Modern Bioimaging Techniques for Elemental Tissue Analysis: Key Parameters, Challenges and Medical Impact
Abstract
1. Introduction
2. Brief Characteristic of Bioimaging Techniques
- Heating of the sample surface by laser;
- Ablation of sample surface components;
- Laser-induced creation of microplasma;
- Dissociation (break down) of ablated materials into ions and atoms at excited state;
- Emission of electromagnetic radiation (in two steps: first, continuously; and second, radiation characteristic of the elements of the ablated sample).
3. Parameters Relevant to the Quality of Measurements
3.1. Selectivity of Measurements
3.2. Linearity and Accuracy
3.3. Limits of Detection and Quantification
3.4. Measurement Uncertainty
- Lack of or limited selectivity hinders the application of bioimaging techniques for diagnostic purposes;
- The lack of selectivity is related mainly to matrix effects;
- Complicated procedures for determining linearity can often lead to unreliable quantitative analysis results;
- Selectivity and the resulting accuracy can be assessed using appropriate reference materials (limited availability) or using enriched samples;
- The quantitative bioimaging will be more challenging as the amount of analyte decreases and the matrix becomes more complex;
- Both bias and random error are main components of measurement uncertainty.
4. Application of Bioimaging Techniques in Analysis of Human Tissues
4.1. Laser-Based Technique
4.2. X-Ray-Based Techniques
Sample | Implant/ Group of Patients | Number of Patients/Samples (Without Control) | Element | Technique | Remark | Reference |
---|---|---|---|---|---|---|
lung tissue | healthy and idiopathic pulmonary fibrosis | 2 | Ca, Zn, S, Fe, Al, Cr, Cu, Ti, Mn, P | XRF nano-XRF (100 nm) | mapping | [54] |
tooth | no determinant | 3 + additional samples (stored for more than a decade) | Ca, P, Ba, Zn, W, Zr, Sr, Fe | μXRF | elemental maps | [5] |
P, Ca, Ba, Zn, W, Zr | SEM-EDS | |||||
P, Ca, Ba, Zn, W, Zr | CμXRF | |||||
synovial sheath tissues | hip | 2 | Co, Cr, Mo | μXRF and μXAFS (3 μm resolution) | mapping | [6] |
Co, Cr (speciation) | sub-μXRF and sub-μXANES (600 nm resolution) | mapping | ||||
Co, Cr | nano-XRF and nano-XANES (250 nm resolution) | mass fraction | ||||
peri-implant cancellous bone | hip, knee | 14 | Co, Cr, Ti (main analytes) Fe, S, P, Ca (matrix structures) | μXRF (10, 3 and 2 µm) | mapping/ mass fraction | [18] |
Ti (speciation) | μXANES | |||||
Ti, Zr, Ta | nano-XRF (60 and 30 nm) | mapping | ||||
tissues | dental | 13 | Ti, Zr (main analytes) P, S (matrix structures) | μXRF (resolution from 1 to 20 μm) | particle density (mass fractions) | [7] |
Zr, Zn, Fe, Hf, Y, Sr, Cr, Ni, Nb | nano-XRF (60 nm resolution) | particle density (mass fractions) | ||||
Ti (speciation) | μXANES (between 1 and 10 μm) | |||||
periprosthetic tissue | hip | 7 | Co, Cr, Ti | μXRF | mapping | [19] |
Co, Cr, Ti (speciation) | µXANES | |||||
hair | no determinant | 4 | Hg | nXRF (50 nm) | distribution of mercury | [44] |
Hg | XANES (high resolution) | speciation | ||||
liver | hip | 1 | Co, Cr, Ca | μXRF μXAS | mapping | [20] |
blood | Co, Cr | - | quantitatively | |||
bone and mucosal tissues | dental | 12 | Ca, Ti, Fe, P | XRF | - | [45] |
soft tissue, bone marrow, mineralized bone tissue | hip | 13 | Co, Cr | μXRF (80 µm resolution) | mapping and mass fraction | [21] |
periprosthetic bone marrow | hip, knee | 8 | Co, Cr and Mo | nano-XRF (60 nm resolution) | bioimaging | [43] |
