Noninvasive estimation of dynamic pressures in vitro and in vivo using the subharmonic response from microbubbles

The purpose of this study was to develop and validate a noninvasive pressure estimation technique based on subharmonic emissions from a commercially available ultrasound contrast agent and scanner, unlike other studies that have either adopted a single-element transducer approach and/ or use of in-house contrast agents. Ambient pressures were varied in a closed-loop flow system between 0 and 120 mmHg and were recorded by a solid-state pressure catheter as the reference standard. Simultaneously, the ultrasound scanner was operated in pulse inversion mode transmitting at 2.5 MHz, and the unprocessed RF data were captured at different incident acoustic pressures (from 76 to 897 kPa). The subharmonic data for each pulse were extracted using band-pass filtering with averaging, and subsequently processed to eliminate noise. The incident acoustic pressure most sensitive to ambient pressure fluctuations was determined, and then the ambient pressure was tracked over 20 s. In vivo validation of this technique was performed in the left ventricle (LV) of 2 canines. In vitro, the subharmonic signal could track ambient pressure values with r(2) = 0.922 (p < 0.001), whereas in vivo, the subharmonic signal tracked the LV pressures with r(2) > 0.790 (p < 0.001) showing a maximum error of 2.84 mmHg compared with the reference standard. In conclusion, a subharmonic ultrasound-based pressure estimation technique, which can accurately track left ventricular pressures, has been established.     

Simulation of noninvasive blood pressure estimation using ultrasound contrast agent microbubbles

The microbubble ultrasound contrast agent (UCA) has been widely recognized as a potential noninvasive tool for blood pressure measurement. However, UCA indices such as the shift in the resonance frequency and echo amplitude have problems of low resolution, nonlinear relationship with blood pressure, etc. In this paper, a novel UCA index, the shift in the subharmonic optimal driving frequency (SSODF) of microbubbles, is proposed. The effectiveness of the index for estimating blood pressure was evaluated by performing a microbubble acoustic response simulation. The behavior of commercial UCA microbubbles was investigated as a function of the driving acoustic pressure (in kilopascals) and ambient overpressure (in millimeters of mercury). Simulation results showed that for a 1.6-μm-diameter microbubble, SSODF increased linearly with the overpressure in a range of 0 to 200 mmHg and was maximum (2.07 MHz) at 380 kPa. Changes of the overpressure as small as 5 mmHg can be detected using SSODF. For a population of microbubbles with a Gaussian size distribution (mean diameter: 1.6 μm, standard deviation: 0.2 μm), SSODF was 1.7 MHz at 280 kPa. With further experimental validation, the proposed method may be developed as a novel noninvasive technique for accurate blood pressure measurement.     

In vivo acceleration of ultrasonic tissue heating by microbubble agent

The ultrasonic power absorbed by a microbubble in its continuous wave response is estimated through numerically solving a version of the Rayleigh-Plesset equation. At an ultrasonic frequency of 3 MHz, a resonant microbubble, approximately 1.1 microm in radius, showed an absorption cross section of about 0.005 mm2 in its low power response. This estimation predicts that the tissue ultrasonic absorption will be doubled when such microbubbles are delivered to the tissue at a concentration of about eight bubbles/mm3 in tissue. An exteriorized murine kidney was exposed to focused ultrasound at 3.2 MHz in degassed saline, and the tissue temperature change was measured. With an intravenous bolus administration of a microbubble agent, the ultrasonically induced temperature elevation was multiplied by up to five times. The enhancement in temperature elevation gradually decreased as the microbubble agent was eliminated from the body. The experimental results agreed with the prediction in the order of magnitude. This effect may have a potential use to enhance the throughput as well as the selectivity of focused ultrasound treatment.     

