Multimodal intravascular ultrasound and photoacoustic (IVUS/PA) imaging is a promising diagnostic tool for cardiovascular diseases like atherosclerosis. IVUS/PA catheters typically require two independent transducers due to different frequency requirements, potentially increasing the catheter size. To facilitate multimodal imaging within conventional catheter dimensions, we designed, fabricated, and characterized a dual-transducer acoustic stack where a low-frequency (LF) PA receiver sits as a matching layer for the high-frequency (HF) US transducer. While the HF transducer operates around 50 MHz, the LF receiver targets frequencies below 15 MHz to capture most of the PA energy from atherosclerotic plaque lipids. Simulation results reveal that this configuration could increase the sensitivity of the HF transducer by 3.54 dB while maintaining bandwidth. Phantom experiments with fabricated stacks showed improved performance for the US transducer, validating the enhanced sensitivity and bandwidth. Following improvements in stack fabrication, the proposed acoustic stack is a viable design that can significantly enhance diagnostic accuracy for atherosclerosis, providing high-resolution, multifrequency imaging within a compact catheter form factor.@en

Background
Clot composition, contraction, and mechanical properties are likely determinants of endovascular thrombectomy success. A pre-interventional estimation of these properties is hypothesized to aid in selecting the most suitable treatment for different types of thrombi. Here we determined the association between the aforementioned properties and computed tomography (CT) characteristics using human blood clot analogues.

Methods
Clot analogues were prepared from the blood of 4 healthy human donors with 5 red blood cell (RBC) volume suspensions: 0%, 20%, 40%, 60% and 80% RBCs. Contraction was measured as the weight of the contracted clots as a percentage of the original suspension. The clots were imaged using CT with and without contrast to quantify clot density and density increase. Unconfined compression was performed to determine the high strain compressive stiffness. The RBC content was analysed using H&E staining.

Results
The 5 RBC suspensions formed only two groups of clots, fibrin-rich (0% RBCs) and RBC-rich (>90% RBCs), as determined by histology. The density of the fibrin-rich clots was significantly lower (31-38HU) compared to the RBC-rich clots (72-89HU), and the density increase of the fibrin-rich clots was significantly higher (82-127HU) compared to the RBC-rich clots (3-17HU). The compressive stiffness of the fibrin-rich clots was higher (178–1624 kPa) than the stiffness of the RBC-rich clots (6–526 kPa). Additionally, the degree of clot contraction was higher for the fibrin-rich clots (89–96%) compared to the RBC-rich clots (11–77%).

Conclusions
CT imaging clearly reflects clot RBC content and seems to be related to the clot contraction and stiffness. CT imaging might be a useful tool in predicting the thrombus characteristics. However, future studies should confirm these findings by analysing clots with intermediate RBC and platelet content.
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Ultrasound contrast-mediated medical imaging and therapy both rely on the dynamics of micron- and nanometer-sized ultrasound cavitation nuclei, such as phospholipid-coated microbubbles and phase-change droplets. Ultrasound cavitation nuclei respond non-linearly to ultrasound on a nanosecond time scale that necessitates the use of ultra-high-speed imaging to fully visualize these dynamics in detail. In this study, we developed an ultra-high-speed optical imaging system that can record up to 20 million frames per second (Mfps) by coupling two small-sized, commercially available, 10-Mfps cameras. The timing and reliability of the interleaved cameras needed to achieve 20 Mfps was validated using two synchronized light-emitting diode strobe lights. Once verified, ultrasound-activated microbubble responses were recorded and analyzed. A unique characteristic of this coupled system is its ability to be reconfigured to provide orthogonal observations at 10 Mfps. Acoustic droplet vaporization was imaged from two orthogonal views, by which the 3-D dynamics of the phase transition could be visualized. This optical imaging system provides the temporal resolution and experimental flexibility needed to further elucidate the dynamics of ultrasound cavitation nuclei to potentiate the clinical translation of ultrasound-mediated imaging and therapy developments.

