Hydrogel production method, hydrogel production device, hydrogel, and elastography evaluation phantom containing hydrogel

Abstract

Provided is a hydrogel which has high homogeneity and in which a three-dimensional network structure is formed with covalent bonds, a production method therefor, a production device therefor, and an elastography evaluation phantom containing the hydrogel.　In production of a hydrogel which has high homogeneity and in which a three-dimensional network structure is formed with covalent bonds, a solution obtained by adding, to a solvent, at least a starting material monomer of the hydrogel, a crosslinking agent, and a polymerization initiator is stirred, and the stirring is stopped in response to detection of a drastic temperature change of the solution.

Description

Hydrogel preparation method, hydrogel preparation device, hydrogel, and hydrogel-containing phantom for elastography evaluation

[0001] The present invention relates to a hydrogel production method for producing a hydrogel, a hydrogel production device, a hydrogel, and a phantom for elastography evaluation containing the hydrogel.

[0002] Because there is a correlation between disease and functional disorders and the stiffness (viscoelasticity) of biological tissues, measurements such as viscoelastic modulus are used for staging and other purposes. While invasive methods are the mainstream for quantitatively measuring the viscoelasticity of biological tissues, they not only place a significant burden on patients, but also present the risk of damaging the physical properties of tissues by removing them from the body. Therefore, elastography (a viscoelasticity measurement method) has been proposed as a non-invasive and quantitative method for diagnosing the viscoelastic modulus inside the body.

[0003] The main practical examples of elastography include MRE (MR elastography) using MRI (magnetic resonance imaging) and USE (ultrasound elastography) using ultrasound. Currently, several elastography systems equipped with MRE and USE are commercially available, but the measurement values ​​differ depending on the elastography method, manufacturer, product, etc., and there is a problem that diagnosis cannot be made using the same standard. Standardization of elastography systems requires a reference object that can be used in both MRE and USE systems. Therefore, development of a biological mimetic phantom with material properties similar to those of a living body that meets the standards set by the quantitative imaging biomarkers alliance (QIBA) is underway.

[0004] Hydrogels (chemical gels) with a three-dimensional network structure formed by covalent bonds, such as polyacrylamide gel, are preferably used as materials for biomimetic phantoms for elastography evaluation (see Patent Documents 1 and 2). When used as biomimetic phantoms for USE, such hydrogels have insoluble particles with particle sizes ranging from several tens of nanometers to several hundreds of micrometers dispersed therein as ultrasound scatterers, but when used for MRE, they can be used without the addition of scatterers.

[0005] International Publication No. 2005 / 107599 (pages 4 to 9, Figure 4); Japanese Patent Application Laid-Open No. 2018-41055 (Claims, Examples); Japanese Patent Application Laid-Open No. 61-247440 (page 3, bottom right column, line 3 from the bottom to page 4, top left column, line 3)

[0006] Examples of methods for manufacturing biomimetic phantoms using chemical gels include, for example, a method described in Patent Document 1, in which a solution containing the raw material monomers of the hydrogel and a crosslinker (N,N'-methylenebisacrylamide) is degassed while being stirred, followed by the addition of a polymerization initiator (ammonium persulfate) and a polymerization accelerator (TEMED), and the solution is gently poured into a mold, and the container is cooled to prevent temperature rise due to heat generation associated with the polymerization reaction. Alternatively, for example, a method described in Patent Document 2, in which a solution containing the raw material monomers of the hydrogel and a crosslinker is stirred while the polymerization initiator and polymerization accelerator are added, and the chemical reaction is allowed to proceed while continuing to stir, and after sufficient polymerization is confirmed, the stirring is stopped and the solution is cooled.

[0007] However, as described in Patent Document 3, chemical gels such as polyacrylamide gels tend to become non-homogenized during cross-linking polymerization (gelation), making it particularly difficult to uniformly disperse non-soluble microparticles. Therefore, the method of Patent Document 1 requires that the size of the non-soluble microparticles be limited to those with a specific gravity of 1 to 5 and a diameter of 5 μm or less, limiting the types of biomimetic phantoms that can be produced. Furthermore, as in the method of Patent Document 2, stirring is continued during the chemical reaction, and stirring is stopped when resistance from the solution is felt. However, this is difficult to measure by hand, and the resistance of the solution is often stopped too early to avoid the risk of the reaction proceeding too quickly and causing failure. Therefore, although the hydrogel is homogeneous during stirring and the non-soluble microparticles are uniformly dispersed when they are added, the homogeneity of the hydrogel is lost when stirring is stopped and the non-soluble microparticles precipitate (see Figure 1(b)).

[0008] The present invention was made in response to these problems, and aims to provide a hydrogel production method, a hydrogel production apparatus, a hydrogel, and an elastography evaluation phantom containing said hydrogel, which are capable of producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonds. In particular, the present invention aims to provide a hydrogel production method, a hydrogel production apparatus, a hydrogel, and an elastography evaluation phantom containing said hydrogel, which are capable of producing a highly homogeneous hydrogel in which the amount of precipitation of non-soluble particles, especially microparticles, is reduced, even when said particles are used. Another aim is to provide a hydrogel production method and a hydrogel production apparatus that use an objective indicator for determining when to stop stirring during gelation, and that can be easily automated.

