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Arsana, K. G. .., Saladino, G., Brodin, B., Toprak, M. & Hertz, H. (2024). Laboratory Liquid-Jet X-ray Microscopy and X-ray Fluorescence Imaging for Biomedical Applications. International Journal of Molecular Sciences, 25(2), Article ID 920.
Open this publication in new window or tab >>Laboratory Liquid-Jet X-ray Microscopy and X-ray Fluorescence Imaging for Biomedical Applications
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2024 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 25, no 2, article id 920Article in journal (Refereed) Published
Abstract [en]

Diffraction-limited resolution and low penetration depth are fundamental constraints in optical microscopy and in vivo imaging. Recently, liquid-jet X-ray technology has enabled the generation of X-rays with high-power intensities in laboratory settings. By allowing the observation of cellular processes in their natural state, liquid-jet soft X-ray microscopy (SXM) can provide morphological information on living cells without staining. Furthermore, X-ray fluorescence imaging (XFI) permits the tracking of contrast agents in vivo with high elemental specificity, going beyond attenuation contrast. In this study, we established a methodology to investigate nanoparticle (NP) interactions in vitro and in vivo, solely based on X-ray imaging. We employed soft (0.5 keV) and hard (24 keV) X-rays for cellular studies and preclinical evaluations, respectively. Our results demonstrated the possibility of localizing NPs in the intracellular environment via SXM and evaluating their biodistribution with in vivo multiplexed XFI. We envisage that laboratory liquid-jet X-ray technology will significantly contribute to advancing our understanding of biological systems in the field of nanomedical research.

Place, publisher, year, edition, pages
MDPI AG, 2024
Keywords
bioimaging, cell imaging, liquid-jet X-ray source, multiplexed imaging, nanomedicine, stain-free imaging, X-ray fluorescence imaging, X-ray microscopy
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:kth:diva-343205 (URN)10.3390/ijms25020920 (DOI)001151313100001 ()38255992 (PubMedID)2-s2.0-85183335794 (Scopus ID)
Note

QC 20240209

Available from: 2024-02-08 Created: 2024-02-08 Last updated: 2024-02-22Bibliographically approved
Vogt, C., Saladino, G., Shaker, K., Arsenian-Henriksson, M., Hertz, H., Toprak, M. & Brodin, B. (2023). Organ uptake, toxicity and skin clearance of ruthenium contrast agents monitored in vivo by x-ray fluorescence. Nanomedicine, 18(18), 1161-1173
Open this publication in new window or tab >>Organ uptake, toxicity and skin clearance of ruthenium contrast agents monitored in vivo by x-ray fluorescence
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2023 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 18, no 18, p. 1161-1173Article in journal (Refereed) Published
Abstract [en]

Aims: To investigate the distribution and toxicity of ruthenium nanoparticles (Ru NPs) injected intravenously in mice.

Methods: We synthesized Ru NPs, followed their biodistribution by x-ray fluorescence (XRF) imaging and evaluated organ toxicity by histopathology and gene expression.

Results: Ru NPs accumulated, mainly in liver and spleen, where they were phagocyted by tissue macrophages, giving a transient inflammation and oxidative stress response that declined after 2 weeks. Ru NPs gradually accumulated in the skin, which was confirmed by microscopic examination of skin biopsies.

Conclusion: Ru NP toxicity in recipient organs is transient. Particles are at least partially excreted by the skin, supporting a role for the skin as a nanoparticle clearing organ.

