Tissue-mimicking Material Research Articles

Liquid-crystalline nanoarchitectures for tissue engineering.

Hierarchical orders are found throughout all levels of biosystems, from simple biopolymers, subcellular organelles, single cells, and macroscopic tissues to bulky organs. Especially, biological tissues and cells have long been known to exhibit liquid crystal (LC) orders or their structural analogues. Inspired by those native architectures, there has recently been increased interest in research for engineering nanobiomaterials by incorporating LC templates and scaffolds. In this review, we introduce and correlate diverse LC nanoarchitectures with their biological functionalities, in the context of tissue engineering applications. In particular, the tissue-mimicking LC materials with different LC phases and the regenerative potential of hard and soft tissues are summarized. In addition, the multifaceted aspects of LC architectures for developing tissue-engineered products are envisaged. Lastly, a perspective on the opportunities and challenges for applying LC nanoarchitectures in tissue engineering fields is discussed.

Chemical Items Used for Preparing Tissue-Mimicking Material of Wall-Less Flow Phantom for Doppler Ultrasound Imaging.

The wall-less flow phantoms with recognized acoustic features (attenuation and speed of sound), interior properties, and dimensions of tissue were prepared, calibrated, and characterized of Doppler ultrasound scanning demands tissue-mimicking materials (TMMs). TMM phantoms are commercially available and ready-made for medical ultrasound applications. Furthermore, the commercial TMM phantoms are proper for ultrasound purpose or estimation of diagnostic imaging techniques according to the chemical materials used for its preparation. However, preparing a desirable TMM for wall-less flow phantom using a specific chemical material according to the specific applications is required for different flow. In this review, TMM and wall-less flow phantoms prepared using different chemical materials and methods were described. The chemical materials used in Doppler ultrasound TMM and wall-less flow phantoms fabricated over the previous decades were of high interest in this review.

On accuracy estimation of ultrasonic thermometry technique with heated wire method

A test object with a heated wire introduced into a tissue-mimicking material and a method for determining the coefficient of ultrasonic thermal strain are described. The accuracy of the developed ultrasonic thermometry method is estimated using data of thermistor sensor measurements of time-dependent axisymmetric temperature field around the heated wire.

Backward-Mode Photoacoustic Imaging Using Illumination Through a CMUT With Improved Transparency.

In this paper, we describe a capacitive micromachined ultrasonic transducer (CMUT) with improved transparency for photoacoustic imaging (PAI) with backside illumination. The CMUT was fabricated on a glass substrate with indium-tin oxide bottom electrodes. The plate was a 1.5- silicon layer formed over the glass cavities by anodic bonding, with a 1- silicon nitride passivation layer on top. The fabricated device shows approximately 30%-40% transmission in the wavelength range from 700 to 800 nm and approximately 40%-60% transmission in the wavelength range from 800 to 900 nm, which correspond to the wavelength range commonly used for in vivo PAI. The center frequency of the CMUT was 3.62 MHz in air and 1.4 MHz in immersion. Two preliminary PAI experiments were performed to demonstrate the imaging capability of the fabricated device. The first imaging target was a 0.7-mm diameter pencil lead in vegetable oil as a line target with a subwavelength cross section. A 2-mm-diameter single CMUT element with an optical fiber bundle attached to its backside was linearly scanned to reconstruct a 2-D cross-sectional PA image of the pencil lead. We investigated the spurious signals caused by the light absorption in the 1.5- silicon plate. For pencil lead as a strong absorber and also a strong reflector, the received echo signal due to the acoustic excitation generated by the absorption in silicon is approximately 30 dB lower than the received PA signal generated by the absorption in pencil lead at the wavelength of 830 nm. The second imaging target was a "loop-shape" polyethylene tube filled with indocyanine green solution ( ) suspended using fishing lines in a tissue-mimicking material. We formed a 3-D volumetric image of the phantom by scanning the transducer in the - and -directions. The two experimental imaging results demonstrated that CMUTs with the proposed structure are promising for PAI with backside illumination.

Magnetic field probes for time‐domain monitoring of RF exposure within tissue‐mimicking materials for MRI‐compatible medical device testing

A new RF B/H field probe for time-domain monitoring of RF electromagnetic-radiated exposure during medical device testing inside the lossy tissue-mimicking material is presented. The probe was tuned and matched for a centre frequency of 127.6 MHz to optimise the response for testing within typical 3T MRI scanners or RF exposure platforms. A 5 mm radius loop was chosen as a trade-off between spatial resolution and sensitivity and fabricated on a double-sided FR4 PCB. In the presented scheme, a low-noise RF amplifier was employed to reduce the sensitivity of the probe to induce voltage on the transmission lines and to improve accuracy. The implemented probe was found to provide acceptable spatial resolution and sensitivity for reliable B/H field mapping for this application.

