Ultrasound phantom and method for manufacturing the ultrasound phantom

Abstract

To provide an ultrasonic phantom even when being repeatedly used over time, securing reproducibility and temporal stability.SOLUTION: An ultrasonic phantom includes water, agar, polysaccharide thickeners and water retention aid, and when a temperature of solating an aqueous dispersion of agar due to temperature rise is defined as a first phase transmission point and a temperature of gelatinizing the solated aqueous solution due to temperature drop is defined as a second phase transition point, in a temperature region of the second phase transition point or more and the first phase transition point or less, the polysaccharide thickeners do not have a phase transition point of gelatinizing aqueous solution of the polysaccharide thickeners due to temperature drop. A polarization term δP of Hansen solubility parameter of the water retention aid is 13.0 MPa0.5 or more.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to ultrasound phantoms and methods for manufacturing ultrasound phantoms. [Background technology]

[0002] Tissue-mimicking phantoms that mimic body tissues are used to calibrate and implement functions in medical diagnostic equipment, such as acoustic wave (e.g., ultrasound) diagnostic equipment, magnetic resonance imaging (MRI), computed tomography (CT), X-ray diagnostic equipment, and near-infrared imaging (NIRI). These equipment utilizes electromagnetic waves, such as ultrasound, X-rays, and light, and monitors physical phenomena such as scattering, refraction, reflection, absorption, diffraction, and interference to diagnose patient diseases.

[0003] In recent years, ultrasound diagnostic equipment equipped with a function for quantitatively evaluating the stiffness (elastic modulus) of organs using shear wave elastography (SWE) has become known. This method calculates the Young's modulus within organs by observing the propagation speed of shear waves generated by ultrasound, making it possible to quantitatively evaluate stiffness. Patent Document 1 discloses an elastography device that improves the image quality of elastic modulus images by superimposing the transmission position of burst waves into the living body on an ultrasound image, making it easier for the surgeon to visualize the effects of shear waves, which have the tendency to reflect at the boundary between tissues of different hardness. Ultrasound phantoms are used to calibrate elastography devices to calculate the stiffness and stiffness distribution of tissues in vivo. Ultrasound phantoms made from hydrogels containing agar are known to provide good ultrasonic characteristics. Ultrasound phantoms made from hydrogels are sometimes referred to as hydrogel phantoms or agar phantoms. Patent Document 2 discloses a hydrogel phantom that uses a hydrogel containing mixed agarose, known as the main component of agar, as a layer mimicking in vivo tissue. Patent Document 2 further discloses that the hydrogel phantom contains aluminum oxide powder and silicon carbide of different particle sizes to adjust the acoustic wave attenuation characteristics and mimic a fat layer. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2015-054056 [Patent Document 2] International Publication No. 2009 / 010898 Summary of the Invention [Problem to be solved by the invention]

[0005] However, when applying an agar-based hydrogel such as that disclosed in Patent Document 2 to the calibration of an elastography device, improvements are sometimes desired in terms of reproducibility and stability over time. When a phantom made of agar is repeatedly used as an elasticity phantom, the elastic modulus and acoustic propagation characteristics may change irreversibly. Because calibration of elastography devices is performed irregularly, an agar phantom that ensures reproducibility and stability over time is desired. The reproducibility and stability over time desired for such an ultrasound phantom include the reproducibility and stability over time of acoustic wave propagation characteristics.

[0006] The present disclosure provides an ultrasound phantom that ensures reproducibility and stability over time even when used repeatedly over time, and a method for manufacturing the same. [Means for solving the problem]

[0007] An ultrasound phantom according to an embodiment of the present disclosure contains water, agar, a thickening polysaccharide, and a water retention aid, The temperature at which the aqueous dispersion of agar turns into a sol by heating is defined as a first phase transition point, Agar dispersion in water When the temperature at which the solated aqueous solution gels upon cooling is defined as a second phase transition point, the thickening polysaccharide does not have a phase transition point at which an aqueous solution of the thickening polysaccharide gels upon cooling in a temperature range from the second phase transition point to the first phase transition point, The polarization term δP of the Hansen solubility parameter of the water retention aid is 13.0 MPa 0.5 That's all Ultrasound phantom. [Effects of the Invention]

[0008] According to the present disclosure, it is possible to provide an ultrasound phantom that ensures reproducibility and stability over time even when used repeatedly over time, and a method for manufacturing the same. DETAILED DESCRIPTION OF THE INVENTION

[0009] In the present disclosure, unless otherwise specified, the expressions "XX or more and YY or less" or "XX to YY" representing a numerical range mean a numerical range including the lower and upper limits, which are the endpoints. When a numerical range is described in stages, the upper and lower limits of each numerical range can be combined in any way.

[0010] <Agar (A)> Agar is a mucilage extracted from red algae such as Amakusa and Gracilaria, and is a polysaccharide composed of at least agarose and agaropectin. Any agar can be used regardless of its place of production or origin. To adjust the gel strength, so-called low-strength agar (disclosed, for example, in JP-A-5-317008) may be used, in which the molecules are cleaved by acid treatment. It is preferable to use powdered agar.

