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On the interplay of shell structure with low- and high-frequency mechanics of multifunctional magnetic microbubbles
KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.ORCID iD: 0000-0002-3699-396X
KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.ORCID iD: 0000-0002-9604-0511
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2014 (English)In: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 10, no 1, 214-226 p.Article in journal (Refereed) Published
Abstract [en]

Polymer-shelled magnetic microbubbles have great potential as hybrid contrast agents for ultrasound and magnetic resonance imaging. In this work, we studied US/MRI contrast agents based on air-filled poly(vinyl alcohol)-shelled microbubbles combined with superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs are integrated either physically or chemically into the polymeric shell of the microbubbles (MBs). As a result, two different designs of a hybrid contrast agent are obtained. With the physical approach, SPIONs are embedded inside the polymeric shell and with the chemical approach SPIONs are covalently linked to the shell surface. The structural design of hybrid probes is important, because it strongly determines the contrast agent's response in the considered imaging methods. In particular, we were interested how structural differences affect the shell's mechanical properties, which play a key role for the MBs' US imaging performance. Therefore, we thoroughly characterized the MBs' geometric features and investigated low-frequency mechanics by using atomic force microscopy (AFM) and high-frequency mechanics by using acoustic tests. Thus, we were able to quantify the impact of the used SPIONs integration method on the shell's elastic modulus, shear modulus and shear viscosity. In summary, the suggested approach contributes to an improved understanding of structure-property relations in US-active hybrid contrast agents and thus provides the basis for their sustainable development and optimization.

Place, publisher, year, edition, pages
2014. Vol. 10, no 1, 214-226 p.
Keyword [en]
Geometric feature, High frequency HF, Imaging performance, Integration method, Physical approaches, Structural differences, Structure property relation, Superparamagnetic iron oxide nanoparticles
National Category
Medical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-134611DOI: 10.1039/c3sm51560eISI: 000327849000024Scopus ID: 2-s2.0-84889577207OAI: oai:DiVA.org:kth-134611DiVA: diva2:667092
Funder
EU, FP7, Seventh Framework Programme, 245572
Note

QC 20150626

Available from: 2013-11-25 Created: 2013-11-25 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Ultrasound Contrast Agents Loaded with Magnetic Nanoparticles: Acoustic and Mechanical Characterization
Open this publication in new window or tab >>Ultrasound Contrast Agents Loaded with Magnetic Nanoparticles: Acoustic and Mechanical Characterization
2013 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

The current methodologies in body scanning diagnostic uses different simultaneous imaging modalities like Ultrasound (US), magnetic resonance imaging (MRI), single photon emission tomography (SPECT) and positron emission tomography (PET). The field requires combination of different modalities for effective use in clinical diagnostics. Such incorporation of different modalities has already been achieved. For example, PET-CT hybrid scanner is designed to acquire align functional and anatomical images and recently US-MRI scanner has successfully shown to improve diagnosis of prostate cancer. The non ionizing radiation hybrid US-MRI is of great interest in health care industry. Further these US and MRI modalities uses different contrast agents like micro-sized gas bubbles (MBs) encapsulated by surfactant for US and superparamagnetic nanoparticles for MRI imaging modalities to further enables new diagnostic opportunities and therapeutic applications. Recently in our 3MiCRON project, we have developed the multimodal contrast agent that could be supported for both US and MRI. This was achieved by coating the magnetic nanoparticles to the poly vinyl alcohol (PVA) surfactant shelled MBs. The nanoparticles in the shell effect the structure can alter the MBs performance as an ultrasound contrast agent. The present thesis is conducted to examine the acoustic and mechanical properties of such multimodal contrast agents.

These multimodal contrast agents were prepared by coating the surface of PVA-shelled MBs by two following strategies: (1) The superparamagnetic iron oxide (Fe3O4) nano-particles (SPIONs) were chemically anchored to the surface of poly vinyl alcohol (PVA) shelled MBs namely MBs-chem and (2) in the second strategy the SPIONs were physical entrapped into the PVA shell while formation of PVA surface on the gas bubble were named as MBs-phys. To understand the scattering efficiency and viscoelastic properties of these modified agents, we investigated the backscattering power, attenuation coefficient and phase velocity measurements. Our acoustic experimental results indicate that both the modified MBs and non-modified plain PVA-shelled ultrasound contrast agents have the same echogenic response. The investigation of mechanical properties of modified MBs revealed that the attached SPIONs on the PVA shell has reduced the stiffness of MBs-chem shell, while, the SPIONs inside the shell has increased MBs-phys stiffness. As a result, MBs-chem exhibits soft shell behavior under ultrasound exposure than both MBs-phys. Finally, the images were obtained through the MRI investigations at the department of Radiology, Karolinksa Institute, has demonstrated that both MB types have enough magnetic susceptibility that further provides good detectability in vitro and in vivo. As an outlook, the modified magnetic gas bubbles, i.e. both MBs-chem and MBs-phys can be proposed as a potential contrast agent for both US and MR imaging and can be further utilized in potential therapeutic applications.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2013. viii, 40 p.
Series
Trita-STH : report, ISSN 1653-3836 ; 2013:6
Keyword
Ultrasound contrast agents, SPION nanoparticles, harmonic oscillation, backscattering power, attenuation coefficient, phase velocity, nonlinear equation of motion
National Category
Medical Engineering
Identifiers
urn:nbn:se:kth:diva-134616 (URN)978-91-7501-951-2 (ISBN)
Presentation
2013-12-06, Room 7B, Alfred Nobels Allé 8 Flemingsberg, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

