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Polymer-shelled Ultrasound Contrast Agents: Characterization and Application
KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Marcus Wallenberg Laboratory MWL.ORCID iD: 0000-0002-3699-396X
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ultrasound-based imaging technique is probably the most used approach for rapid investigationand monitoring of anatomical and physiological conditions of internal organs and tissues.Ultrasound-based techniques do not require the use of ionizing radiation making the tests anexceptionally safe and painless. Operating in the frequency range between 1 to 15 MHz, medicalultrasound provides reliable visual and quantitative information from both superficial structuressuch as muscles and tendons, and also deeper organs such as liver and kidney. From the technicalpoint of view medical ultrasound has a good spatial and temporal resolution. Ultrasound machineis mobile or even portable, which makes it truly bedside modality. And last but not the least,ultrasound investigations are cheaper in comparison to other real time imaging techniques.

Ultrasound imaging techniques can be greatly improved by the use of contrast agents to enhancethe signal from the area of interest (e.g. cardiac or liver tissues) relative to the background.Typically ultrasound contrast agent (UCA) is a suspension of the microbubbles consisting of agas core encapsulated within the solid shell. Generally these devices are injected systemically andfunction to passively enhance the ultrasound echo. In recent years, the UCAs have evolved frombeing just a visualization tool to become a new multifunctional and complex device for drug orgene therapy and targeted imaging.

The overall objective of the project is to test novel polymer shelled microbubbles (MBs) as apossible new generation of ultrasound contrast agents.

During the first year of the project an innovative criterion based on cross-correlation analysis toassess the pressure threshold at which ultrasonic waves fracture the polymer shell of microbubblehas been developed. In addition, acoustic properties of these microbubbles which are relevant totheir use both as contrast agents and drug carriers for localized delivery have been preliminarytested. Furthermore, in order to reconstruct viscoelastic properties of the shell the originalChurch’s model (1995) has been implemented. In collaboration with Karolinska Institutet, imagesof the microbubbles have been acquired with conventional imaging system. These imagesdemonstrate the potential of the novel polymer-shelled microbubbles to be used as contractenhancing agents.

The objective of the second year was to describe the acoustic and mechanical properties ofdifferent types of microbubbles synthesised under varied conditions. This task was divided in twointerrelated parts. In the first part acoustic characterization has been completed in low intensityregion with the study of backscattered power, attenuation and phase velocity. In order torecalculate mechanical properties of the shell existing theoretical model has been furtheriimodified to accommodate the frequency dependence of viscoelastic properties andsimultaneously fit the attenuation and phase velocity data. The results concerning acoustic andmechanical properties of the microbubbles have been sent as a feedback to the manufacture inorder to optimize fabrication protocol for effective image acquisition. In the second part acousticcharacterization has been performed in high intensity region under varied parameters ofexperimental set-up. The results that illustrate the dependence of the fracture pressure thresholdon the system parameters allows us to discuss the potential role of polymer-shelled UCAs as drugcarriers and formulate the protocol for save, localized, cavitation-mediated drug delivery.

For the third year the major task was to move on from the bulk volume in vitro tests towards themicrocapillary study and even further to incorporate the microcapillary into the tissue mimickingultrasound phantom. The last study has the objective to take into account the wave propagationthrough tissue. And last but not the least, the application of the polymer-shelled microbubblesfor evaluation of perfusion characteristics, i.e. capillary volume and velocity of the flow, has beenperformed. Similar tests are carried out with commercially available phospholipid-shelled UCA.Using destruction/replenishment technique it is suggested that the novel polymer-shelledmicrobubbles have a potential for a more accurate perfusion evaluation compared to that ofcommercially available phospholipid-shelled UCA.

In conclusion, proposed polymer-shelled gas-core microbubbles provide a viable system to beused among the next generation of ultrasound contrast agents, which facilitate not only imageenhancement relevant to diagnostics but also localized and specific drug delivery for non-invasivetherapy even in acute conditions.

