Tissue-mimicking Material Research Articles

Proof-of-Concept Prototype for Noninvasive Intracranial Pressure Monitoring Using Ocular Hemodynamics Under Applied Force

Studies have suggested that elevated cerebrospinal fluid (CSF) pressure can have a damaging effect on the optic nerve and visual acuity. There is need for a noninvasive CSF pressure measurement technique. A portable device for noninvasive intracranial pressure (ICP) monitoring would have a significant impact on clinical care. A proof-of-concept prototype is used to test the feasibility of a technique for monitoring ICP changes. The proposed methodology utilizes transcranial Doppler ultrasonography to monitor blood flow through the ophthalmic and central retinal arteries while forces are applied to the cornea by a controlled actuator. Control algorithms for the device were developed and tested using an integrated experimental platform. Preliminary results using tissue-mimicking materials show the ability to differentiate between materials of differing stiffness that simulates different levels of ICP. These experiments are an initial step toward a handheld noninvasive ICP monitoring device.

Assessment of Spectral Doppler for an Array-Based Preclinical Ultrasound Scanner Using a Rotating Phantom

Velocity measurement errors were investigated for an array-based preclinical ultrasound scanner (Vevo 2100, FUJIFILM VisualSonics, Toronto, ON, Canada). Using a small-size rotating phantom made from a tissue-mimicking material, errors in pulse-wave Doppler maximum velocity measurements were observed. The extent of these errors was dependent on the Doppler angle, gate length, gate depth, gate horizontal placement and phantom velocity. Errors were observed to be up to 172% at high beam–target angles. It was found that small gate lengths resulted in larger velocity errors than large gate lengths, a phenomenon that has not previously been reported (e.g., for a beam–target angle of 0°, the error was 27.8% with a 0.2-mm gate length and 5.4% with a 0.98-mm gate length). The error in the velocity measurement with sample volume depth changed depending on the operating frequency of the probe. Some edge effects were observed in the horizontal placement of the sample volume, indicating a change in the array aperture size. The error in the velocity measurements increased with increased phantom velocity, from 22% at 2.4 cm/s to 30% at 26.6 cm/s. To minimise the impact of these errors, an angle-dependent correction factor was derived based on a simple ray model of geometric spectral broadening. Use of this angle-dependent correction factor reduces the maximum velocity measurement errors to <25% in all instances, significantly improving the current estimation of maximum velocity from pulse-wave Doppler ultrasound.

Attenuation Correction and Normalisation for Quantification of Contrast Enhancement in Ultrasound Images of Carotid Arteries

An automated attenuation correction and normalisation algorithm was developed to improve the quantification of contrast enhancement in ultrasound images of carotid arteries. The algorithm first corrects attenuation artefact and normalises intensity within the contrast agent-filled lumen and then extends the correction and normalisation to regions beyond the lumen. The algorithm was first validated on phantoms consisting of contrast agent-filled vessels embedded in tissue-mimicking materials of known attenuation. It was subsequently applied to in vivo contrast-enhanced ultrasound (CEUS) images of human carotid arteries. Both in vitro and in vivo results indicated significant reduction in the shadowing artefact and improved homogeneity within the carotid lumens after the correction. The error in quantification of microbubble contrast enhancement caused by attenuation on phantoms was reduced from 55% to 5% on average. In conclusion, the proposed method exhibited great potential in reducing attenuation artefact and improving quantification in contrast-enhanced ultrasound of carotid arteries.

Comparison between experimental and computational methods for the acoustic and thermal characterization of therapeutic ultrasound fields.

For high intensity therapeutic ultrasound (HITU) devices, pre-clinical testing can include measurement of power, pressure/intensity and temperature distribution, acoustic and thermal simulations, and assessment of targeting accuracy and treatment monitoring. Relevant International Electrotechnical Commission documents recently have been published. However, technical challenges remain because of the often focused, large amplitude pressure fields encountered. Measurement and modeling issues include using hydrophones and radiation force balances at HITU power levels, validation of simulation models, and tissue-mimicking material (TMM) development for temperature measurements. To better understand these issues, a comparison study was undertaken between simulations and measurements of the HITU acoustic field distribution in water and TMM and temperature rise in TMM. For the specific conditions of this study, the following results were obtained. In water, the simulated values for p+ and p- were 3% lower and 10% higher, respectively, than those measured by hydrophone. In TMM, the simulated values for p+ and p- were 2% and 10% higher than those measured by hydrophone, respectively. The simulated spatial-peak temporal-average intensity values in water and TMM were greater than those obtained by hydrophone by 3%. Simulated and measured end-of-sonication temperatures agreed to within their respective uncertainties (coefficients of variation of approximately 20% and 10%, respectively).

