Epinephrine-induced Effects on Cerebral Microcirculation and Oxygenation Dynamics Using Multimodal Monitoring and Functional Photoacoustic Microscopy.

BACKGROUND: The administration of epinephrine after severe refractory hypotension, shock, or cardiac arrest restores systemic blood flow and major vessel perfusion but may worsen cerebral microvascular perfusion and oxygen delivery through vasoconstriction. The authors hypothesized that epinephrine induces significant microvascular constriction in the brain, with increased severity after repetitive dosing and in the aged brain, eventually leading to tissue hypoxia. METHODS: The authors investigated the effects of intravenous epinephrine administration in healthy young and aged C57Bl/6 mice on cerebral microvascular blood flow and oxygen delivery using multimodal in vivo imaging, including functional photoacoustic microscopy, brain tissue oxygen sensing, and follow-up histologic assessment. RESULTS: The authors report three main findings. First, after epinephrine administration, microvessels exhibited severe immediate vasoconstriction (57 ± 6% of baseline at 6 min, P < 0.0001, n = 6) that outlasted the concurrent increase in arterial blood pressure, while larger vessels demonstrated an initial increase in flow (108 ± 6% of baseline at 6 min, P = 0.02, n = 6). Second, oxyhemoglobin decreased significantly within cerebral vessels with a more pronounced effect in smaller vessels (microvessels to 69 ± 8% of baseline at 6 min, P < 0.0001, n = 6). Third, oxyhemoglobin desaturation did not indicate brain hypoxia; on the contrary, brain tissue oxygen increased after epinephrine application (from 31 ± 11 mmHg at baseline to 56 ± 12 mmHg, 80% increase, P = 0.01, n = 12). In the aged brains, microvascular constriction was less prominent yet slower to recover compared to young brains, but tissue oxygenation was increased, confirming relative hyperoxia. CONCLUSIONS: Intravenous application of epinephrine induced marked cerebral microvascular constriction, intravascular hemoglobin desaturation, and paradoxically, an increase in brain tissue oxygen levels, likely due to reduced transit time heterogeneity.

Stretchable Nanolayered Thermoelectric Energy Harvester on Complex and Dynamic Surfaces.

Thermoelectric generators (TEGs) provide a unique solution for energy harvesting from waste heat, presenting a potential solution for green energy. However, traditional rigid and flexible TEGs cannot work on complex and dynamic surfaces. Here, we report a stretchable TEG (S-TEG) (over 50% stretchability of the entire device) that is geometrically suitable for various complex and dynamic surfaces of heat sources. The S-TEG consists of hot-pressed nanolayered p-(Sb2Te3) and n-(Bi2Te3)-type thermoelectric couple arrays and exploits the wavy serpentine interconnects to integrate all units. The internal resistance of a 10 × 10 array is 22 ohm, and the output power is ∼0.15 mW/cm2 at ΔT = 19 K on both developable and nondevelopable surfaces, which are much improved compared with those of existing S-TEGs. The energy harvesting of S-TEG from the dynamic surfaces of the human skin offers a potential energy solution for the wearable devices for health monitoring.

High-speed wide-field multi-parametric photoacoustic microscopy.

Capable of imaging blood perfusion, oxygenation, and flow simultaneously at the microscopic level, multi-parametric photoacoustic microscopy (PAM) has quickly emerged as a powerful tool for studying hemodynamic and metabolic changes due to physiological stimulations or pathological processes. However, the low scanning speed poised by the correlation-based blood flow measurement impedes its application in studying rapid microvascular responses. To address this challenge, we have developed a new, to the best of our knowledge, multi-parametric PAM system. By extending the optical scanning range with a cylindrically focused ultrasonic transducer (focal zone, 76µm×4.5mm) for simultaneous acquisition of 500 B-scans, the new system is 112 times faster than our previous multi-parametric system that uses a spherically focused transducer (focal diameter, 40 µm) and enables high-resolution imaging of blood perfusion, oxygenation, and flow over an area of 4.5×1mm2 at a frame rate of 1 Hz. We have demonstrated the feasibility of this system in the living mouse ear. Further development of this system into reflection mode will enable real-time cortex-wide imaging of hemodynamics and metabolism in the mouse brain.

A combined ultrasonic B-mode and color Doppler system for the classification of breast masses using neural network.