Place, publisher, year, edition, pages
Future Medicine Ltd, 2023
Keywords
contrast agents, imaging nanoparticles, in vivo imaging, medical imaging, metal nanoparticles, nanoparticle clearance, nanotoxicity, x-ray fluorescence
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:kth:diva-338020 (URN)10.2217/nnm-2023-0061 (DOI)001061631900001 ()37665018 (PubMedID)2-s2.0-85172828110 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2016.0057
Note

QC 20231013

Available from: 2023-10-12 Created: 2023-10-12 Last updated: 2024-02-22Bibliographically approved
Häggmark, I., Shaker, K., Nyren, S., Al-Amiry, B., Abadi, E., Segars, W. P., . . . Hertz, H. (2023). Phase-contrast virtual chest radiography. Proceedings of the National Academy of Sciences of the United States of America, 120(1), Article ID e2210214120.
Open this publication in new window or tab >>Phase-contrast virtual chest radiography
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2023 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 1, article id e2210214120Article in journal (Refereed) Published
Abstract [en]

Respiratory X-ray imaging enhanced by phase contrast has shown improved airway visualization in animal models. Limitations in current X-ray technology have nevertheless hindered clinical translation, leaving the potential clinical impact an open question. Here, we explore phase-contrast chest radiography in a realistic in silico framework. Specifically, we use preprocessed virtual patients to generate in silico chest radiographs by Fresnel-diffraction simulations of X-ray wave propagation. Following a reader study conducted with clinical radiologists, we predict that phase-contrast edge enhancement will have a negligible impact on improving solitary pulmonary nodule detection (6 to 20 mm). However, edge enhancement of bronchial walls visualizes small airways (<2 mm), which are invisible in conventional radiography. Our results show that phase-contrast chest radiography could play a future role in observing small-airway obstruction (e.g., relevant for asthma or early-stage chronic obstructive pulmonary disease), which cannot be directly visualized using current clinical methods, thereby motivating the experimental development needed for clinical translation. Finally, we discuss quantitative requirements on distances and X-ray source/detector specifications for clinical implementation of phase-contrast chest radiography.

Place, publisher, year, edition, pages
Proceedings of the National Academy of Sciences, 2023
Keywords
X-ray imaging, phase contrast, chest radiography, virtual clinical trial
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:kth:diva-329855 (URN)10.1073/pnas.2210214120 (DOI)000998800300001 ()36580596 (PubMedID)2-s2.0-85145140030 (Scopus ID)
Note

QC 20230626

Available from: 2023-06-26 Created: 2023-06-26 Last updated: 2023-06-26Bibliographically approved
Twengström, W., Moro, C. F., Romell, J., Larsson, J. C., Sparrelid, E., Björnstedt, M. & Hertz, H. (2022). Can laboratory x-ray virtual histology provide intraoperative 3D tumor resection margin assessment?. Journal of Medical Imaging, 9(3), Article ID 031503.
Open this publication in new window or tab >>Can laboratory x-ray virtual histology provide intraoperative 3D tumor resection margin assessment?
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2022 (English)In: Journal of Medical Imaging, ISSN 2329-4302, E-ISSN 2329-4310, Vol. 9, no 3, article id 031503Article in journal (Refereed) Published
Abstract [en]

Purpose:

Surgery is an essential part of the curative plan for most patients affected with solid tumors. The outcome of such surgery, e.g., recurrence rates and ultimately patient survival, depends on several factors where the resection margin is of key importance. Presently, the resection margin is assessed by classical histology, which is time-consuming (several days), destructive, and basically only gives two-dimensional information. Clearly, it would be advantageous if immediate feedback on tumor extension in all three dimensions were available to the surgeon intraoperatively.

Approach:

We investigate a laboratory propagation-based phase-contrast x-ray computed tomography system that provides the resolution, the contrast, and, potentially, the speed for this purpose. The system relies on a liquid-metal jet microfocus source and a scintillator-coated CMOS detector. Our study is performed on paraffin-embedded non-stained samples of human pancreatic neuroendocrine tumors, liver intrahepatic cholangiocarcinoma, and pancreatic serous cystic neoplasm (benign).

Results:

We observe tumors with distinct and sharp edges having cellular resolution (similar to 10 mu m) as well as many assisting histological landmarks, allowing for resection margin assessment. All x-ray data are compared with classical histology. The agreement is excellent.