Simultaneous measurement of sound pressure and temperature of tissue mimicking material by an optical fiber Brag grating sensor

An optical fiber Bragg grating (FBG) sensor is capable of simultaneous measurement of sound pressure and temperature. The FBG is a type of refractive index grating constructed in a short segment of optical single mode fiber that reflects particular wavelengths of light. This Bragg wavelength depends on both of the sound pressure and the temperature. We reported the simultaneous measurement of sound pressure and temperature in water under the conditions of medical application. In this study, temperature rise of a tissue mimicking material (TMM) caused by exposure to ultrasound in the range of 0.3 to 5 MPa were measured. The TMM is made of agar-gel with Glycerin solution of 11.21%. The FBG of 1 mm in length constructed in the optical fiber of 0.25 mm in diameter was used in the experiments. As a result, as the measured sound pressure was 5 MPa, the measured temperature rise was 6.0 degree. Thus this sensor is capable of simultaneous measurement of sound pressure and temperature rise of biological tissues exposed to the ultrasound. [This study was supported by MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2013–2017.]

On measurement of the acoustic nonlinearity parameter using the finite amplitude insertion substitution (FAIS) technique

The acoustic nonlinearity parameter, B/A, is an important parameter which defines the way a propagating finite amplitude acoustic wave progressively distorts when travelling through any medium. One measurement technique used to determine its value is the finite amplitude insertion substitution (FAIS) method which has been applied to a range of liquid, tissue and tissue-like media. Importantly, in terms of the achievable measurement uncertainties, it is a relative technique. This paper presents a detailed study of the method, employing a number of novel features. The first of these is the use of a large area membrane hydrophone (30 mm aperture) which is used to record the plane-wave component of the acoustic field. This reduces the influence of diffraction on measurements, enabling studies to be carried out within the transducer near-field, with the interrogating transducer, test cell and detector positioned close to one another, an attribute which assists in controlling errors arising from nonlinear distortion in any intervening water path. The second feature is the development of a model which estimates the influence of finite-amplitude distortion as the acoustic wave travels from the rear surface of the test cell to the detector. It is demonstrated that this can lead to a significant systematic error in B/A measurement whose magnitude and direction depends on the acoustic property contrast between the test material and the water-filled equivalent cell. Good qualitative agreement between the model and experiment is reported. B/A measurements are reported undertaken at (20 ± 0.5) °C for two fluids commonly employed as reference materials within the technical literature: Corn Oil and Ethylene Glycol. Samples of an IEC standardised agar-based tissue-mimicking material were also measured. A systematic assessment of measurement uncertainties is presented giving expanded uncertainties in the range ±7% to ±14%, expressed at a confidence level close to 95%, dependent on specimen details.

Characterisation of Elastic and Acoustic Properties of an Agar-Based Tissue Mimicking Material.

As a first step towards an acoustic localisation device for coronary stenosis to provide a non-invasive means of diagnosing arterial disease, measurements are reported for an agar-based tissue mimicking material (TMM) of the shear wavepropagation velocity, attenuation and viscoelastic constants, together with one dimensional quasi-static elastic moduli and Poisson's ratio. Phase velocity and attenuation coefficients, determined by generating and detecting shear waves piezo-electrically in the range 300Hz-2kHz, were 3.2-7.5ms(-1) and 320dBm(-1). Quasi-static Young's modulus, shear modulus and Poisson's ratio, obtained by compressive or shear loading of cylindrical specimens were 150-160kPa; 54-56kPa and 0.37-0.44. The dynamic Young's and shear moduli, derived from fitting viscoelastic internal variables by an iterative statistical inverse solver to freely oscillating specimens were 230 and 33kPa and the corresponding relaxation times, 0.046 and 0.036s. The results were self-consistent, repeatable and provide baseline data required for the computational modelling of wave propagation in a phantom.

