JP6915328B2 - Manufacturing method of three-dimensional structure - Google Patents

Description

The present invention relates to a method for manufacturing a three-dimensional structure.

In recent years, technology for forming fine three-dimensional structures such as cylinders made of brittle materials such as hydrogels and biomaterials with a high aspect ratio that can be used for artificial models of blood vessels, microchannels, and observation experiments of biomaterials. The need is increasing.

A microchannel device that performs a chemical reaction, extraction, analysis, etc. can be used as a kit used for a chemical reaction test. In addition, because it has excellent controllability of reaction conditions, it is suitable for efficient synthesis of high-purity compounds, chemical reactions using interfaces between fluids, extraction, etc., and has been developed in a wide range of fields such as environment, biotechnology, drug discovery, medicine, and food. Expected.

Therefore, even if it is a brittle and soft material such as a biomaterial or hydrogel, if a fine three-dimensional structure with a high aspect ratio can be formed, it can be used not only as a member for observing chemical reactions or as an artificial blood vessel model, but also as a flexible shape and pH. It is possible to form a swellable / contractible microchannel that is responsive and temperature responsive.

When a three-dimensional structure made of a low-strength material is molded using a molding mold made of metal or plastic, there has been a problem of shape collapse or breakage due to strong mechanical damage that occurs at the time of mold release. Therefore, a method has been proposed in which a support structure of a gel material is used when producing a three-dimensional structure of a material having low strength, and finally the support structure of the gel material is removed (see, for example, Patent Document 1).

However, since the gel material has a low viscosity enough to be extruded from the tip of a syringe and it is difficult to stack the gel material while maintaining its shape, it cannot be used as a molding mold for producing a three-dimensional structure having a high aspect ratio.

The present invention has been made in view of the above points, and an object of the present invention is to provide a manufacturing method capable of manufacturing a three-dimensional structure in a gel state having a high aspect ratio with a small release load.

The method for producing this three-dimensional structure is to obtain a first gel-like member which is a temperature-responsive hydrogel having a sol-gel transition temperature, which is sol-gelized at a temperature lower than the sol-gel transition temperature and gelled at a temperature higher than the sol-gel transition temperature. A first step of producing a sol-gel having a cavity at least partially provided by using it, a second step of filling the cavity with a second solution and curing it, and the first step and the second step. The first step and the second step are repeated on the upper part of the structure manufactured in the above step, and the third step of manufacturing the laminated structure, the atmosphere, the base material serving as the base of the sol-gel process, or the above. It has a fourth step of setting the modeling mold to the sol-gel transition temperature or lower, removing the modeling mold which is the laminated portion of the first gel-like member from the laminated structure, and producing a modeling object.

According to the disclosed technique, a gel-like three-dimensional structure having a high aspect ratio can be produced with a small release load.

It is a figure which illustrates the structure of the modeling object which concerns on 1st Embodiment (FIG. 1 (a) perspective view of the modeling object, FIG. 1 (b) sectional view of the modeling object, FIG. 1 (c) modeling. Top view of the object). It is a perspective view which illustrates the structure of the modeling mold which concerns on 1st Embodiment. It is a schematic diagram of the laminating apparatus for manufacturing which concerns on 1st Embodiment. It is a figure which illustrates the structure which performed the process A in the manufacturing method which concerns on 1st Embodiment (FIG. 4 (a) figure which executed small steps 1, 2 and 3 and FIG. 4 (b) small process 4 4 (c) top view). It is a figure which illustrates the structure which executed the process B in the manufacturing method which concerns on 1st Embodiment (FIG. 5 (a) figure which executed small process 5, FIG. 5 (b) figure which executed small process 6 ). It is a figure which illustrates the structure which performed the process C in the manufacturing method which concerns on 1st Embodiment (the figure which repeated the process A of FIG. 6 (a), (the process 5 of FIG. 6 (b) process B is executed. 6 (c) A diagram in which step 6 of step B is executed). It is a figure which illustrates the structure which performed the step D in the manufacturing method which concerns on 1st Embodiment. It is a figure which illustrates the appearance that the modeling mold collapsed in a comparative example. It is a figure which illustrates the structure of the modeling object and the modeling mold which concerns on Example 2 (FIG. 9 (a) modeling object, FIG. 9 (b) modeling). It is a figure which illustrates the structure of the modeling object of Example 3 which concerns on 2nd Embodiment (FIG. 10 (a) perspective view, FIG. 10 (b) sectional view).

Hereinafter, embodiments will be described with reference to the drawings. In each drawing, the same components may be designated by the same reference numerals, and duplicate description may be omitted.

In the following embodiments, a method for manufacturing a tubular structure will be described as an example of a method for manufacturing a three-dimensional structure according to the present invention. However, the method for producing a three-dimensional structure according to the present invention is not limited to the method for producing a tubular structure, and a three-dimensional structure in a gel state having a high aspect ratio, which is required to be produced with a small release load. It can be widely applied to manufacturing methods.

(Embodiment 1)
<Structure of modeling object 2000>
FIG. 1 is a diagram illustrating a tubular structure according to the present embodiment. In the present specification, even if the material is a flexible member and can be freely deformed, it is a tubular structure as long as it has a shape provided with a space (cavity) penetrating in at least one direction. And. Hereinafter, for convenience of explanation, the tubular structure to be manufactured is referred to as a modeling object.

