Search

Abstract Current malaria diagnostics are invasive, lack sensitivity, and rapid tests are plagued by deletions in target antigens. Here we introduce the Cytophone, an innovative photoacoustic flow cytometer platform with high-pulse-rate lasers and a focused ultrasound transducer array to noninvasively detect and identify malaria-infected red blood cells (iRBCs) using specific wave shapes, widths, and time delays generated from the absorbance of laser energy by hemozoin, a universal biomarker of malaria infection. In a population of Cameroonian adults with uncomplicated malaria, we assess our device for safety in a cross-sectional cohort (n = 10) and conduct a performance assessment in a longitudinal cohort (n = 20) followed for 30 ± 7 days after clearance of parasitemia. Longitudinal cytophone measurements are compared to point-of-care and molecular assays (n = 94). Cytophone is safe with 90% sensitivity, 69% specificity, and a receiver-operator-curve-area-under-the-curve (ROC-AUC) of 0.84, as compared to microscopy. ROC-AUCs of Cytophone, microscopy, and RDT compared to quantitative PCR are not statistically different from one another. The ability to noninvasively detect iRBCs in the bloodstream is a major advancement which offers the potential to rapidly identify both the large asymptomatic reservoir of infection, as well as diagnose symptomatic cases without the need for a blood sample.

Abstract Retinal degeneration, a leading cause of irreversible low vision and blindness globally, can be partially addressed by retina prostheses which stimulate remaining neurons in the retina. However, existing electrode-based treatments are invasive, posing substantial risks to patients and healthcare providers. Here, we introduce a completely noninvasive ultrasonic retina prosthesis, featuring a customized ultrasound two-dimensional array which allows for simultaneous imaging and stimulation. With synchronous three-dimensional imaging guidance and auto-alignment technology, ultrasonic retina prosthesis can generate programmed ultrasound waves to dynamically and precisely form arbitrary wave patterns on the retina. Neuron responses in the brain’s visual center mirrored these patterns, evidencing successful artificial vision creation, which was further corroborated in behavior experiments. Quantitative analysis of the spatial-temporal resolution and field of view demonstrated advanced performance of ultrasonic retina prosthesis and elucidated the biophysical mechanism of retinal stimulation. As a noninvasive blindness prosthesis, ultrasonic retina prosthesis could lead to a more effective, widely acceptable treatment for blind patients. Its real-time imaging-guided stimulation strategy with a single ultrasound array, could also benefit ultrasound neurostimulation in other diseases.

Food waste (FW) from large dining facility has been a pressing environmental challenge in China recently. This study developed an innovative species-specific feeding strategy for producing pigeon meat and excellent manure from FW. Adding FW to the feed of pigeons significantly increased their feed intake and promoted their growth although the pigeons showed a strong aversion to the FW. We produced a “super manure” with exceptionally high nitrogen (N) content (mean = 10.77 % on a dry basis, 8.04–12.57 %, n = 264) by feeding slowly-growing pigeon species (Columba livia vs. and Caoge Huzhou 11) with protein-high commercial feed and FW. A significant negative relationship between the N and carbon (C) contents in the pigeon manure was found, with C depletion higher than N depletion. Furthermore, the N content in the anaerobic composting (AnC) manure was 29.16 % higher than that in the FW. Fourier transform infrared (FT-IR) analysis and stable isotopes δ13C and δ15N in the manure clearly identified the transformations of nutrients during pigeon feeding and the AnC process. This study opens a path for producing N-high manure using protein-high food waste.

Photoacoustic imaging is a novel biomedical imaging modality that has emerged over the recent decades. Due to the conversion of optical energy into the acoustic wave, photoacoustic imaging offers high-resolution imaging in depth beyond the optical diffusion limit. Photoacoustic imaging is frequently used in conjunction with ultrasound as a hybrid modality. The combination enables the acquisition of both optical and acoustic contrasts of tissue, providing functional, structural, molecular, and vascular information within the same field of view. In this review, we first described the principles of various photoacoustic and ultrasound imaging techniques and then classified the dual-modal imaging systems based on their preclinical and clinical imaging applications. The advantages of dual-modal imaging were thoroughly analyzed. Finally, the review ends with a critical discussion of existing developments and a look toward the future.

Abstract The performance of ultrasonic transducers is largely determined by the piezoelectric properties and geometries of their active elements. Due to the brittle nature of piezoceramics, existing processing tools for piezoelectric elements only achieve simple geometries, including flat disks, cylinders, cubes and rings. While advances in additive manufacturing give rise to free-form fabrication of piezoceramics, the resultant transducers suffer from high porosity, weak piezoelectric responses, and limited geometrical flexibility. We introduce optimized piezoceramic printing and processing strategies to produce highly responsive piezoelectric microtransducers that operate at ultrasonic frequencies. The 3D printed dense piezoelectric elements achieve high piezoelectric coefficients and complex architectures. The resulting piezoelectric charge constant, d 33 , and coupling factor, k t , of the 3D printed piezoceramic reach 583 pC/N and 0.57, approaching the properties of pristine ceramics. The integrated printing of transducer packaging materials and 3D printed piezoceramics with microarchitectures create opportunities for miniaturized piezoelectric ultrasound transducers capable of acoustic focusing and localized cavitation within millimeter-sized channels, leading to miniaturized ultrasonic devices that enable a wide range of biomedical applications.