OBJECTIVES: To develop a dual-modal neural network model to characterize ultrasound (US) images of breast masses. MATERIALS AND METHODS: A combined US B-mode and color Doppler neural network model was developed to classify US images of the breast. Three datasets with breast masses were originally detected and interpreted by 20 experienced radiologists according to Breast Imaging-Reporting and Data System (BI-RADS) lexicon ((1) training set, 103212 masses from 45,433 + 12,519 patients. (2) held-out validation set, 2748 masses from 1197 + 395 patients. (3) test set, 605 masses from 337 + 78 patients). The neural network was first trained on training set. Then, the trained model was tested on a held-out validation set to evaluate agreement on BI-RADS category between the model and the radiologists. In addition, the model and a reader study of 10 radiologists were applied to the test set with biopsy-proven results. To evaluate the performance of the model in benign or malignant classifications, the receiver operating characteristic curve, sensitivities, and specificities were compared. RESULTS: The trained dual-modal model showed favorable agreement with the assessment performed by the radiologists (κ = 0.73; 95% confidence interval, 0.71-0.75) in classifying breast masses into four BI-RADS categories in the validation set. For the binary categorization of benign or malignant breast masses in the test set, the dual-modal model achieved the area under the ROC curve (AUC) of 0.982, while the readers scored an AUC of 0.948 in terms of the ROC convex hull. CONCLUSION: The dual-modal model can be used to assess breast masses at a level comparable to that of an experienced radiologist. KEY POINTS: • A neural network model based on ultrasonic imaging can classify breast masses into different Breast Imaging-Reporting and Data System categories according to the probability of malignancy. • A combined ultrasonic B-mode and color Doppler neural network model achieved a high level of agreement with the readings of an experienced radiologist and has the potential to automate the routine characterization of breast masses.

Isotropic-resolution photoacoustic microscopy with multi-angle illumination.

We have developed photoacoustic microscopy (PAM) with three-dimensional (3D) micron-level spatial resolution. With multi-angle illumination, PAM images from different view angles can be simultaneously acquired for multi-view deconvolution, without the rotation of imaging targets. A side-by-side comparison of this multi-angle-illumination PAM (MAI-PAM) and conventional PAM, which share the same ultrasonic detector, was performed in phantoms and live mice. The phantom study showed that MAI-PAM achieved a high axial resolution of 3.7 µm, which was 10-fold higher than that of conventional PAM and approached the lateral resolution of 2.7 µm. Furthermore, the in vivo study demonstrated that MAI-PAM was able to image the 3D microvasculature with isotropic spatial resolution.

Confocal Shear Wave Acoustic Radiation Force Optical Coherence Elastography for Imaging and Quantification of the In Vivo Posterior Eye.

Retinal diseases, such as age-related macular degeneration (AMD), are the leading cause of blindness in the elderly population. Since no known cures are currently present, it is crucial to diagnose the condition in its early stages so that disease progression is monitored. Recent advances show that the mechanical elasticity of the posterior eye changes with the onset of AMD. In this work, we present a quantitative method of mapping the mechanical elasticity of the posterior eye using confocal shear wave acoustic radiation force optical coherence elastography (SW-ARF-OCE). This technique has been developed and validated with both an ex-vivo porcine tissue model and a customized in-vivo rabbit model, which both showed the quantified elasticity variations between different layers. This study verifies the feasibility of using this technology for the quantification and diagnosis of retinal diseases from the in-vivo posterior eye.

High-Speed Integrated Endoscopic Photoacoustic and Ultrasound Imaging System.

Endoscopic integrated photoacoustic and ultrasound imaging has the potential for early detection of the cancer in the gastrointestinal tract. Currently, slow imaging speed is one of the limitations for clinical translation. Here, we developed a high speed integrated endoscopic PA and US imaging system, which is able to perform PA and US imaging simultaneously up to 50 frames per second. Using this system, the architectural morphology and vasculature of the rectum wall were visualized from a Sprague Dawley rat in-vivo.

A Novel Racing Array Transducer for Noninvasive Ultrasonic Retinal Stimulation: A Simulation Study.

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.

Novel Configurations of Ultrahigh Frequency (≤600 MHz) Analog Frontend for High Resolution Ultrasound Measurement.

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.

Fabrication and Characterization of High-Frequency Ultrasound Transducers Based on Lead-Free BNT-BT Tape-Casting Thick Film.

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.

High-Resolution Shear Wave Imaging of the Human Cornea Using a Dual-Element Transducer.

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.

An adjustable multi-scale single beam acoustic tweezers based on ultrahigh frequency ultrasonic transducer.

