JP6969080B2 - Hydrogel structure, and its manufacturing method and application - Google Patents

Description

The present invention relates to a hydrogel structure, and a method and application thereof.

Vascular treatment mainly includes treatment of aneurysms (aneurysms), bypassing, cutting, and anastomosis of blood vessels.
These vascular treatments are often performed by intubating a catheter, which is a wire-shaped instrument, into the blood vessel. Regarding the catheter intubation, it is necessary to perform a procedure training, and the procedure training is performed using an animal other than a human when the human body is not used, or by using a blood vessel model.

However, in the above-mentioned procedure training, when an animal other than human is used, blood vessels exist in the body, so catheter intubation is performed by irradiating the affected area with X-rays to visualize the blood vessels. Therefore, when the procedure training is repeatedly performed, there is a problem that the X-ray exposure dose of the operator increases.
Therefore, a catheter treatment simulator formed of a transparent material has been proposed (see, for example, Patent Document 1).

It is also used for a blood vessel model that imitates a patient's blood vessel (see, for example, Patent Document 2), a vascular lesion model formed from a plurality of small lesions having different hardness (for example, see Patent Document 3), and a preoperative simulation. A method for manufacturing a blood vessel model (see, for example, Patent Document 4) has been proposed.

An object of the present invention is to provide a hydrogel structure in which the texture when a medical device such as a catheter is inserted is close to that of an actual blood vessel or the like.

The hydrogel structure of the present invention as a means for solving the above-mentioned problems contains water and a polymer, has a hollow tube shape, and has a coefficient of static friction of at least a part of the inner wall of the hollow tube shape. It is 1 or less.

According to the present invention, it is possible to provide a hydrogel structure in which the texture at the time of insertion of a medical device such as a catheter is close to that of an actual blood vessel or the like.

FIG. 1 is a schematic view showing an example of a blood vessel model (hydrogel structure) of the present invention. FIG. 2 is a schematic view showing an example of the blood vessel model (hydrogel structure) of the present invention. FIG. 3A is a schematic top view showing an example of a hydrogel structure to which a transparent hard body is attached. FIG. 3B is a schematic side view showing an example of a hydrogel structure to which a transparent hard body is attached. FIG. 4 is a schematic view showing an example of a modeled body manufacturing process using a three-dimensional modeling apparatus used in the method for manufacturing a hydrogel structure of the present invention. FIG. 5 is a schematic view showing an example (additive manufacturing method) of a three-dimensional modeling apparatus used in the method for manufacturing a hydrogel structure of the present invention. FIG. 6 is a schematic view showing an example of mixing the first liquid and the second liquid by the droplet ejection method. FIG. 7 is a schematic view showing an organ model in which the outer shape imitates the shape of an organ (liver) as one form of the hydrogel structure of the present invention.

(Hydrogel structure, blood vessel model, and organ model)
The hydrogel structure of the present invention contains water and a polymer, has a hollow tube shape, has a static friction coefficient of at least a part of the inner wall of the hollow tube shape of 0.1 or less, and is the hydrogel structure. It is preferable that the hydrogel further contains a mineral and contains the water in a three-dimensional network structure formed by complexing the polymer and the mineral. The hydrogel means a gel containing water as a main component.
The hydrogel structure of the present invention has a problem that the conventional catheter treatment simulator cannot be applied to 3D printing that can reproduce a complicated shape and a shape according to patient personal data because the manufacturing method is limited depending on the material used. In addition, the created blood vessel model can only be placed on a two-dimensional plane, and has the disadvantage that the actual three-dimensional structure cannot be reproduced. It is also based on the finding that there is a problem that it cannot be applied.
Further, the hydrogel structure of the present invention is produced by three-dimensionally modeling a flexible material such as silicone rubber in the conventional blood vessel model, but it is an opaque model and the texture is also the same as that of an actual blood vessel. Is based on the finding that there is a problem that is different.
Further, the hydrogel structure of the present invention has a problem that, in the conventional vascular lesion model, a plurality of materials are required to form a plurality of small lesions having different hardness. In addition, it is based on the finding that it is difficult to reproduce a detailed structure because it is modeled by a mold, and it is difficult to model based on patient personal data.
Furthermore, the hydrogel structure of the present invention can form a somewhat complicated shape by the conventional method for manufacturing a blood vessel model, but the transmittance of the blood vessel model is not high, and the texture is similar to that of an actual blood vessel. Is based on the finding that there is a problem that is different.

The blood vessel model of the present invention comprises the hydrogel structure of the present invention.
The blood vessel model is not particularly limited and may be appropriately selected depending on the intended purpose, but it is preferable to reproduce the blood vessel model based on the shape of the blood vessel of the site to be treated by the patient.
The organ model of the present invention comprises the hydrogel structure of the present invention, and its outer shape imitates the shape of an organ.

The hydrogel structure, blood vessel model, and organ model of the present invention can be suitably used for catheter intubation procedure training or preoperative simulation.

In the hydrogel structure of the present invention, for example, the tip portion of the hollow tube may be thin, the middle portion may be thin, and one end opening may be thinner than the other end opening. Further, it may be branched or dendritic, and a vascular shape as shown in FIG. 1 is preferable.
The structure may be communicated, may have a closed portion in a part of the pipe, or may have a closed end. Further, the hollow pipe may be a double pipe or may be laminated.

The hydrogel structure of the present invention has a hollow tube shape.
The hollow tube shape is not particularly limited as long as it is hollow, and can be appropriately selected depending on the purpose such as shape, structure, and size.
The shape is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the tip of the hollow tube may be thin, the middle part may be thin, and the opening at one end may be thin. It may be thinner than the other end opening. Further, it may be branched or dendritic, and a vascular shape as shown in FIG. 1 is preferable.
The structure may be communicated, may have a closed portion in a part of the pipe, or may have a closed end. Further, the hollow pipe may be a double pipe or may be laminated.
The size is not particularly limited and may be appropriately selected depending on the intended purpose.

The hollow tube shape includes, for example, blood vessels, lymphatic vessels, esophagus, nasal cavity, external auditory canal, pharynx, throat, oral cavity, trachea, bronchi, bronchi, gastric, small intestine (for example, duodenum, jejunum, ileum, etc.), large intestine (for example, duodenum, jejunum, ileum, etc.) For example, the shape of the cecum, colon, ileum, anal canal, etc.), pancreatic duct, cystic duct, esophagus, bile duct, etc. can be used for various preoperative simulations, procedure practice, and the like.

The hydrogel structure having the blood vessel shape can be suitably used as a blood vessel model.
The blood vessel model is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include those that reproduce arteries, veins, capillaries and the like.
FIG. 1 is a schematic view showing an example of a blood vessel model (hydrogel structure) of the present invention. As shown in FIG. 1, it has a blood vessel wall portion 51 and a blood vessel cavity portion 50. By adjusting the thickness of the blood vessel wall, the texture at the time of catheter insertion can be changed. For example, by increasing the thickness of the blood vessel membrane, it is possible to reproduce the texture of a blood vessel or the like that has been hardened due to a disease or the like.
The hydrogel structure may be provided with a liquid inflow port and a liquid circulation device may be attached in order to allow a liquid imitating blood to flow into the blood vessel model.

FIG. 2 is a schematic view showing an example of the hydrogel structure of the present invention. As shown in FIG. 2, the handleability and storage stability are improved by forming a structure in which the blood vessel model 52 having the blood vessel cavity portion 50 and the blood vessel wall portion 51 made of hydrogel is covered with another structure 53. Can be done. The other structure 53 may be a hydrogel, and in that case, the other structure 53 may also have a structure that also serves as a blood vessel wall portion 51 (in the other structure 53 that is a hydrogel). Hydrogel structure containing the cavity 50).

Further, the other structure 53 may have an outer shape imitating an organ, and can be suitably used as an organ model.

The organ model is not particularly limited and can be appropriately selected according to the purpose, and can reproduce any internal organs in the human body. For example, the brain, heart, bladder, as shown in FIG. Liver, kidney, pancreas, spleen, gallbladder, uterus, etc.

