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Small-Animal Imaging with Liquid-Metal-Jet X-Ray Sources
KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.ORCID iD: 0000-0002-9487-669X
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Small-animal x-ray imaging is an important tool for medical research. The penetration power of x-rays makes it possible to investigate the 3D structure of small animals and other thick biological samples by computed tomography (CT). However, small-animal x-ray imaging often requires high resolution due to the small structures involved, and short exposure times due to sample movement. This constitutes a challenge, since these two properties require compact x-ray sources with parameters that are not widely available.

In this Thesis we present the first application of liquid-metal-jet sources for small-animal imaging. This source concept was invented at KTH just over ten years ago. The use of a high-speed metal jet as electron-beam target, instead of a solid anode, enables higher x-ray flux while maintaining a small x-ray spot for high-resolution imaging. In the present work, a liquid-metal jet source with a higher-energy spectrum has been developed. It has stronger 24 keV radiation compared to previous sources, which makes it more suitable for imaging of small animals and other few-cm-thick objects, which require the higher penetration of 20-35 keV x-rays.

We have applied the liquid-metal-jet x-ray sources for whole-body imaging of sacrificed mice and zebrafish. With high-resolution absorption-contrast CT we have visualized fine bone details of mice. We have also used phase contrast, a new method that can considerably improve imaging of, e.g., soft tissue, for demarcation of mm-sized tumors inside a full mouse and for mouse cartilage imaging. In zebrafish imaging, we have exploited the greatly enhanced contrast of phase-imaging to resolve single muscle fibers (and possibly even myofibrils) in whole zebrafish in a laboratory setting for the first time. The muscle structures have diameters in the 5-7 μm range and extremely low contrast, which makes them difficult to observe.

With phase contrast, we have demonstrated low-dose and high-resolution angiography of mouse and rat organs and tissues ex vivo. We show detection of blood vessels with diameters below 10 μm with radiation doses compatible with living small animals, which is not possible with absorption contrast and iodinated contrast agents. In addition, we have investigated the vascular network of tumors in mouse ears and visualized the chaotic arrangement of newly-formed blood vessels.

Finally, we present the first results from a new high-power liquid-metal-jet x-ray source prototype, operating at 10× the power of our previous sources, with the same x-ray spot size. This source constitutes an important step towards future in-vivo small-animal laboratory imaging with high resolution.

Abstract [sv]

Röntgenavbildning av små försöksdjur är en viktig metod inom medicinsk forskning. Röntgenstrålar penetrerar material, vilket gör det möjligt att undersöka 3D-strukturen hos försöksdjur och andra tjocka biologiska prov med hjälp av datortomografi (CT). Tyvärr kräver smådjursavbildning ofta dels hög upplösning, eftersom de relevanta strukturerna är små, dels korta exponeringstider, eftersom objektet tenderar att röra sig. Detta är en utmaning, då båda egenskaperna kräver kompakta röntgenkällor med speciella egenskaper som inte är brett tillgängliga.

I denna avhandling visar vi den första användningen av metallstråleröntgenkällor för avbildning av hela smådjur. Den här typen av röntgenkälla uppfanns vid KTH för drygt tio år sedan. Genom att låta elektronerna träffa en stråle av flytande metall, istället för en solid metallanod, kan vi generera mer röntgenstrålning men samtidigt behålla en liten källpunkt, vilket behövs för avbildning med hög upplösning. En ny metallstrålekälla utvecklades som en del av denna avhandling. Den ger ett röntgenspektrum med högre energier, vilket gör källan mer lämpad än tidigare källor för avbildning av små försöksdjur och andra centimetertjocka biologiska objekt.

Vi har använt metallstrålekällor för att avbilda intakta, avlivade möss och zebrafiskar. Med högupplöst absorptions-CT har vi detekterat små bendetaljer inuti möss. Vi har även använt faskontrastavbildning, en ny metod som avsevärt kan förbättra avbildning av mjukvävnad, till att demarkera millimeterstora tumörer inuti en hel mus, samt för avbildning av brosk i leder hos möss. Faskontrast ger en kraftig förstärkning av kontrasten i bilden, vilket även har använts för att för första gången detektera individuella muskelfibrer (och eventuellt även myofibriller) inuti zebrafiskar med en kompakt röntgenkälla. Muskelstrukturerna har diametrar på 5-7 μm och låg kontrast, vilket gör dem svåra att observera.

Med hjälp av faskontrast har vi utvecklat en metod för att avbilda blodkärl med diametrar under 10 μm inuti organ och vävnader från möss och råttor ex vivo, med stråldoser som är kompatibla med studier av levande smådjur. Detta är inte möjligt med konventionell absorptionskontrast och jod-baserade kontrastmedel. Vi har dessutom avbildat nyformade blodkärl kring tumörer i musöron och observerat kärlens kaotiska struktur.