breast, ovarian tissue | various cancers | 60 (samples) | Zn, Fe, Cu, Ca | μXRF | mapping particle density | [8] |
soft tissues | dental | 31/36 | C, N, Na, K, O (controls) Ca, P, Ti, Zr, Al, Si, F, Cl, Fe, Zn, Pt, S, Mg, Br, Pb, Ni, Ba, Bi, La | SEM-EDS | mean percentages represent the composition of the elements | [55] |
periprosthetic tissue | hip | 53 | Cr, Co, Mo, Ti, V, Fe, P, O | SEM-EDS TEM-EDS | mapping | |
Cr | XRD | crystalline structures | [22] | |||
blood | Co, Cr | - | quantitatively | |||
tissue | patients who had tongue and/or lip piercings | 16 | C, K, Ca, O, Na, Mg, Al, Cr, Mn, Fe, Co, Si, S | SEM-EDS | semi-quantitatively | [56] |
smears of mucosa | Ca, C, O, Na, Mg, Al., Mo, Si | |||||
capsular tissue, deep hip tissue granuloma tissue | hip | 26 | Ti, Cr, Co, Fe, Ca, Mo, C, Cl, Si, P | SEM-EDS | qualitatively | [39] |
blood serum | Co, Cr, Ti | - | - | |||
tissues | Cr, Al | XRD | crystalline structures | |||
fallopian tube or uterine horn tissue | intrauterine device | 10 | endogenous particles contain Na, P, S, Ca, Cl, K, Fe, Sn, Si, Al, Ca, Fe, Ti, Sb -based Au, Al, Pt | SEM-EDS | qualitatively | [9,57] |
red bone marrow (postmortem) | hip, knee | 6 | particles of combined Co, Cr, Mo, Fe, Ni, Ti, Al, V | SEM-EDS (resolution from 50 nm to 6 μm) | qualitatively | [58] |
skin and lymphatic tissues tattooed skin | tattooed skin (postmortem) | 20 (skin) 25 (lymph node) | Br, T, P, Cl, P, S, K, Ca | μXRF (from 0.5 µm to 5 µm) | mapping | [23] |
Ti | μXANES (from 1 µm to 10 µm) | speciation | ||||
skin and lymph node tissues | tattooed skin (postmortem) | 5 | Fe, Cr, Ni, Ti, Cu | nano-XRF (50 nm) | elemental maps | [10] |
Cr, Ni | XANES | speciation | ||||
periprosthetic tissues | hip | 18 | Cr, Co, Mo, Si, Ca, P, Na | SEM-EDS | elemental composition | [37] |
synovial fluid | hip | 40 | Co, Cr particles | SEM-EDS | semi quantitatively | [33] |
periprosthetic tissue | hip | 1 | Cr, Co, Ta, C, O, S, Ti, N, Na | SEM-EDS | area fractions | [51] |
postmortem neuronal tissues | gadolinium-based contrast agents brain magnetic resonance examinations | 13 | C, Cs, Cu, Gd, O, Os, Pb, Ti, V | TEM-EDS | distribution | [52] |
cardiac, hepatic splenic postmortem tissues | hip, knee | 5/13 | Co, Cr | LA-ICP-MS | distribution | [24] |
Co, Cr, Ti | μXRF (5, 3 μm) | mapping | ||||
μXANES (3 μm) | speciation |
4.3. Alternative Techniques Potentially Applicable to Bioimaging
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Feature | LA-ICP-MS | LIBS | XRF | SEM-EDS | TEM-EDS |
---|---|---|---|---|---|
Full Name | Laser Ablation Inductively Coupled Plasma Mass Spectrometry | Laser-Induced Breakdown Spectroscopy | X-ray Fluorescence | Scanning Electron Microscopy with Energy-Dispersive X-ray | Transmission Electron Microscopy with Energy-Dispersive X-ray |
Spatial Resolution | 5–100 µm | ~10–100 µm | ~0.05–100 µm | ~1 µm | <20 nm |
Detection Limit (LOD) | µg/kg | mg/kg | mg/kg | Tenths of weight % | Tenths of weight % |
Quantification | Yes | Yes | Yes | Semi-quantitative | Semi-quantitative |
Sample Destruction * | Semi-non-destructive | Non-/minimally destructive | No | No | No |
Suitable Sample State | Solid (flat and polished) | Solid (minimal preparation) | Solid (minimal preparation) | Solid (degreased and dried) | Ultrathin slices (~100–150 nm) |
Light Element Detection | Limited | Yes (H, C, N detectable) | Limited | Limited | Limited |