[0009] To solve the above problems, the present invention provides a method for producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonds, the method comprising: stirring a solution containing at least raw material monomers for the hydrogel, a crosslinking agent, and a polymerization initiator in a solvent; and stopping the stirring in response to a sudden change in temperature of the solution. According to this feature, by stopping the stirring in response to a sudden change in temperature of the solution that occurs during gelation, the reaction solution can be stirred until just before gelation, thereby producing a highly homogeneous hydrogel.

[0010] According to another aspect of the present invention, there is provided a method for producing a highly homogeneous hydrogel having a three-dimensional network structure formed by covalent bonds, the method comprising: stirring a solution containing at least raw material monomers for the hydrogel, a crosslinking agent, a polymerization initiator, and non-soluble microparticles in a solvent; and halting the stirring upon detecting a sudden temperature change in the solution. This feature allows the non-soluble microparticles to be uniformly stirred until just before gelation, thereby suppressing precipitation regardless of the type, size, specific gravity, etc. of the non-soluble microparticles, thereby enabling the production of a highly homogeneous hydrogel in which the non-soluble microparticles are uniformly dispersed with high reproducibility and the amount of precipitation is reduced.

[0011] In another aspect of the present invention, the hydrogel is a polyacrylamide polymer. According to this feature, the three-dimensional network structure of the hydrogel made of the polyacrylamide polymer has cross-linking points formed by covalent bonds, resulting in a structurally stable hydrogel.

[0012] In yet another aspect of the present invention, a polymerization accelerator is added to the solution at a predetermined timing, which allows the timing of the rapid temperature change of the solution due to the heat of polymerization, and therefore the timing of the gelation of the solution, to be determined according to the compounding ratio of the materials in the solution, thereby making it possible to obtain a hydrogel with higher reproducibility and higher homogeneity, and also to obtain a hydrogel in which the non-soluble microparticles are uniformly dispersed and the amount of precipitation thereof is reduced.

[0013] In yet another aspect of the present invention, stirring is stopped within 10 seconds from the start of the rapid temperature change of the solution. This feature allows the reaction solution to be stirred until just before gelation, thereby obtaining a highly homogeneous hydrogel. Furthermore, when non-soluble microparticles are added to the solution, the non-soluble microparticles can be uniformly stirred until just before gelation, thereby obtaining a hydrogel in which the non-soluble microparticles are uniformly dispersed and the amount of precipitation is further reduced.

[0014] In yet another aspect of the present invention, the sudden temperature change of the solution is characterized by a gradient of 0.01 to 1.0 (where the vertical axis of the graph represents the liquid temperature (°C) and the horizontal axis represents time (seconds)). According to this feature, in a graph showing the relationship between temperature change and liquid level change accompanying stirring of a solution, a sudden temperature change can be detected by a temperature change such that the gradient of the graph increases from 0.01 to 1.0 when the vertical axis represents the liquid temperature (°C) and the horizontal axis represents time (seconds).

[0015] Another aspect of the present invention provides a hydrogel preparation apparatus for preparing a highly homogeneous hydrogel having a three-dimensional network structure formed by covalent bonds. The apparatus includes: a stirring means capable of stirring a solution containing at least the raw material monomers of the hydrogel, a crosslinking agent, and a polymerization initiator in a solvent; a control unit for controlling the stirring means; a temperature measuring means capable of measuring the temperature of the solution; and a temperature change detecting means capable of detecting a sudden change in the temperature of the solution. The control unit is characterized by stopping the stirring of the solution by the stirring means in response to a sudden change in the temperature of the solution detected by the temperature change detecting means. According to this feature, by stopping the stirring in response to a sudden change in the temperature of the solution without overlooking the short-term change from a sudden change in the temperature of the solution that occurs during gelation to gelation, non-soluble particles in the solution can be uniformly stirred until just before gelation, thereby producing a highly homogeneous hydrogel. Furthermore, since the stirring can be stopped based on a measurable temperature change as an indicator, the apparatus can be easily automated. In particular, the control unit can be configured to perform optimal control using known methods such as machine learning.

[0016] A hydrogel according to another aspect of the present invention is a hydrogel whose main component is a polyacrylamide polymer, whose upper density is in a ratio of 0.985 to 1.000 relative to the lower density, and whose three-dimensional network structure is formed by covalent bonds.

[0017] In yet another aspect of the present invention, the phantom contains insoluble particles, and the insoluble particles are at least one selected from aluminum oxide, titanium oxide, silicon oxide, tungsten, nickel, molybdenum, polyethylene, polystyrene, and graphite powder. This feature allows various types of insoluble particles to be added depending on the phantom specifications, making it usable as a dual-purpose phantom for MRE and USE.

[0018] In yet another aspect of the present invention, the non-soluble microparticles at the bottom are more distributed in the inner diameter portion than in the outer diameter portion, resulting in a hydrogel in which the non-soluble microparticles at the bottom are uniformly dispersed and the amount of sedimentation is further reduced.

[0019] In yet another aspect of the present invention, a phantom for elastography evaluation according to another aspect of the present invention is characterized by containing the hydrogel. With this feature, the hydrogel has high homogeneity and can satisfy the standards required for standardization of elastography systems.

