WO2014181329A1 - Doped metal oxide nanoparticles of and uses thereof - Google Patents
Doped metal oxide nanoparticles of and uses thereof Download PDFInfo
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- WO2014181329A1 WO2014181329A1 PCT/IL2014/050406 IL2014050406W WO2014181329A1 WO 2014181329 A1 WO2014181329 A1 WO 2014181329A1 IL 2014050406 W IL2014050406 W IL 2014050406W WO 2014181329 A1 WO2014181329 A1 WO 2014181329A1
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Definitions
- the present invention in some embodiments thereof, relates to material science and, more particularly, but not exclusively, to doped metal oxide nanoparticles, processes of preparing same, surface coatings containing same and uses thereof in, for example, reducing or preventing growth of microorganisms.
- nosocomial infections caused by antibiotic-resistant bacteria result in patient suffer and mortality and impose a substantial burden on the medical system due to extended periods of hospitalization.
- the economic impact of managing infections caused by nosocomial infections is substantial, and current costs are estimated to be more than $4 billion annually [Harrison and Lederberg (ed.), Antimicrobial resistance: issues and options. National Academy Press, Washington, D.C. pp. 1-7, 1998].
- biofilms to killing and their pervasive involvement in implant-related infections has prompted research in the area of biocidal surfaces/coatings.
- anti-biofilm coatings may also be in use for various industrial applications such as drinking water distribution systems and food packaging.
- fungi Another class of difficult to eradicate microorganisms includes fungi.
- the number of antifungal agents is limited and most are non-specific as to the organism affected and can be detrimental to the environment, inducing toxicity to plant and animals.
- Inorganic metal oxides such as ZnO, MgO, and CuO are being increasingly used in antimicrobial applications.
- the key advantages of using inorganic oxides compared to organic antimicrobial agents are their stability, robustness, and long shelf-life.
- Oxygen is essential for most living organisms, but is also a precursor of reactive oxygen species (ROS), which can damage cellular components such as proteins, lipids and nucleic acids.
- ROS include oxygen-containing ions (e.g., superoxide; ⁇ 0 " ), small molecules that contain peroxide (e.g., hydrogen peroxide; H 2 O 2 ), free radicals (e.g., hydroxyls; ⁇ ) and singlet oxygen (Droge et al. Physiol. Rev. 2002, 82:47-95; Lee et al. Aust. J. Chem. 2011, 64, 604).
- Sonochemistry is concerned with the effect of ultrasonic irradiation on chemical systems.
- the chemical effects of ultrasonic irradiation arise from acoustic cavitation, namely, the formation, growth, and implosive collapse of bubbles in a liquid medium.
- the compression of the bubbles during cavitation is more rapid than the thermal transport, which generates short-lived, localized hotspot bubbles reaching temperatures as high as 5000 K, pressures of roughly 1000 Atm, and heating and cooling rates above 1 x 10 10 K/s (A. reiterate, Ultrason. Sonochem., 2004, 11 (2)).
- Ultrasonic irradiation has been proven as an effective technique for the synthesis of nanomaterials (R. Gottesman, et al. Langmuir 2011, 27(2), 720). This technique further enables controlling the particle size of the product by varying the concentration of the precursors in the solution.
- Ultrasonic irradiation has been proven as being effective for the deposition of nanoparticles on polymeric matrices since the high-velocity fluid agitation, shock waves and energetic jets that are created during the compression of the bubbles near a solid substrate, propel the newly-formed nanoparticles at the solid substrate at a very high speed (>100 m/s), which has been shown as being sufficient to embed the particles in the substrate (Y. Didenko and K. S. Suslick, Nature, 2002, 418, 394).
- sonochemistry as a coating route further enables combining the synthesis of various nanomaterials and their deposition on various substrates in a single operation without the aid of a binder.
- U.S. Patent Application having Publication No. 2011/0097957 teaches a system for preparing antimicrobial fabrics, coated sonochemically with metal oxide nanoparticles to thereby form uniform deposition of the metal oxide.
- Huan-Ming et al. teach sonochemical synthesis of ZnO nanoparticles Doped with Mg.
- the Mg-doped ZnO nanoparticles exhibit bright, stable photoluminescence both in colloidal dispersions and in the solid state and are formed by doping Mg ions into ZnO nanoparticles by sonochemical synthesis.
- the preparation of Mg-doped ZnO is performed by applying sonication procedure on already synthesized ZnO nanoparticles in the presence of magnesium acetate.
- WO 2011/033040 teaches a method of preparing ZnO nanoparticles doped with Cu or Mg. WO 2011/033040 teaches that Cu-doped or Mg-doped ZnO nanoparticles have a higher antibacterial activity than ZnO nanoparticles.
- doped metal oxide nanoparticles can be readily prepared, for example, by utilizing ultrasonic irradiation, both in solution and is and/or on a variety of substrates, and that such doped metal oxide nanoparticles exhibit exceptional, and even synergistic, antimicrobial and anti-biofouling activity, which exceeds that of non-doped metal oxide nanoparticles.
- composition-of-matter comprising at least one nanoparticle composite, the at least one nanoparticle composite comprising a metal oxide and ions of a metallic element included in a crystal lattice of the metal oxide, wherein the metal oxide is selected from the group consisting of copper oxide and magnesium oxide and the metallic element is selected from the group consisting of zinc, copper and magnesium, and wherein the metallic element is different from the metal in the metal oxide.
- the metal oxide is copper oxide and the metallic element is zinc.
- the metal oxide is magnesium oxide and the metallic element is zinc.
- metal oxide is copper oxide and the metallic element is magnesium.
- an atomic ratio of the metal oxide and the ions of the metallic element in the at least one nanoparticle composite ranges from 10: 1 to 4: 1.
- the atomic ratio is about
- the composition-of-matter is prepared by subjecting a mixture of a first and a second metal precursor to high intensity ultrasonic irradiation, wherein the first metal precursor forms the metal oxide and the second metal precursor comprises the metallic element.
- the composition-of-matter comprises a plurality of the nanoparticle composites.
- composition-of-matter is characterized by an X-Ray Powder Diffraction which is devoid of peaks at positions that correspond to a pristine metal oxide of the metallic element.
- the composition-of-matter is characterized by an X-Ray Powder Diffraction exhibiting at least one peak at a position and/or width that is different from a position and/or width of a corresponding peak in an X-Ray Powder Diffraction of the metal oxide.
- the position of the at least one peak is different from the position of the corresponding peak in the X-Ray Powder Diffraction of the metal oxide by at least 0.01°.
- the composition-of-matter is characterized by a crystal lattice exhibiting at least one cell parameter that is different from a corresponding cell parameter of a pristine crystal lattice of the metal oxide.
- the cell parameter is different from a corresponding cell parameter of a pristine crystal lattice of the metal oxide by at least 0.005.
- composition-of-matter comprising at least one nanoparticle composite, the at least one nanoparticle composite comprising a metal oxide and ions of a metallic element included in a crystal lattice of the metal oxide, is the composition-of-matter being characterized by at least one of:
- an X-Ray Powder Diffraction exhibiting at least one peak at a position and/or width that is different from a position and/or width of a corresponding peak in an X-Ray Powder Diffraction of the metal oxide;
- a crystal lattice exhibiting at least one cell parameter that is different from a corresponding cell parameter of a pristine crystal lattice of the metal oxide.
- the position of the at least one peak is different from the position of the corresponding peak in the X-Ray Powder Diffraction of the metal oxide by at least 0.01°.
- the cell parameter is different from a corresponding cell parameter of the pristine crystal lattice of the metal oxide by at least 0.005.
- an atomic ratio of the metal oxide and the ions of the metallic element in the at least one nanoparticle composite ranges from 10: 1 to 4: 1.
- the atomic ratio is about 8: 1.
- the metal oxide is selected from the group consisting of copper oxide, magnesium oxide, zinc oxide, calcium oxide, aluminum oxide, titanium oxide, gallium oxide and ferric oxide.
- the metallic element is selected from the group consisting of copper, zinc, magnesium, calcium, aluminum, titanium, ferrous, zirconium, hafnium, yttrium, and gallium.
- the composition-of- matter is prepared by subjecting a mixture of a first and a second metal precursor to high intensity ultrasonic irradiation, wherein the first metal precursor forms the metal oxide and the second metal precursor comprises the metallic element.
- composition-of-matter comprising at least one nanoparticle composite, the at least one nanoparticle composite comprising a metal oxide and ions of a metallic element included in a crystal lattice of the metal oxide, as described in any of the embodiments herein, the composition-of-matter being prepared by subjecting a mixture of a first and a second metal precursor to high intensity ultrasonic irradiation, wherein the first metal precursor forms the metal oxide and the second metal precursor comprises the metallic element.
- the at least one nanocomposite structure is represented by the formula: ⁇ ,
- y is a value of from 0.8 to 0.9
- X is a value from 0.1 to 0.2
- the composition-of-matter comprises a plurality of the nanoparticle composites, wherein an average diameter of the nanoparticle composites is less than about 300 nm.
- the average diameter is less than about 35 nm.
- the composition-of-matter further comprises a substrate, wherein a plurality of the nanoparticle composites is incorporated in and/or on at least a portion of the substrate.
- the substrate is or forms a part of an article.
- the article is selected from the group consisting of a medical device, a pharmaceutical, cosmetic or cosmeceutic product, a fabric, a bandage, a microelectronic device, a microelectromechanic device, a photovoltaic device, a microfluidic device, an article having a corrosivable surface, an agricultural device, a package, a sealing article, a fuel container and a construction element.
- the substrate comprises or is made of a polymer, a paper, a textile, wood, wool, leather, fur, a metal, carbon, a biopolymer and/or silicon, and the likes, as described herein.
- the substrate is a pharmaceutical, cosmetic or cosmeceutic product, and the nanoparticle composites are incorporated within the formulation.
- a process of preparing a composition-of-matter comprising at least one nanoparticle composite, the at least one nanoparticle composite comprising a metal oxide and ions of a metallic element included in a crystal lattice of the metal oxide, the process comprising subjecting a mixture of a first and a second metal precursor to high intensity ultrasonic irradiation, wherein the first metal precursor forms the metal oxide and the second metal precursor comprises the metallic element.
- the mixture further comprises an aqueous solution.
- the aqueous solution further comprises a water-miscible solvent.
- the solution has a pH higher than 7.
- a molar ratio of the first and the second precursor ranges from 4: 1 to 1: 1.
- the molar ratio is about
- a concentration of each of the first and second metal precursors in the aqueous solution independently ranges from 0.005M to 0.5M.
- each of the first and second metal precursors is independently a water-soluble salt of the metal of the metal oxide and the metallic element, respectively.
- the salt is independently selected from the group consisting of an acetate, a nitrate, and a chloride of the metal or the metallic element, respectively.
- the irradiation is carried out using ultrasonic waves at a frequency of at least 20 kHz.
- the irradiation is carried out using ultrasonic waves of at least 1 kW.
- the composition-of- matter further comprises a substrate and wherein a plurality of the nanoparticle composites is incorporated in and/or on at least a portion of the substrate, the process comprising contacting the substrate or a portion thereof with the mixture of the first and the metal precursors.
- the contacting is effected by immersing the substrate or a portion thereof in an aqueous solution which comprises the first and second metal precursors.
- an aqueous solution which comprises the first and second metal precursors.
- the article is selected from the group consisting of a medical device, a therapeutic, cosmetic or cosmeceutic product, a fabric, a bandage, a microelectronic device, a microelectromechanic device, a photovoltaic device, a microfluidic device, an article having a corrosivable surface, an agricultural device, a package, a sealing article, a fuel container and a construction element.
- the article is a medical device configured for topical application, and the microorganism is P. Acne.
- a pharmaceutical, cosmetic or cosmeceutic product comprising any one of the compositions-of-matter described herein, incorporated in a pharmaceutical, cosmetic or cosmeceutical formulation forming the product.
- the formulation is in a form of a paste, a cream, a lotion, a foam, a gel, an emulsion, an ointment, a soap, a pladget, a swab, a suppository, a dressing, a solution, a mousse, a pad, a wipe, and a patch.
- a plurality of the nanoparticle composites is dispersed in the formulations.
- the product is for use in treating medical, cosmetic or cosmeceutic conditions, optionally in combination with an active agent, as described herein.
- FIG. 1 presents comparative spectra of X-Ray diffraction pattern of sonochemically prepared ZnO nanoparticles (spectrum a), CuO nanoparticles (spectrum b) and Zn-doped CuO nanoparticles (3: 1 Cu:Zn precursors molar ratio) according to some embodiments of the present invention (spectrum c).
- FIGs. 2A-D present X-Ray diffraction patterns of the product obtained from a mid- 3: 1 Cu:Zn precursors mixture by applying ultrasonic irradiation (FIG. 2A); of the product obtained from a 3: 1 Cu:Zn precursors mixture upon application of microwave irradiation (FIG. 2B), application of thermal reaction (FIG. 2C); and of the product obtained from a 4: 1 Cu:Zn precursors mixture by applying ultrasonic irradiation (FIG. 2D).
- the sharp lines present standard values of reflection lines of CuO in FIGs. 2A-C and of CuO and ZnO in FIG. 2D.
- FIG. 3 presents comparative spectra obtained from DSC analysis of (3: 1) Zn-doped CuO nanoparticles according to some embodiments of the present invention, upon annealing at 550 °C under both inert (spectrum a) and oxidizing conditions (spectrum b).
- FIGs. 4A-B present a superposition of spectra obtained from several measurements of Zeta potential of Zn-doped CuO nanoparticles according to some embodiments of the present invention (FIG. 4A) and (non-doped) CuO nanoparticles (FIG. 4B) in Brain-Heart medium.
- FIG. 5 is a bar graph showing the weight loss percentage of catheters coated with Zn-doped CuO nanoparticles according to some embodiments of the present invention immersed in saline, 1 % growth medium and artificial urine.
- FIGs. 6A-B present SEM images of bare cotton fabric (FIG. 6A) demonstrating a smooth texture of the fabric, and cotton fabric coated with Zn-doped CuO nanoparticles according to some embodiments of the present invention (FIG. 6B) using the ultrasonic irradiation, demonstrating the homogeneously coating thereon.
- FIGs. 7A-C present HR-SEM images of Zn-doped CuO nanoparticles' coating on a cotton fabric produced by the ultrasonic irradiation of copper acetate monohydrate and zinc acetate dehydrate precursors in concentrations of: 0.0075 M and 0.0025 M, respectively (referred to as “medium” or “med") (FIG. 7A); 0.015 M and 0.005 M, respectively (referred to as “high") (FIG. 7B); 0.00375 M and 0.00125 M, respectively (referred to as "low”) (FIG. 7C).
- FIG. 7D is a histogram showing the size distribution, as determined by "Scion image” software of the particles deposited on the coated fibers as obtained by the “medium” concentration.
- FIGs. 8A-C present HR-SEM images demonstrating an artificial tooth having metal oxide nanoparticles coating, produced by the ultrasonic irradiation, applied thereon.
- FIG. 8A presents a reference image of a bare surface the artificial tooth.
- FIG. 8B presents an image of the tooth surface having a coating comprising Zn-doped CuO nanoparticles applied thereon.
- FIG. 8C presents an image of the tooth surface having a coating comprising CuO nanoparticles applied thereon.
