Nanotechnol Rev 2018; 7(5): 413–441

Review

Attarad Ali, Abdul-Rehman Phull and Muhammad Zia* Elemental zinc to zinc nanoparticles: is ZnO NPs crucial for life? Synthesis, toxicological, and environmental concerns https://doi.org/10.1515/ntrev-2018-0067 Received June 21, 2018; accepted July 21, 2018; previously published­ 1 Introduction online September 18, 2018 Over the last few decades, nanotechnology has wit- Abstract: The semi-conducting material zinc is one of nessed an incredible development in the fastest-grow- the essential trace elements for humans, is a co-factor of ing domain of science and technology because metal more than 300 enzymes, and plays an important role in oxide nanoparticles (NPs) are progressively being used maintaining vital cellular functions. Deficiency of zinc in many industrial applications. Among the different may lead to cancer initiation; however, a high concentra- metals, zinc attracts more attention because of its strong tion also has toxic effects that might be life threatening. reducing potential, moderate reactivity, and having five The toxicity can be addressed by the disequilibrium of stable isotopes. Among the different zinc-based nano- zinc-mediated proteins and oxidative stress that produce structures like sulfide, ferrite, phosphide, selenide, nascent oxygen, hydroxyl radicals, and other reactive oxy- and telluride, zinc oxide (ZnO) is most attractive due to gen species. Zinc-based nanoparticles (NPs) are among its vast applicability, being eco-friendly, and its diverse the most important and multifunctional compounds. physiochemical properties. A general description of zinc, Zinc oxide (ZnO) NPs exhibit attractive antimicrobial and its importance and NPs, are described in Figure 1. ZnO photocatalytic properties due to the smaller particle size NPs have been reported as being of different shapes, and increased particle surface reactivity. Further, these sizes, and structures (Figure 2). They have also been are more biocompatible compared to other metallic NPs, reported in one-dimensional (1D), 2D, and 3D structures. easily synthesizable, and have high selectivity, enhanced The 1D structures constitute the major group, containing cytotoxicity, and are a promising anticancer agent. How- nanorods, tubes, needles, wires, ribbons, belts, combs, ever, some of the pertinent concerns regarding nano-zinc helixes, springs, and rings. The 2D structures of ZnO still needs to be clarified. Current research also demon- are found as nanosheets/nanoplates and nanopellets, strates their usage in wastewater treatment, textile, med- whereas flower, snowflakes, dandelion, and coniferous icine, etc. This review covers the importance of zinc for urchin-like, etc., are examples of 3D ­structures [1]. living systems and its NPs, with more emphasis on ZnO ZnO is a bio-safe material that possesses photocataly- NPs. A comprehensive overview of ZnO NPs, their synthe- sis and photo-oxidizing influences on chemical and biolog- sis, characterization techniques, crystal structure, proper- ical species, respectively [2–4]. Bulk ZnO, compared to ZnO ties, and brief industrial applications are presented. NPs, is a bio-safe material. Indeed, various studies have already revealed the potential toxicity of ZnO NPs based on Keywords: biologics; cytotoxicity; nanoparticles (NPs); their size, shape, and concentration, etc. [5, 6]. Although photocatalysis; zinc oxide (ZnO). ZnO has been permitted for cosmetic uses by the U.S. FDA (Food and Drug Administration), the detailed toxicological profile and the mechanism of cytotoxicity for ZnO nano- *Corresponding author: Muhammad Zia, Department of materials is, thus far, not fully understood [7]. Besides, Biotechnology, Quaid-i-Azam University, Islamabad 45320, ZnO NPs are also reported to have a good biocompatibility Pakistan, e-mail: [email protected] with human cells, and the ZnO has been documented as a Attarad Ali: Department of Biotechnology, Quaid-i-Azam University, Islamabad 45320, Pakistan safe material by the FDA [8, 9], although the intrinsic cyto- Abdul-Rehman Phull: Department of Biochemistry, Shah Abdul Latif toxicity of ZnO NPs against certain human cell lines has University, Khairpur, Sindh 66020, Pakistan raised some apprehension concerning potential health 414 A. Ali et al.: Elemental zinc to zinc nanoparticles

Figure 1: General description of zinc metal and zinc NPs concerning synthesis, applications, and toxicity.

A B C D

E F G H

Figure 2: ZnO electron microscopic nanostructures: (A) needles, rods, and wires; (B) helixes and springs; (C) nanopellets/nanocapsules; (D) flower, snowflakes, and dandelion; (E) peanut-like; (F) interwoven particle hierarchy; (g) raspberry, nanosheet/nanoplate; (H) circular/round or sphere shaped [1–3]. A. Ali et al.: Elemental zinc to zinc nanoparticles 415 hazards [10]. On the other hand, their inherent cytotoxic- state of +2 and having an atomic number 30, and is bluish ity indicates a necessary quality against pathogenic cells if white in color. It is hard and brittle and a good conductor the properties are precisely tailored [7, 11]. Certainly, recent of electricity. It has low melting and boiling points and studies have revealed that ZnO NPs have cytotoxic effects is dissolvable in both acids and alkalis. Zinc is ecologi- toward cancerous cells, while at the same concentration, cally pervasive and present in the earth’s crust at about ZnO NPs have negligible effects on normal cells, leading 70 mg/1000 mg [21]. Likewise, according to proportion, it to speculation that they can be used in cancer treatment. is found abundantly (0.02%) in the earth’s crust carrying However, for more widespread applicability, ZnO NPs an elemental ranking of 24 in the periodic table. It has are currently being used in modified forms, for example, five stable isotopes and never occurs as a free element on through appropriate surface coatings with complementary earth [22]. The zinc metal remained unknown for a long polymeric materials [12, 13] or green synthesis approaches time because it boils or vaporizes easily from its compos- (capping with phytochemicals) and bio-inspired manufac- ites on heating. In nature, some of the prominent ores of turing [14, 15] that could boost their biocompatibility. zinc are (1) zincite or zinc oxide (ZnO); (2) sphalerite or Biodegradability and low toxicity are the most impor- zinc blende or zinc sulfide (ZnS); (3) smithsonite or zinc tant features of these nanomaterials. Zinc (Zn) is a crucial spar or zinc carbonate (ZnCO3); (4) willemite or zinc sili- 2+ trace element for mature individuals (Zn ~10 mg/day cate (ZnSiO3), and (5) franklinite [(Zn, Mn, Fe)O(Fe,Mn2) is allowed), and it is involved in numerous parameters O3] [23]. of metabolism. The surface of ZnO is chemically rich The zinc metal is now prominently used in galvaniz- with -OH groups that can easily be modified by several ing other metals by laying down a thin layer of zinc on the surface-adorning­ molecules. ZnO NPs have various dis- surface of a second metal because it does not corrode as tinctive properties such as semiconducting, deodorizing, easily as iron or other metals. Furthermore, the zinc metal photocatalytic, piezoelectric, pyroelectric, and required sublimates easily during the formation process of zinc biocompatibility [16]. Therefore, they have gained many from its ore. applications in industry, for instance as transducers and Zinc ions are absorbed deeply into soils at pH 5 or sensors, in ceramic processing, and in medical care [10, 17]. more and are likely to have slight mobility [24]. In natural They are extensively used in several products, such as wall waters, several forms of zinc can be found like metal- paints, toothpaste, sunscreens, beauty agents, textiles, and organic complexes, hydrated ions, or metal-inorganic in building materials. Because of their distinctive proper- complexes. Hydrated Zn+ may be hydrolyzed to form ZnO ties, i.e. reduced size and high surface area ratio, the bio- or Zn(OH)2. However, ZnS may be formed in anaerobic logical safety of NPs has received global attention from the environments. In aquatic organisms the bio-concentra- scientific world [10]. ZnO NPs can easily enter water when tion factor (BCF) values of zinc is 1000 and 2000 for fresh- they are immersed in water through bathing, washing, and water fish and marine fish, respectively [25]. swimming as they are a common constituent of sunscreens [16]. The consideration and investigation of nano-specific toxicity are significant for the safe design and environ- 1.2 Zinc in the human body mental risk assessment of NPs, although ZnO NPs have been reported to lack excess toxicity for various organisms Zinc is organically known as a helper molecule that assists [18–20]. about 300 enzymes, which are involved in various bodily The objective of this article is to review the semi- functions. After iron, zinc is the most vital and richest trace conducting material zinc and its chemical compounds element in the human body and has been estimated to be and nanostructures focusing on ZnO as biologics. The 30 mm (2–4 g) of the total body zinc content. The maximum potential applications of ZnO in industry, agriculture, the quantity of zinc occurs in parts of the eye, liver, kidney, environment, and toxicological threats as related to envi- bones, muscles, prostate, and brain [26]. Weak vision like ronmental release and possible effects on plants, humans, cloudy cataracts and poor night vision have been con- and animals are reviewed. nected to zinc deficiency. A low zinc concentration in puts the human body at risk for alopecia (hair loss from eye- lashes and eyebrows), greater vulnerability to infection, 1.1 Zinc and mental lethargy. Almost 15 mg/day (zinc) of trace quan- tities is required in the human diet to fulfill the demands of Zinc, also called as spelter, is a trace mineral. It is a dia- all body fluids and tissues. Zinc also plays an essential role magnetic fairly active transition metal with an oxidation in the immune system along with the maintenance and 416 A. Ali et al.: Elemental zinc to zinc nanoparticles integrity of cellular components (molecules and or mem- development during childhood, adolescence, and in brane stability, etc.) [22]. A number of enzymes are regu- pregnancy [31]. Various studies of zinc have shown anti- lated by zinc that are involved in homeostasis and other oxidant properties (vary as to its effectiveness) that may up-keeping bodily functions. It also participates in control- defend against earlier aging and aids in expediting the ling polynucleotide transcription by playing a crucial role healing process after an injury [34, 35]. Gastroenteritis in genetic expression. The volume-dependent absorption is intensely reduced by the absorption of zinc, and this of zinc occurs throughout the small intestine. However, the effect might be owing to the direct antimicrobial action loss of zinc from the body occurs through the skin, kidney, of Zn2+ in the gastrointestinal tract or to the ingestion of and intestines [27]. Zinc deficiency in humans causes cell zinc and reproduce from immune cells [36]. Zinc signal- impairment and malignancy development that eventually ing is used by the cells of the immune system, prostrate, may lead to cancer. Thus, in the prevention and treatment salivary gland, and intestines as one way to communicate of various cancers, the zinc-accelerated cancer chemopre- with other cells [37]. Zinc is stored in specific synaptic vention is effective. vesicles in the brain by glutamatergic neurons and can Zinc deficiency usually occurs due to insufficient zinc control the excitability of the brain [38]. It has neurotox- absorption or intake, greater losses of body zinc, or more icity, signifying zinc homeostasis and, thus, has impli- requirements for zinc [28]. Zinc scarcity is manifested by cations in the functioning of the brain and the central the loss of appetite, growth retardation, and impaired nervous system and also plays a vital role in learning immune function [29], along with hair loss, malabsorp- activity by its involvement in synaptic plasticity [38]. tion, hypogonadism in males, sickle cell disease, delayed Zinc is commonly bonded and transported by sexual maturation, acrodermatitis enteropathica, impo- albumin (60%, less affinity) and 10% remains freely avail- tence, malignancy, chronic renal disease, diarrhea, dia- able in the blood plasma [39]. Iron is also transported by betes, chronic liver disease, skin/eye lesions, and other transferring, and too much iron can lessen the absorp- chronic illnesses particularly in severe cases. Taste abnor- tion of zinc and vice versa [40]. Irrespective of zinc con- malities, weight loss, altered cognition, impaired appe- sumption, its concentration stays moderately constant in tite, and delayed healing of wounds can also take place the blood plasma. Zinc may be stored in metallothionein [30, 31]. reserves and also transported in metal carriers of ZnT and Numerous zinc passages sustain an essential stabil- ZIP assemblage transporter proteins [26]. Metallothio- ity as regards life and cell death, regulating the intracel- neins are competent in regulating and ingesting zinc by lular movements of zinc and unrestricted quantity of the 15–40% in the intestinal cells [41]. Furthermore, concen- metal. Although a smaller concentration of zinc could tration of zinc mostly harms copper absorption as metal- result in the origination and development of cancer, a lothioneins absorb both metals [42]. greater concentration of zinc also has a damaging effect Carboxypeptidase and carbonic anhydrase are two on health. A greater zinc quantity surpasses the capabil- zinc-containing enzymes that are important for the diges- ity of the zinc homeostasis system causing breakdown of tion of proteins and processes of carbon dioxide (CO2) regu- zinc transferring assemblage of the plasma membrane lation, respectively [43]. During the digestion of proteins in and subsequently an enhanced intracellular zinc concen- vertebrate blood, carboxypeptidase cuts peptide linkages tration that eventually triggers apoptosis leading to cell in which a coordinate covalent bond is formed between death [32]. the C=O group attached to zinc and the terminal peptide that results in a positive carbon charge. The resulting com- posite develops a hydrophobic pocket on the enzyme near 1.3 Biological role of Zn the zinc attracting the non-polar part of the protein being