The coefficient of static friction of at least a part of the inner wall of the hollow tube shape of the hydrogel structure is 0.1 or less, preferably 0.05 or less. When the coefficient of static friction is 0.1 or less, it is possible to produce a hydrogel structure which is closer to the texture of a living body and whose texture when a medical device such as a catheter is inserted is also close to that of an actual blood vessel or the like. The lower limit of the coefficient of static friction is not particularly limited, but is preferably 0.01 or more, and more preferably 0.02 or more. The coefficient of static friction is measured from the cut surface by cutting the hydrogel structure in the central portion of the hollow tube in the longitudinal direction. For example, using a ball-on-plate method using a surface measuring instrument (device name: TYPE: 38, manufactured by Shinto Kagaku Co., Ltd.), the probe can be dropped onto the blood vessel equivalent and the coefficient of static friction can be measured by point contact. can. The coefficient of static friction is preferably uniform over the entire inner wall of the hollow tube.

The coefficient of static friction of at least a part of the inner wall of the hollow tube shape of the hydrogel structure is inside the hydrogel structure, for example, a solvent, oil, a surfactant that can be used as a lubricant for wet wire drawing, or the like. Can be adjusted by applying. These may be applied to the inner wall of the hydrogel structure or may be flowed into the tube in the form of a liquid.
The solvent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include water and organic solvents. These may be used alone or in combination of two or more. Among these, an organic solvent is preferable from the viewpoint of preventing absorption by the hydrogel structure, and a high boiling point solvent is preferable from the viewpoint of preventing drying.

The oil is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include mineral oil, synthetic oil such as silicone, vegetable oil, wax and animal oil.

The surfactant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a nonionic surfactant, an anionic surfactant, a cationic surfactant, an amphoteric surfactant and the like can be selected. Can be mentioned. These may be used alone or in combination of two or more. Among these, nonionic surfactants are preferable because they are not easily affected by the electrolyte in the hydrogel structure.

The nonionic surfactant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene alkyl phosphate ester, poly Examples thereof include oxyethylene fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, fatty acid monoglyceride, sucrose fatty acid ester, and higher fatty acid alkanolamide.

The anionic surfactant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, alkyl sulfate, alkyl sulfate ether, alkyl amide ether sulfate, alkyl aryl polyether sulfate, monoglyceride sulfate, and alkyl sulfonate can be selected. Acid, alkylamide sulfonic acid, alkylarylsulfonic acid, olefin sulfonic acid, paraffin sulfonic acid, alkylsulfosuccinic acid, alkyl ether sulfosuccinic acid, alkylamide sulfosuccinic acid, alkylsuccinamide acid, alkylsulfoacetate, alkyl phosphate, alkylphosphate, Examples thereof include metal salts such as acyl sulfonic acid, acyl isethionic acid and acyl-N-acyl taurine, ammonium salts, amine salts, amino alcohol salts, magnesium salts, and basic amino acid salts.

The cationic surfactant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, stearyltrimethylammonium chloride, behenyltrimethylammonium chloride, chloride. Examples thereof include cetyltrimethylammonium, myristyldimethylbenzylammonium chloride, lanolin acetate fatty acid aminopropylethyldimethylammonium, dicocoyldimethylammonium chloride, lauryltrimethylammonium chloride, ethyl sulfate branched fatty acid aminopropylethyldimethylammonium and the like.

The amphoteric tenside is not particularly limited and may be appropriately selected depending on the intended purpose. For example, an amide amino acid type amphoteric tenside having an alkyl group, an alkenyl group or an acyl group having 8 or more and 24 or less carbon atoms. , Secondary amide type or tertiary amide type imidazoline type amphoteric tenside, carbobetaine type, amide betaine type, sulfobetaine type, hydroxysulfobetaine type having an alkyl group having 8 or more and 24 or less carbon atoms, an alkenyl group or an acyl group. Examples thereof include amphoteric tensides and amide sulfobetaine amphoteric tenside agents. Specifically, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, stearyldihydroxyethyl betaine, laurylhydroxsulfobetaine, bis (stearyl-N-hydroxyethylimidazolin) chloracetic acid complex, lauryldimethylamino. Examples thereof include betaine acetate, cocoylamidepropylbetaine and cocoylalkylbetaine.

The transmittance of the hydrogel structure in the visible light region is preferably 80% or more, more preferably 85% or more, further preferably 90% or more, and particularly preferably 95% or more. When the transmittance is 80% or more, the inside of the hydrogel structure can be visualized. The transmittance is measured by cutting at the center of the hollow portion, fixing both ends on the substrate, and using, for example, a spectrophotometer (device name: UV-3100, manufactured by Shimadzu Corporation, using an integration unit). be able to. The visible light region means a wavelength region having a wavelength of 400 nm or more and 700 nm or less.
As a method for measuring the transmittance, the hydrogel structure is cut in the longitudinal direction to form a flat plate-shaped sample. At this time, in order to prevent diffused reflection due to the influence of the unevenness of the sample surface, the measurement is performed using the integrating sphere unit. Further, when measuring the details, it is also possible to measure using an optical fiber or the like. The flat plate shape may be defined as long as the irradiation light can irradiate a flat portion of the sample, and the shape of the sample may be curved or may be flat.

The 10-point average value of the maximum inner diameter of at least a part of the hydrogel structure is preferably 10 mm or less, more preferably 1.0 mm or less, further preferably 0.5 mm or less, and particularly preferably 0.3 mm or less. The maximum inner diameter can be measured using a digital microscope (device name: VHX-5000, manufactured by KEYENCE CORPORATION).
The 10-point average value of the maximum inner diameter is a value measured in a close portion where the outer diameters of the hydrogel structures are the same. If the maximum inner diameter cannot be measured at 10 points in the proximity portion where the outer diameter of the hydrogel structure is the same, the average value of the measurable points is used. The outer diameter can be measured using a digital microscope (device name: VHX-5000, manufactured by KEYENCE CORPORATION).

In the hydrogel structure, water, a polymer, and if necessary, a mineral, a water-soluble organic solvent, and other components are mixed by an appropriate method and inked as a hydrogel precursor, and this ink is used in an appropriate method. Can be obtained by curing.

<Polymer>
The polymer is not particularly limited and may be appropriately selected depending on the intended purpose, but a water-soluble polymer is preferable because the hydrogel contains water as a main component. By containing the water-soluble polymer, the strength of the hydrogel containing water as a main component can be maintained.
The water solubility of the water-soluble polymer means that, for example, when 1 g of the water-soluble polymer is mixed with 100 g of water at 30 ° C. and stirred, 90% by mass or more of the water-soluble polymer is dissolved.

Examples of the polymer include polymers having an amide group, an amino group, a hydroxyl group, a tetramethylammonium group, a silanol group, an epoxy group and the like.

The polymer may be a homopolymer (homopolymer), a heteropolymer (copolymer), may be unmodified, or may have a known functional group introduced therein. It may be in the form of a salt or in the form of a salt. Of these, homopolymers are preferred.

The polymer can be obtained by polymerizing a polymerizable monomer. The polymerizable monomer will be described later in the method for producing a hydrogel structure.

The water-soluble polymer is obtained by polymerizing a polymerizable monomer, and examples of the polymerizable monomer include acrylamide, N-substituted acrylamide derivative, N, N-di-substituted acrylamide derivative, and N-substituted methacrylamide derivative. Examples thereof include N, N-di-substituted methacrylamide derivatives. These may be used alone or in combination of two or more.

By polymerizing the polymerizable monomer, a water-soluble polymer having an amide group, an amino group, a hydroxyl group, a tetramethylammonium group, a silanol group, an epoxy group and the like can be obtained. The water-soluble polymer having an amide group, an amino group, a hydroxyl group, a tetramethylammonium group, a silanol group, an epoxy group and the like is an advantageous constituent component for maintaining the strength of an aqueous gel.

The content of the polymer is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.5% by mass or more and 20% by mass or less with respect to the total amount of the hydrogel structure.

<Minerals>
The mineral is not particularly limited and may be appropriately selected depending on the intended purpose. However, since the hydrogel contains water as a main component, a layered clay mineral that can be uniformly dispersed in water at the level of primary crystals is used. Water-swellable layered clay minerals are preferable, and water-swellable layered clay minerals are more preferable.

The water-swellable layered clay mineral presents a state in which two-dimensional disk-shaped crystals having a unit lattice in the crystal are stacked, and when the water-swellable layered clay mineral is dispersed in water, each single-layer state is exhibited. It separates with and becomes a disk-shaped crystal.

The water-swellable clay mineral is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include water-swellable smectite and water-swellable mica. These may be used alone or in combination of two or more. Among these, water-swellable hectorite containing sodium as an interlayer ion, water-swellable montmorillonite, water-swellable saponite, and water-swellable synthetic mica are preferable, and water-swellable hectorite is suitable because a highly elastic bolus can be obtained. More preferred. The water swelling property means that water molecules are inserted between layers of layered clay minerals and dispersed in water.
The mineral may be appropriately synthesized or may be a commercially available product.