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Modern Implantable Medical Devices (IMDs) are vulnerable to security attacks because of their wireless connectivity to the outside world. One of the main security challenges is establishing trust between the IMD and an external reader/programmer in order to facilitate secure communication. Numerous device-pairing schemes have been proposed to address this specific challenge. However, they alone cannot protect against a battery-depletion attack in which the adversary is able to keep the IMD occupied with continuous authentication requests until the battery empties. As a result, energy harvesting has been employed as an ancillary mechanism for implementing Zero-Power Defense (ZPD) functionality in order to protect against such a low-cost attack. In this paper, we propose SecureEcho, a device-pairing scheme based on MHz-range ultrasound that establishes trust between the IMD and an external reader. In addition, SecureEcho achieves ZPD without requiring any energy harvesting, which significantly reduces the design complexity. We also provide a proof-of-concept implementation and a first ever security evaluation of the ultrasound channel, which proves that it is infeasible for the attacker to eavesdrop or insert messages even from a range of a few millimeters.

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Intravascular ultrasound (IVUS) is a well-established diagnostic method that provides images of the vessel wall and atherosclerotic plaques. We investigate the potential for phased-array IVUS utilizing coded excitation (CE) for improving the penetration depth and image signal-to-noise ratio (SNR). It is realized on a new experimental broadband capacitive micromachined ultrasound transducer (CMUT) array, operated in collapse mode, with 96 elements placed at the circumference of a catheter tip with a 1.2- {mm} diameter. We characterized the array performance for CE imaging and showed that the -6-dB device bandwidth at a 30-V dc biasing is 25 MHz with a 20-MHz center frequency, with a transmit sensitivity of 37 kPa/V at that frequency. We designed a linear frequency modulation code to improve penetration depth by compensating for high-frequency attenuation while preserving resolution by a mismatched filter reconstruction. We imaged a wire phantom and a human coronary artery plaque. By assessing the image quality of the reconstructed wire phantom image, we achieved 60- and 70- mu{mathrm {m}} axial resolutions using the short pulse and coded signal, respectively, and gained 8 dB in SNR for CE. Our developed system shows 20-frames/s, pixel-based beam-formed, real-time IVUS images.

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Ultrasound insonification of microbubbles can locally increase vascular permeability to enhance drug delivery. To control and optimize the therapeutic potential, we need to better understand the underlying biological mechanisms of the drug delivery pathways. The aim of this in vitro study was to elucidate the microbubble-endothelial cell interaction using the Brandaris 128 ultra-high-speed camera (up to 25 Mfps) coupled to a custom-built Nikon confocal microscope, to visualize both microbubble oscillation and the cellular response. Sonoporation and opening of cell-cell contacts by single α_Vβ₃-targeted microbubbles (n = 152) was monitored up to 4 min after ultrasound insonification (2 MHz, 100–400 kPa, 10 cycles). Sonoporation occurred when microbubble excursion amplitudes exceeded 0.7 μm. Quantification of the influx of the fluorescent model drug propidium iodide upon sonoporation showed that the size of the created pore increased for larger microbubble excursion amplitudes. Microbubble-mediated opening of cell-cell contacts occurred as a cellular response upon sonoporation and did not correlate with the microbubble excursion amplitude itself. The initial integrity of the cell-cell contacts affected the susceptibly to drug delivery, since cell-cell contacts opened more often when cells were only partially attached to their neighbors (48%) than when fully attached (14%). The drug delivery outcomes were independent of nonlinear microbubble behavior, microbubble location, and cell size. In conclusion, by studying the microbubble–cell interaction at nanosecond and nanometer resolution the relationship between drug delivery pathways and their underlying mechanisms was further unraveled. These novel insights will aid the development of safe and efficient microbubble-mediated drug delivery.

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In this study, we demonstrate a 12x36 mm motorized capsule for OCT imaging of the esophagus. The capsule produces unobstructed images by using a distal reflector design, thus avoiding shadow caused by the motor wires. The motor synchronous control enables three working modes: circumferential imaging, angular sector imaging and accurate beam positioning. Distortion artifacts shown in the sector imaging were found to be induced by velocity changes of the motor. We specifically characterized the motor speed and found a symmetric and repeatable behavior during sector scanning. Resampling of the sector images A-lines was carried out to achieve uniform angular spacing according to the measured speed profile. Also, distortion between consecutive sector frames was corrected using image registration to achieve stable imaging.