QC 20131126

Available from: 2013-11-26 Created: 2013-11-26 Last updated: 2013-11-26Bibliographically approved
2. Nano-Engineered Contrast Agents: Toward Multimodal Imaging and Acoustophoresis
Open this publication in new window or tab >>Nano-Engineered Contrast Agents: Toward Multimodal Imaging and Acoustophoresis
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diagnostic ultrasound (US) is safer, quicker and cheaper than other diagnostic imaging modalities. Over the past two decades, the applications of US imaging has been widened due to the development of injectable, compressible and encapsulated microbubbles (MBs) that provide an opportunity to improve conventional echocardiographic imaging, blood flow assessment and molecular imaging. The encapsulating material is manufactured by different biocompatible materials such as proteins, lipids or polymers. In current research, researchers modify the encapsulated shell with the help of advanced molecular chemistry techniques to load them with dyes (for fluorescent imaging), nanoparticles and radioisotopes (for multimodal imaging) or functional ligands or therapeutic gases (for local drug delivery). The echogenicity and the radial oscillation of MBs is the result of their compressibility, which undoubtedly varies with the encapsulated shell characteristics such as rigidity or elasticity.

In this thesis, we present acoustic properties of novel type of polyvinyl alcohol (PVA)-shelled microbubble (PVA-MB) that was further modified with superparamagnetic iron oxide nanoparticles (SPIONs) to work as a dual-modal contrast agent for magnetic resonance (MR) imaging along with US imaging. Apparently, the shell modification changes their mechanical characteristics, which affects their acoustic properties. The overall objective of the thesis is to investigate the acoustic properties of modified and unmodified PVA-MBs at different ultrasound parameters.

The acoustic and mechanical characterization of SPIONs modified PVA-MBs revealed that the acoustical response depends on the SPION inclusion strategy. However they retain the same structural characteristics after the modification. The modified MBs with SPIONs included on the surface of the PVA shell exhibit a soft-shelled behavior and produce a higher echogenicity than the MBs with the SPIONs inside the PVA shell. The fracturing mechanism of the unmodified PVA-MBs was identified to be different from the other fracturing mechanisms of conventional MBs. With the interaction of high-pressure bursts, the air gas core is squeezed out through small punctures in the PVA shell. During the fracturing, the PVA-MBs exhibit asymmetric (other modes) oscillations, resulting in sub- and ultra-harmonic generation. Exploiting the US imaging at the other modes of the oscillation of the PVA-MBs would provide an opportunity to visualize very low concentrations of (down to single) PVA-MBs. We further introduced the PVA-MBs along with particles mimicking red blood cells in an acoustic standing-wave field to observe the acoustic radiation force effect. We observed that the compressible PVA-MBs drawn toward pressure antinode while the solid blood phantoms moved toward the pressure node. This acoustic separation method (acoustophoresis) could be an efficient tool for studying the bioclearance of the PVA-MBs in the body, either by collecting blood samples (in-vitro) or by using the extracorporeal medical procedure (ex-vivo) at different organs.

Overall, this work contributes significant feedback for chemists (to optimize the nanoparticle inclusion) and imaging groups (to develop new imaging sequences), and the positive findings pave new paths and provide triggers to engage in further research. 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. x, 53 p.
Series
TRITA-STH : report, ISSN 1653-3836 ; 2015:5
Keyword
Nano-engineered microbubbles, SPION nanoparticles, Acoustic characterization of MBs, Fracturing mechanism of MBs, Opto-acoustics, Acoustophoresis
National Category
Medical Laboratory and Measurements Technologies Medical Image Processing Nano Technology Signal Processing Polymer Technologies
Research subject
Physics; Järnvägsgruppen - Ljud och vibrationer; Technology and Health
Identifiers
urn:nbn:se:kth:diva-172397 (URN)978-91-7595-648-0 (ISBN)
Public defence
2015-09-22, 3221, Alfred Nobels Álle 8, Hudding, 09:00 (English)
Opponent
Supervisors
Projects
3MiCRON
Funder
EU, FP7, Seventh Framework Programme, 245572
Note

QC 20150827

Available from: 2015-08-26 Created: 2015-08-20 Last updated: 2015-08-27Bibliographically approved

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Grishenkov, DmitryHärmark, JohanHebert, Hans

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