The commercially available product is not particularly limited and may be appropriately selected depending on the intended purpose. For example, synthetic hectorite (Raponite XLG, manufactured by RockWood), SWN (Coop Chemical Ltd.), fluorinated hectorite. SWF (manufactured by Coop Chemical Ltd.) and the like can be mentioned. These may be used alone or in combination of two or more.

The content of the mineral is not particularly limited and may be appropriately selected depending on the intended purpose. However, from the viewpoint of elastic modulus and hardness of the hydrogel structure, 1% by mass with respect to the total amount of the hydrogel structure. 40% by mass or more is preferable, and 1% by mass or more and 25% by mass or less is more preferable.

<Organic solvent>
In the present invention, an organic solvent can be added in order to enhance the moisturizing property of the hydrogel structure.
Examples of the organic solvent include water-soluble organic solvents and the like. The water solubility of the water-soluble organic solvent means that the organic solvent can be dissolved in water in an amount of 30% by mass or more.

The water-soluble organic solvent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, etc. Alkyl alcohols with 1 to 4 carbon atoms such as tert-butyl alcohol; amides such as dimethylformamide and dimethylacetamide; ketones or ketone alcohols such as acetone, methylethylketone and diacetone alcohol; ethers such as tetrahydrofuran and dioxane; Ethylene glycol, propylene glycol, 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, diethylene glycol, triethylene glycol, 1,2,6-hexanetriol, thio Polyhydric alcohols such as glycols, hexylene glycols and glycerins; polyalkylene glycols such as polyethylene glycols and polypropylene glycols; ethylene glycol monomethyl (or ethyl) ethers, diethylene glycol methyl (or ethyl) ethers, triethylene glycol monomethyls (or ethyls) Lower alcohol ethers of polyhydric alcohols such as ethers; alkanolamines such as monoethanolamine, diethanolamine, triethanolamine; N-methyl-2-pyrrolidone, 2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone And so on. These may be used alone or in combination of two or more. Among these, polyhydric alcohol, glycerin and propylene glucol are preferable, and glycerin and propylene glucol are more preferable from the viewpoint of moisturizing property.

The content of the organic solvent is preferably 10% by mass or more and 50% by mass or less with respect to the total amount of the hydrogel structure. When the content is 10% by mass or more, the effect of preventing drying can be sufficiently obtained. Further, when it is 50% by mass or less, the mineral is uniformly dispersed.

<Water>
As the water, for example, ion-exchanged water, ultrapure filtered water, reverse osmosis water, pure water such as distilled water, and ultrapure water can be used.
Other components such as an organic solvent may be dissolved or dispersed in the water depending on the purpose of imparting moisturizing property, antibacterial property, conductivity, hardness adjustment and the like.

The water content is preferably 10% by mass or more and 99% by mass or less, more preferably 50% by mass or more and 98% by mass or less, and particularly preferably 60% by mass or more and 97% by mass or less with respect to the total amount of the hydrogel structure. ..

<Other ingredients>
The other components are not particularly limited and may be appropriately selected depending on the intended purpose. For example, a stabilizer, a surface treatment agent, a polymerization initiator, a colorant, a viscosity modifier, an adhesive-imparting agent, and oxidation. Examples thereof include inhibitors, antiaging agents, cross-linking accelerators, ultraviolet absorbers, plasticizers, preservatives, dispersants, and surfactants.

The surface of the hydrogel structure of the present invention is preferably covered with a transparent hard body.
FIG. 3A is a schematic top view showing an example of the hydrogel structure 60 to which the transparent hard body 61 is attached. FIG. 3B is a schematic side view showing an example of the hydrogel structure 60 to which the transparent hard body 61 is attached. As shown in FIGS. 3A and 3B, the surface is covered with a transparent hard body 61, which further maintains the shape of the blood vessel model and improves the handleability at the time of treatment and the storage stability of the blood vessel model (). It is possible to improve the drought resistance and antiseptic property, that is, to reduce the water vapor permeability and oxygen permeability of the hard body), and to improve the appearance of the blood vessel model.

The material for forming the hard body is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a highly transparent plastic material such as an acrylic resin or a polycarbonate resin, or a highly transparent inorganic material such as glass. And so on.
The shape and average thickness of the hard body are not particularly limited and may be appropriately selected depending on the intended purpose.

(Procedure practice tool)
The procedure training tool of the present invention has at least one selected from a hydrogel structure, a blood vessel model, and an organ model, and at least one of a catheter and an endoscope, and other members as needed. Has.

The catheter is not particularly limited and may be appropriately selected depending on the intended purpose. For example, angiography catheter, balloon catheter, cerebrovascular catheter, cancer catheter treatment, vascular indwelling catheter, suction indwelling catheter, urinary tract catheter. And so on.

The endoscope is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a laryngeal endoscope, a bronchoscope, an upper gastrointestinal endoscope, a duodenal endoscope, a small intestinal endoscope, and a colonoscope can be selected. Examples include endoscopy, thoracoscope, cystoscope, biliary tract, and angioscopy.

The hydrogel structure, blood vessel model, and organ model of the present invention can be used for catheter intubation procedure training and preoperative simulation.
The catheter intubation procedure training referred to here is to intubate a catheter into a blood vessel model and train the procedure until the catheter reaches a target location. At this time, training is also included in which the thickness of the catheter is changed according to the purpose, a stent, a wire, a balloon, etc. are provided at the tip, and the treatment is performed at the assumed site of the affected area.
Selecting the optimal catheter according to the shape of the blood vessel is also part of the training, and it is useful to handle one or more catheters and the hydrogel structure of the present invention as a set.

For such training, it is preferable to resemble the actual condition in the blood vessel. The blood vessel model or structure of the present invention is composed of hydrogel, and its texture is very similar to that of a living body, which makes it a useful material. It is also useful to provide a mechanism for flowing a liquid in the hydrogel structure and to train in a state where blood flow is generated.
Conventionally, since there are few transparent blood vessel models, it is also a useful point of the present invention that training that has been performed by irradiating and visualizing X-rays can now be performed without the risk of X-ray exposure. ..

(Manufacturing method of hydrogel structure)
The method for producing the hydrogel structure of the present invention is not particularly limited, but for example, a columnar core portion (support) is formed by using a core portion forming material (support forming material), and the columnar core portion is formed. A tubular portion is formed so as to be covered with a hydrogel forming material, and then the columnar core portion is removed. Preferably, the friction of the inner wall of the pipe is reduced after the columnar core is removed. At this time, it is preferable to use a layered manufacturing method such as a conventionally known material jet method (a method of forming a three-dimensional object by laminating by repeating a layer forming step and a layer curing step). The coating may be such that at least a part of the columnar core portion is covered with the hydrogel forming material, and it is preferable that the coating is entirely covered. Further, it is preferable that both the core forming material (support forming material) and the hydrogel forming material are active energy ray-curable compositions. The number of repetitions varies depending on the size, shape, structure, etc. of the hydrogel structure to be produced and cannot be unconditionally specified, but the accuracy is as long as the average thickness per layer is in the range of 10 μm or more and 50 μm or less. Well, it is possible to model without peeling.

The friction reduction of the inner wall of the pipe can be performed, for example, by applying a liquid to the inner wall of the pipe, reducing the surface roughness of the inner wall of the pipe, or the like.
As the liquid, for example, it can be used as a solvent, a surfactant, an oil, or a wet wire drawing lubricant. These can be applied by passing the liquid through the inner wall of the pipe or by passing it as steam. Further, the support (columnar core portion) described later may be liquefied and removed, and at the same time, the friction of the inner wall of the pipe may be reduced by the friction reducing component contained in the support.

Hereinafter, an example of a method for manufacturing a hydrogel structure by the above-mentioned material jet method will be described in detail.

<< Layer forming step and layer forming means >>
The layer forming step is a step of discharging a hydrogel forming material containing water and a polymerizable monomer and a support forming material to be removed later to form a layer made of these materials.
The support forming material is applied to a position different from that of the hydrogel forming material, and after curing, becomes a support for supporting the hydrogel constituent portion. In the present invention, since the hollow tube shape is formed, the hollow upper portion thereof is in a state of being supported by the support at the time of laminating. The above-mentioned "position different from the hydrogel forming material" means that the position where the support forming material is applied and the position where the hydrogel forming material is applied do not overlap, and the position where the support forming material is applied and the position where the support forming material is applied. , The position where the hydrogel forming material is applied may be adjacent to each other.