Raman spectroscopy using a spatial heterodyne spectrometer: proof of concept

The use of a spatial heterodyne interferometer-based spectrometer (SHS) for Raman spectroscopy is described. The motivation for this work is to develop a small, rugged, high-resolution ultraviolet (UV) Raman spectrometer that is compatible with pulsed laser sources and that is suitable for planetary space missions. UV Raman is a particular technical challenge for space applications because dispersive (grating) approaches require large spectrographs and very narrow slits to achieve the spectral resolution required to maximize the potential of Raman spectroscopy. The heterodyne approach of the SHS has only a weak coupling of resolution and throughput, so a high-resolution UV SHS can both be small and employ a wide slit to maximize throughput. The SHS measures all optical path differences in its interferogram simultaneously with a detector array, so the technique is compatible with gated detection using pulsed lasers, important to reject ambient background and mitigate fluorescence (already low in the UV) that might be encountered on a planetary surface where samples are uncontrolled. The SHS has no moving parts, and as the spectrum is heterodyned around the laser wavelength, it is particularly suitable for Raman measurements. In this preliminary report we demonstrate the ability to measure visible wavelength Raman spectra of liquid and solid materials using an SHS Raman spectrometer and a visible laser. Spectral resolution and bandpass are also discussed. Separation of anti-Stokes and Stokes Raman bands is demonstrated using two different approaches. Finally spectral bandpass doubling is demonstrated by forming an interference pattern in both directions on the ICCD detector followed by analysis using a two-dimensional Fourier transform.     

DOA estimation for non-Gaussian signals using fourth-order cumulants

A novel method based on fourth-order cumulants (FOC) is proposed for direction of arrival (DOA) estimation with uniform linear array (ULA). The method can be applied in the situation that the non-Gaussian independent and coherent signals coexist with unknown coloured Gaussian noise. The method comprises two steps: the first step is to estimate the independent signals, and then they are eliminated; the second step is to resolve the coherent signals with the reconstructed FOC matrix of coherent signals. The proposed method can also be extended to the scenario when independent, partially correlated and coherent signals coexist, and the number of signals resolved by our method can exceed the number of array elements. Simulation results demonstrate the effectiveness and efficiency of our method.     

微泡超声造影剂材料研究进展

超声造影剂(UCA)是一类能够显著增强医学超声检测信号的诊断药剂,UCA的出现,开创了无创超声医学的一个新领域.本文对目前应用于微泡超声造影剂的各种材料进行了评述,并按膜材料的不同,从制备角度出发介绍了一些最新的造影剂,介绍了微泡超声造影剂目前在靶向制剂领域的融合,文中还介绍了我们开展的一些工作.     

超声微泡造影剂的低频动力学行为

低频超声联合微泡造影剂有可能用于治疗肿瘤,因此开展造影剂低频的动力学特性研究是十分重要的。将低频声场(26.2kHz)中有壳和无壳的微泡造影剂视为以流体为负载的非线性振子,由带耗散函数的拉格朗日方程导出在不可压缩的粘滞流体中造影剂球对称振动的运动方程,利用球谐振腔和Mie散射技术对CO2微泡和带人白蛋白壳的全氟丙烷造影剂微泡进行了气泡散射光强I(t)曲线的实验测定,结果与数值模拟曲线相一致。表明:有壳和无壳的造影剂微泡在低频稳态空化时同样呈现大幅膨胀、迅速塌缩和回弹的非线性振荡;如处于内径较小的微血管中,微泡周期性大幅度(>血管内径)膨胀收缩将会引起血管轴向破裂,形成微血管栓塞;而在塌缩相,微泡内的气体被急剧压缩,泡内压强急剧增大,易在泡壁不稳定处形成高速微射流,诱发内皮细胞损伤而形成血栓。     

High frequency nonlinear B-scan imaging of microbubble contrast agents

It was previously shown that it is possible to produce nonlinear scattering from microbubble contrast agents using transmit frequencies in the 14-32 MHz range, suggesting the possibility of performing high-frequency, nonlinear microbubble imaging. In this study, we describe the development of nonlinear microbubble B-scan imaging instrumentation capable of operating at transmit center frequencies between 10 and 50 MHz. The system underwent validation experiments using transmit frequencies of 20 and 30 MHz. Agent characterization experiments demonstrate the presence of nonlinear scattering for the conditions used in this study. Using wall-less vessel phantoms, nonlinear B-scan imaging is performed using energy in one of the subharmonic, ultraharmonic, and second harmonic frequency regions for transmit frequencies of 20 and 30 MHz. Both subharmonic and ultraharmonic imaging modes achieved suppression of tissue signals to below the noise floor while achieving contrast to noise ratios of up to 26 and 17 dB, respectively. The performance of second harmonic imaging was compromised by nonlinear propagation and offered no significant contrast improvement over fundamental mode imaging. In vivo experiments using the subharmonic of a 20 MHz transmit pulse show the successful detection of microvessels in the rabbit ear and in the mouse heart. The results of this study demonstrate the feasibility of nonlinear microbubble imaging at high frequencies     