- FIGs. 8D-E present histograms showing the size distribution of the Zn-doped CuO (FIG. 8D) and non-doped CuO (FIG. 8E) nanoparticles applied on the coated artificial tooth.
- FIGs. 9A-B present photographs showing an uncoated catheter (FIG. 9A) and a catheter coated with Zn-doped CuO nanoparticles by ultrasonic irradiation, according to some embodiments of the present invention (FIG. 9B).
- FIGs. 10A-B present HR-SEM images showing a silicon urinary catheter having Zn- doped CuO nanoparticle coating deposited on the external surface of the catheter (FIG. 10A) and the internal surface of the catheter (FIG. 10B).
- FIGs. 11A-C present spectra showing superposition of measured and simulated RBS analysis.
- FIG. 11 A shows the analysis of a bare tooth surface.
- FIG. 1 IB shows the analysis of tooth surface having Zn-doped CuO nanoparticles coating deposited thereon by the sonochemical method, with the arrow marking a peak indicative of the presence of elemental Cu.
- FIG. 11C shows the analysis of tooth surface having CuO nanoparticles coating deposited thereon by the sonochemical method, with the arrow marking a peak indicative of the presence of elemental Cu.
- FIGs. 12A-B present RBS analysis spectra of tooth surfaces coated, by the ultrasonic irradiation, with Zn-doped CuO (Figure 12A) and CuO nanoparticles (Figure 12B), showing depth compositional of the tooth substrate (upper graphs) and depth compositional the nanoparticle coating (lower graphs).
- FIGs. 13A-C present FIB-SEM images of an uncoated tooth (control; FIG. 13A), a tooth coated with Zn-doped CuO nanoparticles by the sonochemical method (FIG. 13B), and a tooth coated with CuO nanoparticles by the sonochemical method, with the red markings indicating the thickness of the coating.
- FIGs. 14A-B present a bar graph (b) showing the relative intensity correlated to the integrate area of ESR signals (a) originating from aqueous suspensions of Zn-doped CuO, CuO and ZnO as detected by DMPO spin adduct (FIG. 14A); and ESR spectra of Zn-doped CuO before (the spectrum showing stronger quartet signal) and after (the spectrum showing weaker quartet signal) a further addition of DMSO to a Zn-doped CuO- and DMPO containing suspension, with the arrows marking the features of the spectrum corresponding to the DMPO-CH 3 spin adduct.
- FIG. 15 presents an ESR spectrum detected following addition of TEMP and DMPO to Zn-doped CuO nanoparticle-containing suspension, with the arrows marking signal features corresponding to singlet oxygen.
- FIGs. 16A-E present ESR spectra corresponding to the signal of the DMPO-OH spin adduct originating from an aqueous suspension of: Zn-doped CuO nanoparticles (FIG. 16A), Zn-doped CuO nanoparticles upon being heated at 300 °C under air (FIG. 16B), Zn- doped CuO nanoparticles upon being heated at 550 °C under air (FIG. 16C), Zn-doped CuO nanoparticles upon being heated at 550 °C under nitrogen (FIG. 16D).
- FIG. 16E shows the ESR signal of DMPO solution, for a reference.
- FIGs. 17A-D present comparative plots showing the effect of coating a fabric with Zn-doped CuO, CuO, and ZnO nanoparticles, compared with uncoated fabric (control), on the viable count of Staphylococcus aureus (FIG. 17A), Escherichia coli (FIG. 17B), resistant MRSA (FIG. 17C), and MDR E. coli (FIG. 17D), after 30 minutes of treatment in nutrient broth (NB) media.
- NB nutrient broth
- FIG. 18 is a bar graph showing the percentage of killed Candida albicans upon contacting a fabric coated with Zn-doped CuO for 60 minutes and 180 minutes in nutrient broth (NB) medium (error bars represent standard deviation of uncertainty).
- FIGs. 19A-B present comparative plots showing bacterial growth (FIG. 19A) and a bar graph (FIG. 19B), showing viability of Streptococcus mutans in the presence of suspensions Zn-doped CuO nanoparticles, and CuO nanoparticles compared with untreated bacteria-containing saline medium (control) (FIG. 19A), (error bars represent standard deviation of uncertainty).
- FIG. 20 presents comparative plots showing the growth of S. mutans in Brain-Heart (BH) media for 24 hours in the presence of CuO nanoparticles and Zn 2+ , Cu 2+ ions or Zn 2+ ions, wherein the ions are at their saturated concentrations in BH (error bars represent standard deviation of uncertainty).
- BH Brain-Heart
- FIG. 21 is a bar graph showing the effect of coating an artificial tooth with Zn-doped
- FIG. 22 presents TEM images showing the morphological changes in S. mutans cells, upon treatment with CuO nanoparticles, and with Zn-doped CuO nanoparticles, compared to control untreated cells, at a scale bar of 0.5 micron (upper panel) and 200 nm (lower panel), with arrows marking the cell surface or the cell membrane of the bacterial cells.
- FIG. 23 is a bar graph showing the variation of fluorescence intensity in S. mutans cell samples upon treatment with the CuO nanoparticles and with Zn-doped CuO nanoparticles, compared to untreated samples (control) (error bars represent standard deviation of uncertainty).
- FIG. 24 is a bar graph showing the effect of Zn-doped CuO nanoparticles, CuO nanoparticles, and H 2 0 2 (1 mM) on malondialdehyde (MDA) concentration in S. mutans samples compared with untreated samples (control) (error bars represent standard deviation of uncertainty).
- FIGs. 25A-C are bar graphs showing the bacterial survival % upon contacting a silicon urinary catheter coated with Zn-doped CuO nanoparticles with E. coli (FIG. 25A), S. aureus (FIG. 25B), P. mirabilliis (FIG. 25C) (error bars represent standard deviation of uncertainty).
- FIGs. 26A-B are bar graphs presenting the biofilm volume of E. coli (FIG. 26A) and S. aureus (FIG. 26B) formed on uncoated glass substrate (control) and on glass substrates coated with either ZnO nanoparticles, CuO nanoparticles or Zn-doped CuO nanoparticles (error bars represent standard deviation of uncertainty).
- FIG. 27 is a bar graph presenting the biofilm biomass quantification of S. mutans formed on an uncoated artificial tooth substrate (control) and on teeth coated with either CuO nanoparticles or Zn-doped CuO nanoparticles (error bars represent standard deviation of uncertainty).
- FIG. 28 present HRSEM images showing the morphological changes of S. mutans biofilm on a tooth coated with CuO nanoparticles, tooth coated with Zn-doped CuO nanoparticles, vis a vis the control of biofilm formation on a bare tooth.
- FIGs. 29A-D present photographs of the hen's egg test chorioalantoic membrane (HET-CAM) blood vessels following irritation tests with saline (FIG. 29 A), or with NaOH (0.1M) (FIG. 29B), and of extracts of uncoated catheter (FIG. 29C), and of a catheter coated with Zn-doped CuO (FIG. 29D).
- HET-CAM hen's egg test chorioalantoic membrane
- FIGs. 30A-F are bar graphs presenting the effect of saline (negative control) lipopolysaccharides (LPS) (positive control) and extracts of: uncoated catheter and Zn- doped CuO coated catheter on the inducement of the following cytokine in mouse: IL-12 (FIG. 30A), MIP-1- a (FIG. 30B) TNF-a (FIG. 30C), IL-1- ⁇ (FIG. 30D), IL-6 (FIG. 30E), IL-10 (FIG. 30F), as assessed in a supernatant of spleen cells following 22 hours of incubation.
- the present invention in some embodiments thereof, relates to material science and, more particularly, but not exclusively, to doped metal oxide nanoparticles, processes of preparing same, surface coatings containing same and uses thereof in, for example, reducing or preventing growth of microorganisms.
- the present inventors have contemplated that doping metal oxide nanoparticles with a metallic element would impart, modulate or enhance the anti-microbial activity of the metal oxide nanoparticles.
- the present inventors While reducing the present invention to practice, the present inventors have utilized an ultrasonic irradiation methodology both for the synthesis of the doped metal oxide nanoparticles and for incorporation of the doped metal oxide nanoparticles onto/into various substrates.
- the present inventors have shown that metallic element was successfully doped in the crystal lattice of the metal oxide nanoparticles, when metal precursors of the metallic element and the metal oxide were used at certain molar ratios, and when a sonochemical (high intensity ultrasonic irradiation) methodology was used for their preparation.
- the present inventors have also shown that the doped metal oxide nanoparticles exhibited improved antimicrobial and/or antibiofilm activities, compared to corresponding pristine (non-doped) metal oxide nanoparticles.
- Embodiments of the present invention therefore relate to nanoparticle composites comprising a metal oxide and ions of a metallic element included in a crystal lattice of the metal oxide, and to compositions-of-matter comprising said nanoparticle composites.
- composition-of-matter comprising at least one nanoparticle composite which comprises a metal oxide and ions of a metallic element included in a crystal lattice of said metal oxide.
- nanoparticle or “nanoparticle composite”, which are used herein interchangeably, describe a particle featuring a size of at least one dimension thereof (e.g., diameter, length) that ranges from about 1 nanometer to 1000 nanometers.
- the size of the particle described herein represents an average size of a plurality of nanoparticle composites or nanoparticles.
- the average size (e.g., diameter, length) ranges from about 1 nanometer to 500 nanometers. In some embodiments, the average size ranges from about 1 nanometer to about 300 nanometers. In some embodiments, the average size ranges from about 1 nanometer to about 200 nanometers. In some embodiments, the average size ranges from about 1 nanometer to about 100 nanometers. In some embodiments, the average size ranges from about 1 nanometer to 50 nanometers, and in some embodiments, it is lower than 35 nm.
- the average size is about 1 nm, about 2 nm, about 3 nm, about 4 nm, about 5 nm, about 6 nm, about 7 nm, about 8 nm, about 9 nm, about 10 nm, about 11 nm, about 12 nm, about 13 nm, about 14 nm, about 15 nm, about 16 nm, about 17 nm, about 18 nm, about 19 nm, about 20 nm, about 21 nm, about 22 nm, about 23 nm, about 24 nm, about 25 nm, about 26 nm, about 27 nm, about 28 nm, about 29 nm, about 30 nm, about 31 nm, about 32 nm, about 33 nm, about 34 nm, about 35 nm, about 36 nm, about 37 nm, about 38 nm, about 40 nm, about 42 nm, about 44 nm, about 10 n
- the particle can be generally shaped as a sphere, a rod, a cylinder, a ribbon, a sponge, and any other shape, or can be in a form of a cluster of any of these shapes, or can comprises a mixture of one or more shapes.
- the composition-of-matter comprises a plurality of nanoparticles, and at least 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 95 %, 98 %, 99%, 99.9 %, or all of the nanoparticles are nanoparticle composites as described herein, e.g., in shape and average size.
- At least some, and in some embodiments, most of the nanoparticles or nanoparticle composites are generally shaped as spheres.
- the plurality of nanoparticle composites comprises nanoparticle composites which are the same or different, preferably at least 50 %, 60 %, 70 %, 80 %, 90 %, 95 %, 98 %, 99%, 99.9 %, or all of the nanoparticle composites are the same.
- nanoparticles are made of at least two components, namely, made of non-pristine substances. It is noted that nanoparticles as described herein, which are doped metal oxide nanoparticles, are also referred to herein simply as doped nanoparticles.
- metal oxide describes natural, isolated and/or synthetically prepared metal oxide substances.
- a metal oxide comprises one or more metal atoms and one or more oxygen atoms, wherein one or more of the metal atom(s) is in association with one or more oxygen atoms as further defined and discussed hereinafter.
- the metal atoms and the oxygen atoms are joined together via ionic bonds, such that cations of the metal atoms are associated with oxygen anions.
- the metal oxides include, without limitation, oxides of alkali metals, alkaline earth metals, lanthanides, actinides, transition metals, metalloids, or any other metals.
- the metal oxide can include an oxide:metal atomic ratio ranging from 4: 1 to 1: 1.
- Exemplary metal oxides include, without limitation, oxides of magnesium, titanium, aluminum, zirconium, calcium, scandium, vanadium, chromium, manganese, ferrite, cobalt, nickel, copper and zinc, and more preferably metal oxides of copper, zinc, magnesium, titanium, zirconium, aluminum, and calcium.
- the metal oxide is of a divalent metal, and can be represented as "BO", which B being a metal atom capable of forming a BO metal oxide.
- the metal oxide is CuO, MgO or ZnO.
- the metal oxide is CuO or MgO.
- the metal oxide is CuO.
- a crystal lattice is unique periodic and systematic arrangement of atoms or ions found in a crystal in an ordered structure, and is represented by three-dimensional configuration of points connected by lines used to describe the orderly arrangement of the atoms or ions in a crystal. Each point represents one or more atoms in the actual crystal.
- the lattice is divided into a number of identical blocks, or unit cells, that are repeated in all directions to form a geometric pattern. Lattices are typically classified according to their dominant symmetries: isometric, trigonal, hexagonal, tetragonal, orthorhombic, monoclinic, and triclinic.
- the unit cell is the smallest component of the crystal lattice and describes the 3D arrangement of atoms in a crystal.
- the unit cell is represented in terms of its lattice parameters which are the lengths of the cell edges (a, b and c) and the angles between them (alpha, beta and gamma), while the positions of the atoms inside the unit cell are described by the set of atomic positions (x, , j, , zd measured from a lattice point.
- X-ray Powder Diffraction is typically used to determine the crystal arrangement of a crystal lattice.
- X-ray powder diffraction patterns can be measured with an X-ray diffractometer Cu K a or Cr K a radiation by standard methods described, for example, by B. D. Cullity and S. R. Stock (Elements of X-ray Diffraction, 3rd ed., New York: Prentice Hall, 2001).
- the unit cell parameters can be determined by Rietveld refinement of the powder diffraction data.
- the X-ray crystalline size also can be determined by analysis of peak shifting or peak broadening in a powder diffraction pattern of a sample containing an internal Si standard using the single-peak Scherrer method or the Warren- Averbach method as discussed in detail, for example, by H. P. Klug and L. E. Alexander (X-ray Diffraction Procedures for Polycrystalline and Amorphous Materials, New York: Wiley, 1974, 618- 694).
- defects As used herein the term "defect" or grammatical diversions thereof, when related to crystal lattice, relates to crystals featuring crystallographic irregularities compared to an ideal arrangement of the components forming the crystal.
- Defects as known in the art, include but not limited to: point defects, which include but are not limited to: vacancy defects, interstitial defects, Frenkel defect, substitutional defect, antisite defects, topological defects, line defects which include but are not limited to: dislocations, planar defects and bulk defects.
- a "defect" in the crystal lattice can be induced by doping, as described herein.
- the metallic element is a metallic element
- a nanoparticle composite as described in any one of the embodiments herein includes a metal oxide and a metallic element included in a crystal lattice of the metal oxide, wherein the metallic element is different from the metal in the metal oxide.
- atoms of the metallic element are introduced into the crystal lattice of the metal oxide, and, in some embodiments, atoms (e.g., as positive ions) of the metallic element replace some of the atoms of the metal oxide (e.g., ions of the metal in the metal oxide).