Sample Preparation Complexity | Medium (polishing, standards) | Low (clean surface) | Low (minimal preparation) | Medium (mounting, coating with Au/C) | High (FIB, ultramicrotomy, thinning to electron transparency) |
Analysis Time | Minutes to hours (mapping) | Seconds to minutes | Seconds to minutes | Minutes per point or map | Long (due to preparation and imaging) |
LA-ICP-MS | LIBS | XRF | SEM-EDS |
---|---|---|---|
laser energy ablation area isobaric interferences polyatomic interferences doubly charged ions plasma robustness dwell time instrumental drift gas flows | laser energy ablation area readout time delay surface roughness gate width measurement atmosphere repetition rate | absorption effects power of the excitation source type of radiation source signal intensity for speciation topography of the layer measurement atmosphere | power of the excitation source measurement atmosphere surface topography sample conductivity |
Analyte | Internal Standard | Reference |
---|---|---|
157Gd, 158Gd, 160Gd, 31P, 44Ca | 103Rh, 115In | [11] |
54Fe, 56Fe, 63Cu, 65Cu, 64Zn, 68Zn | 197Au (pseudo-internal standard) | [40] |
194Pt,195Pt,196Pt, 13C, 31P, 34S | 97Au (pseudo-internal standard) | [36] |
23Na, 24Mg, 25Mg, 39K, 42Ca, 44Ca, 55Mn, 56Fe, 57Fe, 58Ni, 60Ni, 63Cu, 64Zn, 65Cu, 66Zn | 115In, 197Au (pseudo-internal standard) | [17] |
27Al, 49Ti, 51V | 34S | [13] |
54Fe, 56Fe, 63Cu, 65Cu | 69Ga, Rh | [16] |
Na, Mg, P, K, Ca, Ti, Cr, Ni, Cu, Zn, Pb | C, S | [26] |
Isotope | IDL [µg/g] | IQL [µg/g] | MDL [µg/g] | MQL [µg/g] |
---|---|---|---|---|
23Na | 5.7 [17] | |||
26Mg | 14 [32] | 10.6 [17] 419 [32] | ||
24Mg | 2.3 [17] | |||
27Al | 0.83/0.24 1 [34] | 2.5/0.72 1 [34] | 4.8/1.8 1 [34] | 14/5.3 1 [34] |
2.2 [13] | 6.9 [13] | |||
4.1 [32] | 14 [32] | |||
39K | 13.2 [17] | |||
43Ca | 450 [32] | 1174 [32] | ||
49Ti | 0.78/0.55 1 [34] | 2.4/1.7 1 [34] | 0.84/1.5 1 [34] | 2.5/4.4 1 [34] |
1.1 [13] | 8.1 [13] | |||
14 [32] | 21 [32] | |||
51V | 0.24/0.1 1 [34] | 0.73/0.30 1 [34] | 0.58/0.82 1 [34] | 1.8/2.5 1 [34] |
0.80 [13] | 4.6 [13] | |||
55Mn | 1.8 [32] | 0.1 [17] 4.7 [32] | ||
56Fe | 5 2 [16] | 18 2 [16] | 0.8 [17] | |
57Fe | 43 [32] | 3.4 [17] 98 [32] | ||
58Ni | 0.1 [17] | |||
60Ni | 0.4 [17] | |||
63Cu | 1 2 [16] | 4 2 [16] | 0.1 [17] 6.5 [32] | |
65Cu | 0.2 [17] | |||
64Zn | 0.1 [17] | |||
66Zn | 18 [32] | 0.2 [17] 61 [32] | ||
157Gd,158Gd,160Gd | 3.0 [11] | 9.0 [11] | ||
195Pt | 1.6 [36] |
Sample | Implant/ Group of Patients | Number of Patients/Samples (Without Control) | Element | Technique | Remark | Reference |
---|---|---|---|---|---|---|
gastric cancer cells | human cell line | - | Zn | LA-ICP-MS | 35 μm spot size | [49] |
skin biopsy samples | nephrogenic systemic fibrosis | 1 | Gd, Ca, P | LA-ICP-MS | KED 1 50 μm spot size | [11] |
oral mucosa tissues | dental | 30 | Ti, Al, V, S | LA-ICP-MS (quantitatively) | 50 μm spot size | [13] |
oral mucosa tissues | dental | no information | Ti, Al, Ca, Mg, Zn, Cu, Fe, Mn, S, C | LA-ICP-MS (quantitatively) | 25 μm spot size | [32] |
oral mucosa tissues | dental | 12 | Ti, Al, V S, C, Mg, Ca | LA-ICP-MS (quantitatively) | 100 μm spot size | [34] |
white and grey matter and frontal cortex tissues (postmortem) | Alzheimer’s disease | 4 | P, Fe, C | LA-ICP-MS (quantitative imaging) | CRC 2 80 × 80 μm laser beam | [12] |
liver | Wilson’s disease | 3 | Fe, Cu, Ga | LA–ICP–MS (elemental bioimaging) | KED 1 100 μm spot size | [16] |
tissue | human malignant mesothelioma | 1 | Na, Mg, K, Ca, Mn, Fe, Ni, Cu, Zn, In, Au | LA-ICP-MS (elemental bioimaging) | 40 μm laser diameter | [17] |