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Ultrasound insonification of microbubbles can locally enhance drug delivery, but the microbubble–cell interaction remains poorly understood. Because intracellular calcium (Ca_i ²⁺) is a key cellular regulator, unraveling the Ca_i ²⁺ fluctuations caused by an oscillating microbubble provides crucial insight into the underlying bio-effects. Therefore, we developed an optical imaging system at nanometer and nanosecond resolution that can resolve Ca_i ²⁺ fluctuations and microbubble oscillations. Using this system, we clearly distinguished three Ca_i ²⁺ uptake profiles upon sonoporation of endothelial cells, which strongly correlated with the microbubble oscillation amplitude, severity of sonoporation and opening of cell–cell contacts. We found a narrow operating range for viable drug delivery without lethal cell damage. Moreover, adjacent cells were affected by a calcium wave propagating at 15 μm/s. With the unique optical system, we unraveled the microbubble oscillation behavior required for drug delivery and Ca_i ²⁺ fluctuations, providing new insight into the microbubble–cell interaction to aid clinical translation.

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Prospective identification of lipid-rich vulnerable plaque has remained an elusive goal. Intravascular photoacoustics, a hybrid optical and ultrasonic technology, was developed as a tool for lipid-rich plaque imaging. Here, we present the first in vivo images of lipid-rich coronary atherosclerosis acquired with this new technology in a large animal model, and relate them to independent catheter-based imaging and histology.

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In interventional electrophysiology, catheter-based radiofrequency (RF) ablation procedures restore cardiac heart rhythm by interrupting aberrant conduction paths. Real-time feedback on lesion formation and post-treatment lesion assessment could overcome procedural challenges related to ablation of underlying structures and lesion gaps. This study aims to evaluate real-time visualization of lesion progression and continuity during intra-atrial ablation with photoacoustic (PA) imaging, using clinically deployable technology. A PA-enabled RF ablation catheter was used to ablate and illuminate porcine left atrium, both excised and intact in a passive beating heart ex-vivo, for photoacoustic signal generation. PA signals were received with an intracardiac echography catheter. Using the ratio of PA images acquired with excitation wavelengths of 790 nm and 930 nm, ablation lesions were successfully imaged through circulating saline and/or blood, and lesion gaps were identified in real-time. PA-based assessment of RF-ablation lesions was successful in a realistic preclinical model of atrial intervention.

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We demonstrate a tethered motorized capsule for unobstructed optical coherence tomography (OCT) imaging of the esophagus. By using a distal reflector design, we avoided the common shadow artifact induced by the motor wires. A synchronous driving technique features three types of beam-scanning modes of the capsule, i.e., circumferential beam scanning, localized beam scanning, and accurate beam positioning. We characterized these three modes and carried out ex vivo imaging experiments using the capsule. The results show that the capsule can potentially be a useful tool for diagnostic OCT imaging and OCT-guided biopsy and therapy of the esophagus.

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Controlling microbubble-mediated drug delivery requires the underlying biological and physical mechanisms to be unraveled. To image both microbubble oscillation upon ultrasound insonification and the resulting cellular response, we developed an optical imaging system that can achieve the necessary nanosecond temporal and nanometer spatial resolutions. We coupled the Brandaris 128 ultra-high-speed camera (up to 25 million frames per second) to a custom-built Nikon A1R+ confocal microscope. The unique capabilities of this combined system are demonstrated with three experiments showing microbubble oscillation leading to either endothelial drug delivery, bacterial biofilm disruption, or structural changes in the microbubble coating. In conclusion, using this state-of-the-art optical imaging system, microbubble-mediated drug delivery can be studied with high temporal resolution to resolve microbubble oscillation and high spatial resolution and detector sensitivity to discern cellular response. Combining these two imaging technologies will substantially advance our knowledge on microbubble behavior and its role in drug delivery.

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Photoacoustic signals can have very large bandwidth and large dynamic range. With appropriate electrical impedance matching, off-resonance PVDF transducers offer the bandwidth and sensitivity to fully capture these signals. Minimizing pitch and kerf in ultrasound transducer to improve lateral resolution is of great importance. Kerfless arrays, where the electrodes are patterned onto the piezoelectric material, fulfill such a demand and are simpler to manufacture. We have manufactured and characterized a kerfless off resonance PVDF array of 10 elements with dimensions of 1mm×1.5mm×28μm(w×h×t) both numerically and experimentally for PA imaging. We matched the high impedance of the PVDF elements with low impedance of acquisition system through an appropriate LNA (26 dB amplification over 10 MHz BW). PA signals from a tungsten wire with a diameter of 35 μm were received with our device, and compared to those recorded with a 0.2 mm needle hydrophone. Based on simulation and measurement results, the phase change in the off-resonance PVDF is negligible. The crosstalk between adjacent elements is −30dB. We measured a sensitivity for our array of about 1.38 μV/Pa at 3 MHz. The RMS output noise level is 240 uV over the entire bandwidth (10Hz-10 MHz).@en

