INTRODUCTION:

To synthesize, design, manipulate and application of materials at the nanometre size scale (1 to 100 nm) is called as nanotechnology. Nanotechnology has dynamically developed as an important field of modern research with potential effects in electronic and medicine^1-3. At this size there are many significant changes in many material properties that are normally not seen in the same materials at bigger scales. The extremely small size and large surface area to volume ratio that leads to the significant differences in biological, catalytic activity, mechanical properties, melting point optical absorption, thermal and electrical conductive properties makes it different material as compared to their bulk form ⁴. Bio-nanotechnology has emerged up as integration between biotechnology and nanotechnology for developing biosynthetic and environmental-friendly technology for synthesis of nanomaterials. Nanobiotechnology describes an application of biological systems for the production of new functional material such as nanoparticles.

Metal-based nanotherapeutics with controllable features such as particle size and porosity, are valuable for biomedical applications of drug delivery and therapeutic activity. At present, according to their chemical composition, nanoparticles are largely classified in five categories: metallic nanoparticles in which Au, Ag, Zn etc.; nanoparticles of metal and nonmetal oxides nanomaterials which includes FeO, ZnO etc., semiconductor nanocrystals such as ZnS, CdSе, ZnSe, CdS, etc., carbon nanoparticles like; fullerenes, nanotubes, grapheme, diamond); polymers viz; dendrimers of different composition and quantum dots^5-9. Zinc nanoparticles are included in three categories. Zinc oxide NPs have been highlighted as promising metal-based nanodrugs due to the fact of their biocompatibility, selectivity, and high potency ^10,11. They have a wide band gap energy (3.3 eV) and a high excitation binding energy (60 meV) at room temperature with thermal and mechanical stability. Zinc oxide NPs have been extensively used in applications related to optical, chemical sensing, semiconducting, and piezoelectric research^12-15. They also have photocatalytic functions that allow them to be used in purification and disinfection processes^16-18.

Nanoscale materials can be produced using a variety of traditional physical and chemical processes. But now biological methods to synthesize materials via environment-friendly green chemistry based techniques are used, in which no harsh, toxic, and expensive chemicals are used, which were commonly used in conventional physical and chemical processes. Nanobiotechnology represents an economic alternative for chemical and physical methods of nanopaticles formation. In this review, we summarized the synthesis techniques, physicochemical properties, unique structures of ZnO NPs, the evaluation tools of X-ray dffraction , scanning electron microscopy , transmission electron microscopy analysis. We also discussed conventional synthesis techniques and green synthesis. The biomedical applications of ZnO nanoparticles are also discussed.

SYNTHESIS TECHNIQUES:

The nanoparticles of Zinc oxide are synthesized by either conventional or non-conventional methods^19,20. Physical, chemical, and biological (green) synthesis techniques are among the conventional methods, whereas, micro-fluidic reactor-based synthesis is considered as a non-conventional method. In this work we are going to discuss only the convention method.

Conventional Methods

The two approaches which are: top-down and bottom-up approaches, used to synthesize nanomaterials. The top-down approach involves physically slicing or cutting bulk materials into nano-sized materials²¹. The bottom-up approach, on the other hand, uses atoms and molecules to build nanostructures through chemical or biological synthesis ²². Biological synthesis, which is otherwise referred to as “green synthesis,” is desirable due to the simplest, most efficient, reproducible, and ecologically responsible option²³.

Physical Methods

Physical methods include arc plasma, thermal evaporation, physical vapor deposition, ultrasonic irradiation, and laser ablation. These processes are chemically pure and technically simple, which makes them ideal for carrying out industrial processes at high production rates ^24–27. This is one of the most commonly physical methods used for converting bulk materials into nanomaterials via condensation and evaporation by using electrical arc discharge is arc plasma²⁸. ZnO thin films and nano ZnO rods can be synthesized via deposition on substrates using thermal evaporation²⁹. Histidine - based ZnO nanoparticles could be prepared by sonochemical synthesis using ultrasonic irradiation for different timings³⁰. Colloidally suspended ZnO nanoparticles can be synthesized by pulsed laser ablation technique with an Nd:YAG laser³¹.

