Method for producing a temperature-responsive hydrogel and temperature-responsive hydrogel

Abstract

The present invention provides a method for manufacturing a temperature-responsive hydrogel that can be produced more easily than conventional methods, and also provides a temperature-responsive hydrogel. [Solution] In the method for producing temperature-responsive hydrogel 1, the mixed solution 8 is gelled by the physical crosslinking of the raw materials of the physically crosslinked gel due to a change in temperature, and the excess portion that has bulged out from the depressions 11 is removed to produce a mixed gel 12 for each depression 11 (mixed gel production step). Next, the surface of the mixed gel 12 is covered with a covering substrate 15, and the mixed gel 12 is cured by chemical crosslinking of the temperature-responsive polymer through a curing treatment to obtain a temperature-responsive hydrogel 1 for each depression 11 (curing step).

Description

Technical Field

[0001] The present invention relates to a method for producing a temperature-responsive hydrogel and a temperature-responsive hydrogel. Background Art

[0002] In recent years, research has been conducted to apply hydrogels to drug delivery systems (DDS) and sensors. In order to use hydrogels in DDS and sensors, for example, it is necessary for the hydrogel to change its morphology in response to changes in ambient temperature. Non-Patent Documents 1 and 2 disclose that a layered hydrogel is produced by laminating materials having different physical properties on the front and back sides, and the morphology of the hydrogel is deformed due to the difference in elastic modulus of the materials when the temperature changes. Prior Art Documents Non-Patent Documents

[0003] Non-Patent Document 1 Wu et al., “Recent progress in the shape deformation of polymeric hydrogels from memory to actuation”Chemical Science,2021,12,6472-6487. Non-Patent Document 2 Malachowski et al., “Stimuli-Responsive Theragrippers for Chemomechanical Controlled Release”Angewandte Chemie International Edition,2014,53,8045-8049. Summary of the Invention Problems to be Solved by the Invention

[0004] However, conventional layered temperature-responsive hydrogels have complicated manufacturing processes, such as requiring multiple molding steps using molds and then aligning the resulting molded bodies to form the layered structure, which presents many challenges for practical application.

[0005] Therefore, the present invention aims to provide a method for producing a temperature-responsive hydrogel that can be manufactured more easily than conventional methods, and to provide a temperature-responsive hydrogel. [Means for solving the problem]

[0006] The present invention provides a method for producing a temperature-responsive hydrogel, comprising: a solution preparation step of preparing a mixed solution containing a raw material for a chemically crosslinked gel containing a temperature-responsive polymer and a raw material for a physically crosslinked gel that gels upon temperature change; an inflow step of pouring the mixed solution into a mold substrate having a plurality of recesses of a predetermined shape formed on its surface; a mixed gel preparation step of gelling the mixed solution by physical crosslinking of the raw material for the physically crosslinked gel due to temperature change, removing the excess portion bulging out of the recesses to produce a mixed gel for each recess; a curing step of covering the surface of the mixed gel with a coating substrate and curing the mixed gel by chemical crosslinking of the temperature-responsive polymer through a curing treatment to obtain a temperature-responsive hydrogel for each recess; and a separation step of separating the temperature-responsive hydrogel from the coating substrate and the recesses, respectively, to obtain a plurality of temperature-responsive hydrogels having an uneven shape on one side corresponding to the shape of the recesses and having different surface areas on the front and back sides.

[0007] Furthermore, the temperature-responsive hydrogel of the present invention comprises a chemically crosslinked gel formed by chemically crosslinking a temperature-responsive polymer and a physically crosslinked gel, and has an uneven surface on one side, with different surface areas on the front and back sides. [Effects of the Invention]

[0008] According to the present invention, a temperature-responsive hydrogel that changes shape in response to temperature changes can be manufactured without going through complicated manufacturing processes such as the alignment of molded bodies as in the past, thus making it easier to manufacture than in the past. [Brief explanation of the drawing]