[0011] Agar has a first phase transition point at which an aqueous dispersion of agar turns into a sol upon heating and a second phase transition point at which the solated aqueous solution turns into a gel upon cooling. An aqueous dispersion of agar is prepared by dispersing agar in water. The first phase transition point is the temperature at which the aqueous dispersion turns into a sol upon heating. The second phase transition point is the temperature at which the solated aqueous solution turns into a gel upon cooling.

[0012] Preferably, the first phase transition point is the temperature at which agar dissolves in water and the aqueous dispersion, in which 1.0 mass % agar is dispersed in water, is heated from room temperature (25°C) to form a solubilized solution. The second phase transition point is preferably the temperature at which an aqueous solution of solubilized agar gels when the aqueous solution is left at room temperature and cooled. Generally, the first phase transition point is between 85°C and 99°C, and the second phase transition point is between 30°C and 45°C. In the present specification, a distinction is made between an equilibrium state in which a specific component is "dissolved" in water to form an aqueous solution and an equilibrium state in which a specific component is "dispersed" in water to form a dispersion.

[0013] In this disclosure, gel refers to a solid state, and sol refers to a state with fluidity. Viscoelasticity measurement can be used to distinguish between gel and sol. Specifically, the determination can be made using a dynamic viscoelasticity measuring device according to the following procedure. Dynamic viscoelasticity measuring devices are available in two types: a shear type that applies stress in the horizontal direction, and a compression and tension type that applies stress in the vertical direction. We will use the shear type. The value of tan δ, which is the ratio of the storage modulus to the loss modulus, is calculated, and if it is 1.0 or less, it is determined to be a gel, and if it is greater than 1.0, it is determined to be a sol. In this case, a measurement frequency of 0.5 Hz or 1 Hz can be used, taking into account the tracking ability of the gel and the measuring jig. It is desirable that the strain during measurement be 0.01% or more and 0.1% or less. If the strain is less than 0.01%, the gel cannot be moved sufficiently, making the measurement unreliable, and if it is greater than 0.1%, the measuring jig will slip, reducing the reliability of the measurement. Viscoelasticity measuring devices that can be used An example of this is the MCR302 sold by Anton Paar Japan Co., Ltd.

[0014] Agar is a hydrogel material that dissolves in water when heated above 85°C, becoming a sol, and undergoes a structural transition to a gel when cooled below 45°C. In the sol state, the polymer chains contained in the agar disentangle and dissolve in water, liquefying it. On the other hand, upon cooling, the polymer chains in the agar form a double helix structure, and as cooling progresses, they form even more highly entangled structures, resulting in gelation. Based on this gelation mechanism, the Young's modulus of the ultrasound phantom correlates with the agar concentration and can be adjusted from soft to hard gels. Ultrasound phantoms are required to simulate various organs, and a wide range of Young's moduli is required. Agar can be used effectively to adjust this Young's modulus.

[0015] In the ultrasound phantom, it is preferable that at least a portion of the water is hydrated with the agar, and it is preferable that the agar is gelled. Also, in the ultrasound phantom, it is preferable that the agar forms a hydrogel with at least a portion of the water. That is, it is preferable that the ultrasound phantom is in a hydrogel state. The water content of the ultrasound phantom is, for example, preferably 50.00 mass% or more and 99.50 mass% or less, more preferably 70.00 mass% or more and 99.00 mass% or less, even more preferably 80.00 mass% or more and 98.00 mass% or less, and even more preferably 80.00 mass% or more and 95.00 mass% or less. The ultrasound phantom may contain a thickening polysaccharide, a water retention aid, etc. in the hydrogel formed by water and agar.

[0016] The amount or content of agar is preferably 0.25 to 20.00 parts by mass when the total mass of water and water retention aid is 100.00 parts by mass, and in order to obtain a uniform phantom free of bubbles, etc., it is preferably 0.50 to 10.00 parts by mass, more preferably 1.00 to 10.00 parts by mass, even more preferably 1.25 to 10.00 parts by mass, and even more preferably 1.50 to 10.00 parts by mass.

[0017] By adjusting the amount within the above range, ultrasound phantoms with various Young's moduli can be produced. By using an amount of 0.25 parts by mass or more, gelation occurs more easily when cooled. On the other hand, by using an amount of 10.00 parts by mass or less, the viscosity of the agar melted by heating is appropriate, making it easier to obtain a more uniform ultrasound phantom.

[0018] <Thickening polysaccharide (B)> The ultrasound phantom contains a thickening polysaccharide (B) different from agar (A). The thickening polysaccharide does not have a phase transition point at which an aqueous solution of the thickening polysaccharide gels upon decreasing temperature within a temperature range from the second phase transition point to the first phase transition point. The aqueous solution of the thickening polysaccharide is a second aqueous dispersion in which the thickening polysaccharide is dispersed in water, which is then converted into a sol upon increasing temperature. Specifically, the temperature at which an aqueous dispersion of 1.0% by mass of agar (A) dispersed in water dissolves in water and turns into a sol when the temperature is raised from room temperature is defined as the first phase transition point, and the temperature at which an aqueous solution of the solated agar turns into a gel when the aqueous solution is left at room temperature and cooled is defined as the second phase transition point. The thickening polysaccharide (B) is preferably a thickening polysaccharide that does not have a sol-to-gel phase transition point in a temperature range from the second phase transition point to the first phase transition point in a 1.0% by mass aqueous dispersion of the thickening polysaccharide.

