The Agency [Part 1-3] [APK]
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One health care software company, Epic Systems, has partnered with Apple and released versions of the Epic scheduling, billing, and clinical support app for the iPhone and iPad.4 PatientKeeper Mobile Clinical Results provides physicians with access to patient clinical data via either Apple or Android mobile devices.7 Teamviewer is a general-purpose record maintenance and access app that can be installed on mobile devices, allowing remote access to desktop PCs.5 In the absence of such apps, a virtual private network (VPN) log-in can often be obtained from the hospital to allow remote secure access into the in-house network through the Internet to view records for emergency consultations.5
XPS is the most popular surface analysis method and provides information about the chemical composition and the chemical nature of the compounds in the near surface region . Here, the sample is irradiated with X-rays, usually of an energy of 1253.6 (Mg Kα) or 1486.6 eV (Al Kα) and the ejected photo- and Auger electrons are analyzed in an energy spectrometer. The information depth of ca. 10 nm makes this method highly suitable for chemical analysis of nanoparticles.
According to the information on the JRC repository , both materials selected are rutile having a primary particle size of 21 nm (from XRD measurements) and an Al-coating; one material is hydrophobic (JRCNM62001a) and the other one (JRCNM62002a) hydrophilic. It remains to apply the surface analytical methods selected here and infer the characterization results.
Titanium dioxide nanoparticles imaged by SEM with a secondary electron InLens detector at 5 kV beam voltage: (a) JRCNM62001a and (b) JRCNM62002a. The samples have been prepared as dry powder on an aluminum sample holder.
In the vast majority of publications, the most relevant instrumental parameters applied for the measurement of an electron micrograph are specified. These are: beam acceleration voltage, pixel size and pixel number, area of the field-of-view, type of detector, working distance, type of cathode and model of microscope and the type of sample preparation. Other parameters like acquisition time or beam current, sometimes decisive for the accurate visualization of sensitive nanoobjects, are mostly not specified. Beam damage and contamination are often encountered issues at the analysis of nanoparticles. The set of full meta data for SEM micrographs as to be saved in a standardized unique format is in an advanced phase of development at ISO (ISO/FDIS 20171) . Of particular importance for metrological dimensional measurements of nanoparticles by electron microscopy, the traceable calibration of the pixel size should be a requirement in any laboratory. Usually, in accredited laboratories, the calibration state of the electron microscope at well-defined acquisition conditions, i.e., the so-called calibration of image magnification, is performed regularly according to the ISO standard ISO 16700:2016  based on a reference to certified reference materials. The evaluation of the resolution of an SEM is specified in ISO/TS 24597:2011 . Another standardization project addressing more criteria for a complete qualification of a SEM for quantitative measurements is in progress at ISO (ISO/PRF TS 21383) .
One of the most critical points in the accurate measurement of the nanoparticle sizes is the exact knowledge of the threshold for particle segmentation in SEM images. Various thresholding approaches such as Otsu, maximum entropy or IsoData can be applied, e.g., by easy selection from a pop-up menu in ImageJ. A comparative study is presented in . The challenging physical modeling of the electron signals in SEM and the use of reference nanoparticles with known size are key in the evaluation of realistic measurement uncertainties associated with the particle size distribution. In the case of STEM-in-SEM the modeling of the signals of transmitted electrons is more straightforward, see e.g., .
The state of the art in the standardized measurement of the nanoparticle size and shape distribution by TEM is given by the very recently published ISO 21363:2020 . Therein not only the exact measurement and analysis protocols (manually and automated) are described, but seven case studies are given in detail in the annexes: discrete spheroidal nanoparticles, size mixture, shape mixture, amorphous aggregates, nanocrystalline aggregates, low aspect ratio nanoparticles and nanoparticles with specific crystal habitats. A similar standard project is still in development as ISO/PRF 19749  for SEM measurement, and includes also representative case studies. An overview with all available ISO standards in use and in development for the measurement of the morphology and chemistry of nanoparticles can be found in .
