WO2025143213A1 - Hydrogel production method, hydrogel production device, hydrogel, and elastography evaluation phantom containing hydrogel - Google Patents

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 phantom for elastography evaluation containing hydrogel

The present invention relates to a hydrogel production method, a hydrogel production device, a hydrogel, and a phantom for elastography evaluation that contains the hydrogel.

Since there is a correlation between disease and functional disorders and the hardness (viscoelasticity) of biological tissue, measurements such as the viscoelastic modulus are used for diagnosing disease staging. Invasive methods are the mainstream for quantitatively measuring the viscoelasticity of biological tissue, but not only are these methods a heavy burden on the patient, but removing the biological tissue from the body can also damage its physical properties. For this reason, elastography (a viscoelasticity measurement method) has been proposed as a method for non-invasively and quantitatively diagnosing the viscoelastic modulus inside the body.

The main practical examples of elastography are MRE (MR elastography) using MRI (magnetic resonance imaging) and USE (ultrasound elastography) using ultrasound. Currently, several elastography systems equipped with MRE and USE are on the market, but the measurement values differ depending on the elastography method, manufacturer, product, etc., and diagnosis cannot be made with the same standards. Standardization of elastography systems requires a reference object that can be used by both MRE and USE systems, so development of a biological 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.

Hydrogels (chemical gels) with a three-dimensional mesh 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 a biomimetic phantom for USE, such hydrogels have insoluble particles with a particle size of several tens of nanometers to several hundreds of micrometers dispersed inside as ultrasound scatterers, but when used for MRE, they can be used without the addition of scatterers.

WO 2005/107599 (pages 4 to 9, Figure 4) JP 2018-41055 A (Claims, Examples) JP-A-61-247440 (page 3, lower right column, line 3 from the bottom to page 4, upper left column, line 3)

A method for manufacturing a biological phantom using a chemical gel is, for example, as described in Patent Document 1, in which a solution containing the raw material monomers of the hydrogel and a crosslinking agent (N,N'-methylenebisacrylamide) is degassed while stirring, then a polymerization initiator (ammonium persulfate) and a polymerization accelerator (TEMED) are added, and the solution is gently poured into a mold, and the container is cooled to prevent a rise in temperature due to heat generation accompanying the polymerization reaction. Alternatively, for example, as described in Patent Document 2, a method is also available in which a polymerization initiator and a polymerization accelerator are added while stirring a solution containing the raw material monomers of the hydrogel and a crosslinking agent, and the chemical reaction is allowed to proceed while continuing to stir, and after sufficient polymerization is confirmed, stirring is stopped and the solution is cooled.

However, as described in Patent Document 3, chemical gels such as polyacrylamide gels have a tendency to become non-homogenized during cross-linking polymerization (gelation), and it is particularly difficult to uniformly disperse non-soluble particles when they are added. Therefore, in the method of Patent Document 1, the size of the non-soluble particles must be limited to those with a specific gravity of 1 to 5 and a diameter of 5 μm or less, which limits the types of biomimetic phantoms that can be manufactured. In addition, as in the method of Patent Document 2, when stirring is continued during the progress of a chemical reaction, the stirring is stopped when the resistance of the solution is felt, but the resistance of the solution is vague because it relies on the sense of touch, and there is a tendency to stop too early to avoid the risk of the reaction proceeding too far and failing. Therefore, although the hydrogel is homogeneous during stirring, and when non-soluble particles are added, the particles are also uniformly dispersed, there is a drawback in that the homogeneity of the hydrogel is lost while waiting for the solution to gel after stirring is stopped, and the non-soluble particles also precipitate (see Figure 1 (b)).

The present invention has been made with a focus on these problems, and aims to provide a hydrogel production method, a hydrogel production device, a hydrogel, and a phantom for elastography evaluation containing said hydrogel, which can obtain a highly homogeneous hydrogel in which a three-dimensional mesh structure is formed by covalent bonds. In particular, the present invention aims to provide a hydrogel production method, a hydrogel production device, a hydrogel, and a phantom for elastography evaluation containing said hydrogel, which can obtain a highly homogeneous hydrogel in which the amount of precipitation of the particles is reduced, even when non-soluble particles, especially microparticles, are used. Furthermore, the present invention aims to provide a hydrogel production method and a hydrogel production device that use an objective indicator for the timing to stop stirring during gelation and that can be easily automated.

