Partner: N. de Jong |
Supervision of doctoral theses
1. | 2004-09-17 | Postema Michiel (Universiteit Twente) | Medical bubbles | 1247 |
Recent publications
1. | Postema M.♦, ten Cate F.J.♦, Schmitz G.♦, de Jong N.♦, van Wamel A.♦, Generation of a droplet inside a microbubble with the aid of an ultrasound contrast agent: first result, Letters in Drug Design and Discovery, ISSN: 1570-1808, DOI: 10.2174/157018007778992847, Vol.4, pp.74-77, 2007 Abstract: New ultrasound contrast agents that incorporate a therapeutic compound have become of interest. Such an ultrasound contrast agent particle might act as the vehicle to carry a drug or gene load to a perfused region of interest. The load could be released with the assistance of ultrasound. Generally, an increase in shell thickness increases the acoustic amplitude needed to disrupt a bubble. High acoustic amplitudes, however, have been associated with unwanted effects on cells. It would be interesting to incorporate a droplet containing drugs or genes inside a microbubble carrier. A liquid core surrounded by a gas encapsulation has been referred to as antibubble. In this paper, the creation of an antibubble with the aid of ultrasound has been demonstrated with high-speed photography. Keywords:Antibubble, Ultrasound contrast agent, Drug delivery, High-speed photography Affiliations:
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2. | Postema M.♦, Bouakaz A.♦, ten Cate F.J.♦, Schmitz G.♦, de Jong N.♦, van Wamel A.♦, Nitric oxide delivery by ultrasonic cracking: Some limitations, Ultrasonics, ISSN: 0041-624X, DOI: 10.1016/j.ultras.2006.06.003, Vol.44, pp.e109-e113, 2006 Abstract: Nitric oxide (NO) has been implicated in smooth muscle relaxation. Its use has been widespread in cardiology. Due to the effective scavenging of NO by hemoglobin, however, the drug has to be applied locally or in large quantities, to have the effect desired. We propose the use of encapsulated microbubbles that act as a vehicle to carry the gas to a region of interest. By applying a burst of high-amplitude ultrasound, the shell encapsulating the gas can be cracked. Consequently, the gas is released upon which its dissolution and diffusion begins. This process is generally referred to as (ultra)sonic cracking. Nitric oxide, Sonic cracking Affiliations:
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3. | Postema M.♦, van Wamel A.♦, ten Cate F.J.♦, de Jong N.♦, High-speed photography during ultrasound illustrates potential therapeutic applications of microbubbles, Medical Physics, ISSN: 0094-2405, DOI: 10.1118/1.2133718, Vol.32, No.12, pp.3707-3711, 2005 Abstract: Ultrasound contrast agents consist of microscopically small encapsulated bubbles that oscillate upon insonification. To enhance diagnostic ultrasound imaging techniques and to explore therapeutic applications, these medical microbubbles have been studied with the aid of high-speed photography. We filmed medical microbubbles at higher frame rates than the ultrasonic frequency transmitted. Microbubbles with thin lipid shells have been observed to act as microsyringes during one single ultrasonic cycle. This jetting phenomenon presumably causes sonoporation. Furthermore, we observed that the gas content can be forced out of albumin-encapsulated microbubbles. These free bubbles have been observed to jet, too. It is concluded that microbubbles might act as a vehicle to carry a drug in gas phase to a region of interest, where it has to be released by diagnostic ultra- sound. This opens up a whole new area of potential applications of diagnostic ultrasound related to targeted imaging and therapeutic delivery of drugs such as nitric oxide. Keywords:High-speed photography, Ultrasound contrast agent, Therapeutic microbubbles Affiliations:
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4. | Postema M.♦, Bouakaz A.♦, Versluis M.♦, de Jong N.♦, Ultrasound-Induced Gas Release from Contrast Agent Microbubbles, IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, ISSN: 0885-3010, DOI: 10.1109/TUFFC.2005.1504026, Vol.52, No.6, pp.1035-1041, 2005 Abstract: We investigated gas release from two hard- shelled ultrasound contrast agents by subjecting them to high-mechanical index (MI) ultrasound and simultaneously capturing high-speed photographs. At an insonifying frequency of 1.7 MHz, a larger percentage of contrast bubbles is seen to crack than at 0.5 MHz. Most of the released gas bubbles have equilibrium diameters between 1.25 and 1.75 m. Their disappearance was observed optically. Free gas bubbles have equilibrium diameters smaller than the bubbles from which they have been released. Coalescence may account for the long dissolution times acoustically observed and published in previous studies. After sonic cracking, the cracked bubbles stay acoustically active. Keywords:Sonic cracking Affiliations:
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5. | Postema M.♦, de Jong N.♦, Schmitz G.♦, The physics of nanoshelled microbubbles, Biomedical Engineering-Biomedizinische Technik, ISSN: 1862-278X, Vol.50, No.S1, Supplement, pp.748-749, 2005 Abstract: Nanoshelled microbubbles are suitable markers for perfused areas in ultrasonic imaging, and have potential applications in therapy. With radii up to 5 microns, their resonance frequencies are in the lower megahertz range. We explored the physics of nanoshelled microbubbles, with special attention to the influence of the nanoshell on the oscillation offset with respect to the driving phase. Microbubbles above resonance size oscillate π rad out of phase with respect to microbubbles under resonance size. As the damping becomes less, this transition in offset becomes more abrupt. Therefore, the damping due to the friction of the nanoshell can be derived from this abruptness. We support our results with some high-speed optical observations of oscillating microbubbles in an ultrasonic field. Affiliations:
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6. | Postema M.♦, ten Cate F.J.♦, Lancée C.T.♦, Schmitz G.♦, de Jong N.♦, van Wamel A.♦, Ultrasonic destruction of medical microbubbles: an overview, Ultraschall in der Medizin, ISSN: 0172-4614, Vol.26, pp.S32-S33, 2005 Abstract: Purpose: Microbubble, Ultrasound Affiliations:
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7. | Postema M.♦, Marmottant P.♦, Lancée Ch.T.♦, Hilgenfeldt S.♦, de Jong N.♦, Ultrasound-induced microbubble coalescence, ULTRASOUND IN MEDICINE AND BIOLOGY, ISSN: 0301-5629, DOI: 10.1016/j.ultrasmedbio.2004.08.008, Vol.30, No.10, pp.1337-1344, 2004 Abstract: We studied the interaction of ultrasound contrast agent bubbles coated with a layer of lipids, driven by 0.5 MHz ultrasound. High-speed photography on the submicrosecond timescale reveals that some bubbles bounce off each other, while others show very fast coalescence during bubble expansion. This fast coalescence cannot be explained by dissipation-limited film drainage rates. We conclude that the lipid shell ruptures upon expansion, exposing clean free bubble interfaces that support plug flow profiles in the film and inertia-limited drainage whose time scales match those of the observed coalescence. Keywords:Microbubble coalescence, Ultrasound contrast agent, Film drainage, High-speed photography Affiliations:
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8. | Postema M.♦, Van Wamel A.♦, Lancee Ch.T.♦, De Jong N.♦, Ultrasound-induced encapsulated microbubble phenomena, ULTRASOUND IN MEDICINE AND BIOLOGY, ISSN: 0301-5629, DOI: 10.1016/j.ultrasmedbio.2004.02.010, Vol.30, No.6, pp.827-840, 2004 Abstract: When encapsulated microbubbles are subjected to high-amplitude ultrasound, the following phenomena have been reported: oscillation, translation, coalescence, fragmentation, sonic cracking and jetting. In this paper, we explain these phenomena, based on theories that were validated for relatively big, free (not encapsulated) gas bubbles. These theories are compared with high-speed optical observations of insonified contrast agent microbubbles. Furthermore, the potential clinical applications of the bubble-ultrasound interaction are explored. We conclude that most of the results obtained are consistent with free gas bubble theory. Similar to cavitation theory, the number of fragments after bubble fission is in agreement with the dominant spherical harmonic oscillation mode. Remarkable are our observations of jetting through contrast agent microbubbles. The pressure at the tip of a jet is high enough to penetrate any human cell. Hence, liquid jets may act as remote-controlled microsyringes, delivering a drug to a region-of-interest. Encapsulated microbubbles have (potential) clinical applications in both diagnostics and therapeutics. Keywords:Encapsulated microbubbles, Ultrasound contrast agent, Radiation forces, Coalescence, Fragmentation, Jets Affiliations:
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9. | Postema M.♦, Bouakaz A.♦, de Jong N.♦, Noninvasive microbubble-based pressure measurements: a simulation study, Ultrasonics, ISSN: 0041-624X, DOI: 10.1016/j.ultras.2003.12.007, Vol.42, No.1-9, pp.759-762, 2004 Abstract: This paper describes a noninvasive method to measure local hydrostatic pressures in fluid filled cavities. The method is based on the disappearance time of a gas bubble, as the disappearance time is related to the hydrostatic pressure. When a bubble shrinks, its response to ultrasound changes. From this response, the disappearance time, and with it the hydrostatic pressure, can be determined. Noninvasive pressure measurement, Blood pressure, Microbubble, Sonic cracking Affiliations:
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10. | Postema M.♦, van Wamel A.♦, Schmitz G.♦, de Jong N.♦, Slingerende belletjes, gerichte medicijnbezorging en microïnjectienaalden, Klinische fysica, ISSN: 0168-7026, Vol.3+4, pp.6-9, 2004 Abstract: Ultrasound contrast agents consist of microscopically small encapsulated bubbles that oscillate upon insonification. To enhance diagnostic ultrasound imaging techniques and to explore therapeutic applications, these medical bubbles have been studied with the aid of high-speed photography. We filmed medical bubbles at higher frame rates than the ultrasonic frequency transmitted. Microbubbles have - among others - been observed to fragment and jet during one single ultrasonic cycle. Gas was released from encapsulated microbubbles. It is concluded that bubbles might act as a vehicle to carry a drug in gas phase to a region of interest, where it has to be released by ultrasound whose amplitudes are still in the diagnostic range. Keywords:Oscillating bubbles, Targeted drug delivery, Micro-injection needles Affiliations:
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11. | Postema M.♦, Bouakaz A.♦, Chin C.T.♦, de Jong N.♦, Simulations and Measurements of Optical Images of Insonified Ultrasound Contrast Microbubbles, IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, ISSN: 0885-3010, DOI: 10.1109/TUFFC.2003.1201465, Vol.50, No.5, pp.523-536, 2003 Abstract: Ultrasound contrast agents (UCAs) are used in a clinical setting to enhance the backscattered signal from the blood pool to estimate perfusion and blood flow. The UCAs consist of encapsulated microbubbles, measuring 1–10 m in diameter. Acoustic characterization of UCAs is generally carried out from an ensemble of bubbles. The measured signal is a complicated summation of all signals from the individual microbubbles. Hence, characterization of a single bubble from acoustic measurements is complex.