Conclusion:

We conclude that the method has potential for intraoperative three-dimensional virtual histology.

Place, publisher, year, edition, pages
SPIE-Intl Soc Optical Eng, 2022
Keywords
human resection margin assessment, phase-contrast tomography, propagation-based imaging
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:kth:diva-315850 (URN)10.1117/1.JMI.9.3.031503 (DOI)000819039300003 ()35155718 (PubMedID)2-s2.0-85133709793 (Scopus ID)
Note

QC 20220721

Available from: 2022-07-21 Created: 2022-07-21 Last updated: 2022-07-21Bibliographically approved
Saladino, G. M., Kilic, N. I., Shaker, K., Li, Y., Hamawandi, B., Vogt, C., . . . Toprak, M. (2022). Functional Coatings for X-ray Fluorescent Nanoparticles. In: Proceedings of the 6th International Conference on Theoretical and Applied Nanoscience and Nanotechnology, TANN 2022: . Paper presented at Proceedings of the 6th International Conference on Theoretical and Applied Nanoscience and Nanotechnology, TANN 2022, Niagara Falls, Canada, Jun 2 2022 - Jun 4 2022. Avestia Publishing
Open this publication in new window or tab >>Functional Coatings for X-ray Fluorescent Nanoparticles
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2022 (English)In: Proceedings of the 6th International Conference on Theoretical and Applied Nanoscience and Nanotechnology, TANN 2022, Avestia Publishing , 2022Conference paper, Published paper (Refereed)
Abstract [en]

In recent years, the design and synthesis of bio-compatible coatings leading to hybrid nanoparticles (NPs) as the contrast agents have gained substantial relevance. Furthermore, the addition of several functionalities for bio-imaging applications represents a key step for non-invasive bio-diagnostics. In this context, we design and utilize hybrid nanostructures for X-ray fluorescence computed tomography (XFCT). The combination of a ceramic or metallic core–based on MoO2, Rh or Ru–with a protective shell allows the generation of bio-compatible nanohybrids for dual mode bio-imaging, where the core NPs constitute the X-ray fluorescence (XRF) contrast agents [1]–[3]. Core NPs are synthesized via polyol, hydrothermal or microwave-assisted hydrothermal methods, yielding uniform shape and high dispersibility in aqueous media. Different approaches have been pursued for the fabrication of a bio-compatible shell coating. A modified sol-gel based silica coating process, doped with a commercial fluorophore (Cy5.5), was developed and shown to be applicable to both ceramic and metallic NPs [4], forming core-shell NPs with both optical and X-ray fluorescence properties. Alternatively, carbon quantum dots (CQDs) were synthesized via citrate pyrolysis using microwave-assisted hydrothermal method, exhibiting uniform size distribution (1.6±0.4 nm) and excitation-independent emission (440 nm). Conjugation of these CQDs, via cross-linking, with Rh NPs led to excitation-independent hybrid NPs, with a red-shifted emission wavelength (520 nm), attributed to the reduction of pyrrolic nitrogen on CQDs [5]. These hybrid NPs exhibit improved in vitro biocompatibility in comparison with bare XRF contrast agents. Furthermore, the optical fluorescence–provided by Cy5.5 or CQDs–allows the localization of the NPs in the intracellular environment while the XRF signal from the core NPs is utilized for XFCT, in small animals, leading to both a microscopic and macroscopic bio-imaging contrast agent.

