A Stable Phantom Material for Optical and Acoustic Imaging.

Establishing tissue-mimicking biophotonic phantom materials that provide long-term stability are imperative to enable the comparison of biomedical imaging devices across vendors and institutions, support the development of internationally recognized standards, and assist the clinical translation of novel technologies. Here, a manufacturing process is presented that results in a stable, low-cost, tissue-mimicking copolymer-in-oil material for use in photoacoustic, optical, and ultrasound standardization efforts. The base material consists of mineral oil and a copolymer with defined Chemical Abstract Service (CAS) numbers. The protocol presented here yields a representative material with a speed of sound c(f) = 1,481 ± 0.4 m·s-1 at 5 MHz (corresponds to the speed of sound of water at 20 °C), acoustic attenuation α(f) = 6.1 ± 0.06 dB·cm-1 at 5 MHz, optical absorption µa(λ) = 0.05 ± 0.005 mm-1 at 800 nm, and optical scattering µs'(λ) = 1 ± 0.1 mm-1 at 800 nm. The material allows independent tuning of the acoustic and optical properties by respectively varying the polymer concentration or light scattering (titanium dioxide) and absorbing agents (oil-soluble dye). The fabrication of different phantom designs is displayed and the homogeneity of the resulting test objects is confirmed using photoacoustic imaging. Due to its facile, repeatable fabrication process and durability, as well as its biologically relevant properties, the material recipe has high promise in multimodal acoustic-optical standardization initiatives.

The effect of source backing materials and excitation pulse durations on laser-generated ultrasound waveforms.

In this article, it is shown experimentally that a planar laser-generated ultrasound source with a hard reflective backing will generate higher acoustic pressures than a comparable source with an acoustically matched backing when the stress confinement condition is not met. Furthermore, while the source with an acoustically matched backing will have a broader bandwidth when the laser pulse is short enough to ensure stress confinement, the bandwidths of both source types will converge as the laser pulse duration increases beyond stress confinement. The explanation of the results is supported by numerical simulations.

Development and testing of a system for controlled ultrasound hyperthermia treatment with a phantom device.

Hyperthermia is the process of raising tissue temperatures in the range 40 - 45 °C for a prolonged time (up to hours). Unlike in ablation therapy, raising the temperature to such levels does not cause necrosis of the tissue but has been postulated to sensitize the tissue for radiotherapy. The ability to maintain a certain temperature in a target region is key to a hyperthermia delivery system. The aim of this work was to design and characterize a heat delivery system for ultrasound hyperthermia able to generate a uniform power deposition pattern in the target region with a closed-loop control which would maintain the defined temperature over a defined period. The hyperthermia delivery system presented herein is a flexible design with the ability to strictly control the induced temperature rise with a feedback loop. The system can be reproduced elsewhere with relative ease and is adaptable for various tumor sizes/locations and for other temperature elevation applications, such as ablation therapy. The system was fully characterized and tested on a newly-designed custom-built phantom with controlled acoustic and thermal properties and containing embedded thermocouples. Additionally, a layer of thermochromic material was fixed above the thermocouples and the recorded temperature increase was compared to the RGB (red, green, and blue) color-change in the material. The transducer characterization allowed for input voltage to output power curves to be generated, thus allowing for comparison of power deposition to temperature increase in the phantom. Additionally, the transducer characterization generated a field map of the symmetric field. The system was capable of increasing the temperature of the target area by 6 °C above body temperature and maintain the temperature to within ±0.5 °C over a defined period. The increase in temperature correlated with the RGB image analysis of the thermochromic material. The results of this work have the potential to contribute towards increasing confidence in the delivery of hyperthermia treatment to superficial tumors. The developed system could potentially be used for phantom or small animal proof-of-principle studies. The developed phantom test device may be used for testing other hyperthermia systems.

On the Importance of Consistent Insonation Conditions During Hydrophone Calibration and Use.