- Metal-doped, non-metal doped, and un-doped metal oxides can be characterized by measurement of their X-ray powder diffraction patterns, elemental compositions, and average particle sizes.
- crystal lattice parameters of doped or un- doped (pristine) metal oxide nanoparticles can be determined from powder X-ray diffraction ("XRPD") patterns.
- the metallic element, or dopant, in the nanoparticle composites as described herein can be, for example, and without limitation, magnesium, copper, zinc, titanium, aluminum, scandium, vanadium, chromium, manganese, ferrous, cobalt, nickel, and any combination of the foregoing, and in some embodiments, can be, for example, copper, zinc, magnesium, titanium, zirconium, aluminum, hafnium, calcium and any combination thereof.
- the metallic element is copper, zinc, and/or magnesium.
- the atomic ratio of the metal oxide and the metallic element in the crystal-lattice doped metal oxide ranges from 50:1 to 1:10, or from 10:1 to 1:10, or from 10:1 to 1:5, or from 10:1 to 1:1, or from 10:1 to 2:1, or from 10:1 to 3:1 or from 10:1 to 4:1, or from 10:1 to 5:1.
- the atomic ratio is about 49:1, about 48:1, about 47:1, about 46:1, about 45:1, about 44:1, about 43:1, about 42:1, about 41:1, about 40:1, about 39:1, about 38:1, about 37:1, about 36:1, about 35:1, about 34:1, about 33:1, about 32:1, about 31:1, about 30:1, about 29:1, about 28:1, about 27:1, about 26:1, about 25:1, about 24:1, about 23:1, about 22:1, about 21:1, about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1, including any value therebetween.
- the atomic ratio of the metal oxide and the metallic element in the crystal-lattice doped metal oxide ranges from 10: 1 to 4: 1 or from 10: 1 to 5: 1, and can be, for example, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1 or 4:1, including any value therebetween.
- the atomic ratio is about 8:1.
- a doped metal oxide as described in any of the embodiments herein is represented by the Formula:
- A is a metallic element (dopant, as described in any one of the respective embodiments)
- B is the metal of the metal oxide, according to any one of the respective embodiments
- x and y in the Formula are such that y/x represents the atomic ratio of the metal oxide to metallic element, as described herein.
- the y/x ratio ranges from 100: 1 to 1: 1, or from 100: 1 to 2: 1, or from 100: 1 to 3: 1, or from 100: 1 to 4: 1, or from 50: 1 to 4: 1, or from 40: 1 to 4: 1, or from 30: 1 to 4: 1, or from 20: 1 to 4: 1, or from 15: 1 to 4: 1 or from 10: 1 to 4: 1.
- x ranges from 0.2 to 0.1 and y ranges from 0.8 to 0.9, and the y/x ratio ranges from 20: 1 to 4: 1 or from 10: 1 to 4: 1.
- y is 0.9 and x is 0.1; or y is 0.89, or 0.88, or 0.87, or 0.86, or 0.85, or 0.84, or 0.83, or 0.82, or 0.81, or 0.80, and x is 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18 or 0.19 or 0.20, respectively.
- y is 0.88 and x is about 0.11.
- y/x is about 8: 1.
- the atomic (stoichiometric) ratio between the metal of the metal oxide lattice and the metallic element doped in the crystal lattice of the metal oxide is determined by inductively coupled plasma (ICP).
- XRPD measurements of crystal lattice-doped substances such as metal oxides typically show a shift in the position of refraction angle peaks compared to pristine, non- doped metal oxide. These measurements are also indicative of a formation of a biphasic mixture of different metal oxides, in cases where doping is not effected.
- Figure 2A presents representative XRD reflection lines of a product obtained from med-3: lCu:Zn precursors mixture as designated hereinthroughout, subjected to ultrasonic irradiation, showing that the pattern of the product (spectrum) is shifted in comparison to the monoclinic CuO (lines, international powder diffraction file (PDF) (80- 1916).
- PDF international powder diffraction file
- a composition-of-matter as described herein comprises at least one nanoparticle composite which is a crystal lattice- doped metal oxide, as described in any one of the respective embodiments herein, and the composition-of-matter and/or the nanoparticle composite (or a plurality of nanoparticle composites) is characterized by at least one of:
- an X-Ray Powder Diffraction exhibiting at least one peak at a position and/or width that is different from a position and/or width of a corresponding peak in an X-Ray Powder Diffraction of a pristine crystal lattice of the metal oxide;
- a crystal lattice exhibiting at least one cell parameter that is different from a corresponding cell parameter of a pristine crystal lattice of the metal oxide.
- peak position refers to the reflection peaks along the 2 ⁇ refractive angle axis in a XRPD spectrum, and refers to the peak position at any peak intensity.
- the peak position is denoted by the 2 theta angle.
- an XRPD pattern of the composition-of-matter or of the nanoparticle composites comprised therein do not include peaks in intensity higher than 100 counts, or higher than 50 counts, which correspond to e.g., international standard values of XRPD pattern of a metal oxide of the metallic element. That is, the nanoparticle composite is characterized as devoid of a metal oxide of the metallic element.
- devoid of in this regard it is meant no more than 1 %, or no more than 0.1 %, or no more than 0.01 % of the metal oxide of the metallic element, by weight.
- XRPD measurements or XRD measurements of a composition-of-mater or of a plurality of nanoparticle composites as described herein exhibits a shift at a peak position of at least one peak with respect to the peak positions of a pristine (non-doped) metal oxide.
- a shift is observed in at least one, at least 2, at least 3, at least 4, at least 5, etc. or in all of the peak positions, with respect to the peak positions of pristine metal oxide.
- a shift in the one or more peak positions is of at least 0.01°, and can be, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6,0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5°, and even more.
- the shift can be the same or different in size and direction, for each peak position which is shifted.
- XRPD measurements or XRD measurements of a composition-of-mater or of a plurality of nanoparticle composites as described herein exhibits a different peak width of at least one peak with respect to the width of corresponding peaks at corresponding positions of a pristine (non-doped) metal oxide.
- a different peak width is observed in at least one, at least 2, at least 3, at least 4, at least 5, etc. or in all of the peak positions, with respect to the peak positions of pristine metal oxide.
- a change is peak width is measured by a change in the full width at half maximum (FWHM) of the peak.
- the full width at half maximum (FWHM) of the peak in the one or more peak positions is broadened with respect to corresponding peaks of a pristine metal oxide by at least 5%, at least 10%, and can be for example, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30 %.
- both shift in peak position and broadening of peak width is observed in one or all of the peaks, with respect to the peaks of a pristine metal oxide.
- a difference in the cell parameter can be a difference of any one or all of the parameters a, b and c of a cell unit, as measured by XRD measurements.
- one or all of the cell parameters is different from the corresponding cell parameter of the crystal lattice of a corresponding pristine metal oxide by at least 0.001, or by at least 0.005, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, or higher values.
- composition-of-matter or by a nanoparticle composite or a plurality thereof, as described herein.
- the composition-of-matter is such that the metal oxide is copper oxide (CuO) or magnesium oxide (MgO), and the metallic element is magnesium (Mg), zinc (Zn) or copper (Cu), wherein said metallic element is different from said metal in said metal oxide.
- the metal oxide is copper oxide (CuO) or magnesium oxide (MgO)
- the metallic element is magnesium (Mg), zinc (Zn) or copper (Cu), wherein said metallic element is different from said metal in said metal oxide.
- the metal oxide is CuO and the metallic element is Zn, forming Zn-doped CuO nanoparticles (or nanoparticle composites).
- the nanoparticle composites are represented by the Formula Zn x Cu y O, with x and y as described hereinabove.
- the atomic ratio y/x in Zn x Cu y O ranges of from 50:1 to 1:1. In some embodiments the atomic ratio y/x ranges is 50:1. In some embodiments the atomic ratio y/x ranges can be about 49:1, about 48:1, about 47:1, about 46:1, about 45:1, about 44:1, about 43:1, about 42:1, about 41:1, about 40:1, about 39:1, about 38:1, about 37:1, about 36:1, about 35:1, about 34:1, about 33:1, about 32:1, about 31:1, about 30:1, about 29:1, about 28:1, about 27:1, about 26:1, about 25:1, about 24:1, about 23:1, about 22:1, about 21:1, about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or
- the atomic ratio y/x in Zn x Cu y O is about 8:1.
- the metal oxide is CuO and the metallic element (dopant) is Mg, forming Mg-doped CuO nanoparticles (or nanoparticle composites).
- the nanoparticle composites are represented by the Formula Mg x Cu y O, with x and y as described hereinabove.In some embodiments the ratio y/x in Mg x Cu y O ranges of from 50:1 to 1:1. In some embodiments the ratio y/x ranges is 50:1.
- the ratio y/x ranges can be about 49:1, about 48:1, about 47:1, about 46:1, about 45:1, about 44:1, about 43:1, about 42:1, about 41:1, about 40:1, about 39:1, about 38:1, about 37:1, about 36:1, about 35:1, about 34:1, about 33:1, about 32:1, about 31:1, about 30:1, about 29:1, about 28:1, about 27:1, about 26:1, about 25:1, about 24:1, about 23:1, about 22:1, about 21:1, about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1, including any value therebetween.
- the metal oxide is MgO and the metallic element (dopant) is
- the nanoparticle composites are represented by the Formula Zn x Mg y O, with x and y as described hereinabove.
- the ratio y/x in Zn x Mg y O ranges of from 50: 1 to 1: 1. In some embodiments the ratio y/x ranges is 50: 1. In some embodiments the ratio y/x ranges can be about 49:1, about 48:1, about 47:1, about 46:1, about 45:1, about 44:1, about 43:1, about 42:1, about 41:1, about 40:1, about 39:1, about 38:1, about 37:1, about 36:1, about 35:1, about 34:1, about 33:1, about 32:1, about 31:1, about 30:1, about 29:1, about 28:1, about 27:1, about 26:1, about 25:1, about 24:1, about 23:1, about 22:1, about 21:1, about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1 including any
- the metal oxide is MgO and the metallic elelment (dopant is Cu), forming Cu-doped MgO nanoparticles (or nanoparticle composites).
- the nanoparticle composites are represented by the Formula Cu x Mg y O, with x and y as described hereinabove.
- the ratio y/x in Cu x Mg y O ranges of from 50:1 to 1:1. In some embodiments the ratio y/x ranges is 50:1. In some embodiments the ratio y/x ranges can be about 49:1, about 48:1, about 47:1, about 46:1, about 45:1, about 44:1, about 43:1, about 42:1, about 41:1, about 40:1, about 39:1, about 38:1, about 37:1, about 36:1, about 35:1, about 34: 1, about 33: 1, about 32: 1, about 31: 1, about 30: 1, about 29: 1, about 28: 1, about 27: 1, about 26: 1, about 25: 1, about 24: 1, about 23: 1, about 22: 1, about 21: 1, about 20: 1, about 19: 1, about 18: 1, about 17: 1, about 16: 1, about 15: 1, about 14: 1, about 13: 1, about 12: 1, about 11: 1, about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, about 2: 1, or about 1:
- the metal oxide is CuO and the metallic element is Zn.
- the atomic ratio of Cu to Zn is about 8: 1.
- the metal oxide is CuO and the metallic element is Mg. In exemplary embodiments, the metal oxide is MgO and the metallic element is Cu or Zn.
- compositions-of-matter as described herein are characterized by XRD patterns as described herein, namely, by an X-Ray Powder Diffraction which is devoid of peaks at positions that correspond to a pristine metal oxide of said metallic element, as described herein; and/or an X-Ray Powder Diffraction exhibiting at least one peak at a position and/or width that is different from a position and/or width of a corresponding peak in an X-Ray Powder Diffraction of said metal oxide, as described herein; and/or by a crystal lattice exhibiting at least one cell parameter that is different from a corresponding cell parameter of a pristine crystal lattice of said metal oxide.
- compositions-of-matter described herein, and any embodiments thereof, including exemplary compositions-of-matter as described herein can be prepared by any method known if the art for obtaining crystal-lattice doped metal oxides.
- composition-of-matter as described herein in any of the embodiments thereof, including exemplary compositions-of-matter as described herein, is prepared by subjecting a mixture of a first and a second metal precursor to high intensity ultrasonic irradiation.
- Such compositions-of-matter are also referred to herein as "sonochemically-prepared” .
- the terms "sonochemical”, “ultrasonic irradiation”, “sonication” and grammatical diversions thereof, are used herein interchangeably, and refer to a method of exposure to sonic power, generally in the ultrasonic range of frequencies.
- 'sonochemistry refers to the study or use of sonochemical irradiation.
- ultrasonic irradiation is applied on a mixture (e.g., an aqueous solution) of metal precursors (e.g., metal ion salts) as described herein (e.g., copper acetate monohydrate or zinc acetate dihydrate).
- metal precursors e.g., metal ion salts
- the ultrasonic irradiation is applied by a Ti-horn apparatus.
- the ultrasonic irradiation frequency applied during the sonication is of about at least 10 kHz, and can be about 10 kHz, about 20 kHz, about 30 kHz, about 40 kHz, about 50 kHz, about 60 kHz, about 70 kHz, about 80 kHz, about 90 kHz, or about 100 kHz including any value therebetween, or higher values.
- the ultrasonic irradiation frequency applied during the sonication is 20 kHz.
- the ultrasonic irradiation is applied at wave of at least 100 W, at least 200 W, at least 300 W, at least 400 W, at least 500 W, at least 600 W, at least 700 W, at least 800 W, at least 900 W, or at least lkW.
- the ultrasonic irradiation is applied at a wave of 750
- the ultrasonic irradiation is applied at a wave of 750 W, at at least 10 % efficiency, at at least 20 % efficiency, at at least 30 % efficiency, at at least 40 % efficiency, at at least 50 % efficiency, at at least 60 % efficiency, at at least 70 % efficiency, at at least 80 % efficiency, at at least 90 % efficiency, or at 100 % efficiency.
- sonication is performed at at least 10 W cm intensity, at at least 15 W cm —2 intensity, at at least 20 W cm—2 intensity, at at least 25 W cm—2 intensity, at at least 30 W cm —2 intensity, at at least 35 W cm—2 intensity, at at least 40 W cm—2 intensity, at at least 45 W cm —2 intensity, at at least 50 W cm—2 intensity, at at least 55 W cm—2 intensity, at at least 60 W cm —2 intensity, at at least 65 W cm—2 intensity, at at least 70 W cm—2 intensity, at at least 75 W cm—2 intensity, at at least 80 W cm—2 intensity, at at least 85
- the ultrasonic irradiation is applied at 45 W cm intensity.
- the ultrasonic irradiation is effected as described hereinabove.
- the sonication (high intensity ultrasonic irradioation) is effected on an aqueous solution comprising the mixture of metal precursors.
- the process comprises, prior to the sonication, preparing a mixture comprising an aqueous solution of a first metal precursor and a second metal precursor, as described herein.
- the aqueous solution further comprises a water-miscible solvent. In some embodiments, the aqueous solution further comprises ethanol. In some embodiments the solution comprises ethanol at a ratio of 1: 1 (v/v) ethanol: water, 2: 1 (v/v) ethanol: water, 3: 1 (v/v) ethanol: water, 4: 1 (v/v) ethanol: water, 5: 1 (v/v) ethanol: water, 6: 1 (v/v) ethanol: water, 7: 1 (v/v) ethanol: water, 8: 1 (v/v) ethanol: water, 9: 1 (v/v) ethanol: water, 10: 1 (v/v) ethanol: water, 11: 1 (v/v) ethanol: water ,or 12: 1 (v/v) ethanol: water, including any value therebetween.
