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Investigation of the elimination process of a multimodal polymer-shelled contrast agent in rats using ultrasound and transmission electron microscopy
KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.ORCID iD: 0000-0002-9604-0511
KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.ORCID iD: 0000-0002-4757-7232
KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.ORCID iD: 0000-0002-0569-3374
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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.

Place, publisher, year, edition, pages
2015. Vol. 4, no 1, 81-93 p.
Keyword [en]
Contrast agent, polymer, subcellular localization, transmission electron microscope, ultrasound imaging
National Category
Medical Engineering
Research subject
Medical Technology
Identifiers
URN: urn:nbn:se:kth:diva-160905DOI: 10.3233/BSI-140099OAI: oai:DiVA.org:kth-160905DiVA: diva2:792181
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
In thesis
1. Toward increased applicability of ultrasound contrast agents
Open this publication in new window or tab >>Toward increased applicability of ultrasound contrast agents
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
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:nbn:se:kth:diva-163387 (URN)978-91-7595-496-7 (ISBN)
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
2. Structural studies of microbubbles and molecular chaperones using transmission electron microscopy
Open this publication in new window or tab >>Structural studies of microbubbles and molecular chaperones using transmission electron microscopy
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ultrasound contrast agents (CAs) are typically used in clinic for perfusion studies (blood flow through a specific region) and border delineating (differentiate borders between tissue structures) during cardiac imaging. The CAs used during ultrasound imaging usually consist of gas filled microbubbles (MBs) (diameter 1-5 μm) that are injected intravenously into the circulatory system. This thesis partially involves a novel polymer-shelled ultrasound CA that consists of air filled MBs stabilized by a polyvinyl alcohol (PVA) shell. These MBs could be coupled with superparamagnetic iron oxide nanoparticles (SPIONs) in order to serve as a combined CA for ultrasound and magnetic resonance imaging. The first three papers (Paper A-C) in this thesis investigate the structural characteristic and the elimination process of the CA.

In Paper A, two types (PVA Type A and PVA Type B) of the novel CA were analyzed using transmission electron microscopy (TEM) images of thin sectioned MBs. The images demonstrated that the SPIONs were either attached to the PVA shell surface (PVA Type A) or embedded in the shell (PVA Type B). The average shell thickness of the MBs was determined in Paper B by introducing a model that calculated the shell thickness from TEM images of cross-sectioned MBs. The shell thickness of PVA Type A was determined to 651 nm, whereas the shell thickness of PVA Type B was calculated to 637 nm. In Paper C, a prolonged blood elimination time was obtained for PVA-shelled MBs compared to the lipid-shelled CA SonoVue used in clinic. In addition, TEM analyzed tissue sections showed that the PVA-shelled MBs were recognized by the macrophage system. However, structurally intact MBs were still found in the circulation 24 h post injection. These studies illustrate that the PVA-shelled MBs are stable and offer large chemical variability, which make them suitable as CA for multimodal imaging.

This thesis also involves studies (Paper D-E) of the molecular chaperones (Hsp21 and DNAJB6). The small heat shock protein Hsp21 effectively protects other proteins from unfolding and aggregation during stress. This chaperone ability requires oligomerization of the protein. In Paper D, cryo-electron microscopy together with complementary structural methods, obtained a structure model which showed that the Hsp21 dodecamer (12-mer) is kept together by paired C-terminal interactions.The human protein DNAJB6 functions as a very efficient suppressor of polyglutamine (polyQ) and amyloid-β42 (Aβ42) aggregation. Aggregation of these peptides are associated with development of Huntington’s (polyQ) and Alzheimer’s (Aβ42) disease. In Paper E, a reconstructed map of this highly dynamic protein is presented, showing an oligomer with two-fold symmetry, indicating that the oligomers are assembled by two subunits.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2016. xiii, 58 s p.
Series
TRITA-STH : report, ISSN 1653-3836 ; 2016:3
Keyword
Transmission electron microscopy, Contrast agent, Microbubble, Polyvinyl alcohol, Single particle analysis, Heat shock protein, Molecular chaperone
National Category
Structural Biology
Research subject
Technology and Health
Identifiers
urn:nbn:se:kth:diva-186882 (URN)978-91-7729-020-9 (ISBN)
Public defence
2016-06-08, Hörsalen plan 4 Novum, Blickagången 6, 141 57, Huddinge, 10:00 (English)
Opponent
Supervisors
Note

QC 20160527

Available from: 2016-05-27 Created: 2016-05-16 Last updated: 2016-05-27Bibliographically approved

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Härmark, JohanLarsson, Malin K.Hebert, Hans

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