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Table 5 Overview of the commonly employed methods used to qualitatively and quantitatively assess maternal-fetal particle transfer

From: Translocation of (ultra)fine particles and nanoparticles across the placenta; a systematic review on the evidence of in vitro, ex vivo, and in vivo studies

Ref Method (Semi-) Quantitative and/or qualitative assessment Strengths Limitations NPs studied
Imaging techniques
 [23, 24, 33, 37, 63, 69, 95] Bright-field light microscopy [96,97,98,99] NP visualization Easy, rapid, low cost, non-destructive Low contrast, staining artifact, no NP sizing Ag, Au, Fe2O3, Fe3O4, SPIONs, and magnetic NPs
 [24,25,26,27, 32, 33, 89, 90] Confocal microscopy [96, 97, 100] NP visualization High sensitivity, 3D reconstruction (optical sectioning), increased optical resolution (no out-of-focus signals), multiplexing capabilities, non-destructive Photobleaching, uncoupling or leakage of fluorophores, no NP sizing PS, PGMA, SPIONs, and SiO2 NPs
 [61, 62, 73, 89] Ex vivo/in vivo fluorescence imaging [101] NP visualization Easy, low cost, non-invasive, multiplexing capabilities, whole-body imaging possible, not sample destructive, real-time Limited imaging depth (tissue penetration < 1 cm, autofluorescence), photobleaching, uncoupling or leakage of fluorophores, no NP sizing QDs, Au, PS, SiO2, and TiO2 NPs
 [24,25,26,27,28, 35, 40,41,42, 61,62,63, 73, 89] Fluorescence microscopy [96,97,98,99] NP visualization Easy, low cost, multiplexing capabilities, non-destructive Limited (axial) resolution and imaging depth (autofluorescence), photobleaching, uncoupling or leakage of fluorophores, no NP sizing Au, PGMA, PS, SiO2, and TiO2 NPs
 [38, 46] Hyperspectral imaging [102, 103] NP visualization Easy, multiplexing capabilities, improved SNR (differentiation of NP signal from autofluorescence), high specificity, non-destructive No NP sizing Ag and Au NPs
 [71, 89] MRI [96] NP visualization High resolution, non-invasive, non-destructive, whole-body imaging, real-time, not limited by tissue depth Restricted to magnetic NPs, slow image acquisition and long post-processing times, uncoupling of contrast agents, no NP sizing SiO2 and PGMA NPs
 [75, 80, 93] SEM [96, 99] NP-cell interaction and visualization High resolution, combination with EDX for elemental analysis, no quenching/bleaching/uncoupling effects Time-consuming, expensive, destructive, staining and shrinking artifacts, only applicable for electron-dense NPs, no NP sizing, not suitable for living material TiO2 NPs
 [1, 23, 24, 27, 29,30,31,32, 41, 43, 45, 47, 49, 52, 54, 58, 60, 61, 73, 75, 91, 92] TEM [96, 104] Ultrastructural analysis and (subcellular) NP visualization High resolution, combination with EDX for elemental analysis, no quenching/bleaching/uncoupling effects Time-consuming, expensive, destructive, staining and shrinking artifacts, only applicable for electron-dense NPs, no NP sizing, not suitable for living material Ag, Au, BC, DEP, Fe3O4, SiO2, TiO2, and PS NPs
 [1] Two-photon fs pulsed laser microscopy [105] NP visualization High sensitivity and specificity, label-free, non-destructive No NP sizing BC particles
 [71] Ultrasound imaging [106] NP visualization Low cost, real-time, non-destructive Sensitive to blood flow and tissue elasticity, uncoupling of contrast agents, no NP sizing SiO2 NPs
 [61] X-ray microscopy [107, 108] NP visualization High resolution, high specificity and sensitivity, large penetration depth Destructive, radiation damage, no NP sizing Au NPs
Spectroscopic techniques
 [33, 44, 48, 49, 59, 66] AAS [109] Elemental composition, NP quantification (LoD: high ppb range) Accurate, fast, easy, high sensitivity and specificity Time-consuming, expensive, no information on cellular NP localization SPIONs, Ag, Au, and CdO NPs
 [53, 57, 70, 87, 88] Gamma spectroscopy [96] Identification and quantification of radioisotope-labeled NPs High sensitivity and specificity, Expensive, radioactive labeling, radiation safety requirements, limited spatiotemporal resolution Fullerene, Ag, Au, and SiO2 NPs
 [22, 23, 31, 32, 38, 45,46,47, 50,51,52, 55, 58, 60, 61, 64,65,66,67,68, 72, 76,77,78, 81, 83,84,85,86] ICP-MS [110, 111] Elemental composition, NP quantification (LoD: ppt range) Rapid, high sensitivity and specificity, little sample preparation (no labeling needed), high sample throughput (all elements 2–6 min) Chemical interference (e.g., argon from plasma), dissolution of NP, quantification of non-metal-based NPs not possible, no information on cellular NP localization QDs, Ag, Au, CdO, CeO2, Cu, ZnO, and TiO2 NPs
 [54, 62, 74, 82, 93] ICP-OES [112, 113] Elemental composition, NP (cellular internalization) quantification (LoD: low ppb range) Reproducible, high sensitivity and specificity, no chemical interference, little sample preparation (no labeling needed), high sample throughput (5–30 elements/min) Spectral interference, dissolution of NP, quantification of non-metal-based NPs not possible, no information on cellular NP localization QDs, Ag, and SiO2 NPs
 [33] MPS [114] NP quantification High sensitivity, little sample preparation (no labeling nor purification needed) Time-consuming, expensive, quantification of non-magnetic NPs not possible SPIONs
 [69] UV-Vis spectroscopy [115, 116] NP quantification Easy, fast Low sensitivity, no information on cellular NP localization Fe2O3 NPs
Other techniques
 [36] AF4 (UV detection) [117, 118] NP quantification High resolution, highly reproducible, rapid, size separation possible Low sensitivity, no information on cellular NP localization PS NPs
 [27] Flow cytometry [97] NP (cellular uptake) quantification Easy, rapid, high sample throughput, multiplexing capabilities, not sample destructive No information on cellular NP localization, uncoupling or leakage of fluorophores PS NPs
 [27] HPLC (fluorescence detection) [118] NP quantification Rapid, size separation possible No information on cellular NP localization, uncoupling or leakage of fluorophores PS NPs
  1. Abbreviations - AAS atomic absorption spectrometry, Ag silver, Au gold, BC black carbon, CdO cadmium oxide, CeO2 cerium dioxide, Cu copper, DEP diesel exhaust particles, EDX energy-dispersive X-ray spectroscopy, Fe2O3 iron oxide, Fe3O4 iron oxide or magnetite, fs femtosecond, ICP-MS inductively coupled plasma-mass spectrometry, ICP-OES inductively coupled plasma-optical emission spectrometry, LoD limit of detection, MRI magnetic resonance imaging, NP nanoparticle, PGMA poly(glycidyl methacrylate), PS polystyrene, QD quantum dot, TEM transmission electron microscopy, TiO2: titanium dioxide, SEM scanning electron microscopy, SiO2 silicon dioxide or silica, SPIONs superparamagnetic iron oxide nanoparticles, TEM transmission electron microscopy, TiO2 titanium dioxide, UV ultraviolet, UV-Vis ultraviolet-visible, ZnOs zinc oxide