Abstract Photo-mediated Ultrasound Therapy (PUT), as a new anti-vascular technique, can promote cavitation activity to selectively destruct blood vessels with a significantly lower amount of energy when compared to energy level required by other laser and ultrasound treatment therapies individually. Here, we report the development of a high speed PUT system based on a 50-kHz pulsed laser to achieve faster treatment, decreasing the treatment time by a factor of 20. Furthermore, we integrated it with optical coherence tomography angiography (OCTA) for real time monitoring. The feasibility of the proposed OCTA-guided PUT was validated through in vivo rabbit experiments. The addition of OCTA to PUT allows for quantitative prescreening and real time monitoring of treatment response, thereby enabling implementation of individualized treatment strategies.

Ultrasound A-scan is an important tool for quantitative assessment of ocular lesions. However, its usability is limited by the difficulty of accurately localizing the ultrasound probe to a lesion of interest. In this study, a transparent LiNbO3 single crystal ultrasound transducer was fabricated, and integrated with a widefield fundus camera to guide the ultrasound local position. The electrical impedance, phase spectrum, pulse-echo performance, and optical transmission spectrum of the ultrasound transducer were validated. The novel fundus camera-guided ultrasound probe was tested for in vivo measurement of rat eyes. Anterior and posterior segments of the rat eye could be unambiguously differentiated with the fundus photography-guided ultrasound measurement. A model eye was also used to verify the imaging performance of the prototype device in the human eye. The prototype shows the potential of being used in the clinic to accurately measure the thickness and echogenicity of ocular lesions in vivo.

Functional ultrasound (fUS) flow imaging provides a non-invasive method for the in vivo study of cerebral blood flow and neural activity. This study used functional flow imaging to investigate rat brain’s response to ultrasound and colored-light stimuli. Male Long-Evan rats were exposed to direct full-field strobe flashes light and ultrasound stimulation to their retinas, while brain activity was measured using high-frequency ultrasound imaging. Our study found that light stimuli, particularly blue light, elicited strong responses in the visual cortex and lateral geniculate nucleus (LGN), as evidenced by changes in cerebral blood volume (CBV). In contrast, ultrasound stimulation elicited responses undetectable with fUS flow imaging, although these were observable when directly measuring the brain’s electrical signals. These findings suggest that fUS flow imaging can effectively differentiate neural responses to visual stimuli, with potential applications in understanding visual processing and developing new diagnostic tools.

Electronic visual prostheses, or biomimetic eyes, have shown capability of restoring functional vision through electrical pulses artificially initiating neural responses. Here, authors demonstrate a flexible piezo-array for ultrasound-induced retinal stimulation.

The ultrafast wide-field photoacoustic microscopy integrates novel light source, fast scanning mechanism, and machine learning enhancement, which allows high-speed tracking of whole-brain functions in action at capillary level.

Neural modulation plays a major role in delineating the circuit mechanisms and serves as the cornerstone of neural interface technologies. Among the various modulation mechanisms, ultrasound enables noninvasive label-free deep access to mammalian brain tissue. To date, most if not all ultrasonic neural modulation implementations are based on ∼1 MHz carrier frequency. The long acoustic wavelength results in a spatially coarse modulation zone, often spanning over multiple function regions. The modulation of one function region is inevitably linked with the modulation of its neighboring regions. Moreover, the lack of in vivo cellular resolution cell-type-specific recording capabilities in most studies prevents the revealing of the genuine cellular response to ultrasound. To significantly increase the spatial resolution, we explored the application of high-frequency ultrasound. To investigate the neuronal response at cellular resolutions, we developed a dual-modality system combining in vivo two-photon calcium imaging and focused ultrasound modulation. The studies show that the ∼30 MHz ultrasound can suppress the neuronal activity in awake mice at 100-μm scale spatial resolutions, paving the way for high-resolution ultrasonic neural modulation. The dual-modality in vivo system validated through this study will serve as a general platform for studying the dynamics of various cell types in response to ultrasound.

Combining focused optical excitation and high-frequency ultrasound detection, optical-resolution photoacoustic microscopy (OR-PAM) can provide micrometer-level spatial resolution with millimeter-level penetration depth and has been employed in a variety of biomedical applications. However, it remains a challenge for OR-PAM to achieve a high imaging speed and a large field of view at the same time. In this work, we report a new approach to implement high-speed wide-field OR-PAM, using a cylindrically-focused transparent ultrasound transducer (CFT-UT). The CFT-UT is made of transparent lithium niobate coated with indium-tin-oxide as electrodes. A transparent cylindrical lens is attached to the transducer surface to provide an acoustic focal line with a length of 9 mm. The excitation light can pass directly through the CFT-UT from the above and thus enables a reflection imaging mode. High-speed imaging is achieved by fast optical scanning of the focused excitation light along the CFT-UT focal line. With the confocal alignment of the optical excitation and acoustic detection, a relatively high detection sensitivity is maintained over the entire scanning range. The CFT-UT-based OR-PAM system has achieved a cross-sectional frame rate of 500 Hz over the scanning range of 9 mm. We have characterized the system’s performance on phantoms and demonstrated its application on small animal models in vivo. We expect the new CFT-UT-based OR-PAM will find matched biomedical applications that need high imaging speed over a large field of view.

Ocular diseases, such as age-related macular degeneration (AMD) and glaucoma, have had a profound impact on millions of patients. In the past couple of decades, these diseases have been treated using conventional techniques but have also presented certain challenges and limitations that affect patient experience and outcomes. To address this, biomaterials have been used for ocular drug delivery, and a wide range of systems have been developed. This review will discuss some of the major classes and examples of biomaterials used for the treatment of prominent ocular diseases, including ocular implants (biodegradable and non-biodegradable), nanocarriers (hydrogels, liposomes, nanomicelles, DNA-inspired nanoparticles, and dendrimers), microneedles, and drug-loaded contact lenses. We will also discuss the advantages of these biomaterials over conventional approaches with support from the results of clinical trials that demonstrate their efficacy.