The method of applying the forming material as the layer forming step is not particularly limited as long as the droplet can be applied to a target place with appropriate accuracy, and can be appropriately selected depending on the purpose, for example. , Dispenser method, spray method, inkjet method and the like. A known device can be preferably used to carry out these methods.

Among these, the dispenser method is excellent in the quantitativeness of droplets, but the coating area is narrow, and the spray method is able to easily form fine droplets, has a wide coating area, and is excellent in coating property. The quantification of droplets is poor, and scattering occurs due to the spray flow. Therefore, in the present invention, the inkjet method is particularly preferable. The inkjet method has the advantages of better quantification of droplets than the spray method, a wider coating area than the dispenser method, and is preferable in that a complicated three-dimensional shape can be formed accurately and efficiently. ..

In the case of the inkjet method, the nozzle has a nozzle capable of ejecting the forming material. As the nozzle, a nozzle in a known inkjet printer can be preferably used.

-Hydrogel forming material (hydrogel precursor)-
The hydrogel-forming material contains water and a polymerizable monomer, preferably contains a mineral and a water-soluble organic solvent, and further contains a polymerization initiator and other components, if necessary.
As the water, the mineral, the water-soluble organic solvent, and the other components, the same ones as those of the hydrogel structure can be used.

--Polymerizable monomer ---
The polymerizable monomer is a compound having one or more unsaturated carbon-carbon bonds, and a polymerizable monomer polymerized by active energy rays such as ultraviolet rays and electron beams is preferable.
Examples of the polymerizable monomer include monofunctional monomers and polyfunctional monomers. These may be used alone or in combination of two or more.
Examples of the polyfunctional monomer include a bifunctional monomer, a trifunctional monomer, a tetrafunctional or higher functional monomer, and the like.

The monofunctional monomer is a compound having one unsaturated carbon-carbon bond, and is, for example, acrylamide, an N-substituted acrylamide derivative, an N, N-di-substituted acrylamide derivative, an N-substituted methacrylamide derivative, N, N. -Di-substituted methacrylamide derivatives, other monofunctional monomers and the like. These may be used alone or in combination of two or more.

Examples of the N-substituted acrylamide derivative, N, N-di-substituted acrylamide derivative, N-substituted methacrylamide derivative, or N, N-di-substituted methacrylamide derivative include N, N-dimethylacrylamide (DMAA) and N-. Examples include isopropylacrylamide.

Examples of the other monofunctional monomer include 2-ethylhexyl (meth) acrylate (EHA), 2-hydroxyethyl (meth) acrylate (HEA), 2-hydroxypropyl (meth) acrylate (HPA), and acryloylmorpholine (ACMO). ), Caprolactone-modified tetrahydrofurfuryl (meth) acrylate, isobornyl (meth) acrylate, 3-methoxybutyl (meth) acrylate, tetrahydrofurfuryl (meth) acrylate, lauryl (meth) acrylate, 2-phenoxyethyl (meth) acrylate, Examples thereof include isodecyl (meth) acrylate, isooctyl (meth) acrylate, tridecyl (meth) acrylate, caprolactone (meth) acrylate, ethoxylated nonylphenol (meth) acrylate, and urethane (meth) acrylate. These may be used alone or in combination of two or more.

By polymerizing the monofunctional monomer, a water-soluble polymer having an amide group, an amino group, a hydroxyl group, a tetramethylammonium group, a silanol group, an epoxy group and the like can be obtained.

The water-soluble polymer having an amide group, an amino group, a hydroxyl group, a tetramethylammonium group, a silanol group, an epoxy group and the like is an advantageous component for maintaining the strength of the vascular model.

Examples of the bifunctional monomer include tripropylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, tetraethylene glycol di (meth) acrylate, polypropylene glycol di (meth) acrylate, and neopentyl glycol hydroxypivalic acid. Esterdi (meth) acrylate (MANDA), neopentyl glycol hydroxypivalate di (meth) acrylate (HPNDA), 1,3-butanediol di (meth) acrylate (BGDA), 1,4-butanediol di (meth) Acrylate (BUDA), 1,6-hexanediol di (meth) acrylate (HDDA), 1,9-nonanediol di (meth) acrylate, diethylene glycol di (meth) acrylate (DEGDA), neopentyl glycol di (meth) acrylate (NPGDA), tripropylene glycol di (meth) acrylate (TPGDA), caprolactone-modified hydroxypivalate neopentyl glycol ester di (meth) acrylate, propoxylated neopentyl glycol di (meth) acrylate, ethoxy-modified bisphenol A di (meth). Examples thereof include acrylate, polyethylene glycol 200 di (meth) acrylate, polyethylene glycol 400 di (meth) acrylate, and methylenebisacrylamide. These may be used alone or in combination of two or more.

Examples of the trifunctional monomer include trimethylolpropane tri (meth) acrylate (TMPTA), pentaerythritol tri (meth) acrylate (PETA), triallyl isocyanate, and tris (2-hydroxyethyl) isocyanurate tri (meth) acrylate. , Ethoxylated trimethylolpropane tri (meth) acrylate, propoxylated trimethylolpropane tri (meth) acrylate, propoxylated glyceryl tri (meth) acrylate and the like. These may be used alone or in combination of two or more.

Examples of the tetrafunctional or higher functional monomer include pentaerythritol tetra (meth) acrylate, ditrimethylolpropane tetra (meth) acrylate, dipentaerythritol hydroxypenta (meth) acrylate, ethoxylated pentaerythritol tetra (meth) acrylate, and penta (penta). Examples thereof include meth) acrylate ester and dipentaerythritol hexa (meth) acrylate (DPHA). These may be used alone or in combination of two or more.

The content of the monofunctional monomer is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 1% by mass or more and 10% by mass or less, preferably 1% by mass or more, based on the total amount of the hydrogel forming material. More preferably, it is 5% by mass or less. When the content is 1% by mass or more and 10% by mass or less, there is an advantage that the dispersion stability of the mineral in the hydrogel forming material is maintained and the stretchability of the hydrogel structure is improved. The stretchability refers to a property that stretches when the hydrogel structure is pulled and does not break.

The content of the polyfunctional monomer is preferably 0.001% by mass or more and 1% by mass or less, more preferably 0.01% by mass or more and 0.5% by mass or less, based on the total amount of the hydrogel forming material. When the content is 0.001% by mass or more and 1% by mass or less, the elastic modulus and hardness of the obtained hydrogel structure can be adjusted within an appropriate range.

The content of the polymerizable monomer is preferably 0.5% by mass or more and 20% by mass or less with respect to the total amount of the hydrogel forming material. When the content is 0.5% by mass or more and 20% by mass or less, the strength of the hydrogel structure can be made closer to that of human organs.

--Polymerization initiator ---
The polymerization initiator is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a photopolymerization initiator and a thermal polymerization initiator.
As the photopolymerization initiator, any substance that generates radicals by irradiation with light (particularly ultraviolet rays having a wavelength of 220 nm to 400 nm) can be used.

Examples of the photopolymerization initiator include acetophenone, 2,2-diethoxyacetophenone, p-dimethylaminoacetophenone, benzophenone, 2-chlorobenzophenone, p, p'-dichlorobenzophenone, p, p-bisdiethylaminobenzophenone and Michler ketone. , Phenyl, benzoin, benzoin methyl ether, benzoin ethyl ether, benzoin isopropyl ether, benzoin-n-propyl ether, benzoin isobutyl ether, benzoin-n-butyl ether, benzylmethyl ketal, thioxanthone, 2-chlorothioxanthone, 2-hydroxy-2. -Methyl-1-phenyl-1-one, 1- (4-isopropylphenyl) -2-hydroxy-2-methylpropane-1-one, methylbenzoylformate, 1-hydroxycyclohexylphenylketone, azobisisobutyro Examples include nitrile, benzoyl peroxide, di-tert-butyl peroxide and the like. These may be used alone or in combination of two or more.

The thermal polymerization initiator is not particularly limited and may be appropriately selected depending on the intended purpose. For example, an azo-based initiator, a peroxide initiator, a persulfate initiator, a redox (oxidation-reduction) initiator. And so on. These may be used alone or in combination of two or more. Of these, peroxide initiators are preferred.

The peroxide initiator is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include potassium persulfate, sodium persulfate, ammonium persulfate, sodium peroxodisulfate and potassium peroxodisulfate. Be done. These may be used alone or in combination of two or more. Among these, potassium persulfate is preferable.

