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Toward increased applicability of ultrasound contrast agents
KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.ORCID iD: 0000-0002-4757-7232
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ultrasound is one of the most widely used modalities in medical imaging because of its high cost-effectiveness, wide availability in hospitals, generation of real-time images, and use of nonionizing radiation. However, the image quality can be insufficient in some patients. Introducing a contrast agent (CA), which comprises a suspension of 2–6 mm-sized microbubbles, improves the image quality and thus the image analysis. At present, contrast-enhanced ultrasound is frequently used during standard clinical procedures such as kidney, liver, and cardiac (echocardiography) imaging. Multimodality and targeted imaging are future areas for ultrasound CAs. Multimodality imaging may improve diagnostics by simultaneously providing anatomical and functional information. Targeted imaging may allow for identification of particular diseases.

The work within this thesis focused mainly on a novel multimodal polymer-shelled CA with the potential to be target specific. In Study I, the acoustic response was determined in a flow phantom by evaluating the contrast-to-tissue-ratio when using contrast sequences available in clinical ultrasound systems. This study showed that a high acoustic pressure is needed for optimal visualization of the polymer-shelled CA. In Study II, the in vivo performance of this CA was evaluated in a rat model, and the blood elimination time and subcellular distribution were determined. In Study III, the efficiency in endocardial border delineation was assessed in a pig model. The polymer-shelled CA had a significantly longer blood circulation time than the commercially available CA SonoVue, which is favorable for target-specific CA, in which a long circulation time increases the probability of target-specific binding. Transmission electron microscopic analysis of tissue sections from liver, kidney, spleen and lungs, obtained at different time points after CA injection showed that macrophages were responsible for the elimination of the polymer-shelled CA. A higher dose of the polymer-shelled CA was needed to obtain similar endocardial border delineation efficiency as that obtained using SonoVue. The results of Studies I–III demonstrate that the polymer-shelled CA has potential applicability in medical imaging.

Current guidelines for contrast-enhanced echocardiography are limited to cases of suboptimal image quality or when there is a suspicion of structural abnormalities within the left ventricle. It may be hypothesized that the wider use of contrast-enhanced echocardiography may help to detect some diseases earlier. Study IV assessed the diagnostic outcomes after contrast administration in patients without indications for CA use. The myocardial wall motion score index and ejection fraction were evaluated by experienced and inexperienced readers, and a screening for left ventricular structural abnormalities was performed. More cases of wall motion and structural abnormalities were detected in the contrast-enhanced analysis. Intra- and interobserver variability was lower with the use of CAs. This study suggests that the more widespread use of CAs instead of the current selective approach may contribute to earlier detection of cardiovascular disease.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. , xii, 51 p.
Series
TRITA-STH : report, ISSN 1653-3836 ; 2015:3
Keyword [en]
Contrast agent, Contrast-to-tissue-ratio, Echocardiography, Endocardial border, Microbubbles, Multimodal, Phantom, Polymer, Ultrasound, Wall motion score index.
National Category
Medical Image Processing
Research subject
Technology and Health
Identifiers
URN: urn:nbn:se:kth:diva-163387ISBN: 978-91-7595-496-7 (print)OAI: oai:DiVA.org:kth-163387DiVA: diva2:799866
Public defence
2015-04-28, 3-221, Alfred Nobels Allé 10, Huddinge, 10:00 (Swedish)
Opponent
Supervisors
Note

QC 20150401

Available from: 2015-04-01 Created: 2015-03-31 Last updated: 2015-04-01Bibliographically approved
List of papers
1. Visualization of multimodal polymer-shelled contrast agents using ultrasound contrast sequences: an experimental study in a tissue mimicking flow phantom
Open this publication in new window or tab >>Visualization of multimodal polymer-shelled contrast agents using ultrasound contrast sequences: an experimental study in a tissue mimicking flow phantom
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2013 (English)In: Cardiovascular Ultrasound, ISSN 1476-7120, E-ISSN 1476-7120, Vol. 11, 33- p.Article in journal (Refereed) Published
Abstract [en]

Background: A multimodal polymer-shelled contrast agent (CA) with target specific potential was recently developed and tested for its acoustic properties in a single element transducer setup. Since the developed polymeric CA has different chemical composition than the commercially available CAs, there is an interest to study its acoustic response when using clinical ultrasound systems. The aim of this study was therefore to investigate the acoustic response by studying the visualization capability and shadowing effect of three polymer-shelled CAs when using optimized sequences for contrast imaging. Methods: The acoustic response of three types of the multimodal CA was evaluated in a tissue mimicking flow phantom setup by measuring contrast to tissue ratio (CTR) and acoustic shadowing using five image sequences optimized for contrast imaging. The measurements were performed over a mechanical index (MI) range of 0.2-1.2 at three CA concentrations (10(6), 10(5), 10(4) microbubbles/ml). Results: The CTR-values were found to vary with the applied contrast sequence, MI and CA. The highest CTR-values were obtained when a contrast sequence optimized for higher MI imaging was used. At a CA concentration of 106 microbubbles/ml, acoustic shadowing was observed for all contrast sequences and CAs. Conclusions: The CAs showed the potential to enhance ultrasound images generated by available contrast sequences. A CA concentration of 106 MBs/ml implies a non-linear relation between MB concentration and image intensity.