[0020] 1A is a schematic diagram showing a hydrogel of the present invention in which non-soluble microparticles are uniformly dispersed, and FIG. 1B is a schematic diagram showing a conventional hydrogel in which non-soluble microparticles have precipitated, impairing uniformity. It is a schematic diagram showing the basic structure of a polyacrylamide gel as an example of a hydrogel according to an embodiment of the present invention. It is a schematic diagram showing changes in liquid level during stirring of a solution according to an embodiment of the present invention. It is a schematic diagram showing a hydrogel stirring device according to an embodiment of the present invention. It is a photograph showing the shape of an inclined blade turbine-type stirring blade according to an embodiment of the present invention. It is a schematic diagram showing a modified example of a hydrogel stirring device according to an embodiment of the present invention. It is a diagram showing the relationship between temperature change and liquid level change during stirring of solution A-1 in Example 1 of the present invention. It is a diagram showing the relationship between temperature change and liquid level change during stirring of solution A-2 in Example 1. It is a diagram showing the relationship between temperature change and liquid level change during stirring of solution A-3 in Example 1. It is a diagram showing the temperature change during stirring of solutions B-1, B-2, and B-3 in Example 2 of the present invention. It is a diagram showing the temperature change during stirring of solutions L and H in Example 3 of the present invention. (a) is a cross-sectional photograph showing the precipitation of a hydrogel obtained by a conventional hydrogel preparation method, and (b) is a cross-sectional photograph showing the precipitation of a hydrogel obtained by the hydrogel preparation method of the present invention. (a) is a photograph showing the precipitation of non-soluble microparticles at the bottom of a hydrogel obtained by the conventional hydrogel preparation method, and (b) is a photograph showing the precipitation of non-soluble microparticles at the bottom of a hydrogel obtained by the hydrogel preparation method of the present invention. (a) is an MRI image obtained by MRI analysis of a hydrogel obtained by the conventional hydrogel preparation method, and (b) is an MRI image obtained by MRI analysis of a hydrogel obtained by the hydrogel preparation method of the present invention. (a) is a diagram showing the results of density comparison in regions approximately 1 cm thick above and below the MRI image of a hydrogel obtained by the conventional hydrogel preparation method, and (b) is a diagram showing the results of density comparison in regions approximately 1 cm thick above and below the MRI image of a hydrogel obtained by the hydrogel preparation method of the present invention.

[0021] Hereinafter, embodiments of the present invention will be described. However, the present invention can be embodied in many different forms and is not limited to the following embodiments and examples.

[0022] The hydrogel production method and hydrogel production apparatus according to the present embodiment can produce highly homogeneous hydrogels that can be used as phantoms for elastography evaluation using magnetic resonance imaging (MRI) or ultrasound diagnostic equipment. Furthermore, the hydrogel production method and hydrogel production apparatus according to the present embodiment can produce highly homogeneous hydrogels with high reproducibility.

[0023] In the hydrogel preparation method of this embodiment, a solution containing at least the raw material monomers of the hydrogel, a crosslinking agent, and a polymerization initiator added to a solvent is stirred, and the stirring is stopped upon detection of a sudden temperature change in the solution that occurs during gelation. This allows the reaction solution to be stirred until just before gelation, thereby obtaining a highly homogeneous hydrogel. Furthermore, even when non-soluble microparticles are added to the solution, the non-soluble microparticles can be uniformly stirred until just before gelation, so that the non-soluble microparticles are uniformly dispersed with high reproducibility regardless of the type, size, specific gravity, etc. of the non-soluble microparticles, thereby making it possible to obtain a highly homogeneous hydrogel with reduced sedimentation (see FIG. 1(a)). The solution may optionally contain a thickener, T １ ・T ２ Relaxation time adjusters, electrolytes, dispersants, etc. may also be added.

[0024] In this embodiment, a rapid temperature change specifically refers to a state in which the temperature change immediately before the start of rapid polymerization (e.g., a temperature increase of 0.1°C within 4 seconds) is five times faster than the temperature change before polymerization (e.g., a temperature increase of 0.1°C or more in 20 seconds or more). The rapid temperature change is a factor of the time required for the temperature change described above that varies depending on conditions such as the composition and blending ratio of the materials in the solution and the timing of adding the polymerization initiator and polymerization accelerator. However, the reproducibility is high, and the factor is 3 times, preferably 5 times, and more preferably 10 times. Furthermore, a rapid temperature change refers to a temperature change in which the slope of a graph showing the relationship between temperature change and liquid level change associated with stirring of the solution (described below), where the vertical axis represents liquid temperature (°C) and the horizontal axis represents time (seconds), increases by preferably 0.01 to 1.0, more preferably 0.01 to 0.6.

[0025] In the hydrogel preparation method of this embodiment, the hydrogel is preferably a hydrogel having a three-dimensional network structure formed by covalent bonds. Such hydrogels have superior long-term stability compared to physical gels such as agar gel and gelatin gel, which are formed by physical bonds (hydrogen bonds) formed by cooling. Furthermore, they can reproduce both the elastic and viscous properties of biological tissue without adding a thickener to the solvent of the solution used to prepare the hydrogel.