<<< Curing process and curing means >>>
The curing step is a step of irradiating a predetermined region of the hydrogel forming material layer or the support forming material layer formed by the curing means with active energy rays to cure.

Examples of the means for curing the layer include an ultraviolet (UV) irradiation lamp, an electron beam, and the like. Further, it is preferable that a mechanism for removing ozone is provided.
Examples of the type of the ultraviolet (UV) irradiation lamp include a high-pressure mercury lamp, an ultra-high pressure mercury lamp, a metal halide, and an ultraviolet light emitting diode (UV-LED).
The ultra-high voltage mercury lamp is a point light source, but the DeepUV type, which has improved light utilization efficiency in combination with an optical system, can irradiate in a short wavelength region.
The metal halide is effective for colored substances because it has a wide wavelength region, and a halide of a metal such as Pb, Sn, or Fe is used and can be selected according to the absorption spectrum of the polymerization initiator. The lamp used for curing is not particularly limited and may be appropriately selected depending on the purpose. For example, commercially available lamps such as H lamps, D lamps, V lamps manufactured by Fusion Systems, etc. are used. Can be used.
The emission wavelength of the ultraviolet light emitting diode is not particularly limited and may be appropriately selected depending on the intended purpose. Generally, there are 365 nm, 375 nm, 385 nm, 395 nm and 405 nm, but the wavelength of the ultraviolet light emitting diode can be selected. Considering the influence of color, short wavelength light emission is more advantageous so that the absorption of the polymerization initiator is increased. Among these, an ultraviolet light emitting diode (UV-LED) that generates less heat is used as an ultraviolet (UV) irradiation lamp because it is also used for the three-dimensional model of the present invention, which is a hydrogel that is easily affected by thermal energy. Is preferable.

The cured hydrogel material layer is preferably a hydrogel in which water and a component soluble in water are contained in a three-dimensional network structure formed by a composite of a polymer and a mineral. .. The hydrogel has improved extensibility and can be integrally peeled off without breaking, which greatly simplifies the post-modeling process.

-Support (core) forming material-
The support forming material is not particularly limited as long as it is a support capable of supporting the hydrogel structure of the present invention, but from the viewpoint of removing the support existing in the hollow portion after laminating. , Those exhibiting solubility in a solvent, those exhibiting a phase transition by heating or the like and becoming a liquid, and the like are preferable. Since the hydrogel structure of the present invention is a hydrogel, immersion in water may promote swelling of the modeled object when removing the support forming material, which is not desirable. Therefore, those showing solubility in a solvent that does not attack the hydrogel are preferable, and those having a phase change of solid at 25 ° C. but liquid at 50 ° C. are preferable. If the support forming material is a material that undergoes a phase change, it can be easily removed after the formation of the hydrogel structure.
Further, the support forming material (core forming material) that supports the inside of the hollow shape in the hydrogel structure of the present invention and the support forming material that supports the outside of the structure may be the same or different. Further, it is not necessary to fill the inside of the hollow with a support, and it is sufficient that the hollow has a minimum support shape that can be supported. In this case, removal can be performed more efficiently than when the hollow is filled with a support.

The support forming material contains a polymerizable monomer, and if necessary, a polymerization initiator, a coloring agent, and the like, and these can be the same as the hydrogel forming material described above.
The phase-changing material is, for example, a liquid in the state before curing, and is solidified by irradiating with active energy rays such as ultraviolet rays as in the case of hydrogel, so that the environment is at room temperature (25 ° C.). Below, those having the property of being in a solid state and being liquid in an environment of 60 ° C. can be mentioned.

In one embodiment, a monofunctional ethylenically unsaturated monomer (A) having a linear chain having 14 or more carbon atoms, a polymerization initiator (B), and a solvent (C) capable of dissolving the monomer (A) are used. It is preferable to include it.

<Monofunctional ethylenically unsaturated monomer (A) having a linear chain with 14 or more carbon atoms>
The monofunctional ethylenically unsaturated monomer (A) having a linear chain having 14 or more carbon atoms is not particularly limited and may be appropriately selected depending on the intended purpose. For example, acrylates such as stearyl acrylate and docosyl acrylate. Methacrylates such as stearyl methacrylate and docosyl methacrylate; acrylamides such as palmityl acrylamide and stearyl acrylamide; vinyls such as vinyl stearate and vinyl docosylate can be mentioned. These may be used alone or in combination of two or more. Among these, acrylates and acrylamide derivatives are preferable from the viewpoint of photoreactivity, and stearyl acrylate is more preferable from the viewpoint of solubility in a solvent.

Examples of the polymerization reaction of the monomer (A) include radical polymerization, ionic polymerization, coordination polymerization, ring-opening polymerization and the like. Among these, radical polymerization is preferable from the viewpoint of controlling the polymerization reaction. Therefore, the monomer (A) having a hydrogen bonding ability is preferably an ethylenically unsaturated monomer. Among these, monofunctional ethylenically unsaturated monomers are preferable from the viewpoint of meltability.

<Polymerization initiator (B)>
The polymerization initiator (B) is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include a thermal polymerization initiator and a photopolymerization initiator. Among these, a photopolymerization initiator is preferable when forming a three-dimensional object.

As the photopolymerization initiator, any substance that generates radicals by irradiation with light (particularly ultraviolet rays having a wavelength of 220 nm or more and 400 nm or less) can be used.
Examples of the photopolymerization initiator include acetophenone, 2,2-diethoxyacetophenone, p-dimethylaminoacetophenone, benzophenone, 2-chlorobenzophenone, p, p'-dichlorobenzophenone, p, p-bisdiethylaminobenzophenone and Michler ketone. , Phenyl, benzoin, benzoin methyl ether, benzoin ethyl ether, benzoin isopropyl ether, benzoin-n-propyl ether, benzoin isobutyl ether, benzoin-n-butyl ether, benzylmethyl ketal, thioxanthone, 2-chlorothioxanthone, 2-hydroxy-2. -Methyl-1-phenyl-1-one, 1- (4-isopropylphenyl) 2-hydroxy-2-methylpropane-1-one, methylbenzoylformate, 1-hydroxycyclohexylphenylketone, azobisisobutyronitrile , Benzoyl peroxide, di-tert-butyl peroxide and the like. These may be used alone or in combination of two or more. Further, it is preferable to select a photopolymerization initiator that matches the ultraviolet wavelength of the ultraviolet irradiation device.

<Solvent (C) capable of dissolving the monomer (A)>
The solvent (C) is not particularly limited as long as it is a solvent capable of dissolving the monomer (A), and can be appropriately selected depending on the intended purpose, thereby preventing a significant decrease in the crystallinity of the polymer side chain. From the point of view, it is preferable to have a linear chain having 6 or more carbon atoms.
Examples of the solvent (C) having a linear chain having 6 or more carbon atoms include esters such as hexyl acetate and octyl acetate; alcohols such as hexanol, decanol, and dodecanol.

The support forming material (active energy ray-curable liquid composition) may contain 20% by mass or more and 70% by mass or less of the monofunctional ethylenically unsaturated monomer (A) having a linear chain having 14 or more carbon atoms. It is preferably contained in an amount of 30% by mass or more and 60% by mass or less. Further, it is preferable to contain the photopolymerization initiator (B) in an amount of 0.5% by mass or more and 10% by mass or less, and more preferably 3% by mass or more and 6% by mass or less.

In order to obtain a cured product from the liquid support forming material, for example, it is preferable to irradiate the ^{cured product with an ultraviolet exposure amount of 200 mJ / cm 2 or more by an ultraviolet irradiation device to cure the product.} As the ultraviolet irradiation device, the same device that cures the hydrogel structure can also be used.

When the monomer (A) contains the polymerization initiator (B) and is irradiated with ultraviolet rays to form a polymer, the solvent (C) is retained by the polymer. The polymer (A) becomes a solid by arranging carbon chains in an environment of 25 ° C. When the solvent (C) is retained in the polymer (A), it has an effect of suppressing shrinkage and warpage due to crystallization. Further, the solvent (C) having a linear chain having 6 or more carbon atoms is preferable from the viewpoint of curability.
Further, it is preferable that the solvent (C) capable of dissolving the monomer (A) is a non-reactive compound that does not react with the polymerization initiator (B).
In the present invention, the solvent (C) capable of dissolving the monomer (A) means a solvent in which the monomer (A) dissolves in the solvent (C) to form a uniform liquid.
In the present invention, the non-reactive compound means a compound that does not chemically react even when irradiated with ultraviolet rays.
When the solvent (C) is non-reactive, it does not chemically react with the photopolymerization initiator and does not inhibit the polymerization reaction of the monomer or the crystallization of the polymer side chain, which is preferable.

