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Nano-Engineered Contrast Agents: Toward Multimodal Imaging and Acoustophoresis
KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. (Contrast Enhanced Ultrasound Imaging)ORCID iD: 0000-0003-0129-3442
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 [en]
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: urn:nbn:se:kth:diva-172397ISBN: 978-91-7595-648-0 (print)OAI: oai:DiVA.org:kth-172397DiVA: diva2:847644
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
List of papers
1. Magnetite Nanoparticles Can Be Coupled to Microbubbles to Support Multimodal Imaging
Open this publication in new window or tab >>Magnetite Nanoparticles Can Be Coupled to Microbubbles to Support Multimodal Imaging
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2012 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 13, no 5, 1390-1399 p.Article in journal (Refereed) Published
Abstract [en]

Microbubbles (MBs) are commonly used as injectable ultrasound contrast agent (UCA) in modern ultrasonography. Polymer-shelled UCAs present additional potentialities with respect to marketed lipid-shelled UCAs. They are more robust; that is, they have longer shelf and circulation life, and surface modifications are quite easily accomplished to obtain enhanced targeting and local drug delivery. The next generation of UCAs will be required to support not only ultrasound-based imaging methods but also other complementary diagnostic approaches such as magnetic resonance imaging or computer tomography. This work addresses the features of MBs that could function as contrast agents for both ultrasound and magnetic resonance imaging. The results indicate that the introduction of iron oxide nanoparticles (SPIONs) in the poly(vinyl alcohol) shell or on the external surface of the MBs does not greatly decrease the echogenicity of the host MBs compared with the unmodified one. The presence of SPIONs provides enough magnetic susceptibility to the MBs to accomplish good detectability both in vitro and in vivo. The distribution of SPIONs on the shell and their aggregation state seem to be key factors for the optimization of the transverse relaxation rate.

Keyword
Ultrasound Contrast Agents, Iron-Oxide Nanoparticles, Active Polymeric Microbubbles, Coated Microbubbles, Acoustic Properties, Induced Fracture, In-Vitro, Part I, Delivery, Shell
National Category
Medical Engineering
Identifiers
urn:nbn:se:kth:diva-96726 (URN)10.1021/bm300099f (DOI)000303951600019 ()2-s2.0-84861134310 (Scopus ID)
Note

QC 20150626

Available from: 2012-06-12 Created: 2012-06-11 Last updated: 2017-12-07Bibliographically approved
2. Acoustic characterization and contrast imaging of microbubbles encapsulated by polymeric shells coated or filled with magnetic nanoparticles
Open this publication in new window or tab >>Acoustic characterization and contrast imaging of microbubbles encapsulated by polymeric shells coated or filled with magnetic nanoparticles
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2013 (English)In: Journal of the Acoustical Society of America, ISSN 0001-4966, E-ISSN 1520-8524, Vol. 134, no 5, 3918-3930 p.Article in journal (Refereed) Published
Abstract [en]

The combination of superparamagnetic iron oxide nanoparticles with polymeric air-filled microbubbles is used to produce two types of multimodal contrast agents to enhance medical ultrasound and magnetic resonance imaging. The nanoparticles are either covalently linked to the shell or physically entrapped into the shell. In this paper, the characterization of the acoustic properties (backscattered power, fracturing pressure, attenuation and dispersion of the ultrasonic wave) and ultrasound imaging of the two types of magnetic microbubbles are presented. In vitro B-mode images are generated using a medical ultrasound scanner by applying a nonconventional signal processing technique that is suitable to detect polymeric bubbles and based on the combination of multipulse excitation and chirp coding. Even if both types of microbubbles can be considered to be effective ultrasound contrast agents, the different structure of the shell loaded with nanoparticles has a pronounced effect on the echogenicity and the detection sensitivity of the imaging technique. The best results are obtained using microbubbles that are externally coated with nanoparticles. A backscattered power of 20 dB was achieved at lower concentration, and an increment of 8 dB in the contrast-to-tissue ratio was observed with respect to the more rigid microbubbles with particles entrapped into the shell.