Slutligen presenterar vi de första resultaten från en prototyp av en ny högeffektskälla. Källan har tio gånger högre effekt än tidigare metallstrålekällor, men bibehåller samma storlek på källpunkten. Den här högeffektskällan är ett viktigt steg mot framtida laboratoriebaserad avbildning av levande små försöksdjur med hög upplösning.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. , ix, 69 p.
Series
TRITA-FYS, ISSN 0280-316X ; 2015:19
Keyword [en]
X-ray, x-ray imaging, small animal, phase contrast, tomography
National Category
Physical Sciences
Research subject
Physics
Identifiers
URN: urn:nbn:se:kth:diva-163169ISBN: 978-91-7595-487-5 (print)OAI: oai:DiVA.org:kth-163169DiVA: diva2:799651
Public defence
2015-04-24, Sal FA32, Albanova Universitetscentrum, Roslagstullsbacken 21, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

QC 20150331

Available from: 2015-03-31 Created: 2015-03-27 Last updated: 2015-04-01Bibliographically approved
List of papers
1. Phase retrieval in X-ray phase-contrast imaging suitable for tomography
Open this publication in new window or tab >>Phase retrieval in X-ray phase-contrast imaging suitable for tomography
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2011 (English)In: Optics Express, ISSN 1094-4087, E-ISSN 1094-4087, Vol. 19, no 11, 10359-10376 p.Article in journal (Refereed) Published
Abstract [en]

In-line phase-contrast X-ray imaging provides images where both absorption and refraction contribute. For quantitative analysis of these images, the phase needs to be retrieved numerically. There are many phase-retrieval methods available. Those suitable for phase-contrast tomography, i.e., non-iterative phase-retrieval methods that use only one image at each projection angle, all follow the same pattern though derived in different ways. We outline this pattern and use it to compare the methods to each other, considering only phase-retrieval performance and not the additional effects of tomographic reconstruction. We also outline derivations, approximations and assumptions, and show which methods are similar or identical and how they relate to each other. A simple scheme for choosing reconstruction method is presented, and numerical phase-retrieval performed for all methods.

National Category
Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:kth:diva-34364 (URN)10.1364/OE.19.010359 (DOI)000290852800033 ()21643293 (PubMedID)2-s2.0-79957611071 (Scopus ID)
Funder
Swedish Research Council
Note

QC 20110705

Available from: 2011-07-05 Created: 2011-06-07 Last updated: 2017-12-11Bibliographically approved
2. A 24 keV liquid-metal-jet x-ray source for biomedical applications
Open this publication in new window or tab >>A 24 keV liquid-metal-jet x-ray source for biomedical applications
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2011 (English)In: Review of Scientific Instruments, ISSN 0034-6748, E-ISSN 1089-7623, Vol. 82, no 12, 123701- p.Article in journal (Refereed) Published
Abstract [en]

We present a high-brightness 24-keV electron-impact microfocus x-ray source based on continuous operation of a heated liquid-indium/gallium-jet anode. The 30–70 W electron beam is magnetically focused onto the jet, producing a circular 7–13 μm full width half maximum x-ray spot. The measured spectral brightness at the 24.2 keV In Kα line is 3 × 109 photons/(s × mm2 × mrad2 × 0.1% BW) at 30 W electron-beam power. The high photon energy compared to existing liquid-metal-jet sources increases the penetration depth and allows imaging of thicker samples. The applicability of the source in the biomedical field is demonstrated by high-resolution imaging of a mammography phantom and a phase-contrast angiography phantom.

Place, publisher, year, edition, pages
American Institute of Physics (AIP), 2011
Keyword
x-ray imaging, x-ray source, phase contrast
National Category
Medical Equipment Engineering
Identifiers
urn:nbn:se:kth:diva-62137 (URN)10.1063/1.3664870 (DOI)000298643100029 ()22225218 (PubMedID)2-s2.0-84855323212 (Scopus ID)
Funder
Swedish Research Council
Note

QC 20120118

Available from: 2012-01-18 Created: 2012-01-18 Last updated: 2017-12-08Bibliographically approved
3. X-ray phase contrast for CO2 microangiography
Open this publication in new window or tab >>X-ray phase contrast for CO2 microangiography
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2012 (English)In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 57, no 9, 2603-2617 p.Article in journal (Refereed) Published
Abstract [en]

We demonstrate a laboratory method for imaging small blood vessels using x-ray propagation-based phase-contrast imaging and carbon dioxide (CO2) gas as a contrast agent. The limited radiation dose in combination with CO2 being clinically acceptable makes the method promising for small-diameter vascular visualization. We investigate the possibilities and limitations of the method for small-animal angiography and compare it with conventional absorption-based x-ray angiography. Photon noise in absorption-contrast imaging prevents visualization of blood vessels narrower than 50 mu m at the highest radiation doses compatible with living animals, whereas our simulations and experiments indicate the possibility of visualizing 20 mu m vessels at radiation doses as low as 100 mGy. Experimental computed tomography of excised rat kidney shows blood vessels of diameters down to 60 mu m with improved image quality compared to absorption-based methods. With our present prototype x-ray source, the acquisition time for a tomographic dataset is approximately 1 h, which is long compared to the 1-20 min common for absorption-contrast micro-CT systems. Further development of the liquid-metal-jet microfocus x-ray sources used here and high-resolution x-ray detectors shows promise to reduce exposure times and make this high-resolution method practical for imaging of living animals.