digested [26]. The carbonic-anhydrase transforms CO2 into The key functional role of zinc in cellular metabolism bicarbonate, and the similar enzyme converts bicarbonate involves DNA synthesis, protein synthesis, cell division, again into CO2 for exhalation via the lungs (Figure 3) [44]. immune function, wound healing, and its being essen- This conversion takes place almost 1 million times slower tial for the catalytic activity of over 200 enzymes [33]. when this enzyme is lacking at pH 7, the normal pH of Zinc is potentially bonded with almost 10% of the human blood, or it would need a pH 10 or greater [45]. proteins, besides hundreds that transport and circulate In zinc fingers (Figure 3B), the zinc works a virtuously zinc. Furthermore, it is a necessary element for sensing structural role [46], and these zinc fingers are proteins that smell and taste [30], supporting ordinary growth and produce fragments of some transcription factors. Such A. Ali et al.: Elemental zinc to zinc nanoparticles 417

Figure 3: (A) Zn atom observable in the middle of the human carbonic anhydrase. (B) The two histidine side chains in Zn fingers, which coordinate with the Zn ion (green). proteins identify the DNA base sequences throughout the description of zinc NP characteristics are presented in transcription and replication of the DNA. The structure of Table 2. the finger is assisted and maintained by each of the 9 or 10 Zn2+ ions in a zinc finger, which are coordinately bonded to four amino acids in the transcription factor [47]. The 2.1 Zinc sulfide nanoparticles transcription factor uses the fingers to precisely bind with the DNA sequence by wrapping around the DNA helix Zinc sulfide (ZnS) is well known due to its use as phos- [48]. The zinc ion coordinates with cysteine, aspartic acid, phors, in field emission display, as optical coating, as histidine, and glutamic acid amino acid side chains [49]. ­dielectric filters, electro-optic modulators, window mate- The flexible coordination geometry of metal also allows rial, as photoconductors, reflectors, optical sensors, its proteins to consume it, to promptly shift conformations to use in other light-emitting materials, and most important, execute biological reactions [50]. its use as a direct gap semiconductor [51]. Beside these, the chemical stability of ZnS is more promising than that of other chalcogenides. 1.4 Zinc compounds ZnS synthesis has been reported through the chemi- cal precipitation method, the spray-based method, the Zinc does not exist freely in nature. It occurs in a +2 oxida- sol-gel method, the mechano-chemical route, the elec- tion state. The predominant zinc minerals are zincite (zinc trospinning technique, and the ultrasonic radiation oxide), smithsonite (zinc carbonate), and sphalerite (zinc method [52, 63–65]. ZnS responds to ultraviolet radiation sulfide). Almost 55 zinc minerals exist in nature. Some if the band gap energy is 3.68 eV for optical interband most common zinc minerals with their basic information transition. ZnS produces visible luminescence when the are listed in Table 1. transition state localizes in the band gap state with emis- Other important zinc compounds include zinc fluo- sion and absorption peaks at around 420 nm [53]. The rosilicate (ZnSiF6), zinc hydrosulfite (ZnS2O4), zinc sulfate band gap energy plays an important role for ZnS to be

(ZnSO4), zinc fluoride, zinc hydride, zinc nitrate, zinc applied as a photocatalyst for the removal of organic pol- ammonium nitrite, zinc cyanide, zinc permanganate, and lutants and toxic water pollutants from the environment zinc chlorate, etc. [51]. ZnS nanomaterials were applied for the photodeg- radation of organic pollutants including benzene deriva- tives, halogenated derivatives, dyes, and p-nitrophenol 2 Zinc nanoparticles in wastewater treatment [34]. However, the applications of ZnS NPs are limited There are various types of zinc NPs, and some that are because of the high cost of large-scale production, diffi- important are discussed here. Furthermore, a short culties in separation, recovery, and recycling. 418 A. Ali et al.: Elemental zinc to zinc nanoparticles

Table 1: Zinc compounds, its percentage, and uses.

Zn compounds Formula Mineral name % Zn Uses

Zinc oxide ZnO Zincite 80.3 Paints, ointments, cosmetics, cement, glass, automobile tires, fabricated rubber products, plumbing fixtures, glue, matches, tiles, ceramics, and porcelains, feed additives, seed treatment, inks, zinc green, electrostatic copying paper and color photography, flame retardant, semiconductor manufacturing, and as an ultraviolet absorber in plastics Zinc sulfide ZnS Sphalerite 67.0 Bleaching agent for textiles, straw, vegetable oils, and other products; brightening agent for paper and beet and cane sugar juice

Zinc silicate Zn2SiO4 Willemite 58.5 Hardening agent for concrete

Zinc silicate hydroxylate Zn4Si2O7(OH)2 · H2O Hemimorphite 54.2 Mothproofing agent; hardener for concrete

Zinc hydroxide carbonate Zn5(OH)6(CO3)2 Hydrozincite 56.0 Textile, wood, and food industries

Zinc carbonate ZnCO3 Smithsonite 52.0 Manufacture of rayon; supplement in animal feeds; dyeing of textiles; and wood preservative

Zinc ferromanganate (Zn,Fe,Mn)(Fe,Mn)2O4 Franklinite 15–20 Wood preservatives

Zinc acetate (Zn(C2H3O2)2) Acetic acid, 29–36 Wood preservative; dye for textiles; additive for animal galzin feed; glazing for ceramics

Zinc arsenate (Zn3(AsO4)2) Arsenic acid 41.4 Wood preservative; insecticide

Zinc borate (ZnB4O7) Trizinc diborate, 45–63 Fireproofing of textiles; prevents the growth of fungus zinc borate and mildew

Zinc chloride (ZnCl2) Zinc butter 46–48 Solder (for welding metals); fireproofing; food preservative; additive in antiseptics and deodorants; treatment of textiles; adhesives; dental cement; petroleum refining; and embalming and taxidermy products

Zinc phosphide (Zn3P2) Arrex, Denkarin 76 Rodenticide (rat killer) Grains, Deviphos

2.2 Zinc ferrite nanoparticles conversion. The long minority diffusion length and large

optical absorption coefficient permit Zn3P2 to be used as The unique physical and chemical properties of spinel- a high current collection efficiency [57]. The presence of structured ferrite NPs along with technological applica- Zn and P, the most abundant, inexpensive, and nontoxic tions in biomedicine, ferrofluids, radar absorbent, gas materials make them more promising [58]. These proper- sensors, high-density magnetic recording media, and ties also favor the deployment of this material in devices photocatalysis caught the interest of scientists in recent such as solar cells, light polarization indicators, infra- years. Change in properties with the change in particle red (IR), lasers, and ultraviolet (UV) sensors [55]. Based size of ZnFe2O4 also makes them attractive [54, 66]. on wide properties, many kinds of heterojunctions, such

Zinc ferrite nanopowders in a broader size range as In ZnO/Zn3P2, ITO/Zn3P2, Zn3P2/ZnSe, Mg/Zn3P2, and

(5–45 nm in size, depending on the annealing tempera- P/Zn3P2, were designed [57]. Zn3P2 are mostly prepared as ture) were prepared by the co-precipitation method from thin films and synthesis of other NPs [68] and nanotrum- the corresponding nitrate precursors and thermal treat- pets are prepared with ZnO layer coated on the surface [57]. ing of the obtained precursor at different temperatures Zn3P2 exhibits a pronounced quantum size effect because

[67]. ZnFe2O4 was successfully used as a photocatalyst for of the large excitonic radii [68]. Zn3P2 has been synthesized phenol degradation and oxidative dehydrogenation of using the thermal-assisted pulsed laser ablation process in n-butane to butane [55]. a single-zone horizontal tube furnace [57, 69].

