resin for dental application inhibit Candida albicans biofilm

Toward understanding the purely geometric effects of silver nanoparticles on potential application as ocular therapeutics via treatment of bacterial keratitis

Oxidative stress induced antimicrobial efficacy of chitosan and silver nanoparticles coated Gutta-percha for endodontic applications

Regenerated cellulose nanofibers from cellulose acetate: Incorporating hydroxyapatite (HAp) and silver (Ag) nanoparticles (NPs), as a scaffold for tissue engineering applications

Physicochemical and biological assessment of silver nanoparticles immobilized Halloysite nanotubes-based resin composite for dental applications

Biogenic synthesis and antimicrobial activity of silica-coated silver nanoparticles for esthetic dental applications

Lightweight aerogels based on bacterial cellulose/silver nanoparticles/polyaniline with tuning morphology of polyaniline and application in soft tissue engineering

In vitro analysis of green fabricated silver nanoparticles (AgNPs) against Pseudomonas aeruginosa PA14 biofilm formation, their application on urinary catheter

Green synthesis of silver nanoparticles from Curcuma longa L. and coating on the cotton fabrics for antimicrobial applications and wound healing activity

Greenly synthesized silver nanoparticles for supercapacitor and electrochemical sensing applications in a 3D printed microfluidic platform

Laser synthesis of surfactant-free silver nanoparticles for toxic dyes degradation and SERS applications

Incorporation of silver ion on structural and optical characteristics of CeO 2 nanoparticles: White LED applications

Quantitative analysis of glucose by using (PVP and MA) capped silver nanoparticles for biosensing applications

Carboxymethyl cellulose/cellulose nanocrystals immobilized silver nanoparticles as an effective coating to improve barrier and antibacterial properties of paper for food packaging applications

Controlled size green synthesis of bioactive silver nanoparticles assisted by chitosan and its derivatives and their application in biofilm preparation

Green synthesis and characterization of Camellia sinensis mediated silver nanoparticles for antibacterial ceramic applications

A green approach for the synthesis of silver nanoparticles by Chlorella vulgaris and its application in photocatalytic dye degradation activity

Composition Comprising Amino acid Polymers and a Bioactive Agent and Method of Preparing Thereof

Microcellular foamed HIPS Electromagnetic Shielding Material and Preparation Method and Application thereof. Chinese Patent No. CN11196105A

Preparation Method of Nano-Silver Slow-Release Antibacterial Agent. Chinese Patent No. CN111973794A

Mobile Device for Cleaning and Disinfecting Room Air That Can Be Operated Using a Temperature Difference

Australian Patent No. AU2020227091A1

Synthetic Fiber with Semi-Permanent Antibacterial and Anti-Fungal Properties and Uses Thereof. Korean Patent No. KR102163245B1

A System that Provides Local Cooling to the Brain and Spinal Cord

Method of Reducing an Organic Pollutant in Contaminated Water

Medicine for Treating ant Bite and Its Medicine Applying Plaster. Chinese Patent No. CN111671844A

Trypsin Detection film, Preparation Method and Application Thereof and Trypsin Detection Kit. Chinese Patent No. CN111

Synthesis of biocompatible silver nanoparticles by a modified polyol method for theranostic applications: Studies on red blood cells, internalization ability and antibacterial activity

Silver nanoparticles and its polymer nanocomposites-Synthesis, optimization, biomedical usage, and its various applications

Plant-based fabrication of silver nanoparticles and their application

Band structure, morphology, functionality, and size-dependent properties of metal nanoparticles

Green synthesis and characterization of silver nanoparticles fabricated using Anisomeles indica: Mosquitocidal potential against malaria, dengue and Japanese encephalitis vectors

Structural, morphological and magnetic properties of nickel-carbon nanocomposites prepared by solid-phase pyrolysis of Ni phthalocyanine

Fabrication of antibacterial surface via UV-inducing dopamine polymerization combined with co-deposition Ag nanoparticles

The progress of silver nanoparticles in the antibacterial mechanism, clinical application and cytotoxicity