-Surface tension-
The surface tension of the support forming material in the present invention is not particularly limited and may be appropriately selected depending on the intended purpose. For example, at 25 ° C., 20 mN / m or more and 45 mN / m or less is preferable, and 25 mN / m or more. More preferably, it is 34 mN / m or less. When the surface tension is 20 mN / m or more, the ejection is stable at the time of modeling, the ejection direction does not bend or the ejection does not occur, and when the surface tension is 45 mN / m or less, the ejection nozzle for modeling or the like is used. When filling the liquid, it can be completely filled. The surface tension can be measured using, for example, a surface tension meter (automatic contact angle meter DM-701, manufactured by Kyowa Interface Science Co., Ltd.).

-Viscosity-
The viscosity of the support forming material in the present invention is preferably 1,000 mPa · s or less, more preferably 300 mPa · s or less, further preferably 100 mPa · s or less, and 3 mPa · s or more and 20 mPa · s or less at 25 ° C. It is particularly preferable, and most preferably 6 mPa · s or more and 12 mPa · s or less. If the viscosity exceeds 1,000 mPa · s, the head may not be discharged even if the temperature is raised. The viscosity can be measured in an environment of 25 ° C. using, for example, a rotary viscometer (VISCOMATE VM-150III, manufactured by Toki Sangyo Co., Ltd.).

<<< Removal process and removal means >>>
The removing step is a step of removing the support including the columnar core portion.
Examples of the removal of the columnar core portion include liquefaction by heat and the use of an insoluble solvent for the tubular portion. The term "insoluble" means, for example, that 90% by mass or more of the tubular portion is not dissolved when 1 g of the tubular portion is mixed with 100 g of water at 30 ° C. and stirred.

<< Other processes and other means >>
The other steps are not particularly limited and may be appropriately selected depending on the intended purpose. For example, a layer smoothing step, a peeling step, a discharge stabilizing step, a molding body cleaning step, a molding body polishing step, and the like. Can be mentioned.

FIG. 4 is a schematic view showing an example of a modeled body manufacturing process using a three-dimensional modeling apparatus used in the method for manufacturing a hydrogel structure of the present invention.
The three-dimensional modeling apparatus 10 forms a hydrogel from the head unit 12 on the modeled object support substrate 14 by using a head unit in which ink jet heads (forming material ejection means) that can be moved in either direction of arrows A and B are arranged. The material is laminated by injecting the support forming material from the head unit 11 and curing the hydrogel forming material by the adjacent UV irradiator 13.
That is, the support forming material (support material) is injected from the head unit 12 and solidified to form a first support layer having a reservoir, and the hydrogel forming material is applied to the reservoir of the first support layer. It is jetted from the head unit 11, the hydrogel forming material is irradiated with UV light to be cured, and further smoothed by using a smoothing member 16 to form a first modeled object layer.

Next, a support forming material is sprayed onto the first support layer and solidified to laminate a second support layer having a reservoir, and hydrogel is formed in the reservoir of the second support layer. A material is jetted, UV light is irradiated, a second modeled object layer is laminated on the first modeled object layer, and further smoothing is performed to manufacture a modeled body 17.
When a roller-shaped smoothing member is used, the smoothing effect is more effectively exhibited by rotating the roller in the direction in which the roller is reversed with respect to the operation direction.

Further, in order to keep the gap between the head unit 11, the head unit 12, and the UV irradiator 13 and the model 17 and the support 18 constant, the stages 15 are laminated while being lowered according to the number of times of lamination.

Further, as the three-dimensional modeling apparatus 10, it is possible to add a recovery mechanism for forming materials, a recycling mechanism, and the like. It may be provided with a blade for removing the forming material adhering to the nozzle surface or a detection mechanism for a non-ejection nozzle. It is also preferable to control the environmental temperature inside the device at the time of modeling.

By using the above-mentioned device, it is possible to control the composition distribution and shape according to the condition of the treatment site of the individual patient, and to form a blood vessel model or organ model having a patient-specific shape and physical property distribution. Can be done.

For example, using the personal data of the person to be treated (patient), it is possible to have the shape of the blood vessel of the affected part to be catheterized and to provide the hardness distribution (composition distribution) of the blood vessel as needed. In this case as well, it is created based on the individual patient data.

As a method for giving a composition distribution, the amount of the solvent contained in the hydrogel may be adjusted. This can be realized by using a device having a mechanism for ejecting a plurality of compositions from each inkjet head by the method using the inkjet.

As the first liquid, a hydrogel forming material (hereinafter, also referred to as “Liquid A”) is used and discharged from the first head. Further, as the second liquid, a liquid consisting of a solvent capable of diluting the hydrogel forming material, mainly water and a solvent soluble in water (hereinafter, also referred to as “Liquid B”) is used, and the second head is used. Discharge from. Further, a support forming material used for forming a hollow tube of a blood vessel model is used as a third liquid and discharged from a third head.
A predetermined amount of the liquid A and the liquid B is printed from each inkjet head, and it is possible to precisely control the amount ratio of the liquid dropped on the same place.

Hereinafter, specific embodiments of the method for producing the hydrogel structure of the present invention will be described.
A method for obtaining hydrogel structures having different hardness, compressive stress and elastic modulus will be described in more detail.
First, the surface data or solid data of the three-dimensional shape designed by the three-dimensional CAD or the three-dimensional shape captured by the three-dimensional scanner or the digitizer is converted into the STL format and input to the laminated modeling apparatus.

Next, the compressive stress distribution of the three-dimensional shape is measured. The method is not particularly limited, but for example, by using MR Elastography (hereinafter referred to as MRE), compressive stress distribution data having a three-dimensional shape is obtained, and this data is input to the laminated modeling apparatus. Based on the input compressive stress data, the mixing ratio of the liquid A and the liquid B to be discharged at the position corresponding to the three-dimensional shape data is determined.

Based on this input data, the modeling direction of the three-dimensional shape to be modeled is determined. The modeling direction is not particularly limited, but usually the direction in which the Z direction (height direction) is the lowest is selected.
After determining the modeling direction, the projected area of the three-dimensional shape on the XY plane, the XY plane, and the YY plane is obtained. The obtained block shape is sliced in the Z direction with a single layer thickness. The thickness of the layer depends on the material used, but is usually 20 μm or more and 60 μm or less. When there is only one model to be modeled, this block shape is arranged so as to come to the center of the Z stage (a table on which the model objects descend by one layer for each layer model). Further, when a plurality of block shapes are formed at the same time, the block shapes are arranged on the Z stage, but it is also possible to stack the block shapes. These block shaping, round slice data (slice data: contour line data), and placement on the Z stage can be automatically created by specifying the material to be used.

Next, the modeling process is carried out. FIG. 5 is a schematic view showing an example of a three-dimensional modeling apparatus used in the method for manufacturing a hydrogel structure of the present invention. FIG. 6 is a schematic view showing an example of mixing the first liquid and the second liquid by the droplet ejection method. The different heads α and β (FIG. 5) are moved in both directions to discharge the liquid A and the liquid B into a predetermined region at a predetermined ratio to form dots. At that time, as shown in FIG. 6, it is possible to mix the liquid A and the liquid B at the dots to obtain a predetermined mixing ratio. Further, by forming continuous dots, it is possible to prepare a mixed liquid film of liquid A and liquid B having a predetermined mixing ratio in a predetermined region. Then, the mixed liquid film of the liquid A and the liquid B is cured by irradiating it with ultraviolet (UV) light to form a hydrogel film (layer) having a predetermined mixing ratio in a predetermined region as shown in FIG. Can be done.

After forming one layer of the hydrogel film (layer), the stage (FIG. 5) descends by the height of one layer. By forming continuous dots on the hydrogel film again, a mixed liquid film of liquid A and liquid B having a predetermined mixing ratio in a predetermined region is produced. The mixed liquid film of the liquid A and the liquid B is cured by irradiating it with ultraviolet (UV) light to form a hydrogel film. By repeating these laminations, three-dimensional modeling becomes possible.