Intravascular ultrasound is an imaging modality used to visualize atherosclerosis from within the inner lumen of human arteries. Complex lesions like chronic total occlusions require forward-looking intravascular ultrasound (FL-IVUS), instead of the conventional side-looking geometry. Volumetric imaging can be achieved with 2D array transducers, which present major challenges in reducing cable count and device integration. In this work we present an 80-element lead zirconium titanate (PZT) matrix ultrasound transducer for FL-IVUS imaging with a front-end application-specific integrated circuit (ASIC) requiring only 4 cables. After investigating optimal transducer designs we fabricated the matrix transducer consisting of 16 transmit (TX) and 64 receive (RX) elements arranged on top of an ASIC having an outer diameter of 1.5 mm and a central hole of 0.5 mm for a guidewire. We modeled the transducer using finite element analysis and compared the simulation results to the values obtained through acoustic measurements. The TX elements showed uniform behavior with a center frequency of 14 MHz, a -3 dB bandwidth of 44 % and a transmit sensitivity of 0.4 kPa/V at 6 mm. The RX elements showed center frequency and bandwidth similar to the TX elements, with an estimated receive sensitivity of 3.7 μV/Pa. We successfully acquired a 3D FL image of three spherical reflectors in water using delay-and-sum beamforming and the coherence factor method. Full synthetic aperture acquisition can be achieved with frame rates on the order of 100 Hz. The acoustic characterization and the initial imaging results show the potential of the proposed transducer to achieve 3D FL-IVUS imaging.

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Intravascular photoacoustic/ultrasound imaging (IVPA/US) can image the structure and composition of atherosclerotic lesions identifying lipid-rich plaques ex vivo and in vivo. In the literature, multiple IVPA/US catheter designs were presented and validated both in ex-vivo models and preclinical in-vivo situations. Since the catheter is a critical component of the imaging system, we discuss here a catheter design oriented to imaging plaque in a realistic and translatable setting. We present a catheter optimized for light delivery, manageable flush parameters and robustness with reduced mechanical damage risks at the laser/catheter joint interface. We also show capability of imaging within sheath and in water medium.

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Atrial fibrillation is a cardiac arrhythmia stemming from abnormal electrical conduction/impulse formation in the atria. To restore cardiac rhythm an RF ablation (RFA) procedure, interrupting aberrant electrical patterns, is commonly performed. One way of improving the procedure (current success rate 60%) is to enable visual feedback on lesion progression, thereby reducing complications linked to over-ablation and mitigating recurrent conductivity due to under-ablation. To visualize the ablation process, we propose photoacoustic (PA) imaging using an ablation catheter for light delivery and an ICE (Intracardiac Echo) catheter for signal reception In this work, we demonstrate two PA-enabled ablation catheters which provide sufficient optical intensity to image fresh and ablated porcine tissue ex vivo.

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In this study we present a combined optical sizing and acoustical characterization technique for the study of the dynamics of single freely-floating ultrasound contrast agent microbubbles exposed to long burst ultrasound excitations up to the milliseconds range. A co-axial flow device was used to position individual microbubbles on a streamline within the confocal region of three ultrasound transducers and a high-resolution microscope objective. Bright-field images of microbubbles passing through the confocal region were captured using a high-speed camera synchronized to the acoustical data acquisition to assess the microbubble response to a 1-MHz ultrasound burst. Nonlinear bubble vibrations were identified at a driving pressure as low as 50 kPa. The results demonstrate good agreement with numerical simulations based on the shell-buckling model proposed by Marmottant et al. [J. Acoust. Soc. Am. 118, 3499-3505 (2005)]. The system demonstrates the potential for a high-throughput in vitro characterization of individual microbubbles.

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Detailed information about the response of microbubbles to long ultrasound pulses (>100 cycles) is hampered by the limited time span ultra fast-framing cameras (> 10 MHz) cover. We therefore developed a new imaging mode for the Brandaris 128 camera [1], facilitating high speed imaging during small time windows (segments), equally distributed over a relatively large time span.

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