In order to solve the above problems, the method for producing a hydrogel of the present invention comprises the steps of:
A method for producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonds, comprising the steps of:
The method is characterized in that a solution containing at least the raw material monomers of the hydrogel, a crosslinking agent, and a polymerization initiator in a solvent is stirred, and the stirring is stopped in response to detection of a sudden change in temperature of the solution.
According to this feature, by stopping the stirring in response to the sudden temperature change of the solution that occurs during gelation, the reaction solution can be stirred until just before gelation, so that a highly homogeneous hydrogel can be obtained.

A method for producing a hydrogel according to another aspect of the present invention includes the steps of:
A method for producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonds, comprising the steps of:
The method is characterized in that a solution containing at least the raw material monomers of the hydrogel, a crosslinking agent, a polymerization initiator, and non-soluble microparticles in a solvent is stirred, and the stirring is stopped upon detection of a sudden temperature change of the solution.
According to this feature, the non-soluble microparticles can be uniformly stirred until just before gelation, thereby suppressing precipitation regardless of the type, size, specific gravity, etc. of the non-soluble microparticles, and the non-soluble microparticles are uniformly dispersed with high reproducibility, thereby producing a highly homogeneous hydrogel with a reduced amount of precipitation.

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, so that a structurally stable hydrogel can be obtained.

In still another aspect of the present invention, a polymerization accelerator is added to the solution at a predetermined timing.
According to this feature, the timing of the sudden temperature change of the solution due to the heat of polymerization, and therefore the timing of the gelation of the solution, can be determined according to the compounding ratio of the materials in the solution, making it possible to obtain a hydrogel with higher reproducibility and homogeneity, and also to obtain a hydrogel in which non-soluble microparticles are uniformly dispersed and the amount of precipitation is reduced.

In still another embodiment of the present invention, the stirring is stopped within 10 seconds after the start of the rapid temperature change of the solution.
According to this feature, the reaction solution can be stirred until just before gelation, thereby making it possible to obtain a highly homogeneous hydrogel. Furthermore, when non-soluble microparticles are added to the solution, the non-soluble microparticles can be stirred uniformly until just before gelation, thereby making it possible to obtain a hydrogel in which the non-soluble microparticles are uniformly dispersed and the amount of precipitation is further reduced.

In yet another aspect of the present invention, the rapid temperature change of the solution is characterized in that the gradient of the gradient is 0.01 to 1.0 (where the vertical axis of the graph represents the solution 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 slope of the graph increases from 0.01 to 1.0 when the vertical axis represents liquid temperature (°C) and the horizontal axis represents time (seconds).

An apparatus for producing a hydrogel according to another aspect of the present invention comprises:
An apparatus for producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonds, comprising:
A stirring means capable of stirring a solution obtained by adding at least raw material monomers of the hydrogel, a crosslinking agent, and a polymerization initiator to a solvent, and a control unit for controlling the stirring means;
A temperature measuring means capable of measuring the temperature of the solution;
A temperature change detection means capable of detecting a sudden change in temperature of the solution,
The control unit is characterized in that it stops the stirring of the solution by the stirring means in response to detection of a sudden change in temperature of the solution by the temperature change detection means.
According to this feature, by stopping the stirring in response to the rapid temperature change of the solution that occurs during gelation without overlooking the short-time change from the rapid temperature change of the solution to gelation, the non-soluble particles in the solution can be uniformly stirred until just before gelation, so that a highly homogeneous hydrogel can be obtained. Furthermore, since the stirring can be stopped based on the index of a measurable temperature change, it can be easily adapted to automation. In particular, the control unit can be configured to perform optimal control using known methods such as machine learning.

A hydrogel according to another aspect of the present invention comprises:
The hydrogel is composed mainly of a polyacrylamide polymer, the density of the upper portion being 0.985 to 1.000 in terms of the density ratio to the lower portion, and has a three-dimensional network structure formed by covalent bonds.

