WFUMB Safety Symposium on Echo-Contrast Agents: nature and types of ultrasound contrast agents.
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Equipment Design↗
Biomedical subjects
Nico de Jong
Publications and source records attributed to Nico de Jong.
Sonoporation from jetting cavitation bubbles.
The fluid dynamic interaction of cavitation bubbles with adherent cells on a substrate is experimentally investigated. We find that the nonspherical collapse of bubbles near to the boundary is responsible for cell detachment. High-speed photography reveals that a wall bounded flow leads to the detachment of cells. Cells at the edge of the circular area of detachment are found to be permanently porated, whereas cells at some distance from the detachment area undergo viable cell membrane poration (sonoporation). The wall flow field leading to cell detachment is modeled with a self-similar solution for a wall jet, together with a kinetic ansatz of adhesive bond rupture. The self-similar solution for the delta-type wall jet compares very well with the full solution of the Navier-Stokes equation for a jet of finite thickness. Apart from annular sites of sonoporation we also find more homogenous patterns of molecule delivery with no cell detachment.
Biophysics↗
Nitric oxide delivery by ultrasonic cracking: some limitations.
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. To test if the quantities of released gas are high enough to allow for NO-delivery in small vessels (ø<200 microm), we analyzed high-speed optical recordings of insonified stiff-shelled microbubbles. These microbubbles were subjected to ultrasonic cracking using 0.5 or 1.7 MHz ultrasound with mechanical index MI>0.6. The mean quantity released from a single microbubble is 1.7 fmol. This is already more than the NO production of a 1mm long vessel with a 50 microm diameter during 100 ms. However, we simulated that the dissolution time of typical released NO microbubbles is equal to the half-life time of NO in whole blood due to scavenging by hemoglobin (1.8 ms), but much smaller than the extravascular half-life time of NO (>90 ms). We conclude that ultrasonic cracking can only be a successful means for nitric oxide delivery, if the gas is released in or near the red blood cell-free plasma next to the endothelium. A complicating factor in the in vivo situation is the variation in blood pressure. Although our simulations and acoustic measurements demonstrate that the dissolution speed of free gas increases with the hydrostatic pressure, the in vitro acoustic amplitudes suggest that the number of released microbubbles decreases at higher hydrostatic pressures. This indicates that ultrasonic cracking mostly occurs during the expansion phase.
Capsules↗
Vibrating microbubbles poking individual cells: drug transfer into cells via sonoporation.
Ultrasound contrast microbubbles have the ability to enhance endothelial cell permeability and thus may be used as a new way to deliver drugs. It facilitates the transfer of extracellular molecules into cells activated through ultrasound driven microbubbles. The present study is designed to correlate the relationship between microbubble induced cell deformation and enhanced cell membrane permeability. Propidium iodide (PI) was used as a membrane integrity probe. Using high-speed imaging of vibrating microbubbles against endothelial cells and imaging transport of PI into these cells showed a direct correlation between cell deformation and resulting cell membrane permeability. The membrane permeabilization lasted for a short period without affecting endothelial cells viability. We identified that microbubbles are crucial to enhance transient cell membrane permeability. Thus, permeability of individual cells is increased. The roles of ultrasound contrast microbubbles as the trigger for improved drug efficacy are discussed.
Animals↗
Nonlinear intravascular ultrasound contrast imaging.
Nonlinear contrast agent imaging with intravascular ultrasound (IVUS) is investigated using a prototype IVUS system and an experimental small bubble contrast agent. The IVUS system employed a mechanically scanned single element transducer and was operated at a 20 MHz transmit frequency (F20) for second harmonic imaging (H40), and at a 40 MHz transmit frequency (F40) for subharmonic imaging (SH20). Characterization experiments were performed with agent and tissue phantom signals acquired during transducer rotation. The suppression of transmit frequency tissue signals was achieved using a combination of pulse-inversion and bandpass filtering. H40 was found to improve the contrast-to-tissue signal ratio (CTR) by up to 22 dB relative to F20, but suffered from tissue propagation harmonics at higher pressures (>0.3 MPa). SH20 was also shown to be possible at a range of pressures (approximately 0.25 to 1.8 MPa), with tissue signals suppressed to near the noise floor. Coronary phantom experiments demonstrated the detection of agent in 1 mm diameter vessels outside a larger 4 mm diameter vessel in which the IVUS catheter was situated. These results suggest the feasibility of harmonic IVUS contrast imaging, which may have applications in coronary lumen boundary detection and vasa vasorum imaging.
Blood Vessels↗
High frequency nonlinear scattering from a micrometer to submicrometer sized lipid encapsulated contrast agent.
