In this study, a novel approach is presented to overcome the challenge of replacing conventional opaque ultrasound transducers (OUTs) with transparent ultrasound transducers (TUTs) that seamlessly integrate optical and ultrasound components. TUTs offer a design that seamlessly combines optical and ultrasound modalities, providing a convenient solution to overcome challenges such as beam combiner or off-axis problems. However, their performance has been significantly limited due to acoustic impedance mismatch. To address the acoustic impedance mismatch problem, transparent composite-based matching and backing layers are utilized with acoustic impedances exceeding 7 and 4 MRayl, respectively. These layers facilitate the development of an ultrasensitive and wideband TUT with a single resonance frequency and a pulse-echo bandwidth of over 60%, equivalent to traditional OUTs. The TUT demonstrates exceptional performance, with over 80% optical transparency, maximizing acoustic power transfer efficiency, maintaining spectrum flatness, and minimizing ringdowns. Such capabilities enable high-contrast and high-definition dual-modal ultrasound and photoacoustic imaging in both animals and humans. Notably, these imaging modalities achieve a penetration depth of over 15 mm, utilizing a 30MHz TUT. We believe this advancement opens up new possibilities for non-invasive imaging applications, offering enhanced diagnostic capabilities and potential insights into biological structures at greater depths.
Ultraviolet photoacoustic microscopy (UV-PAM) has emerged as a promising medical imaging technique for alternative histopathology, relying on the inherent optical absorption of DNA/RNA. However, traditional UV-PAM faces resolution challenges compared to clinical histological methods, limiting the observation of cellular structures. This limitation stems from the constraints of conventional reflection-mode UV-PAM systems, utilizing opto-ultrasound beam combiners or ring-shaped ultrasound transducers. These components impose constraints on numerical apertures (NA), thereby limiting spatial resolution. On the flip side, transmission-mode UV-PAM encounters difficulties in imaging thick specimens due to signal attenuation. In this study, we introduce an innovative solution – the development of an ultraviolet-transparent ultrasound transducer (UV-TUT) – overcoming these limitations and enabling high-resolution UV-PAM system. The UV-TUT significantly enhances both NA and lateral resolution, outperforming previous reflection-mode UV-PAM systems. With an impressive light transmission efficiency in the UV region and sensitivity four times greater than traditional ring-shaped ultrasound transducers, the UV-TUT lays the foundation for improved imaging capabilities. Leveraging the capabilities of the UV-TUT, we exploited a UV-PAM system, showcasing superior performance for imaging mouse brain tissue sections compared to conventional opto-ultrasound beam combiner-based UV-PAM. Furthermore, our application of photoacoustic histopathology on uterine cancer tissue sections demonstrated image quality comparable to microscopy images, providing valuable insights for accurate histopathological analysis. This work signifies a significant advancement in UV-PAM system, holding the promise to enhance the clinical utility of alternative histopathology with unprecedented resolution and imaging capabilities.
Photoacoustic (PA) imaging has become one of the promising biomedical imaging technologies in the past decade, thanks to its advantages of structural, functional, imaging capabilities and seamless integration with conventional ultrasound imaging. Endoscopic photoacoustic and ultrasound (ePAUS) is the combination of PA imaging technology and endoscopic ultrasound (EUS). In the design of the ePAUS, it is ideal to align the optical beam of the laser and the acoustic beam of the transducer on the same axis to achieve high spatial resolution and long imaging range. Existing ePAUS uses a ring transducer or a beam combiner to obtain a coaxial or rather an off-axis arrangement. However, the ring transducer has a problem in that the diameter and acoustic side lobes are large, and the beam combiner has a disadvantage in that the structure is complicated and the acoustic loss due to multiple acoustic reflections is large. Our approach to solving this problem is the development of ePAUS based on a miniaturized transparent ultrasonic transducer (TUT). In this study, lead-magnesium- niobate lead-titanate and Indium Tin Oxide-based ultra-small TUT was fabricated, and the performance of center frequency of 28.1 MHz and bandwidth of 51.5% was obtained. Thereafter, quasi-focus was used by combining a multimode optical fiber and a gradient index lens, and coaxial alignment was achieved by arranging the optical axis perpendicular to the optically transparent TUT. This results in high spatial resolution and long imaging distances, and the imaging performance of the probe is demonstrated by imaging the rectum and vagina of the rat in vivo.