Place, publisher, year, edition, pages
Stockholm: KTH , 2010. , xii, 40 p.
Series
Trita-AVE, ISSN 1651-7660
Keyword [en]
ultrasound, contrast agents, microbubbles, polymer, perfusion
National Category
Fluid Mechanics and Acoustics Other Engineering and Technologies not elsewhere specified Cardiac and Cardiovascular Systems Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:kth:diva-12120ISBN: 978-91-7415-572-3 (print)OAI: oai:DiVA.org:kth-12120DiVA: diva2:302306
Public defence
2010-03-26, F3, Lindstedsvägen 26, KTH, 13:00 (English)
Opponent
Supervisors
Projects
“Systems for insitu theranostics using micro-particles triggered by ultra-sound (SIGHT) (FP6-IST-2005-2.5.2, 2006- 2010)
Note
QC20100723Available from: 2010-03-08 Created: 2010-03-05 Last updated: 2010-07-23Bibliographically approved
List of papers
1. Characterization of ultrasound-induced fracture of polymer-shelled ultrasonic contrast agents by correlation analysis
Open this publication in new window or tab >>Characterization of ultrasound-induced fracture of polymer-shelled ultrasonic contrast agents by correlation analysis
2007 (English)In: Journal of the Acoustical Society of America, ISSN 0001-4966, E-ISSN 1520-8524, Vol. 122, no 4, 2425-2430 p.Article in journal (Refereed) Published
Abstract [en]

Beyond a characteristic value of the negative peak pressure, ultrasound fracture the shell of ultrasonic contrast agents (UCAs). Existing criteria for ascertaining this threshold value exploit the dependence of the amplitude of the UCA acoustic response on the incident pressure. However, under the common experimental conditions used in this work, these criteria appear to be unreliable when they are applied to UCAs that are stabilized by a thick polymeric shell. An alternative criterion for determining the onset of shell fracture is introduced here, which uses variations of the shape of the acoustic time-domain response of an UCA suspension. Experimental evidence is presented that links the changes of the cross-correlation coefficient between consecutive time-domain signals to the fracture of the shells, and consequent release of air microbubbles. In principle, this criterion may be used to characterize similar properties of other types of particles that cannot undergo inertial cavitation.

National Category
Fluid Mechanics and Acoustics
Identifiers
urn:nbn:se:kth:diva-12113 (URN)10.1121/1.2769618 (DOI)000250027000055 ()17902876 (PubMedID)2-s2.0-34848875053 (Scopus ID)
Note
QC20100723Available from: 2010-03-05 Created: 2010-03-05 Last updated: 2017-12-12Bibliographically approved
2. Characterization of acoustic properties of PVA-shelled ultrasound contrast agents: linear properties (Part I)
Open this publication in new window or tab >>Characterization of acoustic properties of PVA-shelled ultrasound contrast agents: linear properties (Part I)
2009 (English)In: Ultrasound in Medicine and Biology, ISSN 0301-5629, E-ISSN 1879-291X, Vol. 35, no 7, 1127-1138 p.Article in journal (Refereed) Published
Abstract [en]

This work examines the linear acoustic behavior of ultrasound contrast agents made of three types of poly (vinyl alcohol) (PVA) shelled microbubbles manufactured at different pH and temperature conditions. Back-scattered power, attenuation coefficient and phase velocity of ultrasonic waves propagating through suspensions of PVA contrast agents were measured at temperature values ranging between 24 degrees C and 37 degrees C in a frequency range from 3 MHz to 13 MHz. Enhancement of the backscattered power higher than 20 dB and displaying a weak dependence on temperature was observed. Attenuation and phase velocity, on the other hand, showed higher sensitivity to temperature variations. A modified version of the Church model, which accounts for the dispersion of the dynamic modulus of the PVA shells, was developed to simultaneously fit the attenuation and phase velocity data at 24 degrees C. The frequency dependence of the storage modulus was found to be that of semiflexible polymeric networks. On the other hand, the frequency dependence of the dynamic loss modulus suggests that additional mechanisms, which may be related to the finite dimensions of the shell and/or to its inhomogeneity, may play a significant role in the dissipation of the acoustic energy. For the microbubbles of interest, this model predicts frequency dependent resonance frequency higher than 100 MHz.

National Category
Fluid Mechanics and Acoustics
Identifiers
urn:nbn:se:kth:diva-12114 (URN)10.1016/j.ultrasmedbio.2009.02.002 (DOI)000267956300010 ()2-s2.0-67649372687 (Scopus ID)
Note
QC20100723Available from: 2010-03-05 Created: 2010-03-05 Last updated: 2017-12-12Bibliographically approved
3. Characterization of acoustic properties of PVA-shelled ultrasound contrast agents: ultrasound-induced fracture (Part II)
Open this publication in new window or tab >>Characterization of acoustic properties of PVA-shelled ultrasound contrast agents: ultrasound-induced fracture (Part II)
2009 (English)In: Ultrasound in Medicine and Biology, ISSN 0301-5629, E-ISSN 1879-291X, Vol. 35, no 7, 1139-1147 p.Article in journal (Refereed) Published
Abstract [en]