2.3 Zinc phosphide nanoparticles 2.4 Zinc selenide (ZnSe) nanoparticles

Zn3P2 is a novel optoelectronic material containing a direct Selenides are widely used as optical recording materials, band gap of 1.4–1.6 eV, the optimum range for solar energy optical filters, laser materials, thermoelectric supersonic A. Ali et al.: Elemental zinc to zinc nanoparticles 419

Table 2: Zinc NPs, synthesis, characteristics, and properties.

Zn NP Synthesis precursor Size Shape variation Characteristic applications References

Zinc sulfide NPs Zinc acetate, sodium ~50 nm, Zinc-blended Optical coating, electro-optic [51–53] sulfide, EDTA 4–7 nm structure modulator, photocatalyst, of ZnS cubic photoconductors, optical nanocrystals, powder sensors, dielectric filter Zinc ferrite NPs Ferric nitrate, zinc 17–31 nm spinel-structured gas sensor, semiconductor [54–56] nitrate, poly (vinyl ferrite NPs photocatalysis, high-density pyrrolidone) (PVP) magnetic recording media, radar-absorbent materials Zinc phosphide NPs tri-n-octylphosphine, ~8 nm Tetragonal phased Solar cells, infrared (IR) and [57–59] methylzinc tree-shaped ultraviolet (UV) sensors, lasers, nanostructures light polarization step indicators as nanobelts, and nanowires Zinc selenide NPs Zinc acetate, sodium 20–60 nm Spherical shape, Blue diode lasers, supersonic [60, 61] selenite nano size and materials, photovoltaic solar smooth surface cells, optical filters, optical recording materials, solar cells Zinc telluride NPs Zinc acetate, sodium 2.6 nm, Spherical shape, Optoelectronics and photonics, [61, 62] telluride ~50–70 nm Small spheres or nano-sized semiconductor faceted particles, particles Uniform hexagonal shape

materials, cooling materials, solar cells, and sensors. and electronic devices [77]. All those are dependent on Because of the diverse properties and industrial applica- the crystal structure and particle size. Several researchers tions, selenide is a material of current interest [70]. employed various techniques for synthesizing ZnTe NPs ZnSe has a band gap of 2.7 eV [71] and is used as a such as the electrodeposition method, chemical synthe- semiconductor material for photovoltaic solar cells and sis, thermal evaporation, microwave irradiation, a sub- blue diode lasers. ZnSe NPs are normally prepared by limation technique, spray pyrolysis, microwave plasma, physical methods [69] though the chemical synthesis and electrical conduction [75]. route, which is economical, effective, and in bulk mode [60]. Beside these, hydrothermal and solvo-thermal syn- thesis for hollow ZnSe microspheres has also been estab- lished [72]. Reiss et al. [73] reported on the synthesis of 3 Zinc oxide, nanomaterial of the ZnSe NPs in octadene (non-coordinating solvent) by zinc present stearate with a selenium reaction. The synthesized ZnSe NPs demonstrate absorption features in the range of 390– Zinc oxide NPs are used as an additive in various indus- 440 nm [72]. trial products and materials including glass, ceramics, cement, rubbers, ointments, lubricants, paints, foods, fire retardants, plastics, pigments, adhesives, ferrites, seal- 2.5 Zinc telluride nanoparticles ants, batteries, first-aid tapes, etc. [78]. It is a wide-band gap semiconductor having numerous other favorable Zinc telluride is a Group II–VI semiconductor compound properties with good transparency, photochemical stabil- with a band gap of 2.26 eV [60] at room temperature. ZnTe ity, strong room temperature luminescence, and high elec- usually has a cubic crystal structure (zinc blende or sphal- tron mobility. The intrinsic doping of this semiconductor erite), but can also be synthesized as hexagonal crystals is the n-type because of zinc interstitials or oxygen vacan- (wurtzite structure) [74, 75]. ZnTe has potential applica- cies [79]. Such properties are valued in emergent applica- tions in the fields of light-emitting diodes, solar cells, tions for heat-protecting windows, transparent electrodes high-efficiency multi-junction solar cells, photodetectors, in energy saving, liquid crystal displays, light-emitting optoelectronic devices [62], terahertz (THz) devices [76], diodes, and thin-film transistors in electronics. ZnO has 420 A. Ali et al.: Elemental zinc to zinc nanoparticles a potential biocompatibility over many other metal oxides can be used in field emission devices and dye-sensitized and has explored many pronounced applications in solar cells [85]. current antiviral, antimicrobial, biomedical, and environ- ZnO shows three main crystalline structures: the hex- mental areas [17, 80]. agonal wurtzite, zinc blende, and periodically observed rock salt [86]. Wurtzite is the most common and ther- modynamically stable ZnO structure at ambient condi- 3.1 ZnO crystal structure tions. It has a lattice parameter spacing a = 0.325 nm and c = 0.521 nm, the ratio c/a ~ 1.6, i.e. close to the perfect The chemical co-precipitation method for ZnO NPs syn- value for the hexagonal cell c/a = 1.633. Four oxygen atoms thesis has been proven as a versatile and powerful tech- are bounded with each tetrahedral Zn atom and vice nique for growing 1D nanomaterials [81]. The process is versa [4]. It is generally demonstrated schematically as normally carried out in aqueous medium of zinc nitrate various alternating planes of zinc and oxygen ions that or zinc acetate and hexamine at about 90°C, followed by are arranged along the c-axis. The tetrahedral coordina- the provision of a basic environment. Some additives, for tion in ZnO results in a non-central symmetric structure example, polyethylenimine (PEI) or polyethylene glycol resulting in pyroelectricity and piezoelectricity. Further, (PEG), can develop the aspect ratio of the ZnO nanowires the polar surfaces of ZnO are its essential characteristic, [80]. ZnO nanowire doping was attained by the addition and the basal plane is its most common polar surface [87]. of extra metal nitrates or other salts to the growth solution A spontaneous polarization along the c-axis and the [82]. The morphology of the resulting nanostructures can normal dipole moment as well as the divergence in surface be modified by changing the environmental conditions, energy take place by the production of positively charged precursor concentration, and others (e.g. the pH and zinc Zn-(0001) and negatively charged O-(000ī) surfaces due to concentration) or the thermal treatment (e.g. heating rate the oppositely charged ions. Commonly, the polar surfaces and temperature) [83]. During the synthesis, ZnO with pre- have facets or show huge surface reconstructions to main- seeding substrates create sites for homogeneous nuclea- tain a stable structure, but ZnO-(0001) are exceptions: tion of ZnO crystals. Common pre-seeding techniques they are atomically flat, stable, and without reconstruc- include spin coating of ZnO NPs, in situ thermal decom- tion. The other two most generally observed facets for ZnO position of zinc acetate crystallites, and the use of physi- are {2īī0} and {01ī0}, which have a lower energy than the cal vapor deposition methods to deposit thin films of ZnO {0001} facets and are non-polar surfaces [88]. The struc- [84]. Pre-seeding can be achieved in combination with top ture of zinc blende is metastable that could be stabilized down patterning approaches like prior to growth, nano- by growing ZnO on substrates with a cubic lattice struc- sphere lithography, and electron beam lithography to des- ture. Such crystal structures with tetrahedral geometry ignate nucleation sites. Such interlinked ZnO nanowires are shown in Figure 4, where the black and whitish-gray

Zn atom Oxygen atom Oxygen atom Zn atom Zn atom Oxygen atom C = 5.207 λ

a = b = 3.249 λ Wurtzite Rocksalt Zinc-blende

Figure 4: ZnO crystal structures of wurtzite (tetrahedral coordination of ZnO), zinc blende, and rock salt. Revised from Sirelkhatim et al. [4]. A. Ali et al.: Elemental zinc to zinc nanoparticles 421

– circles indicate Zn and oxygen atoms, respectively, for CB e Wurtzite, while the black and whitish-gray circles show O e– and Zn atoms, respectively, for the zinc blende and rock Reduction

ellow) .. hv Vo salt structures [89]. At a comparatively high pressure of (Y about 10 GPa, ZnO transforms to the rock salt design [90]. Oi˝ (Green) = 3.2 eV 2.0 eV g

Oxidation + E h 2.4 eV

+ VB 3.2 Growth directions of ZnO structures h ZnO ZnO has structurally three types of fast growth ­directions: (2īī0) (±[2īī0], ±[ī2ī0], ±[īī20]); (01ī0) (±[01ī0], Figure 6: Band structure and charge transfer pathways of ZnO nanocrystal with oxygen defects [93]. ±[10ī0], ±[1ī00]); and ±[0001]. Together with the polar sur- faces, ZnO shows a wide range of novel structures that can be grown by tuning the growth rates along these directions ZnO NPs are the key technological materials that have due to the atomic terminations [2]. Relative surface activi- gained a vast consideration owing to their distinguished ties of various growth facets are one of the most promising performance in optics, electronics, biologics, environ- factors determining the particle morphology under given ment, photonics, etc. These particles have currently a conditions. Under controlled growth conditions, a crystal wide range of mainly biological (drug/gene delivery, bio- has macroscopically different kinetic parameters for dif- sensing, cancer therapy, biomaterials for shape memory ferent crystal planes. Therefore, a crystallite will develop polymers like molecular switches, tissue engineering, generally into a 3D object with a low index, well-defined, nanomachines that can act as biological mimetic, anti- and crystallographic faces after an early period of nuclea- microbial actions, environmental applications, etc. tion and incubation. Figure 5A–D displays some charac- [17, 80, 91]. Synthesis of ZnO thin films as catalysts, teristic growth morphologies of ZnO (1D) nanostructures. sensors, and transducers has been applicable since the Because of the lower energy, these structures are likely 1960s. At room temperature, the ZnO band gap is 3.37 eV. to maximize the areas of the {2īī0} and {01ī0} facets. The The UV emission is an attribute of direct exciton transi- shape displayed in Figure 4 is ruled by polar surfaces that tion that recombines with holes in the valence band or grow by introducing planar defects parallel to the polar in traps near the valence bond with detection at 370 nm. surfaces [90]. Twins and planar defects are identified For this reason, many point defects have been suggested, infrequently parallel to the (0001) plane; however, dislo- i.e. oxygen interstitials, zinc vacancies, oxygen vacan- cations are occasionally observed. cies, zinc interstitials, antisite oxygen, and surface states [92]. The band structure and charge transfer pathway of the ZnO nanocrystal with a band gap (3.2 eV) for various applications are shown in Figure 6.

