Skip to main content
NCBI home page
Journal of Ultrasound logoLink to Journal of Ultrasound
. 2022 Nov 21;26(2):505–515. doi: 10.1007/s40477-022-00746-4

Characterization of a fat tissue mimicking material for high intensity focused ultrasound applications

Antria Filippou 1, Irene Louca 1, Christakis Damianou 1,✉
PMCID: PMC10247632  PMID: 36414928

Abstract

Purpose

Tissue-mimicking materials (TMMs) have a prominent role in validating new high intensity focused ultrasound (HIFU) therapies. Agar-based TMMs are often developed mimicking the thermal properties of muscle tissue, while TMMs simulating fat tissue properties are rarely developed. Herein, twelve agar-based TMMs were iteratively developed with varied concentrations of agar, water, glycerol and propan-2-ol, and characterized for their suitability in emulating the thermal conductivity of human fat tissue.

Methods

Varied agar concentrations (2%, 4%, 6%, 8%, 12%, 16% and 20% w/v) were utilized for developing seven water-based TMMs, while a 20% w/v agar concentration was utilized for developing two water/alcohol-based TMMs (50% v/v water and 50% v/v either glycerol or propan-2-ol) and three alcohol-based TMMs (varied glycerol and propan-2-ol concentrations). Thermal conductivity was measured for all TMMs, and the tissue mimicking material (TMM) exhibiting thermal conductivity closest to human fat was considered the optimum fat TMM and was further characterized using ultrasound (US) and Magnetic Resonance Imaging (MRI).

Results

For the seven water-based TMMs an inverse linear trend was observed between thermal conductivity and increased agar concentration, being between 0.524 and 0.445 W/m K. Alcohol addition decreased thermal conductivity of the two water/alcohol-based TMMs to about 0.33 W/m K, while in the alcohol-based TMMs, increased concentrations of propan-2-ol emerged as a modifier of thermal conductivity. The optimum fat TMM (33.3% v/v glycerol and 66.7% v/v propan-2-ol) exhibited a 0.231 W/m K thermal conductivity, and appeared hypoechoic on US images and with increased brightness on T1-Weighted MRI images.

Conclusion

The optimum fat TMM emulates the thermal conductivity of human fat tissue and exhibits a fat-like appearance on US and MRI images. The TMM is cost-effective and has a long lifespan and possesses great potential for use in HIFU applications as a fat TMM.

Keywords: Fat, Phantom, TMM, Thermal conductivity, HIFU

Introduction

Tissue-mimicking materials (TMMs) otherwise known as phantoms, have a prominent role in biomedical research, since they are manufactured to mimic biological tissue for enabling easy and accurate validation and quality control of emerging systems and therapies [1]. Employment of TMMs with tissue-like properties can provide an understanding on the efficacy and hazards of the investigated system or therapy, prior to clinical trials [1]. With the continuous development of novel applications, different types of therapies are being examined. One of these, is the use of High Intensity Focused Ultrasound (HIFU) for therapeutic and palliative purposes. HIFU employs ultrasonic transducers that focus within the targeted tissue to raise its temperature to necrotic levels [2]. As a result, characteristic lesions of coagulative necrotic cells are formed in the tissue at the focus of the transducer [2].

To enable data reproducibility, TMMs should maintain structural, chemical, and mechanical stability over time [3]. Additionally, the materials utilized should be non-toxic, provide ease of use as well as be cost-effective [3]. The time and shape of lesion formation for any emerging HIFU systems or applications must be well examined before use in clinical trials. For this purpose, TMMs developed with materials that mimic the magnetic, acoustic, and thermal properties of human tissues are much needed. Generally, human soft tissues include a combination of muscles, fat, ligaments, tendons, fibrous tissue, nerves, synovial membranes and blood vessels [4]. Commonly, the majority of TMMs are developed to mimic soft tissue, with numerous anthropomorphic phantoms accurately mimicking the anatomy, shape and functionality of several soft tissue types [5]. Nevertheless, the majority of soft TMMs have a homogeneous structure [5]. Due to variations in the physical properties of different soft tissue types, the homogeneous TMMs should be developed to largely mimic soft tissues [5], and through judicious selection of additional inclusions further customized for mimicking specific tissue types.

Normally, for diagnostic and therapeutic applications of ultrasound (US) the developed tissue alternatives have an aqueous base [5], following the vast use of water in the calibration of US systems [6, 7]. However, water has a substantially lower propagation speed of sound (1480 m/s) and a relatively minimal attenuation coefficient (0.0022 dB/cm MHz) compared to human soft tissues and therefore alone is not a suitable soft tissue mimicking material (TMM) [5]. Nevertheless, the use of an ethanol–water solution provides increased propagation speed of sound, similar to soft tissue levels (1540 m/s) [8]. Notably, aqueous phantoms consisting of an agar [9] or gelatin base [10] are widely available, easily reproduced, and with their mixture with a variety of materials, can mimic the acoustic, magnetic or thermal characteristics of human tissues [5, 11]. Agar is a biopolymer, arising from algae, that is soluble in hot water, where it undergoes hysteresis to form a gel once the agar-water solution is cooled below 45 °C [12]. Gel creation occurs for temperatures up to 60 °C, due to the formation of intra- and inter-molecular hydrogen bonds between the agar and water molecules [13], as evidenced by spectroscopic techniques [14]. Increased concentrations of agar are related to a decreased pore size [12, 15] that leads to closer formation of the water-agar hydrogen bonds [15], and thus increased mechanical properties of the water-agar gel [16]. Specifically, agar-based TMMs have reported emulating soft tissue properties, while simultaneously reporting with a comparative mechanical strength [1]. Moreover, the agar or gelatin-based hydrogels enable reproducible results since several chemical compounds such as methyl paraben [17], thimerosal [16], Germall-plus [16], sodium azide [18], benzoic acids [19] or benzalkonium chloride [20] are often added to prevent bacterial growth, thus prolonging the lifespan of the TMMs. Use of chemical preservatives combined with TMM storage in airtight containers, with the TMM surrounded by a solution of its liquid components [20] or distilled water [19], results in stability of the TMM and reusability for a period of several months [19, 20].