[0026] The main ingredient of the hydrogel is preferably a polyacrylamide polymer, for example, one with a molecular weight of approximately 1,000 to 1,000,000. The polyacrylamide polymer may be a derivative of polyacrylamide itself, a mixture of multiple polymers, or a copolymer in which acrylamide or its derivatives are used as the monomer. In this embodiment, the hydrogel is preferably a polyacrylamide gel, as this allows for the creation of a phantom that satisfies requirements such as long-term stability, reproducibility, uniformity, viscoelasticity, and strength similar to those of living tissue. In this embodiment, the term "main ingredient" refers to a material that accounts for 40% by weight or more, preferably 60% by weight or more, and more preferably 80% by weight of the entire hydrogel.

[0027] For example, as shown in Figure 2, polyacrylamide gel is a polymer in which polyacrylamide, the main chain, is three-dimensionally linked by N,N'-methylenebisacrylamide, a polyacrylamide copolymer cross-linking agent, and has a basic structure in which a three-dimensional network structure is the basic polymer skeleton and a solvent such as distilled water is contained therein. Note that the insoluble particles are dispersed almost uniformly in the solvent portion.

[0028] In addition, in the hydrogel preparation method of this embodiment, various types of non-soluble microparticles can be added to the hydrogel depending on the phantom specifications. Examples of non-soluble microparticles include oxide microparticles such as aluminum oxide, titanium oxide, and silicon oxide; metal microparticles such as tungsten, nickel, and molybdenum; resin particles such as polyethylene and polystyrene; and graphite powder. Furthermore, by adding aluminum oxide, which is a scatterer for ultrasound measurement, to polyacrylamide gel as a non-soluble microparticle, a hydrogel that can be used as a dual-purpose phantom for MRE and USE can be prepared.

[0029] In the hydrogel preparation method of this embodiment, a polymerization accelerator is added to the solution being stirred at a predetermined timing, which allows the timing of the rapid temperature change of the solution due to the heat of polymerization, and therefore the timing of the gelation of the solution, to be determined according to the compounding ratio of the materials in the solution, thereby making it possible to obtain a hydrogel with higher reproducibility and high homogeneity, in which the non-soluble microparticles are uniformly dispersed and the amount of precipitation is reduced.

[0030] In addition, in the hydrogel preparation method of this embodiment, by stopping stirring within 10 seconds, preferably within 5 seconds, and more preferably within 3 seconds of the timing of the sudden temperature change of the solution, the reaction solution can be stirred until just before gelation, thereby obtaining a highly homogeneous hydrogel. Furthermore, when non-soluble microparticles are added, the non-soluble microparticles can be uniformly stirred until just before gelation, thereby obtaining a hydrogel in which the non-soluble microparticles are uniformly dispersed and the amount of precipitation is reduced. Note that the timing of stopping stirring varies depending on conditions such as the time from the sudden temperature change to the completion of gelation, which varies depending on the composition and blending ratio of the materials in the solution, and the specific gravity of the non-soluble microparticles relative to the solution. However, because the timing is highly reproducible, it can be adjusted to the optimal timing depending on the conditions.

[0031] Furthermore, the inventors' research has confirmed that the shape of the liquid surface changes as the solution undergoes a chemical reaction and ultimately gels. Specifically, as shown in Figure 3 , in the initial state, the viscosity of the solution is low, and the centrifugal force caused by stirring is strong, resulting in a cone-like shape that rises toward the outside. Next, as time passes, the viscosity of the solution gradually increases as the chemical reaction begins, and the centrifugal force caused by stirring weakens, causing the outer liquid surface to drop and the liquid surface to approach horizontal. As time passes, the solution begins to become more viscous and entangles itself around the stirrer, causing the liquid surface to rise from the center, ultimately resulting in gelation. The point at which the outer liquid surface begins to drop is called the "start of outer liquid level drop," and the point at which the central liquid surface begins to rise is called the "start of central liquid level rise."

[0032] Because a sudden change in the temperature of the solution occurs between the time when the outer liquid level starts to drop and the time when the central liquid level starts to rise, stirring may be stopped when the liquid level approaches a horizontal state. Because changes in the liquid level are subtle and difficult to confirm visually, it is preferable to detect subtle changes in the liquid level in real time, for example, from video footage. The horizontal state refers to a state in which the difference between the liquid level near the inner wall of the stirring vessel, i.e., the outer liquid level of the solution, and the liquid level near the stirring bar, i.e., the central liquid level of the solution, is preferably 0 to 2.0 mm, more preferably 0 to 1.0 mm.

[0033] In the hydrogel preparation method of this embodiment, the solution is preferably stirred mechanically rather than manually, from the viewpoint of improving the reproducibility of the preparation. Furthermore, in mechanical stirring, increasing the stirring speed can improve the homogeneity of the solution and reduce the amount of precipitation when non-soluble microparticles are used. However, if the stirring speed is too high, air bubbles remain after the solution gels, which not only creates signal loss areas when imaging with an MRI or ultrasound measuring device, but also causes errors in viscoelasticity measurements. For these reasons, it is preferable to stir the solution at the highest stirring speed possible without generating air bubbles on the liquid surface.