Development of surface-coated polylactic acid/polyhydroxyalkanoate (PLA/PHA) nanocomposites. Polymers

Fabrication and characterization of an electrospun PHA/graphene silver nanocomposite scaffold for antibacterial applications

Optical and structural studies of silver nanoparticles

Silver-based antibacterial and virucide biopolymers: Usage and potential in antimicrobial packaging

Hierarchically structured porous materials for energy conversion and storage

Preparation of dendritic copper nanostructures and their characterization for electroreduction

Potential of silver nanoparticle-coated polyurethane foam as an antibacterial water filter

Mechanism of adsorption of single and double stranded DNA on gold and silver nanoparticles: Investigating some important parameters in bio-sensing applications

Surface enhanced Raman scattering substrate with high-density hotspots fabricated by depositing Ag film on TiO 2 -catalyzed Ag nanoparticles

Synthesis of silver nanoparticles: Chemical, physical and biological methods

Synthesis, properties, and optical applications of noble metal nanoparticlebiomolecule conjugates

Gold and silver nanoparticles in sensing and imaging: Sensitivity of plasmon response to size, shape, and metal composition

Nanoparticles for bioanalysis

Building with bubbles: The formation of high surface area honeycomb-like films via hydrogen bubble templated electrodeposition

Silver nanoparticle-decorated carbon nanotubes as bifunctional gas-diffusion electrodes for zinc-air batteries

Caulerpa racemosa: A marine green alga for eco-friendly synthesis of silver nanoparticles and its catalytic degradation of methylene blue

Debut, A. Ficus carica (fig) fruit mediated green synthesis of silver nanoparticles and its antioxidant activity: A comparison of thermal and ultrasonication approach

Cytokinin response in pepper plants (Capsicum annuum L.) exposed to silver nanoparticles

Plant response to engineered metal oxide nanoparticles

Toxicity of silver ions and differently coated silver nanoparticles in Allium cepa roots

Phytotoxicity of silver nanoparticles to peanut (Arachis hypogaea L.): Physiological responses and food safety

Anti-algae efficacy of silver nanoparticles to Microcystis aeruginosa: Influence of NOM, divalent cations, and pH

Contrasting silver nanoparticle toxicity and detoxification strategies in Microcystis aeruginosa and Chlorella vulgaris: New insights from proteomic and physiological analyses

A review on plants extract mediated synthesis of silver nanoparticles for antimicrobial applications: A green expertise

Recent advances in edible polymer based hydrogels as a sustainable alternative to conventional polymers

Production of the polyhydroxyalkanoate biopolymer by Cupriavidus necator using beer brewery wastewater containing maltose as a primary carbon source

Fruit waste (peel) as bio-reductant to synthesize silver nanoparticles with antimicrobial, antioxidant and cytotoxic activities

New approaches in improving the shelf life of minimally processed fruit and vegetables

Current practices in bread packaging and possibility of improving bread shelf life by nanotechnology

Green synthesis of silver nanoparticles using Pimpinella anisum seeds: Antimicrobial activity and cytotoxicity on human neonatal skin stromal cells and colon cancer cells

Antioxidant and antibacterial activity and preliminary toxicity analysis of four varieties of avocado

Antimicrobial and cytotoxicity effects of synthesized silver nanoparticles from Punica granatum peel extract

Bacterial extracellular polysaccharides involved in biofilm formation

A review on functionalized gold nanoparticles for biosensing applications

An overview of the plant-mediated green synthesis of noble metal nanoparticles for antibacterial applications

Synthesis of silver nanoparticles utilizing various biological systems: Mechanisms and applications-A review

Synthesis and biological characterization of silver nanoparticles derived from the cyanobacterium Oscillatoria limnetica

Biosynthesis of silver nanoparticles as catalyst by spent coffee ground/recycled poly(ethylene terephthalate) composites. Food Bioprod

Biosynthesis of silver nanoparticles using pre-hydrolysis liquor of Eucalyptus wood and its effective antimicrobial activity