The modeling object 2000 of the present embodiment is a hollow portion 2001 penetrating in the vertical direction as shown in a perspective view illustrating the modeling object 2000 which is a cylindrical structure according to the present embodiment of FIG. 1A. Is a cylindrical member provided with. FIG. 1 (b) is a cross-sectional view taken along the line I-I of FIG. 1 (a) in the vertical direction. Further, FIG. 1 (c) is a top view. In the present specification, as shown in FIG. 1A, the Z direction when the modeling object 2000 is erected upright so that the space through which the modeling object 2000 penetrates is upright is defined as the vertical direction. The directions in the present specification are for convenience of explaining the manufacturing process, and do not limit the usage of the tubular structure.

The modeling object 2000 is a flexible and soft tube-shaped member made of, for example, a gelled material of κ-carrageenan (tricrystal, CSK-01). The outer diameter is 3 mm, the thickness of the outer wall is 0.9 mm, and the height is about 10 mm. For example, it can be used as an artificial blood vessel model. Further, as will be described later, the shape of the modeling object 2000 is not limited to the cylinder. It is possible to model various shapes such as square cylinders and triangular cylinders.

<Manufacturing method of modeling object 2000>
<Modeling type 1000>
In order to manufacture the modeling object 2000, the modeling mold 1000 is required. FIG. 2 is a diagram illustrating a modeling mold 1000 for manufacturing a modeling object 2000. The modeling mold 1000 shown in FIG. 2 is provided with an annular (cylindrical) hollow space in the vertical direction. More specifically, it is composed of two members, a tubular member and a pillar-shaped member provided in a hollow space inside the tubular member. Hereinafter, the tubular member will be referred to as a tubular modeling die 1001, the columnar member will be referred to as a columnar modeling die 1002, and the combination of these two will be referred to as a modeling die 1000. Further, the space between the tubular molding die 1001 and the columnar molding die 1002 is defined as a space 1003.

The tubular molding die 1001 and the columnar molding die 1002 are arranged on the base material 102 as a base so that the columnar molding die 1002 does not come into contact with the inner wall of the tubular molding die 1001. Further, it is preferable that the heights of the tubular molding die 1001 and the columnar molding die 1002 are equal to each other, or that the columnar molding die 1002 is higher. The reason is that the manufacturing method will be described later, but the material of the modeling object 2000 is injected into the space 1003 to produce the modeling object 2000. Therefore, when the height of the columnar modeling die 1002 is formed lower than that of the tubular modeling die 1001, the height hollow portion 2001 of the modeling object 2000 cannot be penetrated in the vertical direction, and the modeling object 2000 is formed into a cylinder. This is because it does not have a shape. The base material 102 may be attached with a solution as a material for the modeling mold 1000 or the modeling object 2000, and examples thereof include metal, glass, and plastic film, but the substrate 102 is not particularly limited.

<Solution>
In the present embodiment, the three-dimensional modeling object 2000 is modeled by using two types of polymers, a polymer for the modeling model 1000 and a polymer forming the modeling object 2000. In the present specification, the polymer used as the material of the modeling mold 1000 is referred to as the polymer A, and the solution of the polymer A is referred to as the solution A. Further, the polymer used as the material of the modeling object 2000 is referred to as polymer B, and the solution of the polymer B is referred to as solution B. Note that solution A and solution B have different sol-gel transition temperatures. Further, the modeling object 2000 may be formed by using two or more kinds of polymers B.

<Explanation of solution A (first solution)>
Solution A is a solution that serves as a material for modeling mold 1000. As the solution A, a solution of a temperature-responsive hydrogel-forming polymer used as a temperature-responsive sol-gel transition material is used. The temperature-responsive sol-gel transition material will be described in detail below.

The sol-gel transition material refers to a polymer material that exhibits a sol-gel transition, which is a reversible phase transition phenomenon between a sol and a gel. In particular, the polymer A, which is a hydrogel-forming polymer, is not particularly limited as long as the solution A has a sol-gel transition temperature that sol-gels at a temperature lower than the sol-gel transition temperature and gels at a temperature higher than the sol-gel transition temperature. In the present embodiment, the sol state refers to a fluid state, and the gel state refers to a state in which the fluid is thickened and loses fluidity.

Methyl cellulose is shown in Patent Document 2 (Patent 501951) as an example of a hydrogel-forming polymer having a sol-gel transition temperature in which a solution sol-gels at a temperature lower than the sol-gel transition temperature and gels at a temperature higher than the sol-gel transition temperature. 8-arms PEG-block-PLLA-cholesterol conjugate, Poly [(Glc-Asp) -r-DL-LA] -g-PEG, Pluronic® shown in Patent Document 3 (Patent 5264103). There are poloxamers 407 commercially available under the names of F127 and Kolliphor® P407. However, these are examples and are not limited. Among the hydrogel-forming polymers, poloxamer 407 (hereinafter referred to as poloxamer) is designated as polymer A because the solution undergoes a sol-gel transition at around room temperature of around 23 to 28 degrees Celsius, is easily available, and has been used. Most preferably used.

In addition, the solution can adjust the sol-gel transition temperature by changing the concentration of the polymer and the additives. In this embodiment, as an example, an example in which a poloxamer aqueous solution is used as the polymer solution A having a sol-gel transition temperature will be described. In the case of an aqueous poloxamer solution, the sol-gel transition temperature can be adjusted by changing the concentration of poloxamer. For example, at a concentration of 15 weight percent, the sol-gel transition temperature is around 30 to 40 degrees. For a 20 weight percent concentration, the sol-gel transition temperature is about 20 degrees. The sol-gel transition temperature can also be adjusted by adding an additive. When sodium chloride is added to a 25% by weight poloxamer aqueous solution, the sol-gel transition temperature becomes around 5 to 10 degrees.