3.3 Easy synthesis of ZnO NPs

ZnO NPs can easily be synthesized by numerous tech- niques, such as green, metallurgical, solid, liquid (i.e. chemical), and gaseous. In the metallurgical approach, the ZnO NPs could be achieved by the roasting of a suitable zinc ore through a direct or indirect process [3]. Thanks to the development of the methods of obtain- ing ZnO NPs that enables precise control of the ZnO NPs’ size that extensive scientific research is possible today. It is also worth mentioning that such properties as band gap, conductivity, or magnetic properties can be controlled by Figure 5: Typical growth morphologies of 1D ZnO nanostructures doping ZnO NPs with ions of transition metals (e.g. Co, and the corresponding facets [2]. Mn, Cr, Ni, Fe, V). Nevertheless, the chemical techniques 422 A. Ali et al.: Elemental zinc to zinc nanoparticles are the most reliable, economical, and environmentally cooling (via mixing with cool gas) by expansion through friendly and also offer flexibility for controlling the shape a nozzle [95]. A reactant gas is provided to the vapor in and size of prepared NPs. There are a variety of chemi- this process, i.e. cooled at a controlled rate and condensed cal techniques (Table 3), for example, the precipitation to produce NPs. Fully dense and discrete particles with process, the hydrothermal, mechanochemical process, average sizes ranging from 8 to 75 nm of defined crystal- physical vapor, solvo-thermal, sol-gel, micro-emulsion linity were prepared by the PVS method [96]. methods, etc. Some of the important synthesis techniques are briefly discussed in the following. 3.3.3 Other miscellaneous chemical methods

3.3.1 Mechanochemical processing (MCP) The distinctive versatility and properties of ZnO paved the way to use numerous chemical methods to produce more MCP is a novel, simple, and economical technique of promisingly functional ZnO nanostructures. Compared to achieving large-scale detached NPs. A large diversity of other nano-metal oxides, ZnO nanostructures reflect the other crystalline NPs, such as ZnO, ZnS, CdS, CeO2, and richest nano-configuration assembly [2, 4]. Each nano-

SiO2 can also be synthesized by this simple approach structure has specific physicochemical, electrical, optical, [93, 94]. This method entails two processes of conven- and structural properties, allowing significant applica- tional ball milling for the reduction of physical size and tions. Some important characteristics of these techniques chemical reactions that are activated mechanically during such as functioning precursor, solvents, reaction condi- grinding at the nanoscale. The precursors used in this pro- tions along with size and morphology of the created NP cedure are sodium carbonate (Na2CO3) and zinc chloride are presented in Table 3.

(ZnCl2) that are milled simultaneously in a ball mill to gen- The selected approach typically depends on the erate sodium chloride (NaCl) and zinc carbonate (ZnCO3) desired application, as various techniques produce differ- through a chemical exchange reaction and ball-powder ent morphologies and sizes of particles. A diversity of ZnO collisions. On heating fine zinc carbonate converts into NPs with different growth morphologies were success- ZnO NPs (Figure 6). The size of the obtained ZnO NPs fully manufactured by adjusting the growth conditions (Table 3) depends on the milling time and the heat treat- [2]. The most adopted synthesis techniques include the ment [94, 115]. Therefore, there is an optimum grinding hydrothermal and thermal evaporation of ZnO powders time to obtain ZnO NPs with the minimum average size. at 1400°C, sol-gel technique, double-jet precipitation, Conversely, increasing the temperature of the heat treat- solution synthesis, self-combustion, vapor-liquid-solid ment process causes an increase in the size of the ZnO NPs technique, polymerized complex method, and simple [116]. MCP is typically an appropriate method for large- thermal sublimation [118]. Numerous researchers also scale ZnO NP production owing to its low cost and sim- used the solution process system to fabricate ZnO nano- plicity. Furthermore, this technique is promising from an structures. Wahab et al. [119] synthesized flower-shaped environmental point of view as the reactions involve evic- ZnO nanostructures using dihydrated zinc acetate and tion of organic solvents [117]. Besides, drawbacks of this NaOH at 90°C by the solution process approach. The sci- method during milling may be particle agglomeration that entists also synthesized prickly sphere-like and prism-like could be minimized by the existence of a salt matrix in the ZnO through a decomposition process at 100°C for 13 h reaction, i.e. eventually separated by a simple washing [4]. Most of the nanostructures are imperative factors for process before calcination. the biological and environmental applications, as each morphology accounts for a certain mechanism of action [80, 120]. Therefore, a greater number of scientists were 3.3.2 Physical vapor synthesis (PVS) encouraged to attain selective nanostructured ZnO for dif- ferent methodical experiments. Plasma arc energy is employed to a solid precursor to produce vapor at a high temperature in the PVS method. When the precursor is inserted into the plasma to induce 3.4 Capping/doping of ZnO NPs with foreign reactions, the plasma arc provides the desired energy materials leading to super saturation and particle nucleation. This reaction process causes complete decomposition into The implanting of foreign metals on ZnO nanostruc- atoms that again react or condense to create particles on tures and the doping methods to improve the functional A. Ali et al.: Elemental zinc to zinc nanoparticles 423

Table 3: Synthesis techniques, precursors, preferred solvents, conditions, and the resultant morphology of ZnO NPs.

Technique Precursor Medium/solvent Conditions during Size (nm) Morphology References preparation

Mechano-chemical Zinc chloride, De-ionized water Calcination: 2 h, 20–30 nm Hexagonal, [94]

Na2CO3 and NaCl 400‒800°C regular Physical vapor Solid ore Plasma, gas, vapor, Heat, reactive carrier 8–75 nm Rod, sphere [95, 96] diethylzinc (DEZ), gas (helium) oxygen Simple Zinc acetate, Double distilled Drying: overnight, 80 (l), Nanorod, [34, 97–99] precipitation zinc nitrate, zinc water 100°C calcination: 30–60 (d) nano-flakes sulfate, etc 300‒500°C (may change with precursor types) Microwave Zinc acetate 1-Butyl-3- Precursor 37–47 Sphere, average [100] decomposition dehydrate, zinc methylimidazolium concentration: crystallite size acetyl-acetonate bis (tri-fluoro-methyl- 2.5‒10 wt%; sulfonyl) imide microwave heating: (BMIM) (NTf2) 800 W, 4 min; drying: 75°C in air Hydrothermal Zinc acetate Poly-vinyl- Reaction: 180°C; 5 μm (l), Nanorod, [101, 102] dehydrate pyrrolidone (PVP) drying: 80°C in 50–200 (d) hexagonal vacuum oven; prismatic calcinations: 400–600°C Microwave zinc nitrate, zinc Ethanol, imidazolium Microwave heating: 10–80 nm Hexagonal wurtzite, [103] hydrothermal acetyl-acetonate tetrafluoroborate 2 min, 90°C; nanorod and drying: 2 h, 60°C nanowire, mulberry- (may change with like, hollow precursor types) Wet chemical Zinc nitrate Sodium hydroxide Solution incubation: 20–30 Wurtzite, acicular, [104, 105] hexahydrate (NaOH) as precursors 50‒55 min, 101°C rod, flowers, and soluble starch as dumbbell, rice stabilizing agent flakes, and rings Sol-gel (gelatin Zinc nitrate Distilled water and Aging: 96 h, ambient 30–60 Circular and [106] media) gelatin as substrate temperature, hexagonal calcination: 2 h, 500 °C Solvo-thermal Zinc acetate, Ethanol, Reaction: 10‒48 h, 60–100 nm Hexagonal [107] zinc nitrate imidazolium 120‒250°C (wurtzite) structure, tetrafluoroborate hollow spheres, ionic liquid nano-flowers, nanorods Micro-emulsion Zinc acetate, Heptane, hexanol, Reaction: 24 h, 15–24 nm Hexagonal wurtzite, [1, 108] zinc nitrate, zinc triton, benzene, 60‒70°C; drying: spherical chloride, etc ethanol, diethyl 1 h, 100°C; ether, chloroform, calcination: 3 h, acetone, methanol, 300‒500°C (may glycerol, etc change with precursor types)

Deposition process Zinc acetate, P3HT (poly(3- Atmospheric O2, 20–60 nm Dumbbell, [108, 109] zinc nitrate, CdS hexylthiophene) pressure 1.3 Pa, nanofibers, rod pulsed laser, drying: 2 h, 400–700°C Microwave Zinc nitrate Deionized Ultrasonic 80–100 nm Hexagonal wurtzite, [110] irradiation water, HMT irradiation: 30 min, rod, nanowire (hexamethylene- 80°C; drying: 2 h, tetramine) 60°C 424 A. Ali et al.: Elemental zinc to zinc nanoparticles

Table 3 (continued)

Technique Precursor Medium/solvent Conditions during Size (nm) Morphology References preparation