Optical resolution photoacoustic microscopy (OR-PAM) provides high optical contrast and lateral resolution. However, the resolution of a typical OR-PAM using an objective lens is limited to not exceeding Abbe's optical diffraction limit. In this study, a lensless shear force scanning PAM is presented. Instead of a lens, the system uses an imaging probe that combines a non-coated tapered fiber with a quartz tuning fork (QTF). A shear force feedback mechanism is used to maintain a tens of nm (near-field) distance between the fiber tip and the sample. With the system, PA signals generated in the near field of a gold sputtered glass sample were successfully acquired. We also performed 2D PA scanning experiments and obtained PA images of gold cube samples with high lateral resolution. This study demonstrates the existence of a near field PA signal and shows its potential for super-resolution scanning PAM.
Fusion sensors, including photoplethysmograms, cameras, microphones, ultrasound sensors, and accelerometers, are commonly used in mobile and wearable healthcare electronics to measure bio-signals. However, small size is in high demand, but integrating multiple sensors into small mobile or wearable devices is challenging. This study presents two new opto-ultrasound sensors: (1) a wearable device with both photoplethysmography (PPG) and ultrasound (US) capabilities, and (2) a PPG sensor built-in mobile smartphone with an integrated US sensor using a transparent ultrasound transducer (TUT). The TUT has a center frequency of 6 MHz, a 50% bandwidth, and is 82% transparent in the visible and near-infrared ranges. To demonstrate its potential, we developed a wearable device combining photoplethysmography and ultrasound capabilities and fused the TUT to the smartphone. We used this setup to measure heart rates optically and acoustically in human subjects and to calculate oxygen saturation optically through the TUT. This proof-of-concept represents a unique fusion of sensors for small mobile and wearable devices that aim to improve digital healthcare. The results of this research can serve as a basis for innovative development of sensor-based high-tech industrial applications such as healthcare, automobiles, robots, and drones.
Sharing the same acoustic imaging principle, photoacoustic (PA) imaging is available to be done simultaneously with ultrasound (US) imaging, while still discrepancy between two modalities exists as PA imaging relatively suffers with higher depth attenuation and low signal contrast compared to the US imaging. In order to balance the PA to the level of US, we designed an application-specific integrated circuit (ASIC) preamplifier built in with selective switching protocol to amplify only the PA signal. The preamplifier accepts two distinct triggers: synchronized to the Q-switch trigger given with actual beam emission, preamplifier switches and amplifies the PA signal with customized gain. On the other hand, within the flashlamp trigger given before the Q-switch trigger (approx. 300 μs), the preamp is switched off and the US acquisition bypasses amplification. The preamp affords single channel, and we implemented the designed preamplifier to the acoustic-resolution 3D PAUS scanner installed with 5-MHz single-element focused transducer. The signal-to-noise ratio (SNR) and according penetration depth enhancement was well validated by imaging both carbon leads and wire phantoms under optically turbid media (5% diluted milk), measured to be ~ 16.8 dB at 25 mm and 10.6 dB at 33.7 mm, respectively. To fully demonstrate the improvement of PA images under practical circumstance, the bimodal whole-body image of a healthy anesthetized nude Balb/c mouse was acquired with and without the preamplifier. As a result, the organs (spleen, liver, cecum) and vasculatures lying down in the deeper region were unveiled from preamplifier-applied PA images. Above all, our proposed switchable preamplifier well preserved PA signal of weak level against sequentially acquired with high intensity US signals, extending the penetration depth and increasing the PA image contrast. Further extension toward multichannel application would be helpful to translate array US transducer-based simultaneous PA/US imaging toward clinical practice.
Heart and blood vessels called the cardiovascular system closely interact with each other to control cardiac output and maintain vital activities. To observe heartbeat and vascular changes, high-resolution high-speed photoacoustic microscopy (PAM) and/or photoplethysmography (PPG) that are applied technologies of optics have been utilized in preclinical and clinical studies. Herein, we have embedded PPG sensing functionality in a high-speed PAM system to simultaneously perform microvascular imaging and heart rate measurement. In human fingers, we observed capillaries’ movements in blood vessel images from PAM, and moreover found that this phenomenon is due to pulsation by directly comparing between the capillaries’ movements and pulsation-dominant PPG signals. Further, the cardiac cycle could be extracted by quantifying the capillaries’ movements in consecutive blood vessel images, and this periodicity from PAM agreed with that from that of PPG sensing. From these results, the high-speed PAM with PPG could be potentially used as clinical tools for monitoring the changes in multiple cardiovascular information in response to internal and/or external circumstances.