As an example of the additive, a combination of methyl cellulose and sorbitol used for food additives is also easily available, and the sol-gel transition temperature of the solution can be adjusted to less than 40 degrees. In addition to the above, additives include particles such as polyacrylic particles and chitosan, thickeners, dyes, fluorescent dyes, fibers, dispersants, organic solvents, etc., but these are examples and are not limited. do not have.

By using the property that the sol-gel transition temperature changes depending on the concentration of the polymer and the addition of additives, the solution A, which is the material of the modeling mold 1000, is sol-ized rather than the temperature at which the solution B, which is the material of the modeling object 2000, solidifies. Adjust the sol-gel transition temperature to a low level. That is, by producing the modeling mold 1000 and the modeling object 2000 using solutions having different temperatures that cause a state change, it is possible to simultaneously control the state change of each solution by the temperature change.

More specifically, the solution B is gelled while the solution A is in the gel state from the state in which the solution A in the gel state and the solution B in the sol state are present at the same time. Further, the temperature can be changed again to control the state change of the two kinds of solutions, such as solizing the solution A and leaving the solution B in the gel state. Since one polymer A can be adjusted to a solution having a different sol-gel transition temperature depending on the concentration of the polymer and changes in additives, the materials of the solution A and the solution B can be combined in various ways.

<Explanation of solution B (second solution)>
Solution B (second solution) is a solution that is a material for the modeling object 2000. The polymer B, which is the raw material of the solution B, can be gelled even if the solution A is in a gel state, that is, it can be solidified (cured) even in a temperature range higher than the sol-gel transition temperature of the polymer A. There are no particular restrictions as long as it is a suitable material. Examples include resins and gels. Further, the solution B may contain particles and the like.

In the present embodiment, the modeling mold 1000 and the modeling object 2000 were prepared using two different types of polymers, but two types of solutions having different temperature responsiveness were prepared from one type of polymer, and each of them was prepared. It is also possible to prepare the modeling mold 1000 and the modeling object 2000 with the solution of.

<Manufacturing method>
The modeling object 2000 is manufactured by sequentially executing the large steps of step A, step B, step C, and step D. Step A is a step of modeling a part of the modeling mold 1000 by sequentially executing at least step 1, step 2 and step 3, which are small steps. Further, step A may include step 4, which is a small step, after executing step 3. Step B is a step of injecting the solution B into the space 1003 of the modeling die 1000 formed in the step A by sequentially executing the small steps of the steps 5 and 6, and gelling and solidifying the solution B. Step C is a step of repeating steps A and B until the modeling mold 1000 and the modeling object 2000 have an arbitrary height and shape. Step D is a step of removing the modeling mold 1000 from the modeling object 2000.

Table 1 shows the states of the solutions A and B and the changes in the temperature of the atmosphere for each step. In this specification, the atmosphere represents the air around the laminated modeling apparatus. For example, when a constant temperature bath is used, it means air whose temperature is regulated inside the constant temperature bath, and when no special temperature adjustment is performed indoors, it means room temperature.

工程Aは、溶液Aを用いて、上下方向に貫通する環状の空間が設けられた第１ゲル状部材を作製する第１ゲル状部材作製工程である。第１ゲル状部材は、造形型１０００もしくは造形型１０００の一部を称する。

Step A is a first gel-like member manufacturing step of producing a first gel-like member provided with an annular space penetrating in the vertical direction using the solution A. The first gel-like member refers to a modeling mold 1000 or a part of the modeling mold 1000.

The method of laminating a part of the modeling die 1000 will be described below, but a single layer may be used as long as it can be formed into a desired shape, and it is not always necessary to laminate a plurality of layers. In the present embodiment, a modeling method using the pneumatic dispenser 104 shown in FIG. 3 will be described as an example from the viewpoint of easy device configuration. In the present embodiment, for convenience of explanation, even a single layer is referred to as laminated modeling.

The details of the step A will be described with reference to FIG. Further, step A includes steps 1, step 2, step 3, and step 4, which are small steps. The details of the small steps will be described in detail below, but when the first gel-like member is a single layer, it is achieved by sequentially executing the steps 1, step 2, and step 3. When a plurality of layers are laminated as the first gel-like member, it is achieved by sequentially executing step 1, step 2, step 3, and step 4.

In step 1, a syringe 101 in which the gel-like solution A as shown in FIG. 3 is injected is prepared, the upper part of the syringe 101 is pressurized with compressed air, and the tip of the syringe nozzle 105 below the syringe 101 is placed on the drive stage 103. The solution A is discharged toward the base material 102. Examples of the method for discharging the solution A include mechanical extrusion, electrostatic discharge, and the like in addition to the pneumatic dispenser 104 shown in the present embodiment, but the discharge method is not particularly limited.

In step 2, the syringe 101 and the base material 102 are relatively moved in the horizontal direction. The syringe nozzle 105 may be moved, or the drive stage 103 and the base material 102 may be moved, but it is preferable to move the syringe 101 so that the shape of the discharged solution A does not collapse.

In step 3, as shown in FIG. 4A, the solution A is discharged onto the base material 102 in steps 1 and 2, and the solution A is further formed into an arbitrary shape. FIG. 4A is a vertical cross-sectional view of the first gel-like member for one layer of the solution A.