Solution Zinc acetate Ethanol: ethylene- Ultrasonication 60–80 nm Spherical [111] combustion di-hydrate glycol (volume ratio and centrifugation, of 60/40) drying: 50°C in air, 5 h Microwave solvo- Zinc acetate Water, 2-propanol Using a closed 25–50 Irregular and [112–114] thermal dihydra solution, ethylene vessel as reactor spheroidal glycol in conventional nanostructures microwave oven, heating for 3 min, centrifugation, washing, and drying

bioactive agent became a topic among various scientists. 3.4.1 Green synthesis of ZnO NPs Different shapes of doped and undoped ZnO NPs were prepared by the simple wet chemical method and were Currently, ZnO NPs are fastidiously studied due to their annealed [121]. The resulting ZnO samples were examined large bandwidth, simplicity, non-toxic, high exciton-bind- against different microbial strains, and consequently, the ing energy, easy fabrication, biocompatible, biosafe, envi- ZnO-doped samples showed considerable significant ronment friendly, and they have potential applications activity (37% higher than undoped ZnO). Such results are like antibacterial, antioxidant, antifungal, photocatalysts, medically valuable particularly in controlling different anti-inflammatory, wound healing, cosmetic, food, anti- bacterial infections such as in skin creams/lotions and diabetic, and optic properties [127, 128]. Because of the or in UV protection. Some antibacterial tests are typi- large rate of toxic chemicals and extreme environment cally carried out in cell culture media or aqueous media. employed in the conventional physio-chemical manufac- ZnO is almost insoluble in water, and during synthesis, turing approaches of these NPs, green methods employ- it agglomerates rapidly with water owing to high polar- ing the use of plants, fungus, bacteria, and algae were ity that leads to the deposition. Issues of non-dissolution, adopted. The synthesis conditions could further be opti- aggregation, settling, or re-precipitation inhibit the fab- mized for maximal and narrow size range preparation of rication processes. At this point, most of the scientists ZnO NPs. In recent years, due to low-cost, variety in shape resolve this issue by adding certain additives that have and size, stability, large-scale production, eco-friend- no substantial effect on bioactivity. Polyvinylpyrrolidone liness, and methodological easiness of NPs, there is a (PVP), polyethylene glycol (PEG), poly (a, c, l-glutamic great stress on the utility of plant materials (the most pre- acid) (PGA), poly (a, c, l-glutamic acid), and PVA were ferred source) such as the leaf, root, or shoot powders and used as doping agents and as stabilizers to boost ZnO flowers in the form of solvent-based extracts as capping morphology and modify the sizes for numerous biologi- and stabilizing agents for the synthesis of pure ZnO NPs cal activities [122–124]. Some investigators used suitable [127, 129]. These natural strains and plant extracts secrete deflocculants or capping agents [99, 125, 126] such as some phytochemicals that act as both a reducing agent sodium carbonate (Na2CO3) or sodium silicate (Na2-SiO3). and capping or stabilization agent; e.g. synthesis of ZnO After doping or adding dispersants, such blends were nanoflowers of uniform size from cell soluble proteins of treated with a vigorous vortex (likely for 5 min) or set Bacillus licheniformis exhibited enhanced photocatalytic aside overnight with magnetic stirring and then ultra- activity and so there was a degradation of methylene blue sonicated (for 20–30 min) to avoid deposition and aggre- (MB) pollutant dye, which clearly showed the photo-sta- gation of particles. Last, the characterization of ZnO NPs bility of ZnO NPs. Biologically reducing means the reduc- is needed to recognize effect-impacted stability such as tion of metal or metal oxide ions to zero valence metal morphology, structural, pH solution, surface properties, NPs by the action of phytochemicals such as vitamins, and particle size; plus, these factors sequentially have polysaccharides, amino acids, alkaloids, polyphenolic influences on the bioactivities. compounds, and terpenoids secreted from plants [129, A. Ali et al.: Elemental zinc to zinc nanoparticles 425

130]. ZnO NPs are readily soluble in biological fluids and in Table 4, and furthermore, characterization techniques tend to amass easily under different physiological condi- are reviewed in detail in various recent papers [13, 53, 98, tions. However, the physicochemical properties of these 106, 118, 133]. NPs have an impact on the bioavailability [128]. Extensive research is needed to perform on ZnO NP pharmacokinet- 3.6 Biocompatibility of ZnO NPs ics (drug movement) and bioavailability, which are still looked-for understanding and required to establish the ZnO NPs exhibit reasonable biocompatibility. The FDA exact mechanism in human beings. generally recognized their bulkier form as a harmless (GRAS) material. As discussed earlier, zinc is an essential 3.5 Characterization techniques co-factor in several cellular mechanisms; therefore, zinc NPs may also demonstrate biocompatibility. ZnO could The synthesized ZnO NPs prepared through numerous simply be biodegraded, or such particles can take part in methods were further studied using various characteriza- the active nutritional cycle of the human body [36, 142]. tion techniques according to their analytical parameters Furthermore, ZnO NPs have several biomedical applica- (such as morphology, size, agglomeration, etc.), as shown tions, for example, in biomedical imaging (consists of

Table 4: Summary of analytical techniques to conduct physicochemical characterization and monitoring of ZnO NPs (in living systems mostly).

Technique Analysis Parameters studied References

Fourier transform infrared Structural analysis Chemical changes in polymers after NP [131] spectroscopy (FTIR) incorporation, photostability measurements Scanning electron Structural analysis Morphological characterization [118, 131] microscopy (SEM) Transmission electron Structural analysis Physical examination and dispersion quality of [131] microscope (TEM) NPs in the polymeric matrix X ray diffraction (XRD) Shape and structure Crystallinity and visualization of NP structure [131–133] Electron microscopy and size Selected-area electron Shape perkiness Confirmation of the preferential orientation of [118, 133] diffraction (SED) nanocrystals instead of irregular shapes/rings UV-Vis spectroscopy Polymers/matrices/protein Transmission optical spectra [134] (125) binding affinity Atomic force microscopy Polymers/matrices/protein Topographic characterization and surface [135] (126) binding affinity morphology of nanomaterial Thermogravimetric Property measurements Weight variation measurement of samples as a [131] analysis (TGA) function of temperature/time, with controlled temperature programming Dynamic light scattering Size and charge Changes in the hydrodynamic diameter of NP [17, 136] (DLS) Analytical ultracentrifugation Ultra-sonication De-agglomeration Uses sound energy to disrupt large aggregates [137] (128) of NPs Inductively coupled mass Dissolution For detecting elemental composition of the [138] (129) spectrometry nanomaterial Photoluminescence Physical properties Measurement of quantum size effects on [133] (124) spectroscopy (PLS) (spectrofluorimeter increasing and reducing band gap energy measures PL spectrum dispersed in water) Fluorescence Polymers/organics/protein Measures change in fluorescence spectra due [139] (130) spectroscopy binding affinity to NP-protein interaction Braunauer-Emmet-Teller Surface area Measures specific surface area using [134] (123) method adsorption of gas on the surface Nuclear magnetic Polymers/organics/protein Depends on magnetic properties of atomic [140] (131) resonance structural changes after nuclei to predict structure binding Confocal microscopy NP uptake Visualization of fluorescent NPs in vitro [141] (132) 426 A. Ali et al.: Elemental zinc to zinc nanoparticles fluorescence, positron emission tomography, magnetic observed. Identification and isolation of organic polymers resonance along with dual-modality imaging), biosens- (OP) constituting the NP-OP are important to recognize the ing, gene delivery, drug delivery, and various arrays of bio-reactivity of NPs. The interactions of NP surfaces with molecules of interest. Over the next era, a lot of scientific separate organics were studied using a range of analytical investigations in this field will flourish, and more research techniques (Table 5). Electrostatic force acts as a repulsive exertion is required to progress biodegradable/biocom- force, while depletion and Van der Waals forces are attrac- patible ZnO nano-daisies for potential clinical translation tive in nature. The changes in the dipole moment of elec- [143]. trons give rise to Van der Waals forces that induce a dipole The physicochemical interaction between the surface moment in the contiguous atoms. Thus, the quantum of biological constituents and nanomaterial surface deals mechanical dance of electrons arises from these kinds of with the kinetic and thermodynamic exchanges among diverse forces that play a significant role in NP interac- the interfaces [144]. It comprises the interaction of bio- tion with the cellular surface and their passive attainment logical membranes with NPs and the interaction among inside the cell [149, 150]. This bonding interaction with NPs themselves. Several forces, for example, electrostatic the cell surface is preferred by the improved and adjust- forces, van der Waals forces, solvo-phobic, solvation, and able NPs’ surface area rendering to cell surface receptor depletion forces, applied on such interactions in media, and the relative NP size with biomolecules/ligands that affect the agglomeration rate of NPs with biomolecules causes passive uptake and adhesive interactions inside [122]. The knowledge of such interactions is imperative for the cell, which boycotts the phagocytic process [151]. NPs the suitable dispersion of NPs with slight agglomeration in can directly interact with cell organelles and cytoplasmic media. Moreover, by studying these interactions, the usage proteins through this passive uptake that leads to a greater of optimal polymers and surfactants to stabilize NPs can be cytotoxicity. They can be confined at any place inside the

Table 5: Brief description of properties of ZnO NPs and effect capping/doping agents on size.

Capping/doping agent Size before Size after Properties Synthesis References capping (nm) capping (nm) methodology

Ethylene glycol (EG) 65 ± 1.2 91 ± 6.3 Photocatalytic, antibacterial, Chemical [99, 126] antibiofilm activities co-precipitation method Polyethylene glycol 34 26 Antidiabetic, antioxidant, Co-precipitation [123, 124] (PEG) antibacterial activity method Polyethylene glycol 90 10.70 Antibacterial activity Precipitation method [123, 145] (PEG) Polyvinyl alcohol (PVA) 65 ± 1.2 60 ± 1.9 Photocatalytic, antibacterial, Chemical [123, 124, 126] antibiofilm activities co-precipitation method Ascorbic acid (AsA) 90 13.20 Antibacterial activity Precipitation method [99, 123, 145] Polyvinyl pyrrolidone 65 ± 1.2 52 ± 2.3 Photocatalytic, antibacterial, Chemical [123, 126] (PVP) antibiofilm activities co-precipitation method Polyvinyl pyrrolidone 30–50 25–40 Antidiabetic assay, antioxidant, Co-precipitation [123, 124] (PVP) antibacterial activity method Polysorbate 80 (T-80) 90 7.58 Antibacterial activity Precipitation method [126, 145] Gelatin (GE) 65 ± 1.2 134 ± 6.2 Photocatalytic, antibacterial, Chemical [99, 126] antibiofilm activities co-precipitation method Mercaptoacetic acid 90 8.84 Antibacterial activity Precipitation method [99, 145] (MAA) Cobolt (Co) 32 45 – Freeze-drying route [99, 146] Magnesium (Mg) 26 22 Antibacterial activity Co-precipitation [126, 147] technique Citrus cellulose 50 – Photocatalytic, antibacterial Chemical [34, 97, 148] activity co-precipitation A. Ali et al.: Elemental zinc to zinc nanoparticles 427 cell comprising the cytoplasm, outer membrane, mito- releasing antimicrobial ions mainly Zn2+ ions and forma- chondria, DNA, lipid vesicles, nuclear membrane, nucleus, tion of reactive oxygen species (ROS) [161, 162], NP pen- etc., which is detrimental to these cell organelles and even- etration inside the cell, membrane dysfunction, and even tually leads to cell death [152, 153]. ROS produced on the surface of the NPs can also damage the cell [150, 162]. The antibacterial activity of ZnO NPs varies with the 3.6.1 Antimicrobial activity of ZnO nanoparticles variation in particle size, and an inverse relationship exists between the size and efficacy of ZnO NPs [122, Antimicrobial agents are drugs with the ability to inhibit or 163]. The effects of ZnO NPs and Zn ion in eukaryotes and damage bacterial growth, whereas they are not detrimen- prokaryotes are depicted in Figure 7. tal to the host. Such compounds perform as chemothera- peutic agents for the prevention or treatment of bacterial 3.6.2 Anticancer activity infections [4]. Several researchers studied the antibacte- rial activity of ZnO NPs (Table 6) using the colony-forming Numerous in vitro studies showed that ZnO NPs exhibit unit test, culture turbidity, and cell viability. Nair et al. selective cytotoxicity toward cancerous cells (Table 6). [152] concluded that antibacterial activity is enhanced by Hanley recommended that compared to normal cells, reducing the initial number of bacterial cells having 102 ZnO NPs show 28–35 times more selective toxicity toward against 106 CFUs, although there are some variations in cancerous cells [165, 166], which can also additionally be the established laboratory techniques and protocols in the exploited in the in vivo condition by selectively targeting estimation of bactericidal activity [160]. ZnO NPs toward cancer cells [154]. Researchers investigated the morphology of bacterial variations induced by ZnO NPs, but several concerns were referred to the antibacterial activity. The precise toxicity 3.6.3 Biosensor and bioimaging mechanism is still controversial, is not fully explained, and requires deep explanations of queries within the Fast electron transfer kinetics and biocompatibility of spectrum of antibacterial activity [27]. In the literature, the ZnO make this material favorable to modify biomolecules distinct mechanisms that were proposed are documented and immobilization of biomimic membranes. The domi- as follows: ZnO NPs’ direct interaction with the cell walls nant property of ZnO nanowire for sensing pH in a liquid causing damage to the integrity of the bacterial cell [122], medium has made their applications in electrical sensors