Chemical Methods

Chemical methods include microemulsion, sol–gel, precipitation, hydrothermal, solvothermal, and chemical vapor deposition. The most common chemical method for preparing nanomaterial is the wet chemical synthesis, which is based on the physical states of the solid and liquid phases¹³. For large scale synthesis (industrial-scale), capping agents/stabilizers are used extensively to control particle size and to prevent the agglomeration, in spite of their toxicity. Triethylamine (TEA), mercaptoacitic acid, thioglycerol, mercapto-ethenol and polyethylene glycol are some capping agents, although they have immunogenic and necrotic potential. Microemulsion synthesis techniques use stabilizers to produce thermodynamically stable fluid droplets from immiscible phases of hydrocarbon and water³². Compounds of zinc and alkali are used to precipitates of ZnO NPs and collected by filtration or centrifugation in the precipitation technique³³. Hydrothermal and solvothermal techniques involve the material synthesis under heated aqueous and non-aqueous conditions respectively^34,35. However, these methods have been known to produce heterogeneous growth. The synthesis method affects the structure, morphology, composition, and assembly of the prepared ZnO nanocrystals..

Biological Methods

Biological methods to produce nanomaterials (eco-friendly) involve microorganisms (bacteria, fungi, yeast, algae, and phage), DNA, proteins, and plant extracts. Zinc oxide NPs can be synthesized in appropriate microorganisms using various enzymes and biochemical pathways. Bacteria including Bacillus megaterium, Halomonas elongate, Sphingobacterium thalpophilum and Staphylococcus aureus have been used to synthesize ZnO NPs. Fungal species including Aspergillus niger and Candida albicans can also synthesize ZnO NPs. Pichia kudriavzevii and Pichia fermentans as yeast systems are normally used to synthesize ZnO NPs. In yeast, hexagonal wurtzite ZnO NPs were produced. In algae, Chlamydomonas reinhardtii and Sargassum muticum were used to synthesize ZnO NPs. A phage-directed system of bacteriophage exposing ZnO-binding peptides on pIII or pVIII phage coat protein produced photoluminescent wurtzite ZnO NPs^36-41. The DNA, amino acids, and proteins can also be used for the ZnO NP synthesis. L-alanine, gelatin, and egg albumin were used for ZnO NP synthesis^42-44. Plant extracts are attractive for use in the biological synthesis of metal oxide NPs due to the presence of components such as flavonoids, terpenoids, and polysaccharides¹³. Calotropis procera leaf extract, Matricaria chamomilla (flower)/ Oleaeuropaea L. (leaf)/ Lycopersiconesculentum M. (fruit) extract, Pelargonium graveolens leaf-extracted geranium oil, and Thymus vulgaris leaf extract have been used to synthesize ZnO NPs and ZnO-Ag nanocomposites^45-47. Zinc oxide NPs synthesized from plant extracts have been applied for dye photo degradation, antimicrobial applications, and solar photo-catalysis. We have prepared ZnO nanoparticles by Green Synthesis using Ocimum tenuiflorum leaves (Tulsi plant).

EXPERIMENTAL

The Ocimum tenuiflorum leaves were first washed many times with water and dried in sunlight. 10gm of dried leaves with 100 ml distilled water were taken in a borosil beaker and boiled for 10 min. until solution turns in reddish colour. The leaves extract were filtered by the filter paper. Then 5 gm of zinc nitrate was added to the leaf extract and heated, when temperature reaches to 70^oC it reduces to deep reddish paste. This paste was then dried at temperature >80^oC for 80minutes. The dried light red/yellow powders of zinc oxide nanoparticles were obtained. The ZnO nanoparticles so obtained were preserved in the air-tight containers and characterized by different characterization techniques to determine the crystallinity, morphology, particle size by XRD, SEM, and TEM analysis.

CHARACTERIZATION TOOLS

Characterization tools are necessary to identify the properties of synthesized nanomaterials. Some tools used to determine the crystallinity, morphology, particle size/size distribution, and surface characteristics (specific surface area and porosity) of ZnO NPs include XRD, SEM, TEM, and BET analysis.