In step 4, as shown in FIG. 4B, the solution A is discharged again and laminated on the upper part of the structure of the solution A prepared in the step 3. FIG. 4 (b) is a cross-sectional view in the vertical direction in which four layers are laminated. Further, FIG. 4 (c) is a top view showing the line AA common to FIGS. 4 (a) and 4 (b).

In step A, steps 1 to 4 are repeated until the shape and height become arbitrary, and the solution A is laminated. Further, the step A is performed in an atmosphere equal to or higher than the sol-gel transition temperature. Therefore, the solution A is consistently held in a gel state from discharge to lamination.

As a method of keeping the solution A above the sol-gel transition temperature, a heating mechanism such as heating the drive stage 103 and the syringe 101 with a Pelche element or modeling in a heating environment inside a constant temperature bath can be used. However, the atmosphere may be equal to or higher than the sol-gel transition temperature, and when the room temperature is higher than the sol-gel transition temperature, a heating mechanism is not required.

Step B is a second gel-like member filling step in which the annular space (space 1003) created in step A is filled with the solution B to be the second gel-like member. In the present embodiment, as an example, the sol-state solution B is filled in the space 1003 and gelled by sequentially executing the small steps, step 5 and step 6. However, the solution B is not limited to the one in the sol state, and when the step B is completed, the space 1003 may be filled with the gel-state member which is a part of the modeling object 2000. The step of pouring into the space 1003 is referred to as a small step 5, and the step of curing is referred to as a small step 6, which will be described in detail below.

In step 5, as shown in FIG. 5A, the uncured sol solution B is injected into the space 1003 of the first gel-like member with a syringe 101. Further, the step 5 is performed in a state where the first gel-like member is held at a temperature equal to or higher than the sol-gel transition temperature so that the first gel-like member does not become sol-gel. The method of holding the model 1000 at a temperature equal to or higher than the sol-gel transition temperature is the same as the holding means for laminating the model 1000 in step A described above. The means for injecting the uncured solution B includes a pipette, a dropper, a syringe and the like, but is not particularly limited. 5 (a), because the solution B to specify whether a sol state or a gel state, referred to as solution B sol state B _S.

In step 6, as shown in FIG. 5B, the solution B injected into the space 1003 of the first gel-like member is cured. The type of solution B and the curing method are not particularly limited. When step 6 is performed, the structure is present in which solution A and solution B are not mixed in a gel state. In FIG. 5B, since the solution B is in a gel state, it is referred _{to as B g.}

The curing method of the solution B includes UV irradiation, heat dissipation, addition of a cross-linking agent, etc., depending on the type of the solution B, but is not particularly limited. Any material that cures over time may be left as it is.

Examples of the solution that cures by UV irradiation include UV resin.

Examples of the solution that cures by heat dissipation include agarose gel, carrageenan gel, gelatin gel and the like. These solutions are heated from the gel state to a sol-gel transition temperature or higher to dissolve in the sol state, injected into the space 1003 of the modeling mold 1000 (first gel-like member), and cured by dissipating heat to the temperature of the modeling mold 1000. You may let me.

As a curing method by adding a cross-linking agent, before injecting the solution B into the space 1003 of the modeling mold 1000, the cross-linking agent is added to the solution B, and the gel stage is gradually cured before the solution B is completely cured. A method of injecting and naturally curing after infusion may be used. For example, calcium chloride is added to an aqueous solution of sodium alginate, borax is added to an aqueous solution of polyvinyl alcohol, and the like. When water is added to a powder called alginate impression material, which is a mixture of sodium alginate, a sparingly soluble calcium salt, and a chelating agent, and mixed, it has the property of gradually curing in a few minutes to a dozen minutes. The solution B may be cured by mixing the alginate impression material with water, immediately injecting it into the space 1003 of the molding die 1000, and leaving it to stand for several minutes to ten and several minutes.

Further, in the structure, the space 1003 may be filled with the solution B so that the upper surface of the first gel-like member and the upper surface of the cured solution B (hereinafter referred to as the second gel-like member) are flush with each other. preferable. Further, the molding method according to the present embodiment is an effective molding method even when the material of the modeling object 2000 or the material of the modeling mold 1000 is a gel-like brittle member. One of the features that contributes to this effect is that the second gel-like member plays a role as a support material. The detailed effect will be described later.

In the present embodiment, since the modeling mold 1000 is laminated and molded with the gel-like solution, dents and steps may be formed between the layers. Therefore, in order to prevent the dents and steps from being transferred to the modeling object 2000, it is preferable to remove the unevenness from the surface of the modeling mold 1000 before injecting the solution B into the space 1003 of the modeling mold 1000. As an example, after the execution or completion of the step A, the step can be removed by lowering the temperature of the atmosphere to slightly approach the sol-gel transition temperature and sol-forming only the periphery of the first gel-like member.

As shown in FIG. 6, step C is a step of repeating steps A and B on the upper part of the structure formed by steps A and B until the height and shape of the target modeling object 2000 are reached. That is, after the solution B is cured by any of the above-mentioned methods, as shown in FIG. 6A, the process A is repeated and laminated on the upper part of the structure. Then, as shown in FIG. 6 (b), the solution B is injected into the space 1003 as in step B, and as shown in FIG. 6 (c), the solution B filled in the space as in step C is poured. Let it cure.