Place, publisher, year, edition, pages
Avestia Publishing, 2022
National Category
Materials Chemistry
Identifiers
urn:nbn:se:kth:diva-338379 (URN)10.11159/tann22.129 (DOI)2-s2.0-85173044731 (Scopus ID)
Conference
Proceedings of the 6th International Conference on Theoretical and Applied Nanoscience and Nanotechnology, TANN 2022, Niagara Falls, Canada, Jun 2 2022 - Jun 4 2022
Note

Part of proceedings ISBN 9781990800030

QC 20231023

Available from: 2023-10-23 Created: 2023-10-23 Last updated: 2023-10-23Bibliographically approved
Saladino, G., Vogt, C., Brodin, B., Shaker, K., Kilic, N. I., Andersson, K., . . . Hertz, H. (2022). XFCT-MRI hybrid multimodal contrast agents for complementary imaging. Nanoscale, 15(5), 2214-2222
Open this publication in new window or tab >>XFCT-MRI hybrid multimodal contrast agents for complementary imaging
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2022 (English)In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 15, no 5, p. 2214-2222Article in journal (Refereed) Published
Abstract [en]

Multimodal contrast agents in biomedical imaging enable the collection of more comprehensive diagnostic information. In the present work, we design hybrid ruthenium-decorated superparamagnetic iron oxide nanoparticles (NPs) as the contrast agents for both magnetic resonance imaging (MRI) and X-ray fluorescence computed tomography (XFCT). The NPs are synthesized via a one-pot polyol hot injection route, in diethylene glycol. In vivo preclinical studies demonstrate the possibility of correlative bioimaging with these contrast agents. The complementarity allows accurate localization, provided by the high contrast of the soft tissues in MRI combined with the elemental selectivity of XFCT, leading to NP detection with high specificity and resolution. We envision that this multimodal imaging could find future applications for early tumor diagnosis, improved long-term treatment monitoring, and enhanced radiotherapy planning.

Place, publisher, year, edition, pages
Royal Society of Chemistry (RSC), 2022
National Category
Radiology, Nuclear Medicine and Medical Imaging Medical Image Processing
Identifiers
urn:nbn:se:kth:diva-330074 (URN)10.1039/d2nr05829d (DOI)000910968100001 ()36625091 (PubMedID)2-s2.0-85146170864 (Scopus ID)
Note

QC 20230626

Available from: 2023-06-26 Created: 2023-06-26 Last updated: 2024-02-22Bibliographically approved
Twengström, W., Moro, C. F., Romell, J., Larsson, J. C., Sparrelid, E., Bjornstedt, M. & Hertz, H. (2021). Can laboratory x-ray virtual histology provide intraoperative 3D tumor resection margin assessment?. In: Muller, B Wang, G (Ed.), DEVELOPMENTS IN X-RAY TOMOGRAPHY XIII: . Paper presented at Conference on Developments in X-Ray Tomography XIII, AUG 01-05, 2021, San Diego, CA. SPIE-Intl Soc Optical Eng, 11840, Article ID 118400Q.
Open this publication in new window or tab >>Can laboratory x-ray virtual histology provide intraoperative 3D tumor resection margin assessment?
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2021 (English)In: DEVELOPMENTS IN X-RAY TOMOGRAPHY XIII / [ed] Muller, B Wang, G, SPIE-Intl Soc Optical Eng , 2021, Vol. 11840, article id 118400QConference paper, Published paper (Refereed)
Abstract [en]

Surgery is an essential part of the curative plan for most patients affected with solid tumors. The outcome of such surgery, e.g., recurrence rates and ultimately patient survival, depends on several factors where the resection margin is of key importance. Presently the resection margin is assessed by classical histology, which is time-consuming (several days), destructive, and basically only gives two-dimensional information. Clearly it would be advantageous if immediate feedback on tumor extension in all three dimensions were available to the surgeon intra-operatively. In the present paper we investigate a laboratory propagation-based phase-contrast x-ray computed tomography (CT) system that provides the resolution, contrast, and, potentially, the speed for this purpose. The system relies on a liquid-metal jet micro-focus source and a scintillator-coated CMOS detector. The study is performed on paraffin-embedded non-stained samples of human pancreatic neuroendocrine tumors, liver intrahepatic cholangiocarcinoma, and pancreatic serous cystic neoplasm (benign). We observe tumors with distinct and sharp edges having cellular resolution (similar to 10 mu m) as well as many assisting histological landmarks, allowing for resection margin assessment. All x-ray data is compared with classical histology. The agreement is excellent, and we conclude that the method has potential for intra-operative three-dimensional virtual histology.