[0034] An example of the hydrogel-preparing apparatus of this embodiment will be described with reference to Fig. 4. As shown in Fig. 4, the hydrogel-preparing apparatus of this embodiment includes a stirring vessel and a stirring bar as stirring means capable of stirring the above-described solution, a thermometer as temperature measuring means capable of measuring the temperature of the solution, and a control unit as temperature change detecting means capable of detecting a sudden temperature change in the solution. In this embodiment, the thermometer is fixed integrally to a drive unit that rotates and drives the stirring bar.

[0035] The control unit is connected to a thermometer and a drive unit, and the control unit can automatically stop stirring the solution with the stirrer by sending a stop signal to the drive unit or by stopping the power supply to the drive unit in response to the detection of a sudden change in the temperature of the solution measured by the thermometer. This makes it possible to uniformly stir the solution until just before gelation by stopping stirring in response to a sudden change in the temperature of the solution without overlooking the short-term changes from the sudden change in temperature of the solution that occurs during gelation to gelation.

[0036] Furthermore, by arranging the stirring blade near the bottom of the stirring vessel, the solution at the bottom of the stirring vessel and the insoluble fine particles that have settled at the bottom can be efficiently stirred in the solution, and foaming on the liquid surface of the solution can be suppressed. Note that the stirring bar is preferably arranged so that the lower end of the stirring blade is close to the bottom of the stirring vessel, at a position approximately 1 to 5 mm above the bottom.

[0037] In addition, in order to efficiently stir while stirring the precipitate that forms at the bottom of the stirring vessel, it is preferable that the shape of the stirring blade is an inclined blade turbine type (see Figures 4 and 5) that generates an axial flow (a vertical flow). Furthermore, from the viewpoint of solution stirring efficiency and preventing the generation of bubbles, it is preferable that the outer diameter of the stirring blade is 50% or more of the inner diameter of the stirring vessel (note that in Figure 6, it is about 80%).

[0038] In the hydrogel-preparation apparatus of this embodiment, after stirring of the solution is stopped, the stirrer and thermometer must be quickly removed from the solution before gelation progresses. For example, as shown in FIG. 6 , the hydrogel-preparation apparatus is configured to stir the solution while the stirring vessel is placed on a lifting platform connected to the control unit. As a result, the control unit can automatically stop stirring the solution with the stirrer in response to detecting a sudden temperature change in the solution, as described above, and can lower the lifting platform to move the stirring vessel downward and automatically remove the stirrer and thermometer from the solution. Furthermore, the configuration for removing the stirrer and thermometer from the solution may be freely selected, and the stirrer and thermometer may be automatically removed from the solution by moving them upward.

[0039] The hydrogel-preparing apparatus of this embodiment may also include a material supplying means for automatically supplying a specified amount of polymerization initiator and polymerization accelerator into the solution at a predetermined timing, thereby making it possible to reliably determine the timing of the rapid temperature change of the solution due to the heat of polymerization, and therefore the timing of gelation of the solution, in accordance with the compounding ratio of the materials in the solution.

[0040] Furthermore, the hydrogel-preparing apparatus of this embodiment may be configured to automatically determine the timing for adding the polymerization accelerator and the timing for stopping stirring by inputting the composition and blending ratio of the materials in the solution into the control unit. In order to improve the accuracy of the control unit, it is also possible to apply a known machine learning method.

[0041] As described above, the hydrogel preparation method and hydrogel preparation apparatus of this embodiment can stir the reaction solution until just before gelation by stopping stirring in response to the sudden temperature change of the solution that occurs during gelation, thereby producing a highly homogeneous hydrogel. Furthermore, even when non-soluble microparticles are used, the non-soluble microparticles in the solution can be stirred uniformly, thereby suppressing precipitation regardless of the type, size, specific gravity, etc. of the non-soluble microparticles, and producing a highly homogeneous hydrogel in which the non-soluble microparticles are uniformly dispersed with high reproducibility and the amount of precipitation is reduced.

[0042] Furthermore, by using not only a sudden change in the temperature of the solution but also a change in the liquid level of the solution as an indicator for stopping stirring, it is possible to obtain a highly homogeneous hydrogel in which the non-soluble microparticles are uniformly dispersed with higher reproducibility and the amount of precipitation is reduced.

[0043] The hydrogel obtained by the hydrogel preparation method and hydrogel preparation apparatus of this embodiment is a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonds. In a further aspect, the hydrogel has non-soluble microparticles uniformly dispersed throughout the hydrogel, no precipitation of non-soluble microparticles occurs at the bottom of the hydrogel, and the thickest part of the precipitation is less than 2 mm or is localized. Because the hydrogel of the present invention is highly homogeneous, it can be suitably used as a phantom for evaluating elastography.

[0044] In this embodiment, "localized" refers to a state in which the area of ​​the precipitate of non-soluble microparticles at the bottom of the hydrogel where the precipitate is 2 mm or more thick occupies 70% or less, preferably 50% or less, and more preferably 30% or less of the entire bottom surface, and the thickness of the precipitate at its thickest point is preferably less than 2 mm, preferably less than 1.0 mm, and more preferably less than 0.5 mm.

[0045] Furthermore, the hydrogel of this embodiment is highly homogeneous, and the density ratio in a region approximately 1 cm thick above and below the hydrogel is preferably 0.985 to 1.000, more preferably 0.0.988 to 1.000.