The optic nerve is the second cranial nerve (CN II) that connects and transmits visual information between the retina and the brain. Severe damage to the optic nerve often leads to distorted vision, vision loss, and even blindness. Such damage can be caused by various types of degenerative diseases, such as glaucoma and traumatic optic neuropathy, and result in an impaired visual pathway. To date, researchers have not found a viable therapeutic method to restore the impaired visual pathway; however, in this paper, a newly synthesized model is proposed to bypass the damaged portion of the visual pathway and set up a direct connection between a stimulated visual input and the visual cortex (VC) using Low-frequency Ring-transducer Ultrasound Stimulation (LRUS). In this study, by utilizing and integrating various advanced ultrasonic and neurological technologies, the following advantages are achieved by the proposed LRUS model: 1. This is a non-invasive procedure that uses enhanced sound field intensity to overcome the loss of ultrasound signal due to the blockage of the skull. 2. The simulated visual signal generated by LRUS in the visual-cortex-elicited neuronal response in the visual cortex is comparable to light stimulation of the retina. The result was confirmed by a combination of real-time electrophysiology and fiber photometry. 3. VC showed a faster response rate under LRUS than light stimulation through the retina. These results suggest a potential non-invasive therapeutic method for restoring vision in optic-nerve-impaired patients using ultrasound stimulation (US).

The purpose of this study is to develop a method for delivering antiinflammatory agents of high molecular weight (e.g., Avastin) into the posterior segment that does not require injections into the eye (i.e., intravitreal injections; IVT). Diseases affecting the posterior segment of the eye are currently treated with monthly to bimonthly intravitreal injections, which can predispose patients to severe albeit rare complications like endophthalmitis, retinal detachment, traumatic cataract, and/or increased intraocular. In this study, we show that one time moderate intensity focused ultrasound (MIFU) treatment can facilitate the penetration of large molecules across the scleral barrier, showing promising evidence that this is a viable method to deliver high molecular weight medications not invasively. To validate the efficacy of the drug delivery system, IVT injections of vascular endothelial growth factor (VEGF) were used to create an animal model of retinopathy. The creation of this model allowed us to test anti-VEGF medications and evaluate the efficacy of the treatment. In vivo testing showed that animals treated with our MIFU device improved on the retinal tortuosity and clinical dilation compared to the control group while evaluating fluorescein angiogram (FA) Images.

Objective. Retinal degeneration involving progressive deterioration and loss of function of photoreceptors is a major cause of permanent vision loss worldwide. Strategies to treat these incurable conditions incorporate retinal prostheses via electrically stimulating surviving retinal neurons with implanted devices in the eye, optogenetic therapy, and sonogenetic therapy. Existing challenges of these strategies include invasive manner, complex implantation surgeries, and risky gene therapy. Methods and Results. Here, we show that direct ultrasound stimulation on the retina can evoke neuron activities from the visual centers including the superior colliculus and the primary visual cortex (V1), in either normal-sighted or retinal degenerated blind rats in vivo. The neuron activities induced by the customized spherically focused 3.1 MHz ultrasound transducer have shown both good spatial resolution of 250 μm and temporal resolution of 5 Hz in the rat visual centers. An additional customized 4.4 MHz helical transducer was further implemented to generate a static stimulation pattern of letter forms. Conclusion. Our findings demonstrate that ultrasound stimulation of the retina in vivo is a safe and effective approach with high spatiotemporal resolution, indicating a promising future of ultrasound stimulation as a novel and noninvasive visual prosthesis for translational applications in blind patients.

Large aperture ultrasonic arrays can be implemented by tiling together multiple pretested modules of high-density acoustic arrays with closely integrated multiplexing and buffering electronics to form a larger aperture with high yield. These modular arrays can be used to implement large 1.75D array apertures capable of focusing in elevation for uniform slice thickness along the axial direction which can improve image contrast. An important goal for large array tiling is obtaining high yield and sensitivity while reducing extraneous image artifacts. We have been developing tileable acoustic-electric modules for the implementation of large array apertures utilizing Application Specific Integrated Circuits (ASICs) implemented using 0.35 μm high voltage (50 V) CMOS. Multiple generations of ASICs have been designed and tested. The ASICs were integrated with high-density transducer arrays for acoustic testing and imaging. The modules were further interfaced to a Verasonics Vantage imaging system and were used to image industry standard ultrasound phantoms. The first-generation modules comprise ASICs with both multiplexing and buffering electronics on-chip and have demonstrated a switching artifact which was visible in the images. A second-generation ASIC design incorporates low switching injection circuits which effectively mitigate the artifacts observed with the first-generation devices. Here, we present the architecture of the two ASIC designs and module types as well imaging results that demonstrate reduction in switching artifacts for the second-generation devices.

Argus II retinal prosthesis is the US Food and Drug Administration (FDA) approved medical device intended to restore sight to a patient’s blind secondary to retinal degeneration (i.e., retinitis pigmentosa). However, Argus II and most reported retinal prostheses require invasive surgery to implant electrodes in the eye. Recent studies have shown that focused ultrasound can be developed into a non-invasive retinal prosthesis technology. Ultrasound energy focused on retinal neurons can trigger the activities of retinal neurons with high spatial-temporal resolution. This paper introduces a novel design and simulation of a ring array transducer that could be used as non-invasive ultrasonic retinal stimulation. The array transducer is designed in the shape of a racing ring with a hemisphere surface that mimics a contact lens to acoustically couple with the eye via the tear film and directs the ultrasound to avoid the high acoustic absorption from the crystalline lens. We will describe the design methods and simulation of the two-dimensional pattern stimulation. Finally, compared with other existing retinal prostheses, we show that the ultrasound ring array is practical and safe and could be potentially used as a non-invasive retinal prosthesis.