In yet another aspect of the present invention, the composition contains insoluble microparticles, and is characterized in that the insoluble microparticles are at least one selected from aluminum oxide, titanium oxide, silicon oxide, tungsten, nickel, molybdenum, polyethylene, polystyrene, and graphite powder.
According to this feature, various kinds of non-soluble particles can be added according to the phantom specifications, and the phantom can be used as a dual-purpose phantom for MRE and USE.

In still another embodiment of the present invention, the non-soluble fine particles at the bottom are distributed in a larger amount in the inner diameter portion than in the outer diameter portion.
According to this feature, the non-soluble fine particles at the bottom are uniformly dispersed, resulting in a hydrogel with a further reduced amount of precipitation.

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.
This feature allows the hydrogel to have high homogeneity and meet the standards required for standardization of elastography systems.

FIG. 1A is a schematic diagram showing the 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, resulting in loss of uniformity. FIG. 1 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. 4 is a schematic diagram showing a change in liquid level accompanying stirring of a solution in an embodiment of the present invention. FIG. FIG. 1 is a schematic diagram showing a hydrogel stirring device according to an embodiment of the present invention. FIG. 2 is a photograph showing the shape of an inclined blade turbine type agitator blade according to an embodiment of the present invention. FIG. 13 is a schematic diagram showing a modified example of the hydrogel stirring device in the embodiment of the present invention. FIG. 1 is a diagram showing the relationship between temperature change and liquid level change accompanying stirring of solution A-1 in Example 1 of the present invention. FIG. 1 is a graph showing the relationship between temperature change and liquid level change accompanying stirring of solution A-2 in Example 1. FIG. 1 is a graph showing the relationship between temperature change and liquid level change accompanying stirring of solution A-3 in Example 1. FIG. 13 is a diagram showing temperature changes accompanying stirring of solutions B-1, B-2, and B-3 in Example 2 of the present invention. FIG. 11 is a diagram showing temperature changes accompanying stirring of solutions L and H in Example 3 of the present invention. FIG. 1A is a cross-sectional photograph showing the precipitation of a hydrogel obtained by a conventional hydrogel production method, and FIG. 1B is a cross-sectional photograph showing the precipitation of a hydrogel obtained by the hydrogel production method of the present invention. FIG. 1A is a photograph showing the precipitation state of non-soluble microparticles at the bottom of a hydrogel obtained by a conventional hydrogel production method, and FIG. 1B is a photograph showing the precipitation state of non-soluble microparticles at the bottom of a hydrogel obtained by the hydrogel production method of the present invention. FIG. 1A is an MRI image of a hydrogel obtained by a conventional hydrogel preparation method, and FIG. 1B is an MRI image of a hydrogel obtained by the hydrogel preparation method of the present invention. FIG. 1A is a diagram showing the results of density comparison in a region approximately 1 cm thick above and below an MRI image of a hydrogel obtained by a conventional hydrogel production method, and FIG. 1B is a diagram showing the results of density comparison in a region approximately 1 cm thick above and below an MRI image of a hydrogel obtained by the hydrogel production method of the present invention.

The following describes an embodiment of the present invention. However, the present invention can be implemented in many different forms and is not limited to the embodiments and examples shown below.

The hydrogel production method and hydrogel production device according to this embodiment can produce highly homogeneous hydrogel that can be used as a phantom for evaluating elastography using a magnetic resonance imaging device (MRI) or an ultrasound diagnostic device. Furthermore, the hydrogel production method and hydrogel production device according to this embodiment can produce highly homogeneous hydrogel with high reproducibility.

In the hydrogel preparation method of the present embodiment, a solution containing at least the raw material monomers, crosslinking agent, and polymerization initiator of the hydrogel added to a solvent is stirred, and the stirring is stopped in response to detection of a sudden temperature change of the solution that occurs during gelation. This allows the reaction solution to be stirred until just before gelation, so that a highly homogeneous hydrogel can be obtained. Furthermore, even when non-soluble fine particles are added to the solution, the non-soluble fine particles can be uniformly stirred until just before gelation, so that the non-soluble fine particles are uniformly dispersed with high reproducibility regardless of the type, size, specific gravity, etc. of the non-soluble fine particles, and a highly homogeneous hydrogel in which the amount of precipitation is reduced (see FIG. 1(a)) can be obtained. In addition, a thickener, a _T1 / _T2 relaxation time regulator, an electrolyte, a dispersant, etc. may be added to the solution as necessary.

