Nico de Jong

Acoustic droplet vaporization is initiated by superharmonic focusing.

Significance This work explains the long-standing puzzle of the physical mechanisms underlying acoustic droplet vaporization (ADV). ADV makes use of low-boiling-point perfluorocarbon droplets that become metastable once injected into the body, where they can be activated by high-intensity ultrasound. How ultrasound can physically trigger the vaporization remained elusive, also given the large mismatch between the ultrasound wavelength and the droplet size. Here we show that vaporization is preceded by nonlinear propagation of the ultrasound wave generating superharmonics. These high-frequency waves focus efficiently within the droplet, triggering vaporization. ADV shows great potential for advanced medical diagnosis and therapy. Our new understanding allows for further reduction of the required pressure amplitudes, thereby minimizing the adverse effects on healthy tissue. Acoustically sensitive emulsion droplets composed of a liquid perfluorocarbon have the potential to be a highly efficient system for local drug delivery, embolotherapy, or for tumor imaging. The physical mechanisms underlying the acoustic activation of these phase-change emulsions into a bubbly dispersion, termed acoustic droplet vaporization, have not been well understood. The droplets have a very high activation threshold; its frequency dependence does not comply with homogeneous nucleation theory and localized nucleation spots have been observed. Here we show that acoustic droplet vaporization is initiated by a combination of two phenomena: highly nonlinear distortion of the acoustic wave before it hits the droplet and focusing of the distorted wave by the droplet itself. At high excitation pressures, nonlinear distortion causes significant superharmonics with wavelengths of the order of the droplet size. These superharmonics strongly contribute to the focusing effect; therefore, the proposed mechanism also explains the observed pressure thresholding effect. Our interpretation is validated with experimental data captured with an ultrahigh-speed camera on the positions of the nucleation spots, where we find excellent agreement with the theoretical prediction. Moreover, the presented mechanism explains the hitherto counterintuitive dependence of the nucleation threshold on the ultrasound frequency. The physical insight allows for the optimization of acoustic droplet vaporization for therapeutic applications, in particular with respect to the acoustic pressures required for activation, thereby minimizing the negative bioeffects associated with the use of high-intensity ultrasound.

High-Definition Imaging of Carotid Artery Wall Dynamics

The carotid artery (CA) is central to cardiovascular research, because of the clinical relevance of CA plaques as culprits of stroke and the accessibility of the CA for cardiovascular screening. The viscoelastic state of this artery, essential for clinical evaluation, can be assessed by observing arterial deformation in response to the pressure changes throughout the cardiac cycle. Ultrasound imaging has proven to be an excellent tool to monitor these dynamic deformation processes. We describe how a new technique called high-frame-rate ultrasound imaging captures the tissue deformation dynamics throughout the cardiac cycle in unprecedented detail. Local tissue motion exhibits distinct features of sub-micrometer displacements on a sub-millisecond time scale. We present a high-definition motion analysis technique based on plane wave ultrasound imaging able to capture these features. We validated this method by screening a group of healthy volunteers and compared the results with those for two patients known to have atherosclerosis to illustrate the potential utility of this technique.

Lipid Shedding from Single Oscillating Microbubbles

Lipid-coated microbubbles are used clinically as contrast agents for ultrasound imaging and are being developed for a variety of therapeutic applications. The lipid encapsulation and shedding of the lipids by acoustic driving of the microbubble has a crucial role in microbubble stability and in ultrasound-triggered drug delivery; however, little is known about the dynamics of lipid shedding under ultrasound excitation. Here we describe a study that optically characterized the lipid shedding behavior of individual microbubbles on a time scale of nanoseconds to microseconds. A single ultrasound burst of 20 to 1000 cycles, with a frequency of 1 MHz and an acoustic pressure varying from 50 to 425 kPa, was applied. In the first step, high-speed fluorescence imaging was performed at 150,000 frames per second to capture the instantaneous dynamics of lipid shedding. Lipid detachment was observed within the first few cycles of ultrasound. Subsequently, the detached lipids were transported by the surrounding flow field, either parallel to the focal plane (in-plane shedding) or in a trajectory perpendicular to the focal plane (out-of-plane shedding). In the second step, the onset of lipid shedding was studied as a function of the acoustic driving parameters, for example, pressure, number of cycles, bubble size and oscillation amplitude. The latter was recorded with an ultrafast framing camera running at 10 million frames per second. A threshold for lipid shedding under ultrasound excitation was found for a relative bubble oscillation amplitude >30%. Lipid shedding was found to be reproducible, indicating that the shedding event can be controlled.