Photoacoustic microscopy (PAM) is an emerging imaging method combining light and sound. However, limited by the laser’s repetition rate, state-of-the-art high-speed PAM technology often sacrifices spatial sampling density (i.e., undersampling) for increased imaging speed over a large field-of-view. Deep learning (DL) methods have recently been used to improve sparsely sampled PAM images; however, these methods often require time-consuming pre-training and large training dataset with ground truth. Here, we propose the use of deep image prior (DIP) to improve the image quality of undersampled PAM images. Unlike other DL approaches, DIP requires neither pre-training nor fully-sampled ground truth, enabling its flexible and fast implementation on various imaging targets. Our results have demonstrated substantial improvement in PAM images with as few as 1.4 % of the fully sampled pixels on high-speed PAM. Our approach outperforms interpolation, is competitive with pre-trained supervised DL method, and is readily translated to other high-speed, undersampling imaging modalities.

Based on known cDNAs of rice starch synthase isoforms, we constructed dsRNA interference vectors for starch synthase I (SSI) to produce transgenic plants containing starch with a moderately high amylose content. We investigated the effect of SSI suppression on grain quality traits, starch biosynthesis, and amylopectin chain distribution in rice plants exposed to two different temperature regimes. The activities and transcripts of BEs, DBEs, and other SS isoforms were further investigated to clarify the effect of SSI suppression on these key enzymes and their specific isoforms under different temperature treatments. Suppression of SSI by RNAi altered grain starch component and amylopectin chain distribution, but it exerted only a slight effect on total starch content (%) and accumulation amount (mg kernel−1) and on starch granule morphology and particle size distribution. Under normal temperature (NT), insignificant differences in kernel weight, chalky kernel proportion, chalky degree, and starch granule morphology between SSI-RNAi line and its wild type (WT) were observed. However, amylose content (AC) level and granule-bound starch synthase (GBSS) activity in rice endosperms were markedly increased by SSI-RNAi suppression. The chalky kernel proportion and chalky degree of SSI-RNAi lines were significantly higher than those of WT under high temperature (HT) exposure at filling stage. Inhibition of SSI by RNAi affected amylopectin chain distribution and raised starch gelatinization temperature (GT) in two ways: directly from the SSI deficiency itself and indirectly by reducing BEIIb amounts in an SSI-deficient background. The deficiency of SSI expression led to an alteration in the susceptibility of grain chalkiness occurrence and starch gelatinization temperature to HT exposure, owing to a pleiotropic effect of SSI deficiency on the expression of other genes associated with starch biosynthesis. Keywords: Rice, Starch synthase I, RNA interference, Grain quality, Amylopectin, High temperature

Abstract There is an urgent need for enhancing climate change resilience in rice production. Here, we report a reflective algal mulching‐based culture practice to attain a simple and low‐cost biological method for enhancement of climate change resilience. The dense mulching of Rhizoclonium sp. in field water highly reflected sunlight in the visible and infrared regions, thus significantly decreasing the root zone temperature, and significantly and simultaneously mitigated CO2, CH4, and N2O emissions through gas retention and removal in the field water layer, as well as reducing gas production. The algae could also enhance rice growth and soil fertility.

Abstract Simultaneous photoacoustic and ultrasound (PAUS) imaging has attracted increasing attention in biomedical research to probe the optical and mechanical properties of tissue. However, the resolution for majority of the existing PAUS systems is on the order of 1 mm as the majority are designed for clinical use with low-frequency US detection. Here we developed a concurrent PAUS microscopy that consists of optical-resolution photoacoustic microscopy (OR-PAM) and high-frequency US pulse-echo imaging. This dual-modality system utilizes a novel coaxial dual-element ultrasonic transducer (DE-UST) and provides anatomical and functional information with complementary contrast mechanisms, achieving a spatial resolution of 7 μm for PA imaging and 106 μm for US imaging. We performed phantom studies to validate the system’s performance. The vasculature of a mouse’s hind paw was imaged to demonstrate the potential of this hybrid system for biomedical applications.

Photoacoustic (PA) imaging is able to provide extremely high molecular contrast while maintaining the superior imaging depth of ultrasound (US) imaging. Conventional microscopic PA imaging has limited access to deeper tissue due to strong light scattering and attenuation. Endoscopic PA technology enables direct delivery of excitation light into the interior of a hollow organ or cavity of the body for functional and molecular PA imaging of target tissue. Various endoscopic PA probes have been developed for different applications, including the intravascular imaging of lipids in atherosclerotic plaque and endoscopic imaging of colon cancer. In this paper, the authors review representative probe configurations and corresponding preclinical applications. In addition, the potential challenges and future directions of endoscopic PA imaging are discussed.

The state-of-the-art three-dimensional biomedical imaging often requires specific tissue preparation that may alter the physical properties of the specimen causing loss of information. Here Wong et al. develop a microtomy-assisted photoacoustic microscopy that allows imaging of biological samples without labelling agents and with reduced sectioning.

Abstract Cardiovascular diseases are the leading cause of fatalities in the United States. Atherosclerotic plaques are one of the primary complications that can lead to strokes and heart attacks if left untreated. It is essential to diagnose the disease early and distinguish vulnerable plaques from harmless ones. Many methods focus on the structural or molecular properties of plaques. Mechanical properties have been shown to change drastically when abnormalities develop in arterial tissue. We report the development of an acoustic radiation force optical coherence elastography (ARF-OCE) system that uses an integrated miniature ultrasound and optical coherence tomography (OCT) probe to map the relative elasticity of vascular tissues. We demonstrate the capability of the miniature probe to map the biomechanical properties in phantom and human cadaver carotid arteries.

