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Evaluation of the Dual-Modal usage of contrast agents by means of Synchrotron X-ray Computed Microtomography and Magnetic Resonance Imaging using Macrophages loaded with Barium Sulfate and Gadolinium Nanoparticles for Detection and Monitoring in Animal Disease Models
Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär ytfysik och nanovetenskap. Linköpings universitet, Tekniska fakulteten.
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

¨This thesis focuses on evaluating the dual-modal Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) capabilities of contrast agents. For such purposes a gadolinium based contrast agent is of high interest, due to its paramagnetic properties, which while present inside a magnetic field will hence interact with the protons spins of water (in tissue and fat) and shorten their the T1 relaxation time, thereby creating a positive image contrast in MRI. Furthermore, the X-ray Mass Attenuation Coefficient (MAC) of gadolinium is relatively high, thus suggesting its potential use, also as a CT contrast agent.

Gadolinium nanoparticles (GdNPs) can be loaded into cells, such as macrophages, which offers the possibility to track cells inside entire organisms. In the first step the uptake of GdNPs inside cells was investigated, together with a test for toxicity. To show the potential of using GdNP loaded macrophages for functional imaging of inflammation, an acute allergic airway inflammation mouse model (mimicking asthma in humans) was used and analyzed by in-situ synchrotron phase contrast CT. In the first step this approach was evaluated using macrophages loaded with a clinical contrast agent containing barium sulphate (BaSO4), since this agent is known to provide high contrast in CT. In the ultimate step a combination of both BaSO4 and GdNP loaded macrophages was used in the same asthmatic mouse model and analyzed by dual modal Synchrotron phase contrast CT and Micro Magnetic Resonance Imaging (μ-MRI).

Complementary results in terms of the biodistribution of injected macrophages could only be obtained by the combination of both synchrotron phase contrast CT and μ-MRI, where the first modality allows a detailed localization of clustered BaSO4 loaded macrophages, but fails to detect single macrophages, which could instead be indirectly observed by μ-MRI as an increase of the T1-contrast, coming from the soft tissue of mice injected with GdNP loaded macrophages.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2015. , s. 73
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1707
Nationell ämneskategori
Fysik Radiologi och bildbehandling
Identifikatorer
URN: urn:nbn:se:liu:diva-122607DOI: 10.3384/diss.diva-122607ISBN: 978-91-7685-936-0 (tryckt)OAI: oai:DiVA.org:liu-122607DiVA, id: diva2:868740
Disputation
2015-12-07, Planck, Fysikhuset, Campus Valla, Linköping, 10:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-11-11 Skapad: 2015-11-11 Senast uppdaterad: 2015-12-02Bibliografiskt granskad
Delarbeten
1. Quantitative evaluation of a single-distance phase-retrieval method applied on in-line phase-contrast images of a mouse lung
Öppna denna publikation i ny flik eller fönster >>Quantitative evaluation of a single-distance phase-retrieval method applied on in-line phase-contrast images of a mouse lung
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2014 (Engelska)Ingår i: Journal of Synchrotron Radiation, ISSN 0909-0495, E-ISSN 1600-5775, Vol. 21, s. 784-789Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Propagation-based X-ray phase-contrast computed tomography (PBI) has already proven its potential in a great variety of soft-tissue-related applications including lung imaging. However, the strong edge enhancement, caused by the phase effects, often hampers image segmentation and therefore the quantitative analysis of data sets. Here, the benefits of applying single-distance phase retrieval prior to the three-dimensional reconstruction (PhR) are discussed and quantified compared with three-dimensional reconstructions of conventional PBI data sets in terms of contrast-to-noise ratio (CNR) and preservation of image features. The PhR data sets show more than a tenfold higher CNR and only minor blurring of the edges when compared with PBI in a predominately absorption-based set-up. Accordingly, phase retrieval increases the sensitivity and provides more functionality in computed tomography imaging.