Imaging Microvasculature with Contrast-Enhanced Ultraharmonic Ultrasound

Atherosclerotic plaque neovascularization was shown to be one of the strongest predictors of future cardiovascular events. Yet, the clinical tools for coronary wall microvasculature detection in vivo are lacking. Here we report an ultrasound pulse sequence capable of detecting microvasculature invisible in conventional intracoronary imaging. The method combines intravascular ultrasound with an ultrasound contrast agent, i.e., a suspension of microscopic vascular acoustic resonators that are small enough to penetrate the capillary bed after intravenous administration. The pulse sequence relies on brief chirp excitations to extract ultraharmonic echoes specific to the ultrasound contrast agent. We implemented the pulse sequence on an intravascular ultrasound probe and successfully imaged the microvasculature of a 6 days old chicken embryo respiratory organ. The feasibility of microvasculature imaging with intravascular ultrasound sets the stage for a translation of the method to studies of intra-plaque neovascularization detection in humans.

Viability of endothelial cells after ultrasound-mediated sonoporation: Influence of targeting, oscillation, and displacement of microbubbles

Microbubbles (MBs) have been shown to create transient or lethal pores in cell membranes under the influence of ultrasound, known as ultrasound-mediated sonoporation. Several studies have reported enhanced drug delivery or local cell death induced by MBs that are either targeted to a specific biomarker (targeted microbubbles, tMBs) or that are not targeted (non-targeted microbubbles, ntMBs). However, both the exact mechanism and the optimal acoustic settings for sonoporation are still unknown. In this study we used real-time uptake patterns of propidium iodide, a fluorescent cell impermeable model drug, as a measure for sonoporation. Combined with high-speed optical recordings of MB displacement and ultra-high-speed recordings of MB oscillation, we aimed to identify differences in MB behavior responsible for either viable sonoporation or cell death. We compared ntMBs and tMBs with identical shell compositions exposed to long acoustic pulses (500-50,000cycles) at various pressures (150-500kPa). Propidium iodide uptake highly correlated with cell viability; when the fluorescence intensity still increased 120s after opening of the pore, this resulted in cell death. Higher acoustic pressures and longer cycles resulted in more displacing MBs and enhanced sonoporation. Non-displacing MBs were found to be the main contributor to cell death, while displacement of tMBs enhanced reversible sonoporation and preserved cell viability. Consequently, each therapeutic application requires different settings: non-displacing ntMBs or tMBs are advantageous for therapies requiring cell death, especially at 500kPa and 50,000cycles, whereas short acoustic pulses causing limited displacement should be used for drug delivery.

A Prototype PZT Matrix Transducer With Low-Power Integrated Receive ASIC for 3-D Transesophageal Echocardiography

This paper presents the design, fabrication, and experimental evaluation of a prototype lead zirconium titanate (PZT) matrix transducer with an integrated receive ASIC, as a proof of concept for a miniature three-dimensional (3-D) transesophageal echocardiography (TEE) probe. It consists of an array of 9 × 12 piezoelectric elements mounted on the ASIC via an integration scheme that involves direct electrical connections between a bond-pad array on the ASIC and the transducer elements. The ASIC addresses the critical challenge of reducing cable count, and includes front-end amplifiers with adjustable gains and microbeamformer circuits that locally process and combine echo signals received by the elements of each 3 × 3 subarray. Thus, an order-of-magnitude reduction in the number of receive channels is achieved. Dedicated circuit techniques are employed to meet the strict space and power constraints of TEE probes. The ASIC has been fabricated in a standard 0.18-μm CMOS process and consumes only 0.44 mW/channel. The prototype has been acoustically characterized in a water tank. The ASIC allows the array to be presteered across ±37° while achieving an overall dynamic range of 77 dB. Both the measured characteristics of the individual transducer elements and the performance of the ASIC are in good agreement with expectations, demonstrating the effectiveness of the proposed techniques.

Photoacoustic imaging of carotid artery atherosclerosis

Abstract. We introduce a method for photoacoustic imaging of the carotid artery, tailored toward detection of lipid-rich atherosclerotic lesions. A common human carotid artery was obtained at autopsy, embedded in a neck mimicking phantom and imaged with a multimodality imaging system using interstitial illumination. Light was delivered through a 1.25-mm-diameter optical probe that can be placed in the pharynx, allowing the carotid artery to be illuminated from within the body. Ultrasound imaging and photoacoustic signal detection is achieved by an external 8-MHz linear array coupled to an ultrasound imaging system. Spectroscopic analysis of photoacoustic images obtained in the wavelength range from 1130 to 1250 nm revealed plaque-specific lipid accumulation in the collagen structure of the artery wall. These spectroscopic findings were confirmed by histology.