We present a multimodal imaging system that seamlessly integrates ultrasound imaging, photoacoustic imaging, and optical coherence tomography using a transparent ultrasonic transducer. We demonstrate the system’s use in imaging responses to mouse body in vivo.
Multi-modal imaging technique has significantly spotlighted since it can provide a variety of information by combining the complementary merits of several single-modal imaging. In particular, in order to compensate for each shortcoming and improve image quality, an integrated optical and ultrasonic imaging system is being actively researched. However, the non-transparency of the ultrasound transducer made it difficult to integrate the optical and ultrasound imaging system. In previous study, we introduced the transparent ultrasound transducer (TUT) and dual-modal photoacoustic imaging (PAI)/ultrasound imaging (USI) system using the TUT. In this study, we present the multi-modal imaging system integrated with PA, US and optical coherence tomography (OCT). OCT has the advantage of acquiring anatomical information at optical resolution under subsurface and transparent media. To explore the usefulness of the multi-modal imaging system, we have successfully performed in vivo animal experiments: 1) eye imaging experiments and 2) subcutaneous melanoma imaging. In PAI, blood vessels and melanoma are clearly visualized. In OCT, the morphological information in shallow depth are observed in detail. In USI, the melanoma boundary and surrounding tissues are clearly confirmed. These results show that TUT based multi-modal imaging system can serve as a comprehensive in various applications.
Cerebrovascular and cardiovascular diseases such as stroke and coronary artery disease show a significant number of cases with a high mortality rate. Early detection of risk factors is important to prevent cerebrovascular and cardiovascular diseases. Measurements of carotid artery stenosis, blood flow rate, and the wall thickness of vessels by 2D and Doppler mode ultrasound are preferred choices due to advantages of their easy access, non-invasiveness, and safety. However, the current ultrasound imaging system with handheld type probes is not suitable for continuous monitoring and imaging, and the manual measurement is required by qualified personnel at a given time interval. Therefore, it is not an ideal solution for collecting continuous time-series data. We developed a 32-element, patch-type linear array transducer with a small footprint of 11.73 mm x 8 mm, which is an acceptable size to be attached over the carotid artery in the neck area. We evaluated the performance of the developed array transducer using the pulse-echo system and obtained its representative center frequency of 4.5 MHz, bandwidth (-6 dB) 64%, and sensitivity -47 dB. We also implemented a compact tabletop ultrasound system capable of 2D-mode real-time imaging of carotid artery and Doppler measurement of blood flow. In addition, with the tissue-mimicking phantom, we evaluated the performance of the developed system by collecting 2D images and Doppler spectrogram. The -6 dB lateral resolutions of the ultrasound system were 0.76, 0.61, and 1.33 mm at 15, 25, and 35 mm, respectively, and the peak velocity of the Doppler signal was close to 100 cm/s.
Calcium signaling is a second messenger that triggers physiological changes at the cellular level, such as proliferation, differentiation, or apoptosis. It was recently found that calcium dynamics play a vital role in many studies, including cancer, Alzheimer’s disease, and Parkinson’s disease, and we studied how intracellular signaling pathways work by ultrasound mechanotransduction. However, since ultrasound mechanotransduction does not yet have many experimental results by the quantified ultrasound parameters, little is known about the mechanism between ultrasound parameters and calcium dynamics. We investigate calcium level changes using different frequencies of ultrasound to study intracellular signal pathways of fibroblasts, which may function as one of the contributing factors of tissue repair. We quantified a few major ultrasound stimulation parameters, i.e., operating frequency, beam width, and acoustic pressure. Three 40 MHz ultrasound transducers with different f-numbers (0.8, 1.0, and 1.5) were designed and fabricated. During the cell stimulation, ultrasound waves with different frequencies (36, 45, and 69 MHz) but the same beam width and same acoustic pressure were exerted on the cells. The cell lines used were NIH/3T3 fibroblasts. At the fixed acoustic pressure and beam width, intracellular calcium level increased more rapidly at higher frequencies, which shows that the intracellular signal pathways of fibroblasts may be mainly dependent upon the frequency used for stimulation.