Keyword
Angiography, Blood vessels, Carbon dioxide, Dosimetry, Image quality, Imaging techniques, Visualization, X ray apparatus, X rays
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:kth:diva-95082 (URN)10.1088/0031-9155/57/9/2603 (DOI)000303046200015 ()22505599 (PubMedID)2-s2.0-84860168376 (Scopus ID)
Funder
Swedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20120522

Available from: 2012-05-22 Created: 2012-05-14 Last updated: 2017-12-07Bibliographically approved
4. X-ray phase-contrast CO2 angiography for sub-10 mu m vessel imaging
Open this publication in new window or tab >>X-ray phase-contrast CO2 angiography for sub-10 mu m vessel imaging
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2012 (English)In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 57, no 22, 7431-7441 p.Article in journal (Refereed) Published
Abstract [en]

X-ray in-line phase contrast has recently been combined with CO2 angiography for high-resolution small-animal vascular imaging at low radiation dose. In this paper we further investigate the potential and limitations of this method and demonstrate observation of vessels down to 8 mu m in diameter, considerably smaller than the 60 mu m previously reported. Our in-line phase-contrast imaging system is based on a liquid-metal-jet-anode x-ray source and utilizes free-space propagation to convert phase shifts, caused by refractive index variations, into intensity differences. Enhanced refractive index variations are obtained through injection of CO2 gas into the vascular system to replace the blood. We show rat-kidney images with blood vessels down to 27 mu m in diameter and mouse-ear images with vessels down to 8 mu m. The minimum size of observable blood vessels is found to be limited by the penetration of gas into the vascular system and the signal-to-noise ratio, i.e. the allowed dose. The diameters of vessels being gas-filled depend on the gas pressure and follow a simple model based on surface tension. A theoretical signal-to-noise comparison shows that this method requires 1000 times less radiation dose than conventional iodine-based absorption contrast for observing sub-50 mu m vessels.

Keyword
Future-Prospects, Angiogenesis, Retrieval, Agents
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:kth:diva-109639 (URN)10.1088/0031-9155/57/22/7431 (DOI)000310838700017 ()2-s2.0-84869037603 (Scopus ID)
Funder
Swedish Research Council, VR 2009-3142Knut and Alice Wallenberg Foundation, KAW 2011.0136
Note

QC 20130109

Available from: 2013-01-09 Created: 2013-01-08 Last updated: 2017-12-06Bibliographically approved
5. First application of liquid-metal-jet sources for small-animal imaging: High-resolution CT and phase-contrast tumor demarcation
Open this publication in new window or tab >>First application of liquid-metal-jet sources for small-animal imaging: High-resolution CT and phase-contrast tumor demarcation
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2013 (English)In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 40, no 2, 021909- p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Small-animal studies require images with high spatial resolution and high contrast due to the small scale of the structures. X-ray imaging systems for small animals are often limited by the microfocus source. Here, the authors investigate the applicability of liquid-metal-jet x-ray sources for such high-resolution small-animal imaging, both in tomography based on absorption and in soft-tissue tumor imaging based on in-line phase contrast. Methods: The experimental arrangement consists of a liquid-metal-jet x-ray source, the small-animal object on a rotating stage, and an imaging detector. The source-to-object and object-to-detector distances are adjusted for the preferred contrast mechanism. Two different liquid-metal-jet sources are used, one circulating a Ga/In/Sn alloy and the other an In/Ga alloy for higher penetration through thick tissue. Both sources are operated at 40-50 W electron-beam power with similar to 7 mu m x-ray spots, providing high spatial resolution in absorption imaging and high spatial coherence for the phase-contrast imaging. Results: High-resolution absorption imaging is demonstrated on mice with CT, showing 50 mu m bone details in the reconstructed slices. High-resolution phase-contrast soft-tissue imaging shows clear demarcation of mm-sized tumors at much lower dose than is required in absorption. Conclusions: This is the first application of liquid-metal-jet x-ray sources for whole-body small-animal x-ray imaging. In absorption, the method allows high-resolution tomographic skeletal imaging with potential for significantly shorter exposure times due to the power scalability of liquid-metal-jet sources. In phase contrast, the authors use a simple in-line arrangement to show distinct tumor demarcation of few-mm-sized tumors. This is, to their knowledge, the first small-animal tumor visualization with a laboratory phase-contrast system.