In this embodiment, a sudden temperature change means, as a specific example, a state in which the temperature change just before polymerization begins to progress rapidly (for example, within 4 seconds to rise by 0.1°C) is 5 times faster than the temperature change before polymerization (for example, 20 seconds or more to rise by 0.1°C). Note that the magnification of the time required for this sudden temperature change varies depending on conditions such as the composition of the materials in the solution, the compounding ratio, and the timing of adding the polymerization initiator and polymerization accelerator, but the reproducibility is high, and the magnification is 3 times, preferably 5 times, and more preferably 10 times. In addition, a sudden temperature change means a temperature change in which the slope of a graph showing the relationship between temperature change and liquid level change due to stirring of the solution described below, when the vertical axis is liquid temperature (°C) and the horizontal axis is time (seconds), increases preferably to 0.01 to 1.0, more preferably 0.01 to 0.6.

In addition, in the hydrogel production method of this embodiment, the hydrogel is preferably a hydrogel in which a three-dimensional network structure is formed by covalent bonds. Such hydrogels have superior long-term stability compared to physical gels such as agar gel and gelatin gel that are formed by physical bonds (hydrogen bonds) caused by cooling, and can reproduce both the elastic and viscous properties of biological tissues without adding a thickener to the solvent of the solution used to produce the hydrogel.

The main raw material of the hydrogel is preferably a polyacrylamide polymer, for example, one with a molecular weight of about 1000 to 1,000,000. The polyacrylamide polymer may be a derivative other than polyacrylamide itself, a mixture of multiple polymers, or a copolymer with acrylamide or its derivatives as a monomer. In this embodiment, the hydrogel is preferably a polyacrylamide gel from the viewpoint of being able to produce a phantom that satisfies conditions such as long-term stability, reproducibility of production, uniformity, viscoelasticity close to that of living tissue, and strength. In this embodiment, the main raw material refers to a material that is mixed in an amount of 40% by weight or more, preferably 60% by weight or more, and more preferably 80% by weight, of the entire hydrogel.

For example, as shown in Figure 2, polyacrylamide gel is a polymer in which the main chain of polyacrylamide is three-dimensionally linked by the polyacrylamide copolymer crosslinking agent N,N'-methylenebisacrylamide, and has a basic structure in which the basic polymer skeleton is a three-dimensional mesh structure and contains a solvent such as distilled water. The non-soluble fine particles are dispersed almost uniformly in the solvent portion.

In addition, in the hydrogel production 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. By adding aluminum oxide, which is a scatterer for ultrasound measurement, as a non-soluble microparticle to polyacrylamide gel, a hydrogel that can be used as a dual-use phantom for MRE and USE can be produced.

In addition, in the hydrogel production method of this embodiment, a polymerization accelerator is added to the solution being stirred at a predetermined timing. This makes it possible to determine the timing of the sudden temperature change of the solution due to the heat of polymerization, and therefore the timing of the gelation of the solution, according to the compounding ratio of the materials in the solution, and therefore makes it possible to obtain a hydrogel with higher reproducibility and high homogeneity, in which non-soluble microparticles are uniformly dispersed and the amount of precipitation is reduced.

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

The inventors' research has also confirmed that the shape of the liquid surface changes as the solution undergoes a chemical reaction and finally gels. In detail, 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, causing the liquid surface to take on a cone-like shape that becomes higher 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 become closer to horizontal. As time passes, the solution becomes more viscous and becomes entangled around the stirrer, causing the liquid surface to rise from the center, eventually gelling. The point at which the outer liquid surface starts to drop is called the "start of outer liquid surface drop," and the point at which the central liquid surface starts to rise is called the "start of central liquid surface rise."