The hydrogel structure thus three-dimensionally shaped has different mixing ratios of solutions A and B in the hydrogel in which the liquid film of FIG. 5 is three-dimensionalized, and the elastic modulus can be continuously changed. By adjusting the compounding ratio pattern for each fault, a hydrogel structure having partially arbitrary physical characteristics can be obtained.

Further, by placing an ultraviolet (UV) light irradiator adjacent to the inkjet head that injects the hydrogel forming material, the time required for the smoothing process can be saved, and high-speed modeling is possible.

The hardness of the hydrogel structure used in the present invention can be arbitrarily changed by changing the composition ratio while using the same material by combining the hydrogel forming material and the diluted solution. Therefore, it is possible to easily provide the hardness distribution of blood vessels according to personal data by using a plurality of inkjet heads and changing the ratio of the two when modeling by the inkjet method.

The hydrogel has a structure containing a large amount of water and is extremely close to the composition of the human body and has a texture very close to that of the human body. Combining this with 3D printing is very useful in forming blood vessel models.

Since the hydrogel structure, blood vessel model, and organ model of the present invention can be produced by 3D printing technology, it is possible to form a model that reproduces this shape and physical properties based on the patient's affected area data. .. Therefore, it can be usefully used for simulation before difficult surgery.
For example, in conventional surgery (stent insertion into aneurysm), the shape of the aneurysm is read from an X-ray image, and a stent that seems to have an appropriate shape is selected intraoperatively and used. However, this is done based on the experience of the doctor (operator), and there were many cases where it took time to make a decision or the optimum one could not be selected.
Regarding the issue of what shape of member (stent, etc.) should be selected according to the shape and physical properties of the aneurysm, it is possible to increase the success rate of surgery by considering it before surgery. You can expect it.

Hereinafter, examples of the present invention will be described, but the present invention is not limited to these examples.
The 10-point average value of the maximum inner diameter of the structure was measured as follows.

(10-point average value of maximum inner diameter)
Using a digital microscope (device name: VHX-5000, manufactured by KEYENCE CORPORATION), measure the maximum inner diameter at 10 points in the proximity part where the outer diameter of the structure is the same, calculate the average value, and calculate the average value. And said. When the maximum inner diameter could not be measured at 10 points in the proximity portion where the outer diameter of the hydrogel structure was the same, the average value of the measurable points was used. The outer diameter was measured using a digital microscope (device name: VHX-5000, manufactured by KEYENCE CORPORATION).

(Preparation Example 1 of Hydrogel Forming Material)
<Preparation of Hydrogel Forming Material 1>
Hereinafter, the ion-exchanged water that has been degassed under reduced pressure for 30 minutes is referred to as pure water.
First, while stirring the pure water 60.0 parts by _{weight, [Mg 5.34 Li 0.66 Si 8} O 20 (OH) 4] Na as layered clay mineral _- synthetic hectorite (trade having a composition of _0.66 Name: Laponite XLG, manufactured by RockWood Co., Ltd.) was added little by little so as to have a total of 6.0 parts by mass, and the mixture was stirred to prepare a dispersion. Next, 0.3 parts by mass of etidronic acid was added as a dispersant for synthetic hectorite.
Next, the obtained dispersion was passed through a column of activated alumina as a polymerizable monomer to remove the polymerization inhibitor, and 22.0 parts by mass of acryloylmorpholin (manufactured by KJ Chemicals Co., Ltd.), methylenebisacrylamide (organic cross-linking agent). , Tokyo Kasei Kogyo Co., Ltd.) 0.2 parts by mass and 10.2 parts by mass of glycerin as an antidrying agent were added and mixed.
Next, 0.4 parts by mass of N, N, N', N'-tetramethylethylenediamine was added as a polymerization accelerator, and then 0.6 parts by mass of Irgacure184 (manufactured by BASF) was added as a polymerization initiator and mixed by stirring. bottom.
After stirring and mixing, degassing under reduced pressure was carried out for 10 minutes. Subsequently, impurities and the like were removed by filtration to obtain a homogeneous hydrogel-forming material 1. The composition is shown in Table 1 below.

In Table 1, the product names of the ingredients and the names of the manufacturing companies are as follows.
・ Acryloyl morpholine: manufactured by KJ Chemicals Co., Ltd. ・ Methylenebisacrylamide: manufactured by Tokyo Kasei Kogyo Co., Ltd. ・ Synthetic hectorite :: manufactured by RockWood, trade name: Laponite XLG
・ Glycerin: manufactured by Sakamoto Pharmaceutical Industry Co., Ltd. ・ Etidronic acid: manufactured by Tokyo Chemical Industry Co., Ltd. ・ N, N, N', N'-tetramethylethylenediamine: manufactured by Tokyo Chemical Industry Co., Ltd.

(Preparation Example 1 of Support (Core) Forming Material)
<Preparation of support forming material 1>
1-Dodecanol (manufactured by Tokyo Kasei Kogyo Co., Ltd.) 58.0 parts by mass, stearyl acrylate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) 48.0 parts by mass, and Irgacure 819 (manufactured by BASF) 4.0 parts by mass are stirred and mixed. The support forming material 1 was prepared by dissolving. The composition is shown in Table 2 below.

In Table 2, the product names of the ingredients and the names of the manufacturing companies are as follows.
・ Stearyl acrylate: manufactured by Tokyo Chemical Industry Co., Ltd. ・ 1-dodecanol: manufactured by Tokyo Chemical Industry Co., Ltd. ・ Irgacure 819: manufactured by BASF

(Example 1)
Using the modeling apparatus shown in FIG. 4, the hydrogel forming material 1 and the support forming material 1 (both are active energy ray-curable compositions) were discharged, and curing was repeated with ultraviolet rays to prepare a laminated model. Next, the laminated model is allowed to stand in a constant temperature bath at 50 ° C. for 30 minutes to remove it by liquefying the columnar core portion which is a cured product of the support forming material 1, and further, with warm water at 50 ° C. By washing away the remaining columnar core portion, a hydrogel structure (blood vessel model) having a hollow tube shape as shown in FIG. 2 was obtained. The hydrogel structure was a block of 100 mm × 100 mm × 10 mm including a tubular flow path corresponding to a blood vessel, and the 10-point average value of the maximum inner diameter of the hollow tube was 3 mm.
The obtained structure is cut in the longitudinal direction at the hollow tube portion, and the transmittance in the wavelength range of 400 nm or more and 700 nm or less is measured from the cross section with a commercially available spectrophotometer (device name: UV-3100, manufactured by Shimadzu Corporation). , Using an integration unit). As a result, the transmittance was 93% on average in the wavelength range of 400 nm or more and 700 nm or less.

(Example 2)
For the structure obtained in the same manner as in Example 1, glycerin (manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.) was used from the entrance of the hollow portion of the structure using a syringe (trade name: syringe with injection needle, manufactured by Terumo Corporation). Glycerin was applied to the inner wall of the hollow tube by passing the liquid through the hollow tube.

(Example 3)
Silicone oil was applied to the inner wall of the hollow tube by passing a liquid through the structure obtained in the same manner as in Example 1 using silicone oil (trade name: KF96L, manufactured by Shin-Etsu Chemical Co., Ltd.).

(Example 4)
By passing a liquid through the structure obtained in the same manner as in Example 1 using polyoxyethylene alkyl ether (trade name: Emargen 1108, manufactured by Kao Corporation), the inner wall of the hollow tube is made of polyoxyethylene alkyl. Ether was applied.

(Comparative Example 1)
A 100 mm × 100 mm × 10 mm silicone rubber block was produced by molding a liquid silicon material for molding (trade name: RTV # 1406, manufactured by Shin-Etsu Chemical Co., Ltd.) with a mold. By making a hole in the central portion of the silicone block using a drill having a diameter of 3 mm, a silicone rubber structure for catheter practice having the same shape as in Example 1 was obtained. When the transmittance was measured in the same manner as in Example 1, the transmittance was 35% on average in the wavelength range of 400 nm or more and 700 nm or less.

(Comparative Example 2)
In Comparative Example 1, a vinyl chloride structure for catheter practice was obtained in the same manner as in Comparative Example 1 except that the silicone rubber was changed to vinyl chloride (trade name: PVC plate, manufactured by Takiron Co., Ltd.). When the transmittance was measured in the same manner as in Example 1, an average transmittance of 15% was shown in the wavelength range of 400 nm or more and 700 nm or less.

(Comparative Example 3)
A polyethylene structure for catheter practice was obtained in the same manner as in Comparative Example 1 except that the silicone rubber was changed to polyethylene (trade name: soft polyethylene plate, manufactured by Shimonoseki Packing Co., Ltd.) in Comparative Example 1. When the transmittance was measured in the same manner as in Example 1, an average transmittance of 28% was shown in the wavelength range of 400 nm or more and 700 nm or less.