[0009] [Figure 1] This is a perspective view showing the structure of the temperature-responsive hydrogel according to this embodiment. 1A is a perspective view showing the state of the temperature-responsive hydrogel when it is swollen at room temperature, and 1B is a perspective view showing the state of the temperature-responsive hydrogel when it is contracted at high temperature. [Figure 2] This flowchart shows a method for producing a temperature-responsive hydrogel according to this embodiment. [Figure 3] 3A is a cross-sectional view showing the structure of the mold substrate, 3B is a cross-sectional view showing the structure of the mixed gel fabricated on the surface of the mold substrate, 3C is a cross-sectional view illustrating the planarization treatment performed on the surface of the mixed gel, 3D is a cross-sectional view illustrating the curing treatment performed on the mixed gel, and 3E is a cross-sectional view showing the state of the temperature-responsive hydrogel when the coating substrate is separated from the mold substrate. [Figure 4] 4A is a TEM image of multiple temperature-responsive hydrogels prepared in a validation test, 4B is a TEM image of a temperature-responsive hydrogel cooled to 25°C, and 4C is a TEM image of a temperature-responsive hydrogel heated to 60°C. [Figure 5] This schematic diagram illustrates a method for manufacturing a temperature-responsive hydrogel according to another embodiment, where 5A is a cross-sectional view showing the state when a mold substrate into which a mixed solution has been poured is pressed against a coating substrate, and 5B is a schematic diagram showing the state when the coating substrate is moved relative to the mold substrate while being pressed against it. [Modes for carrying out the invention]

[0010] Embodiments of the present invention will be described in detail below with reference to the drawings. In the following description, the same reference numerals are used for identical components, and redundant descriptions are omitted.

[0011] <This embodiment> <Composition of temperature-responsive hydrogels> Figures 1A and 1B are perspective views showing the structure of the temperature-responsive hydrogel 1 according to this embodiment. Figure 1A is a perspective view showing the state of the temperature-responsive hydrogel 1 when it is in a swollen state at room temperature, and Figure 1B is a perspective view showing the state of the temperature-responsive hydrogel 1 when it is in a contracted state at high temperature. The temperature-responsive hydrogel 1 consists of a single layer structure formed from materials with the same physical properties on both sides. The temperature-responsive hydrogel 1 reversibly changes its morphology from a swollen state as shown in Figure 1A to a contracted state as shown in Figure 1B, for example, when the ambient temperature changes.

[0012] The temperature-responsive hydrogel 1, for example, is in a swollen state as shown in Figure 1, 1A, when the ambient temperature is room temperature (e.g., 25°C), and changes from the swollen state to the contracted state as shown in Figure 1, 1B, when the ambient temperature rises to or above the body temperature (e.g., 37°C). Conversely, the temperature-responsive hydrogel 1 is in a contracted state as shown in Figure 1, 1B, when the ambient temperature is above the body temperature, and changes from the contracted state to the swollen state as shown in Figure 1, 1A, when the ambient temperature drops to room temperature.

[0013] As shown in Figure 1A, the temperature-responsive hydrogel 1 at room temperature has a predetermined thickness and a three-dimensional shape in which, for example, a plurality of petal-shaped protrusions 2a are arranged radially from the central part 2b. When the temperature-responsive hydrogel 1 according to this embodiment is in a swollen state, for example, its width is approximately 100 to 300 [μm], and when it is in a contracted state, its width is approximately 40 to 120 [μm]. The temperature-responsive hydrogel 1 has a thickness of, for example, 12 to 25 [μm]. The width (size) and thickness of the temperature-responsive hydrogel 1 are examples and can be freely changed by selecting the size, depth, shape, etc. of the recesses 11, which will be described later.

[0014] One surface (hereinafter referred to as the front surface) 2 of the temperature-responsive hydrogel 1 and the other surface (hereinafter referred to as the back surface) 3 facing the front surface 2 have different surface shapes, and the surface areas of the front and back surfaces (front surface 2 and back surface 3) are different. A fine pattern of irregularities is formed on the surface 2 of the protruding portion 2a. The central part 2b has a polygonal outer shape in plan view, and its surface 2 is flat. In this embodiment, the surface 2 of the protruding portion 2a has grooves 4a formed at predetermined intervals, which extend linearly along the width direction perpendicular to the radial lines extending radially from the central part 2b as a fine pattern. In Figure 1A, for example, the dimension of the grooves 4a in the short direction is about 3 [μm], and the grooves 4a are formed at intervals of 3 [μm].

[0015] In the temperature-responsive hydrogel 1, the back surface 3 of the protruding portion 2a and the central portion 2b (not shown) is formed to be flat, similar to the surface 2 of the central portion 2b, and the surface area of ​​surface 2 is larger than the surface area of ​​back surface 3. Due to its chemical properties, the temperature-responsive hydrogel 1 in this embodiment dissolves in the aqueous medium and swells when the ambient temperature is low (i.e., room temperature), and shrinks as the polymer condenses as the ambient temperature rises. In addition, because the temperature-responsive hydrogel 1 has multiple grooves 4a formed on the surface 2 and the surface areas of the front and back surfaces are different, when it shrinks at high temperatures, each protruding portion 2a curves in an arc shape toward the back surface 3 side due to the curvature at the grooves 4a with lower strength (Figure 1, 1B).