Hydrophones are generally calibrated in acoustic fields with temporally localized (short pulse) or long duration (tone burst) signals. Free-field conditions are achieved by time gating any reflections from the hydrophone body, mounting structures, and surrounding water tank boundaries arriving at the active sensing element. Consequently, the sensitivity response of the hydrophone is a result of direct waves incident on its active element, free from any contaminating effects of reflections. However, when using tone bursts below 400 kHz to calibrate hydrophones, it may not be possible to isolate the direct wave from reflection artifacts. This means that the sensitivity responses derived at these frequencies using short pulse and tone burst signals might not be comparable as they can be characteristic of the acoustic field interaction with either/both the hydrophone active element alone or the hydrophone active element and body. Therefore, there is a need to consider an appropriate calibration method for a given hydrophone type, depending on whether the eventual application employs short pulse or tone burst acoustic fields. This article presents the findings from a short study comprising four needle-type hydrophones of active element diameters in the range of 1-4 mm. These hydrophones were calibrated from 30 kHz to 1.6 MHz using established calibration methodologies within the underwater acoustics (UWA) and ultrasound (US) areas employed at the National Physical Laboratory (NPL), Teddington, U.K. In UWA tone, burst acoustic fields are used, while in US, it is short pulses. The 2- and 4-mm-diameter needle hydrophones showed the largest variation at the overlapping frequencies, in which the maximum disagreement of UWA calibration was 30% relative to US calibration. For the 4-mm hydrophone, UWA calibration exhibited resonant sensitivity structure between 100 and 450 kHz, but which was absent in US calibration. This observed behavior was further investigated theoretically by using a validated acoustic wave solver to confirm the resonant sensitivity structure seen in the case of UWA calibration. The work contained within illustrates the need to ensure that the method of calibration is carefully considered in the context of the duration of the acoustic signals for which the hydrophone is intended.

Dissemination of the Acoustic Pascal: The Role and Experiences of a National Metrology Institute.

Hydrophones are pivotal measurement devices ensuring medical ultrasound acoustic exposures comply with the relevant national and international safety criteria. These devices have enabled the spatial and temporal distribution of key safety parameters to be determined in an objective and standardized way. Generally based on piezoelectric principles of operation, to convert generated voltage waveforms to acoustic pressure, they require calibration in terms of receive sensitivity, expressed in units of [Formula: see text]Pa-1. Reliable hydrophone calibration with associated uncertainties plays a key role in underpinning a measurement framework that ensures exposure measurements are comparable and traceable to internationally agreed units, irrespective of where they are carried out globally. For well over three decades, the U.K. National Physical Laboratory (NPL) has provided calibrations to the user community covering the frequency range 0.1-60 MHz, traceable to a primary realization of the acoustic pascal through optical interferometry. Typical uncertainties for sensitivity are 6%-22% (for a coverage factor k = 2), degrading with frequency. The article specifically focuses on the dissemination of the acoustic pascal through NPL's calibration services that are based on a comparison with secondary standard hydrophones previously calibrated using the NPL primary standard. The work demonstrates the stability of the employed dissemination protocols by presenting representative calibration histories on a selection of commercially available hydrophones. Results reaffirm the guidance provided within international standards for regular calibration of a hydrophone in order to underpin measurement confidence. The process by which internationally agreed realizations of the acoustic pascal are compared and validated through key comparisons (KCs) is also described.

Sweetness and positivity together aren't a happy ending: Case controlled study amongst severe COVID-19 for impact of diabetes mellitus on survival.

Background: India is the epicenter of diabetes mellitus (DM). The relationship between COVID and DM in age/gender-matched non-diabetics has not been studied yet. The role of DM in predicting the disease severity and outcome in COVID patients might provide new insight for effective management. Methods: We conducted a prospective comparative study at a COVID care center from 25th April-31st May 2021. Among 357 severe-COVID patients screened, all consecutive diabetes (n-113) and age/gender-matched non-diabetes (n-113) patients were recruited. All diabetics and non-diabetics at admission were subjected to high resolution computed tomography (HRCT) chest and inflammatory markers (C-reactive protein (CRP), D-dimer, ferritin, interleukin-6 (IL-6), lactate dehydrogenase (LDH), Neutrophil-Lymphocyte Ratio (NLR)) before starting anti- COVID therapy. Statistical analysis was done using JMP 15·0 ver·3·0·0. Results: The prevalence of DM among the screened population (n-357) was 38·37%. The mean age of the study population was 61y with male preponderance (57%). There was no statistical difference in the HRCT-score or inflammatory markers in the two groups except for higher NLR (p-0·0283) in diabetics. Diabetics had significantly inferior overall survival (OS) (p-0·0251) with a 15d-OS of diabetics vs. non-diabetics being 58·87%, 72·67%, and 30d-OS of diabetics vs. non-diabetics being 46·76%, 64·61%, respectively. The duration of the hospital stay was not statistically different in the two groups (p-0·2). Conclusion: The mortality is significantly higher in severe-COVID patients with DM when compared to age/gender-matched non-diabetics. There was no significant difference in most inflammatory markers/CT at admission between the two groups.