Acoustic Properties of Small Animal Soft Tissue in the Frequency Range 12–32 MHz

Quality assurance phantoms are made of tissue-mimicking materials (TMMs) the acoustic properties of which mimic those of soft tissue. However, the acoustic properties of many soft tissue types have not been measured at ultrasonic frequencies >9 MHz. With the increasing use of high-frequency ultrasound for both clinical and pre-clinical applications, it is of increasing interest to ensure that TMMs accurately reflect the acoustic properties of soft tissue at these higher frequencies. In this study, the acoustic properties of ex vivo brain, liver and kidney samples from 50 mice were assessed in the frequency range 12–32 MHz. Measurements were performed within 6 min of euthanasia in a phosphate-buffered saline solution maintained at 37.2 ± 0.2 °C. The measured mean values for the speed of sound for all organs were found to be higher than the International Electrotechnical Commission guideline recommended value for TMMs. The attenuation coefficients measured for brain, liver and kidney samples were compared with the results of previous studies at lower frequencies. Only the measured kidney attenuation coefficient was found to be in good agreement with the International Electrotechnical Commission guideline. The information provided in this study can be used as a baseline on which to manufacture a TMM suitable for high-frequency applications.

Ultrasound imaging characterization on tissue mimicking materials for cardiac tissue phantom: Texture analysis perspective

Cardiac tissue phantom is a synthetic physical model to mimic the characteristics of actual cardiac tissues. Tissue Mimicking Materials have been widely used as materials for medical imaging phantom. In cardiac ultrasound imaging, phantoms have been used for system verification, simulation and training for cardiovascular radiography. In this study, we aimed to characterize the structure of cardiac tissue phantom by performing ultrasound imaging and texture analysis. The phantom samples were developed by mixing Silicone Rubber with Calcium Carbonate in different percentages. Ultrasound imaging with various Dynamic Range settings (30, 60, and 90 dB) was used to scan the phantom samples. First-, Second-, and Higher order Statistical Texture Analyses were used to quantify structural features of the phantom samples. As comparison, one ultrasound image of adult heart was also characterized. The results show that the addition of Calcium Carbonate affected the imaging structure of the phantom samples. Textural comparison with the ultrasound image of adult heart confirmed that phantom with Silicon Rubber and 8% of Calcium carbonate had closest texture features.

Determination of Acoustic Cavitation Probabilities and Thresholds Using a Single Focusing Transducer to Induce and Detect Acoustic Cavitation Events: II. Systematic Investigation in an Agar Material

In the accompanying article (Part I), a method is described to determine acoustic cavitation probabilities in tissue-mimicking materials (TMMs) using a high-intensity focused ultrasound (HIFU) transducer for both inducing and detecting the acoustic cavitation events, and its suitability for different sonication modes like continuous wave, single pulses (with pulse lengths from microseconds to milliseconds) and repeated burst signals is discussed. In Part II, the use of the method for a systematic study of the dependence of the acoustic cavitation thresholds in 3% (by weight) agar phantoms on the temporal sonication parameters is discussed. The values obtained at a frequency of 1.06 MHz, ranging from (0.58 ± 0.12) MPa for a 3-s continuous wave mode sonication to (5.2 ± 1.0) MPa for single shots with a length of 10 wave cycles, are discussed and interpreted on the basis of literature values and their self-consistency.

Determination of Acoustic Cavitation Probabilities and Thresholds Using a Single Focusing Transducer to Induce and Detect Acoustic Cavitation Events: I. Method and Terminology

A method to determine acoustic cavitation probabilities in tissue-mimicking materials (TMMs) is described that uses a high-intensity focused ultrasound (HIFU) transducer for both inducing and detecting the acoustic cavitation events. The method was evaluated by studying acoustic cavitation probabilities in agar-based TMMs with and without scatterers and for different sonication modes like continuous wave, single pulses (microseconds to milliseconds) and repeated burst signals. Acoustic cavitation thresholds (defined here as the peak rarefactional in situ pressure at which the acoustic cavitation probability reaches 50%) at a frequency of 1.06 MHz were observed between 1.1 MPa (for 1 s of continuous wave sonication) and 4.6 MPa (for 1 s of a repeated burst signal with 25-cycle burst length and 10-ms burst period) in a 3% (by weight) agar phantom without scatterers. The method and its evaluation are described, and general terminology useful for standardizing the description of insonation conditions and comparing results is provided. In the accompanying second part, the presented method is used to systematically study the acoustic cavitation thresholds in the same material for a range of sonication modes.