[0016] As described above, the temperature-responsive hydrogel 1 of the present embodiment has a fine pattern formed on the front surface 2 by grooves 4a, which makes the surface areas of the front surface 2 and the back surface 3 different, thereby controlling the bending direction and bending mode (degree of contraction) of the protruding portions 2a. In this example, the temperature-responsive hydrogel 1 is configured such that a plurality of grooves 4a are respectively provided in petal-shaped protruding portions 2a, but the present invention is not limited thereto. As long as the surface areas of the front and back sides of the front surface 2 and the back surface 3 are different, the shape of the grooves 4a, the shape of the protruding portions 2a, and the like may be various other shapes such as curved grooves and elliptical protruding portions. In addition, for the temperature-responsive hydrogel 1, it is preferable to adjust the fine pattern on the front surface 2 and the outer contour shapes of the protruding portions 2a and the central portion 2b according to applications such as drug delivery systems (DDS) and sensors, for example. In order to obtain a desired bending mode, the shape, width, length, and depth of the irregularities on the front surface 2 of the protruding portions 2a may be changed, and the front surface 2 of the protruding portions 2a may also be formed into irregularities such as circular shapes, polygonal shapes, and patterns.

[0017] When the temperature-responsive hydrogel 1 is used in a drug delivery system (DDS), for example, a drug or the like is supported in the grooves 4a of the temperature-responsive hydrogel 1 which is in a swollen state at an ambient temperature such as room temperature (e.g., 25°C). The temperature-responsive hydrogel 1 supporting the drug or the like is injected into the blood vessels of a human body or an animal. When the temperature of the temperature-responsive hydrogel 1 rises due to body temperature, the hydrogel enters a contracted state, and the grooves 4a expand, thereby allowing the drug or the like to be released into the blood vessel. In addition, the temperature-responsive hydrogel 1 can be placed in various environments, and changes in ambient temperature can be detected by observing changes in the morphology of the temperature-responsive hydrogel 1, so the hydrogel can also be used as a sensor.

[0018] The temperature-responsive hydrogel 1 includes a chemically crosslinked gel and a physically crosslinked gel. The chemically crosslinked gel is a polymer obtained by chemical crosslinking of a temperature-responsive polymer to form a gel, and is formed from a raw material of the chemically crosslinked gel containing the temperature-responsive polymer. The physically crosslinked gel is a polymer obtained by gelation of a raw material of the physically crosslinked gel due to temperature change, and is formed from the raw material of the physically crosslinked gel.

[0019] As the temperature-responsive polymer, for example, any polymer containing at least one or more selected from (meth)acrylamide-based, N-vinylamide-based, (meth)acrylate-based and polyether-based polymers may be used.

[0020] Examples of the (meth)acrylamide-based polymer include NIPAM (N-isopropylacrylamide) gel, NEAM (N-ethylacrylamide), NPAM (N-propylacrylamide), and NIPMAM (N-isopropylmethacrylamide).

[0021] Examples of the N-vinylamide-based polymer include VCL (N-vinylcaprolactam).

[0022] Examples of the (meth)acrylate-based polymer include HEMA (2-hydroxyethyl methacrylate).

[0023] Examples of polyether-based polymers include Pluronic, PEOEMA (poly(2-ethoxyethyl methacrylate)), and PMEMA (poly(2-methoxyethyl methacrylate)).

[0024] Furthermore, as a raw material for the chemically crosslinked gel, a wizard gel, which is known as a self-healing material, may be used.

[0025] Raw materials for the chemically crosslinked gel include, if necessary, a crosslinking agent such as MBAA (N,N'-methylenebis(acrylamide)) and a polymerization initiator such as TPO (diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide).

[0026] As a raw material for the physically crosslinked gel, for example, any material containing at least one or more selected from agar, gelatin and collagen may be used.

[0027] <Method for producing temperature-responsive hydrogel> Next, the method for producing the temperature-responsive hydrogel 1 in this embodiment will be described. Figure 2 is a flowchart showing the method for producing the temperature-responsive hydrogel 1. As shown in Figure 2, first, in step S1, the raw materials for the chemically crosslinked gel and the raw materials for the physically crosslinked gel described above are mixed in a solvent to produce a mixed solution (solution preparation step). As the solvent, for example, an aqueous solution of SDS (sodium dodecyl sulfate) (sodium dodecyl sulfate solution) or a liquid such as water can be used. The ratio in which the raw materials for the chemically crosslinked gel and the raw materials for the physically crosslinked gel are dissolved in the solvent is preferably, for example, 7:1 by weight. By adjusting the ratio of the raw materials for the chemically crosslinked gel and the raw materials for the physically crosslinked gel, a balance between physical and chemical crosslinking can be achieved, allowing the structure to be maintained with the physically crosslinked gel while deformation can be achieved with the temperature-responsive chemically crosslinked gel. A polymerization initiator may also be added. As a polymerization initiator, for example, TPO (diphenyl (2,4,6-trimethylbenzoyl)phosphine oxide) or Irgacure 2959 can be used. A mixed solution may be prepared by dissolving the raw materials for the chemically crosslinked gel, the raw materials for the physical crosslinked gel, and the polymerization initiator in water, and then mixing in SDS. Alternatively, an aqueous solution of SDS may be prepared, and then the raw materials for the chemically crosslinked gel, the raw materials for the physical crosslinked gel, and the polymerization initiator may be dissolved in it to create a mixed solution.