Since 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 of the solution approaches a horizontal state. Note that since the liquid level change is a subtle change and difficult to confirm visually, it is preferable to detect subtle changes in the liquid level in real time, for example, from video footage. A horizontal state is a state in which the difference between the height of the liquid level near the inner wall of the stirring vessel, i.e., the outer side of the solution, and the height of the liquid level near the stirrer, i.e., the central side of the solution, is preferably 0 to 2.0 mm, more preferably 0 to 1.0 mm.

In addition, in the hydrogel production method of this embodiment, the solution is preferably stirred mechanically rather than manually, from the viewpoint of improving production reproducibility. 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 increased too much, air bubbles remain after the solution gels, which not only creates signal missing areas when imaging with an MRI or ultrasonic measuring device, but also becomes a source of error in viscoelasticity measurements. For these reasons, it is preferable to stir the solution at the highest stirring speed possible within the range in which air bubbles do not form on the liquid surface.

An example of the hydrogel production device of this embodiment will be described with reference to FIG. 4. As shown in FIG. 4, the hydrogel production device of this embodiment includes a stirring vessel and a stirrer as stirring means capable of stirring the above-mentioned solution, a thermometer as temperature measurement means capable of measuring the temperature of the solution, and a control unit as temperature change detection means capable of detecting a sudden change in temperature of the solution. In this embodiment, the thermometer is fixed integrally to the drive unit that rotates and drives the stirrer.

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 cutting off 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 gelling by stopping stirring in response to the sudden temperature change of the solution, without overlooking the short period of time from the sudden change in temperature of the solution that occurs during gelling to gelling.

In addition, by arranging the stirring blade near the bottom of the stirring vessel, the solution at the bottom of the stirring vessel and non-soluble 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. It is preferable that the stirring bar is arranged so that the lower end of the stirring blade is close to the bottom of the stirring vessel, approximately 1 to 5 mm above the bottom.

Furthermore, in order to efficiently stir while stirring the precipitate that forms at the bottom of the stirring vessel, it is preferable that the stirring blade shape is an inclined blade turbine type (see Figures 4 and 5) that generates an axial flow (vertical flow). Furthermore, from the viewpoint of the solution stirring efficiency and preventing the generation of air 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%).

In addition, in the hydrogel production device of this embodiment, after stirring of the solution is stopped, it is necessary to quickly remove the stirrer and thermometer from the solution before gelation progresses. For example, as shown in FIG. 6, the hydrogel production device is configured to be able to stir the solution with the stirring container placed on a lifting platform connected to the control unit, so that the control unit can automatically stop stirring the solution with the stirrer in response to detection of a sudden temperature change in the solution as described above, and can automatically remove the stirrer and thermometer from the solution by moving the stirring container downward by lowering the lifting platform. In addition, the configuration for removing the stirrer and thermometer from the solution may be freely selected, and the stirrer and thermometer may be configured to be automatically removed from the solution by moving them upward.

The hydrogel preparation device of this embodiment may also be equipped with a material injection means for automatically injecting a specified amount of polymerization initiator and polymerization accelerator into the solution at a predetermined timing. This makes it possible to reliably determine the timing of the sudden temperature change of the solution due to the heat of polymerization, and therefore the timing of the gelation of the solution, according to the compounding ratio of the materials in the solution.

The hydrogel preparation device 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 mixing ratio of the materials in the solution into the control unit. It is also possible to apply known machine learning techniques to improve the accuracy of the control unit.

As described above, the hydrogel production method and hydrogel production 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, so that a highly homogeneous hydrogel can be obtained. Furthermore, even when non-soluble microparticles are used, the non-soluble microparticles in the solution can be stirred uniformly, so that precipitation is suppressed regardless of the type, size, specific gravity, etc. of the non-soluble microparticles, and the non-soluble microparticles are uniformly dispersed with high reproducibility, resulting in a highly homogeneous hydrogel with reduced amount of precipitation.

In addition to the sudden temperature change of the solution, by using the change in the liquid level of the solution as an indicator for stopping the 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.

The hydrogel obtained by the hydrogel production method and hydrogel production apparatus of this embodiment is a highly homogeneous hydrogel in which a three-dimensional mesh structure is formed by covalent bonds. In a further aspect, the hydrogel has non-soluble microparticles uniformly dispersed in it, there is no precipitation of non-soluble microparticles 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.