- the solution comprises ethanol at a ratio of 9: 1 (v/v) ethanol: water.
- the pH of the solution of the first and the second metal precursor is adjusted, optionally while subjecting the solution to ultrasonic irradiation, to a basic pH, higher than 7.
- the pH is adjusted to at least 8.
- the pH is adjusted to at least 9.
- the pH is adjusted to at least 10.
- the pH is adjusted to at least 11.
- the pH is adjusted to at least 12.
- the pH is adjusted to at least 13.
- the pH is adjusted to 14.
- the pH is adjusted to about 8.
- the pH is adjusted by adding an alkaline aqueous solution to the sonicated mixture or solution.
- the pH is adjusted by adding an ammonia solution.
- the ultrasonic irradiation is applied on the mixture or solution for at least 1 minute.
- the sonicated solution is applied for at least 5 minutes, for at least 10 minutes, for at least 15 minutes, for at least 20 minutes, for at least 25 minutes, for at least 30 minutes, for at least 35 minutes, for at least 40 minutes, for at least 45 minutes, for at least 50 minutes, for at least 55 minutes, for at least 60 minutes, for at least 65 minutes, for at least 70 minutes, for at least 75 minutes, or for at least 80 minutes.
- the ultrasonic irradiation is applied on the mixture or solution for at least 30 minutes.
- the sonicated mixture or solution is maintained at a temperature that ranges from 10 °C to 60 °C, during the sonication procedure. In some embodiments the sonicated mixture or solution is maintained at temperature that ranges from 20 °C to 50 °C, or from 25 °C to 45 °C, or from 30 °C to 50 °C.
- the sonicated mixture or solution is maintained at 30 °C.
- the first metal precursor is such that forms the metal oxide.
- the first metal precursor is such that comprises the metallic dopant.
- the first metal precursor and the second metal precursors are each independently, a water soluble salt, which is capable of forming, preferably in the presence of air (oxygen) and/or water, a corresponding metal oxide.
- water soluble it is meant that the K sp of the salt in water is at least 10 "10 , at least 10 “9 , at least 10 “8 , at least 10 “7 , at least 10 “6 , at least 10 “5 , at least 10 “4 , at least 10 "3 , at least 10 "2 , or at least 10 "1 .
- each of the water soluble salts can independently be, for example, acetate salt, a nitrate salt a chloride salt, a bromide salt, an iodine salt, a sulfate salt, or a hydroxide salt. Any other water soluble salt is also contemplated.
- any of the water soluble salts as described herein can be utilized in a form of a hydrate thereof (e.g., monohydrate, dehydrate, trihydrate, tetsrahydrate, etc.).
- Exemplary water soluble magnesium salts include, without limitation, magnesium acetate (e.g., tetrahydrate), magnesium nitrate, magnesium chloride, magnesium bromide, magnesium iodine, magnesium sulfate, magnesium chlorate, or magnesium hydroxide.
- Exemplary water soluble copper salts include, without limitation, copper acetate, copper nitrate, copper chloride, copper bromide, copper sulfate, or copper chlorate.
- Exemplary water soluble zinc salts include, without limitation, zinc acetate, zinc nitrate, zinc chloride, zinc bromide, zinc sulfate, zinc chlorate, zinc chlorate, or zinc hydroxide.
- Exemplary water soluble calcium salts include, without limitation, calcium acetate, calcium nitrate, calcium chloride, calcium bromide, calcium iodide, calcium sulfate, calcium chlorate, calcium oxide, calcium hydroxide, or calcium sulfate.
- Exemplary water soluble aluminum salts include, without limitation, aluminum acetate, aluminum nitrate, aluminum chloride, aluminum bromide, aluminum sulfate, aluminum chlorate, or aluminum sulfate.
- each of the water soluble salts are the corresponding acetate salts of the metals (namely, of the metal oxide and of the metallic element).
- the first metal precursor is a Cu precursor, namely a copper salt such as, for example, copper acetate monohydrate and the second metal precursor is a Zn precursor, namely a zinc salt, for example, zinc acetate dihydrate, and the nanoparticle composite is Zn x Cu y O, as described herein in respective embodiments.
- the first metal precursor is a Cu precursor, namely a copper salt, for example copper acetate monohydrate and the second metal precursor is a Mg precursor, namely, a Mg salt, for example, magnesium acetate tetrahydrate, and the nanoparticle composite is Mg x Cu y O, as described herein in respective embodiments.
- the first metal precursor is a Ng precursor, namely, a Mg salt, for example, magnesium acetate tetrahydrate and the second metal precursor is a Cu precursor, namely a copper salt, for example, copper acetate monohydrate, and the nanoparticle composite is Cu x Mg y O, as described herein in respective embodiments.
- the first metal precursor is a Mg precursor, namely, a Mg salt, for example, the magnesium acetate tetrahydrate and the second metal precursor is a Zn precursor, namely a zinc salt, for example, zinc acetate dihydrate, and the nanoparticle composite is Zn x Mg y O, as described herein in respective embodiments.
- the molar ratio of the first and the second metal precursor salts ranges from 50:1 to 1:50, or from 40:1 to 1:40, or from 30:1 to 1:30, or from 20:1 to 1:20, or from 12:1 to 1:12.
- the molar ratio of first metal precursor and the second metal precursor is 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, or 1:2, including any value therebetween.
- the molar ratio of copper acetate monohydrate and the zinc acetate dihydrate ranges from 12:1 to 1:12. In some embodiments, the molar ratio of copper acetate monohydrate and the zinc acetate dihydrate is 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, or 1:2, including any value therebetween.
- the molar ratio of copper acetate monohydrate and the magnesium acetate tetrahydrate ranges from 12: 1 to 1: 12. In some embodiments, the molar ratio of copper acetate monohydrate and the zinc acetate dihydrate is 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, or 1:2, including any value therebetween. In some embodiments, the molar ratio of magnesium acetate tetrahydrate and the zinc acetate dihydrate ranges from 12: 1 to 1: 12.
- the molar ratio of copper acetate monohydrate and the zinc acetate dihydrate is 12: 1, 11: 1, 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: 1, 3: 1, 2: 1, 1: 1, 1: 12, 1: 11, 1 : 10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1 :2, including any value therebetween.
- the molar ratio of magnesium acetate tetrahydrate and the copper acetate monohydrate ranges from 12: 1 to 1: 12. In some embodiments, the molar ratio of copper acetate monohydrate and the zinc acetate dihydrate is 12: 1, 11: 1, 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: 1, 3: 1, 2: 1, 1 : 1, 1 : 12, 1: 11, 1: 10, 1:9, 1:8, 1:7, 1:6, 1:5, 1 :4, 1 :3, 1 :2, including any value therebetween.
- the molar ratio of the first metal precursor and the second metal precursor is 3: 1.
- the first metal precursor is a Cu precursor as described herein and the second metal precursor is a Zn precursor as described herein.
- the molar ratio of copper acetate monohydrate and the zinc acetate dehydrate is 3: 1.
- the total molar concentration of the first and the second metal precursor salts ranges from about 0.0025M to about 5M.
- the total molar concentration of the first and the second metal precursor salts ranges from about 0.005M to about 1M.
- the total molar concentration of the first and the second metal precursor salts ranges from about 0.01M to about 0.1M.
- the total molar concentration of the first and the second metal precursor salts ranges from about 0.01M to about 0.1M.
- the total molar concentration of copper acetate monohydrate and the zinc acetate dihydrate ranges from about 0.0025M to about 5M.
- the total molar concentration of the copper acetate monohydrate and the zinc acetate dihydrate ranges from about 0.005M to about 1M. In some embodiments, the total molar concentration of the copper acetate monohydrate and the zinc acetate dihydrate ranges from about 0.01M to about 0.1M.
- the total molar concentration of the copper acetate monohydrate and the zinc acetate dihydrate ranges from about 0.01M to about 0.1M.
- the total molar concentration of the copper acetate monohydrate and the zinc acetate dihydrate is 0.02M.
- the total molar concentration of the copper acetate monohydrate and the zinc acetate dihydrate is 0.01M.
- the total molar concentration of the copper acetate monohydrate and the zinc acetate dihydrate is 0.005M.
- the total molar concentration of copper acetate monohydrate and the magnesium acetate tetrahydrate ranges from about 0.0025M to about 5M.
- the total molar concentration of the copper acetate monohydrate and the magnesium acetate tetrahydrate ranges from about 0.005M to about 1M.
- the total molar concentration of the copper acetate monohydrate and the magnesium acetate tetrahydrate ranges from about 0.01M to about 0.1M.
- the total molar concentration of the copper acetate monohydrate and the magnesium acetate tetrahydrate ranges from about 0.01M to about 0.1M.
- the total molar concentration of zinc acetate dihydrate and the magnesium acetate tetrahydrate ranges from about 0.0025M to about 5M.
- the total molar concentration of the zinc acetate dihydrate and the magnesium acetate tetrahydrate ranges from about 0.005M to about 1M.
- the total molar concentration of the zinc acetate dihydrate and the magnesium acetate tetrahydrate ranges from about 0.01M to about 0.1M.
- the total molar concentration of the zinc acetate dihydrate and the magnesium acetate tetrahydrate ranges from about 0.01M to about 0.1M. It is noted that the molar ratio of the first and the second metal precursors determined, at least in part, the atomic ratio between the metal of the metal oxide and the metallic element in the crystal-lattice doped metal oxide nanoparticles as described herein.
- a substrate or article incorporating the nanoparticle composite :
- a composition- according to any one of the respective embodiments further comprises a substrate, and a plurality of nanoparticle composites as described in any of the respective embodiments, is incorporated in and/or on at least a portion of the substrate.
- a substrate having incorporated in and/or on at least a portion thereof, metal-doped metal oxide nanoparticles (nanoparticle composites) as described herein.
- a substrate having incorporated in and/or on at least a portion thereof a sonochemically-prepared composition-of-matter as described herein in any of the respective embodiments.
- a portion thereof it is meant, for example, a surface or a portion thereof, and/or a body or a portion thereof, of solid or semi-solid substrates; or a volume or a part thereof, of liquid, gel, foams and other non-solid substrates.
- substrates of widely different chemical nature can be successfully utilized for (e.g., sonochemically) incorporating (e.g., depositing on a surface thereof) metal-doped metal oxide nanoparticles thereon, as described herein.
- sonochemically incorporating
- metal-doped metal oxide nanoparticles thereon as described herein.
- the nanoparticle composites successfully form a uniform and homogenously coating on the substrate's surface upon ultrasonic irradiation thereof; and (ii) the resulting coating imparts long-lasting desired properties (e.g., antimicrobial properties) to the substrate's surface.
- compositions-of-matter further comprising a substrate as described herein can be prepared by contacting the substrate, or a portion thereof, with the first and second metal precursors as described herein, or a solution containing same, as described in any of the respective embodiments, and subjecting the substrate and the precursors mixture or solution to ultrasonic irradiation, as described in any of the respective embodiments.
- the contacting is effected by immersing the substrate or a portion thereof in a solution containing the first and second metal precursors.
- Substrate usable according to some embodiments of the present invention can therefore be hard (rigid) or soft, solid, semi-solid, or liquid substrates, and may take a form of a foam, a solution, an emulsion, a lotion, a gel, a cream or any mixture thereof.
- Substrate usable according to some embodiments of the present invention can have, for example, organic or inorganic surfaces, including, but not limited to, glass surfaces; porcelain surfaces; ceramic surfaces; silicon or organosilicon surfaces, metallic surfaces (e.g., stainless steel); MICA, polymeric surfaces such as, for example, plastic surfaces, rubbery surfaces, paper, wood, fabric in a woven, knitted or non-woven form, mineral (rock or glass), surfaces, wool, silk, cotton, hemp, leather, fur, feather, skin, hide, pelt or pelage) surfaces, plastic surfaces and surfaces comprising or made of polymers such as but not limited to polypropylene (PP), polycarbonate (PC), high-density polyethylene (HDPE), polyester (PE), unplasticized polyvinyl chloride (PVC), and fluoropolymers including but not limited to polytetrafluoroethylene (PTFE, Teflon®); or can comprise or be made of any of the foregoing substances, or any mixture thereof.
- polypropylene PP
- the nanoparticles size in and/or on the substrate is about
- the doped metal oxide nanoparticles size is in a range of 10 to 80 nm. In yet further embodiments the nanoparticles size is about 25 nm. In some embodiments the nanoparticles size is about 10 nm. In some embodiments the nanoparticles size is less than 10 nm.
- the nanoparticle composites are in form of one or more layers of a continuous film.
- the thickness of the film is at least 30 nm.
- the thickness of the film is at least 40 nm, at least 50 or at least 60 nm.
- the film forms a part or is a coating on the substrate.
- the substrate incorporating nanoparticle composites as described herein is or forms a part of an article.
- an article e.g., an article-of-manufacturing
- a substrate incorporating tin and/or on at least a portion thereof a composition-of-matter or nanoparticle composites, as described in any one of the respective embodiments herein.
- the articles can be prepared sonochemically, e.g., by contacting the article or a portion thereof, as described herein, with metal prescursors as described herein, and subjecting the mixture to ultrasonic irradiation, as described herein.
- a substrate forming the article, and incorporating the nanoparticle composites is prepared as described herein, and is then used to construct the article.
- the article can be any article which can benefit from the antimicrobial and/or anti- biofilm formation activities of the nanoparticle composites.
- Exemplary articles include, but are not limited to, medical devices, pharmaceutical, cosmetic or cosmeceutic products, fabrics, bandages, microelectronic devices, microelectromechanic devices, photovoltaic devices, microfluidic devices, articles having a corrosivable surface, agricultural devices, packages, sealing articles, fuel containers and construction elements.
- Non-limiting examples of medical devices which can incorporate nanoparticle composites beneficially include catheters, tubing, endotracheal tubing, vaginal devices such as tampons, prosthetic devices, medical or cosmetic implants, artificial joints, artificial valves, needles, intravenous access devices, cannula, stents, biliary stents, cardiovascular stents, cardiac surgery devices, nephrostomy tubes, vascular grafts, infusion pumps, adhesive patches, sutures, fabrics, meshes, polymeric surgical tools or instruments, intubation devices, orthopedic surgery devices, pacemakers, endoscope components, dental surgery devices, veterinary surgery devices, bone scaffolds, hemodialysis tubing or equipment, blood exchanging and transfusion devices, implantable prostheses, bandages, ophthalmic devices, wound dressings, breast implants, pacemakers, heart valves, replacement joints, catheters, catheter access ports, dialysis tubing, gastric bands, shunts, screw plates, artificial spinal disc replacements, internal implantable defibri
- the medical device is an implantable medical device, including medical devices that are implanted transiently or permanently.
- medical devices that are implanted transiently or permanently.
- examples include an indwelling catheter or an intubation device such as a tracheal tube.
- indwelling catheters include urinary catheters, central venous catheters, biliary vascular catheters, pulmonary artery catheters, peripheral venous catheters, arterial lines, central venous catheters, peritoneal catheters, epidural catheters and central nervous system catheters.