[0019] A 1.0% by mass aqueous dispersion of a thickening polysaccharide preferably does not have a sol-to-gel phase transition point in the temperature range of 10°C to 95°C, more preferably does not have a sol-to-gel phase transition point in the temperature range of 5°C to 99°C, and even more preferably does not have a sol-to-gel phase transition point in the temperature range of 0°C to 100°C. "Not having a phase transition point in the above temperature range" means that there is no sol-to-gel phase transition point when the temperature is increased from the lower limit of the above temperature range, and when the temperature is decreased from the upper limit of the above temperature range. In the present specification, when expressing the concentration of an aqueous dispersion or aqueous solution, 1.0 mass % is expressed as a weighted concentration of 0.95 mass % or more and 1.04 mass % or less.

[0020] The inventors believe that the fact that the thickening polysaccharide (B) does not have the above-mentioned phase transition point indicates that the thickening polysaccharide has fluidity in the above temperature range in the ultrasound phantom. That is, the thickening polysaccharide preferably exists in a sol state in the above temperature range. Because the thickening polysaccharide is a sol (fluid) in the above temperature range, it is thought that the fluid thickening polysaccharide is uniformly dispersed in the sol-state agar by heating.

[0021] The thickening polysaccharide to be used may be one whose gelation factor is not dependent on temperature changes within the above temperature range. The thickening polysaccharide (B) is preferably a water-soluble thickening polysaccharide. The thickening polysaccharides described below may be used alone or in combination. When using a mixture of multiple thickening polysaccharides, a combination that does not have a sol-to-gel phase transition point within the above temperature range should be selected.

[0022] The inventors' investigations have revealed that when using agar gel as an ultrasound phantom, it is necessary to improve its brittleness and suppress syneresis. This is presumably because the gel tissue that constitutes the agar phantom breaks down due to the repeated pressure when an ultrasound probe is pressed against the agar phantom. Since the thickening polysaccharide does not have the aforementioned phase transition point, the thickening polysaccharide (B) has fluidity and viscosity in the hydrogel of agar and water in the ultrasound phantom, which is thought to improve brittleness. This makes the ultrasound phantom less likely to break when the probe is pressed against it, making it possible to use it repeatedly.

[0023] The thickening polysaccharide is not particularly limited as long as it does not have the above-mentioned phase transition point, and known thickening polysaccharides can be used. Thickening polysaccharides are those formed by glycosidic bonds of monosaccharides such as aldose monosaccharides typified by glucose, galactose, mannose, xylose, etc., or derivatives of aldose monosaccharides such as glucuronic acid and deoxysugars.

[0024] The thickening polysaccharide preferably has a side chain, and is preferably a thickening polysaccharide having at least one selected from the group consisting of a sugar chain selected from monosaccharides (such as aldose monosaccharides or derivatives thereof) and derivatives thereof, and polysaccharides and derivatives thereof, and a carboxymethyl group, a salt of a carboxymethyl group, a carboxy group, and a salt of a carboxy group, bound as a side chain.

[0025] When the side chain is a polysaccharide, the polysaccharide side chain includes a saccharide that generates two or more molecules of monosaccharides upon hydrolysis. Preferred examples of thickening polysaccharides having side chains include guar gum, diutan gum, xanthan gum, cellulose derivatives, etc. For example, sodium salt of carboxymethyl cellulose is a cellulose derivative having a sodium salt of a carboxymethyl group in the side chain.

[0026] The derivatives in the monosaccharide derivatives and polysaccharide derivatives include derivatives in which the hydroxyl group of the monosaccharide or polysaccharide is substituted with at least one group selected from the group consisting of a hydroxypropyl group, a hydroxypropyltrimonium chloride group, a carboxymethyl group, a salt of a carboxymethyl group, a phosphate group, a hydroxyethyl group, a hydroxypropylmethyl group, etc. Preferably, the group consisting of a hydroxypropyl group, a carboxymethyl group, or a salt of a carboxymethyl group is substituted. and derivatives substituted with at least one selected from the group consisting of: Examples of the salt include sodium salts, potassium salts, and ammonium salts, with sodium salts being preferred.

[0027] These polysaccharides with side chains tend to have a high 1.0% mass viscosity, which is the viscosity value when dissolved in water at 1.0% mass. This is thought to be due to the high affinity of the sugars and carboxyl groups in the side chains with water. Therefore, adding a small amount can further improve the brittleness of ultrasound phantoms. The 1.0% mass viscosity value of thickening polysaccharides is preferably 100 mPa·s or more and 10,000 mPa·s or less, more preferably 200 mPa·s or more and 9,000 mPa·s or less, and even more preferably 300 mPa·s or more and 8,000 mPa·s or less. The 1.0% mass viscosity value can be measured using a rotational viscometer. The viscosity in this case was measured using a dynamic viscoelasticity measuring device, MCR302, available from Anton Paar Japan Co., Ltd., using a 25 mm diameter parallel plate. The measurement was performed at a rotational speed of 5 ( / s).