Stable tissue-mimicking materials and an anatomically realistic, adjustable head phantom for electrical impedance tomography

Objective. To develop dielectrically accurate, easy to mould solid tissue-mimicking materials (TMMs) for use with electrical impedance tomography (EIT) and combine them into a head phantom with realistic anatomy and adjustable pathological lesions. Methods. The conductivity profiles of fat and blood, which span those of most biological tissues, along with aggregate models of the tissues of the head external to the brain, the tissues of the brain, and the cerebellum are identified across the 1 kHz–1 MHz band. TMM mixtures made from polyurethane, graphite, carbon black and either acetone or isopropanol are fabricated to emulate the conductivity profiles of the reference tissues. 3D-printed anatomically realistic moulds of the head and brain are used to cast a two-layer head and brain phantom with cylindrical holes left to allow addition of phantom pathological lesions such as haemorrhages. Results. The TMM spans a wide biological range of fat to blood and is adjustable to match any target tissue. Uniquely, the material is mechanically stable and easy to mould. The fabricated head phantom has excellent anatomic realism, and can represent a healthy brain or one with pathological lesions. The added lesions are easy to adjust in terms of size, shape, and material properties. Conclusion. The presented TMMs can be used to fabricate realistic phantoms for use in EIT studies of most tissue sets. Significance. These TMMs are an important development in phantom technology for EIT; the sample head phantom demonstrates the value and flexibility of the TMMs.

Estimates for the acoustical stimulation and heating of multiphase biotissue.

Low-intensity, unfocused, ultrasound-induced diathermy can produce undesired temperature increases at the interface of adjacent tissues within the body; particularly, at the interface of soft tissue and bone. This study provides a computational framework for predicting an upper bound on the temperature profile within a multiphase system composed of gel pad (water), tissue and bone from an input of acoustic energy, at frequencies and power levels consistent with applications of therapeutic hyperthermia. The model consists of solving a (one-dimensional) spatially discretized bioheat transfer equation via finite-difference method and updating the solution in time with a forward-Euler scheme. Simulations are then compared to experimental data to determine the energy-to-heat conversion factors within each constituent material using thermocouple-embedded, tissue-mimicking phantom material, with and without bone. Viscous heating artifacts from the presence of the thermocouples in the experimental phantom tissue are accounted for via additional experimental methods similar to those described by Morris et al. (Phys Med Biol 53:4759, 2008). Finally, an example application of the model is presented via prediction of the maximum temperature at the tissue-bone interface, as well as the peak temperatures in the composite structure at the end of a prescribed 2-min sonication, of blood-perfused, human soft-tissue at 1, 2 and 3MHz frequencies and a spatial peak temporally averaged intensity of [Formula: see text]. The results of this simulation are then related to comparable experimental studies in the literature.

Effect of Stone Size and Composition on Ultrasonic Propulsion Ex Vivo

To evaluate in more detail the effectiveness of a new designed more efficient ultrasonic propulsion for large stones and specific stone compositions in a tissue phantom model. In the first clinical trial of noninvasive ultrasonic propulsion, urinary stones of unknown compositions and sizes up to 10 mm were successfully repositioned. The study included 8- to 12-mm stones of 4 different primary compositions (calcium oxalate monohydrate, ammonium acid urate, calcium phosphate, and struvite) and a renal calyx phantom consisting of a 12 mm × 30 mm well in a 10-cm block of tissue-mimicking material. Primary outcome was the number of times a stone was expelled over 10 attempts, with ultrasonic propulsion burst duration varying from 0.5 seconds to 5 seconds. Overall success rate at expelling stones was 95%. All calcium oxalate monohydrate and ammonium acid urate stones were expelled 100% of the time. The largest stone (12 mm) became lodged within the 12-mm phantom calyx 25% of the time regardless of the burst duration. With the 0.5-second burst, there was insufficient energy to expel the heaviest stone (0.88 g), but there was sufficient energy at the longer burst durations. With a single burst, ultrasonic propulsion successfully moved most stones at least 3 cm and, regardless of size or composition, expelled them from the calyx. Ultrasonic propulsion is limited to the stones smaller than the calyceal space, and for each burst duration, related to maximum stone mass.