This paper reports the fabrication, characterization, and microparticle manipulation capability of an adjustable multi-scale single beam acoustic tweezers (SBAT) that is capable of flexibly changing the size of "tweezers" like ordinary metal tweezers with a single-element ultrahigh frequency (UHF) ultrasonic transducer. The measured resonant frequency of the developed transducer at 526 MHz is the highest frequency of piezoelectric single crystal based ultrasonic transducers ever reported. This focused UHF ultrasonic transducer exhibits a wide bandwidth (95.5% at -10 dB) due to high attenuation of high-frequency ultrasound wave, which allows the SBAT effectively excite with a wide range of excitation frequency from 150 to 400 MHz by using the "piezoelectric actuator" model. Through controlling the excitation frequency, the wavelength of ultrasound emitted from the SBAT can be changed to selectively manipulate a single microparticle of different sizes (3-100 µm) by using only one transducer. This concept of flexibly changing "tweezers" size is firstly introduced into the study of SBAT. At the same time, it was found that this incident ultrasound wavelength play an important role in lateral trapping and manipulation for microparticle of different sizes. Biotechnol. Bioeng. 2017;114: 2637-2647. © 2017 Wiley Periodicals, Inc.

High-Frequency Ultrasonic Imaging with Lead-free (Na,K)(Nb,Ta)O3 Single Crystal.

Lead-free (Na,K)(Nb,Ta)O3 (KNNT) piezoelectric single crystal has been successfully grown using the top-seeded solution growth technique. The electromechanical coupling factors are very high ( k33 = 0.827, kt = 0.646), and the dielectric loss tangent is as low as 0.004. Acoustic impedance was calculated to be 26.5 MRayl. From the single crystal, a single element transducer was fabricated. The transducer achieved a 57.6% -6 dB bandwidth and 32.3 µm axial resolution at the center frequency of 45.4 MHz, which can identify the cornea of porcine eyeball with high resolution. Comparison between KNNT single crystal and lead-based single crystal was discussed. The results suggest that this single crystal transducer is an excellent candidate to replace lead-containing transducer for high-frequency ultrasonic imaging applications.

Acoustic Radiation Force Optical Coherence Elastography of Corneal Tissue.

We report on a real-time acoustic radiation force optical coherence elastography (ARF-OCE) system to map the relative elasticity of corneal tissue. A modulated ARF is used as excitation to vibrate the cornea while OCE serves as detection of tissue response. To show feasibility of detecting mechanical contrast using this method, we performed tissue-equivalent agarose phantom studies with inclusions of a different stiffness. We obtained 3-D elastograms of a healthy cornea and a highly cross-linked cornea. Finally we induced a stiffness change on a small portion of a cornea and observed the differences in displacement.

Ultrasonic Transducer-Guided Electrochemical Impedance Spectroscopy to Assess Lipid-Laden Plaques.

Plaque rupture causes acute coronary syndromes and stroke. Intraplaque oxidized low density lipoprotein (oxLDL) is metabolically unstable and prone to induce rupture. We designed an intravascular ultrasound (IVUS)-guided electrochemical impedance spectroscopy (EIS) sensor to enhance the detection reproducibility of oxLDL-laden plaques. The flexible 2-point micro-electrode array for EIS was affixed to an inflatable balloon anchored onto a co-axial double layer catheter (outer diameter = 2 mm). The mechanically scanning-driven IVUS transducer (45 MHz) was deployed through the inner catheter (diameter = 1.3 mm) to the acoustic impedance matched-imaging window. Water filled the inner catheter to match acoustic impedance and air was pumped between the inner and outer catheters to inflate the balloon. The integrated EIS and IVUS sensor was deployed into the ex vivo aortas dissected from the fat-fed New Zealand White (NZW) rabbits (n=3 for fat-fed, n= 5 normal diet). IVUS imaging was able to guide the 2-point electrode to align with the plaque for EIS measurement upon balloon inflation. IVUS-guided EIS signal demonstrated reduced variability and increased reproducibility (p < 0.0001 for magnitude, p < 0.05 for phase at < 15 kHz) as compared to EIS sensor alone (p < 0.07 for impedance, p < 0.4 for phase at < 15 kHz). Thus, we enhanced topographic and EIS detection of oxLDL-laden plaques via a catheter-based integrated sensor design to enhance clinical assessment for unstable plaque.

Transparent Lead lanthanum zirconate titanate (PLZT) ceramic fibers for High-frequency Ultrasonic Transducer Applications.