High-frequency, nonlinear flow imaging of microbubble contrast agents

It has been shown that nonlinear scattering can be stimulated from microbubble contrast agents at high-transmit frequencies (14-32 MHz). This work was extended to demonstrate the feasibility of nonlinear contrast imaging through modifications of existing ultrasound biomicroscopy linear B-scan imaging instrumentation. In this study, we describe the development and evaluation of prototype coherent flow imaging instrumentation for nonlinear microbubble imaging using transmit frequencies from 10 to 50 MHz. Phantom validation experiments were conducted to demonstrate color and power flow imaging using nonlinear 10 MHz (subharmonic) scattering induced by a 20 MHz transmit frequency. In vivo flow imaging of a rabbit ear microvessel was successfully performed. This work indicates the feasibility of performing flow imaging at high frequencies using nonlinear scattering from microbubbles.     

A fundamental limit on delay estimation using partially correlatedspeckle signals

Delay estimation is used in ultrasonic imaging to estimate blood or soft tissue motion, to measure echo arrival time differences for phase aberration correction, and to estimate displacement for tissue elasticity measurements. In each of these applications delay estimation is performed using speckle signals which are at least partially decorrelated relative to one another. Delay estimates which utilize such data are subject to large errors known as false peaks and smaller magnitude errors known as jitter. While false peaks can sometimes be removed through nonlinear processing, jitter errors place a fundamental limit on the performance of delay estimation techniques. The authors apply the Cramer-Rao Lower Bound to derive an analytical expression which predicts the magnitude of jitter errors incurred when estimating delays using radio frequency (RF) data from speckle targets. The analytical expression presented includes the effects of signal decorrelation due to physical processes, corruption by electronic noise, and a number of other factors. Simulation results are presented which show that the performance of the normalized cross correlation algorithm closely matches theoretical predictions. These results indicate that for poor signal to noise ratios (0 dB) a small improvement in signal to noise ratio can dramatically reduce jitter magnitude. At high signal to noise ratios (30 dB) small amounts of signal decorrelation can significantly increase the magnitude of jitter errors     

In vivo optical imaging and dynamic contrast methods for biomedical research

This paper provides an overview of optical imaging methods commonly applied to basic research applications. Optical imaging is well suited for non-clinical use, since it can exploit an enormous range of endogenous and exogenous forms of contrast that provide information about the structure and function of tissues ranging from single cells to entire organisms. An additional benefit of optical imaging that is often under-exploited is its ability to acquire data at high speeds; a feature that enables it to not only observe static distributions of contrast, but to probe and characterize dynamic events related to physiology, disease progression and acute interventions in real time. The benefits and limitations of in vivo optical imaging for biomedical research applications are described, followed by a perspective on future applications of optical imaging for basic research centred on a recently introduced real-time imaging technique called dynamic contrast-enhanced small animal molecular imaging (DyCE).     

Computational hyperspectral interferometry for studies of brain function: proof of concept

Hyperspectral interferometric microscopy uses a unique combination of optics and algorithm design to extract information. Local brain activity rapidly changes local blood flow and red blood cell concentration (absorption) and oxygenation (color). We demonstrate that brain activity evoked during whisker stimulation can be detected with hyperspectral interferometric microscopy to identify the active whisker-barrel cortex in the rat brain. Information about constituent components is extracted across the entire spectral band. Algorithms can be flexibly optimized to discover, detect, quantify, and visualize a wide range of significant biological events, including changes relevant to the diagnosis and treatment of disease.     