Abstract In clinical decision making, in addition to anatomical information, biomechanical properties of soft tissues may provide additional clues for disease diagnosis. Given the fact that most of diseases are originated from micron sized structures, an elastography imaging system of fine resolution (~100 µm) and deep penetration depth capable of providing both qualitative and quantitative measurements of biomechanical properties is desired. Here, we report a newly developed multi-functional ultrasonic micro-elastography imaging system in which acoustic radiation force impulse imaging (ARFI) and shear wave elasticity imaging (SWEI) are implemented. To accomplish this, the 4.5 MHz/40 MHz transducer were used as the excitation/detection source, respectively. The imaging system was tested with tissue-mimicking phantoms and an ex vivo chicken liver through 2D/3D imaging. The measured lateral/axial elastography resolution and field of view are 223.7 ± 20.1/109.8 ± 6.9 µm and 1.5 mm for ARFI, 543.6 ± 39.3/117.6 ± 8.7 µm and 2 mm for SWEI, respectively. These results demonstrate that the promising capability of this high resolution elastography imaging system for characterizing tissue biomechanical properties at microscale level and its translational potential into clinical practice.

The crystalline lens and cornea comprise the eye’s optical system for focusing light in human vision. The changes in biomechanical properties of the lens and cornea are closely associated with common diseases, including presbyopia and cataract. Currently, most in vivo elasticity studies of the anterior eye focus on the measurement of the cornea, while lens measurement remains challenging. To better understand the anterior segment of the eye, we developed an optical coherence elastography system utilizing acoustic radiation force excitation to simultaneously assess the elasticities of the crystalline lens and the cornea in vivo. A swept light source was integrated into the system to provide an enhanced imaging range that covers both the lens and the cornea. Additionally, the oblique imaging approach combined with orthogonal excitation also improved the image quality. The system was tested through first ex vivo and then in vivo experiments using a rabbit model. The elasticities of corneal and lens tissue in an excised normal whole-globe and a cold cataract model were measured to reveal that cataractous lenses have a higher Young’s modulus. Simultaneous in vivo elasticity measurements of the lens and cornea were performed in a rabbit model to demonstrate the correlations between elasticity and intraocular pressure and between elasticity and age. To the best of our knowledge, we demonstrated the first in vivo elasticity of imaging of both the lens and cornea using acoustic radiation force-optical coherence elastography, thereby providing a potential powerful clinical tool to advance ophthalmic research in disorders affecting the lens and the cornea.

Endoscopic dual-modality photoacoustic (PA) and ultrasound (US) imaging has the capability of providing morphology and molecular information simultaneously. An ultrasonic transducer was applied for detecting PA signals and performing US imaging which determines the sensitivity and performance of a dual-modality PA/US system. In our study, a miniature single element 32-MHz lead magnesium niobate-lead titanate (PMN-PT) epoxy 1–3 composite based ultrasonic transducer was developed. A miniature endoscopic probe based on this transducer has been fabricated. Using the dual modality PA/US system with a PMN-PT/epoxy 1–3 composite based ultrasonic transducer, phantom and in vivo animal studies have been conducted to evaluate the performance. The preliminary results show enhanced bandwidths of the new ultrasonic transducer and improved signal-to-noise ratio of PA and US images of rat colorectal wall compared with PMN-PT and lead zirconate titanate (PZT) composite based ultrasonic transducers. Keywords: Photoacoustic imaging, Ultrasound imaging, Endoscopic imaging, Gastrointestinal, Ultrasonic transducer, PMN-PT epoxy 1-3 composite, Composite based ultrasonic transducer

Ultrasound is an emerging method for non-invasive neuromodulation. Studies in the past have demonstrated that ultrasound can reversibly activate and inhibit neural activities in the brain. Recent research shows the possibility of using ultrasound ranging from 0.5 to 43 MHz in acoustic frequency to activate the retinal neurons without causing detectable damages to the cells. This review recapitulates pilot studies that explored retinal responses to the ultrasound exposure, discusses the advantages and limitations of the ultrasonic stimulation, and offers an overview of engineering perspectives in developing an acoustic retinal prosthesis. For comparison, this article also presents studies in the ultrasonic stimulation of the visual cortex. Despite that, the summarized research is still in an early stage; ultrasonic retinal stimulation appears to be a viable technology that exhibits enormous therapeutic potential for non-invasive vision restoration.

Piezoelectric composites are considered excellent core materials for fabricating various ultrasonic devices. For the traditional fabrication process, piezoelectric composite structures are mainly prepared by mold forming, mixing, and dicing-filing techniques. However, these techniques are limited on fabricating shapes with complex structures. With the rapid development of additive manufacturing (AM), many research fields have applied AM technology to produce functional materials with various geometric shapes. In this study, the Mask-Image-Projection-based Stereolithography (MIP-SL) process, one of the AM (3D-printing) methods, was used to build BaTiO3-based piezoelectric composite ceramics with honeycomb structure design. A sintered sample with denser body and higher density was achieved (i.e., density obtained 5.96 g/cm3), and the 3D-printed ceramic displayed the expected piezoelectric and ferroelectric properties using the complex structure (i.e., piezoelectric constant achieved 60 pC/N). After being integrated into an ultrasonic device, the 3D-printed component also presents promising material performance and output power properties for ultrasound sensing (i.e., output voltage reached 180 mVpp). Our study demonstrated the effectiveness of AM technology in fabricating piezoelectric composites with complex structures that cannot be fabricated by dicing-filling. The approach may bring more possibilities to the fabrication of micro-electromechanical system (MEMS)-based ultrasonic devices via 3D-printing methods in the future.