[0046] Here, a hydrogel was actually produced using the hydrogel production method and hydrogel production device of the example according to the above embodiment, and the effects thereof were confirmed. A specific description will be given below.

[0047] In this Example 1, 58 g of acrylamide, a raw material for the hydrogel, and 0.3 g of N,N'-methylenebisacrylamide, a cross-linking agent, were added to 500 g of distilled water, a solvent, to which 3 wt% of aluminum oxide, as insoluble fine particles, with a particle size of approximately 5 to 10 μm was added. In this Example 1, hydrogels were prepared using three solutions A-1, A-2, and A-3, each having the same material blending ratio.

[0048] In this Example 1, solutions A-1, A-2, and A-3 were stirred using the hydrogel production apparatus shown in FIG. 4. The stirring vessel used had dimensions of 15 cm in height and 11 cm in internal diameter, and the stirring blade of the stirrer was an inclined blade turbine type, positioned 2 mm above the bottom of the stirring vessel. Furthermore, by using the hydrogel production apparatus of this Example 1, it is possible to produce cylindrical hydrogels with a diameter of 11 cm and a height of approximately 11 cm. Other conditions for producing the hydrogel in this Example 1 are shown in Table 1.

[0049]

[0050] As shown in Table 1, the stirring speed was set to the highest speed (150 rpm) within the range in which bubbles were not generated on the liquid surface during stirring. The solution, which had been stored in a refrigerator at approximately 10°C, was removed and the temperature of the solution was raised while stirring at room temperature (25°C). When the solution temperature rose to 13.8°C, a polymerization initiator was added, and a polymerization accelerator was added to the solution at a predetermined timing. In this Example 1, the solution was allowed to gel without removing the stirrer and thermometer from the solution in order to observe the change in the liquid surface until the end.

[0051] The relationship between temperature change and liquid level change in three solutions A-1, A-2, and A-3 is shown in Figures 7 to 9, respectively. In Figures 7 to 9, the point in time when the polymerization accelerator was added to the solution is indicated as 0 seconds on the graph. The timing at which a sudden temperature change occurs in the solution is indicated by a circle with a two-dot chain line.

[0052] As shown in Fig. 7, for solution A-1, the temperature change began to increase 234 seconds after the addition of the polymerization accelerator, and a sudden change in solution temperature was detected 242 seconds later (shown by a white circle in Fig. 7), between the start of the outer liquid level drop at 241 seconds and the start of the central liquid level rise at 252 seconds. Thus, for solution A-1, the point at which the sudden change in solution temperature occurred was 10 seconds before the start of the central liquid level rise.

[0053] 8, in solution A-2, the temperature change began to increase 132 seconds after the addition of the polymerization accelerator, and a rapid temperature change was detected between the start of the outer liquid level drop at 137 seconds and the start of the central liquid level rise at 153 seconds, and at 147 seconds (shown by the white circle in FIG. 8). Thus, in solution A-2, the time at which the rapid temperature change occurred was 6 seconds before the start of the central liquid level rise.

[0054] 9, in solution A-3, the temperature change began to increase 134 seconds after the addition of the polymerization accelerator, and a rapid temperature change was detected 153 seconds later (shown by a white circle in FIG. 9), between the start of the outer liquid level drop at 149 seconds and the start of the central liquid level rise at 158 ​​seconds. Thus, in solution A-3, the time at which the rapid temperature change occurred was 5 seconds before the start of the central liquid level rise.

[0055] These results confirmed that the timing at which a sudden change in solution temperature occurs occurs 5 to 10 seconds before the start of the central liquid level rise. In other words, by using the sudden change in solution temperature as a guide, it was shown that it is possible to predict the start of the central liquid level rise, when the highly viscous solution begins to tangle around the stir bar, and to stop stirring before that time.

[0056] On the other hand, as shown in FIGS. 7 to 9 , it was confirmed that even if the compounding ratio of the materials in the solution is the same, when the timing of adding the polymerization initiator and the polymerization accelerator is different (not constant), there is a difference in the timing at which a rapid temperature change occurs in the solution after the addition of the polymerization accelerator.

[0057] In Example 2, the timing of adding the polymerization initiator and polymerization accelerator was determined to determine the timing at which a sudden change in the solution temperature would occur, and hydrogels were prepared. Specifically, the polymerization initiator was added when the solution temperature rose to 13.8°C, and the timing of adding the polymerization accelerator was determined to be 180 seconds after the polymerization initiator was added. In Example 2, hydrogels were prepared using three solutions B-1, B-2, and B-3, which had the same material blending ratios as in Example 1. In Example 2, the same hydrogel preparation apparatus as in Example 1 was used, and hydrogels were prepared under the same conditions as in Example 1. For solution B-2, stirring was stopped upon detection of a sudden temperature change.

[0058] The temperature changes in the three solutions B-1, B-2, and B-3 are shown in Figure 10. In Figure 10, the time when the polymerization accelerator was added to the solution is shown as 0 seconds on the graph.