A water-agar or water-gelatin mixture is most frequently used for muscle-like TMMs [21] due to water having similar thermal conductivity with muscle tissue [22], thus resulting in a TMM with muscle-like thermal conductivity [21]. The thermal conductivities of human tissues were measured by Hatfield et al. [23], and were found between 0.435 and 0.510 W/m K for muscle tissues and 0.161–0.197 W/m K for fat tissues. Materials having a low thermal conductivity are of great interest due to their potential use in phantoms simulating fat tissues. Ogiwara et al. [24] measured the thermal conductivity of ten liquid alcohols between 20 and 70 °C. Thermal conductivity decreased with increasing temperature, with pure ethanol ranging between 0.155 and 0.161 W/m K [24]. Woolf et al. [25] measured the thermal conductivity of olive oil between 0 and 140 °C. The thermal conductivity was inversely proportional to increasing temperature, acquiring values between 0.161 and 0.169 W/m K [25]. Similarly, Turgut et al. [26] measured the thermal conductivity of olive, sunflower and corn oils between temperatures of 25 and 80 °C. Olive oil had the smallest variation with temperature, with its conductivity having values of 0.163 and 0.166 W/m K, while sunflower oil had thermal conductivity values between 0.162 and 0.168 W/m K [26]. Corn oil exhibited the greatest effect on its thermal conductivity with temperature difference, with its thermal conductivity having values between 0.154 and 0.165 W/m K [26]. Wrenick et al. [27] examined the thermal conductivity of two different groups, II and V, of engine oils between 50 and 200 °C. Group II had thermal conductivities in the interval 0.13–0.138 W/m K, while the values for Group V were in the range of 0.12–0.15 W/m K [27]. Lavrykov et al. [28] examined the thermal properties of different types of commercially available paper sheets with the thermal conductivity of each sample dependent upon its density, thickness and percentage ash content. All 57 samples had their thermal conductivities between 0.0740 and 0.1816 W/m K [28]. Watson et al. [29] measured the thermal properties of butter containing 80% fat and 16% moisture between − 40 and 30 °C, with the thermal conductivity increasing with increasing temperature, obtaining values in the range of 0.243–0.31 W/m K. In the study by Eltom et al. [30] the thermal conductivities of charcoal were measured between a temperature range of 30–90 °C with the thermal conductivity varying with increasing temperature. The thermal conductivity was ranging between 0.07 and 0.1 W/m K; increasing until 40 °C, having constant values between 40 and 70 °C and decreasing from 70 to 90 °C [30]. Takizawa et al. [31] examined the thermal conductivity of liquid glycerol between the temperatures of 20–70 °C with the values obtained being approximately constant and ranging from 0.291 to 0.297 W/m K. Maccarthy et al. [32] measured the thermal conductivities of samples of granulated, extra-fine, caster and icing sugar with the measurements performed between 17.2 and 64.8 °C. The authors [32] concluded that the thermal conductivity increased with increasing particle size and temperature, having values in the interval 0.085–0.167 W/m K.

Although a vast literature exists for phantoms mimicking muscle tissue, not much literature exists for agar or gelatin-based phantoms thermally simulating fat tissue. Robinson et al. [33] developed two TMMs that dielectrically replicated muscle and fat, and calculated their dielectric and thermal properties. For the fat TMM, the authors [33] utilized a mixture of gelatin, ethanediol and polyethene powder and reached a thermal conductivity of 0.29 W/m K. In a study by Yuan et al. [34], a recipe proposed by Lazebnik et al. [35] was modified to simulate both electrical and thermal properties of human fat tissue, for developing a heterogeneous TMM for radiofrequency (RF) ablation. Yuan et al. [34] concluded that the initial use of kerosene by Lazebnik [35], would result in different thermal properties of the developed phantom compared to human fat tissue. Therefore, the authors [34] utilized a water-based solution with added gelatin, saline, pure vegetable oil, and a surfactant to allow for a homogeneous mixture of oil with the aqueous solution. The fat-mimicking compartment of the phantom consisted of 85% oil with its thermal conductivity measured at 0.20 W/m K, thus being in good agreement with the literature value for the thermal conductivity of fat tissue [34]. Similarly, in a study by Liu et al. [36], a heterogeneous agar-based TMM was developed with specific concentrations of sucrose and sodium chloride and varied concentrations of a fat-saturated oil. Notably, a 90% concentration of the fat-saturated oil resulted in a fat TMM having a thermal conductivity of 0.23 W/m K [36]. Correspondingly, Kim et al. [37] developed an agar-based fat TMM for HIFU applications using a combination of water, olive oil, glycerol, surfactant, aluminum oxide and silicon carbide at varied concentrations. Although a 15% concentration of olive oil resulted in a phantom with similar acoustic properties as fat tissue, no measurements of the thermal properties of the fabricated phantom were reported [37].

A TMM with fat tissue-like thermal properties would be of great interest for the HIFU field, due to the presence of intervening fat in extracorporeal use of HIFU [2], as well as the increasing use of HIFU for noninvasive fat-reduction [38, 39]. In an attempt to enhance the available literature for TMMs with thermal properties representative of fat tissue, agar-based TMMs were developed herein and characterized for their suitability in emulating thermal properties of human fat. Agar was preferred since it provides easy handling with minimal change of its properties over time [3], as well as the ability to withstand the high temperatures induced by thermal therapies [21]. Several TMMs were developed in an iterative approach utilizing different concentrations of agar, water and various types of alcohols, to find the ultimate recipe that best resembles the thermal characteristics of human fat tissue. Different alcohols were used, according to their literature values for thermal conductivity; glycerol with a thermal conductivity of 0.291–0.297 W/m K [31] and propan-2-ol with thermal conductivity between 0.127 and 0.133 W/m K [24]. The idea of adding alcohols was based on the fact that the abovementioned alcohols have low conductivity, thus ultimately reducing the thermal conductivity of the fabricated TMMs to desirable levels. More importantly, alcohols have hydroxyl groups (–OH) [40], therefore intra- and inter-molecular hydrogen bondings were expected between the alcohols and agar.