Ort, förlag, år, upplaga, sidor
Wiley-Blackwell, 2014
Nyckelord
computed tomography; phase-contrast imaging; phase retrieval; lung imaging
Nationell ämneskategori
Fysik
Identifikatorer
urn:nbn:se:liu:diva-109252 (URN)10.1107/S1600577514009333 (DOI)000338124300019 ()24971975 (PubMedID)
Tillgänglig från: 2014-08-12 Skapad: 2014-08-11 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
2. Functionalized synchrotron in-line phase-contrast computed tomography: a novel approach for simultaneous quantification of structural alterations and localization of barium-labelled alveolar macrophages within mouse lung samples
Öppna denna publikation i ny flik eller fönster >>Functionalized synchrotron in-line phase-contrast computed tomography: a novel approach for simultaneous quantification of structural alterations and localization of barium-labelled alveolar macrophages within mouse lung samples
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2015 (Engelska)Ingår i: Journal of Synchrotron Radiation, ISSN 0909-0495, E-ISSN 1600-5775, Vol. 22, s. 143-155Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Functionalized computed tomography (CT) in combination with labelled cells is virtually non-existent due to the limited sensitivity of X-ray-absorption-based imaging, but would be highly desirable to realise cell tracking studies in entire organisms. In this study we applied in-line free propagation X-ray phase-contrast CT (XPCT) in an allergic asthma mouse model to assess structural changes as well as the biodistribution of barium-labelled macrophages in lung tissue. Alveolar macrophages that were barium-sulfate-loaded and fluorescent-labelled were instilled intratracheally into asthmatic and control mice. Mice were sacrificed after 24 h, lungs were kept in situ, inflated with air and scanned utilizing XPCT at the SYRMEP beamline (Elettra Synchrotron Light Source, Italy). Single-distance phase retrieval was used to generate data sets with ten times greater contrast-to-noise ratio than absorption-based CT (in our setup), thus allowing to depict and quantify structural hallmarks of asthmatic lungs such as reduced air volume, obstruction of airways and increased soft-tissue content. Furthermore, we found a higher concentration as well as a specific accumulation of the barium-labelled macrophages in asthmatic lung tissue. It is believe that XPCT will be beneficial in preclinical asthma research for both the assessment of therapeutic response as well as the analysis of the role of the recruitment of macrophages to inflammatory sites.

Ort, förlag, år, upplaga, sidor
International Union of Crystallography, 2015
Nyckelord
phase-contrast CT; single-distance phase retrieval; functional CT imaging
Nationell ämneskategori
Fysik
Identifikatorer
urn:nbn:se:liu:diva-113733 (URN)10.1107/S1600577514021730 (DOI)000346850200022 ()25537601 (PubMedID)
Anmärkning

Funding Agencies|European Commission [230739]; Deutsche Forschungsgemeinschaft (DFG) [DU 1403/1-1]; EXTREMA COST action [MP1207]

Tillgänglig från: 2015-01-30 Skapad: 2015-01-29 Senast uppdaterad: 2017-12-05
3. Quantification of structural alterations in lung disease—a proposed analysis methodology of CT scans of preclinical mouse models and patients
Öppna denna publikation i ny flik eller fönster >>Quantification of structural alterations in lung disease—a proposed analysis methodology of CT scans of preclinical mouse models and patients
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2015 (Engelska)Ingår i: Biomedical Physics & Engineering Express, ISSN 2057-1976, Vol. 1, nr 3, artikel-id 035201Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In this paper we have established a general investigative methodology for quantitative computed tomography (CT) lung image analysis in the sagittal, coronal and transversal orientation of lungs with various lung diseases. Mean values were recorded for the two parameters percentage volume and structural thickness based on stripe shaped volumes of interest (VOIs) from the XY (transversal), YZ (sagittal) and ZX (coronal) orientation, placed out in the left and right lung side. A one-way ANOVA with Tukey–Kramer 90% simultaneous confidence intervals for pair wise comparison of means was performed on each considered parameter, in order to detect any statistically significant differences in between the samples. This methodology was first tested on high resolution synchrotron micro-computed tomography images of a preclinical asthma mouse model, injected with barium sulfate filled alveolar macrophages, with the purpose of marking out asthmatic inflammation sites. Preclinical mouse models are today commonly used as artificial models for studying various human diseases, e.g. asthma. Therefore, in order to translate our methodology protocol also to clinical applications the proposed methodology was also tested on lung data sets of patients, with various lung diseases. The presented general methodology was proven to be successful for the quantification of lung structural differences in an asthma mouse model, as well as being applicable also on patient lungs with various lung diseases. The outlined analysis protocol was tested on images obtained only by means of CT, but could also potentially be applied on images of the lung obtained by other 3D-imaging techniques.