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 accounts for 70% or less, preferably 50% or less, and more preferably 30% or less of the entire bottom surface. It is also preferable that the thickness of the precipitate at its thickest point is less than 2 mm, preferably less than 1.0 mm, and more preferably less than 0.5 mm.

The hydrogel of this embodiment is also 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, and more preferably 0.0.988 to 1.000.

Here, we actually produced hydrogel using the hydrogel production method and hydrogel production device of the example of the above embodiment, and confirmed its effects. The details are explained below.

In this Example 1, 58 g of acrylamide, the raw material of the hydrogel, and 0.3 g of N,N'-methylenebisacrylamide, the cross-linking agent, were added to 500 g of distilled water, the solvent, to which was added 3% by weight of aluminum oxide with a particle size of approximately 5 to 10 μm as non-soluble fine particles. In this Example 1, the hydrogel was produced using three solutions A-1, A-2, and A-3, which had the same compounding ratio of materials.

In this Example 1, solutions A-1, A-2, and A-3 were stirred using the hydrogel production device shown in Figure 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, and was positioned 2 mm above the bottom of the stirring vessel. By using the hydrogel production device 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.

As shown in Table 1, the stirring speed was set to the maximum speed (150 rpm) within the range where bubbles were not generated on the liquid surface during stirring. The solution that had been stored in a refrigerator at approximately 10°C was removed, and the temperature of the solution was increased while stirring at room temperature (25°C). When the temperature of the solution had risen 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 stirrer and thermometer were left in the solution to gel in order to observe the change in the liquid surface until the end.

The relationship between temperature change and liquid level change in three solutions A-1, A-2, and A-3 are shown in Figures 7 to 9, respectively. Note that in Figures 7 to 9, the point in time when the polymerization accelerator is added to the solution is shown as 0 seconds on the graph. The timing at which a sudden change in solution temperature occurs is also shown circled with a two-dot chain line.

As shown in Figure 7, in solution A-1, the temperature change began to become larger 234 seconds after the addition of the polymerization accelerator, and a sudden change in solution temperature was detected 242 seconds later (indicated by the white circle in Figure 7), between the start of the outer liquid level drop after 241 seconds and the start of the central liquid level rise after 252 seconds. Thus, in 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.

Furthermore, as shown in Figure 8, in solution A-2, the temperature change began to become larger 132 seconds after the addition of the polymerization accelerator, and a sudden change in solution temperature was detected between the point at which the outer liquid level started to drop after 137 seconds and the point at which the central liquid level started to rise after 153 seconds, and at 147 seconds (shown by the white circle in Figure 8). Thus, in solution A-2, the point at which the sudden change in solution temperature occurred was 6 seconds before the central liquid level started to rise.

Furthermore, as shown in Figure 9, in solution A-3, the temperature change began to become larger 134 seconds after the addition of the polymerization accelerator, and a sudden change in solution temperature was detected 153 seconds later (shown by the white circle in Figure 9), between the start of the outer liquid level drop after 149 seconds and the start of the central liquid level rise after 158 seconds. Thus, in solution A-3, the point at which the sudden change in solution temperature occurred was 5 seconds before the start of the central liquid level rise.

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

On the other hand, as shown in Figures 7 to 9, even if the solution has the same material mixing ratio, if the timing of adding the polymerization initiator and polymerization accelerator is different (not constant), there is a difference in the timing at which a sudden temperature change occurs in the solution after the polymerization accelerator is added.

In this Example 2, the timing of adding the polymerization initiator and polymerization accelerator was determined to determine the timing at which a sudden change in temperature of the solution occurs, and hydrogel was produced. In detail, the polymerization initiator was added when the temperature of the solution 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 this Example 2, hydrogel was produced using three solutions B-1, B-2, and B-3, which had the same material blend ratio as in Example 1. In this Example 2, the same hydrogel production device as in Example 1 was used, and hydrogel was produced under the same conditions as in Example 1. Stirring was stopped in solution B-2 upon detection of a sudden change in temperature.