In the literature, alcohols have reportedly been utilized in varied concentrations as additives in agar or gelatin-based hydrogels for adjusting certain physical properties of the TMMs. Most commonly, glycerol is employed to adjust the ultrasonic propagation speed of the TMM [16, 37, 41], while varied concentrations of 1-propanol have also been utilized in this regard in gelatin-based hydrogels [19]. Varied alcohol concentrations have an insignificant effect on the attenuation coefficient of the TMM [16], with additional inclusions such as graphite [19] or aluminum oxide powder [20] employed in varying concentrations to regulate the attenuation coefficient of agar or gelatin-based water/alcohol TMMs [19, 20]. Nevertheless, the effect of varied alcohol concentrations on the thermal properties of TMMs has not been investigated. Therefore, in this study, the effect of varied concentrations of two types of alcohol (glycerol and propan-2-ol) on the thermal properties of agar-based TMMs is described, with the TMM exhibiting a thermal conductivity closest to human fat tissue [23] selected and further characterized for its suitability as a fat TMM using US and magnetic resonance imaging (MRI).

Materials and methods

Preparation of fat TMM

Seven water-based TMMs were initially developed with different percent (%) weight per volume (w/v) concentrations of agar (101,614, Merck KGgA, Darmstadt, Germany) for examining the effect of the varied agar concentration (2%, 4%, 6%, 8%, 12%, 16% and 20% w/v) on the thermal properties of the developed phantom. A similar and simple preparation procedure was followed for production of the seven water-based TMMs. Initially, 500 ml of purified deionized water that had undergone degasification, were placed in a beaker and moderately heated utilizing a hotplate magnetic stirrer (SBS A160, Steinberg Systems, Hamburg, Germany). During the heating process, the water volume was continuously magnetically stirred with its temperature periodically monitored with a digital thermometer (HH806AU, Omega Engineering, Connecticut, USA). Concurrently, an appropriate proportion of granulated agar (101614, Merck KGgA) was pulverized into a fine powder, that was steadily added to the water volume once its temperature slightly exceeded 50 °C. The proportion of agar was carefully selected each time, to result in the corresponding % w/v concentration (2%, 4%, 6%, 8%, 12%, 16%, or 20% w/v). Thereafter, the water-agar solution was continuously stirred and heated until its temperature exceeded 85 °C. This results in breaking of the agar bonds and allows the free hydroxyl groups to form hydrogen bonds with the water solution. Subsequently, the water-agar solution was allowed to cool down to between 50 and 60 °C, while continuously being magnetically stirred. Notably, the water volume that evaporated during the heating procedure was carefully replaced so that the water volume equated the volume that was initially placed in the beaker (500 ml). Once the temperature of the water-agar mixture dropped, the solution was poured inside a specially designed mold. The mold was designed with specific dimensions (6 cm (w) × 15 cm (l) × 6 cm (h)) and was 3D-printed (CR-10, Creality, Shenzhen, China) with Polylactic Acid (PLA) thermoplastic. The mixture was placed in a refrigerator where it was allowed overnight to jellify and completely solidify.

Subsequently, five TMMs were developed with a constant % w/v agar concentration (20% w/v) and utilizing various alcohols, for examining the effect of alcohol addition on the thermal properties. Initially, glycerol (15523, Honeywell, Seelze, Germany) and propan-2-ol (34863, Honeywell) were individually added to a water base with equal % volume per volume (v/v) concentrations of water and alcohol, for investigating the effect of the alcohol type on the thermal properties. In this sense, the following two water/alcohol-based TMMs were developed; one with 50% v/v water and 50% v/v propan-2-ol, and one with 50% v/v water and 50% v/v glycerol. These TMMs were developed following the abovementioned preparation procedure that was slightly differentiated in the sense that initially 500 ml of the water-alcohol mixture were placed in the beaker and heated. The agar concentration was added at the aforementioned temperature threshold (50 °C), with heating and cooling of the solution performed until the mixture reached the aforesaid temperatures (85 °C and 60 °C). The water/alcohol-based TMMs were developed in the PLA mold and were refrigerated overnight. The 0% v/v water and 50% v/v propan-2-ol TMM presented with a slight brown colour and moderate stiffness as shown in Fig. 1.

Fig. 1.

Fig. 1

Open in a new tab

Photo of the agar/water/propan-2-ol-based TMM (20% w/v agar, 50% v/v water and 50% v/v propan-2-ol)

Additionally, glycerol (15523, Honeywell) and propan-2-ol (34863, Honeywell) were utilized together in varied % v/v concentrations for forming a binary liquid alcohol base for examining the effect of a varied alcohol concentration on the thermal properties. In this regard, the following three alcohol-based TMMs were developed; a sample with 100% v/v concentration of glycerol, a sample with 40% v/v glycerol and 60% v/v propan-2-ol and one sample with 33.3% v/v glycerol and 66.7% v/v propan-2-ol. Notably, compared to the water-based and water/alcohol-based phantoms, these three alcohol-based TMMs were developed utilizing a slightly differentiated preparation procedure. Initially, for each sample, the appropriate % v/v alcohol concentrations were placed in the 500 ml beaker for a total alcohol volume of 500 ml. The 500 ml beaker with the alcohol solution was immersed in 300 ml water inside a 1000 ml beaker that was placed on the hotplate magnetic stirrer (SBS A160, Steinberg Systems), thus creating a water bath. The water was continuously heated and magnetically stirred, while during the heating procedure the alcohol solution was manually stirred. The alcohol solution was heated until its temperature was within 70–80 °C, whereupon the agar was added with the appropriate concentration (20% w/v). The powdered agar was gradually added to diminish the formation of agar powder clusters and ensure homogeneous dissolution of agar in the alcohol solution. Thereafter, the agar-alcohol solution continued to be heated in the water bath for approximately half an hour at about 80 °C as shown in Fig. 2. Afterwards, the agar-alcohol solution was removed from the water bath and while manually being stirred was allowed to cool to about 50 °C, whereupon it was poured in the PLA mold and refrigerated overnight. In cases propan-2-ol was utilized in the alcohol base, the propan-2-ol volume that had evaporated throughout the heating procedure was replaced to maintain the appropriate % v/v concentration. The evaporated volume of propan-2-ol was measured by inserting the corresponding initial volume of propan-2-ol in a separate beaker and following the heating procedure for the propan-2-ol solely (no added glycerol or agar) over the same temperatures and timeframe. Therefore, the evaporated volume was equal to the difference between the initial propan-2-ol volume and the volume of propan-2-ol remaining after the end of the heating procedure. The alcohol-based TMMs presented with a light brown colour with their stiffness varying according to the % v/v concentration of the alcohol types. In this regard, the 100% v/v glycerol TMM presented with the highest stiffness as shown in Fig. 3. Contrary, the 33.3% v/v glycerol and 66.7% v/v propan-2-ol TMM presented with the fairest stiffness and was wrapped in a plastic membrane as shown in Fig. 4.