A time-efficient and accurate strain estimation concept for ultrasonic elastography using iterative phase zero estimation

In ultrasonic elastography, the exact estimation of temporal displacements between two signals is the key to estimating strain. An algorithm was previously proposed that estimates these displacements using phase differences of the corresponding base-band signals. A major advantage of these algorithms compared with correlation techniques is the computational efficiency. In this paper, an extension of the algorithm is presented that iteratively takes into account the time shifts of the signals to overcome the problems of aliasing and accuracy in the estimation of the phase shift. Thus, it can be proven that the algorithm is equivalent to the search of the maximum of the correlation function. Furthermore, a robust logarithmic compression is proposed that only compresses the envelope of the signal. This compression does not introduce systematic errors and significantly reduces decorrelation noise. The resulting algorithm is a computationally simple and very fast alternative to conventional correlation techniques, and the accuracy of strain images is improved.     

Digital twinning for smart hospital operations: Framework and proof of concept

Analyzable data capturing physical entity activities is a prerequisite for complex hospital operational decision-makings. However, there is a lack of effective strategies to integrate real-time data from multiple sources for efficient clinical and non-clinical operations in healthcare settings. Drawing on previous explorations of digital twins that facilitate real-time feedback of physical entities, we propose a conceptual framework of digital twinning for smart hospitals, with identified information needs and enabling technologies. A pilot platform is developed and tested in a Shanghai municipal hospital. The results indicate that the digital twinning method enables continuous real-time control of related operational tasks, and further promotes the development of digitization, automation, and intelligence in hospital operations.     

Robust estimation of known signals

Abstract

The nonlinear behavior of reinforced concrete frames with sidesway is governed by two effects: first, the nonlinearity of materials due to cracking and the plastic behavior of materials, and second, the nonlinearity of geometry caused by the second‐order deformation. These two effects may interact, and the whole phenomenon is known as the nonlinearity of geometry and materials.

Reinforced concrete frames are frequently used to resist wind or earthquake forces. These forces will accentuate the complexity of the frame behavior because of the continuous change of the shape of the bending moment diagram. The change of moment diagram will in turn affect the magnitude of the cumulative plastic rotations.

A trial and error method was devised to predict theoretically the moment‐load curves of reinforced concrete frames throughout the loading history. This method utilized the trilinear moment‐curvature curve for critical sections suggested by Macchi [8], as well as the principle of virtual work to express the compatibility condition and to find deflections.

The theoretical prediction was checked by experiments with nine reinforced concrete frame models. The comparison was found to be reasonably good throughout the loading history.     

Nonlinear propagation of ultrasound through microbubble contrast agents and implications for imaging

Microbubble contrast agents produce nonlinear echoes under ultrasound insonation, and current imaging techniques detect these nonlinear echoes to generate contrast agent images accordingly. For these techniques, there is a potential problem in that bubbles along the ultrasound transmission path between transducer and target can alter the ultrasound transmission nonlinearly and contribute to the nonlinear echoes. This can lead to imaging artefacts, especially in regions at depth. In this paper we provide insight, through both simulation and experimental measurement, into the nonlinear propagation caused by microbubbles and the implications for current imaging techniques. A series of investigations at frequencies below, at, and above the resonance frequency of microbubbles were performed. Three specific effects on the pulse propagation (i.e., amplitude attenuation, phase changes, and harmonic generation) were studied. It was found that all these effects are dependent on the initial pulse amplitude, and their dependence on the initial phase of the pulse is shown to be insignificant. Two types of imaging errors are shown to result from this nonlinear propagation: first, that tissue can be misclassified as microbubbles; second, the concentration of microbubbles in the image can be misrepresented. It is found that these imaging errors are significant for all three pulse frequencies when the pulses transmit through a microbubble suspension of 6 cm in path length. It also is found that the first type of error is larger at the bubble resonance frequency.     