[0028] Examples of thickening polysaccharides include at least one selected from the group consisting of xanthan gum, tamarind seed gum, galactomannans (locust bean gum, tara gum, guar gum, etc.), succinoglycan, diutan gum, and derivatives thereof, and cellulose derivatives. The thickening polysaccharide is preferably at least one selected from the group consisting of locust bean gum, tara gum, guar gum, xanthan gum, diutan gum, and derivatives thereof, and cellulose derivatives, and more preferably at least one selected from the group consisting of guar gum, xanthan gum, diutan gum, and derivatives thereof, and cellulose derivatives.

[0029] As with the above, the derivatives of these thickening polysaccharides include derivatives in which the hydroxyl group is substituted with at least one group selected from the group consisting of a hydroxypropyl group, a hydroxypropyltrimonium chloride group, a carboxymethyl group, a salt of a carboxymethyl group, a phosphate group, a hydroxyethyl group, a hydroxypropylmethyl group, etc. Preferred are derivatives in which the hydroxyl group is substituted with at least one group selected from the group consisting of a hydroxypropyl group, a carboxymethyl group, and a salt of a carboxymethyl group. Hydroxypropyl guar is preferred as the guar gum derivative. The presence of the derivative group makes it easier to disentangle the entangled main chain of the thickening polysaccharide (B), improving the solubility and enabling the production of a uniform sol solution.

[0030] The cellulose derivative is preferably at least one selected from the group consisting of carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, and hydroxypropyl methyl cellulose, and salts thereof. Examples of the salt include sodium salts, potassium salts, and ammonium salts, with sodium salts being preferred. In addition to the above, polysaccharides having side chains modified with carboxy groups can also be used. For example, sodium carboxymethylcellulose is more preferred.

[0031] The amount or content of the thickening polysaccharide is preferably 0.50 parts by mass or more and 2.00 parts by mass or less when the total mass of the water and the water retention aid is 100.00 parts by mass. If the thickening polysaccharide is 0.50 parts by mass or more, the brittleness of the phantom can be further improved. Furthermore, by thickening the water contained in the ultrasound phantom, sedimentation of each component can be suppressed. If the thickening polysaccharide is 2.00 parts by mass or less, the viscosity is suitable and handling becomes good. The amount or content of the thickening polysaccharide is more preferably 0.50 parts by mass or more and 1.00 parts by mass or less when the total mass of the water and the water retention aid is 100.00 parts by mass.

[0032] <Moisture retention aid (C)> In order to delay the water separation of the hydrogel, the ultrasound phantom contains a water retention aid other than agar and thickening polysaccharides. The water retention aid is a compound that has the effect of suppressing the evaporation of water. The water retention aid is preferably a water-soluble or water-miscible substance. The water retention aid has a polarization term δP of 13.0 MPa in the HSP (Hansen solubility parameter). 0.5 Use the above.

[0033] The Hansen solubility parameters can be calculated using computer software "Hansen Solubility Parameters in Practice (HSPiP)" and can be determined using known methods. The Hansen solubility parameters in this specification are values ​​calculated using HSPiP version 5.3.05.

[0034] The polarization term δP in the Hansen solubility parameter of the water retention aid (C) is 14.0 MPa 0.5 It is preferable that the pressure is 16.0 MPa or more. 0.5 More preferably, it is 18.0 MPa or more. 0.5 The upper limit is not particularly limited, but is preferably 30.0 MPa. 0.5 or less, and more preferably 25.0 MPa 0.5 More preferably, it is 22.0 MPa or less. 0.5 or less, and even more preferably 20.0 MPa or less 0.5 The inventors' investigations have revealed that the polarization term component ΔP has a higher correlation coefficient with the stable water retention rate than other HSP components.

[0035] Compounds with the above-mentioned effects are sometimes collectively referred to as chaotropic agents. The water retention aid preferably contains a chaotropic agent. A chaotropic agent has the effect of changing the interaction between water molecules in an aqueous solution. By adding a compound with a polarization term dP in the above range as a water retention aid, the interaction between water molecules changes and the water molecules can be strongly attracted. The degree of such interaction is expressed by the polarization term δP, and by using a compound with this value in the above range as a water retention aid (C), it is possible to achieve stability over time as a phantom.

[0036] The inventors' studies have revealed that phantoms made from agar exhibit large changes in water content. Water seeping out of the phantom changes the acoustic characteristics related to ultrasound propagation. Therefore, even if a phantom is created that is adjusted to match the acoustic characteristics of the human body, the characteristics are likely to change over time, and only approximate values ​​can be obtained. Even if the surface of the phantom is covered with a film or other material to prevent evaporation, it is difficult to reduce water seepage (syringe) from the phantom. By using a water retention aid, the water retention aid strongly attracts water molecules, suppressing syneresis and improving stability over time.

[0037] The water retention aid (C) is not particularly limited as long as it satisfies the above polarization term ΔP. For example, the water retention aid can be at least one selected from the group consisting of inositols such as myo-inositol, dimethyl sulfoxide (DMSO), urea, guanidine and guanidine salts, and derivatives thereof. Furthermore, derivatives thereof such as methylated, dimethylated, ethylated, and diethylated derivatives can also be used. The water retention aid (C) preferably contains at least one selected from the group consisting of inositol, dimethyl sulfoxide, and urea.