High-intensity-focused ultrasound and phase-sensitive optical coherence tomography for high resolution surface acoustic wave elastography.

Elastography has the ability of quantitatively evaluating the mechanical properties of soft tissue; thus it is helpful for diagnosis and treatment monitoring of many diseases, for example, skin diseases. Surface acoustic waves (SAWs) have been proven to be a non-invasive, non-destructive method for accurate characterization of tissue elastic properties. Current SAW elastography using high-energy laser pulse or mechanical shaker still have some problems. In order to improve SAW elastography in medical application, a new technique was proposed in this paper, which combines high-intensity-focused ultrasound as a SAWs impulse inducer and phase-sensitive optical coherence tomography as a SAWs detector. A 2% agar-agar phantom and ex-vivo porcine skin were tested. The data were processed by a new algorithm based on the Fourier analysis. The results show that the proposed method has the capability of quantifying the elastic properties of soft tissue-mimicking materials. The lateral resolution of the elastogram has been significantly improved and the different layers in heterogeneous material could also been distinguished. Our improved technique of SAW elastography has a large potential to be widely applied in clinical use for skin disease diagnosis and treatment monitoring.

Natural Rubber Nanocomposite with Human-Tissue-Like Mechanical Characteristic

The blends of synthetic rubber and natural rubber with nanosilica were prepared using a blending technique in presence of different filler volume fraction. The effect of filler on morphological and mechanical characteristics was studied. Utilization of human cadaver in means of medical study has been commonly used primarily as tools of medical teaching and training such as surgery. Nonetheless, human cadaver brought inevitable problems. So it is necessary to find a substitute material that can be used to replace cadavers. In orthopaedics, the materials that resemble in mechanical properties to biological tissues are elastomers such as natural rubber (latex) and synthetic rubber (polyurethanes, silicones). This substitution material needs to consider the potential of Indonesia to help the development of the nation. Indonesia is the second largest country producer of natural rubber in the world. This paper aims to contribute to adjusting the mechanical properties of tissue-mimicking materials (TMMs) to the recommended range of biological tissue value and thus allow the development of phantoms with greater stability and similarity to human tissues. Repeatability for the phantom fabrication process was also explored. Characteristics were then compared to the control and mechanical characteristics of different human body part tissue. Nanosilica is the best filler to produce the best nanocomposite similarities with human tissue. We produced composites that approaching the properties of human internal tissues.

Simultaneous observation of cavitation bubbles generated in biological tissue by high-speed optical and acoustic imaging methods

Acoustic cavitation bubbles are useful for enhancing the heating effect in high-intensity focused ultrasound (HIFU) treatment. Many studies were conducted to investigate the behavior of such bubbles in tissue-mimicking materials, such as a transparent gel phantom; however, the detailed behavior in tissue was still unclear owing to the difficulty in optical observation. In this study, a new biological phantom was developed to observe cavitation bubbles generated in an optically shallow area of tissue. Two imaging methods, high-speed photography using light scattering and high-speed ultrasonic imaging, were used for detecting the behavior of the bubbles simultaneously. The results agreed well with each other for the area of bubble formation and the temporal change in the region of bubbles, suggesting that both methods are useful for visualizing the bubbles.

Laser-enhanced thermal effect of moderate intensity focused ultrasound on bio-tissues

For avoiding extra-damage to healthy tissues surrounding the focal point during high intensity focused ultrasound (HIFU) treatment in medical therapy, to reduce the ultrasonic intensity outside the focal point is expected. Thus, the heating processes induced by moderate intensity focused ultrasound (MIFU) and enhanced by combined irradiation of laser pulses for bio-tissues are studied in details. For fresh bio-tissues, the enhanced thermal effects by pulsed laser combined with MIFU irradiation are observed experimentally. To explore the mechanisms of these effects, several tissue-mimicking materials composed of agar mixed with graphite powders are prepared and studied for comparison, but the laser-enhanced thermal effects in these mimicking materials are much less than that in the fresh bio-tissues. Therefore, it is suggested that the laser-enhanced thermal effects may be mainly attributed to bio-activities and related photo-bio-chemical effects of fresh tissues.