Fig. 2.

Fig. 2

Open in a new tab

Photo of the preparation procedure of the agar/alcohol-based TMM with the agar-alcohol solution heated in a water bath

Fig. 3.

Fig. 3

Open in a new tab

Photo of the agar/glycerol-based TMM (20% w/v agar and 100% v/v glycerol)

Fig. 4.

Fig. 4

Open in a new tab

Photo of the agar/glycerol/propan-2-ol-based TMM (20% w/v agar, 33.3% v/v glycerol and 66.7% v/v propan-2-ol)

Experimental estimation of the thermal properties of the fat TMMs

The thermal conductivity of the various TMMs was experimentally measured within 24 h of fabrication. Prior to the measurements, the TMMs were removed from the refrigerator and were allowed to reach thermal equilibrium with the laboratory environment. The thermal conductivity of each TMM was measured by employing a portable heat transfer analyzer (Isomet model 2104, Applied Precision, Bratislava, Slovakia). Various sensors can be incorporated on the analyzer for automatic measurement of the thermal conductivity, thermal diffusivity, and volumetric heat capacity by utilizing the transient method, where the sensors heat the material under investigation and measure thermal properties from the temperature change rate [42]. A needle sensor (S/N 09030019, Applied Precision) with a measurement range of 0.2–1 W/m K was employed for experimental measurement of the thermal properties of each TMM. The needle sensor was inserted in its entirety centrally along the longitudinal axis of each TMM, since according to the manufacturer a minimum radius of 4 cm of material is required around the needle probe for accurate measurements of the thermal conductivity (5% of reading + 0.001 W/m K). In this sense, the dimensions of the PLA molds that were utilized for production of the TMMs were carefully selected to account for these requirements for accurate experimental measurements of the thermal properties. Although all three thermal properties (thermal conductivity, thermal diffusivity, and volumetric heat capacity) were acquired for each TMM, only thermal conductivity values are reported in the present study. For each TMM, four measurements of the thermal conductivity were acquired, and the average value of thermal conductivity was calculated. Individual measurements of thermal conductivity were rapid, requiring approximately 15–20 min.

Characterization of the fat-soft TMM

The TMM exhibiting the lowest thermal conductivity with a value closest to the range of thermal conductivity for human fat tissue [23], was considered as the ultimate fat TMM and is referred to as such for the rest of this study. For the purposes of simulating the anatomy of human soft tissue [4], the homogeneous fat TMM was placed with an approximate height of 2 cm on top of a homogeneous agar-based phantom doped with silicon dioxide [42–45]. The agar-based phantom was developed with 6% w/v agar (101614, Merck KGgA) and 4% w/v silicon dioxide (S5631, Sigma Aldrich, Missouri, USA) following the same preparation procedure reported by Drakos et al. [43]. These concentrations of agar (6% w/v) and silicon dioxide (4% w/v) were specifically chosen to result in a TMM with similar acoustic properties with human muscle tissue [43] as well as comparable magnetic properties with different body tissues [46]. The agar/silicon dioxide TMM was developed in a 3D-printed (CR-10, Creality) PLA mold with dimensions 7 cm (w) × 9 cm (l) × 6 cm (h). For the rest of the manuscript, the combined fat TMM and agar/silicon dioxide TMM are referred to as the fat-soft TMM.

US imaging of the fat-soft TMM

The fat-soft TMM was imaged utilizing a conventional diagnostic US system (DP-50, Shenzhen Mindray Bio-Medical Electronics Co., Shenzhen, China). The US images were utilized for examining the sonographic appearance and echogenicity of the fat-soft TMM. US images were individually acquired for the soft TMM, the fat TMM as well as the interface of the fat-soft TMM.

MRI imaging of the fat-soft TMM

The fat-soft TMM was placed in a 3 T MRI scanner (Magneton Vida, Siemens Healthineers, Erlangen, Germany) and imaged utilizing a body coil (Body 18, Siemens Healthineers). High-resolution images were acquired on axial plane using T1-Weighted Turbo Spin Echo (T1-W TSE) and T2-Weighted Turbo Spin Echo (T2-W TSE) sequences. The T1-W TSE image was acquired with the following parameters: Repetition Time (TR) = 700 ms, Echo Time (TE) = 12 ms, Echo Train Length (ETL) = 2, Matrix = 256 × 256, Field of View (FOV) = 20 × 20 cm2, Flip Angle (FA) = 160°, Number of Excitations (NEX) = 1 and slice thickness = 10 mm. Correspondingly, the T2-W TSE image was acquired with TR = 2500 ms, TE = 48 ms, ETL = 16, Matrix = 320 × 320, FOV = 20 × 20 cm2, FA = 180°, NEX = 1 and slice thickness = 10 mm.

Results

Experimental estimation of the thermal properties of the fat TMMs

Initially, the thermal conductivities of the seven water-based TMMs having varied % w/v agar concentrations (2%, 4%, 6%, 8%, 12%, 16% and 20% w/v) were measured for assessing the effect of the increasing agar concentration on the thermal conductivity. Increased stiffness of the phantoms was observed with increasing % w/v concentrations of agar. For each TMM, the average value of thermal conductivity from four individual measurements was reported. Figure 5 shows the average thermal conductivity as measured for each of the TMMs having varied % w/v concentrations of agar. Following linear regression analysis (R2 = 0.969), an inverse correlation was observed between thermal conductivity and increased % w/v concentration of agar, with thermal conductivities in the range of 0.524–0.445 W/m K for 2–20% w/v agar concentrations. Nevertheless, only a small decrement of thermal conductivity was observed with increasing % w/v agar concentration, with the thermal conductivity decreased by 0.0042 W/m K for a unit increase in the % w/v agar concentration.

Fig. 5.