[0028] In addition to step S1, a mold substrate is prepared for into which the mixed solution obtained in step S1 is poured. Here, 3A in Figure 3 is a cross-sectional view showing the structure of the mold substrate 10. The mold substrate 10 is made of a silicon substrate such as PDMS (polydimethylsiloxane), and a plurality of recesses 11 having a predetermined shape are formed on its surface at predetermined intervals. In this case, the shape of the recesses 11 of the mold substrate 10 corresponds to the shape of the fine pattern formed on the surface 2 of the temperature-responsive hydrogel 1 shown in 1A in Figure 1. In this embodiment, for example, a transfer substrate having a plurality of convex fine patterns is made by grayscale lithography using a maskless exposure apparatus (D-light DL-1000GS / KCH). Then, the convex shape of the fine pattern of the transfer substrate is transferred to a silicon member, and a mold substrate 10 is made in which a plurality of recesses 11 are formed on its surface at predetermined intervals.

[0029] Next, in step S2, the mixed solution obtained in step S1 is poured into the pre-prepared mold substrate 10 (inflow step). In this embodiment, for example, the mixed solution heated in a constant temperature bath at 95°C for 2 hours is poured into each recess 11 of the mold substrate 10. This fills all the recesses 11 of the mold substrate 10 with the mixed solution 8, as shown in 3B of Figure 3. Furthermore, in order to ensure that the mixed solution 8 reaches the fine details of the recesses 11 which have fine patterns, it is preferable to fill the mold substrate 10 so that the mixed solution bulges out from the surface of the mold substrate 10. In 3B of Figure 3, the mixed solution 8 is raised over the entire surface of the mold substrate 10 due to surface tension. Note that the heating temperature and time in the constant temperature bath are examples and are not limited thereto.

[0030] Next, in step S3, the mixed solution 8 on the mold substrate 10 is cooled to produce a mixed gel 12 (gelling step of the mixed gel production process). In the mixed gel production process, the mixed solution 8 is gelled to produce the mixed gel 12 by polymerizing the physical crosslinking gel raw materials contained in the mixed solution 8 by a temperature change. In the gelling step, the mixed gel 12 is formed, which is a physical gel whose crosslinking is oxygen-independent, in order to prevent polymerization defects during the curing process described later. The mixed solution 8 may be cooled by, for example, lowering the temperature around the mold substrate 10 into which the mixed solution 8 is poured, cooling the mold substrate 10 itself to cool the mixed solution 8 from the mold substrate 10 and gel it, or lowering the ambient temperature while also cooling the mold substrate 10 itself. For example, the mixed solution 8 may be cooled by leaving it at room temperature or in a refrigerator.

[0031] Next, in step S4, as shown in 3C of Figure 3, the surface of the mixed gel 12 that has bulged out of the mold substrate 10 is flattened by a planarization process, leaving the mixed gel 12 in the recesses 11, and a mixed gel 12 is produced for each recess 11 (planarization step of the mixed gel production process). The excess portion of the mixed gel 12 that has bulged out of the recesses 11 is removed.

[0032] As part of the planarization process, for example, the tip of a plate-shaped squeegee 13 is moved along the surface of the mold substrate 10 to remove excess mixed gel 12 that has bulged out of the recesses 11. This removes excess mixed gel 12 between adjacent recesses 11 14, leaving the mixed gel 12 only within the recesses 11, and creating a mixed gel 12 with a flattened surface exposed to the outside for each recess 11. In the mold substrate 10, the mixed gel 12 in adjacent recesses 11 does not come into contact with each other, and the mixed gel 12 is formed for each recess 11.