[0038] The content of the water retention aid in the ultrasound phantom is preferably 1% by mass or more, based on the total mass of water and the water retention aid. This provides a sufficient water retention effect and further suppresses water seepage. The content of the water retention aid is preferably 1.00% by mass or more and 15.00% by mass or less, more preferably 2.00% by mass or more and 10.00% by mass or less, and even more preferably 4.00% by mass or less, based on the total mass of water and the water retention aid. % by mass or more and 8.00% by mass or less.

[0039] Furthermore, since the water retention aid changes the interaction with water, it may change the speed of ultrasound. Since the speed of sound in biological organs is approximately 1535 (m / s), it is sufficient to add it within a range that does not deviate significantly from this value. For example, when ultrasound with a frequency of 3.5 MHz is transmitted through an ultrasound phantom, the speed of the ultrasound is preferably 1525 m / s or more and 1545 m / s or less, more preferably 1528 m / s or more and 1540 m / s or less, and even more preferably 1530 m / s or more and 1537 m / s or less.

[0040] <Other ingredients (D)> Various other components other than agar, thickening polysaccharides, and water retention aids can be added to the ultrasound phantom as needed. For example, the ultrasound phantom may further contain an ultrasound scattering agent. In ultrasound diagnostic devices, images are captured and measured using signals from ultrasound scattered within the phantom that reach the detector. Therefore, adding an ultrasound scattering agent to the part to be measured makes it possible to capture images and measure Young's modulus.

[0041] The scattering efficiency of ultrasound is calculated by the acoustic impedance of the material (= density x sound speed). At the material interface, the scattering efficiency is higher the greater the difference in this value.

[0042] Examples of solid particles that can be used as ultrasound scattering agents include well-known ones such as metals, metal oxides, carbon particles, and spherical polymers. There are no particular limitations on the material of the ultrasound scattering agent, as long as it is a solid with low water solubility. From the perspective of mechanical stability, preferred are carbon crystal particles such as graphite and microdiamond, resin particles such as polyethylene particles, polyethylene hollow spheres, and polystyrene hollow spheres, oxide microparticles such as titanium oxide, alumina oxide, and silicon oxide, and metal microparticles such as tungsten, nickel, and molybdenum. Among these, carbon crystal particles are particularly preferred, taking into account the magnitude of acoustic impedance and dispersibility in water.

[0043] The particle size of the ultrasound scattering agent is determined according to the wavelength of the input ultrasound. When calculated from the wavelength of the ultrasound emitted from the probe of the ultrasound diagnostic device, the particle size of the ultrasound scattering agent is preferably 5 μm or more and 50 μm or less, and more preferably 5 μm to 25 μm.

[0044] However, particles with a particle size of 5 μm or more and high density generally have a high settling velocity, and may separate during the process of agar-agar gelling from a sol. The settling velocity can be calculated using the following Stokes' equation: V=g(ρs-ρ0)d2 / 18η V: Sedimentation velocity, g: Gravitational acceleration, ρs: Particle density, ρ0: Solvent density, d: Particle diameter, η: Solvent viscosity) By adding the thickening polysaccharide (B), the value of η in the Stokes' equation can be increased, thereby delaying the settling of the ultrasound scattering agent.

[0045] The content of the ultrasonic scattering agent can be adjusted appropriately depending on the target scattering effect and is not particularly limited, but when the total mass of water and water retention aid is 100.00 parts by mass, it is preferably 0.50 parts by mass to 20.00 parts by mass, more preferably 1.00 parts by mass to 10.00 parts by mass, and even more preferably 2.00 parts by mass to 7.00 parts by mass.

[0046] The ultrasound phantom may also contain a preservative as another component. Hydrogels are generally prone to mold, so when used for calibration, it is preferable to use a preservative to suppress the effect on physical properties. There are no particular restrictions on the preservatives that can be used, but it is preferable to use one that is water-soluble and has a wide antibacterial spectrum.

[0047] Compounds that can inhibit mold growth include preservatives, disinfectants, and antibacterial agents, such as alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, and benzyl alcohol.

[0048] Among these, parahydroxybenzoic acid esters are preferred because they are water-soluble, have a wide antibacterial spectrum, and are particularly preferred for their minimal effect on the human body. Furthermore, methyl parahydroxybenzoate is particularly preferred from the viewpoint of water solubility.

[0049] For example, in the case of methyl parahydroxybenzoate, if the total mass of water and water retention aid is 100.00 parts by mass, 0.20 to 0.30 parts by mass should be added, and the saturation amount of 0.25 parts by mass is preferred. This ensures sufficient preservative effect.

[0050] The method for producing an ultrasound phantom is not particularly limited. Water, agar, a polysaccharide thickener, and a water-retention aid, as well as other ingredients such as an ultrasound scattering agent and a preservative, if necessary, are mixed. The mixture is then heated to a temperature above the first phase transition point at which the agar dissolves in water (e.g., 85°C to 99°C), dissolving the agar in water to obtain a solution. If necessary, the mixture is stirred or heated until the distribution of the components in the solution becomes uniform. The distribution of the components in the solution includes an equilibrium state in which the components are macroscopically uniformly dispersed in the solvent, and an equilibrium state in which the components are microscopically uniformly dissolved in the solvent at the molecular level. The former includes an ultrasound scattering agent and a preservative, while the latter includes agar, a polysaccharide thickener, and a water-retention aid. The resulting mixture is poured into a mold of the desired shape and cooled to a temperature below the second phase transition point at which the agar gels, to obtain an ultrasound phantom.