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

As shown in Figure 10, a sudden change in temperature was observed in all three solutions at approximately the same time. In other words, by adjusting the timing of the addition of the polymerization initiator and polymerization accelerator, it was shown that 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 gelation of the solution, and to stop stirring, for solutions with the same material blend ratio. In solution B-2, a sudden change in temperature was detected 240 seconds after the addition of the polymerization accelerator, and stirring was stopped four seconds later, at 244 seconds.

In this Example 3, a hydrogel was produced using solution L, which has a different material blend ratio from Examples 1 and 2, and solution H, which contains 2.5 times the amount of crosslinking agent 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.

The temperature changes in the three solutions L and H are shown in Figure 11. Note that in Figure 11, the time when the polymerization accelerator was added to the solution is shown as 0 seconds on the graph.

As shown in Figure 11, a sudden change in temperature was detected in solution L 273 seconds after the addition of the polymerization accelerator, and in solution H 250 seconds after the addition of the polymerization accelerator. This indicates that solution H, which has a higher cross-linking agent concentration, experienced a sudden change in temperature earlier than solution L.

In addition, because solutions B-1, B-2, and B-3 (see FIG. 10) in Example 2 have a higher crosslinker concentration than solution H, a sudden temperature change occurs earlier than in solution H. From this, it is presumed that the higher the crosslinker concentration in the solution, the earlier the timing at which a sudden temperature change occurs. In addition, 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.

Here, in order to confirm the homogeneity of the hydrogel produced by the hydrogel production method and hydrogel production device of the present invention, the bottom surface of the hydrogel produced 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 stirrer and thermometer from the solution.

Comparative Example 1

Cylindrical hydrogels of the same size were produced using an aqueous solution with the same component ratio and the same mixing vessel as used in Example 2. As per the conventional method, stirring was performed manually with a stir bar, and stirring was stopped when resistance was felt.

As shown in FIG. 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), whereas as shown in FIG. 12(b), the precipitates at the bottom of the hydrogel (Example 2) produced by the hydrogel production method and hydrogel production device of the present invention were present only locally, with the area ratio of the precipitates over 2 mm to the entire bottom surface being 0%, and it was confirmed that the thickness was approximately 0.5 mm even at the thickest point.

Comparative Example 2

Next, similar to Comparative Example 1 described above, a more detailed comparison was made between a hydrogel produced by a conventional hydrogel production method (Comparative Example 2) and a hydrogel produced by the hydrogel production method and hydrogel production device of the present invention (Example 2), and the homogeneous dispersion characteristics of the non-soluble microparticles were evaluated.

As shown by the dots in Figures 13(a) and 14(a), the precipitates at the bottom of the hydrogel (Comparative Example 2) produced by the conventional hydrogel production method were present in a ring shape around the outer diameter, with the area ratio of the part with a thickness of 2 mm or more being about 52% and the thickest part being about 5 mm, whereas as shown by the dots in Figures 13(b) and 14(b), the precipitates at the bottom of the hydrogel (Example 2) produced by the hydrogel production method and hydrogel production device of the present invention were present only locally in the center, with the area ratio of the part with a thickness of 2 mm or more being about 3% and the thickest part being about 2 mm. In other words, it was confirmed that the area where precipitates exist is extremely small in the hydrogel produced by the hydrogel production method and hydrogel production device of the present invention compared to the conventional hydrogel production method.

Furthermore, as shown in Figures 14(a) and (b), the hydrogel produced by the hydrogel production method and hydrogel production device of the present invention was confirmed to have high homogeneity as evidenced by the high uniformity of the MRI images, compared to the conventional hydrogel production method. Note that, since the MRI imaging conditions are the same for the MRI images in Figures 14(a) and (b), the high uniformity was confirmed by calculating the standard deviation of the pixel values within the area where the hydrogel is present.

15(a), the density of the hydrogel obtained by the conventional hydrogel preparation method was 1.09 g/ ^cm3 in the upper region about 1 cm thick, and 1.12 g/ ^cm3 in the bottom region about 1 cm thick, which indicates that the density of the bottom is 2.7% higher than that of the upper portion, whereas the density of the hydrogel obtained by the hydrogel preparation method of the present invention was 1.10 g/ ^cm3 in the upper region about 1 cm thick, and 1.11 g/ ^cm3 in the bottom region about 1 cm thick, which indicates that the density of the bottom is 0.9% higher than that of the upper portion. In other words, the density difference between the top and bottom of the hydrogel obtained by the hydrogel preparation method of the present invention was suppressed to about 1/3 of that of the hydrogel obtained by the conventional hydrogel preparation method, and it was quantitatively confirmed that the hydrogel had high homogeneity.