[0059] As shown in Figure 10, a sudden change in solution temperature was observed at approximately the same time for all three solutions. This indicates that, by adjusting the timing of the addition of the polymerization initiator and polymerization accelerator, it is possible to determine the timing of the sudden temperature change in the solution due to thermal polymerization, and therefore the timing of the solution gelling, and to stop stirring, as long as the solutions have the same material ratios. For solution B-2, a sudden change in solution temperature was detected 240 seconds after the addition of the polymerization accelerator, and stirring was stopped 4 seconds later, at 244 seconds.

[0060] In this Example 3, a hydrogel was prepared using Solution L, which had a different material blending ratio from Examples 1 and 2, and Solution H, which contained 2.5 times the amount of crosslinker as Solution L. The amount of distilled water used as the solvent was adjusted so that the total weight of the solutions was the same. The same amounts of polymerization initiator and polymerization accelerator as in Example 2 were added at the same time.

[0061] The temperature changes in the three solutions L and H are shown in Fig. 11. In Fig. 11, the time when the polymerization accelerator was added to the solution is indicated as 0 seconds on the graph.

[0062] As shown in FIG. 11 , a sudden change in temperature was detected in Solution L at 273 seconds after the addition of the polymerization accelerator, and in Solution H at 250 seconds after the addition of the polymerization accelerator. Of the two solutions, Solution H, which had a higher cross-linking agent concentration, showed a sudden change in temperature at an earlier timing than Solution L.

[0063] Solutions B-1, B-2, and B-3 (see FIG. 10) in Example 2 have higher crosslinker concentrations than Solution H, and therefore experience even earlier, more rapid temperature changes than Solution H. From these findings, it is presumed that the higher the crosslinker concentration in a solution, the earlier the timing at which a rapid temperature change occurs. Furthermore, the crosslinker concentration affects the crosslinking points in the three-dimensional network structure of the chemical gel (see FIG. 2), and the partial chains sandwiched between the effective crosslinking points contribute to the storage modulus of the hydrogel.

[0064] To confirm the homogeneity of the hydrogel prepared by the hydrogel preparation method and hydrogel preparation apparatus of the present invention, the bottom of the hydrogel prepared in Example 2 was cut vertically and the thickness of the precipitate of non-soluble fine particles (aluminum oxide) at the bottom of the hydrogel was confirmed. Note that this hydrogel was gelled by stopping stirring 5 seconds after detecting a sudden temperature change in the solution, and then quickly removing the stir bar and thermometer from the solution. Comparative Example 1

[0065] Cylindrical hydrogels of the same size were prepared using an aqueous solution with the same component ratios and the same stirring vessel as those used in Example 2. Stirring was performed manually using a stirring bar according to the conventional method, and stirring was stopped when resistance was felt.

[0066] As shown in Figure 12(a), the precipitates at the bottom of the hydrogel (Comparative Example 1) produced by the conventional hydrogel production method were present over almost the entire surface of the bottom, with a thickness of approximately 5 mm (even at the thickest point, it was approximately 5 mm). In contrast, as shown in Figure 12(b), the precipitates at the bottom of the hydrogel (Example 2) produced by the hydrogel production method and hydrogel production apparatus of the present invention were present only locally, and it was confirmed that the area ratio of the precipitates over the entire bottom surface to the area where the precipitates were 2 mm or more thick was 0%, and that the thickness was approximately 0.5 mm at the thickest point. Comparative Example 2

[0067] Next, similar to the above-mentioned Comparative Example 1, a more detailed comparison was made between a hydrogel prepared by a conventional hydrogel preparation method (Comparative Example 2) and a hydrogel prepared by the hydrogel preparation method and hydrogel preparation apparatus of the present invention (Example 2), and the homogeneous dispersion characteristics of non-soluble microparticles were evaluated.

[0068] As shown by the dots in Figures 13(a) and 14(a), the precipitates at the bottom of the hydrogel (Comparative Example 2) prepared by the conventional hydrogel preparation method were present in a ring-shaped configuration around the outer diameter, with the area of ​​the area greater than 2 mm being approximately 52% and the thickest point being approximately 5 mm. In contrast, as shown by the dots in Figures 13(b) and 14(b), the precipitates at the bottom of the hydrogel (Example 2) prepared by the hydrogel preparation method and hydrogel preparation apparatus of the present invention were present only locally in the center, with the area of ​​the area greater than 2 mm being approximately 3% and the thickest point being approximately 2 mm. In other words, it was confirmed that the area of ​​precipitates was significantly smaller in the hydrogels prepared by the hydrogel preparation method and hydrogel preparation apparatus of the present invention than in the conventional hydrogel preparation method.

[0069] 14(a) and 14(b), the hydrogels produced by the hydrogel production method and hydrogel production apparatus of the present invention exhibited high uniformity in MRI images, confirming their high homogeneity compared to conventional hydrogel production methods. The MRI images in 14(a) and 14(b) were taken under the same MRI conditions, and the high uniformity was confirmed by calculating the standard deviation of pixel values ​​within the region where the hydrogel was present.