The ability to measure the elastic properties of plaques and vessels would be useful in clinical diagnoses, particularly for detecting a vulnerable plaque. This study demonstrates the feasibility of the combination of intravascular ultrasound (IVUS) and acoustic radiation force elasticity imaging for detecting the distribution of stiffness within atherosclerotic arteries ex vivo. A dual-frequency IVUS transducer with two elements was used to induce the propagation of the shear wave (by the 8.5 MHz pushing element) which could be simultaneously monitored by the 31 MHz imaging element. The wave-amplitude image and the wave-velocity image were reconstructed by measuring the peak displacement and wave velocity of shear wave propagation, respectively. System performance was verified using gelatin phantoms. The phantom results demonstrate that the stiffness differences of shear modulus of 1.6 kPa can be distinguished through the wave-amplitude and wave-velocity images. The stiffness distributions of the atherosclerotic aorta from a rabbit were obtained, for which the values of peak displacement and the shear wave velocity were 3.7 ± 1.2 µm and 0.38 ± 0.19 m s−1 for the lipid-rich plaques, and 1.0 ± 0.2 µm and 3.45 ± 0.45 m s−1 for the arterial walls, respectively. These results indicate that IVUS elasticity imaging can be used to distinguish the elastic properties of plaques and vessels.

We developed a near infrared (NIR) virtual intraoperative surgical photoacoustic microscopy (NIR-VISPAM) system that combines a conventional surgical microscope and an NIR light photoacoustic microscopy (PAM) system. NIR-VISPAM can simultaneously visualize PA B-scan images at a maximum display rate of 45 Hz and display enlarged microscopic images on a surgeon's view plane through the ocular lenses of the surgical microscope as augmented reality. The use of the invisible NIR light eliminated the disturbance to the surgeon's vision caused by the visible PAM excitation laser in a previous report. Further, the maximum permissible laser pulse energy at this wavelength is approximately 5 times more than that at the visible spectral range. The use of a needle-type ultrasound transducer without any water bath for acoustic coupling can enhance convenience in an intraoperative environment. We successfully guided needle and injected carbon particles in biological tissues ex vivo and in melanoma-bearing mice in vivo.

Cancer cells undergo a number of biophysical changes as they transform from an indolent to an aggressive state. These changes, which include altered mechanical and electrical properties, can reveal important diagnostic information about disease status. Here, we introduce a high-throughput, functional technique for assessing cancer cell invasion potential, which works by probing for the mechanically excitable phenotype exhibited by invasive cancer cells. Cells are labeled with fluorescent calcium dye and imaged during stimulation with low-intensity focused ultrasound, a non-contact mechanical stimulus. We show that cells located at the focus of the stimulus exhibit calcium elevation for invasive prostate (PC-3 and DU-145) and bladder (T24/83) cancer cell lines, but not for non-invasive cell lines (BPH-1, PNT1A, and RT112/84). In invasive cells, ultrasound stimulation initiates a calcium wave that propagates from the cells at the transducer focus to other cells, over distances greater than 1 mm. We demonstrate that this wave is mediated by extracellular signaling molecules and can be abolished through inhibition of transient receptor potential channels and inositol trisphosphate receptors, implicating these proteins in the mechanotransduction process. If validated clinically, our technology could provide a means to assess tumor invasion potential in cytology specimens, which is not currently possible. It may therefore have applications in diseases such as bladder cancer, where cytologic diagnosis of tumor invasion could improve clinical decision-making.

The purpose of this study is to examine the capability of photoacoustic (PA) imaging (PAI) in assessing the unique molecular and architectural features in ocular tumors. A real-time PA and ultrasonography (US) parallel imaging system based on a research US platform was developed to examine retinoblastoma in mice in vivo and human retinoblastoma and uveal melanoma ex vivo. PA signals were generated by optical illumination at 720, 750, 800, 850, 900 and 950 nm delivered through a fiber optical bundle. The optical absorption spectra of the tumors were derived from the PA images. The optical absorption spectrum of each tumor was quantified by fitting to a polynomial model. The microscopic architectures of the tumors were quantified by frequency domain analysis of the PA signals. Both the optical spectral and architectural features agree with the histological findings of the tumors. The mouse and human retinoblastoma showed comparable total optical absorption spectra at a correlation of 0.95 (p

Biomedical imaging is the key technique and process to create informative images of the human body or other organic structures for clinical purposes or medical science [...]

Neurostimulation has proved to be an effective method for the restoration of visual perception lost due to retinal diseases. However, the clinically available retinal neurostimulation method is based on invasive electrodes, making it a high-cost and high-risk procedure. Recently, ultrasound has been demonstrated to be an effective way to achieve noninvasive neurostimulation. In this work, a novel racing array transducer with a contact lens shape is proposed for ultrasonic retinal stimulation. The transducer is flexible and placed outside the eyeball, similar to the application of a contact lens. Ultrasound emitted from the transducer can reach the retina without passing through the lens, thus greatly minimizing the acoustic absorption in the lens. The discretized Rayleigh–Sommerfeld method was employed for the acoustic field simulation, and patterned stimulation was achieved. A 5 MHz racing array transducer with different element numbers was simulated to optimize the array configuration. The results show that a 512-element racing array is the most appropriate configuration considering the necessary tradeoff between the element number and the stimulation resolution. The stimulation resolution at a focus of 24 mm is about 0.6 mm. The obtained results indicate that the proposed racing array design of the ultrasound transducer can improve the feasibility of an ultrasound retinal prosthesis.