Table 6: Anticancer and antibacterial activities of the ZnO NPs and composites.

NPs/material size (nm) Cancer cells/bacterial strains Effect References

ZnO NPs 21.59 HepG2 Viab. decr 39%, 15 μg/ml [13] ZnO NPs 21.59 A549 Viab. decr 47%, 15 μg/ml [13] ZnO NPs 21.59 BEAS-2B Viab. decr 33%, 15 μg/ml [13] ZnO NPs – Caco-2 cells Sign. 89 mg/ml [154] ZnO NPs 50–70 LoVo Sign. viab. decr. at 10 μg/ml [155] ZnO NPs 19 K. pneumoniae Sign. 500 mg/l [156] ZnO NPs 50–70 B. subtilis Sign. 85.8 mg/l [157] ZnO NPs 50–70 S. aureus Sign. >125 mg/l [157] CdO-ZnO composite ~27 P. vulgaris Sign. 20 μg · ml−1 [158] CdO-ZnO composite ~27 P. aeruginosa Sign. 15 μg · ml−1 [158] ZnO NPs 30 E. coli MIC: 0.4 mg/ml [159] ZnO NPs 50 S. aureus Sign. 10 mg/ml [34] ZnO NPs 50 E. coli Sign. 10 mg/ml [34] ZnO-Cel composite – S. aureus Sign. 10 mg/ml [34] ZnO-Cel composite – E. coli Sign. 10 mg/ml [34]

K. pneumoniae, Klebsiella pneumoniae; B. subtilis, Bacillus subtilis; S. aureus, Staphylococcus aureus; P. vulgaris, Proteus vulgaris; P. aeruginosa, Pseudomonas aeruginosa; E. coli, Escherichia coli; decr., decrease; Sign., significant; MIC, minimal inhibitory concentration; Viab, viability. 428 A. Ali et al.: Elemental zinc to zinc nanoparticles

Figure 7: ROS generation on eukaryotic (A) and prokaryotic (B) cells by ZnO NPs [164]. for biological detection. Beside this, ZnO nanostructures and inflammatory tissues remains appreciably lower than replaced florescent dyes because of their better photolu- in normal tissues. ZnO having both properties (drug carrier minescent properties. The other properties that favor bio- and pH sensitivity) was first suggested in 2010 [155, 174]. imaging and photoluminescence are a tunable emission Thereafter, many researchers developed ZnO nanostruc- wavelength based on quantum size effects, including a tured carriers and designed a system to release the drug at broad absorption, weak self-absorption, narrow and sym- the target tissue, i.e. release of doxorubicin (DOX) to HeLa metric emission band, high stability against photo-bleach- cells in vitro by ZnO and QDs (Figure 8), where ZnO QDs ing, and large Stokes shifts [155–159, 163, 164, 167–169]. are stable at neutral pH, however, rapidly disintegrating at This might be a good replacement of quantum dots (QDs) pH < 6 [175]. The ZnO QD florescent composite can also be because they exhibit toxicity to biological systems, and used to observe drug deliverance [168]. their release may cause environmental pollution [170]. In comparison to QDs, ZnO NPs are of high safety, lack pol- luting effects, have a low price, and have good stability 3.6.4.1 Diagnostic, therapeutic, and dentistry [171], although synthesis of luminescent ZnO is a chal- ZnO NPs have fantastic luminescent properties that are lenge. The aqueous medium may destroy the surface good for biocompatibility, less expensive, and have low defects that are a source of visible fluorescence; however, toxicity that have made these nanomaterials into one of surface modification may resolve this problem [155]. ZnO the key contenders for bio-imaging. The detection of other with polymer core-shell NPs exhibit stable luminescence required characteristics like their capability to form dam- in aqueous solutions and are successfully applied in cell aging ROS, strong adsorption capability, enhanced cata- imaging (Figure 8). lytic efficiency, and greater isoelectric point also upgrades them (ZnO NPs) for diagnostic and therapeutic functions [176]. Moreover, the impregnation of ZnO NPs onto various 3.6.4 Drug delivery biomaterials (polymers) particularly denture-based poly- mers such as polymethyl methacrylate can greatly affect

Drug delivery to a diseased cell is practiced using Fe3O4 NPs, the microbial deposition on their surface. It improves the carbon nanotubes, mesoporous silica NPs, and organic hydrophilicity and hardness, and even after this modifi- polymer nanobeads. The mechanism of entering the cell cation, the roughness parameter does not change. Thus, is simple: through an intracellular endocytic pathway [171, it achieves the requirements of the ISO (International 172] and releasing the drug inside especially when the Organization for Standardization) standards. Because drug, itself, cannot cross the cell membrane. However, a of the hardness with absorbability (within the normal controlled release, i.e. pH, temperature, and light depend- range), enhanced hydrophilicity and lack of substantial ence, is a prerequisite for a focused target [173]. pH sen- deterioration, such nanocomposites (based on ZnO NPs) sitivity plays a critical role in this aspect as pH in tumors can demonstrate a reduced microorganism growth on the A. Ali et al.: Elemental zinc to zinc nanoparticles 429

Figure 8: Photoluminescence of ZnO NPs under UV light (D), luminescence of ZnO inside the cell (E, F), and mice model (G–I) (adopted from Xiong) [169]. denture base and, therefore, meet the requirements for that describes this process was suggested by Padma- clinical (dentistry) use [177]. vathy and Vijayaraghavan [125] and Seven et al. [178] as follows. As a semiconductor material, the ZnO electronic band structure comprises a valence band (VB) and a con- 3.7 UV lighting effect and photocatalysis duction band (CB). Incident radiation with energy more than 3.3 eV rapidly absorbs and, consequently, the elec-

ZnO is more biocompatible than TiO2, and among all the trons transfer to the CB from the VB. Thus, possible pho- inorganic photocatalytic materials, it has great photocata- toreactions are started by this transmission of electrons, lytic efficiency [172, 175]. ZnO has good absorbance [169] and subsequently, free electrons are generated within as well as a better response to UV light; hence, its conduc- the CB, whereas positive holes (h+) are created in the VB tivity vividly improves, and this feature considerably trig- [115]. In the photocatalytic system, such a positive hole gers the interaction with biological (e.g. microorganisms) (h+), a direct oxidant, and imperative for the formation of and environmental (e.g. dyes) parameters [90, 119]. After reactive hydroxyl radicals (OH•), act as the principal oxi- turning off the UV light, the photoconductivity of ZnO per- dants. On the other hand, the electrons of the CB reduce sists for a long time, and it has been attributed to the state oxygen that is adsorbed by the photocatalyst [175, 179]. In of surface electron depletion, i.e. intensely linked to nega- the meantime, Padmavathy and Vijayaraghavan [125] sug- − 2− tive O2 species (O2 ; O2 ), adsorbed on the surface [4]. UV gested a link between the antibacterial activity and photon radiance quickly starts the desorption of insecurely bound reaction in a series (of reactions) that results in the forma-

O2 from the surface prompting enhanced photoconductiv- tion of hydrogen peroxide (H2O2) molecules, which cause ity and reducing the surface electron depletion area [170]. lethal damage by penetrating the membrane. Because of

Photo-induced oxidation that impairs and inactivates photocatalytically triggered H2O2, various researchers also organisms is the process of photocatalysis [171]. ROS, confirmed the cell membrane distraction to unsaturated for example, superoxide ions (O2−) and hydrogen per- phospholipid peroxidation [178, 180–184]. oxide (H2O2), are produced by ZnO NPs in aqueous solu- tion under UV radiation that has phototoxic effects, and these species are highly significant in biologics [168]. This 3.8 Mechanism of Zn ion toxicity process encouraged the use of photocatalytic activity of ZnO NPs in bio-nanomedicine, bionanotechnology, envi- The intracellular release of zinc ions and subsequent gen- ronmental nanotechnology, and for various antimicrobial eration of ROS are the basic processes behind the cytotox- applications. A comprehensive mechanism of reaction icity of zinc NPs. Figure 9 exhibits the whole mechanism 430 A. Ali et al.: Elemental zinc to zinc nanoparticles