Ort, förlag, år, upplaga, sidor
Institute of Physics (IOP), 2015
Nyckelord
lung imaging, asthma mouse model, quantitative image analysis, computed tomography, synchrotron microtomography, phase contrast
Nationell ämneskategori
Medicinsk bildbehandling
Identifikatorer
urn:nbn:se:liu:diva-121940 (URN)10.1088/2057-1976/1/3/035201 (DOI)
Forskningsfinansiär
EU, FP7, Sjunde ramprogrammet, GA 230739Vetenskapsrådet
Tillgänglig från: 2015-10-13 Skapad: 2015-10-13 Senast uppdaterad: 2015-11-11
4. Optimization of the loading efficacy for dual-modal CT/MRI macrophage tracking in lungs of an asthma mouse model
Öppna denna publikation i ny flik eller fönster >>Optimization of the loading efficacy for dual-modal CT/MRI macrophage tracking in lungs of an asthma mouse model
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2015 (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

We present novel cell uptake methodologies related to the usage of MRI/CT contrast agents for the purpose of performing dual-modal cell tracking with macrophages in both MRI and CT. Two different techniques, namely Synchrotron X-rays microtomography and Micro Magnetic Resonance Imaging were used to investigate the contrast  enhancement, as an effect of the MRI/CT contrast agent cell uptake of mouse alveolar macrophages. Macrophages loaded with the  commercial contrast agent Micropaque® CT, containing barium sulphate (BaSO4) immersed in Sorbitol, showed a much higher contrast enhancement in CT, than an MRI/CT contrast agent based on Gadolinium nanoparticles (GdNPs). The CT contrast of GdNPs (at 5 mM of Gd) could be increased, by immersing the GdNPs in Sorbitol, while still maintaining a positive T1-contrast in MRI. The idea of co-loading macrophages with both BaSO4 and GdNP inside the same cells  presented a valid "trade off" between the optimal contrast in CT vs. MRI etc. It was concluded that while optimizing the cell uptake of contrast agent for cell tracking in MRI/CT, it is important to make a "trade off" between the following 3 parameters, 1) optimal contrast in CT, 2) optimal contrast in MRI and 3) metabolic cell activity, depending on the given application. These cell optimization ideas may be of importance to every field aiming to image an inflammatory disease, based on the utilization of contrast agent loaded macrophages.

Nyckelord
Gd2O3 nanoparticle; Gadolinium oxide; dual-modal MRI/CT contrast agent; barium sulphate; macrophages; cell loading efficacy
Nationell ämneskategori
Fysik
Identifikatorer
urn:nbn:se:liu:diva-122602 (URN)
Tillgänglig från: 2015-11-11 Skapad: 2015-11-11 Senast uppdaterad: 2015-11-11Bibliografiskt granskad
5. Dual-modal CT and MRI functional and anatomical imaging using barium sulphate and gadolinium nanoparticle loaded macrophages in a preclinical asthma mouse model
Öppna denna publikation i ny flik eller fönster >>Dual-modal CT and MRI functional and anatomical imaging using barium sulphate and gadolinium nanoparticle loaded macrophages in a preclinical asthma mouse model
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2015 (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Objectives In this study we investigated the potentials of dual-modal CT-MRI macrophage tracking, by a intratracheal instillation of a mixture of either gadolinium nanoparticles or barium sulphate loaded alveolar macrophages into mice of an allergic airway inflammation (asthma) model and their respective healthy control, imaged with Synchrotron X-rays microtomography (SR μCT) and Micro Magnetic Resonance Imaging (μMRI).

Materials and Methods The mice were scanned ex vivo using SRμCT at 22 keV and with a 9.4 Tesla μMRI scanner. The CT and MRI data sets were registered and fused together, followed by quantitative and statistical analysis.

Results The asthmatic sample injected with contrast agent loaded macrophages showed high absorbing spots inside the soft-tissue regions of the lung for the CT data set, as well as higher contrast for the soft-tissue in the MRI data set. Furthermore, the correlation analysis showed a perfect negative correlation between the soft tissue mean grey value in CT and the soft tissue mean grey value in MRI.

Conclusion The dual-modal CT-MRI cell tracking of intratracheally administered macrophages (loaded with contrast agent) in an asthmatic mouse helps to extract synergistic information about the migration  behaviour of macrophages, where clusters of cells were detected in CT, while as a general increase of the soft-tissue contrast could be observed in MRI, due to a homogeneous cell distribution.

Nyckelord
Gadolinium oxide (Gd2O3); alveolar macrophages; asthma; magnetic resonance imaging; Synchrotron X-Ray Computed Microtomography
Nationell ämneskategori
Fysik Radiologi och bildbehandling
Identifikatorer
urn:nbn:se:liu:diva-122603 (URN)
Tillgänglig från: 2015-11-11 Skapad: 2015-11-11 Senast uppdaterad: 2015-11-11Bibliografiskt granskad

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