Piezoelectric arrays are widely used in non-destructive detecting, medical imaging and therapy. However, limited by traditional manufacturing methods, the array’s element is usually designed in simple geometry such as a cube or rectangle, restricting potential applications of the array. This work demonstrates an annular piezoelectric array consisting of different concentric elements printed by Mask-Image-Projection-based Stereolithography (MIP-SL) technology. The printed array displays stable piezoelectric and dielectric properties. Compared to a traditional single element transducer, the ultrasonic transducer with printed array successfully modifies the acoustic beam and significantly improves spatial resolution.

Estimating the corneal elasticity can provide valuable information for corneal pathologies and treatments. Ophthalmologic pathologies will invariably cause changes to the elasticity of the cornea. For example, keratoconus and the phototoxic effects of ultraviolet radiation usually increase the corneal elasticity. This makes a quantitative estimation of the elasticity of the human cornea important for ophthalmic diagnoses. The present study investigated the use of a proposed high-resolution shear wave imaging (HR-SWI) method based on a dual-element transducer (comprising an 8-MHz element for pushing and a 32-MHz element for imaging) for measuring the group shear wave velocity (GSWV) of the human cornea. An empirical Young’s modulus formula was used to accurately convert the GSWV to Young’s modulus. Four quantitative parameters, bias, resolution, contrast, and contrast-to-noise ratio (CNR), were measured in gelatin phantoms with two different concentrations (3% and 7%) to evaluate the performance of HR-SWI. The biases of gelatin phantoms (3% and 7%) were 5.88% and 0.78%, respectively. The contrast and CNR were 0.76, 1.31 and 3.22, 2.43 for the two-side and two-layer phantoms, respectively. The measured image resolutions of HR-SWI in the lateral and axial directions were 72 and 140 μm, respectively. The calculated phase SWV (PSWV) and their corresponding Young’s modulus from six human donors were 2.45 ± 0.48 m/s (1600 Hz) and 11.52 ± 7.81 kPa, respectively. All the experimental results validated the concept of HR-SWI and its ability for measuring the human corneal elasticity.

Single-beam acoustic tweezers (SBAT), used in laboratory-on-a-chip (LOC) device has promising implications for an individual micro-particle contactless manipulation. In this study, a freestanding hydrothermal PZT thick film with excellent piezoelectric property (d33 = 270pC/N and kt = 0.51) was employed for SBAT applications and a press-focusing technology was introduced. The obtained SBAT, acting at an operational frequency of 50MHz, a low f-number (∼0.9), demonstrated the capability to trap and manipulate a micro-particle sized 10μm in the distilled water. These results suggest that such a device has great potential as a manipulator for a wide range of biomedical and chemical science applications.

This paper describes the design of an ultrahigh frequency ultrasound system combined with tightly focused 500 MHz ultrasonic transducers and high frequency wideband low noise amplifier (LNA) integrated circuit (IC) model design. The ultrasonic transducers are designed using Aluminum nitride (AlN) piezoelectric thin film as the piezoelectric element and using silicon lens for focusing. The fabrication and characterization of silicon lens was presented in detail. Finite element simulation was used for transducer design and evaluation. A custom designed LNA circuit is presented for amplifying the ultrasound echo signal with low noise. A Common-source and Common-gate (CS-CG) combination structure with active feedback is adopted for the LNA design so that high gain and wideband performances can be achieved simultaneously. Noise and distortion cancelation mechanisms are also employed in this work to improve the noise figure (NF) and linearity. Designed by using a 0.35 μm complementary metal oxide semiconductor (CMOS) technology, the simulated power gain of the echo signal wideband amplifier is 22.5 dB at 500 MHz with a capacitance load of 1.0 pF. The simulated NF at 500 MHz is 3.62 dB.

A lead-free 0.94(Na0.5Bi0.5) TiO3-0.06 BaTiO3 (BNT-BT) thick film, with a thickness of 60 μm, has been fabricated using a tape-casting method. The longitudinal piezoelectric constant, clamped dielectric permittivity constant, remnant polarization and coercive field of the BNT-BT thick film were measured to be 150 pC/N, 1928, 13.6 μC/cm2, and 33.6 kV/cm, respectively. The electromechanical coupling coefficient kt was calculated to be 0.55 according to the measured electrical impedance spectrum. A high-frequency plane ultrasound transducer was successfully fabricated using a BNT-BT thick film. The performance of the transducer was characterized and evaluated by the pulse-echo testing and wire phantom imaging operations. The BNT-BT thick film transducer exhibits a center frequency of 34 MHz, a −6 dB bandwidth of 26%, an axial resolution of 77 μm and a lateral resolution of 484 μm. The results suggest that lead-free BNT-BT thick film fabricated by tape-casting method is a promising lead-free candidate for high-frequency ultrasonic transducer applications.

In this article, an approach to designing and developing an ultrahigh frequency (≤600 MHz) ultrasound analog frontend with Golay coded excitation sequence for high resolution imaging applications is presented. For the purpose of visualizing specific structures or measuring functional responses of micron-sized biological samples, a higher frequency ultrasound is needed to obtain a decent spatial resolution while it lowers the signal-to-noise ratio, the difference in decibels between the signal level and the background noise level, due to the higher attenuation coefficient. In order to enhance the signal-to-noise ratio, conventional approach was to increase the transmit voltage level. However, it may cause damaging the extremely thin piezoelectric material in the ultrahigh frequency range. In this paper, we present a novel design of ultrahigh frequency (≤600 MHz) frontend system capable of performing pseudo Golay coded excitation by configuring four independently operating pulse generators in parallel and the consecutive delayed transmission from each channel. Compared with the conventional monocycle pulse approach, the signal-to-noise ratio of the proposed approach was improved by 7–9 dB without compromising the spatial resolution. The measured axial and lateral resolutions of wire targets were 16.4 µm and 10.6 µm by using 156 MHz 4 bit pseudo Golay coded excitation, respectively and 4.5 µm and 7.7 µm by using 312 MHz 4 bit pseudo Golay coded excitation, respectively.