[0033] Next, in step S5, as shown in 3D in Figure 3, the surface of the mixed gel 12 (3C in Figure 3) is covered with a light-transmitting covering substrate 15 such as a glass plate, and the mixed gel 12 is cured by a curing process to obtain a temperature-responsive hydrogel 1 for each recess 11 (curing process). In this embodiment, the covering substrate 15 is placed on the surface of the mold substrate 10 to seal the mixed gel 12 formed in the recess 11. By covering the mixed gel 12 with the covering substrate 15 in this way, drying of the mixed gel 12 can be prevented, and the intrusion of oxygen into the mixed gel 12 in the recess 11 can be blocked. Then, a photocuring process (curing process) is performed in this state.

[0034] As part of the photocuring process, UV light 16 is irradiated onto the coated substrate 15. The UV light 16 penetrates the coated substrate 15 and irradiates the mixed gel in each recess 11 of the mold substrate 10. This causes the mixed gel 12 to harden by radical polymerization of the chemical crosslinked gel raw materials contained in the mixed gel 12 through a photocuring reaction, thereby producing a temperature-responsive hydrogel 1. In the photocuring process, it is preferable to increase the degree of adhesion of the temperature-responsive hydrogel 1 to the coated substrate 15 when radical polymerization of the chemical crosslinked gel raw materials is performed to produce the temperature-responsive hydrogel 1, for example, by increasing the output of the UV light 16 or increasing the irradiation time.

[0035] Next, in step S6, the temperature-responsive hydrogel 1 is separated from the mold substrate 10 as shown in 3E of Figure 3 (separation step). In this example, the temperature-responsive hydrogel 1 can be separated from the recess 11 by deforming the mold substrate 10. As a result, the back surface 3 of the temperature-responsive hydrogel 1 remains attached to the surface of the coating substrate 15. Thus, in the separation step, since the temperature-responsive hydrogel 1 is attached to the coating substrate 15, the temperature-responsive hydrogel 1 with a fine pattern can be easily separated from the recess 11. The inner wall shape of the recess 11 is transferred to the surface 2 of the temperature-responsive hydrogel 1, and a shape identical to that inner wall shape is formed. Note that 3E of Figure 3 shows the state in which the temperature-responsive hydrogel 1 is attached to the coating substrate 15.

[0036] Next, in step S7, multiple temperature-responsive hydrogels 1 can be obtained by separating each temperature-responsive hydrogel 1 from the coated substrate 15 (separation step). The temperature-responsive hydrogel attached to the coated substrate 15 can be separated from the surface of the coated substrate 15 by, for example, placing the coated substrate 15 with the temperature-responsive hydrogel 1 attached into a container containing a liquid such as water, and immersing the temperature-responsive hydrogel 1 in the liquid. Alternatively, the temperature-responsive hydrogel 1 may be separated from the surface of the coated substrate 15 by cutting it off with a sharp blade such as a cutter.

[0037] <Verification Test> Next, following the "<Method for Manufacturing Temperature-Responsive Hydrogels>" described above, a temperature-responsive hydrogel 1 was actually manufactured, and a verification test was conducted to confirm the change in morphology of the temperature-responsive hydrogel 1 due to temperature changes. In Example 1, 2.134 g of NIPAM (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and 0.076 g of MBAA (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were dissolved in 10 ml of pure water as raw materials for a chemically crosslinked gel containing a temperature-responsive polymer, and then dissolved in 1.0 g of SDS solution (manufactured by Tokyo Chemical Industry Co., Ltd.) to prepare a solution. 0.1 g of TPO (diphenyl (2,4,6-trimethylbenzoyl)phosphine oxide), a polymerization initiator, was added to the obtained solution. Mixed solution 8 was prepared by adding 0.3 g of agar (agarose KANTO ST (manufactured by Kanto Chemical Co., Ltd.)) as a raw material for a physically crosslinked gel and mixing it.

[0038] On the other hand, in order to fabricate the mold substrate 10, a 3D model was created using 3D CAD (Creo), and then converted to a grayscale image using 3D modeling software (Blender). Using this grayscale image, a silicon substrate with multiple convex fine patterns was fabricated by grayscale lithography using a maskless exposure apparatus (D-light DL-1000GS / KCH), and this was used as the transfer substrate. Next, PDMS was poured onto the surface of the transfer substrate and heated at 100°C to fabricate a mold substrate 10 with multiple recesses 11 formed on the surface at predetermined intervals.

[0039] Then, the prepared mixed solution 8 was heated in a constant temperature bath at 95°C for 2 hours, and then poured onto the mold substrate 10 until the mixed solution 8 bulged out from the surface of the mold substrate 10 due to surface tension.

[0040] Next, the mixed solution 8 was cooled in a refrigerator. To cool the mixed solution 8, the mold substrate 10 was cooled to 5°C for 10 minutes in the refrigerator. As a result, the mixed solution 8 gelled and a mixed gel 12 was obtained. Then, the excess mixed gel 12 that had expanded from the mold substrate 10 was removed with a squeegee 13 to flatten the surface of the mixed gel 12, leaving the mixed gel 12 only in each recess 11.