[0051] That is, the method for producing an ultrasound phantom preferably includes a step of obtaining an ultrasound phantom by cooling a mixture containing water, agar, a thickening polysaccharide, and a water-retention aid, in which the agar is dissolved in water, to a temperature at which the agar gels, thereby obtaining an ultrasound phantom containing a hydrogel containing water, agar, a thickening polysaccharide, and a water-retention aid.

[0052] Furthermore, the method for manufacturing an ultrasound phantom preferably includes the following steps. a step of heating a mixture of water and agar (and a preservative if necessary) to a temperature (first phase transition point) at which the agar dissolves in water, thereby obtaining a solution A in which the agar is dissolved in water; A step of mixing water and a water retention aid to obtain an aqueous solution of the water retention aid, and then mixing a thickening polysaccharide (and an ultrasonic scattering agent, if necessary) to obtain a solution B; A process in which the obtained liquids A and B are mixed and the obtained mixture is cooled to obtain an ultrasound phantom.

[0053] The step of obtaining liquid A and the step of obtaining liquid B may be carried out in either order, or both may be carried out simultaneously. After mixing liquid B, the temperature may be raised. The temperature of liquid B may be raised to a level that reduces the temperature difference between liquid A and liquid B, and it is preferable to heat to a temperature around the first phase transition point (for example, 85°C or higher and 99°C or lower). It is preferable that liquid A and liquid B are mixed uniformly in the container. Mixing is preferably carried out while maintaining a temperature of 85°C or higher and 99°C or lower.

[0054] The resulting mixture is poured into a mold of a desired shape as needed, and heated to a temperature below the second phase transition point ( The agar gels when cooled to room temperature, for example, and an ultrasound phantom can be obtained. The cooling method is not particularly limited, and the agar may be left at room temperature or may be cooled using a desired medium such as water.

[0055] The Young's modulus E of the ultrasound phantom measured using a viscoelasticity measuring device is preferably 50 kPa or more and 2000 kPa or less, more preferably 100 kPa or more and 1500 kPa or less, and even more preferably 120 kPa or more and 1000 kPa or less. The hardness can be adjusted by adjusting the concentration of agar, etc. The ultrasound phantom can have a constant sound speed close to the sound speed in a living body, regardless of hardness.

[0056] The ultrasound phantom can be used as an ultrasound examination phantom for calibration of an ultrasound diagnostic device, such as an ultrasound elastography device, for calculating the accurate Young's modulus of an organ. [Example]

[0057] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. In the following formulations, parts are by weight unless otherwise specified.

[0058] <Material> The materials used in the examples and comparative examples are listed below. [Gelling agent (A)] A-1: Agar; "Agar, powder (Kishida Chemical Co., Ltd.)" [Thickening polysaccharide (B)] B-1: Hydroxypropyl guar; "ESAFLOR4W (Sansho Co., Ltd.)" B-2: Xanthan gum; "Kelzan(R)AP (Sansho Co., Ltd.)" B-3: Diutan gum; "Kercovis DG (Sansho Co., Ltd.)" B-4: Carboxy-modified cellulose; "CEKOL 30000 (Sansho Co., Ltd.)" These are thickening polysaccharides that do not have a sol-to-gel phase transition point in the above-mentioned temperature range. [Water retention aid (C)] C-1: Urea (Kishida Chemical Co., Ltd.) C-2: Dimethyl sulfoxide (DMSO) (Tokyo Chemical Industry Co., Ltd.) C-3: myo-inositol (Tokyo Chemical Industry Co., Ltd.) C-4: Glycerin (Kishida Chemical Co., Ltd.) C-5: Mannitol (Tokyo Chemical Industry Co., Ltd.) [Other ingredients (D)] D-1: Graphite; "Nicabeads(R) ICB1020 (Nippon Carbon Co., Ltd.)" D-2: Methyl parahydroxybenzoate (Kishida Chemical Co., Ltd.)

[0059] <Evaluation method> [Separation rate] The ultrasound phantom was stored in a sealed container with a certain amount of space, and the water separation rate was evaluated by measuring the mass loss rate due to water evaporation or seepage after 24 days. 3 An ultrasound phantom with a diameter of 30 mm and a thickness of 5 mm was placed in the space and stored in a refrigerator (approximately 4°C) for 24 days. A sample without any water retention aid was used as a reference example, and samples with a decreased water separation rate were marked with a 〇, and samples with an increased water separation rate were marked with an ×.