Pulse inversion Doppler: a new method for detecting nonlinear echoes from microbubble contrast agents

A novel technique for the selective detection of ultrasound contrast agents, called pulse inversion Doppler, has been developed. In this technique, a conventional Doppler or color Doppler pulse sequence is modified by inverting every second transmit pulse. Either conventional or harmonic Doppler processing is then performed on the received echoes. In the resulting Doppler spectra, Doppler shifts from linear and nonlinear scattering are separated into two distinct regions that can be analyzed separately or combined to estimate the ratio of nonlinear to linear scattering from a region of tissue. The maximum Doppler shift that can be detected is 1/2 the normal Nyquist limit. This has the advantage over conventional harmonic Doppler that it can function over the entire bandwidth of the echo signal, thus achieving superior spatial resolution in the Doppler image. In vitro measurements comparing flowing agent and cellulose particles suggest that pulse inversion Doppler can provide 3 to 10 dB more agent to tissue contrast than harmonic imaging with similar pulses. Similar measurements suggest that broadband pulse inversion Doppler can provide up to 16 dB more contrast than broadband conventional Doppler. Nonlinear propagation effects limit the maximum contrast obtainable with both harmonic and pulse inversion Doppler techniques.     

In vivo estimation of calcium phosphate cements containing chondroitin sulfate in subcutis

Calcium phosphate cements using an equimolar mixture of tetracalcium phosphate and dicalcium phosphate dihydrate (TeDCPD) for the powder phase were experimentally developed for use in endodontic treatment. The fundamental cement is comprised of TeDCPD kneaded with modified McIlvain's buffer solution containing calboxymethyl cellulose sodium salt (CEM-1). In the liquid phase of the modified one (CEM-2), chondroitin sulfate (CS) was added in place of the salt. The final concentration of CS in CEM-2 is 1%. Another one (CEM-3) contained 2% CS finally in place of the salt. X-ray diffract meter (XRD) was used to examine the crystalline phases of the cements. The tissue compatibility of the cements was examined histologically in the subcutaneous tissue using rats. The XRD results showed no dibasic calcium phosphate phase to be traced in CS containing two cements after 1 day of kneading. There were more multinucleated giant cells appearing around CEM-1 than around CEM-2 or CEM-3 after 4 weeks. Fibroblasts, collagen fibers and small vessels infiltrated into the internal porous structure of CEM-3. Excluding CEM-3, two cements were encapsulated with a dense fibrous connective tissue layer. We conclude that CS, in the experimentally developed cement, contributed to biocompatibility and bioactivity of the cement.     

Quantifying reliability uncertainty from catastrophic and margin defects: A proof of concept

We aim to analyze the effects of component level reliability data, including both catastrophic failures and margin failures, on system level reliability. While much work has been done to analyze margins and uncertainties at the component level, a gap exists in relating this component level analysis to the system level. We apply methodologies for aggregating uncertainty from component level data to quantify overall system uncertainty. We explore three approaches towards this goal, the classical Method of Moments (MOM), Bayesian, and Bootstrap methods. These three approaches are used to quantify the uncertainty in reliability for a system of mixed series and parallel components for which both pass/fail and continuous margin data are available. This paper provides proof of concept that uncertainty quantification methods can be constructed and applied to system reliability problems. In addition, application of these methods demonstrates that the results from the three fundamentally different approaches can be quite comparable.     

Optimal choice of test signals for linear channel estimation using second order statistics

A time-varying acoustic channel may be estimated by an appropriate inference using the output from a periodic test signal. In this paper it is shown how to do this in a way that takes full account of the past history of the background noise and the past history of the channel. An explicit formula is obtained for the optimal linear estimator that may be used for rapid channel estimation for a given test signal when we know the autocovariance or power spectrum of the interfering noise and the autocovariance of the echo channel variation. Given this closed formula for the optimal estimator of the channel impulse response, an efficient method for determining the optimal test signal, subject to a constraint on the test signal power, given the history of the channel and the noise, is developed. We show that if the second order statistics of the channel or the noise are known, then the optimal test signal is not white. The method includes an explicit formula for the optimal test signal given a fixed estimator. A model of channel variation which is realistic while having less complexity than a full second-order statistical model, and therefore is more amenable to robust estimation, is used in the experiments which illustrate the performance of the optimal test signals and the channel estimation method. Matrix calculus identities required for the derivation of this expression for the optimal estimator are stated and proved in the Appendixes 1 and 2.