In this way, it has been confirmed that the hydrogel production method and hydrogel production device of the present invention can uniformly mix 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.

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

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

The thermometer is not limited to being provided separately from the stirrer, but may be integrated into the rotating shaft of the stirrer, for example. This allows the solution to be stirred more uniformly.

Also, before stopping the stirring, the stirring speed may be reduced, for example to half, when a sudden temperature change in the solution is detected, or several seconds after that. This makes it possible to obtain a more homogeneous hydrogel that leaves no stirring marks.

In addition, in the above embodiment, the stirring means is described as stirring the solution in the stirring container using a stirrer having stirring blades, but the stirring means is not limited to this, and the solution in the stirring container may be stirred by vibrating and rotating the stirring container itself, such as a mixer or shaker.
[Industrial Applicability]

The present invention has industrial applicability as a hydrogel production method and hydrogel production device that can obtain highly homogeneous hydrogels that can be used as phantoms for elastography evaluation. Furthermore, the present invention can obtain highly homogeneous hydrogels that can be used as highly homogeneous biological tissue equivalent models (phantoms) that are necessary for the development, adjustment, evaluation, maintenance, inspection, and repair of MRI and ultrasound imaging devices, as well as for interpreting and examining images. Therefore, the hydrogel can be used to compare and evaluate measurement values between various imaging methods, manufacturers, products, etc. that use MRI or ultrasound, and standardization can be carried out based on these results, and the range of applications is wide.

Claims (11)

A method for producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonds, comprising the steps of:
A method for producing a hydrogel, comprising stirring a solution obtained by adding at least the raw material monomers of the hydrogel, a crosslinking agent, and a polymerization initiator to a solvent, and stopping the stirring upon detection of a sudden change in temperature of the solution. A method for producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonds, comprising the steps of:
A method for producing a hydrogel, comprising stirring a solution obtained by adding at least the raw material monomers of the hydrogel, a crosslinking agent, a polymerization initiator, and non-soluble microparticles to a solvent, and stopping the stirring upon detection of a sudden temperature change of the solution. The method for producing a hydrogel according to claim 1 or 2, characterized in that the hydrogel is a polyacrylamide polymer. The method for producing a hydrogel according to claim 1 or 2, characterized in that a polymerization accelerator is added to the solution at a predetermined timing. The method for producing a hydrogel according to claim 1 or 2, characterized in that the stirring is stopped within 10 seconds after the start of the rapid temperature change of the solution. The method for producing a hydrogel according to claim 1 or 2, characterized in that the sudden temperature change of the solution has a slope 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)). An apparatus for producing a highly homogeneous hydrogel in which a three-dimensional network structure is formed by covalent bonds, comprising:
A stirring means capable of stirring a solution obtained by adding at least raw material monomers of the hydrogel, a crosslinking agent, and a polymerization initiator to a solvent, and a control unit for controlling the stirring means;
A temperature measuring means capable of measuring the temperature of the solution;
A temperature change detection means capable of detecting a sudden change in temperature of the solution,
The control unit stops stirring the solution by the stirring means in response to detection of a sudden temperature change of the solution by the temperature change detection means. A hydrogel whose main component is a polyacrylamide polymer, with the density of the upper part being 0.985 to 1.000 compared to the density of the lower part, and in which a three-dimensional mesh structure is formed by covalent bonds. The hydrogel according to claim 8, characterized in that it contains non-soluble microparticles, the non-soluble microparticles being at least one selected from aluminum oxide, titanium oxide, silicon oxide, tungsten, nickel, molybdenum, polyethylene, polystyrene and graphite powder. The hydrogel described in claim 9, characterized in that the non-soluble microparticles at the bottom are more distributed in the inner diameter portion than in the outer diameter portion. A phantom for elastography evaluation comprising the hydrogel according to any one of claims 8 to 10.

Images