X-ray Diffraction (XRD)

X-ray diffraction is a well-established technique for analyzing the size, shape, and crystal structures of inorganic, carbon-based, or complex crystalline materials⁴⁸. It offers high spatial resolution at the atomic scale, but it is limited to crystalline materials and has a lower intensity compared to electron diffraction. Figure 1 shows the XRD pattern of the synthesized ZnO nanoparticles. The XRD suggests that the sample is in pure phase i.e. no impurity traces are seen in the XRD pattern. The peaks obtained at 2θ^o values of 31.62, 34.33, 36.12, 47.33, 56.31, 62.64, 66.03, 67.64, and 68.73 can be attributed to the planes (100), (002), (101), (102), (110), (103), (200) and (112), (201) respectively, with hexagonal crystal structure having cell parameter a = 3.264 Å and c = 5.219 Å (JCPDS file No. 36-1541). Broad diffraction peaks were observed for eco-friendly method with one extra peak attributed to plane (001) obtained at 2θ^o value of 27.82, rest all other peak are slightly shifted towards lower angle side, which may be due to increasing lattice strain and inter planar spacing^49,50. The broadening confirms the nanocrystalline nature of zinc oxide. The sizes of the particles were calculated from the first peak only. The average crystallite size was determined by the Debye Scherrer equation D = kl/bcosq, where D is the average crystallite size, k is Scherrer's constant equal to 0.90, b is the full-width at half-maximum (FWHM), and q is the Bragg's angle ⁵¹. The size of the synthesized ZnO sample was 55nm. The deformation in stress, strain and energy could be calculated by using the uniform deformation model, uniform stress deformation model, and uniform deformation energy density model of the Williamson–Hall method, and by using a size-strain plot.

Scanning Electron Microscopy (SEM)

Scanning electron microscopy is a high-resolution method for estimating size, size distribution, shape, aggregation, dispersion, and crystallinity on the basis of back scattered electrons. It may be used to analyze inorganic, organic, carbon-based, biological, and complex materials and to determine whether they are spherical or equiaxial particles, tubes, flakes, rods, fibers, or of any other shape. Scanning electron microscopy is limited to the analysis of conductive or coated materials under non-physiological conditions. The cryogenic method is required for biomaterials. Various ZnO NP shapes have been reported from SEM analyses, including spheres, rods, nails, ribbons and. The morphology of synthesized ZnO nanoparticles when investigated by scanning electron microscopy showed distinctive and abundant flower-shaped structure [Fig.2]. There are huge hexagonal arrays of nanoparticles assimilated to form flower-shaped bundles. It can be seen that many of the particles are agglomerated, this is due to the formation of ZnO nanoparticles during first few minute of the experiment and later these particles agglomerates and their size becomes larger. The average particle sizes obtained from SEM images was ~ 65 nm, which is well matched with the XRD results.

Transmission Electron Microscopy (TEM)

Transmission electron microscopy measures size and size distribution and confirms the nanomaterial shapes with higher resolution compared to SEM. Aggregation, dispersion (environmental TEM), and crystal structure can also be determined by TEM. Transmission electron microscopy (TEM) is a microscopy technique whereby a beam of highly-focused, mono-energetic beam of electrons is bombarded in vacuum on a very thin solid specimen and interacting with the sample as it passes through. The TEM technique is limited to very thin samples under non-physiological conditions. It can be used to visualize inorganic, organic, carbon-based, biological, and complex materials as spherical and equiaxial particles, tubes, flakes, rods, or fibers. The TEM technique is extensively used to determine the size and morphology of ZnO NPs based on the stabilizer (glycerol)-to-zinc source ratios during the synthesis^52,53. A typical TEM image of synthesized ZnO nanoparticle is shown in Fig.3. The particle size was calculated with the help of the scale shown on the lower right corner of the HRTEM figure, which is 100nm. The average particle size of the prepared samples was in the range 25nm – 30nm. The results are similar but less than the results obtained from the XRD pattern.