liver | Wilson’s disease | 6 | C, Na, Mg, P, S, K, Ca, Ti, Cr, Fe, Mn, Ni, Cu, Zn, Pb | LA-ICP-MS | - | [26] |
tissue | human malignant mesothelioma | 1 | Pt, C, P, S, Au | LA-ICP-MS | 50 μm laser diameter | [36] |
human lens | eye | 5 | Fe, Cu, Zn, Au | LA-ICP-MS (quantitative bioimaging) | 200 μm | [40] |
healthy teeth, deciduous teeth, teeth filled with amalgam and composite restorative materials | - | - | Ca, K, Mg, P, Na, Sr, Cu, Cr, Fe, Ba, Pb, Zn, Hg, Al | LIBS qualitative | - | [50] |
tissue | human tumour | 1 | P, Fe, Cu, Zn, Pt | LA-ICP-MS | mapping 40 μm per pixel | [14] |
C, H, O, Na, K, Ca, Mg | LIBS | - | ||||
skin tissues | various cancers | 3 | P, Al, Mg, Na, Zn, Si, Fe, Cu, Ca | LIBS (multi-elemental imaging) | - | [25] |
colon tissues | colon cancer | 15 | Pb, Cr, Ce, Hg | LIBS | - | [15] |
Feature | LA-ICP-MS | LIBS | XRF | SEM-EDS | TEM-EDS |
---|---|---|---|---|---|
Trace element detection | most suitable | suitable | suitable | limited | limited |
Macro-elements | limited | suitable | limited | limited | limited |
Sample re-analysis | limited | limited | possible | possible | possible |
Depth profile analysis | tens of micrometres | <500 μm | several tens of micrometres | few micrometres | limited by sample thickness |
Speciation | not possible | not possible | possible | not possible | not possible |
Throughput | moderate | high | high | slow | slow |
Operating costs/availability | expensive | moderate | moderate | expensive | very expensive |
Solid samples | suitable | suitable (solid surfaces) | tissue slices | excellent resolution | excellent resolution |
Liquid samples (blood, plasma) | requires dry blood spot or cryogenic ablation | requires drying | plasma, serum with or without dilution; blood need preparation step | difficult due to high vacuum environment | difficult due to high vacuum environment |
Relative sensitivity to matrix effects | high (due to fluctuations in composition, structure and moisture content) | very high (due to laser energy absorption, plasma formation) | moderate to high (due to varying density, thickness and water content) | low to moderate (depend on atomic number and competing absorption-fluorescence effects) | low (due to sample thickness) |
Linear range (in mg/kg) | ~0.01–10,000 | ~10–10,000 | ~1–100,000 | ~100–100,000 | ~100–50,000 |
Maximum mapping area | >cm2 | ~cm2–several cm2 | ~cm2–several cm2 | ~mm2 | <<mm2 |
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Sawicki, J.; Feldo, M.; Skalska-Kamińska, A.; Sowa, I. Modern Bioimaging Techniques for Elemental Tissue Analysis: Key Parameters, Challenges and Medical Impact. Molecules 2025, 30, 2864. https://doi.org/10.3390/molecules30132864
Sawicki J, Feldo M, Skalska-Kamińska A, Sowa I. Modern Bioimaging Techniques for Elemental Tissue Analysis: Key Parameters, Challenges and Medical Impact. Molecules. 2025; 30(13):2864. https://doi.org/10.3390/molecules30132864
Chicago/Turabian StyleSawicki, Jan, Marcin Feldo, Agnieszka Skalska-Kamińska, and Ireneusz Sowa. 2025. "Modern Bioimaging Techniques for Elemental Tissue Analysis: Key Parameters, Challenges and Medical Impact" Molecules 30, no. 13: 2864. https://doi.org/10.3390/molecules30132864
APA StyleSawicki, J., Feldo, M., Skalska-Kamińska, A., & Sowa, I. (2025). Modern Bioimaging Techniques for Elemental Tissue Analysis: Key Parameters, Challenges and Medical Impact. Molecules, 30(13), 2864. https://doi.org/10.3390/molecules30132864