Zinc ion morphologies [19]. Therefore, enviably created ZnO NP structures for different biological and environmental applications could be achieved by controlling solvents, Greater ROS generation Zinc facilated protein activity imbalance precursor types, physicochemical settings, such as pH and temperature, etc. [115], along with shape-directing agents Oxidative stress Membrane penetration [81, 92]. Furthermore, the surface morphology could be determined through surface activity in controlled growth DNA impairment conditions. Necrosis The shape-dependent activities were clarified in Triggering of p53 gene: Apoptosis terms of the active facet percentage in the ZnO NPs. Syn- thesis and growth methods hold several active facets in Cytotoxicity (cell death) NPs. Spherical nanostructures predominantly have (100) facets, while the rod structures of ZnO have (111) and (100) Figure 9: A chart depiction of the whole cytotoxicity of zinc NPs, facets. High-atom-density facets with (111) facets show causing cell death. effective biological activities [197]. The facet-dependent ZnO activities were assessed by limited studies [93, 105, 204]. In this regard, the ZnO nanostructures can efficiently of the cytotoxicity of ZnO NPs. Zinc-dependent protein perform functions and affect their mechanism of inter- activity imbalance or disequilibrium and greater ROS nalization, for example, nanowires, nanospherical, nano- generation causes cytotoxicity. This occurrence results plates, nanoflowers, nanorods, etc., penetrating into the in zinc-created oxidative stress and the imbalance of the microscopic domains of organisms (cells/organelles) or protein activity that ultimately destroy the cell. A less sig- environmental matrices (water/soil/air, etc.) more easily nificant cytotoxicity is presented by soluble extracellular than their general macroscopic conditions [94, 186, 204]. zinc. Certain studies demonstrate the formation of not very Moreover, in the improvement of internalization, it was soluble amorphous zinc-carbonate phosphate precipitates proposed, concerning the involvement of polar facets of (phosphate due to media) on the exposure of extracellular nanostructured ZnO to various activities, that the greater soluble zinc to cell culture and media. Such precipitates number of polar surfaces has greater vacancies of oxygen. are thought to defend the cell from zinc cytotoxicity [185]. Oxygen vacancies are recognized to intensify the produc- Conversely, a cascade of passages interconnected to each tion of ROS and, thus, affect the ZnO photocatalysis. At other takes place on the releasing intracellular soluble zinc present, it was found that ZnO morphologies of greatly ions, i.e. they are responsible for the cytotoxic reaction of exposed (0001)-Zn terminated polar facets obtained the zinc NPs. These activities are further explained in detail by best antimicrobial and photocatalytic results [187–189]. Bisht and Rayamajhi [166] in three major themes of zinc- mediated protein activity disequilibrium, ROS production, oxidative stress, and DNA damage and apoptosis. 4.2 Influence of Zn and ZnO particle size and concentration

4 Other applications of ZnO NPs The lack of zinc stunts development and growth, and causes system dysfunction in animals, plants, and micro- Because of the various physical and chemical properties, bial organisms. The biotic functions of zinc involve struc- ZnO NPs are widely used in many dimensions (Table 7). tural, catalytic, and regulatory functions. It plays an They play an important role in a very wide range of appli- important role in regulating gene expression and main- cations [1, 16], ranging from types of ceramics, pharma- tenance of proteins’ structural integrity. Its deficiency ceuticals to agriculture, environment to human health, in various parts of the world is not explicitly common in and paints to chemicals. humans; however, a wide range of mild deficiency signs are noticed because of the involvement of zinc abundance in metabolic processes. The recommended and estimated 4.1 Morphological effect of ZnO (via factorial analysis) dietary allowance for adults is 11 mg/day for men and 8 mg/day for women, whereas, Several studies reported that the toxicity and naiveté the maximum (tolerable) intake level for adults has been of ZnO NPs are considerably affected by their different established as 40 mg/day in the USA [28–30, 33, 205]. A. Ali et al.: Elemental zinc to zinc nanoparticles 431

Table 7: Summarized applications of ZnO NPs in nearly all fields.

Field or industry Fields/practices References

Rubber Fillers, activator of rubber compounds, polymer matrix, elastomers, etc. [15, As an activator and accelerator in vulcanized rubber tires having longer working life 186–189] Pharmaceutical Medicines, dental pastes, absorber of UV radiations, component of creams, ointments, powders [190–192] and cosmetics (inorganic ZnO as photocatalyst perform better than organic photocatalyst), etc. Textile Absorber of UV radiations in cotton and wool fabrics mostly, self-cleaning and water repellent, super- [2, 15, 192, hydrophobic nature, to impart sunscreen activity to the treated textiles, dye degradation, etc. To 193] enhance the wash fastness, by dipping fabrics in a solution having a specific binder Electronics Sensors, field emitters, photoelectronics, solar cells, photovoltaic and electroluminescent [15, equipment, UV lasers, etc. 194–197] Electrical devices, image recorder, attenuation of light, high temperature lubricant gas turbine engines Environment Photocatalysis ZnO NPs are luminescent materials because of their unique properties like wide band gap (3.37 eV), [15, 16, 80, greater binding energy (60 meV), and radiation hardness nature 198, 199] Photo-degradation and UV degradation of various organic/inorganic pollutants, etc. Antimicrobial Antifungal, antibacterial, antiviral actions, etc. action Wastewater Pollutant removal and disinfectants, due to high chemical stability, oxidation-reduction capability, treatment and toxic-less characteristics. Techniques may include nanomembrane, nanoabsorbent and nanocatalyst technology, pesticide detection, desalination, oxidation of organic pollutants, etc. Biologics Solar cell window, piezo actuator devices, surface acoustic devices, and in gas sensors. [19] Biocompatible material with antiseptic properties DNA and RNA damage has been raising industrial and academic concerns for the safe use of ZnO as an effective UV-shielding agent Exhibiting various catalytic antibacterial, anticorrosive, antifungal, and UV shielding/filtering properties As a demilitarization of chemical biological warfare agent Agriculture Nanofertilizers, pesticide detection, soil moisture, nutrient detection, better-quality crops, etc. [150, 200] Plants Seed germination, growth of stem, roots, and shoots, enhanced antioxidant activities, enzymatic, non-enzymatic molecules, enriched phenolic and flavonoid contents, etc. Biomedical Micronutrients for humans, plants, and animals, cancer treatment (enhanced permeability and [166] retention effect and electrostatic interaction and selective cytotoxicity due to increased ROS present in cancer cells), drug delivery and in therapeutic interventions, etc. (such treatments are in clinical use or the development pipeline) Chemistry Apart from the scorch problems for carboxylated elastomers, ZnO is effectively used and common [15] cross linking agent As a catalyst for the synthesis of coumarins, for carbon-carbon formation in fine chemical hetero Diels-Alder reaction Production of vulcanisates with high tensile strength, tear resistance, and hardness Human health Preventing diarrhea in infants and children, antioxidant and anti-inflammatory agent, effective [142] therapeutic agent, Wilson’s disease and development of age-related macular degeneration (AMD) and its complications and blindness in the elderly age. Zn deficiency causes growth retardation, testicular hypofunction, immune dysfunctions, increased oxidative stress, and increased generation of inflammatory cytokines Other Cement and concrete production (construction processes), ceramic varistors, and piezoelectric [15, 131, applications transducer, methanol production, typographical and offset links, biosensors, production of zinc 151, 201, and/or silicates, vegetable products, Brass, zinc pyrithione in antidandruff shampoos, zinc is used against 202] industries sunburns and on baby diapers to avoid rashes, production process and packing meat, etc. In auto industry, in hydrogen fuel engine, in engine oil, reduces friction, ZnO LEDs used in headlight (more efficient, less power usage, and longer life) In other imperative processes such as catalysis, in Gratzel type solar cells, and short-wavelength light-emitting devices, etc. Water treatment ZnO NPs have photodegradation potential, which can also be enhanced by coupling with other [34, 203]

semiconductors including CdO, SnO2, and TiO2, as feasible approach. ZnO NPs are environment friendly and compatible with organisms, which makes them suitable for the treatment of water and wastewater 432 A. Ali et al.: Elemental zinc to zinc nanoparticles