[0060] [Fragility] When the probe is pressed against the ultrasound phantom by hand, a large force is unintentionally applied, and the ultrasound The phantom may be damaged. The fragility of the ultrasound phantom was verified by imitating the compression caused by pressing a jig against the probe. A compression test was performed using a universal testing machine (RTF-1250, manufactured by A&D Co., Ltd.). An ultrasound phantom with a diameter of 30 mm and a thickness of 50 mm was prepared and compressed at a rate of 2 mm / min. Japanese Patent No. 5787286 discloses the relationship between the force and organ deformation when an ultrasound probe is pressed against a living body. In elastography using an ultrasound diagnostic device, the Young's modulus of the organ itself is quantitatively measured, so it is rare for the probe to be pressed strongly, but it is expected that a force of 500 gf to 1000 gf will be applied. In the brittleness test, an SS curve was drawn in the compression test, and if an inflection point or yield point was observed at a compressive stress of 30 kPa or less, it was considered to be internal collapse, with those with internal collapse being marked with × and those without internal collapse being marked with ◯.

[0061] Young's Modulus Measurements were performed using a viscoelasticity measuring device (MCR302, manufactured by Anton Paar Japan Co., Ltd.) to determine the storage modulus G'. The storage modulus was measured using a cylindrical ultrasound phantom made with a diameter of 30 mm and a thickness of 5 mm. A parallel plate with a diameter of 25 mm was placed in contact with the top of the ultrasound phantom and vibrated to measure the storage modulus G'. The Young's modulus E of the ultrasound phantom is calculated from the storage modulus G' using the Poisson's ratio ν according to the following formula: E=G'·2(1+ν) Because the volume change of the ultrasound phantom during measurement is small, we can assume that the Poisson's ratio is ν = 0.5. From this, E = 3·G', and the Young's modulus E was obtained by multiplying the value of the storage modulus G' by three.

[0062] [Speed ​​of sound] The speed of sound was measured by measuring the time it took for ultrasound to pass through the ultrasound phantom. A jig was used to fix the transducer (V328-SU, Olympus Corporation) with a measurement frequency of 3.5 MHz and a needle-type hydrophone (Toray Engineering D Solutions Co., Ltd.) in water so that the incident angle of the ultrasound signal was 0°. Two types of ultrasound phantom test pieces, 100mm long x 100mm wide and 5mm and 10mm thick, were placed as described above, and a three-cycle sine wave generated by the waveform generator was emitted from the ultrasound oscillator, and the waveform data received by the ultrasound receiver was measured using an oscilloscope. The sound velocity was calculated by averaging the values ​​at thicknesses of 5 mm and 10 mm.

[0063] <How to create an ultrasound phantom> [Manufacturing example] As an example of the manufacturing procedure for an ultrasound phantom, the manufacturing procedure for Example 1 will be described. In other examples and manufacturing examples, this procedure was not changed, and phantoms were manufactured by changing only the type and amount of materials according to the formulations in Tables 1, 2, and 3. The phantom was manufactured by mixing the formulations of Adjustment Solution A, which adjusts the gelling agent, and Adjustment Solution B, which adjusts the water retention aid.

[0064] (Adjustment solution A) 250 g (50.00 parts) of ion-exchanged water, 14.4 g (2.88 parts) of agar, and 1.25 g (0.25 parts) of methyl parahydroxybenzoate were placed in a sealed container and heated in a heating oven at 90°C for 4 hours.

[0065] (Adjustment solution B) A 12% urea solution was prepared by dissolving 220 g (44.00 parts) of ion-exchanged water and 30 g (6.00 parts) of urea in a sealed container. 3.75 g (0.75 parts) of hydroxypropyl guar was added and dissolved. 20 g (4.00 parts) of graphite was then added, thoroughly stirred, and heated in a 90°C oven for 1 hour.

[0066] While Adjustment Solution A and Adjustment Solution B were heated to 90°C, they were mixed so that the amount of ion-exchanged water in Adjustment Solution A and the amount of urea water in Adjustment Solution B were equal, depending on the ratio of their respective components. After stirring for 2 minutes, the mixture was poured into a mold and cooled to obtain an ultrasound phantom.

[0067] [Table 1] In Tables 1, 2, and 3, the numbers for each material indicate the number of parts.

[0068] The results of the water release test are shown in Table 1. The Reference Example, which did not contain a water retention aid, released 19.2% by mass of water in 24 days. On the other hand, Comparative Examples 1 and 2 are examples in which a polyhydric alcohol, which is generally used to adjust the speed of sound, was added. The ΔP values ​​(MPa) of glycerin (Comparative Example 1) and mannitol (Comparative Example 2) 0.5) were 12.7 and 11.2, respectively, both of which were below 13.0. In these cases, the syneresis rate was higher than that of the Reference Example. On the other hand, in Examples 1, 2, and 3, where the ΔP values ​​of the water retention aids were greater than 13.0, the syneresis rate was significantly improved compared to the Reference Example.

[0069] [Table 2]

[0070] In Comparative Example 3, in which no thickening polysaccharide was added, internal collapse was observed at 30 kPa or less. On the other hand, in Examples 4 to 7, in which thickening polysaccharide was added, no internal collapse was observed, and ultrasound phantoms with improved brittleness were obtained.

[0071] [Table 3]

[0072] In Examples 8 to 14, a calibration curve for Young's modulus was prepared, and ultrasound phantoms were obtained by adjusting the concentration of agar (A). Both syneresis and brittleness were improved in all ultrasound phantoms. Furthermore, all Examples had a sound velocity close to the sound velocity in living tissue (1535 m / s), making them suitable for use in calibrating ultrasound diagnostic equipment. As described above, the present disclosure has made it possible to obtain a phantom that significantly improves upon the issues with conventional agar phantoms.