For example, if you want to model a tubular modeling object 2000 of about 2 cm, you can repeat modeling of a structure with a relatively low aspect ratio of about 0.5 cm four times until you reach the desired height (2 cm). good. When the diameter of the object to be modeled 2000 is the same in the vertical direction, the solution A may be discharged into the same shape on the upper part of the first gel-like member laminated up to the previous step. Depending on the shape of the target modeling object 2000, the solution A may be laminated on the cured solution B.

As shown in FIG. 7, the step D is a step of removing the modeling mold 1000 from the modeling object 2000 formed in the target shape. Examples of the removal of the gel-state modeling mold 1000 include a mechanical removal method and a removal method by solification. Since the modeling mold 1000 is in a gel state, it can be mechanically peeled off using tweezers or a trowel. However, the modeling object 2000 and the modeling mold 1000 are brittle and plastic. In particular, the columnar modeling mold 1002 for forming the hollow portion 2001 of the modeling object 2000 is fine, and it is difficult to completely remove the modeling mold 1000 filled in the hollow portion inside by hand. Further, even when the tubular modeling mold 1001 is peeled off, a mechanical load is generated on the modeling object 2000, so that the tubular modeling mold 1001 is easily damaged.

Therefore, it is desirable that the modeling mold 1000 is solified and removed. Since the solution A, which is the material of the modeling mold 1000, is a temperature-responsive sol-gel transition material, the solution A is sol-ized and can be easily removed by cooling the modeling mold 1000 to a temperature lower than the sol-gel formation temperature. Examples of the cooling means include holding the model 1000 in a low temperature state such as a refrigerator or a freezer, and applying a cooled object to the model 1000, but the method is not particularly limited as long as the model 1000 can be cooled.

Further, the shape of the object to be modeled 2000 taken out can be prevented from losing its shape by storing it in a closed state or by immersing it in water.

It is conceivable that the object to be modeled with a high aspect ratio is not modeled in a state where the longitudinal direction of the cylinder is erected in the vertical direction, but is modeled in a state where it is laid down in the horizontal direction using a modeling mold. However, in the present specification, it is necessary to provide a space penetrating in one direction in the object to be modeled. When modeling in a horizontally laid state, the manufacturing method and the shape of the modeling mold become complicated in order to provide a hollow space that penetrates. Further, in order to provide the central hollow space, the pillar-shaped molding must be floated in the air, and the position and dimensions of the hollow space are not stable. In particular, it has been difficult to produce a modeling object (for example, a cylinder) having a substantially circular cross section in the lateral direction. Therefore, when the object is laid down in the horizontal direction, the shape of the object to be modeled is narrowed.

It is also conceivable that the object to be modeled is divided into a plurality of parts so as to be torn in the longitudinal direction, and the objects are bonded to form a tubular shape. However, when the object to be modeled is used as a tube for injection of liquid or filling of materials, the pressure from the hollow space filled with some members to the outside of the object avoids adhesion in the longitudinal direction and causes damage. Probability is high. In addition, when the object to be modeled is modeled with a flexible material, there is a high possibility that the inner space will be crushed in the lateral modeling. Therefore, an object to be modeled with a high aspect ratio and a tubular shape cannot be modeled while lying down in the horizontal direction.

In the method for manufacturing a modeling object according to the present embodiment, the modeling mold 1000 is laminated with a temperature-responsive sol-gel transition material, and the removal method is performed by solification to provide a hollow portion 2001 penetrating in the vertical direction. The modeling object 2000 can be obtained without a mechanical load. From this, it is possible to reduce the mechanical load on the modeled object 2000 that has been modeled as compared with the conventional case, and it is possible to model the modeled object 2000 with a brittle material. Further, even if the modeling object 2000 has a high aspect ratio and a complicated shape, the modeling die 1000 can be solified from the modeling object 2000 and flowed out, so that there is no problem even if fine processing is required.

Then, when the model object 2000 is manufactured, the process A and the process B are repeated so that the model 1000 can be laminated and the model 2000 can be modeled at the same time. By adopting such a modeling method, when the solution A is laminated on the upper part of the structure in the step C, the portion where the gel-like solution A of the base structure is laminated is hardened. It is supported by solution B (second gel-like member). This is because, in the structure, the second gel-like member cured into a tubular shape limits the horizontal deformation of the columnar molding mold 1002 formed by the solution A. When the gel-like solution A is laminated as the modeling mold 1000, the solution A collapses due to its own weight. In particular, in the case of a high aspect ratio having a height in the direction perpendicular to the surface to be installed on the base material 102, it was difficult to stack the modeling molds 1000 at once with a gel-like solution.

However, by laminating the modeling mold 1000 and the modeling object 2000 while gradually gelling, the structure that serves as the base each time includes a first gel-like member and a tubular second gel-like member. Therefore, the injected solution B serves as a holding material for the modeling mold 1000 and can support the lower part. Therefore, even if the modeling object 2000 has a high aspect ratio or the modeling object 2000 has a fine size, the upper part maintains the shape. Can be added to.

In step B, if the injected solution B is left for a long time to cure, the interface of the structure dries. In particular, when the upper surface is dried, adhesion may not be successful when the solution A is discharged to the upper part of the first gel-like member of the structure in step C. Therefore, in order to prevent the structure from drying, it is preferable that the step B is performed in as short a time as possible. Further, the same effect can be obtained by shortening the time for repeating the lamination.

The shape of the modeling object 2000 can be varied in various ways by changing the shapes of the tubular modeling mold 1001 and the columnar modeling mold 1002. For example, if the cylindrical modeling mold 1001 has a cylindrical shape and the columnar modeling mold 1002 has a square pillar, the modeling object 2000 can have a shape in which a square through hole is provided in the cylinder.