Semi-automatic border detection method for left ventricular volume estimation in 4D ultrasound data

We propose a semi-automatic endocardial border detection method for LV volume estimation in 3D time series of cardiac ultrasound data. It is based on pattern matching and dynamic programming techniques and operates on 2D slices of the 4D data requiring minimal user-interaction. We evaluated on data acquired with the Fast Rotating Ultrasound (FRU) transducer: a linear phased array transducer rotated at high speed around its image axis, generating high quality 2D images of the heart. We automatically select a subset of 2D images at typically 10 rotation angles and 16 cardiac phases. From four manually drawn contours a 4D shape model and a 4D edge pattern model is derived. For the selected images, contour shape and edge patterns are estimated using the models. Pattern matching and dynamic programming is applied to detect the contours automatically. The method allows easy corrections in the detected 2D contours, to iteratively achieve more accurate models and improved detections. An evaluation of this method on FRU data against MRI was done for full cycle LV volumes on 10 patients. Good correlations were found against MRI volumes [r=0.94, y=0.72x + 30.3, difference of 9.6 +/- 17.4 ml (Av +/- SD)] and a low interobserver variability for US (r=0.94, y=1.11x - 16.8, difference of 1.4 +/- 14.2 ml). On average only 2.8 corrections per patient were needed (in a total of 160 images). Although the method shows good correlations with MRI without corrections, applying these corrections can make significant improvements.

Fully automated carotid plaque segmentation in combined contrast-enhanced and B-mode ultrasound

Carotid plaque segmentation in B-mode ultrasound (BMUS) and contrast-enhanced ultrasound (CEUS) is crucial to the assessment of plaque morphology and composition, which are linked to plaque vulnerability. Segmentation in BMUS is challenging because of noise, artifacts and echo-lucent plaques. CEUS allows better delineation of the lumen but contains artifacts and lacks tissue information. We describe a method that exploits the combined information from simultaneously acquired BMUS and CEUS images. Our method consists of non-rigid motion estimation, vessel detection, lumen-intima segmentation and media-adventitia segmentation. The evaluation was performed in training (n = 20 carotids) and test (n = 28) data sets by comparison with manually obtained ground truth. The average root-mean-square errors in the training and test data sets were comparable for media-adventitia (411 ± 224 and 393 ± 239 μm) and for lumen-intima (362 ± 192 and 388 ± 200 μm), and were comparable to inter-observer variability. To the best of our knowledge, this is the first method to perform fully automatic carotid plaque segmentation using combined BMUS and CEUS.

Frequency Tuning of Collapse-Mode Capacitive Micromachined Ultrasonic Transducer

HighlightsFrequency tuning of CMUT operated in (deep‐)collapse mode is experimentally quantified.The CMUT is operated at bias voltages up to three times higher than the collapse voltage.Fabricated CMUT operates reliably for single‐use imaging catheter application.Images are constructed based on combinations of driving frequency and bias voltage.Reciprocity measurements indicate the same bias voltage can be used for transmit and receive. &NA; The information in an ultrasound image depends on the frequency that is used. In a clinical examination it may therefore be beneficial to generate ultrasound images acquired at multiple frequencies, which is difficult to achieve with conventional transducers. Capacitive micromachined ultrasonic transducers (CMUTs) offer a frequency response that is tunable by the bias voltage. In this study we investigate this frequency tunability for ultrasonic imaging. We characterized a CMUT array operated at bias voltages up to three times higher than the collapse‐voltage. All elements of the array were connected to a single transmit and receive channel through a bias circuit. We quantified the transmit‐receive and transmit sensitivity as a function of frequency for a range of bias voltages. Impulse response measurements show that the center frequency is modifiable between 8.7 MHz and 15.3 MHz with an applied bias voltage of −50 V to −170 V. The maximum transmit sensitivity is 52 kPa/V at a center frequency of 9.0 MHz with an applied bias voltage of −105 V. The −3 dB transmit range in center frequency accessible with the variable bias voltage is 6.7–15.5 MHz. This study shows that a collapse‐mode CMUT can operate efficiently at multiple center frequencies when the driving pulse and the bias voltage are optimized. We demonstrate the usefulness of frequency tuning by comparing images at different optimal combinations of driving frequency and bias voltage, acquired by linearly moving the transducer across a tissue mimicking phantom.