[0070] Furthermore, as shown in FIG. 15(a), the density of the upper 1 cm thick region of the hydrogel obtained by the conventional hydrogel preparation method was 1.09 g / cm ３ and the density in the bottom area about 1 cm thick is 1.12 g / cm ３ The density of the bottom part is 2.7% higher than that of the top part, whereas the density of the top part of the hydrogel obtained by the hydrogel preparation method of the present invention in a region about 1 cm thick is 1.10 g / cm ３ and the density in the bottom area about 1 cm thick is 1.11 g / cm ３It was confirmed that the density of the bottom was 0.9% higher than that of the top. In other words, the difference in density between the top and bottom of the hydrogel obtained by the hydrogel preparation method of the present invention was suppressed to about one-third of that of the hydrogel obtained by the conventional hydrogel preparation method, and it was quantitatively confirmed that the hydrogel had high homogeneity.

[0071] In this way, it was confirmed that the hydrogel production method and hydrogel production apparatus of the present invention can uniformly stir the reaction solution and the non-soluble microparticles in the solution until just before gelation, thereby suppressing precipitation regardless of the type, size, specific gravity, etc. of the non-soluble microparticles, uniformly dispersing the non-soluble microparticles with high reproducibility, and producing a highly homogeneous hydrogel with reduced precipitation.

[0072] As described above, these embodiments and examples provide a hydrogel production method and a hydrogel production device that can produce a highly homogeneous hydrogel with high reproducibility, and that can produce a hydrogel in which non-soluble microparticles are uniformly dispersed and the amount of precipitation is reduced.

[0073] In the above example, the measurement interval of the thermometer was 1 second, but by using a thermometer with a shorter measurement interval, it becomes possible to detect the timing of a sudden temperature change in the solution with higher accuracy, and to stop stirring at a more appropriate timing.

[0074] Furthermore, the thermometer is not limited to being provided separately from the stirrer, but may be incorporated, for example, into the rotating shaft of the stirrer, which allows the solution to be stirred more uniformly.

[0075] Alternatively, the stirring speed may be reduced, for example, to half the speed when a sudden temperature change in the solution is detected or a few seconds after the detection, before stopping the stirring, which allows for the production of a more homogeneous hydrogel without stirring marks.

[0076] In the above embodiment, the solution in the stirring vessel is stirred by a stirring bar having a stirring blade as the stirring means, but the stirring means is not limited to this, and the solution in the stirring vessel may be stirred by vibrating and rotating the stirring vessel itself, such as a mixer or shaker. [Industrial Applicability]

[0077] The present invention has industrial applicability as a method and apparatus for producing a hydrogel that can be used as a phantom for elastography evaluation and that can produce a highly homogeneous hydrogel. Furthermore, the present invention can produce a highly homogeneous hydrogel that can be used as a highly homogeneous biological tissue-equivalent model (phantom) that is necessary for the development, adjustment, evaluation, maintenance, inspection, and repair of MRI and ultrasound imaging devices, as well as for the interpretation and analysis of images. Therefore, the hydrogel can be used to compare and evaluate measurements made by various imaging methods, manufacturers, and products using MRI or ultrasound, and standardization can be promoted based on these results, leading to a wide range of applications.

Claims

1. A method for producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonding, comprising stirring a solution obtained by adding at least a raw material monomer, a crosslinking agent, and a polymerization initiator of the hydrogel to a solvent, and stopping the stirring in response to detection of a rapid temperature change of the solution.

2. A method for producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonding, comprising stirring a solution obtained by adding at least a raw material monomer, a crosslinking agent, a polymerization initiator, and insoluble fine particles of the hydrogel to a solvent, and stopping the stirring in response to detection of a rapid temperature change of the solution.

3. The method for producing a hydrogel according to claim 1 or 2, wherein the hydrogel is a polyacrylamide-based polymer.

4. The method for producing a hydrogel according to claim 1 or 2, wherein a polymerization accelerator is added to the solution at a predetermined timing.

5. The method for producing a hydrogel according to claim 1 or 2, wherein the stirring is stopped within 10 seconds from the start of the rapid temperature change of the solution.

6. The method for producing a hydrogel according to claim 1 or 2, wherein the rapid temperature change of the solution has a slope of 0.01 to 1.0 (where the vertical axis of the graph is the liquid temperature (°C) and the horizontal axis is the time (seconds)).

7. A hydrogel production apparatus for producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonding, comprising stirring means capable of stirring a solution obtained by adding at least a raw material monomer, a crosslinking agent, and a polymerization initiator of the hydrogel to a solvent, a control unit for controlling the stirring means, temperature measuring means capable of measuring the temperature of the solution, and temperature change detecting means capable of detecting a rapid temperature change of the solution, wherein the control unit stops the stirring of the solution by the stirring means in response to detection of a rapid temperature change of the solution by the temperature change detecting means.

8. A hydrogel mainly composed of a polyacrylamide-based polymer, having a density ratio of the upper part to the lower part of 0.985 to 1.000 and having a three-dimensional network structure formed by covalent bonding.

9. A hydrogel according to claim 8, comprising insoluble fine particles, wherein the insoluble fine particles are at least one selected from aluminum oxide, titanium oxide, silicon oxide, tungsten, nickel, molybdenum, polyethylene, polystyrene, and graphite powder.

10. A hydrogel according to claim 9, wherein the insoluble fine particles at the bottom are distributed more in the inner diameter portion than in the outer diameter portion.

11. An elastography evaluation phantom containing the hydrogel according to any one of claims 8 to 10.

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