[0041] A glass plate was prepared as the covering substrate 15, and the covering substrate 15 was placed on the surface of the mold substrate 10 to block the intrusion of oxygen. Then, UV light (36[W]) was irradiated onto the covering substrate 15, and the UV light was irradiated from the covering substrate 15 toward the mixed gel 12 in each recess 11 for more than 5 minutes.

[0042] After irradiation with UV light, the gelled material formed in each recess 11 was separated from the recess 11 of the mold substrate 10 while remaining attached to the surface of the coated substrate 15 (Figure 3, 3E). When the gelled material attached to the surface of the coated substrate 15 was observed using a TEM (transmission electron microscope), the TEM image shown in Figure 4, 4A was obtained. From Figure 4, 4A, it was confirmed that the inner wall shape of the recess 11 was transferred to the surface of the gelled material, and that a fine pattern almost identical to the 3D model created with 3D CAD was formed. Furthermore, it was confirmed that the gelled material had hardened on the coated substrate 15.

[0043] Next, the surface of the coated substrate 15 to which the gelling substance was attached was immersed in water to separate the gelling substance from the surface of the coated substrate 15. Then, the water containing the separated gelling substance was heated to 25°C, and the gelling substance was observed by TEM, resulting in the TEM image shown in Figure 4, 4B. Furthermore, the water containing the gelling substance was heated to 60°C, and the gelling substance was observed by TEM, resulting in the TEM image shown in Figure 4, 4C.

[0044] From the TEM images shown in Figure 4B and Figure 4C, it was confirmed that at room temperature, the gelling material was in a swollen state. As the temperature was increased from room temperature to 60°C, the swollen gelling material changed to a contracted state. Furthermore, as the temperature was decreased from 60°C back to room temperature, the contracted gelling material changed back to a swollen state. From these results, it was confirmed that the gelling material is a temperature-responsive hydrogel 1 whose morphology reversibly changes in response to changes in ambient temperature.

[0045] As a comparative example, a solution was prepared by dissolving 2.134 g of NIPAM and 0.076 g of MBAA in an SDS solution as raw materials for a chemically crosslinked gel containing a temperature-responsive polymer, without including the raw materials for the physically crosslinked gel, and otherwise in the same manner as in Example 1. Furthermore, 0.1 g of TPO, a polymerization initiator, was added to the solution. The obtained comparative example solution was poured onto the mold substrate 10 until the solution bulged from the surface of the mold substrate 10 due to surface tension. Then, UV light (36 W) was irradiated onto the solution for more than 5 minutes. However, it was confirmed that the solution on the mold substrate 10 had not fully cured. This is thought to be because, when the solution was poured onto the mold substrate 10, oxygen was present in the recessed areas 11 of the microstructure, resulting in localized oxygen excess and preventing radical polymerization from proceeding. In other words, as the curing of the raw materials for the chemically crosslinked gel containing the temperature-responsive polymer begins, the viscosity increases, but polymerization inhibitors such as oxygen at the interfaces of the fine patterns are difficult to degas (degas), and their presence is presumed to gradually increase. As a result, the radical polymerization reaction of the raw materials for the chemically crosslinked gel containing temperature-responsive polymers is inhibited, which is likely to lead to poor curing.

[0046] From the above, it was confirmed that when using a mold substrate 10 having fine patterned recesses 11, even if the solution contains raw materials for a chemically crosslinked gel containing a temperature-responsive polymer that hardens by light irradiation, if it does not contain raw materials for a physically crosslinked gel, it will not harden sufficiently even with light irradiation. In contrast, in a mixed solution containing raw materials for a chemically crosslinked gel that gels with temperature changes in addition to raw materials for a temperature-responsive polymer, it was confirmed that the polymer that has been physically crosslinked and gelled by temperature changes acts as a scaffold, and the raw materials for the chemically crosslinked gel containing a temperature-responsive polymer can be hardened by the curing process without inhibition by polymerization inhibitors such as oxygen at the interface.