Fig. 5

Open in a new tab

Average thermal conductivity of the agar/water-based TMMs having varied % w/v concentrations of agar

Thereafter, thermal conductivity was measured for the five TMMs developed with 20% w/v agar and varied % v/v concentrations of water, glycerol, and propan-2-ol. The thermal conductivity was measured for the two water/alcohol-based TMMs (one 50% v/v water and 50% v/v propan-2-ol, and one 50% v/v water and 50% v/v glycerol) for examining the effect of alcohol type on the thermal conductivity, as well as the three alcohol-based TMMs (one 100% v/v glycerol, one 40% v/v glycerol and 60% v/v propan-2-ol, and one 33.3% v/v and 66.7% propan-2-ol) for investigating the effect of alcohol concentration on the thermal conductivity. Similarly, thermal conductivity measurements for each of the five TMMs were performed four times and the average value of the four measurements was acquired. Figure 6 shows the average value of the thermal conductivity for each of the five TMMs containing alcohols. Figure 6 additionally includes the thermal conductivity value (0.445 W/m K) of the water-based TMM (100% v/v water) with the analogous agar concentration (20% w/v) for comparison purposes. The addition of alcohol decreased the thermal conductivity, with the average thermal conductivity values of the two water/alcohol-based TMMs approximately similar for a 50% v/v concentration of either propan-2-ol (0.33 W/m K) or glycerol (0.327 W/m K). Further reductions in the average thermal conductivity were observed for the three alcohol-based TMMs, with the 100% v/v glycerol TMM reporting a mean thermal conductivity of 0.286 W/m K. Similarly, addition of propan-2-ol in either 60% or 66.7% v/v concentrations further reduced the thermal conductivity to 0.246 W/m K and 0.231 W/m K respectively.

Fig. 6.

Fig. 6

Open in a new tab

Average thermal conductivity of the 20% w/v agar-based TMMs having varied concentrations of water, glycerol and propan-2-ol

Characterization of the fat-soft TMM

The alcohol-based TMM developed with 20% w/v agar, 33.3% v/v glycerol and 66.7% v/v propan-2-ol exhibited the lowest thermal conductivity (0.231 W/m K) and was thus considered as the fat TMM. Therefore, it was removed from the plastic membrane and placed on top of the agar/silicon dioxide, resulting in the fat-soft TMM as shown in Fig. 7.

Fig. 7.

Fig. 7

Open in a new tab

Photo of the fat-soft TMM with the soft TMM developed with a muscle-like recipe (6% w/v agar and 4% w/v silicon dioxide) and the fat TMM developed with the optimum recipe (20% w/v agar, 33.3% v/v glycerol and 66.7% v/v propan-2-ol)

US imaging of the fat-soft TMM

Figure 8 shows the US images acquired for the soft TMM (Fig. 8A), fat TMM (Fig. 8B), and the interface of the fat-soft TMM (Fig. 8C). The soft TMM appeared homogeneous and highly echogenic as shown in Fig. 8A. Contrary, the fat TMM appeared with reduced echogenicity on its acquired US image (Fig. 8B), while it was shown hypoechoic relative to the soft TMM on the US image acquired on the interface of the fat-soft TMM (Fig. 8C).

Fig. 8.

Fig. 8

Open in a new tab

Ultrasound images of the fat-soft TMM individually acquired for a the soft TMM, b fat TMM, and c the interface of the fat-soft TMM with the soft TMM on top and the fat TMM on the bottom

MRI imaging of the fat-soft TMM

Figure 9A and B respectively show the acquired axial T1-W TSE and T2-W TSE images of the fat-soft TMM. Generally, the fat-soft TMM appeared relatively homogeneous with no artifacts on the acquired MRI images. The soft TMM appeared with similar intensity on both images (bottom layer in Fig. 9A and B), while the fat TMM appeared with increased brightness on the T1-W TSE image (top layer in Fig. 9A) and with relatively low brightness on the T2-W TSE image (top layer in Fig. 9B).

Fig. 9.

Fig. 9

Open in a new tab

MRI images of the fat-soft TMM acquired on axial plane with a T1-W TSE, and b T2-W TSE sequences. Soft TMM in bottom layer and fat TMM in top layer

Discussion

In the present study, agar-based TMMs intended for HIFU applications were developed and characterized for their suitability to mimic the thermal properties of human fat tissue, and specifically thermal conductivity. Twelve TMMs were developed in an iterative approach using varied concentrations of agar, water, glycerol, and propan-2-ol, with experimental measurements of their thermal conductivity performed with the transient method [42]. The TMM exhibiting a thermal conductivity closest to the range of thermal conductivities reported for human fat tissue [23], was considered as the optimum fat TMM and was further characterized for its appearance on US and MRI images.

Following the vast use of agar in an aqueous base for TMMs for MRI-guided HIFU applications [44, 45, 47], seven TMMs were initially developed with a water base and varied concentrations of agar (2%, 4%, 6%, 8%, 12%, 16% and 20% w/v) for investigating the effect of the agar concentration on the thermal conductivity. Agar concentration emerged as a modifier of thermal conductivity, with increased % w/v concentrations resulting in reduced thermal conductivity values. Notably, the inverse correlation between increased agar concentration and thermal conductivity observed herein is corroborated by similar relations reported in the studies by Cho et al. [48] and Zhang et al. [49] for the thermal conductivities of other agar-based TMMs. Nevertheless, herein, increased % w/v agar concentrations resulted in minor reductions in thermal conductivity as well as increased stiffness of the phantoms. The latter was expected, since it is widely known that increased mechanical stiffness is observed with increased agar concentrations [16]. Therefore, TMMs with agar concentrations greater than 20% w/v were not investigated, since these would result in TMMs of extreme stiffness that would not only prohibit insertion of the needle sensor in the TMM for measurement of the thermal conductivity, but would also be atypical of the stiffness of human fat tissue.

In this regard, agar concentration was limited to 20% w/v, and glycerol and propan-2-ol were individually added with a 50% v/v concentration in a water base, for forming two water/alcohol-based TMMs. Addition of alcohol decreased the thermal conductivity of the TMM by approximately 25% from the thermal conductivity value of the water-based TMM with the corresponding agar concentration (20% w/v). Alcohol type (glycerol or propan-2-ol) did not seem to affect the thermal conductivity value, since no significant difference was observed between the thermal conductivities of the two water/alcohol-based TMMs, despite the lower range of thermal conductivities reported in the literature for propan-2-ol (0.127–0.133 W/m K) [24] compared to glycerol (0.291–0.297 W/m K) [31].