<Example>
An example of the modeling object 2000 manufactured in the present embodiment will be described. It should be noted that the description that overlaps with the description of the embodiment may be omitted. In addition, the strength was evaluated by the storage elastic modulus of the solution A used in the examples. The storage elastic modulus was measured under the conditions of a rheometer (Anton Parr, MCR301) equipped with a parallel plate sensor having a diameter of 25 mm, a gap of 1 mm from the object to be measured, a frequency of 1 Hz, and a strain of 0.5%. Here, the storage elastic modulus is a value that serves as an index for determining the strength (hardness). If the storage elastic modulus is high, the material is hard, and if it is low, the material is soft and almost liquid.

[Example 1]
Poloxamer 407 (BASF Japan Co., Ltd., Kolliphor), which is a temperature-responsive hydrogel-forming polymer as polymer A-1, with respect to pure water held at 10 ° C or lower using a beaker whose surroundings are cooled with ice. A solution A-1 was prepared by adding (trademark) P407) and stirring and dissolving the solution. The concentration of poloxamer 407 is 20% by weight. Since the sol-gel transition temperature of the solution A-1 is 21 degrees, the solution A-1 was kept at a temperature of 15 degrees with a margin to bring it into a sol state. Then, the temperature of the solution A-1 in a sol state was raised from 15 ° C. to 37 ° C. to obtain a transparent gel. The storage elastic modulus of the obtained transparent gel was measured by the above-mentioned evaluation method and found to be 11000 [Pa].

As step A, the following was executed.

Solution A-1 cooled to 10 degrees was filled in a syringe 101 having a volume of 10 mL, and a syringe nozzle (manufactured by Musashi Engineering) having a tip inner diameter of 100 μm was attached. Next, the syringe 101 was left in an environment of 28 degrees for 10 minutes, and the temperature of the solution A-1 in the syringe 101 was raised from 10 degrees to 28 degrees to change the sol state to the gel state. In this embodiment, the room temperature is 28 degrees. Similarly, in an environment of 28 degrees, the solution A-1 in the gelled syringe 101 is pressurized using a compressed air dispenser 104 (Musashi Engineering: ML-5000XII), and the solution A-1 is pressed from the tip of the syringe nozzle 105. The gel was discharged.

A PET film was laid on the drive stage 103 as a base material 102 on the lower part of the syringe nozzle 105, and the drive stage 103 and the syringe 101 were moved relative to each other to be discharged on the base material 102 in a gel state. A laminate of solution A-1 was prepared. In the examples, a PET film was used as an example of the base material 102. The prepared solution A-1 exists in a gel state in an environment of 28 degrees Celsius, and has the property of not significantly losing its shape, so that it can be laminated.

A schematic diagram is shown in FIG. 4 (b). A structure composed of the tubular molding die 1001 and the columnar molding die 1002 provided inside the tubular molding die 1001 is referred to as a first gel-like member. The first gel-like member is a part of the modeling mold 1000. In the first gel-like member, the outer diameter of the outer wall of the tubular molding die 1001 is 6.0 mm, the thickness of the outer wall is 1.5 mm, the outer diameter of the columnar molding die 1002 is 1.2 mm, and the height is 2.5 mm. rice field.

Next, as step B, the following was executed.

As the polymer B-1, a solution B-1 in which κ-carrageenan (tricrystal, CSK-01), which is a temperature-responsive hydrogel-forming polymer, was dissolved in water at 70 ° C. at a concentration of 2% by weight was prepared. .. The sol-gel transition temperature of solution B-1 is 28 degrees. The prepared solution B-1 at 70 ° C. is cooled and the temperature is lowered from 70 ° C. to 40 ° C. The solution B-1 does not change from the sol state. The reason for lowering the temperature is to bring it closer to the sol-gel transition temperature and to sol it in as short a time as possible.

The syringe was filled with the solution B-1 at 40 degrees, and the solution B-1 was discharged into the space 1003 of the first gel-like member. The solution B-1 filled in the space 1003 immediately after the injection is in a sol state, but after that, the solution B-1 is changed from the sol state to the gel state by leaving it in an environment of 28 degrees for 30 minutes to lower the temperature. I changed it. A tubular member in which the solution B-1 is in the form of a gel is referred to as a second gel-like member.

The structure after being produced by the steps A and B obtains the structure shown in FIG. 5 (b). In this columnar structure, solution A-1 and solution B-1 each exist in a gel state under an environment of 28 degrees, and the outer diameter is 6.0 mm and the height is 2.5 mm.

Next, as step C, the following was executed.

Steps A and B were repeated twice on the upper part of the structure produced by the above steps, and structures having the same shape and height were laminated. More specifically, a structure having the same shape as the first gel-like member formed in the first step A and having a height of 2.5 mm was formed with the solution A-1 on the upper part of the structure. Since the first gel-like member and the upper structure are sufficiently bonded to each other because they are laminated with the same material and shape, the bonded surface can hardly be confirmed with the naked eye.

Further, the solution B-1 at 40 degrees was injected into the space 1003 of the second gel-like member with a syringe 101. Then, the solution B-1 was gelled by leaving it in an environment of 28 degrees for 30 minutes. Further, this step is repeated once more, and finally, the solution A-1 and the solution B-1 in the form in which three first gel-like members and three second gel-like members are laminated in the vertical direction are gelled respectively. The existing columnar structure is formed. The structure has an outer diameter of 6.0 mm and a height of 7.5 mm. The solution B-1 may be filled in the space 1003, and can be poured directly not only from the syringe 101 but also from a dropper or a storage container for the solution.