Keyword
Acoustic shadowing, Contrast agent, Contrast sequences, Contrast to tissue ratio, Flow phantom, Multimodal
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:kth:diva-129627 (URN)10.1186/1476-7120-11-33 (DOI)000324140500001 ()2-s2.0-84883074083 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, 245572
Note

QC 20131003

Available from: 2013-10-03 Created: 2013-10-03 Last updated: 2017-12-06Bibliographically approved
2. Investigation of the elimination process of a multimodal polymer-shelled contrast agent in rats using ultrasound and transmission electron microscopy
Open this publication in new window or tab >>Investigation of the elimination process of a multimodal polymer-shelled contrast agent in rats using ultrasound and transmission electron microscopy
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2015 (English)In: Biomedical Spectroscopy and Imaging, ISSN 2212-8794, Vol. 4, no 1, 81-93 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A novel polymer-shelled contrast agent (CA) with multimodal imaging and target specific potential was developed recently and tested for its acoustical properties using different in-vitro setups.

OBJECTIVE: The aim of this study was to investigate the elimination of three types of the novel polymer-shelled CA, one unmodified and two shell modified versions, in rats.

METHODS: The blood elimination time was estimated by measuring the image intensity, from ultrasound images of the common carotid artery, over time after a bolus injection of the three types of the novel CA. The commercially available CA SonoVue was used as a reference. The subcellular localization of the three CAs was investigated using transmission electron microscopy.

RESULTS: The ultrasound measurements indicated a blood half-life of 17–85 s for the different types of the novel CA, which was significant longer than the blood half-life time for SonoVue. Additionally, CAs were exclusively found in the circulatory system, either taken up by, or found in the vicinity of macrophages.

CONCLUSIONS: Compared to the commercially available CA SonoVue, the blood circulation times for the three types of the novel polymer-shelled CA were prolonged. Moreover, macrophages were suggested to be responsible for the elimination of the CA.

Keyword
Contrast agent, polymer, subcellular localization, transmission electron microscope, ultrasound imaging
National Category
Medical Engineering
Research subject
Medical Technology
Identifiers
urn:nbn:se:kth:diva-160905 (URN)10.3233/BSI-140099 (DOI)
Funder
EU, FP7, Seventh Framework Programme, 245572
Note

QC 20150401

Available from: 2015-03-03 Created: 2015-03-03 Last updated: 2017-08-15Bibliographically approved
3. Endocardial border delineation capability of a novel multimodal polymer-shelled contrast agent
Open this publication in new window or tab >>Endocardial border delineation capability of a novel multimodal polymer-shelled contrast agent
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2014 (English)In: Cardiovascular Ultrasound, ISSN 1476-7120, E-ISSN 1476-7120, Vol. 12, 24- p.Article in journal (Refereed) Published
Abstract [en]

Background: A novel polymer-shelled contrast agent (CA) with multimodal and target-specific potential was developed recently. To determine its ultrasonic diagnostic features, we evaluated the endocardial border delineation as visualized in a porcine model and the concomitant effect on physiological variables. Methods: Three doses of the novel polymer-shelled CA (1.5 ml, 3 ml, and 5 ml [5 x 10(8) microbubbles (MBs)/ml]) and the commercially available CA SonoVue (1.5 ml [2-5 x 10(8) MBs/ml]) were used. Visual evaluations of ultrasound images of the left ventricle were independently performed by three observers who graded each segment in a 6-segment model as either 0 = not visible, 1 = weakly visible, or 2 = visible. Moreover, the duration of clinically useful contrast enhancement and the left ventricular opacification were determined. During anesthesia, oxygen saturation, heart rate, and arterial pressure were sampled every minute and the effect of injection of CA on these physiological variables was evaluated. Results: The highest dose of the polymer-shelled CA gave results comparable to SonoVue. Thus, no significant difference in the overall segment score distribution (2-47-95 vs. 1-39-104), time for clinically sufficient contrast enhancement (20-40 s for both) and left ventricular overall opacification was found. In contrast, when comparing the endocardial border delineation capacity for different regions SonoVue showed significantly higher segment scores for base and mid, except for the mid region when injecting 1.5 ml of the polymer-shelled CA. Neither high nor low doses of the polymer-shelled CA significantly affected the investigated physiological variables. Conclusions: This study demonstrated that the novel polymer-shelled CA can be used in contrast-enhanced diagnostic imaging without influence on major physiological variables.

Keyword
Contrast agent, Echocardiography, Endocardial border delineation, Microbubbles, Polyvinyl alcohol, Porcine, Ultrasound
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:kth:diva-148611 (URN)10.1186/1476-7120-12-24 (DOI)000338893900001 ()2-s2.0-84910120890 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, 3MiCRON (245572)
Note

QC 20150401

Available from: 2014-08-12 Created: 2014-08-11 Last updated: 2017-12-05Bibliographically approved
4. The potential clinical value of contrast-enhanced echocardiography beyond current recommendations
Open this publication in new window or tab >>The potential clinical value of contrast-enhanced echocardiography beyond current recommendations
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Image Processing
Identifiers
urn:nbn:se:kth:diva-163385 (URN)
Note

QS 2015

Available from: 2015-03-31 Created: 2015-03-31 Last updated: 2015-04-01Bibliographically approved

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