3D perfused brain phantom for interstitial ultrasound thermal therapy and imaging: design, construction and characterization

Thermal therapy has emerged as an independent modality of treating some tumors. In many clinics the hyperthermia, one of the thermal therapy modalities, has been used adjuvant to radio- or chemotherapy to substantially improve the clinical treatment outcomes. In this work, a methodology for building a realistic brain phantom for interstitial ultrasound low dose-rate thermal therapy of the brain is proposed. A 3D brain phantom made of the tissue mimicking material (TMM) had the acoustic and thermal properties in the 20–32 °C range, which is similar to that of a brain at 37 °C. The phantom had 10–11% by mass of bovine gelatin powder dissolved in ethylene glycol. The TMM sonicated at 1 MHz, 1.6 MHz and 2.5 MHz yielded the amplitude attenuation coefficients of 62 ± 1 dB m−1, 115 ± 4 dB m−1 and 175 ± 9 dB m−1, respectively. The density and acoustic speed determination at room temperature (~24 °C) gave 1040 ± 40 kg m−3 and 1545 ± 44 m s−1, respectively. The average thermal conductivity was 0.532 W m−1 K−1. The T1 and T2 values of the TMM were 207 ± 4 and 36.2 ± 0.4 ms, respectively. We envisage the use of our phantom for treatment planning and for quality assurance in MRI based temperature determination. Our phantom preparation methodology may be readily extended to other thermal therapy technologies.

Other applications of medical microwaves – Breast tumour classification

This talk addresses the development of imaging techniques for the early detection of breast cancer, based on Ultra Wideband (UWB) radar, a promising emerging technology that exploits the dielectric contrast between normal and tumour tissues at microwave frequencies. Of particular interest in this work are issues related to techniques for classification of potential breast tumours into benign and malignant. This is particularly important given the results from recent studies of the dielectric properties of breast and tumour tissue, which have found that strong similarities exist between the dielectric properties of malignant, benign and normal fibroglandular breast tissue. This creates a more challenging imaging scenario and motivates the development of enhanced signal processing techniques for UWB imaging systems.Tumour growth and development patterns are modelled using Gaussian Random Spheres, using four discrete sizes and four different shapes. Feature extraction methods including Principal Component Analysis (PCA), Independent Component Analysis (ICA) and Discrete Wavelet Transform (DWT), are used to extract the most relevant features from the detailed Radar Target Signatures of the tumours, which are then classified with a number of different classification techniques: Linear Discriminant Analysis (LDA), Quadratic Discriminant Analysis (QDA) and Support Vector Machines (SVM). In addition to these techniques, a number of different multi-stage classification architectures are considered. The feature extraction and classification algorithms are evaluated for both homogeneous and heterogeneous breast tissue models, for a range of different tumour sizes and shapes.Also, the first experimental results using a pre-clinical UWB prototype imaging system for tumour classification based on the shape of tumours. A database of benign and malignant tumour phantoms was created using dielectrically–representative tissue-mimicking material. Classification of benign and malignant tumour models of the experimental data was completed with Linear Discriminant Analysis, Quadratic Discriminant Analysis and Support Vector Machines classifiers.

Towards Comparison of Ultrasound Dose Measurements - Current Capabilities and Open Challenges

The aim of this work is to evaluate measurement methods for dosimetry and exposimetry quantities that were developed in the EMRP project “Dosimetry for Ultrasound Therapy -DUTy” by comparing the measurement results for three common quantities from three national laboratories. It further aims to investigate the general feasibility of possible future (key) comparisons for dosimetry and exposimetry quantities and to identify possible open challenges towards this goal. The general format is similar to a metrological comparison, with which the National Metrological Institutes, NMIs, are already familiar. The first step involved the agreement of the protocol that was to specify the set of transducers to be circulated and the measurement conditions. Two transducers were circulated and different drive voltage levels and pulsing regimes were defined and tissue mimicking materials (TMMs) characteristics were specified. Each lab was asked to prepare the TMMs for their own measurements with the inclusion of formulations and preparation instructions specified in the protocol. Uncertainties of the input data were to be declared by the participating laboratories.