[0047] <Mechanism and Effects> According to the above configuration, the method for producing the temperature-responsive hydrogel 1 involves preparing a mixed solution 8 containing raw materials for a chemically crosslinked gel that includes a temperature-responsive polymer and raw materials for a physically crosslinked gel that gels upon temperature change (solution preparation step). Then, the mixed solution 8 is poured into a mold substrate 10 having a plurality of recesses 11 of a predetermined shape formed on its surface (inflow step). Next, the mixed solution 8 is gelled by the physical crosslinking of the raw materials for the physically crosslinked gel due to the temperature change, and the excess portion that has bulged out from the recesses 11 is removed to produce a mixed gel 12 for each recess 11 (mixed gel production step). Subsequently, the surface of the mixed gel 12 is covered with a covering substrate 15, and the mixed gel 12 is cured by chemical crosslinking of the temperature-responsive polymer through a curing process to obtain a temperature-responsive hydrogel 1 for each recess 11 (curing step). Subsequently, the temperature-responsive hydrogel 1 is separated from the coated substrate 15 and the recessed area 11, respectively, and multiple temperature-responsive hydrogels 1 with different surface areas on the front and back surfaces, each having an uneven surface shape corresponding to the shape of the recessed area 11, can be manufactured (separation step).

[0048] As a result, the method for manufacturing the temperature-responsive hydrogel of this embodiment makes it possible to manufacture a temperature-responsive hydrogel 1 that changes shape in response to temperature changes without going through complicated manufacturing processes such as the alignment of molded bodies as in the conventional method, and thus it can be manufactured more simply than in the conventional method.

[0049] Furthermore, the mixed gel production process according to this embodiment includes a gelation step and a planarization step. In the gelation step, the mixed solution 8 is gelled by physical crosslinking of the raw materials of the physically crosslinked gel due to a temperature change to produce the mixed gel 12. The gelation step ensures that the mixed solution 8 is reliably gelled. In the planarization step performed after the gelation step, the surface of the mixed gel 12 that has bulged from the mold substrate 10 is planarized by a planarization treatment, leaving the mixed gel 12 in the recesses 11, and producing mixed gel 12 in each recess 11. Since the mixed solution 8 is reliably gelled by the gelation step, the surface of the mixed gel 12 can be easily and reliably planarized, and excess mixed gel 12 can be removed, leaving the mixed gel 12 only in the recesses 11.

[0050] <Other Embodiments> In the embodiments described above, the mixed gel preparation process includes a gelation step and a planarization step. However, the present invention is not limited to this, and the mixed solution 8 may be gelled while the gelled surface is planarized at the same time.

[0051] In this case, in the flowchart showing the method for manufacturing a temperature-responsive hydrogel, as shown in Figure 2, the steps from step S2 onward are the following mixed gel manufacturing steps. As shown in Figure 5A, the mixed solution 8 bulging from the recess 11 is pressed onto the temperature-controlled coating substrate 15, and as shown in Figure 5B, the coating substrate 15 is moved relative to the surface. Note that in Figure 5A, the mold substrate 10 into which the mixed solution 8 is poured is pressed onto the coating substrate 15 upside down, but even if the mold substrate 10 is upside down, the mixed solution 8 will not fall out of the recess 11 due to surface tension and the start of gelation of the raw materials for the physically crosslinked gel due to the ambient temperature (other configurations where the mold substrate 10 is not upside down will be described later). The mixed solution 8 and / or mixed gel 12 in contact with the coating substrate 15 gel on the surface of the cooled coating substrate 15 and easily adhere to that surface. Therefore, by moving the coated substrate 15 relative to the surface in the planar direction, the excess portion that has bulged out from the recess 11 remains on the surface of the coated substrate 15, and the excess mixed solution 8 and / or mixed gel 12 can be removed.

[0052] In this way, the mixed solution 8 is gelled by the physical crosslinking of the raw materials of the physically crosslinked gel due to temperature changes, and the mixed solution 8 and / or mixed gel 12 that have swollen out of the recesses 11 are removed, thereby producing a mixed gel 12 for each recess 11. Next, as a curing step, the surface of the mixed gel 12 may be covered with the coating substrate 15 used in the mixed gel production step, and the mixed gel 12 may be cured by a curing treatment to obtain a temperature-responsive hydrogel 1 for each recess 11. As a result, since the curing treatment can be performed with the mixed gel 12 covered by the coating substrate 15, the raw materials of the chemically crosslinked gel containing a temperature-responsive polymer can be cured by a curing treatment without inhibition by polymerization inhibitors such as oxygen at the interface.

[0053] Furthermore, in the other embodiments described above, a case was described in which the mold substrate 10 into which the mixed solution 8 is poured is inverted and pressed against the coating substrate 15, as shown in 5A of Figure 5, but the present invention is not limited to this. In other embodiments, for example, with the surface of the mold substrate 10 into which the mixed solution 8 is poured facing upwards, the temperature-controlled (cooled) coating substrate 15 may be pressed from above toward the surface of the mold substrate 10 located below, and the coating substrate 15 may be moved relative to it in the planar direction. Alternatively, the temperature-controlled (heated) coating substrate 15 may be pressed against the mold substrate 10 after the mixed solution 8 has been poured into it and has begun to increase in viscosity due to cooling at the ambient temperature, thereby redissolving the mixed solution 8, and then the coating substrate 15 may be moved relative to it in the planar direction.