Controlled biosynthesis of silver nanoparticles using sugar industry waste, and its antimicrobial activity

Biogenic silver nanoparticles synthesized from Rhododendron ponticum and their antibacterial, antibiofilm and cytotoxic activities

Grass-mediated biogenic synthesis of silver nanoparticles and their drug delivery evaluation: A biocompatible anti-cancer therapy

Biosynthesis, antibacterial activity and anticancer effects against prostate cancer (PC-3) cells of silver nanoparticles using dimocarpus longan lour. peel extract

Biosynthesis of silver nanoparticles using Citrus grandis peel extract

Biocompatible silver nanoparticles/poly (vinyl alcohol) electrospun nanofibers for potential antimicrobial food packaging applications. Food Packag. Shelf Life

Biosynthesis of silver nanoparticles from Cavendish banana peel extract and its antibacterial and free radical scavenging assay: A novel biological approach

Rapid green synthesis of silver and gold nanoparticles using peels of Punica granatum

Investigation of antioxidant, antibacterial, antidiabetic, and cytotoxicity potential of silver nanoparticles synthesized using the outer peel extract of Ananas comosus (L.)

Biogenic synthesis of AGNP's using Pomelo fruit-characterization and antimicrobial activity against gram +Ve and gram −Ve bacteria

Development and characterization of pomegranate and orange fruit peel extract based silver nanoparticles

Fruit peels waste for the green synthesis of silver nanoparticles with antimicrobial activity against foodborne pathogens

Microwave-assisted green synthesis of silver nanoparticles using orange peel extract

A novel biochemical study of anti-ageing potential of Eucalyptus camaldulensis bark waste standardized extract and silver nanoparticles

Green synthesis, characterization and applications of silver nanoparticle mediated by the aqueous extract of red onion peel

Noble metallic nanoparticles from waste Nypa fruticans fruit husk: Biosynthesis, characterization, antibacterial activity and recyclable catalysis

Photo-mediated biosynthesis of silver nanoparticles using the non-edible accrescent fruiting calyx of Physalis peruviana L. Fruits and investigation of its radical scavenging potential and cytotoxicity activities

Photo-mediated optimized synthesis of silver nanoparticles using the extracts of outer shell fibre of Cocos nucifera L. fruit and detection of its antioxidant, cytotoxicity and antibacterial potential

Phyto-mediated biosynthesis of silver nanoparticles using the rind extract of watermelon (Citrullus lanatus) under photo-catalyzed condition and investigation of its antibacterial, anticandidal and antioxidant efficacy

Potato peel waste as reductant for the biogenesis of gold and silver ultrafine particles. Mater

Silver nanoparticle biosynthesis by using phenolic acids in rice husk extract as reducing agents and dispersants

Silver nanoparticles: Mechanism of antimicrobial action, synthesis, medical applications, and toxicity effects

The potential of silver nanoparticles for antiviral and antibacterial applications: A mechanism of action

A review of the antibacterial effects of silver nanomaterials and potential implications for human health and the environment

Current progress in synthesis, characterization and applications of silver nanoparticles: Precepts and prospects

The biocidal activity of nano-sized silver particles comparing with silver ion

Nanosilver: A nanoproduct in medical application

Mechanistic basis of antimicrobial actions of silver nanoparticles

Electrospun alginate nanofibres impregnated with silver nanoparticles: Preparation, morphology and antibacterial properties

Biogenic synthesis of silver nanoparticles from white rot fungi: Their characterization and antibacterial studies

Bimetallic gold-silver nanoparticles mediate bacterial killing by disrupting the actin cytoskeleton MreB

Bio-catalytic synthesis of silver nanoparticles

Bio-friendly controllable synthesis of silver nanoparticles and their enhanced antibacterial property

Oligodynamic effect of silver nanoparticles: A review

Photobiologic-mediated fabrication of silver nanoparticles with antibacterial activity

Characterization and antimicrobial activity of silver nanoparticles, biosynthesized using Bacillus species