Visual Investigation of Heating Effect in Liver and Lung Induced by a HIFU Transducer

The heating effect produced by a focused ultrasound transducer has been investigated by using visual techniques with a positioning system. Ultrasound power, distance, frequency and harmonics of heating effect was investigated. Three experiments were performed on TMM (Tissue Mimicking Material), sheep liver and sheep lung. HIFU (High Intensity Focused Ultrasound) transducer with a resonance frequency of 1.1MHz and 3.3MHz was used as source. Effect of ultrasound in liver and lung's pieces were displayed and dimension of cauterization has been measured. Previous temperature measurement results for TMM were compared with liver and lung measurement results so that it is possible to transfer the laboratory measurements to the clinical studies. All measurements were carried out in the system at TÜBİTAK UME (The Scientific and Technological Research Council of Turkey, the National Metrology Institute) Ultrasound laboratory.

Design and Manufacture of Polyvinyl Chloride (PVC) Tissue Mimicking Material for Needle Insertion

The polyvinyl chloride (PVC) tissue-mimicking material for needle insertion was manufactured and evaluated. Factorial design of experiment was conducted by changing three factors − the ratio of softener and PVC polymer solution, the mass fraction of mineral oil, and the mass fraction of micro-sized glass beads − to study the indentation hardness, compression elastic modulus and friction and cutting forces in needle insertion of 12 types of soft PVC material. The indentation hardness of the soft PVC material ranged from 5 to 50. The elastic modulus of the soft PVC material was from 6 to 45kPa between 0-0.15 strain. The friction and cutting force during needle insertion also had large ranges, which were from 0.005 to 0.086N/mm and 0.04 to 0.36N respectively. The analysis of variance showed that the ratio of softener and PVC polymer solution had the most significant effect on all of the four properties of the PVC material. The percentage of mineral oil also had statistical significance on these four properties. The glass beads only had effect on the needle insertion cutting force. A nonlinear regression model was applied to find relationships among mechanical properties and the significant factors. The R2 values of the regression analysis results were all larger than 0.9. Four properties of a PVC tissue-mimicking material can be designed to desired values based on these relationships.

Temperature changes caused by the difference in the distance between the ultrasound transducer and bone during 1 mhz and 3 mhz continuous ultrasound: a phantom study.

[Purpose] This study aimed to use a thermograph to observe temperature changes caused by different distances between an ultrasound transducer and bone during 1 MHz and 3 MHz continuous ultrasound emission on a phantom. [Materials and Methods] We observed the distribution of temperature elevations on a phantom consisting of pig ribs and tissue-mimicking material. One megahertz and 3 MHz ultrasound were delivered at 2.0 W/cm2 for 5 minutes. To record the temperature changes on the phantom, we took a screenshot of the thermograph with a digital camera every 20 seconds. [Results] With 1 MHz ultrasound at the distances of 2 and 3 cm, the temperature elevation near the bone was higher than that near the transducer. However, with 3 MHz ultrasound, the temperature elevation was higher near the transducer rather than near the bone. At this point, we consider that there is a possibility of heat injury to internal organs in spite of there being no elevation of skin temperature. [Conclusion] When performing ultrasonic therapy, not only should the frequency be taken into consideration, but also the influence of the absorption coefficient and the reflection of the tissue. We visually confirmed the thermal ultrasound effect by thermography. Special attention to the temperature elevation of the internal organs is necessary to avoid injuries.

Temperature Increase Dependence on Ultrasound Attenuation Coefficient in Innovative Tissue-mimicking Materials

Although high intensity focused ultrasound beams (HIFU) have found rapid agreement in clinical environment as a tool for non invasive surgical ablation and controlled destruction of cancer cells, some aspects related to the interaction of ultrasonic waves with tissues, such as the conversion of acoustic energy into heat, are not thoroughly understood. In this work, innovative tissue-mimicking materials (TMMs), based on Agar and zinc acetate, have been used to conduct investigations in order to determine a relation between the sample attenuation coefficient and its temperature increase measured in the focus region when exposed to an HIFU beam. An empirical relation has been deduced establishing useful basis for further processes of validations of numerical models to be adopted for customizing therapeutic treatments.

Wall-less Flow Phantom for High-Frequency Ultrasound Applications

There are currently very few test objects suitable for high-frequency ultrasound scanners that can be rapidly manufactured, have appropriate acoustic characteristics and are suitably robust. Here we describe techniques for the creation of a wall-less flow phantom using a physically robust konjac and carrageenan-based tissue-mimicking material. Vessel dimensions equivalent to those of mouse and rat arteries were achieved with steady flow, with the vessel at a depth of 1.0 mm. We then employed the phantom to briefly investigate velocity errors using pulsed wave Doppler with a commercial preclinical ultrasound system. This phantom will provide a useful tool for testing preclinical ultrasound imaging systems.