UV-visible absorption spectroscopy

Absorption of light by solution/ powder is one of the oldest and still one of the most useful instrumental methods. UV-visible absorption spectroscopy involves the spectroscopy of photons in the UV-visible region. This means it uses light in the visible, near ultraviolet (UV) and near infrared (NIR) regions. The absorption in the visible ranges directly affects the colour of the chemicals involved. In this region of the electromagnetic spectrum, molecules undergo electronic transitions. This technique is complementary to fluorescence spectroscopy, which deals with transitions from the excited state to the ground state, while absorption measures transitions from the ground state to the excited state. The wavelength of light that a compound will absorb is the characteristic of its chemical structure. Specific regions of the electromagnetic spectrum are absorbed by exciting specific types of molecular and atomic motion to higher energy levels. Absorption of microwave radiation is generally due to excitation of molecular rotational motion. Infrared absorption is associated with vibrational motions of molecules. Absorption of visible and ultraviolet (UV) radiation is associated with excitation of electrons, in both atoms and molecules, to higher energy states. For molecules containing conjugated electron systems however, light in the UV-visible region is adequate. As the degree of conjugation increases, the spectrum shifts to lower energy. The UV–visible absorption spectra of synthesized ZnO nanoparticles by green synthesis as a function of wavelength are shown in Figure 4. The excitonic absorption peak of ZnO nanoparticle was found at 336 nm, which lies much below the band gap wavelength of 388 nm of bulk ZnO⁵⁴. The peak at ~336nm is due to inter band transition of electrons from the more inner shell to the uppermost shell. It may be possible that, due to aggregation and agglomeration, particle size increases and material settled down at the bottom of container causing decrease in the absorbance⁵⁵. Using this data and by using the Tauc relation the band gap was calculated as ~3.86 eV , which is higher than the standard value 3.54 eV. The increase in the band gap of the ZnO nanoparticles with the decrease in particle size may be due to a quantum confinement effect.

Brunauer–Emmett-Teller (BET) Analysis

Brunauer–Emmett-Teller analysis provides the specific surface area and porosity of spherical and equiaxial particles of inorganic, carbon-based, and complex materials⁵⁶. This technique is limited to the analysis of volatile compound-free materials. Furthermore, BET cannot distinguish between particles and nonparticulate porous materials. Mesoporous ZnO thin films were found to have a specific surface area of 14–140 m²/g depending on the synthesis techniques⁵⁷.

BIOMEDICAL APPLICATIONS

The applications of nanoparticles are wide and diverse: interactions of nanomaterials with living cells and tissues, researches in polymer nanocoupling, creation of biohybrid systems i.e. artificial muscles, regenerative medicine (protometrocytes and nervous cells, bone tissue), nanomedicine (drug delivery, cell therapy) and others^58,59. Zinc oxide NPs are studied for biomedical applications because they have wide application such as: anticancer, antidiabetic, antimicrobial, anti-inflammatory, and wound healing activities. They are also used in imaging agents and biosensors^60,61.

The ability of ZnO nanoparticles to absorb a wide spectrum of radiation can be used for manufacturing cosmetic creams, ointments, etc., which protect organism from ultraviolet radiation.

Anticancer Activity

Using nanoparticles in targeted drug delivery provides exciting opportunities for much more safety and effective cancer treatment. The main problem that prevents a fast development of cancer therapy methods is the inability of anticancer drugs to distinguish between healthy and cancerous cells. This is a cause of complications and side effect of chemotherapy. Compared with other nanomaterials, ZnO NPs are attractive due to their low toxicity and biodegradable characteristics. ZnO NPs have acquired tremendous interest in cancer drug delivery because zinc is an essential trace element that regulates the activity of many enzymes to maintain homeostasis in the body⁶². Zinc also plays a role in humeral and cellular immunity, which protects cells against cancer. Zinc deficiency causes the initiation and propagation of cancer cells via DNA mutation and p53 disruption⁶³. Zinc oxide NPs have enhanced permeability and retention (EPR) effects toward cancer cells compared to bulk zinc materials and can kill cancer cells through the generation of reactive oxygen species (ROS)⁶⁴. Zinc oxide NPs have also been studied as tools for the targeted delivery of chemotherapeutics^64,65. It has been found that zinc oxide nanoparticles can selectively kill cancerous cells^66,67. Moreover, the process of interaction between ZnO nanoparticles and cancerous cells can be monitored. For example, the selectivity of nanoparticles may be enhanced if interdependence is found between the proteins attacking cancerous cells (monoclonal antibodies and peptides) and small protein molecules bound to cancerous, or if they are used to deliver drugs to the target. The action of ZnO nanoparticles (cytotoxic effects of zinc oxide nanoflakes (ZnO NFs)) has been studies in a model of human muscle carcinoma⁶⁸.