This paper presents fabrication of transparent lanthanum zirconate titanate (PLZT) fibers using extrusion technique. The diameter of the sintered PLZT fiber is about 400-µm, and the fibers exhibit very good transparency. Measured dielectric constant, remnant polarization and coercive field of PLZT fiber were found to be 2340, 22.5-µC/cm2, and 9.8-kV/cm, respectively. The transparent piezoelectric materials may exhibit great potential for Photoacoustic (PA) imaging and hybrid intravascular imaging combining OCT and ultrasound imaging by using the transparent fiber as the path of light propagation and ultrasonic transducer material. In our study, these transparent PLZT fibers were designed to fabricate two types of high-frequency ultrasonic transducers: small aperture single PLZT fiber/epoxy composite and large aperture 1-3 PLZT fiber/epoxy composite ultrasonic transducers. Besides, a 20-µm tungsten wire phantom and the cornea of the porcine eye were also imaged with the 1-3 PLZT fiber/epoxy composite ultrasonic transducer to demonstrate its imaging capability.

Imaging and characterizing shear wave and shear modulus under orthogonal acoustic radiation force excitation using OCT Doppler variance method.

We report on a novel acoustic radiation force orthogonal excitation optical coherence elastography (ARFOE-OCE) technique for imaging shear wave and quantifying shear modulus under orthogonal acoustic radiation force (ARF) excitation using the optical coherence tomography (OCT) Doppler variance method. The ARF perpendicular to the OCT beam is produced by a remote ultrasonic transducer. A shear wave induced by ARF excitation propagates parallel to the OCT beam. The OCT Doppler variance method, which is sensitive to the transverse vibration, is used to measure the ARF-induced vibration. For analysis of the shear modulus, the Doppler variance method is utilized to visualize shear wave propagation instead of Doppler OCT method, and the propagation velocity of the shear wave is measured at different depths of one location with the M scan. In order to quantify shear modulus beyond the OCT imaging depth, we move ARF to a deeper layer at a known step and measure the time delay of the shear wave propagating to the same OCT imaging depth. We also quantitatively map the shear modulus of a cross-section in a tissue-equivalent phantom after employing the B scan.

Simultaneous photoacoustic microscopy of microvascular anatomy, oxygen saturation, and blood flow.

Capitalizing on the optical absorption of hemoglobin, photoacoustic microscopy (PAM) is uniquely capable of anatomical and functional characterization of the intact microcirculation in vivo. However, PAM of the metabolic rate of oxygen (MRO2) at the microscopic level remains an unmet challenge, mainly due to the inability to simultaneously quantify microvascular diameter, oxygen saturation of hemoglobin (sO2), and blood flow at the same spatial scale. To fill this technical gap, we have developed a multi-parametric PAM platform. By analyzing both the sO2-encoded spectral dependence and the flow-induced temporal decorrelation of photoacoustic signals generated by the raster-scanned mouse ear vasculature, we demonstrated-for the first time-simultaneous wide-field PAM of all three parameters down to the capillary level in vivo.

A sidelobe suppressing near-field beamforming approach for ultrasound array imaging.

A method is proposed to suppress sidelobe level for near-field beamforming in ultrasound array imaging. An optimization problem is established, and the second-order cone algorithm is used to solve the problem to obtain the weight vector based on the near-field response vector of a transducer array. The weight vector calculation results show that the proposed method can be used to suppress the sidelobe level of the near-field beam pattern of a transducer array. Ultrasound images following the application of weight vector to the array of a wire phantom are obtained by simulation with the Field II program, and the images of a wire phantom and anechoic sphere phantom are obtained experimentally with a 64-element 26 MHz linear phased array. The experimental and simulation results agree well and show that the proposed method can achieve a much lower sidelobe level than the conventional delay and sum beamforming method. The wire phantom image is demonstrated to focus much better and the contrast of the anechoic sphere phantom image improved by applying the proposed beamforming method.

Modification of microstructure on PZT films for ultrahigh frequency transducer.

Porous Lead zirconate titanate (PZT) films may have promising applications in high frequency ultrasonic transducers for their capability to modify electrical properties for better electrical and acoustic matching. In this work, porous PZT films in range of several micrometers were fabricated using a chemical solution deposition (CSD) method modified with polyvinylpyrrolidone (PVP) as a pore-foaming agent. The crystalline phase, microstructure and electrical properties of the porous films were investigated as a function of PVP contents, molecular weights and annealing temperatures. It was found that the electrical properties were closely associated with the porosity.