[0054] Furthermore, in other embodiments, the separation step described above may include a modification step described later. For example, after step S6 shown in Figure 2, if necessary, a modification treatment may be performed on the coating substrate 15 to which the back surface 3 of the temperature-responsive hydrogel 1 is attached, and the surface 2 exposed to the outside of the temperature-responsive hydrogel 1 may be modified with a predetermined substance such as a functional group that adsorbs the substance to be adsorbed or a self-healing substance (modification step). In this case, since the back surface 3 of the temperature-responsive hydrogel 1 is attached to the coating substrate 15, only the surface 2 can be modified with a predetermined substance such as a functional group that adsorbs the substance to be adsorbed or a self-healing substance. Then, after the modification step, the temperature-responsive hydrogel 1 is separated from the coating substrate 15. As described above, since the back surface 3 is covered with the coating substrate 15 during the modification step, a temperature-responsive hydrogel 1 can be easily manufactured in which the drug, etc. is not supported on the back surface 3, but only on the grooves 4a of the surface 2. [Explanation of Symbols]

[0055] 1. Temperature-responsive hydrogel 8 Mixed solution 10-inch circuit board 12 Mixed gel 15 Coated substrate

Claims

1. A solution preparation step for preparing a mixed solution containing raw materials for a chemically crosslinked gel containing a temperature-responsive polymer and raw materials for a physically crosslinked gel that gels upon temperature change, An inflow step of pouring the mixed solution into a mold substrate having a plurality of recesses of a predetermined shape formed on its surface, A mixed gel production step involves gelling the mixed solution by physically crosslinking the raw materials of the physically crosslinked gel due to temperature changes, removing the excess portion that has bulged out from the depressions, and producing a mixed gel for each of the depressions. A curing step is to cover the surface of the mixed gel with a coating substrate and cure the mixed gel by chemical crosslinking of the temperature-responsive polymer through a curing treatment to obtain a temperature-responsive hydrogel for each of the recesses, The separation step includes separating the temperature-responsive hydrogel from the coating substrate and the recess, respectively, to obtain a plurality of temperature-responsive hydrogels having an uneven shape corresponding to the shape of the recess on one side and having different surface areas on the front and back sides. A method for producing temperature-responsive hydrogels.

2. The aforementioned mixed gel preparation process is as follows: A gelling step in which the mixed solution is gelled by the physical crosslinking of the raw materials of the physically crosslinked gel due to a temperature change, and the mixed gel is produced. The process includes a planarization step in which the surface of the mixed gel bulging from the mold substrate is planarized by a planarization treatment to leave the mixed gel in the recesses, thereby producing the mixed gel in each of the recesses. A method for producing a temperature-responsive hydrogel according to claim 1.

3. The aforementioned mixed gel preparation process is as follows: By pressing the temperature-controlled coating substrate against the mixed solution bulging out of the recess and moving it relative to it, the mixed solution is gelled by the physical crosslinking of the raw materials of the physically crosslinked gel due to the temperature change, while the mixed solution and / or the mixed gel bulging out of the recess are removed to produce a mixed gel for each recess. The aforementioned curing step is The surface of the mixed gel is then covered with the coating substrate used in the mixed gel preparation process, and the mixed gel is cured by the curing treatment to obtain the temperature-responsive hydrogel for each of the recesses. A method for producing a temperature-responsive hydrogel according to claim 1.

4. The temperature-responsive polymer comprises at least one of NIPAM (N-isopropylacrylamide), VCL (N-vinylcaprolactam), and HEMA (2-hydroxyethyl methacrylate). A method for producing a temperature-responsive hydrogel according to claim 1.

5. The raw materials for the aforementioned physically cross-linked gel include at least one of agar, gelatin, or collagen. A method for producing a temperature-responsive hydrogel according to claim 1.

6. The separation step includes, after separating the temperature-responsive hydrogel from the recess, a modification step in which the back surface of the temperature-responsive hydrogel is attached to the coating substrate, and the surface exposed to the outside of the temperature-responsive hydrogel is modified with a predetermined substance, and after the modification step, the temperature-responsive hydrogel is separated from the coating substrate. A method for producing a temperature-responsive hydrogel according to claim 1.

7. The material comprises a chemically crosslinked gel and a physically crosslinked gel, both formed by chemically crosslinking temperature-responsive polymers, with one surface having an uneven shape and different surface areas on the front and back surfaces. Temperature-responsive hydrogel.

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