A Copolymer-in-Oil Tissue-Mimicking Material With Tuneable Acoustic and Optical Characteristics for Photoacoustic Imaging Phantoms.

Photoacoustic imaging (PAI) standardisation demands a stable, highly reproducible physical phantom to enable routine quality control and robust performance evaluation. To address this need, we have optimised a low-cost copolymer-in-oil tissue-mimickingmaterial formulation. The base material consists of mineral oil, copolymer and stabiliser with defined Chemical Abstract Service numbers. Speed of sound c(f) and acoustic attenuation coefficient α (f) were characterised over 2-10 MHz; optical absorption µa ( λ ) and reduced scattering µs '( λ ) coefficients over 450-900 nm. Acoustic properties were optimised by modifying base component ratios and optical properties were adjusted using additives. The temporal, thermomechanical and photo-stabilitywere studied, alongwith intra-laboratory fabrication and field-testing. c(f) could be tuned up to (1516±0.6) [Formula: see text] and α (f) to (17.4±0.3)dB · cm -1 at 5 MHz. The base material exhibited negligible µa ( λ ) and µs '( λ ), which could be independently tuned by addition of Nigrosin or TiO2 respectively. These properties were stable over almost a year and were minimally affected by recasting. The material showed high intra-laboratory reproducibility (coefficient of variation <4% for c ( f ), α ( f ), optical transmittance and reflectance), and good photo- and mechanical-stability in the relevant working range (20-40°C). The optimised copolymer-in-oil material represents an excellent candidate for widespread application in PAI phantoms, with properties suitable for broader use in biophotonics and ultrasound imaging standardisation efforts.

Modelling laser ultrasound waveforms: The effect of varying pulse duration and material properties.

Optical generation of ultrasound using nanosecond duration laser pulses has generated great interest both in industrial and biomedical applications. The availability of portable laser devices using semiconductor technology and optical fibres, as well as numerous source material types based on nanocomposites, has proliferated the applications of laser ultrasound. The nanocomposites can be deposited on the tip of optical fibres as well as planar hard and soft backing materials using various fabrication techniques, making devices suitable for a variety of applications. The ability to choose the acoustic material properties and the laser pulse duration gives considerable control over the ultrasound output. Here, an analytical time-domain solution is derived for the acoustic pressure waveform generated by a planar optical ultrasound source consisting of an optically absorbing layer on a backing. It is shown that by varying the optical attenuation coefficient, the thickness of the absorbing layer, the acoustic properties of the materials, and the laser pulse duration, a wide variety of pulse shapes and trains can be generated. It is shown that a source with a reflecting backing can generate pulses with higher amplitude than a source with an acoustically-matched backing in the same circumstances when stress-confinement has not been satisfied.

Measurement of the temperature-dependent output of lead zirconate titanate transducers.

The effect of temperature and electrical drive conditions on the output of lead zirconate titanate (PZT) transducers is of particular interest in ultrasound metrology and medical ultrasound applications. In this work, the temperature-dependent output of two single-element PZT transducers was measured between 22 °C and 46 °C. Two independent measurement methods were used, namely radiation force balance measurements and laser vibrometry. When driven at constant voltage using a 50 Ω matched signal generator and amplifier using continuous wave (CW) or quasi-CW excitation, the output of the two transducers increased on average by 0.6 % per degree, largely due to an increase in transducer efficiency with temperature. The two measurement methods showed close agreement. Similar trends were observed when using single cycle excitation with the same signal chain. However, when driven using a pulser (which is not electrically matched), the two transducers exhibited different behaviour depending on their electrical impedance. Accounting for the temperature-dependent output of PZT transducers could have implications for many areas of ultrasound metrology, for example, in therapeutic ultrasound where a coupling fluid at an increased or decreased temperature is often used.