An experimental lipid encapsulated contrast agent comprised substantially of micrometer to submicrometer diameter bubbles was evaluated for its capacity to produce nonlinear scattering in response to high transmit frequencies. Agent characterization experiments were conducted at transmit frequencies of 20 and 30 MHz with bandwidths of 5, 15 and 25% using a broadband focused PVDF transducer. The presence of subharmonic energy was observed for all bandwidths at a wide range of pressures (0.49 to 5.7 MPa and 0.45 to 4.5 MPa for the 20 and 30 MHz cases, respectively). Distinct ultraharmonics were observed only in the 5% bandwidth cases. Second harmonic energy was also present, but this was at least partly due to nonlinear propagation, as indicated by linear scatterer signals. Evidence of destruction was found only at higher peak negative pressures (e.g., >2 MPa for 30 MHz 5% bandwidth pulse). The results suggest that small lipid bubble formulations may be useful for the purposes of high frequency nonlinear contrast imaging.
Acoustics↗
Contrast harmonic intravascular ultrasound: a feasibility study for vasa vasorum imaging.
OBJECTIVE: We sought to investigate feasibility of vasa vasorum imaging using the novel technique of contrast harmonic intravascular ultrasound. METHODS: Prototype intravascular ultrasound (IVUS) instrumentation was developed for the sensitive detection of micro-bubble contrast agents. The technique, "harmonic" imaging, involves transmitting ultrasound at 20 MHz (fundamental) and detecting contrast signals at 40 MHz (second harmonic). Phantom experiments were conducted to investigate the detection of a small vessel in the wall surrounding a larger vessel. In vivo experiments were conducted in atherosclerotic rabbit abdominal aortas. RESULTS: The phantom experiments showed improved small vessel detection in harmonic mode relative to fundamental mode. For the in vivo experiments, harmonic imaging enabled the visualization of contrast agent outside the aortic lumen through a statistically significant (P < 0.001) enhancement of image power, consistent with the detection of adventitial microvessels. These microvessels were not detected in fundamental imaging mode. CONCLUSIONS: These results indicate the feasibility of contrast harmonic intravascular ultrasound as a new technique for vasa vasorum imaging.
Animals↗
Design of a multilayer transducer for acoustic bladder volume assessment.
Catheterization remains the "gold standard" for bladder volume assessment, but it is invasive and introduces the risk of infections and traumas. Therefore, noninvasive bladder volume measurement methods have gained interest. In a preceding study a new technique to measure the bladder volume on the basis of nonlinear ultrasound wave propagation was validated. This paper describes a first prototype of a dedicated multilayer transducer to implement this approach. It is composed of a PZT transducer for transmission and a PVDF layer for reception. Acoustical measurements in a water tank and phantom measurements showed that there is a relation between bladder volume and the harmonic contents of the echo obtained from a region of interest behind the bladder. Simulations with an equivalent transducer model on the basis of KLM-circuit modeling closely matched with the results from the acoustical measurements. The results demonstrated the feasibility of the multilayer transducer design for bladder volume assessment on the basis of nonlinear wave propagation.
Animals↗
Harmonic 3-D echocardiography with a fast-rotating ultrasound transducer.
Although the advantages of three-dimensional (3-D) echocardiography have been acknowledged, its application for routine diagnosis is still very limited. This is mainly due to the relatively long acquisition time. Only recently has this problem been addressed with the introduction of new real-time 3-D echo systems. This paper describes the design, characteristics, and capabilities of an alternative concept for rapid 3-D echocardiographic recordings. The presented fast-rotating ultrasound (FRU)-transducer is based on a 64-element phased array that rotates with a maximum speed of 8 Hz (480 rpm). The large bandwidth of the FRU-transducer makes it highly suitable for tissue and contrast harmonic imaging. The transducer presents itself as a conventional phased-array transducer; therefore, it is easily implemented on existing 2-D echo systems, without additional interfacing. The capabilities of the FRU-transducer are illustrated with in-vitro volume measurements, harmonic imaging in combination with a contrast agent, and a preliminary clinical study.
Echocardiography, Three-Dimensional↗
Rapid and accurate measurement of left ventricular function with a new second-harmonic fast-rotating transducer and semi-automated border detection.