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12. | Postema M.♦, Bouakaz A.♦, Chin C.T.♦, de Jong N.♦, Optical observations of ultrasound contrast agent destruction, ACTA ACUSTICA UNITED WITH ACUSTICA, ISSN: 1610-1928, Vol.89, pp.728, 2003 | |||||||||||||||||||
13. | Postema M.♦, Bouakaz A.♦, de Jong N.♦, March 2002, IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, ISSN: 0885-3010, Vol.49, No.3, pp.c1-c2, 2002 Abstract: The cover page shows a sequence of microscopic image frames of a freely flowing contrast agent microbubble. The frames were taken during one cycle of ultrasound insonification, with a center frequency of 500 kHz. The peak negative acoustic pressure at the region of interest was 0.85 MPa. Each frame corresponds to a 45 x 27 μm2 area. The exposure time of each frame was 10 ns. Interframe times were 330 ns, except for the time between frames e and f, which was 660 ns. The sequence shows a growing gas encapsulated microbubble of 5.3 μm (a) and 17.6 μm (b), and its maximal growth of 22.9 μm (c). After shrinking to 20.2 μm (d), it ruptured (e). The microbubble had been pushed to the lower left side of the frame, apparently by water that was propelled into the microbubble. A subframe shows the negative of the region of interest. Finally, the deformed mcrobubble re-occurred as an assymetric shape (f). Understanding of microbubble-rupturing behavior is neccessary for developments in medical release burst imaging and ultra- sound-guided drug delivery. This work has been supported by the Technology Foundation STW (RKG.5104) and the Interuniversity Cardiology Institute of The Netherlands. Affiliations:
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Conference papers
1. | Postema M.♦, de Jong N.♦, Schmitz G.♦, Nonlinear behavior of ultrasound-insonified encapsulated microbubbles, ISNA 17, Innovation in Nonlinear Accoustics: 17th International Symposium on Nonlinear Acoustics Including the International Sonic Boom Forum, 2005-07-18/07-22, State College (US), DOI: 10.1063/1.2210361, pp.275-278, 2006 Abstract: Ultrasound contrast agents consist of small encapsulated bubbles with diameters below 10 μ m. The encapsulation influences the behavior of these microbubbles when they are insonified by ultrasound. The highly nonlinear behavior of ultrasound contrast agents at relatively high acoustic amplitudes (mechanical index>0.6) has been attributed to nonlinear bubble oscillations and to bubble destruction. For microbubbles with a thin, highly elastic nanoshell, it has been demonstrated that the presence of the nanoshell becomes negligible at high insonifying amplitudes. From our simulations it follows that the Blake critical radius is not valid for microbubble fragmentation. The low maximal excursion observed and simulated for a thick, stiff-shelled microbubble is in agreement with previous acoustic analyses. The ultrasound-induced gas release from stiff-shelled bubbles has been reported. However, we also observed gas release from microbubbles with a thin, elastic shell. Keywords:Ultrasound contrast agent, Encapsulated microbubble, Nanoshell Affiliations:
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2. | Postema M.♦, de Jong N.♦, Schmitz G.♦, van Wamel A.♦, Creating antibubbles with ultrasound, IUS 2005, IEEE International Ultrasonics Symposium, 2005-09-18/09-21, Rotterdam (NL), DOI: 10.1109/ULTSYM.2005.1603013, Vol.2, pp.977-980, 2005 Abstract: Ultrasound contrast agents have been investigated for their potential applications in local drug and gene delivery. A microbubble might act as the vehicle to carry a drug or gene load to a perfused region of interest. The load has to be released with the assistance of ultrasound. We investigate the suitability of antibubbles for ultrasound-assisted local delivery. As opposed to bubbles, antibubbles consist of a liquid core surrounded by a gas encapsulation. Incorporating a liquid drop containing drugs or genes inside an ultrasound contrast agent microbubble, however, is technically challenging. Antibubble, Ultrasound Affiliations:
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3. | Postema M.♦, de Jong N.♦, Schmitz G.♦, Shell rupture threshold, fragmentation threshold, Blake threshold, IUS 2005, IEEE International Ultrasonics Symposium, 2005-09-18/09-21, Rotterdam (NL), DOI: 10.1109/ULTSYM.2005.1603194, Vol.3, pp.1708-1711, 2005 Abstract: The disruption of contrast agent microbubbles has been implicated in novel techniques for high-MI imaging and local drug delivery. At MI>0.6, microbubble fragmentation has been observed with thin-shelled agent (≈10nm), and shell rupture with thick-shelled agent (≈250nm). To predict the disruption of these nanoshelled microbubbles, destruction thresholds have been under investigation. In several studies, the Blake threshold pressure was associated with microbubble destruction. The Blake threshold pressure is the peak rarefactional acoustic pressure at which the critical Blake radius is reached, approximately twice the equilibrium radius, above which a bubble behaves like an inertial cavity. We studied the acoustic pressures at which a thin-shelled microbubble fragments and those at which a thick-shelled microbubble cracks. More specifically, we investigated the validity of the Blake threshold for these phenomena. The oscillating and fragmenting behavior of microbubbles with a 10nm shell was simulated at a driving frequency of 0.5–2 MHz, using a modified Rayleigh-Plesset equation and assuming that fragmentation occurs when the kinetic energy of the microbubble surpasses the instantaneous bubble surface energy. For microbubbles with radii between 1 and 6μm, the fragmentation thresholds lie between 20 and 200 kPa. Generally, the critical radius is much smaller than twice the equilibrium radius. The moment of break-up during the collapse phase is in agreement with high- speed optical observations that were presented previously. Shell rupture, Fragmentation threshold, Blake threshold Affiliations:
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4. | Postema M.♦, Marmottant P.♦, Lancée C.T.♦, Versluis M.♦, Hilgenfeldt S.♦, de Jong N.♦, Ultrasound-induced coalescence of free gas microbubbles, IUS 2004, IEEE International Ultrasonics Symposium, 2004-08-23/08-27, Montreal (CA), DOI: 10.1109/ULTSYM.2004.1417653, Vol.1, pp.1-4, 2004 Abstract: When gas bubbles collide, the following stages of bubble coalescence have been reported: flattening of the opposing bubble surfaces prior to contact, drainage of the interposed liquid film toward a critical minimal thickness, rupture of the liquid film, and formation of a single bubble. During insonification, expanding contrast agent microbubbles may collide with each other, resulting in coalescence or bounce.
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5. | de Jong N.♦, Bouakaz A.♦, van Wamel A.♦, Postema M.♦, Versluis M.♦, Microbubbles for ultrasound imaging and therapy, Workshop on Ultrasound in Biomeasurements, Diagnostics and Therapy, Vol.2, pp.123-126, 2004 | |||||||||||||||||||
6. | Postema M.♦, Bouakaz A.♦, Chin C.T.♦, de Jong N.♦, Optically observed microbubble coalescence and collapse, IUS 2002, IEEE Ultrasonics Symposium, 2002-10-08/10-11, Monachium (DE), DOI: 10.1109/ULTSYM.2002.1192681, Vol.2, pp.1900-1903, 2002 Abstract: Understanding the mechanisms of microbubble destruction is needed for the development of ultrasound guided drug and gene delivery methods and for the improvement of diagnostic ultrasonic contrast agent (UCA) detection methods. We performed 482 experiments on the coalescence and collapse mechanisms of a soft- shelled and a hard-shelled contrast agent, by subjecting an experimental lipid-shelled UCA and the hard-shelled UCA QuantisonTM to 500 kHz, high- pressured ultrasound (MI≈1.0), and recording microscopic images of these events with a fast- framing camera. Results showed that bubble fragmentation into smaller bubbles is the primary mechanism for lipid-shelled contrast microbubble destruction during the first cycles after ultrasound arrival. In 28% of our experimental events with a lipid-shelled UCA, we observed bubble coalescence. The coalescence mechanism was observed to be analog to the process desribed for larger gas bubbles. Repetitive coalescence and fragmentation was clearly recorded with a fast-framing camera. We also demonstrated the formation and collapse of large lipid-shelled bubbles and bubble clusters. Furthermore we showed that sonic cracking is feasible for the hard-shelled contrast agent QuantisonTM. Affiliations:
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7. | Postema M.♦, Bouakaz A.♦, Chin C.T.♦, de Jong N.♦, Real-time optical imaging of individual microbubbles in an ultrasound field, IUS 2001, IEEE International Ultrasonics Symposium, 2001-10-07/10-10, Atlanta (US), DOI: 10.1109/ULTSYM.2001.992044, Vol.2, pp.1679-1682, 2001 Abstract: In this study we analyze the behavior of individual experimental ultrasonic contrast bubbles, insonofied by 500 kHz ultrasound, at acoustic pressures between 0.06 and 0.66 MPa. The oscillations were observed under a microscope with a fast framing camera.
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Conference abstracts
1. | Postema M.♦, Marmottant P.♦, Lancée C.♦, Hilgenfeldt S.♦, de Jong N.♦, Ultrasound-induced microbubble coalescence by parametric instability, 10th Dutch Annual Conference on BioMedical Engineering, pp.177, 2003 |