The 10 kV EDS spectra of the titanium dioxide nanoparticles from Figure 3 taken from sample areas of 8 µm 8 µm: JRCNM62001a (blue) and JRCNM62002a (red). The samples were prepared as dry powder on a silicon wafer. The two spectra have been normalized to the intensity of the Ti Kα peak.
For such sensitive objects like nanoparticles, the preparation procedure for measurements on a substrate in vacuum is crucial for the interpretation of the measurements. Two methods are common for pristine nanoparticles. The first method consists of dispersing and dropping on a silicon wafer. The solvent is evaporated before introducing the sample into vacuum. The other usual method is to measure the pristine (dry) powder. This can be fixed on a double adhesive tape or in a dedicated sample holder with a cavity for the powder. A third method, pressing the powder into a pellet, becomes less popular in the last years, because the sample surface is very likely changed under the high pressure applied. Each method has advantages and disadvantages, which are described in detail elsewhere . In any case, each step of the sample preparation procedure must be specified appropriately. ISO 20579-4  describes the minimum information needed for reporting the handling, preparation and mounting of the samples.
The most difficult part of the data reduction in terms of reliability is the quantification of identified peaks into chemical composition. Usually, net peak areas are used, which are obtained after background subtraction. It can be decided if either the survey or the high-resolution spectra are used, but the results cannot be mixed. For the quantification, three approaches can be used: (i) experimentally determined relative sensitivity factors [67,68], (ii) theoretically derived sensitivity factors  and (iii) specific reference samples. Reference samples are often not available; thus, this latter approach is often not possible, therefore, the other two approaches are discussed further. Experimentally derived sensitivity factors are provided by some manufacturers for their instruments and can be easily used. In contrast, theoretically derived sensitivity factors are published, verified and can be transferred between different instruments and modes. In this approach, the peaks are normalized with the element-specific Scofield relative sensitivity factors, the mean free path length of the photoelectrons and the spectrometer-dependent transmission function . In Table 5, results obtained with the two different approaches are compared. For significant peaks, a relative uncertainty for a confidence interval of 95% below 15% was determined, for traces below 1 at% a quantification is not reliable. These are values that are discussed as uncertainties in the literature, thus, it can be concluded that both approaches led to similar results. Despite this finding, it is necessary to specify the method, which was used for the quantification.
For both particles, Al and Ti along with their oxides can be detected. The presence of Ti-containing ions suggests that either the covering AlOx layer was thinner than the SIMS information depth or the AlOx coating was not completely closed. Table 6 shows that there was no significant difference in the Ti+/Al+ ratio for the 2 particles, which is in accordance with the assumption of similar primary particles having a similar AlOx coating. Differences exist with respect to coverage with organic materials and further inorganic molecules.
Whereas for the particles JRCNM 62001a polysiloxanes, possibly as mixtures with silane-like material, can be detected, for the particles JRCNM 62002a no evidence for the presence of glycerol could be found. Not only are significant glycerol signals missing in the positive polarity, but also fatty acid residues can hardly be detected in the negative polarity. Nevertheless, O-containing hydrocarbons are found with higher intensities for JRCNM 62002a (Table 6). Instead of glycerol, sulfates and phthalic acid anhydride are detected with significant intensities (Table 6). Whether the phthalic acid compound is a contaminant (e.g., adsorption from ambient air) or deliberately administered to the surface needs to be discussed with the producer. The phthalic acid may also be the cause for the higher intensities of the O-containing hydrocarbons.
Differences also exist with respect to the hydrocarbon intensities. Whereas the intensities of aromatic hydrocarbons are higher for the particles JRCNM 62001a, the intensities of aliphatic hydrocarbons are higher for the particles JRCNM 62002a. Given the field-of-view of 325 325 µm2, the data represent an average over many particles. Data from three repetitive measurements showed no significant differences between the analysis positions.
Only with such a complementary experimental approach a comprehensive physico-chemical analysis of the nanoparticles becomes possible. For a reliable analysis the consideration of already available standards and guidelines reflecting the state-of-the-art and a detailed documentation of all steps in the analysis is required, so that based on a minimum of mandatory information the results of the analysis can be reproduced at any time in any laboratory. 59ce067264