Notably, utilization of the two alcohols (glycerol and propan-2-ol) for three alcohol-based TMMs further reduced the thermal conductivity of the TMM. As expected, agar easily dissolved and bonded with the alcohol solutions, with the thermal conductivity of the glycerol-based TMM (100% v/v glycerol) substantially lower than the thermal conductivity of the respective water-based or water/glycerol-based TMMs. Moreover, the thermal conductivity of the 100% v/v glycerol-based TMM reported herein, was comparative to and somewhat lower than the literature value for the thermal conductivity of pure glycerol [31], probably as a result of the added agar. Moreover, due to the lower thermal conductivity of propan-2-ol [24], its addition respectively decreased the thermal conductivity of the TMMs. An increased % v/v concentration of propan-2-ol was a significant modifier of the thermal conductivity of the TMM, reaching up to 20% reduction from the thermal conductivity of the 100% v/v glycerol-based TMM. Notably, utilization of 33.3% v/v glycerol and 66.7% propan-2-ol for a 20% w/v agar concentration, resulted in a TMM with a thermal conductivity value (0.231 W/m K) approximately close to the range of thermal conductivities reported for human fat tissue [23]. In this regard, this specific phantom was considered as the fat TMM and was further evaluated.

US and MRI characterization of the fat TMM was performed following its placement on an agar/silicon dioxide TMM [43] exhibiting similar acoustic [43] and magnetic properties [46] with human soft tissue. In this regard, the combination of the homogeneous fat and soft TMMs were macroscopically simulating human anatomy, where tissues and organs are surrounded by fat [4]. US images of the soft TMM (6% w/v agar and 4% w/v silicon dioxide) showed the developed TMM appearing with similar texture and echogenicity with a phantom of the same recipe as reported in the study by Drakos et al. [43], thus approximating US signal of human soft tissues. Contrary, acquired US images of the fat TMM resulted in minimal echogenicity. Similar US imaging difficulties were previously reported for an agar-based breast fat TMM developed for US and microwave imaging with the artifacts attributed to the increased attenuation of fat tissue [50]. In this regard, hypoechogenicity of the fat TMM developed herein could indicate increased acoustic attenuation, with the fat TMM resembling the sonographic appearance reported clinically for breast fat tissue [51] as well as perirenal and abdominal fat tissues [52]. Correspondingly, the MRI appearance of the fat TMM simulated the MRI visibility of fatty tissues that appear with increased and decreased intensity on T1-Weighted and T2-Weighted images respectively [53].

Generally, utilization of glycerol and propan-2-ol in appropriate concentrations (33.3% v/v glycerol and 66.7% v/v propan-2-ol) resulted in an agar-based (20% w/v) fat TMM with the desirable thermal conductivity. The measured thermal conductivity of the fat TMM (0.231 W/m K) was similar to the thermal conductivity value of the fat-like compartment (90% fat saturated-oil) of a heterogeneous agar-based TMM intended for RF ablation [36], slightly higher than the thermal conductivity of a gelatin-based fat TMM for RF ablation [34], and lower than the thermal conductivity of other gelatin-based fat TMMs [33]. More importantly, the fat TMM proposed in the present study resembles the US and MRI visibility of human fat tissue. As a result, the proposed TMM possesses fat-like thermal, US and MRI properties and could thus have potential use in HIFU applications as a fat TMM, simulating and accounting for thermal energy lost due to intervening fat tissue. Development of the fat TMM is easy and requires a moderate amount of preparation time (~ 1.5 h). Moreover, the materials utilized for the fat TMM are non-toxic, cost-effective, and have a long lifespan, therefore minimal perishability and bacterial contamination are expected. Nevertheless, storage of the fat TMM developed herein is recommended to be performed in an airtight container to prevent the evaporation of propan-2-ol.

Author contributions

All authors contributed to the study conception and design. AF contributed to the drafting of the manucript and the experimental work. IL contributed to the experimental work. CD supervised the experimental work and the drafting of the manuscript. All authors read and approved the final manuscript.

Funding

This work was funded by the Research & Innovation Foundation of Cyprus under the project SOUNDPET (INTEGRATED/0918/0008).Inline graphic

Availability of data and material

All data generated or analyzed in the present study are available from the authors upon request.

Code availability

Not applicable.

Declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

This study was performed on tissue mimicking materials and no human participants or animals were included. In this regard, an approval from an institutional review board or ethics committee was not required.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  • 1.Mobashsher AT, Abbosh AM. Artificial human phantoms: Human proxy in testing microwave apparatuses that have electromagnetic interaction with the human body. IEEE Microw Mag. 2015;16(6):42–62. doi: 10.1109/MMM.2015.2419772. [DOI] [Google Scholar]
  • 2.ter Haar G, Coussios C. High intensity focused ultrasound: Physical principles and devices. Int J Hyperth. 2007;23(2):89–104. doi: 10.1080/02656730601186138. [DOI] [PubMed] [Google Scholar]
  • 3.Ahmad MS, Suardi N, Shukri A, Mohammad H, Oglat AA, Alarab A, Makhamrah O. Chemical characteristics, motivation and strategies in choice of materials used as liver phantom: a literature review. J Med Ultrasound. 2020;28(1):7–16. doi: 10.4103/JMU.JMU_4_19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Hazari A, Maiya AG, Nagda TV. Conceptual biomechanics and kinesiology. Singapore: Springer; 2021. Cellular biomechanics of soft tissues; pp. 19–27. [Google Scholar]
  • 5.Culjat MO, Goldenberg D, Tewari P, Singh RS. A review of tissue substitutes for ultrasound imaging. Ultrasound Med Biol. 2010;36(6):861–873. doi: 10.1016/j.ultrasmedbio.2010.02.012. [DOI] [PubMed] [Google Scholar]
  • 6.Shen C, Lyu L, Wang G, Wu J. A method for ultrasound probe calibration based on arbitrary wire phantom. Cogent Eng. 2019 doi: 10.1080/23311916.2019.1592739. [DOI] [Google Scholar]
  • 7.Wen T, Wang C, Zhang Y, Zhou S. A novel ultrasound probe spatial calibration method using a combined phantom and stylus. Ultrasound Med Biol. 2020;46(8):2079–2089. doi: 10.1016/j.ultrasmedbio.2020.03.018. [DOI] [PubMed] [Google Scholar]
  • 8.Glacomini A. Ultrasonic velocity in ethanol-water mixtures. J Acoust Soc Am. 1947;19(4):701–702. doi: 10.1121/1.1916541. [DOI] [Google Scholar]
  • 9.Burlew MM, Madsen EL, Zagzebski JA, Banjavic RA, Sum SW. A new ultrasound tissue-equivalent material. Radiology. 1980;134(2):517–520. doi: 10.1148/radiology.134.2.7352242. [DOI] [PubMed] [Google Scholar]
  • 10.Cook JR, Bouchard RR, Emelianov SY. Tissue-mimicking phantoms for photoacoustic and ultrasonic imaging. Biomed Opt Express. 2011;2(11):3193–3206. doi: 10.1364/boe.2.003193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.McGarry CK, Grattan LJ, Ivory AM, et al. Tissue mimicking materials for imaging and therapy phantoms: a review. Phys Med Biol. 2020;65:23TR01. doi: 10.1088/1361-6560/abbd17. [DOI] [PubMed] [Google Scholar]
  • 12.Gustavsson PE, Son POL. Journal of chromatography library. Amsterdam: Elsevier Science; 2003. Monolithic polysaccharide materials; pp. 121–141. [Google Scholar]
  • 13.Tako M, Tamaki Y, Teruya T, Takeda Y. The principles of starch gelatinization and retrogradation. Food Nutr Sci. 2014;5(3):280–291. doi: 10.4236/fns.2014.53035. [DOI] [Google Scholar]
  • 14.Gamini A, Toffanin R, Murano E, Rizzo R. Hydrogen-bonding and conformation of agarose in methyl sulfoxide and aqueous solutions investigated by 1H and 13C NMR spectroscopy. Carbohyd Res. 1997;304(3–4):293–302. doi: 10.1016/S0008-6215(97)00232-2. [DOI] [Google Scholar]
  • 15.Kaczmarek K, Mrówczyński R, Hornowski T, Bielas R, Józefczak A. The effect of tissue-mimicking phantom compressibility on magnetic hyperthermia. Nanomaterials. 2019;9(5):803. doi: 10.3390/nano9050803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Madsen EL, Hobson MA, Shi H, Varghese T, Frank GR. Tissue-mimicking agar/gelatin materials for use in heterogeneous elastography phantoms. Phys Med Biol. 2005;50(23):5597–5618. doi: 10.1088/0031-9155/50/23/013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Holt RG, Roy RA. Measurements of bubble-enhanced heating from focused, MHz-frequency ultrasound in a tissue-mimicking material. Ultrasound Med Biol. 2001;27(10):1399–1412. doi: 10.1016/S0301-5629(01)00438-0. [DOI] [PubMed] [Google Scholar]
  • 18.Kato H, Hiraoka M, Ishida T. An agar phantom for hyperthermia. Med Phys. 1986;13(3):396–398. doi: 10.1118/1.595882. [DOI] [PubMed] [Google Scholar]
  • 19.Madsen EL, Zagzebski JA, Banjavie RA, Jutila RE. Tissue mimicking materials for ultrasound phantoms. Med Phys. 1978;5(5):391–394. doi: 10.1118/1.594483. [DOI] [PubMed] [Google Scholar]
  • 20.Ramnarine KV, Anderson T, Hoskins PR. Construction and geometric stability of physiological flow rate wall-less stenosis phantoms. Ultrasound Med Biol. 2001;27(2):245–250. doi: 10.1016/S0301-5629(00)00304-5. [DOI] [PubMed] [Google Scholar]
  • 21.Dabbagh A, Abdullah BJJ, Ramasindarum C, Abu Kasim NH. Tissue-mimicking gel phantoms for thermal therapy studies. Ultrason Imaging. 2014;36(4):291–316. doi: 10.1177/0161734614526372. [DOI] [PubMed] [Google Scholar]
  • 22.Demirel Y. Nonequilibrium thermodynamics transport and rate processes in physical, chemical and biological systems. 3. Amsterdam: Elsevier Science; 2013. [Google Scholar]
  • 23.Hatfield HS, Pugh LGC. Thermal conductivity of human fat and muscle. Nature. 1951;168(4282):918–919. doi: 10.1038/168918a0. [DOI] [PubMed] [Google Scholar]
  • 24.Ogiwara K, Arai Y, Saito S. Thermal conductivities of liquid alcohols and their binary mixtures. J Chem Eng Jpn. 1982;15(5):335–342. doi: 10.1252/jcej.15.335. [DOI] [Google Scholar]
  • 25.Woolf JR, Sibbitt WL. Thermal Conductivity of Liquids. Ind Eng Chem. 1954;46(9):1947–1952. doi: 10.1021/ie50537a049. [DOI] [Google Scholar]
  • 26.Turgut A, Tavman I, Tavman S. Measurement of thermal conductivity of edible oils using transient hot wire method. Int J Food Prop. 2009;12(4):741–747. doi: 10.1080/10942910802023242. [DOI] [Google Scholar]
  • 27.Wrenick S, Sutor P, Pangilinan H, Schwarz EE. Heat transfer properties of engine oils. Proc World Tribol Congr III. 2005;1:595–596. doi: 10.1115/wtc2005-64316. [DOI] [Google Scholar]
  • 28.Lavrykov SA, Ramarao BV. Thermal properties of copy paper sheets. Drying Technol. 2012;30(3):297–311. doi: 10.1080/07373937.2011.638148. [DOI] [Google Scholar]