Ultrasound transducers, one of the most widely used sensors in the era of the fourth Industrial Revolution, have been recognized and used in a variety of industries including medical, automotive, and robotics. In particular, recent research has focused on the development of multi-mode imaging systems that combine ultrasound and optical imaging to improve the accuracy of information acquisition. Unfortunately, its efficient combination has been severely limited due to the inherent opacity of conventional ultrasound transducers. These limitations cause off-axes between the ultrasound (US) and optical signal paths, resulting in low signal-to-ratio and bulky system. This is especially a critical problem for a photoacoustic (PA) imaging system that requires the ultrasonic transducer to detect the photoacoustic signal. Here, we introduce a newly developed optically transparent ultrasound transducer (TUT) to overcome the limitation. We combined the developed TUT with an optical resolution photoacoustic microscopy (OR-PAM). Using a mouse, we successfully acquired in vivo PA and US images and confirmed the feasibility of the TUT and TUT integrated OR-PAM system.
A sub-wavelength convertible Bessel-beam (BB) and Gaussian-beam (GB) photoacoustic microscope (PAM) in reflection-mode has been developed. A miniature ultrasonic transducer was placed in front of the objective with a high numerical aperture and a working distance of a few millimeters to achieve the reflection-mode and sub-wavelength resolution. For BB-PAM system, a conical lens and an achromatic doublet lens were used to achieve extended depth of field (DoF). In particular, it was designed to easily convert the system from BB to GB by removing the two lenses described above, so that the DoF of BB- and GB-PAM can be compared accurately. The 532 nm pulsed laser used in this system was coupled to a single mode fiber. The sample was scanned using X-Y direction motors and the system was controlled using Labview software. The lateral resolution of the focus regions of BB- and GB-PAM obtained were 300 and 260 nm, respectively. As a result of measuring the DoF of BB-PAM, it was about 250 ~ 300 μm, which was about 7 ~ 8 times better than the DoF of GB-PAM. In-vivo vascular structure of a mouse ear was successfully visualized using BB- and GB-PAM to compare the DoF of the two systems. Thus, the system developed in this study confirmed that BBPAM enabled high-resolution imaging at extended DoF than GB-PAM, and further believed that this system could be useful for a variety of biomedical research.
Thomas Cummins, Changhan Yoon, Hojong Choi, Payam Eliahoo, Hyung Ham Kim, Mary Yamashita, Linda Hovanessian-Larsen, Julie Lang, Stephen Sener, John Vallone, Sue Martin, K. Kirk Shung
Image-guided core needle biopsy is the current gold standard for breast cancer diagnosis. Microcalcifications, an important radiographic finding on mammography suggestive of early breast cancer such as ductal carcinoma in situ, are usually biopsied under stereotactic guidance. This procedure, however, is uncomfortable for patients and requires the use of ionizing radiation. It would be preferable to biopsy microcalcifications under ultrasound guidance since it is a faster procedure, more comfortable for the patient, and requires no radiation. However, microcalcifications cannot reliably be detected with the current standard ultrasound imaging systems. This study is motivated by the clinical need for real-time high-resolution ultrasound imaging of microcalcifications, so that biopsies can be accurately performed under ultrasound guidance. We have investigated how high-frequency ultrasound imaging can enable visualization of microstructures in ex vivo breast tissue biopsy samples. We generated B-mode images of breast tissue and applied the Nakagami filtering technique to help refine image output so that microcalcifications could be better assessed during ultrasound-guided core biopsies. We describe the preliminary clinical results of high-frequency ultrasound imaging of ex vivo breast biopsy tissue with microcalcifications and without Nakagami filtering and the correlation of these images with the pathology examination by hematoxylin and eosin stain and whole slide digital scanning.
A dual-element needle transducer for intravascular ultrasound imaging has been developed. A low-frequency element and a high-frequency element were integrated into one device to obtain images which conveyed both low- and high-frequency information from a single scan. The low-frequency element with a center frequency of 48 MHz was fabricated from the single crystal form of lead magnesium niobate-lead titanate solid solution with two matching layers (MLs) and the high frequency element with a center frequency of 152 MHz was fabricated from lithium niobate with one ML. The measured axial and lateral resolutions were 27 and 122 μm, respectively, for the low-frequency element, and 14 and 40 μm, respectively, for the high-frequency element. The performance of the dual-element needle transducer was validated by imaging a tissue-mimicking phantom with lesion-mimicking area, and ex vivo rabbit aortas in water and rabbit whole blood. The results suggest that a low-frequency element effectively provides depth resolved images of the whole vessel and its adjacent tissue, and a high-frequency element visualizes detailed structure near the surface of the lumen wall in the presence of blood within the lumen. The advantages of a dual-element approach for intravascular imaging are also discussed.
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