- the medical device is such that is made of any of the suitable polymeric materials described hereinabove (e.g., at least a portion of the medical device comprises a polymeric material).
- the medical device is a tampon or a vaginal medical device.
- tampon refers to a medical device in the form of a plug made from a mass of absorbent materials which is inserted into a wound or a body site to absorb exuded fluids, such as blood.
- tampons are regarded officially as medical devices in many courtiers around the world, and according to the United States Food and Drug Administration, tampons are a Class II medical device.
- the term "tampon” describes tampons designed to be inserted into the vagina during menstruation to absorb the flow of menstrual fluid.
- the tampon can be a commercially available tampon of any type, composition, absorption rate, size and/or blend.
- Tampons are typically made from cotton, rayon and blends thereof, and are available in different sizes for various conditions and absorbing rates. Tampons may include an applicator, which is a polymeric tube sheathing the absorbent plug for facilitating its insertion into the vagina.
- an applicator which is a polymeric tube sheathing the absorbent plug for facilitating its insertion into the vagina.
- Exemplary vaginal medical condition include, without limitation, bacterial vaginitis (BV), toxic shock syndrome (TSS), toxic shock-like syndrome (TSLS), streptococcal toxic shock syndrome (STSS), vulvovaginal candidiasis (VVC), chronic or persistent yeast infections (RVVC ), a sexual dysfunction, a female reproductive system related disorder and a post-surgery vaginal related condition.
- BV bacterial vaginitis
- TSS toxic shock syndrome
- TSLS toxic shock-like syndrome
- STSS streptococcal toxic shock syndrome
- VVC vulvovaginal candidiasis
- RVVC chronic or persistent yeast infections
- Exemplary packages or containers include, for example, food packages and containers, beverage packages and containers, medical device packages, agricultural packages and containers (of agrochemicals), blood sample or other biological sample packages and containers, and any other packages or containers of various articles.
- Exemplary food packages include packages of dairy products and/or containers for storage or transportation of dairy products.
- exemplary articles of manufacturing include milk storage and processing devices such as, but not limited to, containers, storage tanks, raw milk holding equipments, dairy processing operations conveyer belts, tube walls, gaskets, rubber seals, stainless steel coupons, piping systems, filling machine, silo tanks, heat exchangers, postpasteurization equipments, pumps, valves, separators, and spray devices.
- milk storage and processing devices such as, but not limited to, containers, storage tanks, raw milk holding equipments, dairy processing operations conveyer belts, tube walls, gaskets, rubber seals, stainless steel coupons, piping systems, filling machine, silo tanks, heat exchangers, postpasteurization equipments, pumps, valves, separators, and spray devices.
- the article is an energy harvesting device, for example, a microelectronic device, a microelectromechanic device, a photovoltaic device and the like.
- the article is a microfluidic device, for example, micropumps or micro valves and the like.
- the article includes a sealing part, for example, O rings, and the like.
- the article is, for example, article having a corrosivable surface. In some embodiments, the article is an agricultural device.
- the article is made of textile, for example, cotton, polyester, lycra, wool, silk, and the like, as described herein.
- the article is fuel transportation device.
- the article of manufacture is a construction element, such as, but not limited to, paints, walls, windows, door handles, and the like.
- the article is an element used in water treatment systems (such as for containing and/or transporting and/or treating aqueous media or water), devices, containers, filters, tubes, solutions and gases and the likes.
- the article is an element in organic waste treatment systems
- the article is a pharmaceutical, cosmetic or cosmeceutical product.
- Such products in some embodiments, comprise a pharmaceutical, cosmetic or cosmeceutical formulation incorporating the nanoparticle composites as described herein.
- the product comprises a cosmetic, cosmeceutical or pharmaceutical formulation such as skincare formulations, makeup or dermatological or other topical pharmaceutical formulations, comprising the nanoparticle composites as described herein.
- the formulation can optionally and preferably further comprise a carrier, and optionally additional active agents and/or additives.
- formulation refers to a vehicle in the form of emulsion, lotion, cream, gel etc., that comprises physiologically acceptable carriers and/or excipients and optionally other chemical components such as cosmetically, cosmeceutically or pharmaceutically active agents (e.g., drugs).
- physiologically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
- physiologically suitable carrier refers to an approved carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of a possible active agent.
- excipient refers to an inert substance added to a formulation as described herein to further facilitate processes and administration of the active ingredients.
- the pharmaceutical, cosmetic or cosmeceutical formulation is formulated in a form suitable for topical application on the applied area.
- the formulations can be water based, oil based or silicon based.
- the formulations are colloidal formulations, in which the nanoparticle composites are dispersed, suspended or otherwise distributed in the carrier.
- formulations as described herein can be, for example, skin care products, makeup products (including eye shadows, make-up, lipstic, lacquer, etc., or any other product as described herein).
- a formulation as described is in a form of a cream, an ointment, a paste, a gel, a lotion, a milk, an oil, a suspension, a solution, an aerosol, a spray, a foam, or a mousse.
- Ointments are semisolid preparations, typically based on petrolatum or petroleum derivatives.
- the specific ointment base to be used is one that provides for optimum delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well (e.g., emolliency).
- an ointment base should be inert, stable, nonirritating and nonsensitizing.
- ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
- Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
- Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
- Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.
- Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight.
- Lotions are preparations that are to be applied to the skin surface without friction. Lotions are typically liquid or semiliquid preparations in which solid particles, including the sunscreens-containing microcapsules, are present in a water or alcohol base. Lotions are typically preferred for covering/protecting large body areas, due to the ease of applying a more fluid composition. Lotions are typically suspensions of solids, and oftentimes comprise a liquid oily emulsion of the oil-in-water type. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, such as methylcellulose, sodium carboxymethyl- cellulose, and the like.
- Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in- oil.
- Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
- the oil phase also called the "internal” phase, is generally comprised of petrolatum and/or a fatty alcohol such as cetyl or stearyl alcohol.
- the aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
- the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Reference may be made to Remington: The Science and Practice of Pharmacy, supra, for further information.
- Pastes are semisolid dosage forms in which the bioactive agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gels.
- the base in a fatty paste is generally petrolatum, hydrophilic petrolatum and the like.
- the pastes made from single -phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference may be made to Remington: The Science and Practice of Pharmacy, for further information.
- Gel formulations are semisolid, suspension-type systems.
- Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil.
- Preferred organic macromolecules, i.e., gelling agents are crosslinked acrylic acid polymers such as the family of carbomer polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the trademark CarbopolTM.
- hydrophilic polymers such as polyethylene oxides, polyoxyethylene- polyoxypropylene copolymers and polyvinylalcohol
- cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose
- gums such as tragacanth and xanthan gum
- sodium alginate and gelatin.
- dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.
- Sprays generally provide the active agent in an aqueous and/or alcoholic solution which can be misted onto the skin for delivery.
- Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the active agent can be dissolved.
- the carrier evaporates, leaving concentrated active agent at the site of administration.
- Foam compositions are typically formulated in a single or multiple phase liquid form and housed in a suitable container, optionally together with a propellant which facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application.
- Other foam forming techniques include, for example the "Bag-in-a- can" formulation technique.
- Compositions thus formulated typically contain a low-boiling hydrocarbon, e.g., isopropane. Application and agitation of such a composition at the body temperature cause the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol foaming system.
- Foams can be water-based or hydroalcoholic, but are typically formulated with high alcohol content which, upon application to the skin of a user, quickly evaporates, driving the active ingredient through the upper skin layers to the site of treatment.
- the preparation of the formulation can be carried out by mixing and homogenizing all the ingredients.
- a product comprising such formulations, as described herein, can be prepared, for example, by contacting the formulation with already prepared nanoparticle composites as described herein, or by contacting the formulation with a first and a second metal precursor as described herein and subjecting the obtained mixture to ultrasonic irradiation as described herein in any of the respective embodiments.
- additives and/or agents include humectants, deodorants, antiperspirants, sunless tanning agents, hair conditioning agents, pH adjusting agents, chelating agents, preservatives, emulsifiers, occlusive agents, emollients, thickeners, solubilizing agents, penetration enhancers, anti-irritants, colorants, propellants and surfactants.
- the article is a dye formulation, including any of the formulations described hereinabove, or any other carriers, solvents, etc. incorporating a dye substance.
- topical application and grammatical diversions thereof, is meant to encompass, without limitation, dermal applications, ophthalmic application, vaginal application, rectal application and intranasal application.
- formulation containing the metal-doped metal oxide nanoparticles presented herein can be concocted into any pharmaceutical form normally employed for topical application, such as creams, lotions, ointments, suppositories, powder or oily bases, dressings, solutions, gels, mousses, pastes, soaps, pads, wipes, patches, swabs and pledgets.
- any pharmaceutical form normally employed for topical application such as creams, lotions, ointments, suppositories, powder or oily bases, dressings, solutions, gels, mousses, pastes, soaps, pads, wipes, patches, swabs and pledgets.
- a substrate's surfaces as described herein can further be modified by various chemical and mechanical processes, including, for example, SAMs, PVD, lithography and plasma etching.
- the substrate is made of cotton fabrics from either woven or non-woven cotton bandage.
- the substrate is made of artificial acryl tooth.
- the substrate is made of a glass.
- the substrate is urinary catheters catheter made of silicon.
- a pharmaceutical, cosmetic or cosmeceutical product comprising the compositions-of-matter or the nanoparticle composites as described in any of their respective embodiments herein, for use in treating a medical, cosmetic or cosmeceutic condition, as described herein.
- compositions-of-matter as described herein in the manufacture of a pharmaceutical, cosmetic or cosmeceutical product, which can be used in treating a medical, cosmetic or cosmeceutic condition, as described herein.
- a method of treating a medical, cosmeceutical or cosmetic condition treatable by topical or transdermal administration comprising topically applying a formulation as described herein (e.g., in the context of a pharmaceutical, cosmetic or cosmeceutic product), containing nanoparticle composites as described herein to a skin or mucosal tissue of a subject afflicted by the condition.
- a formulation as described herein e.g., in the context of a pharmaceutical, cosmetic or cosmeceutic product
- Medical, cosmetic or cosmeceutical conditions that can benefit from containing nanoparticle composites as described herein when applied topically, with or without an additional active ingredient, include, but are not limited to, infections caused by pathogenic microorganisms, as discussed in further detail hereinbelow, wounds, particularly when associated with an infection, acne, skin infections, viral blisters such as one caused by herpes, sexual dysfunction such as erectile dysfunction.
- the pharmaceutical, cosmetic or cosmeceutical formulation or product further comprises an antimicrobial agent, as an additional pharmaceutically active agent.
- Microbial infections include any infection caused by a pathogenic microorganism, including, bacterial infection, fungal infection, protozoal infection, viral infection and the like, including molluscum contagiosum (a viral infection of the skin or occasionally of the mucous membranes), fungal nail infections, and cutaneous leishmaniasis.
- a pathogenic microorganism including, bacterial infection, fungal infection, protozoal infection, viral infection and the like, including molluscum contagiosum (a viral infection of the skin or occasionally of the mucous membranes), fungal nail infections, and cutaneous leishmaniasis.
- Topical bodily sites include skin, mucosal tissue, eye, ear, nose, mouth, rectum and vagina.
- an article e.g., a medical device such as a bandage or adhesive patch
- a formulation or a product, as described herein, configured for topical application, whereby a condition treatable by such as article or product or formulation is an infection caused by is P. Acne.
- a method of inhibiting or reducing or retarding the formation of load of a microorganism and/or the formation of a biofilm, in and/or on an article comprises incorporating in and/or on the article any one of the compositions-of-matter as described herein, including any of the respective embodiments thereof.
- the article can be any one of the articles described herein.
- Such articles take advantage of the improved antimicrobial activity exhibited by the nanoparticle composites as described herein.
- antimicrobial activity is referred to as an ability to inhibit (prevent), reduce or retard bacterial growth, fungal growth, biofilm formation or eradicate living bacterial cells, or their spores, or fungal cells or viruses in a suspension or in a moist environment.
- inhibiting or reducing or retarding the formation of load of a microorganism refers to inhibiting reducing or retarding growth of microorganisms and/or eradicating a portion or all of an existing population of microorganisms.
- nanoparticle composites as described herein can be used both in reducing the formation of microorganisms on or in an article, and in killing microorganisms in or on an article or a living tissue.
- the microorganism can be, for example, a unicellular microorganism (prokaryotes, archaea, bacteria, eukaryotes, protists, fungi, algae, euglena, protozoan, dinoflagellates, apicomplexa, trypanosomes, amoebae and the likes), or a multicellular microorganism.
- a unicellular microorganism prokaryotes, archaea, bacteria, eukaryotes, protists, fungi, algae, euglena, protozoan, dinoflagellates, apicomplexa, trypanosomes, amoebae and the likes
- a multicellular microorganism multicellular microorganism
- An article, according to these embodiments, can be also a living tissue, for example, a skin or mucosal tissue, as described herein.
- compositions, articles and methods described herein may be used to produce cell inhibiting surface, or a microbial cell killing surface, that remains active for extended periods.
- Such an antimicrobial surface may not need additional treatment with antimicrobial compositions, clean-up treatments to effect decontamination and cosmetic painting, thereby simplifying upkeep of the physical condition and appearance of microbial infestation prone surfaces.
- the compositions of the present invention may be easily applied to susceptible surfaces in advance of and/or during exposure to a microbial organism.
- the microorganism comprises bacterial cells of bacteria such as, for example, Gram-positive and Gram-negative bacteria.
- biofilm refers to an aggregate of living cells which are stuck to each other and/or immobilized onto a surface as colonies.
- the cells are frequently embedded within a self-secreted matrix of extracellular polymeric substance (EPS), also referred to as “slime”, which is a polymeric sticky mixture of nucleic acids, proteins and polysaccharides.
- EPS extracellular polymeric substance
- the living cells forming a biofilm can be cells of a unicellular microorganism (prokaryotes, archaea, bacteria, eukaryotes, protists, fungi, algae, euglena, protozoan, dinoflagellates, apicomplexa, trypanosomes, amoebae and the likes), or cells of multicellular organisms in which case the biofilm can be regarded as a colony of cells (like in the case of the unicellular organisms) or as a lower form of a tissue.
- a unicellular microorganism prokaryotes, archaea, bacteria, eukaryotes, protists, fungi, algae, euglena, protozoan, dinoflagellates, apicomplexa, trypanosomes, amoebae and the likes
- the biofilm can be regarded as a colony of cells (like in the case of the unicellular organisms)
- the cells are of microorganism origins, and the biofilm is a biofilm of microorganisms, such as bacteria and fungi.
- the cells of a microorganism growing in a biofilm are physiologically distinct from cells in the "planktonic form" of the same organism, which by contrast, are single-cells that may float or swim in a liquid medium.
- Biofilms can go through several life-cycle steps which include initial attachment, irreversible attachment, one or more maturation stages, and dispersion.
- anti-biofilm formation activity refers to the capacity of a substance to effect the prevention of formation of a biofilm of bacterial, fungal and/or other cells, and/or to effect a reduction in the rate of buildup of a biofilm of bacterial, fungal and/or other cells, on a surface of a substrate. This activity is also referred to herein as anti-biofouling activity, or antifouling activity.