Claims

1. An ultrasound phantom, The ultrasound phantom comprises: water, Agar, thickening polysaccharides, and Contains moisture-retaining aids, the agar forms a hydrogel with the water, the thickening polysaccharide and the water retention aid are dispersed in the hydrogel; a first phase transition point is a temperature at which the aqueous dispersion of agar turns into a sol by increasing the temperature, and a second phase transition point is a temperature at which the aqueous solution of the solated agar dispersion turns into a gel by decreasing the temperature, the thickening polysaccharide is in a sol state in a temperature range from the second phase transition point to the first phase transition point, and does not have a phase transition point at which an aqueous solution of the thickening polysaccharide turns into a gel by decreasing the temperature; The polarization term δP of the Hansen solubility parameter of the water retention aid is 13.0 MPa ０．５ That's all Ultrasound phantom.

2. the first phase transition point is in the range of 85°C to 99°C, The ultrasound phantom according to claim 1 , wherein the second phase transition point is between 30° C. and 45° C.

3. The aqueous dispersion of agar is prepared by dispersing agar in water, 3. The ultrasound phantom according to claim 1, wherein the aqueous solution of the thickening polysaccharide is a second aqueous dispersion in which the thickening polysaccharide is dispersed in water, and the second aqueous dispersion is converted into a sol by heating.

4. the first phase transition point is a temperature at which the aqueous dispersion of agar turns into a sol when the temperature of the aqueous dispersion of agar is increased; 4. The ultrasound phantom according to claim 3, wherein the second phase transition point is a temperature at which the solated aqueous solution gels when cooled.

5. 5. The ultrasound phantom according to claim 1, wherein the aqueous solution of the thickening polysaccharide does not have a sol-to-gel phase transition point in the temperature range.

6. 6. The ultrasound phantom according to claim 1, wherein the water retention aid contains a chaotropic agent.

7. 7. The ultrasound phantom according to claim 1, wherein the water retention aid comprises at least one selected from the group consisting of inositol, dimethyl sulfoxide, and urea.

8. The thickening polysaccharide is A sugar chain selected from monosaccharides and derivatives thereof, and polysaccharides and derivatives thereof; and The ultrasound phantom according to any one of claims 1 to 7, wherein at least one selected from the group consisting of a carboxymethyl group, a salt of a carboxymethyl group, a carboxy group, and a salt of a carboxy group is bonded as a side chain.

9. The ultrasound phantom according to any one of claims 1 to 8, wherein the thickening polysaccharide comprises at least one selected from the group consisting of xanthan gum, tamarind seed gum, galactomannan, succinoglycan, and diutan gum, and derivatives thereof, and cellulose derivatives.

10. The ultrasound phantom according to any one of claims 1 to 9, wherein the thickening polysaccharide comprises at least one selected from the group consisting of guar gum, xanthan gum, diutan gum, and derivatives thereof, and cellulose derivatives.

11. The ultrasound phantom according to any one of claims 1 to 10, further comprising an ultrasound scattering agent.

12. The ultrasound phantom according to any one of claims 1 to 11, further comprising an antiseptic.

13. The ultrasound phantom according to any one of claims 1 to 12, wherein the content of the agar is 0.25 parts by mass or more and 20.00 parts by mass or less when the total mass of the water and the water retention aid is 100.00 parts by mass.

14. The ultrasound phantom according to any one of claims 1 to 13, wherein the content of the thickening polysaccharide is 0.50 parts by mass or more and 2.00 parts by mass or less when the total mass of the water and the water retention aid is 100.00 parts by mass.

15. 15. The ultrasound phantom according to any one of claims 1 to 14, wherein the content of the water retention aid is 1.00 mass % or more and 15.00 mass % or less, based on the total mass of the water and the water retention aid.

16. A method for manufacturing an ultrasound phantom according to any one of claims 1 to 15, A method for manufacturing an ultrasound phantom, comprising a step of cooling a mixed liquid containing the water, the agar, the thickening polysaccharide, and the water retention aid, in which the agar is dissolved in the water, to a temperature at which the agar gels, to obtain an ultrasound phantom.

17. A method for preparing a hydrogel comprising: water; agar that forms a hydrogel together with said water; a thickening polysaccharide that is dispersed in said hydrogel and thickens said hydrogel; and a thickening polysaccharide that is dispersed in said hydrogel and thickens said hydrogel. and a water retention aid that suppresses water separation from the ultrasound phantom, The thickening polysaccharide is a fluid that does not have a phase transition point at which an aqueous solution of the thickening polysaccharide gels upon temperature decrease in a temperature range from the second phase transition point to the first phase transition point, where the temperature at which the aqueous dispersion of the agar soli is converted into a sol upon temperature increase is defined as a first phase transition point and the temperature at which the aqueous solution of the soli is converted into a gel upon temperature decrease is defined as a second phase transition point, The water retention aid has a polarization term δP of the Hansen solubility parameter of 13.0 MPa 0.5 or more.

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