Acoustic Assessment of a Konjac–Carrageenan Tissue-Mimicking Material at 5–60 MHz

The acoustic properties of a robust tissue-mimicking material based on konjac–carrageenan at ultrasound frequencies in the range 5–60 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 s−1, respectively. The attenuation exhibited a non-linear dependence on frequency, f (MHz), in the form of a polynomial function: 0.009787f2 + 0.2671f and 0.01024f2 + 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 tissue-mimicking material than is currently available.

Comparison of 3-D synthetic aperture phased-array ultrasound imaging and parallel beamforming.

This paper demonstrates that synthetic aperture imaging (SAI) can be used to achieve real-time 3-D ultrasound phased-array imaging. It investigates whether SAI increases the image quality compared with the parallel beamforming (PB) technique for real-time 3-D imaging. Data are obtained using both simulations and measurements with an ultrasound research scanner and a commercially available 3.5- MHz 1024-element 2-D transducer array. To limit the probe cable thickness, 256 active elements are used in transmit and receive for both techniques. The two imaging techniques were designed for cardiac imaging, which requires sequences designed for imaging down to 15 cm of depth and a frame rate of at least 20 Hz. The imaging quality of the two techniques is investigated through simulations as a function of depth and angle. SAI improved the full-width at half-maximum (FWHM) at low steering angles by 35%, and the 20-dB cystic resolution by up to 62%. The FWHM of the measured line spread function (LSF) at 80 mm depth showed a difference of 20% in favor of SAI. SAI reduced the cyst radius at 60 mm depth by 39% in measurements. SAI improved the contrast-to-noise ratio measured on anechoic cysts embedded in a tissue-mimicking material by 29% at 70 mm depth. The estimated penetration depth on the same tissue-mimicking phantom shows that SAI increased the penetration by 24% compared with PB. Neither SAI nor PB achieved the design goal of 15 cm penetration depth. This is likely due to the limited transducer surface area and a low SNR of the experimental scanner used.

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.

Comparison of four different techniques to evaluate the elastic properties of phantom in elastography: is there a gold standard?

Elastographic techniques used in addition to imaging techniques (ultrasound, resonance magnetic or optical) provide new clinical information on the pathological state of soft tissues. However, system-dependent variation in elastographic measurements may limit the clinical utility of these measurements by introducing uncertainty into the measurement. This work is aimed at showing differences in the evaluation of the elastic properties of phantoms performed by four different techniques: quasi-static compression, dynamic mechanical analysis, vibration-controlled transient elastography and hyper-frequency viscoelastic spectroscopy. Four Zerdine® gel materials were tested and formulated to yield a Young’s modulus over the range of normal and cirrhotic liver stiffnesses. The Young’s modulus and the shear wave speed obtained with each technique were compared. Results suggest a bias in elastic property measurement which varies with systems and highlight the difficulty in finding a reference method to determine and assess the elastic properties of tissue-mimicking materials. Additional studies are needed to determine the source of this variation, and control for them so that accurate, reproducible reference standards can be made for the absolute measurement of soft tissue elasticity.

Preparation of DNA-crosslinked polyacrylamide hydrogels.

Mechanobiology is an emerging scientific area that addresses the critical role of physical cues in directing cell morphology and function. For example, the effect of tissue elasticity on cell function is a major area of mechanobiology research because tissue stiffness modulates with disease, development, and injury. Static tissue-mimicking materials, or materials that cannot alter stiffness once cells are plated, are predominately used to investigate the effects of tissue stiffness on cell functions. While information gathered from static studies is valuable, these studies are not indicative of the dynamic nature of the cellular microenvironment in vivo. To better address the effects of dynamic stiffness on cell function, we developed a DNA-crosslinked polyacrylamide hydrogel system (DNA gels). Unlike other dynamic substrates, DNA gels have the ability to decrease or increase in stiffness after fabrication without stimuli. DNA gels consist of DNA crosslinks that are polymerized into a polyacrylamide backbone. Adding and removing crosslinks via delivery of single-stranded DNA allows temporal, spatial, and reversible control of gel elasticity. We have shown in previous reports that dynamic modulation of DNA gel elasticity influences fibroblast and neuron behavior. In this report and video, we provide a schematic that describes the DNA gel crosslinking mechanisms and step-by-step instructions on the preparation DNA gels.