100 MHz bandwidth planar laser-generated ultrasound source for hydrophone calibration.

High-frequency calibration of hydrophones is becoming increasingly important, both for clinical and scientific applications of ultrasound, and user safety. At present, the calibrations available routinely to the user community extend to 60 MHz. However, hydrophones that can measure beyond this are available, and ultrasonic fields often contain energy at higher frequencies, e.g., generated through nonlinear propagation of high-amplitude ultrasound used for therapeutic applications, and the increasing use of higher frequencies in imaging. Therefore, there is a need for calibrations up to at least 100 MHz, to allow ultrasonic fields to be accurately characterized, and the risk of harmful bioeffects to be properly assessed. Currently, sets of focused piezoelectric transducers are used to meet the pressure amplitude and bandwidth requirements of Primary Standard calibration facilities. However, when the frequency is high enough such that the size of the ultrasound focus becomes less than the hydrophone element's diameter, the uncertainty due to spatial averaging becomes significant, and can be as high as 20% at 100 MHz. As an alternate to piezoelectric transducers, a laser-generated ultrasound calibration source was designed, fabricated, and characterized. The source consists of an optically absorbing carbon-polymer nanocomposite excited by a large-diameter 1064 nm laser pulse of 2.6 ns duration. Peak pressure amplitudes of several Mega-Pascal were readily achievable, and the signal contained measurable frequency components up to 100 MHz. The variation in the pressure amplitudes was less than 2% from its mean over a three-hour test period. The ultrasound beam was sufficiently broad that the uncertainties due to spatial averaging were negligible.

Laser generated ultrasound sources using carbon-polymer nanocomposites for high frequency metrology.

The characterization of ultrasound fields generated by diagnostic and therapeutic equipment is an essential requirement for performance validation and to demonstrate compliance against established safety limits. This requires hydrophones calibrated to a traceable standard. Currently, the upper calibration frequency range available to the user community is limited to 60 MHz. However, high frequencies are increasingly being used for both imaging and therapy necessitating calibration frequencies up to 100 MHz. The precise calibration of hydrophones requires a source of high amplitude, broadband, quasi-planar, and stable ultrasound fields. There are challenges to using conventional piezoelectric sources, and laser generated ultrasound sources offer a promising solution. In this study, various nanocomposites consisting of a bulk polymer matrix and multi-walled carbon nanotubes were fabricated and tested using pulsed laser of a few nanoseconds for their suitability as a source for high frequency calibration of hydrophones. The pressure amplitude and bandwidths were measured using a broadband hydrophone from 27 different nanocomposite sources. The effect of nonlinear propagation of high amplitude laser generated ultrasound on bandwidth and the effect of bandlimited sensitivity response on the deconvolved pressure waveform were numerically investigated. The stability of the nanocomposite sources under sustained laser pulse excitation was also examined.

The Practicalities of Obtaining and Using Hydrophone Calibration Data to Derive Pressure Waveforms.

This paper considers the means by which calibration data are used to convert hydrophone output voltage into pressure. Hydrophone frequency responses are complex-valued quantities, and only by correcting for the magnitude and phase variations, is it possible to accurately recover the original pressure waveform. The limitations of current hydrophone calibration techniques are discussed, and a new method of obtaining hydrophone phase data is presented. Magnitude and phase information is measured via both coarse increment (1 MHz) and fine increment (50 kHz) calibration techniques for three exemplar hydrophones (0.5 mm needle, 0.2 mm needle, and 0.4 mm membrane). Frequently hydrophone calibration data are available at frequency increments that do not match that required by the deconvolution process. Therefore, a variety of methods to interpolate the calibrated system response to obtain correctly spaced data are considered, and two spline interpolation methods are found to offer best performance. Data preconditioning and filtering to address artifacts above and below the 1 to 40 MHz bandwidth of the coarse frequency increment calibration are also investigated, and a simple procedure for selecting an appropriate low-pass filter is presented. The revised calibration data are used to deconvolve the hydrophone frequency response for experimentally derived waveforms. Standard ultrasonic output parameters (such as peak compressional and peak rarefactional pressures, pulse intensity integral, and temporal peak and pulse average acoustic intensities) are calculated from these waveforms. Although the three hydrophones used in this paper are of different types and have a range of active element sizes, all output parameters derived from the deconvolved waveforms have <5% variation from their respective population means (with the majority being within <2%).

Reference characterisation of sound speed and attenuation of the IEC agar-based tissue-mimicking material up to a frequency of 60 MHz.