- the biofilm is formed of bacterial cells (or from a bacterium).
- a biofilm is formed of bacterial cells of Gram-positive and/or Gram-negative bacteria.
- composition of matter as described herein was shown to exhibit anti-biofilm formation (ABF) activity and can thus prevent, retard or reduce the formation of a mass of a biofilm.
- ABSF anti-biofilm formation
- the activity of preventing or reducing the formation of a biofilm may be achieved by a substrate or an article incorporating nanoparticle composites, as described herein.
- preventing in the context of the formation of a biofilm, indicates that the formation of a biofilm is essentially nullified or is reduced by at least 20 %, at least 30 %, at least 40 %, at least 50 %, at least 60 %, at least 70 %, at least 80 %, at least 90 %, including any value therebetween, of the appearance of the biofilm in a comparable situation lacking the presence of the metal-oxide nanoparticles or a composition of matter containing same.
- preventing means a reduction to at least 15 %, 10 % or 5 % of the appearance of the biofilm in a comparable situation lacking the presence of the metal-doped metal oxide nanoparticles or a composition of matter containing same.
- the term "preventing" in the context of antimicrobial indicates that the growth rate of the microorganism cells is essentially nullified or is reduced by at least 20 %, at least 30 %, at least 40 %, at least 50 %, at least 60 %, at least 70 %, at least 80 %, at least 90 %, including any value therebetween, of the appearance of the microorganism in a comparable situation lacking the presence of the metal-doped metal oxide nanoparticles or a composition of matter containing same.
- preventing means a reduction to at least 15 %, 10 % or 5 % of the appearance of the microorganism cells in a comparable situation lacking the presence of the metal-doped metal oxide nanoparticles or a composition of matter containing same.
- Methods for determining a level of appearance of a microorganism cells are known in the art.
- inhibiting, reducing and/or retarding a formation of a biofilm as described herein is reflected by reducing biofilm formation on e.g., a substrate's surface by at least 20 %, at least 30 %, at least 40 %, at least 50 %, at least 60 %, at least 70 %, at least 80 %, at least 90 %, including any value therebetween, compared to the same substrate which does not have said metal-doped metal oxide nanoparticles applied on a surface thereof.
- an article which comprises the composition of matter incorporated in and/or on a substrate.
- a method of inhibiting, reducing and/or retarding a formation of a biofilm in or on a substrate or an article containing the substrate or an article containing the substrate which is effected by sonochmically incorporating in and/or on the substrate an anti-fouling effective amount of a composition-of-matter as described herein, in any one of the respective embodiments.
- Substrates usable in the context of these embodiments of the present invention include any of the substrates described hereinabove.
- Compositions of matter usable in the context of these embodiments include any of the compositions of matter described hereinabove.
- Articles usable in the context of these embodiments include any of the articles of manufacturing described hereinabove.
- articles of manufacturing in which prevention of biofilm formation are of high importance are usable in the context of these embodiments of the present invention.
- compositions of matter as described herein can be incorporated within any of the articles of manufacturing, during manufacture of any of the article described herein.
- the substrates presented herein can be used to modify any industrial or clinical surface to prevent bacterial colonization and biofilm formation.
- compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
- range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
- method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
- treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
- MDR Multi-Drug Resistant
- Tel-Aviv medical center "Ichilov” E. coli - clinical (blood) isolate belonging to sequence type ST131 lineage, producing CTX-M-15 extended-spectrum b-lactamase, and methicillin resistant S. aureus (MRSA) - belonging to USA300 lineage.
- Propionobacterium acnes (P. acnes; strain ATCC 6919) strains were obtained from the ATCC strain collection.
- Candida albicans (a clinical isolated) was obtained from the bacteriological laboratory of the Meir Hospital, Kfar-Sava, Israel. Growth media: Nutrient Broth (NB), Brain Heart (BH) were purchased from Difco, Detroit, MI.Luria Bertani (LB) medium was purchased from Hy-labs, Rehovot, Israel.
- Brain-heart medium supplemented with 0.5% sucrose (denoted BH) and Muller- Hinton (MH) were obtained from BD Biosciences. Glass slides were purchased from Marienfeeld (Germany).
- Cotton fabric was obtained from either woven or non-woven cotton bandage provided by Kopman, Italy.
- the coating was done also on polyester polyester/cotton and cotton bandage.
- Microwave irradiation was performed using a domestic microwave oven modified with reflection system, (Sharp, 1200W, 100% intensity).
- the Cu and Zn concentrations in the cotton fabric were determined by ICP analysis (ULTIMA 2).
- XRD X-ray diffraction
- DSC Differential scanning calorimetric
- the zeta-potential of the nanoparticles (e.g., Zn-CuO, CuO) in BH medium was determined at room temperature (about 25 °C) using a Malvern zetasizer (Malvern Instruments). The procedure was carried out at least three times for each of the individual nanoparticle suspension.
- Leaching studies were carried out on the coated catheter following 72 hours incubation with either saline, artificial urine (consist of: 25 gram/liter urea, 9 gram/liter Sodium chloride, 2.5 gram/liter potassium phosphate monobasic, 2.5 gram/liter sodium phosphate dibasic, 3 gram/liter ammonium chloride, 2 gram/liter creatinine and 3 gram/liter sodium sulfite all purchased from Sigma- Aldrich) and 1% MH medium (BD Biosciences).
- 0.4 gram of a coated catheter was incubated in 2 ml of the tested solution for 72 hours with shaking 50 rpm at 37 °C. Following incubation 1 ml of the solution was taken for probing the presence of leached ions using ICP analysis.
- the cross-section morphology of the coated substrate (e.g., artificial tooth) was studied in regards to the thickness of the coating and the nanoparticles penetration depth profile into the bulk of the substrate was employed by a focused ion beam (FIB) using dual beam system (FEI Helios 600) system with several electron and ion beams up to 30 kV at different angles (52 degrees) that image the substrate sample simultaneously.
- FIB focused ion beam
- FEI Helios 600 dual beam system with several electron and ion beams up to 30 kV at different angles (52 degrees) that image the substrate sample simultaneously.
- the scattering angle of the fixed detector was 169°, and solid angle was 2.7 millisteradians (msr).
- a normal incident beam was used in all measurements. Every sample was mounted in the holder using double-sided, self-adhesive carbon tape.
- NDF version 9.4e software was used.
- SRIM 2003 was used as stopping powers.
- the double- scattering calculation in NDF was employed to fit of the low-energy signal.
- the pulse pileup calculation in NDF uses the algorithm of Wielopolsky & Gardner.
- EBS Enhanced backscattering spectroscopy
- a metal precursor or a mixture of a first and a second metal precursors is dissolved in water (e.g., double distilled water), ethanol is added so as to obtain a solution of e.g., 9: 1 (v/v) ethanol: water, and the solution is subjected to ultrasonic irradiation using high intensity sonication (e.g., using an immersed Ti-horn, 20 kHz, 750 W at 40 % efficiency, Sonics & Materials VCX600 Sonofier).
- water e.g., double distilled water
- ethanol is added so as to obtain a solution of e.g., 9: 1 (v/v) ethanol: water
- the solution is subjected to ultrasonic irradiation using high intensity sonication (e.g., using an immersed Ti-horn, 20 kHz, 750 W at 40 % efficiency, Sonics & Materials VCX600 Sonofier).
- an alkaline aqueous solution e.g., 28-30 % ammonia solution
- the reaction vessel is maintained at 30 °C (e.g., by means of a water bath) for additional 30-60 minutes.
- the obtained solution is thereafter centrifuged, and the obtained nanoparticles are dried under vacuum.
- sonication is performed at 45 W cm intensity.
- Doped metal oxide nanoparticles are similarly prepared while using a mixture of two metal precursors, at varying molar ratios.
- Copper acetate monohydrate (an exemplary Cu precursor) and zinc acetate dihydrate (an exemplary Zn precursor) were used as metal precursors, at the following molar ratios: 4: 1, 3: 1, 2: 1, 1: 1, 1:2, 1:3 and 1 :4, and the procedure described above for preparation of CuO nanoparticles via ultrasonic irradiation was applied.
- the concentration and molar ratio as designated hereinabove as med-3: l Cu:Zn were achieved by dissolving 0.15 grams of copper acetate monohydrate and 0.055 grams of zinc acetate dihydrate in double distilled water (ddH 2 0; 10 ml) while stirring and thereafter adding of ethanol (90 ml) to the solution so as to obtain a solution of 100 ml of 9: 1 (v/v) ethanol: water.
- the Cu precursor was dissolved in 10 ml water, the Zn precursor was added, and ethanol (90 ml) was added to a final volume of 100 ml.
- the obtained solution was subjected to sonication as described hereinabove for CuO nanoparticles.
- the obtained nanoparticles were similarly isolated, washed and dried.
- nanoparticles and/or the precursors mixture used for preparing same can be identified by the molar ratio of the metal precursors used, namely, by indicating 1 : 1 or 2: 1, or 3: 1, etc. before "Cu:Zn" or before Zn-doped CuO, with the left digit in the molar ratio indicating the relative concentration of a Cu precursor.
- Nanoparticles can also be identified by the concentration of the precursors as being medium (med), high or low.
- Deposition of metal oxide nanoparticles on substrates via ultrasonic irradiation In a general procedure, a metal precursor or a mixture of metal precursors is dissolved in water, ethanol is added to obtain e.g., a 9: 1 ethanohwater solution, the substrate is immersed in the solution and the obtained mixture is subjected to ultrasonic irradiation as described hereinabove. The substrate was kept at a constant distance of 2 cm from the sonicator tip during the entire reaction process.
- the obtained coated substrate was thereafter washed twice with double-distilled water and once with ethanol, and then dried under vacuum.
- CuO nanoparticles, ZnO nanoparticles and Zn-doped CuO nanoparticles were deposited on substrates using the exemplary metal precursors indicated hereinabove.
- a mixture of metal precursors at a concentration and molar ratio as designated hereinabove as med-3: l Cu:Zn was used, unless otherwise indicated.
- Nanoparticles coatings on artificial tooth were obtained by placing an artificial acryl tooth directly into the sonochemical reaction medium according to the methodology described above. The tooth was held by a wire to keep it at a constant distance of 2 cm from the sonicator tip during the entire reaction process.
- Nanoparticles coatings on cotton fabric were obtained by placing a cotton fabric (sized e.g., 2 x 3 cm ) in the sonochemical reaction medium according to the methodology described above.
- Nanoparticles coatings on cotton fabric were obtained by placing a glass slide (sized e.g., 2 x 3 cm ) in the sonochemical reaction medium according to the methodology described above.
- Nanoparticles coatings on a catheter were obtained by placing catheter segments (sized e.g., 5 cm) in the sonochemical reaction medium according to the methodology described above. Subjecting Cu precursor and Zn precursor to Microwave Irradiation (Reference Example 1):
- a mixture of metal precursors in a concentration and molar ratio as designated hereinabove as med-3: l Cu:Zn was obtained by dissolving 0.15 grams of Copper acetate monohydrate and 0.055 grams of Zinc acetate dihydrate in double distilled water (ddH 2 0; e.g., 10 ml) while stirring and thereafter adding ethanol (90 ml) to the solution so as to obtain a solution of 100 ml of 9: 1 (v/v) ethanol: water.
- the obtained solution was subjected to microwave irradiation oven using a domestic microwave oven.
- a mixture of metal precursors in a concentration and molar ratio as designated hereinabove as med-3: l Cu:Zn was obtained by dissolving 0.15 grams of Copper acetate monohydrate and 0.055 grams of Zinc acetate dihydrate in double distilled water (ddH 2 0; 10 ml) while stirring and thereafter adding Ethanol (90 ml) to the solution so as to obtain a solution of 100 ml of 9: 1 (v/v) ethanokwater.
- the obtained solution was heated at a heating plate to 60 °C while stirring and 0.8 ml of an aqueous solution of ammonia (28-30 %) was added to the reaction mixture so as to adjust the pH to about 8.
- Zinc acetate dihydrate an exemplary Zn precursor
- magnesium acetate tetrahydrate an exemplary Mg precursor
- Zinc acetate dihydrate an exemplary Zn precursor
- Mg precursor magnesium acetate tetrahydrate
- the Mg precursor is dissolved in water (e.g., 10 ml), and the Zn precursor is then added.
- Ethanol e.g., 90 ml
- an alkaline aqueous solution e.g., 28-30 % ammonia solution
- the reaction vessel is maintained at 30 °C (e.g., by means of a water bath) for additional 30-60 minutes.
- the obtained solution is thereafter centrifuged, and the obtained nanoparticles are dried under vacuum.
- the total concentrations of Zn 2+ and Mg 2+ ions in the aqueous solution are in the range of from 0.05 to 0.005M.
- Copper acetate monohydrate an exemplary Cu precursor
- magnesium acetate an exemplary Mg precursor
- Copper acetate monohydrate an exemplary Cu precursor
- magnesium acetate an exemplary Mg precursor
- the Cu precursor was dissolved in water (e.g., 10 ml), and the Mg precursor was then added. Ethanol (e.g., 90 ml) was thereafter added to a final volume of 100 ml. After a time period ranging from 1 to 10 minutes, an alkaline aqueous solution (e.g., 28-30 % ammonia solution) was added to the sonicated reaction mixture, and the reaction vessel was maintained at 30 °C (e.g., by means of a water bath) for additional 30-60 minutes. The obtained solution was thereafter centrifuged, and the obtained nanoparticles were dried under vacuum.
- water e.g. 10 ml
- Ethanol e.g., 90 ml
- an alkaline aqueous solution e.g., 28-30 % ammonia solution
- the obtained solution was thereafter centrifuged, and the obtained nanoparticles were dried under vacuum.
- Zinc acetate dihydrate an exemplary Zn precursor
- magnesium acetate an exemplary Mg precursor
- copper acetate monohydrate an exemplary Cu precursor
- the Zn precursor is dissolved in water (e.g., 10 ml), and the Mg or Cu precursor is then added.
- Ethanol e.g., 90 ml
- a final volume of 100 ml is thereafter added.
- an alkaline aqueous solution e.g., 28-30 % ammonia solution
- the reaction vessel is maintained at 30 °C (e.g., by means of a water bath) for additional 30- 60 minutes.
- the obtained solution is thereafter centrifuged, and the obtained nanoparticles are dried under vacuum.
- Figure 1 presents XRD patterns of sonochemically-prepared CuO nanoparticles (graph b), ZnO nanoparticles (graph a), and of Zn-doped CuO nanoparticles as obtained from the med-3: lCu:Zn (graph c), all prepared using the procedures described in Example 1 hereinabove.
- Figure 1 presents in graph the XRD of sonochemically-synthesized ZnO.
- PDF international crystallographic powder diffraction file
- Figure 1 further presents, in graph b therein, a representative XRD pattern showing
- the increased width of the diffraction patterns of Zn-doped CuO as compared to those of ZnO or CuO indicates the formation of smaller particle grains, and is further indicative of defects in the crystal lattice, such as dislocations therein, which are assumed to account for the enhanced antimicrobial activity of the nanoparticles.
- Figure 2A presents representative XRD reflection lines of a product obtained by med-3: l Cu:Zn precursors mixture as designated hereinabove, subjected to ultrasonic irradiation.