Finally, as step D, the following was executed.

The columnar structure was placed in a refrigerator set at 4 degrees together with the base material 102, and cooled in an environment of 4 degrees for 2 hours. Then, the sol-gel transition temperature of the solution A-1 falls below 21 ° C., and the solution A-1 which was in a gel state until the step C is sol-ized and flows out from the structure and is removed. FIG. 7 shows a schematic view of the modeling object 2000 of the gelled solution B-1 taken out of the refrigerator. The dimensions of the modeling object 2000 formed by the solution B-1 are an outer diameter of 3.0 mm, an outer wall thickness of 0.9 mm, and an overall height of 7.5 mm.

Through the above steps, a fine cylindrical flexible gel tube having the same diameter and a length of 7.5 mm was completed. In the modeling object 2000, the sol is gelled each time by performing step C a plurality of times. However, since the modeling object 2000 is a material having an affinity, it is adhered to such an extent that the boundary between the layers is not visible. Therefore, there is no strength problem in using the modeling object 2000 as one member.

[Comparative Example 1]
Solution A-1 cooled to 10 degrees was filled in a syringe 101 having a volume of 10 mL, and a syringe nozzle (manufactured by Musashi Engineering) having a tip inner diameter of 100 μm was attached. Next, the syringe 101 was left to stand in an environment of 28 degrees for 10 minutes, and the temperature of the solution A-1 in the syringe was raised from 10 degrees to nearly 28 degrees to change from a sol state to a gel state. Similarly, in an environment of 28 degrees, the solution A-1 in the gelled syringe 101 is pressurized using a compressed air dispenser 104 (Musashi Engineering: ML-5000XII), and the solution A-1 is pressed from the tip of the syringe nozzle 105. The gel was ejected.

By laying a PET film as a base material 102 on the drive stage 103 below the syringe nozzle 105 and the drive stage 103 and moving the drive stage 103 and the syringe 101 relative to each other, the drive stage 103 and the syringe 101 are moved relative to each other on the base material 102 as in the first embodiment. A laminate to be the first gel-like member of the solution A-1 discharged in the gel state was prepared. In this first gel-like member, the outer diameter of the outer wall of the tubular molding die 1001 is 6.0 mm, the thickness of the outer wall is 1.5 mm, the outer diameter of the columnar molding die 1002 is 1.2 mm, and the height is 2.5 mm. be.

Next, unlike the first embodiment, after the execution of the step A, the solution B-1 is not injected into the space 1003 of the first gel-like member of the step B, and the tubular molding mold 1001 and the columnar molding mold 1002 are not injected. Continued stacking of solution A-1 on top of. Then, as shown in the vertical cross-sectional view of the modeling mold 1000 in FIG. 8, the columnar modeling mold 1002 began to bend as a whole when the molding molds 1000 were laminated to a height of about 3.0 mm. After that, the columnar molding mold 1002 was curved each time the lamination was continued. When laminated to a height of 4.0 mm, the length L was 0.7 mm as an index showing the degree of bending of the columnar molding mold 1002. At this time, the dimensional error of the modeling mold 1000 becomes so large that it cannot be repaired, and when the columnar modeling mold 1002 is curved any more, it comes into contact with the inside of the tubular modeling mold 1001 and the modeling mold of the tubular modeling object 2000. Since it cannot be used as a stack, the lamination was stopped.

When it is desired to create a tubular modeling object 2000 by using the modeling mold 1000, a columnar modeling mold 1002 is provided inside the tubular modeling mold 1001 which is an outer wall so as not to come into contact with the inner wall of the tubular modeling mold 1001. Model 1000 is required. However, from Comparative Example 1, it is difficult to laminate a fine structure with a high aspect ratio by itself, especially when a gel material is used for the modeling mold 1000 in order to improve the releasability from the modeling object 2000. It turned out to be. Therefore, from Example 1 and Comparative Example 1, the formation of the modeling mold 1000 and the modeling object 2000 is changed from the sol to the gel each time by the steps B and C, and they are laminated stepwise. Therefore, the effect that the modeling mold 1000 and the modeling object 2000 mutually support each other can be obtained. Partly due to this effect, a tubular structure having a high aspect ratio can be formed as the final modeling object 2000.

It is possible to manufacture a modeling object 2000 having a high aspect ratio such that the ratio of the bottom surface to the height is 1: 2 or more. This ratio is fully applicable because the model of artificial blood vessels requires an outer diameter of 3 mm and a length of 6 mm or more. Further, if a gel tube member having a length of about 5.0 mm can be produced by this method, the cross sections of the objects to be modeled 2000 are vertically bonded to each other by manually (tweezers, etc.) a plurality of members to form a longer tube. It can also be formed.

[Example 2]
Poloxamer 407 (BASF Japan Co., Ltd., Kolliphor), which is a temperature-responsive hydrogel-forming polymer as polymer A-1, with respect to pure water held at 10 ° C or lower using a beaker whose surroundings are cooled with ice. A solution A-2 was prepared by adding (trademark) P407) and stirring and dissolving the solution. The concentration of poloxamer 407 is 20% by weight. Since the sol-gel transition temperature of solution A-2 is 15 degrees, the temperature of solution A-2 was kept at 10 degrees with a margin to bring it into a sol state. Then, the temperature of the solution A-2 in a sol state was raised from 10 ° C. to 37 ° C. to obtain a transparent gel. The storage elastic modulus of the obtained transparent gel was measured by the above-mentioned evaluation method and found to be 14000 [Pa].