  • 29.Watson E. Thermal properties of butter. Can Agric Eng. 1975;17(2):68–71. [Google Scholar]
  • 30.Eltom OMM, Sayigh AAM. A simple method to enhance thermal conductivity of charcoal using some additives. Renew Energy. 1994;4(1):113–118. doi: 10.1016/0960-1481(94)90072-8. [DOI] [Google Scholar]
  • 31.Takizawa S, Murata H, Nagashima A. Measurement of the thermal conductivity of liquids by transient hot-wire method I : measurement at atmospheric pressure. Bull Jpn Soc Mech Eng. 1978;21(152):273–278. doi: 10.1299/jsme1958.21.273. [DOI] [Google Scholar]
  • 32.Maccarthy DA, Fabre N. Thermal conductivity of sucrose. In: Singh RP, Medina AG, editors. Food properties and computer-aided engineering of food processing systems. Dordrecht: Springer; 1989. pp. 105–111. [Google Scholar]
  • 33.Robinson MP, Richardson MJ, Green JL, Preece AW. New materials for dielectric simulation of tissues. Phys Med Biol. 1991;36(12):1565–1571. doi: 10.1088/0031-9155/36/12/002. [DOI] [PubMed] [Google Scholar]
  • 34.Yuan Y, Wyatt C, Maccarini P, et al. A heterogeneous human tissue mimicking phantom for RF heating and MRI thermal monitoring verification. Phys Med Biol. 2012;57(7):2021–2037. doi: 10.1088/0031-9155/57/7/2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Lazebnik M, Madsen EL, Frank GR, Hagness SC. Tissue-mimicking phantom materials for narrowband and ultrawideband microwave applications. Phys Med Biol. 2005;50(18):4371–4384. doi: 10.1088/0031-9155/50/18/001. [DOI] [PubMed] [Google Scholar]
  • 36.Liu Z, Ahmed M, Weinstein Y, Yi M, Mahajan RL, Goldberg NS. Characterization of the RF ablation-induced ‘oven effect’: the importance of background tissue thermal conductivity on tissue heating. Int J Hyperth. 2006;22(4):327–342. doi: 10.1080/02656730600609122. [DOI] [PubMed] [Google Scholar]
  • 37.Kim MS, Kim JY, Du Jung H, Kim JY, Choi HH. A fat-tissue mimic phantom for therapeutic ultrasound. IEIE Trans Smart Process Comput. 2014;3(3):153–157. doi: 10.5573/IEIESPC.2014.3.3.153. [DOI] [Google Scholar]
  • 38.Jewell ML, Solish NJ, Desilets CS. Noninvasive body sculpting technologies with an emphasis on high-intensity focused ultrasound. Aesthetic Plast Surg. 2011;35(5):901–912. doi: 10.1007/s00266-011-9700-5. [DOI] [PubMed] [Google Scholar]
  • 39.Gadsden E, Aguilar MT, Smoller BR, Jewell ML. Evaluation of a novel high-intensity focused ultrasound device for ablating subcutaneous adipose tissue for noninvasive body contouring: Safety studies in human volunteers. Aesthetic Surg J. 2011;31(4):401–410. doi: 10.1177/1090820X11405027. [DOI] [PubMed] [Google Scholar]
  • 40.Chen C, Li WZ, Song YC, Yang J. Hydrogen bonding analysis of glycerol aqueous solutions: a molecular dynamics simulation study. J Mol Liq. 2009;146(1–2):23–28. doi: 10.1016/j.molliq.2009.01.009. [DOI] [Google Scholar]
  • 41.Oglat AA, Matjafri MZ, Suardi N, et al. Chemical items used for preparing tissue-mimicking material of wall-less flow phantom for Doppler ultrasound imaging. J Med Ultrasound. 2018;26(3):123–127. doi: 10.4103/JMU.JMU_13_17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Menikou G, Damianou C. Acoustic and thermal characterization of agar based phantoms used for evaluating focused ultrasound exposures. J Ther Ultrasound. 2017;5:14. doi: 10.1186/s40349-017-0093-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Drakos T, Antoniou A, Evripidou N, et al. Ultrasonic attenuation of an agar, silicon dioxide, and evaporated milk gel phantom. J Med Ultrasound. 2021;29(4):239–249. doi: 10.4103/JMU.JMU_145_20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Menikou G, Dadakova T, Pavlina M, Bock M, Damianou C. MRI compatible head phantom for ultrasound surgery. Ultrasonics. 2015;57:144–152. doi: 10.1016/j.ultras.2014.11.004. [DOI] [PubMed] [Google Scholar]
  • 45.Menikou G, Yiannakou M, Yiallouras C, Ioannides C, Damianou C. MRI-compatible breast/rib phantom for evaluating ultrasonic thermal exposures. Int J Med Robot Comput Assist Surg. 2018;14(1):1–12. doi: 10.1002/rcs.1849. [DOI] [PubMed] [Google Scholar]
  • 46.Antoniou A, Georgiou L, Christodoulou T, Panayiotou N, Ioannides C, Zamboglou N, Damianou C. MR relaxation times of agar-based tissue-mimicking phantoms. J Appl Clin Med Phys. 2022;23:e13533. doi: 10.1002/acm2.13533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Drakos T, Giannakou M, Menikou G, Constantinides G, Damianou C. Characterization of a soft tissue-mimicking agar/wood powder material for MRgFUS applications. Ultrasonics. 2021;113:106357. doi: 10.1016/j.ultras.2021.106357. [DOI] [PubMed] [Google Scholar]
  • 48.Cho J, Prasad B, Kim JK. Near-infrared laser irradiation of a multilayer agar-gel tissue phantom to induce thermal effect of traditional moxibustion. J Innov Opt Health Sci. 2018 doi: 10.1142/S1793545818500335. [DOI] [Google Scholar]
  • 49.Zhang M, Che Z, Chen J, Zhao H, Yang L, Zhong Z, Lu J. Experimental determination of thermal conductivity of water-agar gel at different concentrations and temperatures. J Chem Eng Data. 2011;56(4):859–864. doi: 10.1021/je100570h. [DOI] [Google Scholar]
  • 50.Li S, Fear E, Curiel L. Breast tissue mimicking phantoms for combined ultrasound and microwave imaging. Phys Med Biol. 2021;66:245011. doi: 10.1088/1361-6560/ac3d18. [DOI] [PubMed] [Google Scholar]
  • 51.Venta LA, Dudiak CM, Salomon CG, Flisak ME. Sonographic evaluation of the breast. Radiographics. 1994;14(1):29–50. doi: 10.1148/radiographics.14.1.8128064. [DOI] [PubMed] [Google Scholar]
  • 52.Spencer GM, Rubens DJ, Roach DJ. Hypoechoic fat: a sonographic pitfall. Am J Roentgenol. 1995;164(5):1277–1280. doi: 10.2214/ajr.164.5.7717247. [DOI] [PubMed] [Google Scholar]
  • 53.Bloem JL, Reijnierse M, Huizinga TWJ, Van Der Helm-Van Mil AHM. MR signal intensity: staying on the bright side in MR image interpretation. Rheum Musculoskelet Dis Open. 2018;4:e000728. doi: 10.1136/rmdopen-2018-000728. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data generated or analyzed in the present study are available from the authors upon request.

Not applicable.

Articles from Journal of Ultrasound are provided here courtesy of Springer

RESOURCES