Knowledge of the magnitude of the peak negative pressure, P-thr, at which ultrasound contrast agents fracture is relevant for using these microbubbles both as devices for contrast enhancement purposes, as well as carriers of drugs to be delivered locally. In the second part of this communication, the acoustic properties of three types of microbubbles stabilized by poly (vinyl alcohol) (PVA) shells are further investigated. In particular, the dependence of P-thr on system parameters such as the number of cycles, frequency and exposure is examined. The effects of temperature, blood and, wherever data are available, of the dimension of the microbubbles on P-thr are also considered. The large shelf thickness notwithstanding, the results of this investigation show that at room temperature, PVA contrast agents fracture at negative peak pressure values within the recommended safety limit. Furthermore, P-thr decreases with increasing temperature, radius of the microbubbles and number of cycles of the incident wave. Fatigue seems to be a physical mechanism playing a dominant role in the fracture process. The effect of blood on P-thr varies according to condition under which the microbubbles have been synthesized, although stiffening of the shell is observed in most cases. In conclusion, these results suggest that PVA-shelled microbubbles may offer a potentially viable system to be employed for both imaging and therapeutic purposes.

National Category
Fluid Mechanics and Acoustics
Identifiers
urn:nbn:se:kth:diva-12115 (URN)10.1016/j.ultrasmedbio.2009.03.006 (DOI)000267956300011 ()2-s2.0-67649220692 (Scopus ID)
Note
QC20100723Available from: 2010-03-05 Created: 2010-03-05 Last updated: 2017-12-12Bibliographically approved
4. In vitro contrast-enhanced ultrasound measurements of capillary microcirculation: Comparison between polymer- and phospholipid-shelled microbubbles
Open this publication in new window or tab >>In vitro contrast-enhanced ultrasound measurements of capillary microcirculation: Comparison between polymer- and phospholipid-shelled microbubbles
Show others...
2011 (English)In: Ultrasonics, ISSN 0041-624X, E-ISSN 1874-9968, Vol. 51, no 1, 40-48 p.Article in journal (Refereed) Published
Abstract [en]

The focus of contrast-enhanced ultrasound research has developed beyond visualizing the blood pool and its flow to new areas such as perfusion imaging, drug and gene therapy, and targeted imaging. In this work comparison between the application of polymer- and phospholipid-shelled ultrasound contrast agents (UCAs) for characterization of the capillary microcirculation is reported. All experiments are carried out using a microtube as a vessel phantom. The first set of experiments evaluates the optimal concentration level where backscattered signal from microbubbles depends on concentration linearly. For the polymer-shelled UCAs the optimal concentration level is reached at a value of about 2 x 10(4) MB/ml, whereas for the phospholipid-shelled UCAs the optimal level is found at about 1 x 10(5) MB/ml.

Despite the fact that the polymer shell occupies 30% of the radius of microbubble, compared to 0.2% of the phospholipid-shelled bubble, approximately 5-fold lower concentration of the polymer UCA is needed for investigation compared to phospholipid-shelled analogues. In the second set of experiments, destruction/replenishment method with varied time intervals ranging from 2 ms to 3 s between destructive and monitoring pulses is employed. The dependence of the peak-to-peak amplitude of backscattered wave versus pulse interval is fitted with an exponential function of the time gamma = A( 1 - exp(-beta t)) where A represents capillary volume and the time constant beta represents velocity of the flow. Taking into account that backscattered signal is linearly proportional to the microbubble concentration, for both types of the UCAs it is observed that capillary volume is linearly proportional to the concentration of the microbubbles, but the estimation of the flow velocity is not affected by the change of the concentration. Using the single capillary model, for the phospholipid-shelled UCA a delay of about 0.2-0.3 s in evaluation of the perfusion characteristics is found while polymer-shelled UCA provide response immediately. The latter at the concentration lower than 3.6 x 10(5) MB/ml have no statistically significant delay (p < 0.01), do not cause any attenuation of the backscattered signal or saturation of the receiving part of the system. In conclusion, these results suggest that the novel polymer-shelled microbubbles have a potential to be used for perfusion evaluation.

Keyword
Contrast agents, Polymer, Phospholipid, Capillary Perfusion
National Category
Medical Laboratory and Measurements Technologies
Identifiers
urn:nbn:se:kth:diva-12116 (URN)10.1016/j.ultras.2010.05.006 (DOI)000282897500006 ()2-s2.0-77957931904 (Scopus ID)
Note

manuscript number ULTRAS-D-10-00015 QC20100723 Changed to published

Available from: 2010-03-05 Created: 2010-03-05 Last updated: 2017-12-12Bibliographically approved

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