To support the development of clinical applications of high-frequency ultrasound, appropriate tissue-mimicking materials (TMMs) are required whose acoustic properties have been measured using validated techniques. This paper describes the characterisation of the sound speed (phase velocity) and attenuation coefficient of the International Electrotechnical Commission (IEC) agar-based TMM over the frequency range 1 to 60 MHz. Measurements implemented a broadband through-transmission substitution immersion technique over two overlapping frequency ranges, with co-axially aligned 50 MHz centre-frequency transducers employed for characterisation above 15 MHz. In keeping with usual practice employed within the technical literature, thin acoustic windows (membranes) made of 12-µm-thick Mylar protected the TMM from water damage. Various important sources of uncertainty that could compromise measurement accuracy have been identified and evaluated through a combination of experimental studies and modelling. These include TMM sample thickness, measured both manually and acoustically, and the influence of interfacial losses that, even for thin protective membranes, are significant at the frequencies of interest. In agreement with previous reports, the attenuation coefficient of the IEC TMM exhibited non-linear frequency dependence, particularly above 20 MHz, yielding a value of 0.93 ± 0.04 dB cm(-1) MHz(-1) at 60 MHz, derived at 21 ± 0.5°C. For the first time, phase velocity, measured with an estimated uncertainty of ±3.1 m s(-1), has been found to be dispersive over this extended frequency range, increasing from 1541 m s(-1) at 1 MHz to 1547 m s(-1) at 60 MHz. This work will help standardise acoustic property measurements, and establishes a reference measurement capability for TMMs underpinning clinical applications at elevated frequencies.

acoustic assessment of a konjac­carrageenan tissue-mimicking material aT 5­60 MHZ.

The acoustic properties of a robust tissue-mimicking material based on konjac­carrageenan at ultrasound frequencies in the range 5­60 MHz are described. Acoustic properties were characterized using two methods: a broadband reflection substitution technique using a commercially available preclinical ultrasound scanner (Vevo 770, FUJIFILM VisualSonics, Toronto, ON, Canada), and a dedicated high-frequency ultrasound facility developed at the National Physical Laboratory (NPL, Teddington, UK), which employed a broadband through-transmission substitution technique. The mean speed of sound across the measured frequencies was found to be 1551.7 ± 12.7 and 1547.7 ± 3.3 m s21, respectively. The attenuation exhibited a non-linear dependence on frequency, f (MHz), in the form of a polynomial function: 0.009787f2 1 0.2671f and 0.01024f2 1 0.3639f, respectively. The characterization of this tissue-mimicking material will provide reference data for designing phantoms for preclinical systems, which may, in certain applications such as flow phantoms, require a physically more robust tissuemimicking material than is currently available.

Calibration of miniature medical ultrasonic hydrophones for frequencies in the range 100 to 500 kHz using an ultrasonically absorbing waveguide.

Enhancements to the existing primary standard optical interferometer and narrowband tone-burst comparison calibration methods for miniature medical ultrasonic hydrophones of the membrane type over the frequency range 100 to 500 kHz are described. Improvements were realized through application of an ultrasonically absorbing waveguide made of a low-frequency-absorbing tile used in sonar applications which narrows the spatial extent of the broad acoustic field. The waveguide was employed in conjunction with a sonar multilayered polyvinylidene difluoride (PVDF) hydrophone used as a transmitting transducer covering a frequency range of 100 kHz to 1 MHz. The acoustic field emanating from the ultrasonically absorbing waveguide reduced the significance of diffracted acoustic waves from the membrane hydrophone ring and the consequent interference of this wave with the direct acoustic wave received by the active element of the hydrophone during calibration. Four membrane hydrophone make/ models with ring sizes (defined as the inner diameter of the annular mounting ring of the hydrophone) in the range 50 to 100 mm were employed along with a needle hydrophone. A reference membrane hydrophone, calibrated using the NPL primary standard optical interferometer in combination with the ultrasonically absorbing waveguide, was subsequently used to calibrate the other four hydrophones by comparison, again using the ultrasonically absorbing waveguide. In comparison to existing methods, the use of the ultrasonically absorbing waveguide enabled the low-frequency calibration limit of a membrane hydrophone with a ring diameter of 50 mm to be reduced from 400 kHz to 200 kHz.