This paper describes the design, fabrication, and characterization of tightly focused (ƒ-number close to 1) high frequency needle-type transducers based on lead-free Na0.5Bi4.5Ti3.975Co0.025O15 (NBT-Co) piezo-ceramics. The NBT-Co ceramics, are fabricated through solid-state reactions, have a piezoelectric coefficient d33 of 32 pC/N, and an electromechanical coupling factor kt of 35.3%. The high Curie temperature (670 °C) indicates a wide working temperature range. Characterization results show a center frequency of 70.4 MHz and a −6 dB bandwidth of 52.7%. Lateral resolution of 29.8 μm was achieved by scanning a 10 μm tungsten wire target, and axial resolution of 20.8 μm was calculated from the full width at half maximum (FWHM) of the pulse length of the echo. This lead-free ultrasonic transducer has potential applications in high resolution biological imaging.

We report photoacoustic and ultrasonic endoscopic images of two intact rabbit esophagi. To investigate the esophageal lumen structure and microvasculature, we performed in vivo and ex vivo imaging studies using a 3.8-mm diameter photoacoustic endoscope and correlated the images with histology. Several interesting anatomic structures were newly found in both the in vivo and ex vivo images, which demonstrates the potential clinical utility of this endoscopic imaging modality. In the ex vivo imaging experiment, we acquired high-resolution motion-artifact-free three-dimensional photoacoustic images of the vasculatures distributed in the walls of the esophagi and extending to the neighboring mediastinal regions. Blood vessels with apparent diameters as small as 190 μm were resolved. Moreover, by taking advantage of the dual-mode high-resolution photoacoustic and ultrasound endoscopy, we could better identify and characterize the anatomic structures of the esophageal lumen, such as the mucosal and submucosal layers in the esophageal wall, and an esophageal branch of the thoracic aorta. In this paper, we present the first photoacoustic images showing the vasculature of a vertebrate esophagus and discuss the potential clinical applications and future development of photoacoustic endoscopy.

The in-chlorophyll centre waveband (ICCW) (640-680 nm) is the specific chlorophyll (Chl) absorption band, but the reflectance in this band has not been used as an optimal index for non-destructive determination of plant Chl content in recent decades. This study develops a new spectral index based solely on the ICCW for robust retrieval of leaf Chl content for the first time. A glasshouse experiment for solution-culture of one chlorophyll-deficient rice mutant and six wild types of rice genotypes was conducted, and the leaf reflectance (400-900 nm) was measured with a high spectral resolution (1 nm) spectrophotometer and the contents of chlorophyll a (Chla), chlorophyll b (Chlb) and chlorophyll a+b (Chlt) of the rice leaves were determined. It was found that the reflectance curves from 640 nm to 674 nm and from 675 nm to 680 nm of the low-chlorophyll mutant leaf were drastically steeper than that of the wild types in the ICCW. The new index based on the reflectance variation within ICCW, the difference of the first derivative sum within the ICCW (DFDS_ICCW), was highly sensitive (r = -0.77, n = 93, P0.05) to Chlt when the leaf Chlt was higher than 200 mg/m(2). The best equations of R-ICCW and DFDS_ICCW yielded an RMSE of 78.7, 32.9 and 107.3 mg/m(2), and an RMSE of 37.4, 16.0 and 45.3 mg/m(-2), respectively, for predicting Chla, Chlb and Chlt. The new index could rank in the top 10 for prediction of Chla and Chlt as compared with the 55 existing indices. Additionally, most of the 55 existing Chl-related VIs performed robustly or strongly in simultaneous prediction of leaf Chla, Chlb and Chlt.

Viewing individual cells and ambient microvasculature simultaneously is crucial for understanding tumor angiogenesis and microenvironments. We developed a confocal fluorescence microscopy (CFM) and photoacoustic microscopy (PAM) dual-modality imaging system that can assess fluorescent contrast and optical absorption contrast in biologic samples simultaneously. After staining tissues with fluorescent dye at an appropriate concentration, each laser pulse can generate not only sufficient fluorescent signals from cells for CFM but also sufficient photoacoustic signals from microvessels for PAM. To explore the potential of this system for diagnosis of bladder cancer, experiments were conducted on a rat bladder model. The CFM image depicts the morphology of individual cells, showing not only large polygonal umbrella cells but also intracellular components. The PAM image acquired at the same time provides complementary information on the microvascular distribution in the bladder wall, ranging from large vessels to capillaries. This device provides an opportunity to realize both histologic assay and microvascular characterization simultaneously. The combination of the information of individual cells and local microvasculature in the bladder offers the capability of envisioning the viability and activeness of these cells and holds promise for more comprehensive study of bladder cancer in vivo.

Photoacoustic imaging is a novel biomedical imaging modality that has emerged over the recent decades. Due to the conversion of optical energy into the acoustic wave, photoacoustic imaging offers high-resolution imaging in depth beyond the optical diffusion limit. Photoacoustic imaging is frequently used in conjunction with ultrasound as a hybrid modality. The combination enables the acquisition of both optical and acoustic contrasts of tissue, providing functional, structural, molecular, and vascular information within the same field of view. In this review, we first described the principles of various photoacoustic and ultrasound imaging techniques and then classified the dual-modal imaging systems based on their preclinical and clinical imaging applications. The advantages of dual-modal imaging were thoroughly analyzed. Finally, the review ends with a critical discussion of existing developments and a look toward the future. [ABSTRACT FROM AUTHOR]