Measurement of left ventricular (LV) volume and function are the most common clinical referral questions to the echocardiography laboratory. A fast, practical, and accurate method would offer important advantages to obtain this important information. To validate a new practical method for rapid measurement of LV volume and function. We developed a continuous fast-rotating transducer, with second-harmonic capabilities, for three-dimensional echocardiography (3DE). Fifteen cardiac patients underwent both 3DE and magnetic resonance imaging (reference method) on the same day. 3DE image acquisition was performed during a 10-second breath-hold with a frame rate of 100 frames/sec and a rotational speed of 6 rotations/sec. The individual images were postprocessed with Matlab software using multibeat data fusion. Subsequently, with these images, 12 datasets per cardiac cycle were reconstructed, each comprising seven equidistant cross-sectional images for analysis in the new TomTec 4DLV analysis software, which uses a semi-automated border detection (ABD) algorithm. The ABD requires an average analysis time of 15 minutes per patient. A strong correlation was found between LV end-diastolic volume (r = 0.99; y = 0.95x - 1.14 ml; SEE = 6.5 ml), LV end-systolic volume (r = 0.96; y = 0.89x + 7.91 ml; SEE = 7.0 ml), and LV ejection fraction (r = 0.93; y = 0.69x + 13.36; SEE = 2.4%). Inter- and intraobserver agreement for all measurements was good. The fast-rotating transducer with new ABD software is a dedicated tool for rapid and accurate analysis of LV volume and function.
Adult↗
Left ventricular volume estimation in cardiac three-dimensional ultrasound: a semiautomatic border detection approach.
RATIONALE AND OBJECTIVES: We propose a semiautomatic endocardial border detection method for three-dimensional (3D) time series of cardiac ultrasound (US) data based on pattern matching and dynamic programming, operating on two-dimensional (2D) slices of the 3D plus time data, for the estimation of full cycle left ventricular volume, with minimal user interaction. MATERIALS AND METHODS: The presented method is generally applicable to 3D US data and evaluated on data acquired with the Fast Rotating Ultrasound (FRU-) Transducer, developed by Erasmus Medical Center (Rotterdam, the Netherlands), a conventional phased-array transducer, rotating at very high speed around its image axis. The detection is based on endocardial edge pattern matching using dynamic programming, which is constrained by a 3D plus time shape model. It is applied to an automatically selected subset of 2D images of the original data set, for typically 10 equidistant rotation angles and 16 cardiac phases (160 images). Initialization requires the drawing of four contours per patient manually. We evaluated this method on 14 patients against MRI end-diastole and end-systole volumes. Initialization requires the drawing of four contours per patient manually. We evaluated this method on 14 patients against MRI end-diastolic (ED) and end-systolic (ES) volumes. RESULTS: The semiautomatic border detection approach shows good correlations with MRI ED/ES volumes (r = 0.938) and low interobserver variability (y = 1.005x - 16.7, r = 0.943) over full-cycle volume estimations. It shows a high consistency in tracking the user-defined initial borders over space and time. CONCLUSIONS: We show that the ease of the acquisition using the FRU-transducer and the semiautomatic endocardial border detection method together can provide a way to quickly estimate the left ventricular volume over the full cardiac cycle using little user interaction.
Algorithms↗
High-speed optical observations of contrast agent destruction.
Ultrasound contrast agents are now available since a few years and used for diagnostic purposes. Improved diagnostic decisions have been made possible with new imaging methods that are mainly based on the nonlinear properties of gas microbubbles. Since it is well known that contrast agents are destroyed by ultrasound when the acoustic pressure exceeds a threshold, extremely low acoustic pressures were applied to achieve enhanced contrast image quality. However, destruction of contrast microbubbles is not necessarily undesirable, since it is beneficial in, for example, destruction/reperfusion imaging and recently in drug delivery. We investigate in this experimental study the destruction dynamics of a contrast agent consisting of nitrogen bubbles encapsulated in a double polymer/albumin wall shell. This is accomplished using an ultrafast camera Brandaris that operates at a frame rate of 25 MHz and records 128 frames. The measurements were performed with an ultrasound sine burst of 10 cycles at 1.7 MHz. Different acoustic pressures were applied and various microsphere sizes were examined. The results show three different zones depending on the applied pressure and bubble size: these are nondestruction zone, transient zone and destruction zone. The nondestruction zone is reached for either very small microspheres or low mechanical indices (MI) (<0.3). In the destruction zone lie either large microspheres (5 microm or higher) even when irradiated at low MIs or small microspheres (<5 microm) when the MI is above 0.6. The optical observations revealed that the destruction of the microspheres is characterized by shell rupture and gas release. The release of the gas gives rise to new free microbubble that lasts for a few milliseconds and then disappears due to dissolution. In the transient zone, the microspheres are mainly compressed in the first few cycles but no expansion is induced. After intense compressions, the shell fissures and gas escapes in the last cycles of the burst or during a second burst depending on the initial size and MI. These optical recordings are important to investigate contrast bubble destruction and can help in amplifying or minimizing this process. Indeed, bubble disruption remains the basis of most current sensitive methods for detecting perfusion with contrast agents and is an essential component of perfusion quantification with microbubbles, in addition to drug delivery applications and pressure measurements.