- the obtained data clearly show the pattern of the product (spectrum) is shifted in comparison to the monoclinic CuO (lines, international powder diffraction file (PDF) (80- 1916).
- Figure 2B presents XRD reflection lines of the product obtained upon subjecting med-3: 1 Cu:Zn precursors mixture as designated hereinbelow to microwave irradiation, and show no shifts in the peaks position.
- Figure 2C presents XRD reflection lines of the product obtained upon subjecting med-3: 1 Cu:Zn precursors mixture as designated hereinabove to thermal reaction, and show no shifts in the peaks position.
- Figure 2D presents XRD reflection lines of the product obtained upon subjecting med-4: 1 Cu:Zn precursors mixture as designated hereinbelow to ultrasonic irradiation.
- all the peaks in the XRD spectra can be assigned to monoclinic crystal lattice of CuO without any shifting and broadening of the peaks, as obtained following the sonochemical reaction using pristine copper acetate precursor.
- No peaks under the spectrum assigned to the reflection lines of ZnO PDF 89-7102), which are also provided for reference in Figure 2D.
- Zn-doped nanoparticles describe nanoparticles prepared from a med- 3: 1 Cu:Zn precursors mixture, as described herein, unless otherwise indicated.
- Table 1 presents the percentages of the copper and zinc ions in Zn-doped CuO nanoparticles dissolved from the fabric's coating by adding 0.5M HN0 3
- the results regarding to deposition % in Table 1 were obtained from the reactions starting from various concentrations (i.e., "high”, “medium”, and “low”, as indicated hereinabove) of the precursors in the solution in the presence of a fabric piece immersed therein. In all three concentrations the molar ratio of the precursors are Cu:Zn is 3: 1 prior to the reaction.
- the ICP results indicate that the ratio of Cu:Zn in the dissolved nanoparticles is about 8: 1, that is, originating from a composite with the corresponding molar ratio of
- Zn-doped CuO nanoparticles were studied with respect to their tendency to release ions into a medium.
- Figure 3 presents plots obtained from DSC analysis of Zn-doped CuO nanoparticles, under both inert (plot a) and oxidizing conditions (plot b), demonstrating, for both conditions, one endothermic peak at 100 °C assigned to water evaporation and two exothermic peaks, a broad peak at a temperature range of 130-165 °C and a strong sharper exothermic peak at 240 °C. A sharp exothermic peak appears at 420 °C only in plot b. The exothermic peaks at 130-165 °C and 240 °C are irreversible and do not appear in a second heating cycle.
- the peak at 240 °C may be regarded as indicative of the crystallization of the product.
- Figure 4 shows zeta potential measurements revealing that the average charges of the Zn-doped CuO nanoparticles and CuO nanoparticles were -12 mV and -13.9 mV, respectively.
- Figure 5 presents a bar graph bar showing the leaching properties of catheters coated with Zn-doped CuO nanoparticles immersed in different media (i.e. saline, 1 % growth medium and artificial urine) with the highest loss of the coating in urine i.e., about 12 % and the most minimal loss in saline medium, i.e., less than 1 %. No nanoparticles were detected in the solution by electron microscope or dynamic light scattering (data not shown).
- Figures 6 shows the SEM measurements of cotton fabric coated with Zn-doped CuO nanoparticles carried out in order to study the morphology of the cotton fibers before and after the deposition reaction.
- Figure 6A demonstrates the smooth texture of the pristine cotton fabric.
- the fibers are homogeneously coated with Zn-doped CuO nanoparticles, having a uniform and very high coating density.
- Figures 7A-C show HR-SEM measurements performed for determining the particles size of the Zn-doped CuO nanoparticle coating on the cotton fabric obtained from different concentrations of the corresponding metal acetate precursors.
- Figure 7D presents a histogram presenting the size distribution of the particles deposited on the coated fibers for the "medium” concentration of the precursors as obtained by the "Scion image” Software, demonstrating that the diameter of about 70 % of the primary nanoparticles was in the range of 25-35 nm.
- Figure 8B present HR-SEM images showing a uniformly coated tooth surface with Zn-doped CuO nanoparticles compared to a bare tooth.
- Figure 8C present HR-SEM images showing a uniformly coated tooth surface with CuO nanoparticles compared to a bare tooth.
- Figure 8A presents HR-SEM image of an uncoated tooth.
- Figure 8D presents a histogram showing the size distribution of the Zn-doped CuO nanoparticles deposited on the coated tooth as obtained by the "Scion image” software, demonstrating that the average diameter of the Zn-doped CuO nanoparticles is about 30 nm.
- Figure 8E presents a histogram showing the size distribution of the CuO nanoparticles deposited on the coated tooth as obtained by the "Scion image” software, demonstrating that the average diameter of the CuO nanoparticles is about 70 nm.
- Figures 9A-B presents a photograph showing an uncoated catheter ( Figures 9A) and a catheter coated with Zn-doped CuO nanoparticles ( Figures 9B).
- Figure 10A presents an HR-SEM image showing Zn-doped CuO nanoparticles (sized 80-120 nm) coating the external surface of the catheter.
- Figure 10B presents an HR-SEM image showing Zn-doped CuO nanoparticles (sized 80-120 nm) coating the internal surface of the catheter.
- Figure 11A shows measured and simulated RBS spectra of uncoated teeth surface, for a reference.
- Figures 11B shows measured and simulated RBS spectra demonstrating the coatings of Zn-doped CuO nanoparticles on artificial teeth, and further indicating with an arrow the presence of Cu, as being the only metal element on the coated teeth.
- Figures 11C shows measured and simulated RBS spectra demonstrating the coatings of CuO nanoparticles on teeth, and further indicating with an arrow the presence of Cu as being the only metal element on the coated teeth.
- Figures 12A-B present RBS spectra showing compositional penetration depths of the tooth surfaces coated with Zn-doped CuO ( Figure 12A) and CuO nanoparticles ( Figure 12B) indicating: (i) the formation of coating layers formed by Zn-doped CuO nanoparticles and CuO nanoparticles, with variations in the NP coating thickness; (ii) a deeper penetration of Zn-doped CuO nanoparticles coating (over 1500 x 10 15 atoms/cm 2 ) compared to coating with CuO nanoparticles (about 500 x 10 15 atoms/cm 2 ) ; (iii) higher amount of the Cu in the Zn-doped CuO coating compared to the CuO nanoparticle coatings; (iv) absence of Zn 2+ ions on both coating.
- Figure 13A presents a FIB-SEM image of uncoated tooth, for reference.
- Figures 13B presents a FIB-SEM image showing the layers of the Zn-doped CuO nanoparticles covering the tooth surface.
- the image shows a continuous coating of the Zn- doped CuO nanoparticles, with a 53.9 nm layer thick along the grooves on the tooth surfaces.
- Figures 13C presents a FIB-SEM image showing the layers of the CuO nanoparticles covering the tooth surface.
- the image shows a continuous coating of the CuO nanoparticles, with a 44.6 nm layer thick along the grooves on the tooth surfaces.
- ROS production of aqueous suspensions of ZnO, CuO, and Zn-doped CuO nanoparticles obtained from the med-3: l Cu:Zn precursors mixture described herein were detected using the electron spin resonance (ESR) spin trapping technique coupled with the spin traps: 5,5-dimethyl-l-pyrroline-N-oxide (DMPO) (0.02 M;
- ESR electron spin resonance
- the DMPO reacts with hydroxyl radicals and superoxide anion radicals, to produce DMPO-OH, a relative stable and paramagnetic species, detectable in the ESR technique by producing a typical signal of 1 :2:2: 1 quartet (Makino, K. et al. Int. J. Rad. Appl. Instrum
- aqueous suspensions of nanoparticles were added to the spin trap (e.g., DMPO) and drawn by a syringe into a gas permeable Teflon capillary (Zeus Industries, Raritan, NJ) and then inserted into a narrow quartz tube that is kept open at both ends. The tube was then placed in the ESR cavity and the spectra were recorded on a Bruker ESR lOOd X-band spectrometer.
- spin trap e.g., DMPO
- Teflon capillary Zeus Industries, Raritan, NJ
- the ESR measurement conditions were as follows: frequency, 9.74 GHz; microwave power, 20 mW; scan width, 65 Gauss; resolution, 1024; receiver gain, 2 x 10 5 ; conversion time, 82 millisecond; time constant, 655 millisecond; sweep time, 84 seconds; scans, 2; modulation frequency, 100 kHz.
- the spectrum is processed using Bruker WIN-ESR software version 2.1 1 for baseline correction.
- the peak intensity was calculated by double integration of the peak signals, and the intensity is expressed in arbitrary units.
- DMSO Dimethyl sulfoxide
- TEMP reacts with singlet oxygen leading to the formation of the stable species 2,2,6,6-tetramethyl-4-piperidone-N-oxyl (TEMPO), with a characteristic ESR spectrum comprised of equally intensity triplet. Since the hydroxyl radicals and superoxide anions react with the nitroxyl groups of TEMPO, thereby reversing it to TEMP, further addition of DMPO to the suspensions was needed, so as to remove hydroxyl radicals and superoxide anions from the suspensions. Heated NP samples at various temperatures in air or nitrogen, as indicated hereinabove for the DSC analysis, were further used for subsequent ESR analysis of ROS formation.
- TEMPO 2,2,6,6-tetramethyl-4-piperidone-N-oxyl
- the ESR technique revealed the ROS produced by the different nanoparticles.
- Figure 14A presents ESR spectra as detected following the addition of DMPO to the suspensions of ZnO, CuO and Zn-doped CuO nanoparticles, correlated to the signal of the DMPO-OH spin adducts originating from the same suspensions. It is shown that the signal of the DMPO-OH spin adducts originating from the suspension of Zn-doped CuO. is substantially higher than those of ZnO or CuO nanoparticles.
- Figure 14B further presents features (marked by arrows) corresponding to the DMPO-CH 3 adduct formed from by trapping the methyl radicals, being formed from the initiation of DMSO by the hydroxyl radical, by the DMPO.
- Figure 15 presents ESR signals as detected following the addition of TEMP and DMPO to the Zn-doped CuO nanoparticle suspensions.
- ROS production by the coated bandages was stable for at least 6 months after their preparation (data not shown).
- Figure 16A shows the ESR signal intensity as observed for the Zn-doped CuO nanoparticles for a reference.
- Figure 16C shows an ESR signal with reduced intensity for the suspension of the
- Figure 16D shows a complete diminishing of the ESR signal for the suspension of the Zn-doped CuO sample being formerly heated to 550 °C under nitrogen.
- Figure 16E shows the ESR signal of DMPO solution without the presence of the Zn-doped CuO nanoparticles, for a reference.
- the antibacterial activity of the metal oxide nanoparticles-coated substrates was tested against various bacterial stains.
- Cultures of a bacterial strain are grown overnight in a medium growth (e.g., NB, LB) at 37 °C with aeration and are next transferred into a fresh medium at an initial optical density (OD) at the suitable wavelength (e.g., 595 or 660 nm , Synergy 2, BioTek
- the tested agent (e.g., 1 mg/ml of: Zn +2 ions , Cu +2 ions ZnO nanoparticles, CuO nanoparticles, Zn-doped CuO nanoparticles, coated substrate sized e.g., 2 x 3 cm , with any one of the indicated nanoparticles) is next placed in a vial (e.g., with diameter of 2.5 cm) containing bacteria in saline (e.g., of 4 ml).
- a vial e.g., with diameter of 2.5 cm
- bacteria in saline e.g., of 4 ml
- the microbial suspensions are incubated for up to 3 hours at 37 °C with agitation (e.g., about 170 rpm), and an aliquot (e.g., 100 ⁇ ) is then taken at different time intervals (e.g., 0, 10 and 30 minutes; 1, 2, and 3 hours) and plated after serial 10-fold dilutions in saline on a solid medium-agar (e.g., MH-agar, NB-agar) poured in flat-bottomed petri plates. The plates are next incubated for up to 24 hours at 37 °C.
- agitation e.g., about 170 rpm
- an aliquot e.g., 100 ⁇
- time intervals e.g., 0, 10 and 30 minutes; 1, 2, and 3 hours
- a solid medium-agar e.g., MH-agar, NB-agar
- the viable microbial cell number at the specified times is recorded by counting and averaging the number of bacterial colonies grown on the plate, obtained from the triplicates of three independent experiments, multiplied by the dilution factor and expressed as colony forming units (CFU). Reduction in viability of the bacteria is determined by log(N 0 ), where No and N denote the number of CFUs at the initial (No) and following treatment (N). Non-coated substrate is used as control.
- the antimicrobial viable count tests were examined on the following bacterial strains: E. coli 1313, S. aureus 195, MDR E. coli, and MRSA, as indicated hereinabove.
- the antimicrobial viable count tests were examined for probing the antifungal activity against a clinical isolated Candida albicans
- the antibacterial agent was a substrate (e.g, cotton fabric, artificial tooth, pediatric silicon urinary catheter) coated with Zn-doped CuO nanoparticles thereon.
- a substrate e.g, cotton fabric, artificial tooth, pediatric silicon urinary catheter
- S. mutans 700610 was grown aerobically at 37 °C in BH overnight and were then diluted (1: 100) in fresh media, grown for 8 hours at 37 °C (with shaking (250 rpm).
- Zn- doped CuO or CuO nanoparticles (1 mg/ml) were added to sterile polypropylene tubes (Greiner Bio-One), to which the appropriate volume of the bacterial solution (aboutlO CFU/ml, OD of 0.01 at 595 nm) of S. mutans culture was added.
- an aliquant of 100 ⁇ of each tested cell suspension was added to a well in a 96-well plate that was incubated for 24 hours at 37 °C.
- the bacterial growth was determined spectrophotometrically by measuring the absorbance (OD 595 , Synergy 2, BioTek Instruments) at specified intervals during the incubation period.
- samples of S. mutans 700610 cultures were centrifuged and washed immediately after a treatment without (control) and with either CuO or Zn-doped CuO nanoparticles (0.1 mg/ml).
- the samples were then fixed in 25 % glutaraldehyde/paraformaldehyde (Sigma-Aldrich)] in a cacodilate buffer (Sigma-Aldrich) at room temperature (about 25 °C) for 1 hour.
- the samples were then washed with a cacodilate buffer and fixed in 1 % osmium tetraoxide(Sigma-Aldrich).
- Sample embedding was carried out using a standard protocol as previously described by S. Croft [Methods Molec. Biol. Elec. Microsc. Methods Prot. 1999, 117]. 60 nm thick slices were cut with a diamond knife (LBR ultratome III). The slices were deposited on bare 200 mesh grids, and stained with 2 wt % uranyl acetate (Sigma-Aldrich) for 5 minutes. Finally, the grids were dried in a desiccator and next examined using a JEOL 1200Ex TEM.
- nanoparticles into the bacterial cells e.g., S. mutans
- the bacterial cells e.g., S. mutans 700610
- the bacterial cells were pre-incubated with 10 ⁇ of the dye 5-(and 6-)chloromethyl-2,7- dichlorodihydrofluorescein diacetate, acetyl ester (CM-DCFH-DA; Invitrogen, Molecular Probes) in PBS for 30 minutes thereby allowing the dye to enter the cells.