Keyword
small-animal imaging, liquid-metal-jet, x-ray, CT, tumor demarcation, mouse
National Category
Other Physics Topics
Identifiers
urn:nbn:se:kth:diva-119468 (URN)10.1118/1.4788661 (DOI)000314727700038 ()23387757 (PubMedID)2-s2.0-84873576570 (Scopus ID)
Funder
Swedish Research CouncilVinnova
Note

QC 20130319

Available from: 2013-03-19 Created: 2013-03-14 Last updated: 2017-12-06Bibliographically approved
6. Phase-retrieval methods with applications in composite-material tomography
Open this publication in new window or tab >>Phase-retrieval methods with applications in composite-material tomography
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2013 (English)In: 11th International Conference On X-Ray Microscopy (XRM2012), Institute of Physics Publishing (IOPP), 2013, 012015- p.Conference paper, Published paper (Refereed)
Abstract [en]

In-line phase-contrast x-ray imaging is emerging as a method for observing small details when the contrast in absorption x-ray imaging is low. It gives images with strong edge enhancement, and phase retrieval is necessary to obtain quantitative thickness information. In particular for tomography, clarity can be enhanced by phase retrieval, as here demonstrated on a 3D-weave reinforced composite material. Seven suitable phase-retrieval methods are identified and integrated into a single method, where each version is marked by variations in particular steps. The general method and its variations are outlined and a comparison shows which methods are most suitable in different situations.

Place, publisher, year, edition, pages
Institute of Physics Publishing (IOPP), 2013
Series
Journal of Physics Conference Series, ISSN 1742-6588 ; 463
Keyword
Contrast Tomography, Formulas, Distance, Objects
National Category
Other Physics Topics
Identifiers
urn:nbn:se:kth:diva-139242 (URN)10.1088/1742-6596/463/1/012015 (DOI)000327949000015 ()2-s2.0-84891284501 (Scopus ID)
Conference
11th International Conference on X-ray Microscopy (XRM), AUG 05-10, 2012, Shanghai, China
Note

QC 20140113

Available from: 2014-01-13 Created: 2014-01-08 Last updated: 2015-03-31Bibliographically approved
7. X-ray phase contrast with injected gas for tumor microangiography
Open this publication in new window or tab >>X-ray phase contrast with injected gas for tumor microangiography
Show others...
2014 (English)In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 59, no 11, 2801-2811 p.Article in journal (Refereed) Published
Abstract [en]

We show that the microvasculature of mouse tumors can be visualized using propagation-based phase-contrast x-ray imaging with gas as the contrast agent. The large density difference over the gas-tissue interface provides high contrast, allowing the imaging of small-diameter blood vessels with relatively short exposure times and low dose using a compact liquid-metal-jet x-ray source. The method investigated is applied to tumors (E1A/Ras-transformed mouse embryonic fibroblasts) grown in mouse ears, demonstrating sub-15-mu m-diameter imaging of their blood vessels. The exposure time for a 2D projection image is a few seconds and a full tomographic 3D map takes some minutes. The method relies on the strength of the vasculature to withstand the gas pressure. Given that tumor vessels are known to be more fragile than normal vessels, we investigate the tolerance of the vasculature of 12 tumors to gas injection and find that a majority withstand 200 mbar pressures, enough to fill 12-mu m-diameter vessels with gas. A comparison of the elasticity of tumorous and non-tumorous vessels supports the assumption of tumor vessels being more fragile. Finally, we conclude that the method has the potential to be extended to the imaging of 15 mu m vessels in thick tissue, including mouse imaging, making it of interest for, e.g., angiogenesis research.

Keyword
x-ray, phase-contrast, angiography, tumor, propagation-based, microangiography, gas
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:kth:diva-139504 (URN)10.1088/0031-9155/59/11/2801 (DOI)000336459000016 ()2-s2.0-84900469948 (Scopus ID)
Funder
Swedish Research CouncilSwedish Cancer Society
Note

QC 20140624. Updated from manuscript to article in journal.

Available from: 2014-01-14 Created: 2014-01-14 Last updated: 2017-12-06Bibliographically approved
8. Laboratory phase-contrast x-ray tomography for imaging of zebrafish muscle structure
Open this publication in new window or tab >>Laboratory phase-contrast x-ray tomography for imaging of zebrafish muscle structure
Show others...
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:kth:diva-163393 (URN)
Note

QS 2015

Available from: 2015-04-01 Created: 2015-04-01 Last updated: 2015-04-01Bibliographically approved

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  • Other style
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Output format
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