Synthesis, characterization and biocompatibility of silver nanoparticles synthesized from Nigella sativa leaf extract in comparison with chemical silver nanoparticles

PLLA microcapsules combined with silver nanoparticles and chlorhexidine acetate showing improved antibacterial effect

Anti-adhesion and antibacterial activity of silver nanoparticles supported on graphene oxide sheets

Antimicrobial silver nanomaterials

Phytochemical-assisted synthetic approaches for silver nanoparticles antimicrobial applications: A review

Interactions of nanosilver with Escherichia coli cells in planktonic and biofilm cultures

Antimicrobial activity of multifaceted lactoferrin or graphene oxide functionalized silver nanocomposites biosynthesized using mushroom waste and chitosan

Antibacterial activity of silver-killed bacteria: The "zombies

Enhancement of antibiotics antimicrobial activity due to the silver nanoparticles impact on the cell membrane

Antibacterial activity and mechanism of silver nanoparticles on Escherichia coli

Development of chitosan nanoparticles as a stable drug delivery system for protein/siRNA

Etching silver nanoparticles using DNA. Mater. Horizons

Silver ions caused faster diffusive dynamics of histone-like nucleoid-structuring proteins in live bacteria

Reactive oxygen species (ROS) as pleiotropic physiological signalling agents

Potential antibacterial mechanism of silver nanoparticles and the optimization of orthopedic implants by advanced modification technologies

The disruption of bacterial membrane integrity through ROS generation induced by nanohybrids of silver and clay

Silver nanoparticles induced cell apoptosis, membrane damage of Azotobacter vinelandii and Nitrosomonas europaea via generation of reactive oxygen species

Unraveling the interaction of silver nanoparticles with mammalian and bacterial DNA

Green synthesized silver nanoparticles destroy multidrug resistant bacteria via reactive oxygen species mediated membrane damage

Size-controllable preparation and antibacterial mechanism of thermo-responsive copolymer-stabilized silver nanoparticles with high antimicrobial activity

Silver nanoparticles restrict microbial growth by promoting oxidative stress and DNA damage

Silver as antibacterial toward Listeria monocytogenes

Biosynthesis of silver nanoparticles using leaf extract of Datura alba Nees and evaluation of their antibacterial activity

Some nanoparticles effects on Proteus sp. and Klebsiella sp. Isolated from water

Antibacterial effects of silver nanoparticles on gram-negative bacteria: Influence on the growth and biofilms formation, mechanisms of action

Assessment of antibacterial activity of silver nanoparticles on Pseudomonas aeruginosa and its mechanism of action

Antibacterial activity of silver and zinc nanoparticles against Vibrio cholerae and enterotoxic Escherichia coli

Comparative study on bactericidal effect of silver nanoparticles, synthesized using green technology, in combination with antibiotics on Salmonella typhi

Nanosilver and global public health: International regulatory issues

Selective growth of metallic nanostructures on microstructured copper substrate in solution

Extracellular synthesis and characterization of silver nanoparticles-Antibacterial activity against multidrug-resistant bacterial strains

Mentha arvensis (Linn.)-mediated green silver nanoparticles trigger caspase 9-dependent cell death in MCF7 and MDA-MB-231 cells

Antiviral activity of mycosynthesized silver nanoparticles against herpes simplex virus and human parainfluenza virus type 3

Inhibitory effects of silver nanoparticles on H1N1 influenza A virus in vitro

Systemic and immunotoxicity of silver nanoparticles in an intravenous 28 days repeated dose toxicity study in rats

Facile photochemical synthesis and characterization of highly fluorescent silver nanoparticles

Thermal decomposition as route for silver nanoparticles

Synthesis of silver nanoparticles by γ-ray irradiation in acetic water solution containing chitosan

Synthesis and characterization of Ag/polyaniline core-shell nanocomposites based on silver nanoparticles colloid

Inductively coupled plasma-mass spectrometry in biodistribution studies of (engineered) nanoparticles. In Encyclopedia of Analytical Chemistry

Nano-silver-A review of available data and knowledge gaps in human and environmental risk assessment