Keyword
Ultrasound-Induced Fracture, Agents, Principles, Velocity, Delivery, Device
National Category
Medical Engineering
Identifiers
urn:nbn:se:kth:diva-136492 (URN)10.1121/1.4824337 (DOI)000326640800070 ()2-s2.0-84887450790 (Scopus ID)
Note

QC 20131209

Available from: 2013-12-09 Created: 2013-12-05 Last updated: 2017-12-06Bibliographically approved
3. On the interplay of shell structure with low- and high-frequency mechanics of multifunctional magnetic microbubbles
Open this publication in new window or tab >>On the interplay of shell structure with low- and high-frequency mechanics of multifunctional magnetic microbubbles
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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.

Keyword
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:nbn:se:kth:diva-134611 (URN)10.1039/c3sm51560e (DOI)000327849000024 ()2-s2.0-84889577207 (Scopus ID)
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
4. Assessment of the Viscoelastic and Oscillation Properties of a Nano-engineered Multimodality Contrast Agent
Open this publication in new window or tab >>Assessment of the Viscoelastic and Oscillation Properties of a Nano-engineered Multimodality Contrast Agent
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2014 (English)In: Ultrasound in Medicine and Biology, ISSN 0301-5629, E-ISSN 1879-291X, Vol. 40, no 10, 2476-2487 p.Article in journal (Refereed) Published
Abstract [en]

Combinations of microbubbles (MBs) and superparamagnetic iron oxide nanoparticles (SPIONs) are used to fabricate dual contrast agents for ultrasound and MRI. This study examines the viscoelastic and oscillation characteristics of two MB types that are manufactured with SPIONs and either anchored chemically on the surface (MBs-chem) or physically embedded (MBs-phys) into a polymer shell. A linearized Church model was employed to simultaneously fit attenuation coefficients and phase velocity spectra that were acquired experimentally. The model predicted lower viscoelastic modulus values, undamped resonance frequencies and total damping ratios for MBs-chem. MBs-chem had a resonance frequency of approximately 13 MHz and a damping ratio of approximately 0.9; thus, MBs-chem can potentially be used as a conventional ultrasound contrast agent with the combined functionality of MRI detection. In contrast, MBs-phys had a resonance frequency and damping of 28 MHz and 1.2, respectively, and requires further modification of clinically available contrast pulse sequences to be visualized.

Keyword
Ultrasound contrast agent, Magnetic microbubbles, Fe3O4 nanoparticles, Harmonic oscillation, Viscoelastic properties
National Category
Medical Engineering
Identifiers
urn:nbn:se:kth:diva-155796 (URN)10.1016/j.ultrasmedbio.2014.05.018 (DOI)000343144400017 ()2-s2.0-84926200070 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, FP7-NMP-2009-LARGE-3
Note

QC 20141117

Available from: 2014-11-17 Created: 2014-11-13 Last updated: 2017-12-05Bibliographically approved
5. Unique pumping-out fracturing mechanism of a polymer-shelled contrast agent: An acoustic characterization and optical visualization
Open this publication in new window or tab >>Unique pumping-out fracturing mechanism of a polymer-shelled contrast agent: An acoustic characterization and optical visualization
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2014 (English)In: IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, ISSN 0885-3010, E-ISSN 1525-8955, Vol. 62, no 3, 451-462 p., 7055440Article in journal (Refereed) Published
Abstract [en]