(Comparative Example 4)
In Comparative Example 1, a catheter practice Teflon structure was obtained in the same manner as in Comparative Example 1 except that the silicone rubber was changed to Teflon (trade name: PTFE sheet, manufactured by Chukoh Chemical Industries, Ltd.). When the transmittance was measured in the same manner as in Example 1, no light was dropped in the wavelength range of 400 nm or more and 700 nm or less.

Next, the "texture" and the "coefficient of static friction" were evaluated as follows. The results are shown in Table 3 below.

(Texture)
The obtained structure was subjected to catheter insertion evaluation by a doctor, and the texture of insertion of a catheter (trade name: MV-MS175A, manufactured by Terumo Corporation) was evaluated as "texture" based on the following evaluation criteria.
-Evaluation criteria-
○: The texture is very close to the actual blood vessel ×: The texture is far from the actual blood vessel

(Coefficient of static friction)
The obtained structure was cut in the longitudinal direction at the center of the hollow tube, and the coefficient of static friction of the inner wall of the hollow tube was measured. As a measuring method, a ball-on-plate method using a surface measuring device (device name: TYPE: 38, manufactured by Shinto Kagaku Co., Ltd.) was used, the probe was dropped on the blood vessel equivalent part, and the coefficient of static friction was measured by point contact. ..

As shown in Table 3, it was found that the hydrogel structures of Examples 1 to 4 can have a coefficient of static friction in the range of 0.1 or less.
Since Comparative Examples 1 to 4 have a high coefficient of static friction and low flexibility, they cannot be a blood vessel model that reproduces the texture of a living body, and are not suitable as a catheter treatment practice model.

(Example 5)
The hydrogel structure obtained in the same manner as in Example 1 was built in a glass container. The texture when inserting the catheter did not change, and the handleability was improved.

(Example 6)
The hydrogel structure obtained in the same manner as in Example 1 was built in a container made of polycarbonate resin. The texture when inserting the catheter did not change, and the handleability was improved.

(Example 8)
A catheter was inserted into the hydrogel structure obtained in the same manner as in Example 1 while refluxing silicone oil (trade name: KF96L, manufactured by Shin-Etsu Chemical Co., Ltd.) separately with a pump. The texture when inserting the catheter has improved.

Examples of aspects of the present invention are as follows.
<1> Contains water and polymer
Has a hollow tube shape,
It is a hydrogel structure characterized in that the coefficient of static friction of at least a part of the inner wall of the hollow tube shape is 0.1 or less.
<2> The hydrogel structure according to <1>, wherein the transmittance in the visible light region is 80% or more.
<3> The hydrogel structure according to any one of <1> to <2>, wherein the 10-point average value of the maximum inner diameter in at least a part thereof is 1.0 mm or less.
<4> Contains more minerals
The hydrogel structure according to any one of <1> to <3>, which comprises a hydrogel containing water in a three-dimensional network structure formed by complexing the polymer and the mineral. be.
<5> The hydrogel structure according to any one of <1> to <4>, which further contains a water-soluble organic solvent.
<6> The hydrogel structure according to <5>, wherein the water-soluble organic solvent is a polyhydric alcohol.
<7> A blood vessel model characterized by comprising the hydrogel structure according to any one of <1> to <6>.
<8> An organ model comprising the hydrogel structure according to any one of <1> to <6>, wherein the outer shape thereof imitates the shape of an organ.
<9> At least one of the blood vessel model described in <7> and the organ model described in <8>.
A procedure training tool characterized by having at least one of a catheter and an endoscope.
<10> A method for manufacturing a hydrogel structure having a hollow tube shape.
A columnar core is formed using the core forming material, and the columnar core is coated with the hydrogel forming material to form a tubular portion. After removing the column core, further the inner wall of the pipe is further formed. It is a method for manufacturing a hydrogel structure characterized by reducing friction.
<11> The method for producing a hydrogel structure according to <10>, wherein the coefficient of static friction of at least a part of the inner walls of the hollow tube shape is 0.1 or less.
<12> The method for producing a hydrogel structure according to any one of <10> to <11>, wherein the columnar core portion and the tubular portion are formed by a layered manufacturing method.
<13> The method for producing a hydrogel structure according to any one of <10> to <12>, wherein both the core forming material and the hydrogel forming material are active energy ray-curable compositions.
<14> The method for producing a hydrogel structure according to any one of <10> to <13>, wherein the columnar core portion is removed by liquefaction by heat.
<15> The method for producing a hydrogel structure according to any one of <10> to <13>, wherein an insoluble solvent is used for the tubular portion when the columnar core portion is removed.
<16> The method for producing a hydrogel structure according to any one of <10> to <15>, wherein the 10-point average value of the maximum inner diameter is 1 mm or less in at least a part thereof.
<17> The method for producing a hydrogel structure according to any one of <10> to <16>, wherein the 10-point average value of the maximum inner diameter in at least a part thereof is 0.5 mm or less.
<18> The method for producing a hydrogel structure according to any one of <10> to <17>, wherein the 10-point average value of the maximum inner diameter is 0.3 mm or less in at least a part thereof.
<19> The method for producing a hydrogel structure according to any one of <10> to <18>, wherein the hollow tube has a transmittance of 85% or more in the visible light region.
<20> The method for producing a hydrogel structure according to any one of <10> to <19>, wherein the transmittance of the hollow tube in the visible light region is 90% or more.

The hydrogel structure according to any one of <1> to <6>, the blood vessel model according to <7>, the organ model according to <8>, and the procedure practice tool according to <9>. According to the method for producing a hydrogel structure according to any one of <10> to <20>, the conventional problems can be solved and the object of the present invention can be achieved.

10 Three-dimensional modeling device 11, 12 Head unit 13 UV irradiator 14 Model support substrate 15 Stage 16 Smoothing member 17 Model 18 Support (support material)

Japanese Unexamined Patent Publication No. 2015-69054 Japanese Unexamined Patent Publication No. 2015-219371 Japanese Unexamined Patent Publication No. 2012-189909 Japanese Unexamined Patent Publication No. 2009-273508

Claims (14)

Wherein water and a polymer obtained by polymerizing the acryloyl morpholine,
Has a hollow tube shape,
A hydrogel structure characterized in that the coefficient of static friction of at least a part of the inner wall of the hollow tube shape is 0.1 or less. The hydrogel structure according to claim 1, wherein the transmittance in the visible light region is 80% or more. The hydrogel structure according to any one of claims 1 to 2, wherein the hollow tube shape has a 10-point average value of the maximum inner diameter of 1 mm or less in at least a part of the hollow tube shape. Contains more minerals
The hydrogel structure according to any one of claims 1 to 3, wherein the hydrogel containing the water is contained in a three-dimensional network structure formed by complexing the polymer and the mineral. The hydrogel structure according to any one of claims 1 to 4, further containing a water-soluble organic solvent. A blood vessel model comprising the hydrogel structure according to any one of claims 1 to 5. An organ model comprising the hydrogel structure according to any one of claims 1 to 5, wherein the outer shape thereof imitates the shape of an organ. At least one of the blood vessel model according to claim 6 and the organ model according to claim 7.
A procedure practice tool characterized by having at least one of a catheter and an endoscope. A method for manufacturing a hydrogel structure having a hollow tube shape.
A columnar core portion is formed using the core portion forming material, and the columnar core portion is coated with a hydrogel forming material containing acryloyl morpholine to form a tubular portion, and after the columnar core portion is removed, the columnar core portion is removed. A method for manufacturing a hydrogel structure, which comprises further reducing friction on the inner wall of a pipe. The method for producing a hydrogel structure according to claim 9, wherein the coefficient of static friction of at least a part of the inner walls of the hollow tube shape is 0.1 or less. The method for producing a hydrogel structure according to any one of claims 9 to 10, wherein the columnar core portion and the tubular portion are formed by a layered manufacturing method. The method for producing a hydrogel structure according to any one of claims 9 to 11, wherein both the core forming material and the hydrogel forming material are active energy ray-curable compositions. The method for producing a hydrogel structure according to any one of claims 9 to 12, wherein the columnar core portion is removed by liquefaction by heat. The method for producing a hydrogel structure according to any one of claims 9 to 12, wherein an insoluble solvent is used for the tubular portion when the columnar core portion is removed.

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