Non-invasive Estimation of Temperature during Physiotherapeutic Ultrasound Application Using the Average Gray-Level Content of B-Mode Images: A Metrological Approach

Healing therapies that make use of ultrasound are based on raising the temperature in biological tissue. However, it is not possible to heal impaired tissue by applying a high dose of ultrasound. The temperature of the tissue is ultimately the physical quantity that has to be assessed to minimize the risk of undesired injury. Invasive temperature measurement techniques are easy to use, despite the fact that they are detrimental to human well being. Another approach to assessing a rise in tissue temperature is to derive the material's general response to temperature variations from ultrasonic parameters. In this article, a method for evaluating temperature variations is described. The method is based on the analytical study of an ultrasonic image, in which gray-level variations are correlated to the temperature variations in a tissue-mimicking material. The physical assumption is that temperature variations induce wave propagation changes modifying the backscattered ultrasound signal, which are expressed in the ultrasonographic images. For a temperature variation of about 15°C, the expanded uncertainty for a coverage probability of 0.95 was found to be 2.5°C in the heating regime and 1.9°C in the cooling regime. It is possible to use the model proposed in this article in a straightforward manner to monitor temperature variation during a physiotherapeutic ultrasound application, provided the tissue-mimicking material approach is transferred to actual biological tissue. The novelty of such approach resides in the metrology-based investigation outlined here, as well as in its ease of reproducibility.

A remote temperature sensor for an ultrasound hyperthermia system using the acoustic signal derived from the heating signals

We demonstrate a non-invasive technique, based on the modal frequency shift of a region insonified by a dual-beam ultrasound (US) transducer (region of interest, ROI), to remotely assess the temperature of the region in a tissue-mimicking object. The application is in ultrasound hyperthermia systems for controlled maintenance of tumour temperature during chemotherapy. Towards this, we have characterised the variation of the storage modulus with the temperature of two tissue-mimicking visco-elastic materials. Due to this variation in tissue storage modulus (and viscosity), we have observed a shift in the resonant modes of the ROI, vibrated remotely with a dual-beam focussed ultrasound transducer. A modal analysis of the vibrating ROI is done to identify the modes captured by the detector. A variation in this modal frequency with temperature is computed and matches reasonably well with the experimental measurements. Through this, we demonstrate that an ultrasound hyperthermia system can have a remote temperature sensor without using an additional imaging modality.

Noninvasive and localized acoustic micropumping—An in vitro study of an ultrasound method that enhances drug distribution through a physiologically-relevant material

Acoustic streaming—the displacement of fluid by sound—has been proposed as the mechanism for therapeutic effects, such as drug distribution enhancement, yet there have been no direct observation or characterization of this effect in soft tissue, making it difficult to optimize and control. We aimed to directly observe ultrasound-induced streaming during sonication in a tissue-mimicking material. We hypothesized that existing ultrasound phantoms (e.g., polyacrylamide (PAA) and gelatin) mimic the acoustic properties of tissue, but not the tissue microenvironment. Scanning electron microscopy revealed that gelatin and PAA had closed pores suggesting that they can’t support acoustic streaming. In contrast, macroporous acrylamide (MPPA), a new phantom we created, had interconnected pores resembling the interstitial space of soft tissue. The focal point of a focused ultrasound (FUS) transducer was placed at the distal surface of the MPPA phantom. A model drug (Bromophenol blue) was injected in and around the focal region and different FUS parameters were evaluated. Dye clearance at the hydrogel surface was observed with a video camera. Increasing ultrasound pressure produced higher streaming. Pulsed ultrasound having the same total energy as continuous wave ultrasound produced higher streaming. Using MPPA, we were able to study acoustic streaming under different parameters. Our future work is to optimize ultrasound parameters to maximize acoustic streaming in this material and in in-vivo tissue for enhancing drug distribution.

Broadband Acoustic Measurement of an Agar-Based Tissue-Mimicking-Material: A Longitudinal Study

Commercially available ultrasound quality assurance test phantoms rely on the long-term acoustic stability of the tissue-mimicking-material (TMM). Measurement of the acoustic properties of the TMM can be technically challenging, and it is important to ensure its stability. The standard technique is to film-wrap samples of TMM and to measure the acoustic properties in a water bath. In this study, a modified technique was proposed whereby the samples of TMM are measured in a preserving fluid that is intended to maintain their characteristics. The acoustic properties were evaluated using a broadband pulse-echo substitution technique over the frequency range 4.5–50 MHz at 0, 6 and 12 months using both techniques. For both techniques, the measured mean values for the speed of sound and attenuation were very similar and within the International Electrotechnical Commission-recommended value. However, the results obtained using the proposed modified technique exhibited greater stability over the 1-y period compared with the results acquired using the standard technique.