Place, publisher, year, edition, pages
SPIE-Intl Soc Optical Eng, 2021
Series
Proceedings of SPIE, ISSN 0277-786X
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:kth:diva-315940 (URN)10.1117/12.2593928 (DOI)000825424600022 ()2-s2.0-85123057874 (Scopus ID)
Conference
Conference on Developments in X-Ray Tomography XIII, AUG 01-05, 2021, San Diego, CA
Note

Part of proceedings: ISBN 978-1-5106-4519-6

QC 20220728

Available from: 2022-07-28 Created: 2022-07-28 Last updated: 2022-08-16Bibliographically approved
Saladino, G., Kilic, N. I., Brodin, B., Hamawandi, B., Yazgan, I., Hertz, H. & Toprak, M. (2021). Carbon Quantum Dots Conjugated Rhodium Nanoparticles as Hybrid Multimodal Contrast Agents. Nanomaterials, 11(9), Article ID 2165.
Open this publication in new window or tab >>Carbon Quantum Dots Conjugated Rhodium Nanoparticles as Hybrid Multimodal Contrast Agents
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2021 (English)In: Nanomaterials, E-ISSN 2079-4991, Vol. 11, no 9, article id 2165Article in journal (Refereed) Published
Abstract [en]

Nanoparticle (NP)-based contrast agents enabling different imaging modalities are sought for non-invasive bio-diagnostics. A hybrid material, combining optical and X-ray fluorescence is presented as a bioimaging contrast agent. Core NPs based on metallic rhodium (Rh) have been demonstrated to be potential X-ray Fluorescence Computed Tomography (XFCT) contrast agents. Microwave-assisted hydrothermal method is used for NP synthesis, yielding large-scale NPs within a significantly short reaction time. Rh NP synthesis is performed by using a custom designed sugar ligand (LODAN), constituting a strong reducing agent in aqueous solution, which yields NPs with primary amines as surface functional groups. The amino groups on Rh NPs are used to directly conjugate excitation-independent nitrogen-doped carbon quantum dots (CQDs), which are synthesized through citrate pyrolysis in ammonia solution. CQDs provided the Rh NPs with optical fluorescence properties and improved their biocompatibility, as demonstrated in vitro by Real-Time Cell Analysis (RTCA) on a macrophage cell line (RAW 264.7). The multimodal characteristics of the hybrid NPs are confirmed with confocal microscopy, and X-ray Fluorescence (XRF) phantom experiments.

Place, publisher, year, edition, pages
MDPI AG, 2021
Keywords
X-ray fluorescence, carbon quantum dots, contrast agents, dual-mode imaging, nanomedicine, hybrid nanostructure, bio-imaging
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:kth:diva-303549 (URN)10.3390/nano11092165 (DOI)000701522300001 ()34578481 (PubMedID)2-s2.0-85120871654 (Scopus ID)
Note

QC 20211018

Available from: 2021-10-18 Created: 2021-10-18 Last updated: 2024-02-22Bibliographically approved
Häggmark, I., Shaker, K. & Hertz, H. (2021). In Silico Phase-Contrast X-Ray Imaging of Anthropomorphic Voxel-Based Phantoms. IEEE Transactions on Medical Imaging, 40(2), 539-548
Open this publication in new window or tab >>In Silico Phase-Contrast X-Ray Imaging of Anthropomorphic Voxel-Based Phantoms
2021 (English)In: IEEE Transactions on Medical Imaging, ISSN 0278-0062, E-ISSN 1558-254X, Vol. 40, no 2, p. 539-548Article in journal (Refereed) Published
Abstract [en]