Algorithms↗
Multifrequency transducer for microemboli classification and sizing.
The classification of circulating microemboli as gaseous or particulate matter is essential to establish the relevance of the detected embolic signals. Until now, Doppler techniques have failed to determine unambiguously the nature of circulating microemboli. Recently, a new approach based on the analysis of radio frequency (RF) signal and using the nonlinear characteristics of gaseous bubbles to classify emboli was investigated. The main limitation of these studies was the requirement of two separate transducers for transmission and reception. This paper presents a multi-frequency transducer with two independent transmitting elements and a separate receiving part with a wide frequency band. The transmitting elements are positioned in a concentric design and cover a frequency band between 100 and 600 kHz. The receiving part consists of a polyvinylidene fluoride layer. The new transducer has been tested in vitro using gaseous emboli. It could correctly classify and size air emboli with diameters ranging from 10 microm to 105 microm.
Electromagnetic Phenomena↗
Optical observations of acoustical radiation force effects on individual air bubbles.
Previous studies dealing with contrast agent microbubbles have demonstrated that ultrasound (US) can significantly influence the movement of microbubbles. In this paper, we investigated the influence of the acoustic radiation force on individual air bubbles using high-speed photography. We emphasize the effects of the US parameters (pulse length, acoustic pressure) on different bubble patterns and their consequences on the translational motion of the bubbles. A stream of uniform air bubbles with diameter ranging from 35 microm to 79 microm was generated and insonified with a single US pulse emitted at a frequency of 130 kHz. The bubble sizes have been chosen to be above, below, and at resonance. The peak acoustic pressures used in these experiments ranged from 40 kPa to 120 kPa. The axial displacements of the bubbles produced by the action of the US pulse were optically recorded using a high-speed camera at 1 kHz frame rate. The experimental results were compared to a simplified force balance theoretical model, including the action of the primary radiation force and the fluid drag force. Although the model is quite simple and does not take into account phenomena like bubble shape oscillations and added mass, the experimental findings agree with the predictions. The measured axial displacement increases quasilinearly with the burst length and the transmitted acoustic pressure. The axial displacement varies with the size and the density of the air bubbles, reaching a maximum at the resonance size of 48 microm. The predicted displacement values differ by 15% from the measured data, except for resonant bubbles for which the displacement was overestimated by about 40%. This study demonstrates that even a single US pulse produces radiation forces that are strong enough to affect the bubble position.
Acoustics↗
Harmonic chirp imaging method for ultrasound contrast agent.
Coded excitation is currently used in medical ultrasound to increase signal-to-noise ratio (SNR) and penetration depth. We propose a chirp excitation method for contrast agents using the second harmonic component of the response. This method is based on a compression filter that selectively compresses and extracts the second harmonic component from the received echo signal. Simulations have shown a clear increase in response for chirp excitation over pulse excitation with the same peak amplitude. This was confirmed by two-dimensional (2-D) optical observations of bubble response with a fast framing camera. To evaluate the harmonic compression method, we applied it to simulated bubble echoes, to measured propagation harmonics, and to B-mode scans of a flow phantom and compared it to regular pulse excitation imaging. An increase of approximately 10 dB in SNR was found for chirp excitation. The compression method was found to perform well in terms of resolution. Axial resolution was in all cases within 10% of the axial resolution from pulse excitation. Range side-lobe levels were 30 dB below the main lobe for the simulated bubble echoes and measured propagation harmonics. However, side-lobes were visible in the B-mode contrast images.
Contrast Media↗
Ultrasound-induced gas release from contrast agent microbubbles.
We investigated gas release from two hardshelled 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 microm. 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.
Contrast Media↗
Transducer for harmonic intravascular ultrasound imaging.
A recent study has shown the feasibility of tissue harmonic imaging (THI) using an intravascular ultrasound (IVUS) transducer. This correspondence describes the design, fabrication, and characterization of a THI-optimized piezoelectric transducer with oval aperture of 0.75 mm by 1 mm. The transducer operated at 20 MHz and 40 MHz, and was comprised of a single piezoelectric layer with additional passive layers. The Krimholtz-Leedom-Matthaei (KLM) model was used to iteratively find optimal material properties of the different layers. The transducer characterization showed -6 dB fractional bandwidths of 30% and 25%, and two-way insertion losses of -20 dB and -36 dB, respectively.
Catheterization↗
High-speed photography during ultrasound illustrates potential therapeutic applications of microbubbles.
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 ultrasound. 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.
Biophysical Phenomena↗