This work describes the fracturing mechanism of air-filled microbubbles (MBs) encapsulated by a cross-linked poly(vinyl alcohol) (PVA) shell. The radial oscillation and fracturing events following the ultrasound exposure were visualized with an ultrahigh-speed camera, and backscattered timedomain signals were acquired with the acoustic setup specific for harmonic detection. No evidence of gas emerging from defects in the shell with the arrival of the first insonation burst was found. In optical recordings, more than one shell defect was noted, and the gas core was drained without any sign of air extrusion when several consecutive bursts of 1 MPa amplitude were applied. In acoustic tests, the backscattered peak-to-peak voltage gradually reached its maximum and exponentially decreased when the PVA-based MB suspension was exposed to approximately 20 consecutive bursts arriving at pulse repetition frequencies of 100 and 500 Hz. Taking into account that the PVA shell is porous and possibly contains large air pockets between the cross-linked PVA chains, the aforementioned acoustic behavior might be attributed to pumping gas from these pockets in combination with gas release from the core through shell defects. We refer to this fracturing mechanism as pumping-out behavior, and this behavior could have potential use for the local delivery of therapeutic gases, such as nitric oxide.

National Category
Medical Equipment Engineering Medical Image Processing Medical Materials
Identifiers
urn:nbn:se:kth:diva-159768 (URN)10.1109/TUFFC.2014.006732 (DOI)000351446800006 ()2-s2.0-84924942910 (Scopus ID)
Note

The study was financed by EU-grants (3MiCRON ) and strategic money from the Karolinska Institutet.

QC 20150409

Available from: 2015-02-10 Created: 2015-02-10 Last updated: 2017-12-04Bibliographically approved
6. Investigation of Polymer-Shelled Microbubble Motions in Acoustophoresis
Open this publication in new window or tab >>Investigation of Polymer-Shelled Microbubble Motions in Acoustophoresis
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The objective of this paper is to explore the trajectory motion of microsize (typically smaller than a redblood cell) encapsulated polymer-shelled gas bubbles propelled by radiation force in an acousticstanding-wave field and to compare the corresponding movements of solid polymer microbeads. Theexperimental setup consists of a microfluidic chip coupled to a piezoelectric crystal (PZT) with aresonance frequency of about 2.8 MHz. The microfluidic channel consists of a rectangular chamberwith a width, w, corresponding to one wavelength of the ultrasound standing wave. It creates one fullwave ultrasound of a standing-wave pattern with two pressure nodes at4w and43w and threeantinodes at 0,2w , and w. The peak-to-peak amplitude of the electrical potential over the PZT wasvaried between 1 and 10 volts. From Gor’kov’s potential equation, the acoustic contrast factor, Φ, forthe polymer-shelled microbubbles was calculated to about -60.7. Experimental results demonstratethat the polymer-shelled microbubbles are translated and accumulated at the pressure antinode planes.This trajectory motion of polymer-shelled microbubbles toward the pressure antinode plane is similarto what has been described for other acoustic contrast particles with a negative Φ. First, primaryradiation forces dragged the polymer-shelled microbubbles into proximity with each other at thepressure antinode planes. Then, secondary radiation forces caused them to aggregate at different spotsalong the channel. The relocation time for polymer-shelled microbubbles was 40 times shorter thanthat for polymer microbeads, and in contrast to polymer microbeads, the polymer-shelledmicrobubbles were actuated even at driving voltages (proportional to radiation forces) as low as 1 volt.In short, the polymer-shelled microbubbles demonstrate the behavior attributed to the negativeacoustic contrast factor particles and thus can be trapped at the antinode plane and thereby seperatedfrom solid particles, such as cells. This phenomenon could be utilized in exploring future applications,such as bioassay, bioaffinity, and cell interaction studies in vitro in a well-controlled environment.

Keyword
Acoustophoresis, Ultrasound contrast agent, Radiation force, Ultrasound standing wave, Acoustic contrast factor
National Category
Biomedical Laboratory Science/Technology
Research subject
Physics; Fibre and Polymer Science; Medical Technology
Identifiers
urn:nbn:se:kth:diva-172391 (URN)
Projects
3MiCRON
Funder
EU, FP7, Seventh Framework Programme, 245572
Note

QS 2015. This manuscript is review process.

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

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Kothapalli, Satya V.V.N.

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