In the nanoscale range of NPs, the zinc concentra- (i) the morphology of the NP, concentration, particle size, tions play important roles in various biological activi- porosity and (ii) the chemistry of the media [142, 150, 200– ties. Higher concentration and larger surface area are 203, 205, 208–214]. Peng et al. [207] observed the release responsible for the applications of ZnO NPs [89, 94, 123, of Zn2+ ions at a higher level from spherical structures than 190, 205]. Several investigations show that the size of the from rod structures. Leung et al. [215] demonstrated that NPs is directly proportional to toxicity; furthermore, size such characteristics are influenced by surface modifica- handling is important to fabricate a greater enhanced tions including the liberation of Zn2+ ions and ROS genera- permeation and retention (EPR) effect to enhance an tion on the NP surface. intra-tumor concentration of NPs [191, 205]. Smaller-sized ZnO NPs can easily penetrate even into the cell mem- branes owing to their greater interfacial area, so there is an increase in antimicrobial efficacy. The dissolution of 5 Negative impacts of ZnO NPs Zn2+ from ZnO NPs is considered size dependent. Padma- vathy and Vijayaraghavan [125] described the generation The widespread use of ZnO NPs raised great concerns of H2O2 to be most probably based on the surface area of about their occupational and biological safety [216–218]. ZnO. Greater surface area and high concentration of ROS In various spheres of nanoscience research, they were fre- can be obtained from bioactive NPs. However, most of the quently found to be more toxic compared to some of the studies also endorse that the decrease in particle size will other NPs [26]. Released Zn2+ is an important contributor increase the bioactivities [162, 193, 206]. to this NP toxicity [204]. The mechanism of ZnO NPs tox- icity involves oxidative stress, i.e. revealed by evaluating the human bronchial epithelial cells [217]. These NPs are 4.3 Surface defects ingested by living organisms from aquatic and terrestrial environments where they accumulate, before being elimi- The molecular structure of ZnO NPs depicts surface nated. Because of their small size, NPs occur as foreign defects and surface charges making the surface a poten- elements inside the organisms with their own physico- tial reactive­ site. Though ZnO has simple structure and chemical properties and, thus, the chances of interference formula, it is very rich in chemistry defects [4]. These are increased with normal physiological mechanisms defects and charges play a vital role in bioactivities. of the embryos, growing animals, and adults, and it is These defects deliberately change the particle boundary crucial to recognize their potentially direct or indirect det- properties and characteristics [26]. The spatial configu- rimental effects on living organisms. The ZnO NPs may ration of ZnO arranged randomly enhances the biocidal also be intermingled in the diets of animals that must activity compared with the regularly arranged struc- be considered. The presence of more than one pollutant tures [192]. Some researchers [4, 105, 167] also referred under natural conditions could have a synergistic effect to the toxicity of the nanostructured ZnO to orientation, on their toxicity [218]. Moreover, they could also be toxic whereas no reference was found for crystallographic ori- to algae, invertebrates, and vertebrates [219]. Mechanisms entation [195, 207]. of NP interaction with living cells are unknown. However, it was established that they can bind with membranes, proteins, and DNA, and are able to produce oxidative 4.4 Zinc ion (Zn2+) release stress [220]. Highly engineered ZnO NPs (in greater quan- tity) will lead to human contact and exposures (ingestion, ZnO internalization is controlled by fictionalization, inhalational, and dermal) [204]. They can penetrate the surface chemistry, particle size, and defects. One of skin (particularly through sunscreens) resulting in possi- the main proposed antimicrobial and photocatalytic ble toxicity and infections [199]. A comparative analysis mechanisms for ZnO NPs is the release of zinc ions in of dermal penetration among various animals was per- the medium [24]. The release of Zn2+ significantly affects formed, rating them in the order of rabbit > rat > pig > enzyme system disruption, amino acid metabolism, and monkey > humans. Further, it was also observed that pig active transport inhibition. Despite this, the leaked Zn2+ and rat skin were up to 4 and 9–11 times more permeable in media is responsible for ZnO toxicity, and the release than human skin, respectively [221]. is size dependent. Consequently, ZnO NP toxicity can be Various research has been carried out to determine modified by size decrease and low dissolution rate [10, the effects of ZnO NPs on plant species [150, 216, 218]. 124, 196–199]. Zn2+ release is affected by two main reasons: They can penetrate soil through accidental or intentional A. Ali et al.: Elemental zinc to zinc nanoparticles 433 release. Some NPs are well recognized to affect crop have different modes of action [61, 150]. Currently, the development, yield, and accumulate in the edible parts of discharging of NPs into the environment, e.g. through plants with other tissues as well. The behavior of various the effluent of wastewater treatment plant (WWTP) can NPs in plants is not totally clear. However, NPs (on expos- upsurge the exposure of the ecosystem, which is difficult ing with plant tissue) penetrate into the cell membrane to quantify. However, through modeling exertions, there and cell wall of the epidermis, cortex of the root together may currently be the higher environmental concentra- with a complex series of actions to enter the plant vascu- tions of ZnO (0.432 μg/l in Europe, 0.3 μg/l in the USA) in lar bundle (xylem), and passage to the stele. The xylem the effluent of WWTP that can pose a toxicological hazard acts as the most important vehicle in the circulation and to aquatic organisms [16, 61, 226]. The industrial applica- translocation of NPs to the leaves. The epidermis, cortex, tions of ZnO also have serious health and environmental endodermis, cambium, and xylem accumulate more NPs concerns particularly in the rubber industry where after than the other plant tissues. The NP uptake mechanism the expiry time of the rubber products, various types of is normally considered as an active transport mechanism hazardous compounds are finally released into the litho- that includes several other cellular processes like recy- sphere during their misuse for degradation [1]. The effects cling, signaling, and the regulation of plasma membrane of excess zinc on aquatic organisms are further consid- [216, 218]. Toxicological studies of ZnO NPs on numerous ered as one of the great ecological concerns [43], which plants such as on rye grass exhibited the presence of these can be overwhelmed by reducing zinc levels in rubber NPs’ shrunk root tip and epidermis, reduced biomass, and compounds [227], for example, by replacing the com- cortical cells turned out to be extremely vacuolated and monly used bulk ZnO material with granular nanoscale collapsed [216]. Boonyanitipong et al. [222] observed the ZnO [1, 10]. reduction of the number of roots and stunted the length of rice seedlings (Oryza sativa L), while Raskar and Laware [222] observed the inhibition of chlorophyll biosynthesis along with the efficiency of photosynthesis in Arabidop- 6 Environmental fate and biological sis. Another study by Zafar et al. [150] showed the effects toxicity of ZnO NPs of ZnO NPs on germination and shoot growth of Brassica nigra and so on. The release of synthesized ZnO NPs into the environment ZnO NPs can impose serious toxicity to microbial pop- and exposure to organisms are considered toxic, although ulations (e.g. Daphnia magna, bacteria, etc.), mice, fresh- it is unclear whether this toxicity is caused by such par- water microalga, and human cells [4, 20, 104, 221, 223, 224]. ticles, dissolution to Zn2+, or some amalgamation thereof The toxic nature of ZnO NPs for different bacterial systems [10, 61]. Investigations were carried out to determine the leads to biomedical and antibacterial applications. Their relative solubility of ZnO biological toxicity studies or exposure causes changes in cellular morphology and in matrices used for environmental fate and transport. eventually death of the bacteria due to which, they can Even the dissolution of ZnO is observed in nanopure be used extensively in environmental remediation and as water (5.0–7.40 mg/l of dissolved zinc, as determined by an antibacterial agent. ZnO NPs can induce modifications filtration), but much more dissolution was observed in in microbial enzymatic activities that were observed in the dissolved Zn concentration that exceeded 34 mg/l in numerous in vitro studies. The cell viability is dependent a different medium. Hardwater moderately exhibits low on both the concentration of the particles and exposure Zn solubility, probably due to the precipitation of a zinc time [218]. The effect of ZnO NPs is being observed to be carbonate solid phase. Even after more than 1000 h of relatively higher than that of many other metal-based NPs dissolution, the balanced circumstances according to the such as TiO2 NPs, as reflected by the lower DNA content ZnO solubility was not observed in these matrices. Such and stronger shifts in the bacterial community composi- findings recommend the exertion of a strong influence of tion at the same exposure concentration [218, 225]. solution chemistry on ZnO dissolution and, thus, causing Being very reactive, the ZnO NPs form complexes a limitation on zinc solubility from the precipitation of in the environment. Study of such complexes is obliga- slightly soluble solid phases [90, 204]. tory to evaluate the potential threats [220]. These NPs George et al. [226] recommended that iron doping of have more toxicity than dissolved Zn2+, and these parti- ZnO NPs caused reduced dissolution, thus, there is less cles disintegrate comparatively faster, and released Zn2+ cytotoxicity and prospect for synthesizing safer nanoma- is the primary source of toxicity. Although both ZnO NPs terials. However, another study investigated the effects and Zn2+ are biologically and ecologically noxious, they of Fe-doped ZnO on microbial toxicity [224, 228], and it 434 A. Ali et al.: Elemental zinc to zinc nanoparticles exhibited that water chemistry influenced toxicity greater is still questionable. For example, ZnO NPs may act as a than doping. smart weapon toward multidrug-resistant microbes and a talented substitutional tactic to antibiotics. The in vivo experiments show that ZnO NP exposure via inhalation poses the most significant hazard compared to the other 7 Conclusion itineraries of exposure such as on the skin due to limited uptake and the absence of local effects. There is a dire Zinc is an essential element, necessary for the function need for risk assessment by the dose-response relation- of more than 300 enzymes. This review elaborates the ships. Most of the research works propose that such influ- ephemeral outline of zinc and its multifunctional com- ences are due to Zn2+ causing NP dissolution outside the pounds as ZnO and their applications. Zinc compounds cell. Nano-biotechnologists recommend that cells take and nanostructures possess various interesting proper- up the NPs, after which, dissolution takes place inside ties (piezo- and pyroelectric) including high photostabil- the cell. Beside all the controversies, we are thankful to ity, biodegradability, biocompatibility, a wide range of UV the scientific community who devoted themselves for the absorption, and ZnO has different ranges of nanostruc- betterment of humankind in the field of nanotechnology. tures. Furthermore, the current progresses in electrochem- Still, there are a lot of areas that need exploration, and ical bio-sensing, based on a diversity of nanostructures we hope that material science will flourish in the field of like nanotubes, nanowires, nanoflowers, nanopores, etc., biological science for sustainable health, agriculture, and attracted great interest in environmental and agricultural environment. and biomedical applications. 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Use of a rapid cytotoxicity screening approach to engineer a Abdul-Rehman Phull safer zinc oxide nanoparticle through iron doping. ACS Nano. Department of Biochemistry, Shah Abdul 2009, 4, 15–29. Latif University, Khairpur, Sindh 66020, [227] Hu JS, Ren LL, Guo YG, Liang HP, Cao AM, Wan LJ, Bai CL. Pakistan Mass production and high photocatalytic activity of ZnS nanoporous nanoparticles. Angewandte Chemie. 2005, 117, 1295–1299. [228] Javed R, Yucesan B, Zia M, Gurel E. Elicitation of secondary metabolites in callus cultures of stevia rebaudiana bertoni Abdul Rehman Phull obtained his Master’s degree in Biochemis- grown under ZnO and CuO nanoparticles stress. Sugar Tech. try/Molecular Biology from Quaid-i-Azam University, Islamabad, 2018, 20, 194–201. Pakistan, and his PhD in Biology from Kongju National University, Republic of Korea. Currently, Dr. Abdul Rehman Phull is working as an Assistant Professor of Biochemistry at Shah Abdul Latif Univer- Bionotes sity, Khairpur, Sindh, Pakistan. His research interests include cell biology, enzymology, therapeutic applications of nano-materials, and natural and synthetic molecules. Attarad Ali Department of Biotechnology, Quaid-i-Azam Muhammad Zia University, Islamabad 45320, Pakistan Department of Biotechnology, Quaid-i-Azam University, Islamabad 45320, Pakistan, [email protected]

Attarad Ali did his BS in Environmental Sciences in 2011 at the Uni- Muhammad Zia obtained his PhD degree in Biotechnology from versity of Punjab, Lahore, Pakistan. He completed his MPhil degree Quaid-i-Azam University, Islamabad Pakistan. His current focus area in Environmental Sciences in 2013 at Quaid-i-Azam University (QAU) of research is nanotechnology, nanobiotechnology, and synthesis, Islamabad, Pakistan. He is pursuing his PhD degree (2014–2018) characterization, and applications of nanomaterials. at QAU. During his PhD, he also worked at the University of Florida, USA, under the HEC sponsored IRSIP (scholarship) program. His area of interest is nanoparticle synthesis (doped with polymeric materials), characterization, and their applications in biomedical and environmental domains.