Antidiabetic Activity

Zinc is well known to keep the structural integrity of insulin and has an active role in the secretion of insulin from pancreatic cells. It also participates in insulin synthesis, storage, and secretion. Therefore, ZnO NPs as a novel agent in order for zinc delivery have been developed and evaluated for their antidiabetic potential.Zinc can ameliorate type 1 and type 2 diabetes because of its role in the function of enzymes (>300) to maintain metabolic homeostasis in the body^69,70. As an essential micronutrient, zinc is involved with the synthesis, storage, and secretion of insulin⁷¹. Specifically, zinc enhances the structural integrity of insulin through zinc–insulin hexamers. Zinc also down regulates blood glucose levels by inhibiting glucose absorption and increasing glucose uptake by skeletal muscle and adipose tissue. Nanozinc compounds with insulin and high molecular substances foster prolongation of hypoglycemic drug action in contrast with duration of insulin effect. Moreover, this kind of nanostructure with amphotericin В, antifungal drug of systemic action, decreases nephrotoxic effect of this pharmaceutic ⁷².

Antimicrobial Activity

ZnO NPs can be selected as an antibacterial material because of its superior properties, such as high specific surface area and high activity to block a wide scope of pathogenic agents. Zinc oxide NPs produce antimicrobial activity via adsorption-induced membrane damage and ROS-mediated cellular toxicity⁷³. The antibacterial activity may involve the accumulation of ZnO NPs in the outer membrane or cytoplasm of bacterial cells and trigger Zn²⁺ release, which would cause bacterial cell membrane disintegration, membrane protein damage, and genomic instability, resulting in the death of bacterial cells^74-76. They are effective against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Pseudomonas vulgaris, Bacillus subtilis, Bacillus megaterium, Sarcina lutea, Klebsiella pneumonia, Candida albicans, and Aspergillus niger^73,77. ZnO nanoparticles of less than 30 nm in size display antimicrobial properties, which is now used in textile industry for producing fabrics for cloths. When in contact with human body the fabrics serves as a substrate, on which microbes may grow and this growth of microorganisms can be prevented by using ZnO nanoparticles in the production of fabrics. A study showed that ZnO NPs with an average size about 30nm caused cell death by directly contacting with the phospholipid bilayer of the membrane, destroying the membrane integrity. The addition of radical scavengers such as mannitol, vitamin E, and glutathione could block the bactericidal action of ZnO NPs, potentially revealing that ROS production played a necessary function in the antibacterial properties of ZnO NPs. Zinc oxide NPs are used to deliver gentamicin from the intra- and interparticle pores of host–guest structures⁷³. Jin et al. also demonstrated the antibacterial and antiviral activities of hexagonal ZnO NPs (<100 nm in diameter) with and without UV-A and UV-C irradiation⁷⁸.

Anti-Inflammatory Activity

Inflammation is a part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Since the advent of nanoparticles and considering these biological activities of zinc ions, the anti-inflammatory effects of ZnO NPs have also attracted much attention. Zinc oxide NPs have anti-inflammatory activity in response to pathogens or chemicals. Zinc oxide NPs reduce inflammation by (i) blocking the production of pro -inflammatory cytokines such as interleukin (IL)-1 and IL-18 via inhibiting NF-kB and caspase 1 in activated mast cells and macrophages; (ii) inhibiting mast cell proliferation by increasing p53 and decreasing thymic stromal lymphopoietin production related to IL-13, a TH2 cytokine, along with IL-1 and tumor necrosis factor- and (iii) suppressing lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression^79,80. The anti inflammatory activity of ZnO NPs is not confined to atopic dermatitis treatment but has also shown to be very effective for other inflammatory diseases.

Imaging Agents

Quantum dots are semiconductors of transparent nanoparticles < 10nm. They have unique optical and electronic properties, including fluorescence under light sources for bioimaging applications. ZnO NPs exhibit efficient blue emissions and near-UV emissions, which have green or yellow luminescence related to oxygen vacancies, therefore further extending its application into bio imaging field. In core–shell configurations, the photoluminescent quantum yield of the core emission is boosted and shielded from photo bleaching . In pharmaceutical and biomedical applications, QDs can be used for imaging and drug delivery^81,82. Based on its advanced intrinsic fluorescence, ZnO nanomaterial can also be used as a promising candidate for cell imaging and pathological studies.