- CM-DCFH-DA acetyl ester
- DCFH-DA can cross the cell membrane into the cell and is hydrolyzed by intracellular esterases to nonfluorescent DCFH.
- DCFH In the presence of ROS, DCFH is oxidized to highly fluorescent dichlorofluorescein (DCF). Therefore, the ROS concentration in the cell is directly proportional to the fluorescent intensity of DCF.
- DCF dichlorofluorescein
- Lipid peroxidation is a signature of ROS damage, which often occurs in response to oxidative stress and leads to lipid hydroperoxide formation and can be detected by assaying malondialdehyde-bis-(dimethylacetal)l,l,3,3-tetramethoxypropan (MDA), an oxidation product of polyunsaturated fatty acids and a metabolic marker for lipid peroxidation and metabolic cell damage.
- MDA malondialdehyde-bis-(dimethylacetal)l,l,3,3-tetramethoxypropan
- a homogenate was obtained by lysing 5.0 x 10 6 bacterial cells (e.g., S. mutans 700610) cultured overnight with or without 1 mg/ml of Zn-doped CuO or CuO nanoparticles with 10 % ice-cold TCA. Untreated samples of S. mutans and H 2 0 2 (1 mM) served as controls. The lysis mixture was centrifuged for 15 seconds at 14,000 rpm (centrifuge model 5418, Eppendorf). Aliquots (1 ml) of supernatant were added to 1 ml of 0.6 % 2-Thiobarbituric acid (TBA, Sigma- Aldrich) and heated in a boiling water bath for 10 minutes. The samples were cooled, and the chromogenic complex formed by TBA and MDA (Sigma-Aldrich) binding was determined by absorbance at 535 nm (Ultrospec 2100 pro, Amersham Biosciences). Results:
- Table 3 summarizes the antibacterial properties of cotton fabrics coated with ZnO, CuO, and the Zn-doped CuO nanoparticles tested against E. coli 1313, and S. aureus 195.
- Fabrics coated with pristine CuO or ZnO induced much weaker antibacterial effect with almost no antibacterial activity on the E. coli strains.
- the antibacterial activity of the fabric coated with Zn-doped CuO nanoparticles on the S. aureus was about 10,000 to 100,000 times higher than that of pristine ZnO or CuO nanoparticles coating.
- Table 4 summarizes the antimicrobial activity of cotton fabrics coated with Zn- doped CuO nanoparticles against Methicillin resistant S. aureus (MRSA) and multi-drug resistant (MDR) E. coli, selected for being highly resistant to many of the commercially available antibiotics and extremely difficult to eradicate.
- MRSA Methicillin resistant S. aureus
- MDR multi-drug resistant E. coli
- the Zn-doped CuO nanoparticles exhibited more pronounce antibacterial effect than that of the CuO and ZnO nanoparticles:
- complete killing was already evident in the Zn-doped CuO nanoparticles coating after 10 minutes, whereas the CuO nanoparticles coating exhibited only 3 logs of CFUs reduction, and the ZnO nanoparticles coating exhibited only one log reduction in CFUs after 10 minutes.
- Table 4 and the viability curves in Figure 17D for MDR E. coli further show that while a complete killing of MDR E. coli was achieved after 30 minutes by both Zn- doped CuO nanoparticles and CuO nanoparticles coatings, with the Zn-doped CuO nanoparticles coating the CFUs were reduced by 5 logs after a short treatment of 10 minutes, while the CuO nanoparticles coating exerted only a tiny antibacterial effect in this time duration.
- Table 5 shows antibacterial activity of fabrics coated with Zn-doped CuO nanoparticles as examined against the P. acne.
- P. acnes is another example of MDR bacteria, since 40 % of P. acnes that cause skin wounds are resistant to commonly used topical and oral administrated antibiotics. It is therefore clear that data presented herein, are of highest important introducing a new source for producing new principles, new techniques and new methods which can be utilized against multidrug resistant bacteria.
- Figure 18 shows a bar graph presenting antifungal killing rate upon treatment of fabric coated with Zn-doped CuO nanoparticles, showing about 50 % reduction in Candida albicans cells after 60 minutes and almost 100 % reduction after 180 minutes of treatment.
- Figure 19A present growth curves showing that free CuO nanoparticles did not affect the growth of S. mutans and further showing that Zn-doped CuO nanoparticles delayed the bacterial growth.
- Figure 20 presents the growth curves of S. mutans in media inoculated with either Cu 2+ or Zn 2+ ions at their corresponding concentrations as presented in Table 2 hereinabove over a period of 24 hours, showing no antibacterial effect.
- Figure 22 presents TEM images exhibiting the morphological changes to S. mutans cells, following treatment with CuO nanoparticles or Zn-doped CuO nanoparticles, and further exhibiting the presence of the Zn-doped CuO nanoparticles localized either on the cell surface or within the cell membrane.
- the cell membrane upon treatment with Zn-doped CuO nanoparticles, appeared to be damaged and disorganized, whereas in the case of treatment with the CuO nanoparticles, the cell membrane remained intact, without visible injury.
- Table 6 below presents ICP data of the intracellular level of Cu and Zn following the exposure of the S. mutans cells to Zn-doped CuO nanoparticles.
- Figure 23 presents bars demonstrating the fluorescence intensity in the treated S. mutans cell samples compared to untreated samples (control).
- the addition of Zn-doped CuO nanoparticles increased the MDA concentration in the cells to a level that was higher than the amount produced by the same concentration of CuO.
- the flow cell system was established.
- the system consists of several parts: (1) 2 L media bottle containing 1 % of Muller-Hinton (MH) II Broth Cation-Adjusted, (2) peristaltic pump that supplies the fresh media from the bottle at a defined rate, (3) bubble trap, (4) flow chamber or any other interface in which the bacteria can form biofilm (5) waste bucket, to which the media and bacterial waste is excluded.
- the system is connected by silicone tubing. 4 cm length fragments of the coated catheters where connected through the silicone tubing.
- Bacteria were grown overnight in Muller-Hinton, Bacterial growth was quantified by ODof 595 nm measurement and then diluted to fresh bacterial culture with 3x10 bacteria. This culture was injected into the catheter using a sterile syringe and incubated for 2.5 hours at 37°C. Afterwards, the catheter was connected to the flow cell system. The pump was set to 2 rpm and the fluid flow in the system was accordingly. The experiment was done at 37 °C, for 24 hours. The bacteria where removed from the catheter by mechanical scraping into 1 ml of sterile saline. The viable bacteria were estimate by counting the number of colony-forming units (CFU) on Luria Broth (LB) agar plates.
- CFU colony-forming units
- Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 29213 and Proteus mirabilis were grown in Mueller Hinton (MH) II Broth Cation- Adjusted (BD) media at 37 °C for 15-17 hours. Bacterial growth was quantified by OD of 595 nm measurement and then diluted to the appropriated density. 1 ml of MH with 99 ml of ddH 2 0 used as the operational solution for the catheters experiments. Catheters (Degania Silicone Ltd) are 100% Silicone and in scale of 8 French and were cut into 4 cm length fragments for flow cell experiments.
- Biofilm formation on a substrate e.g, glass slide,
- a substrate e.g, glass slide
- the biofilm system was composed of a polycarbonate chamber into which the tested glass slides (coated and uncoated) were inserted.
- the growth medium was pumped at a constant rate (10 ml/hour) through the chamber.
- the flow cell was initially inoculated with a 0.3 OD595 cell culture of the bacteria (e.g., E. coli 1313 and S. aureus 195 ). The flow was initiated after 1 hour of incubation at room temperature (flow rate of 10 ml/hour), and 1% TSB or 1% TSB-Glu (BD Biosciences) (diluted in ddH 2 0) was used as a growth medium for each bacterial strain, After several days (i.e., 7, 15) the coated substrates were removed from the experimental flow cell and washed with DDW to remove nonattached cells. For imaging, slides were stained using the Live/Dead BacLight kit (Molecular Probes, Invitrogen, manufacturer protocol).
- a OD595 cell culture of the bacteria e.g., E. coli 1313 and S. aureus 195 .
- the flow was initiated after 1 hour of incubation at room temperature (flow rate of 10 ml/hour), and 1% TSB or 1%
- a SYT09/propidium iodide (Molecular Probes, Invitrogen, manufacturer protocol) mixture stain was dissolved in a mixture of 3% DMSO and ddH 2 0 (15 minutes incubation). Viable bacteria with intact cell membranes are stained in green, whereas dead bacteria with damaged membranes are stained in red. Both excitation/emission maxima for these two dyes are 480/500 nm for the SYT09 stain, and 490/635 nm for the propidium iodide. Biofilm formation was monitored using a confocal scanning laser microscope (Leica SPE, San Diego, California, United States).
- a coated substrate e.g., artificial tooth
- a 24-well plate Gibreiner Bio- One
- the teeth were washed twice with ddH 2 0 to remove the non- attached cells, and the biofilm biomass was stained with 1 % crystal violet (CV, Sigma- Aldrich) for 15 minutes at room temperature (i.e. about 25 °C).
- the stained biofilm that formed on the tooth was washed five times with ddH 2 0, and the remaining CV was eluted with absolute ethanol for 15 minutes.
- the bioflm biomass was then determined by measuring the absorbance at OD595.
- the coated substrate was exposed after incubation to Karnovsky's fixative (glutaraldehyde + paraformaldehyde (Sigma-Aldrich) for 1 hour.
- the sample was washed three times with phosphate -buffered saline (PBS) which does not contain Ca 2+ and Mg 2+ ions.
- PBS phosphate -buffered saline
- the samples were immersed for 1 hour in a mixture of titanic acid and a glutamate solution in a 4:5 concentration ratio (Sigma-Aldrich). After three cycles of washing with the PBS, the sample was exposed to an osmium tetraoxide solution (Sigma-Aldrich) for 1 hour.
- Figures 25A-C present diagrams showing the enhanced antifouling activity of Zn- doped CuO nanoparticle coated catheter against the urinary tract pathogens: E. coli ( Figure 25A) S. aureus ( Figure 25B) and P. mirabilis ( Figure 25C).
- Figure 27 shows the antibiofim activity of on artificial teeth coated with either Zn- doped CuO nanoparticles or CuO nanoparticles with the reduction of the biofilm formation by 88 % and 70 %, respectively, compared to a massive biofilm on the uncoated tooth (control).
- Figure 28 presents HRSEM images, demonstrating that no S. mutans biofilm formation was observed on the artificial teeth coated with Zn-doped CuO nanoparticles and CuO nanoparticles.
- HET-CAM In vitro eye irritation hen's egg test chorioalantoic membrane
- test devices Zn-doped CuO nanoparticles coated catheter, positive controls (sodium hydroxide (NaOH 0.1M) and extracted vehicle control and negative control (0.9 % sodium chloride (Saline) for intravenous injection) was applied on the membrane and left in contact for 5 minutes.
- the membrane was examined for vascular potential damage (Hemorrhage, Vascular Lysis & Coagulation). The time taken for injury to occur was recorded during the 5 minutes of observation. Irritancy was scored according to the duration at which damage occurs.
- the objective of this study is to assess the potential of leachable substances in extracts of test devices.
- the test was applied on uncoated catheter and Zn-doped CuO nanoparticles coated catheter to induce cytokine secretion in mouse splenocytes. Cytokine levels were analyzed using Quansys Q-Plex Array Chemiluminescent kit. Each Test Device extract was further diluted with growth medium to dilutions designated as: 100 %, 85 %, 75 %, 50 %, 25 % and 12.5 %. Vehicle control's extract was applied non-diluted (100%). The positive control, Lipopolysaccharides (LPS) which is known as proliferative agent was dissolved with water, cell culture grade, to achieve a stock solution of 2000 ⁇ g/ml.
- LPS Lipopolysaccharides
- PBMCs RPMI Medium supplemented with 10% Heat Inactivated FBS (Fetal Bovine Serum), 2 mM L-Glutamine, 1% non-essential amino acids, 100 U/ml Penicillin and 100 ⁇ g/ml Streptomycin growth medium to achieve final concentration of 2 ⁇ g/ml.
- the IL-12p70, IL-6, IL-1- ⁇ , MIP-1- a, TNF-a and IL-10 cytokines levels were determined following 22 hours of incubation using Quansys Q-PlexTM Array Chemiluminescent kit, according to the manufacture's instruction. The samples were tested as undiluted.
- each Test Device-treated group was subjected to urethral catheterization with the respective coated indwelling urinary catheter and an additional equally sized group, subjected to urethral catheterization with the uncoated indwelling urinary catheter under identical experimental conditions, served as the control device group.
- Figures 29 show representative images of the CAM blood vessels following the irritation treatments.
- Figure 29A presents an image of the CAM blood vessels following the treatment with intravenous injection of 0.9% (Saline), showing no irritating effect on the blood vessels under the CAM with calculated mean irritancy score of 0.
- Figure 29B presents an image of the CAM blood vessels following the treatment with positive control (0.1 M NaOH), showing irritation effect on the blood vessel under the CAM with calculated mean irritancy score of 19.2.
- Figure 29C shows image of the CAM blood vessels following treatment with uncoated catheter extracts showing non-irritant effect.
- Figure 29D shows an image of the CAM blood vessels following treatment with Zn-doped CuO coated catheter extracts showing non-irritant effect.
- Figures 30A-F show that the Zn-doped CuO coated catheter extraction did not induce any cytokines compared to the uncoated catheter.
- Table 7 shows mean group hematology values, determined in NZW rabbits following urethral catheterization with catheter, Zn-CuO-coated catheter or uncoated catheter at the end of a 7-Day exposure period to the indwelling urinary catheters. The tests presented therein demonstrate no in vivo cytotoxicity in the tested values following catheterization with either uncoated or Zn-CuO-coated catheter.
- Lymphocytes (%) 40 3.3 47 7.1
- Table 8 presents mean group biochemistry values, determined in NZW Rabbits following urethral catheterization with catheter Zn-CuO-coated catheter or uncoated catheter at the end of a 7-day exposure period to the indwelling urinary catheters.
- the tests presented therein demonstrate no in vivo cytotoxicity in the tested values following catheterization with either uncoated or Zn-CuO-coated catheter.
- Similar findings of no cytotoxicity were observed in macroscopic findings during urinary tract dissection in NZW Rabbits following urethral catheterization with Zn-CuO- coated catheter (Batch No. 07-13-Zn-CuO) and throughout an exposure period of 7 successive days to the indwelling urinary catheters (data not shown).
- Chloride CI (mEq/L) 5.40 0.138 100 1.8
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Cited By (11)
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US9247734B2 (en) | 2014-05-23 | 2016-02-02 | Robert Sabin | Potentiation of fixed coppers and other pesticides containing copper and supplementing plant nutrition |
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Also Published As
Publication number | Publication date |
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EP2994413A4 (en) | 2017-05-03 |
US20160120184A1 (en) | 2016-05-05 |
CN105377749A (en) | 2016-03-02 |
AU2014264224B2 (en) | 2018-07-05 |
US10172361B2 (en) | 2019-01-08 |
CN105377749B (en) | 2019-05-31 |
ZA201508189B (en) | 2016-12-21 |
AU2014264224A1 (en) | 2015-12-24 |
JP2016525998A (en) | 2016-09-01 |
EP2994413A1 (en) | 2016-03-16 |
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