Propagation-based phase-contrast X-ray imaging is an emerging technique that can improve dose efficiency in clinical imaging. In silico tools are key to understanding the fundamental imaging mechanisms and develop new applications. Here, due to the coherent nature of the phase-contrast effects, tools based on wave propagation (WP) are preferred over Monte Carlo (MC) based methods. WP simulations require very high wave-front sampling which typically limits simulations to small idealized objects. Virtual anthropomorphic voxel-based phantoms are typically provided with a resolution lower than imposed sampling requirements and, thus, cannot be directly translated for use in WP simulations. In the present paper we propose a general strategy to enable the use ofthese phantoms for WP simulations. The strategy is basedon upsampling in the 3D domain followed by projection resulting in high-resolution maps of the projected thickness for each phantom material. These maps can then be efficiently used for simulations of Fresnel diffraction to generate in silico phase-contrast X-ray images. We demonstrate the strategy on an anthropomorphic breast phantom to simulate propagation-based phase-contrast mammography using a laboratory micro-focus X-ray source.

Place, publisher, year, edition, pages
Institute of Electrical and Electronics Engineers (IEEE), 2021
National Category
Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:kth:diva-289582 (URN)10.1109/TMI.2020.3031318 (DOI)000615044900008 ()33055024 (PubMedID)2-s2.0-85100649580 (Scopus ID)
Note

QC 20210204

Available from: 2021-02-04 Created: 2021-02-04 Last updated: 2024-03-15Bibliographically approved
Romell, J., Jie, V. W., Miettinen, A., Baird, E. & Hertz, H. (2021). Laboratory phase-contrast nanotomography of unstained Bombus terrestris compound eyes. Journal of Microscopy, 283(1), 29-40
Open this publication in new window or tab >>Laboratory phase-contrast nanotomography of unstained Bombus terrestris compound eyes
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2021 (English)In: Journal of Microscopy, ISSN 0022-2720, E-ISSN 1365-2818, Vol. 283, no 1, p. 29-40Article in journal (Refereed) Published
Abstract [en]

Imaging the visual systems of bumblebees and other pollinating insects may increase understanding of their dependence on specific habitats and how they will be affected by climate change. Current high-resolution imaging methods are either limited to two dimensions (light- and electron microscopy) or have limited access (synchrotron radiation x-ray tomography). For x-ray imaging, heavy metal stains are often used to increase contrast. Here, we present micron-resolution imaging of compound eyes of buff-tailed bumblebees (Bombus terrestris) using a table-top x-ray nanotomography (nano-CT) system. By propagation-based phase-contrast imaging, the use of stains was avoided and the microanatomy could more accurately be reconstructed than in samples stained with phosphotungstic acid or osmium tetroxide. The findings in the nano-CT images of the compound eye were confirmed by comparisons with light- and transmission electron microscopy of the same sample and finally, comparisons to synchrotron radiation tomography as well as to a commercial micro-CT system were done.

Place, publisher, year, edition, pages
Wiley, 2021
Keywords
bumblebee, compound eyes, laboratory nano-CT, phase contrast, system comparison, glucose, glutaraldehyde, nanotube, osmium tetraoxide, paraformaldehyde, phosphotungstic acid, acceleration, Article, basement membrane, Bombus terrestris, comparative study, compound eye, controlled study, electric field, electron microscopy, histology, illumination, image processing, micro-computed tomography, nonhuman, phase contrast microscopy, photoreceptor cell, reconstruction algorithm, signal noise ratio, transmission electron microscopy, animal, bee, devices, laboratory, procedures, synchrotron, x-ray computed tomography, Animals, Bees, Laboratories, Microscopy, Phase-Contrast, Osmium Tetroxide, Synchrotrons, Tomography, X-Ray Computed, X-Ray Microtomography
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:kth:diva-309236 (URN)10.1111/jmi.13005 (DOI)000648344300001 ()33822371 (PubMedID)2-s2.0-85105346424 (Scopus ID)
Note

QC 20220301

Available from: 2022-03-01 Created: 2022-03-01 Last updated: 2022-06-25Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-2723-6622

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