Wound Healing

As an essential micronutrient, zinc plays the following key roles in wound repair: it contributes to (i) fibrin clot formation, (ii) resolution of the inflammatory response, (iii) induction of cell proliferation, re-epithelization, granulation, and angiogenesis, and (iv) remodeling of the extracellular matrix^83,84. By providing a prolonged supply of zinc to wounds, ZnO NPs are attractive emerging therapeutic agents which effectively penetrate the cell, to modulate the immune system, and to promote disinfection. Their promoted antibacterial action and enhanced re-epithelization have reported in several studies of wounds^85,86. ZnO nanoparticles have shown pronounced anti-inflammatory and reparation action in treating experimental septic wounds.

Biosensors

Biosensors are widely used in healthcare, chemical/biological analysis, environmental monitoring, and food industry. They can be photometric, calorimetric, electrochemical, piezoelectric, among others when categorized based on the detection principles⁸⁷. Nanomaterials, alone or in combination with biologically active substances, are attracting ever-increasing attention since they can provide a suitable platform for the development of high performance biosensors due to their unique properties. ZnO nanomaterials also exhibit various desirable traits for biosensing such as high catalytic efficiency, strong adsorption capability, and high isoelectric point which are suitable for adsorption of certain proteins by electrostatic interaction⁸⁸. Furthermore, high surface area, good biocompatibility/stability, low toxicity, and high electron transfer capability also make them promising nanomaterials for biosensors employed to immobilize various biomolecules such as enzymes, antibodies, and other proteins. The majority of reported ZnO-based biosensors are for the detection of various small molecule analytes such as glucose, phenol, H₂O₂, cholesterol, urea, etc. Zinc oxide NPs have been used as biomedical diagnostic/analytical sensors for detecting gases and biochemicals. In gas sensors, the pore properties are important factors because they allow adsorbates into internal surfaces to ensure adequate adsorption performance. For example, highly sensitive and selective gas sensors of ZnO nanowires/NPs were able to detect ethanol and acetone quickly and accurately.

CONCLUSIONS AND FUTURE WORK:

Nanotechnology has had a revolutionary impact on biomedicine and witnessed tremendous advancement over the last several decades. With sizes less than a few hundred nm, several orders of magnitude smaller than human cells, nanomaterials can exhibit properties distinct from both molecules and bulk solids. Zinc is known to be one of the most essential microelements indispensable for vital functions. Zinc that comes into the organism from food and water is mainly absorbed in small intestine, and then it is transported to blood plasma, where it is bound by albumins and globulins, or to the tissues in which it is deposited in zinc and cadmium accumulating protein. Zinc is included in the structure of metalloenzymes and hormonal complexes. The property of zinc to take part in the processes of forming ligands with organic molecules explains why it is widely available in different biological systems. Zinc and its compounds can open wide possibilities of biomedical applications due to nanosize, optical, chemical, biological and pharmaceutical properties. The researches in this field also have practical importance due to possibility to regulate functional activity of muscles using zinc ions both in states normal and pathological. Zinc oxide NPs have different physicochemical characteristics that can vary depending on the techniques used for synthesis. They show promising potential as therapeutics with anticancer, antidiabetic, antimicrobial, anti-inflammatory, and wound healing activities. Zinc oxide NPs are also used for imaging tools and biosensors. In the near future, it is expected that ZnO NPs can be extensively applied in non-clinical and clinical studies as emerging therapeutic agents. Although ZnO in nanoparticle form is a promising antibacterial agent due to its wide activity against both Gram-positive and Gram-negative bacteria, the exact mechanism of ZnO NPs has not been well established. Synthetic ZnO NPs form one, two, and three dimensional structures, porous network structures may enhance their performance. Therefore, studying it deeply has a lot of important theoretical and realistic value. In the future, we believe ZnO NPs can be explored as antibacterial agents, such as ointments, lotions, and mouthwashes.

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Received on 05.02.2020 Modified on 10.03.2020

Research J. Pharm. and Tech. 2020; 13(4):1636-1644.

DOI: 10.5958/0974-360X.2020.00297.8