As step A, the following was executed. Solution A-2 cooled to 10 degrees was filled in a syringe 101 having a volume of 10 mL, and a syringe nozzle (manufactured by Musashi Engineering) having a tip inner diameter of 100 μm was attached. Next, the syringe 101 was left in an environment of 28 degrees for 10 minutes, and the temperature of the solution A-1 in the syringe 101 was raised from 10 degrees to 28 degrees to change the sol state to the gel state. In this embodiment, the room temperature is 28 degrees. Similarly, in an environment of 28 degrees, the solution A-2 in the gelled syringe 101 is pressurized using a compressed air dispenser 104 (Musashi Engineering: ML-5000XII), and the solution A-2 is pressed from the tip of the syringe nozzle 105. The gel was discharged.

A drive stage 103 was laid under the syringe nozzle 105, and a PET film was laid on the drive stage 103 as a base material 102, and the drive stage 103 and the syringe 101 filled with the solution A-2 were relatively moved. Then, on the PET film (base material 102), the first gel-like form of the solution A-2 composed of a square cylinder as the tubular molding mold 1001 and a square pillar provided in the square cylinder as the columnar molding mold 1002. A member was formed. A schematic diagram is shown in FIG. 9 (b). In the first gel-like member, the outer wall of the tubular molding mold 1001 was 12.0 mm square, the thickness of the outer wall was 3.0 mm, the columnar molding mold 1002 was 3.0 mm square, and the height was 5.0 mm.

Next, as step B, the following was executed. As the polymer B-2, a 2% by weight aqueous solution of sodium alginate (Kimika, IL-2), a 2% by weight aqueous solution of dicalcium phosphate, a 4% by weight aqueous solution of citric acid, and polyacrylic particles having a diameter of 10 μm (Soken Kagaku, MX- Solution B-2 was prepared by mixing 1000) in a ratio of 5: 1: 1: 1. The prepared solution B-2 was immediately injected into the space 1003 of the first gel-like member with a dropper. Then, the solution B-2 was left to stand in an environment of 28 degrees for 5 minutes to gel, and a second gel-like member was formed.

Next, as step C, the following was executed. Similar to Example 1, the formation of the structure having the same shape and height, the injection of the solution B-2 into the space 1003, and the gelation were repeated four times on the first gel-like member at the upper part of the structure. .. Finally, a square columnar structure in which solution A-2 and solution B-2 each existed in a gel state was formed in a shape in which five structures were vertically laminated. The structure had an outer diameter of 12.0 mm and a height of 25.0 mm.

Next, as step D, the following was executed. The square columnar structure was placed in a refrigerator set at 4 degrees together with the base material 102, and cooled in an environment of 4 degrees for 2 hours. Then, the sol-gel transition temperature of the solution A-2 falls below 15 degrees, and the solution A-2, which was in a gel state until the step C, is sol-ized and flows out from the structure and is removed. FIG. 9 (b) shows a schematic view of the object to be modeled 2000 of the gelled solution B-2 taken out of the refrigerator. The dimensions of the square tubular modeling object 2000 formed by the solution B-2 were an outer diameter of 6.0 mm, an outer wall thickness of 1.5 mm, and an overall height of 25.0 mm. The object to be modeled 2000 had a form in which polyacrylic particles were dispersed in a hydrogel of alginic acid and the whole became cloudy.

In Example 2, the same effect as in Example 1 was confirmed.

(Embodiment 2)
Hereinafter, the present embodiment will be described with reference to the drawings. The part that overlaps with the first embodiment may be omitted. Further, in each drawing, the same components may be designated by the same reference numerals, and duplicate description may be omitted.

FIG. 10 illustrates an object to be modeled 3000, which is a member provided with two cylindrical shapes having different diameters according to the present embodiment. The modeling object 3000 shown in FIG. 10A is a member having two cylindrical shapes, a tubular structure 3010 and a tubular structure 3020, and provided with a hollow portion 3001 penetrating in the vertical direction. Further, FIG. 10B is a cross-sectional view in the vertical direction before removing the modeling mold from the modeling object 3000.

The object to be modeled 3000 is a flexible structure made of, for example, a solution of κ-carrageenan (tricrystal, CSK-01), and the thickness of the outer wall is not the same in the vertical direction. .. Further, as will be described later, the shape of the object to be modeled 3000 is not limited to a cylindrical shape, and two or more members having an arbitrary diameter and outer wall thickness can be combined.

The solution for producing the modeling object 3000 is the same as that in the first embodiment. In the method for manufacturing the object to be modeled 3000, first, the large steps A, B, and C are sequentially executed as in the embodiment. Then, the shape is further changed, and steps A, B, and C are repeated on the upper part of the structure. Therefore, it is possible to combine tubular shapes with different inner and outer diameters. After producing the final object to be modeled 3000, step D is executed to sol the solution A and remove it from the object to be modeled 3000.

[Example 3]
First, as step A, the gel-like solution A-1 having a sol-gel transition temperature of 21 degrees was laminated in the same manner as in Example 1 in an environment of 28 degrees. Similar to FIG. 4, the modeling mold 1000 is composed of a tubular modeling mold 1001 and a columnar modeling mold 1002 provided inside the tubular modeling mold 1001, and the outer diameter of the outer wall of the tubular modeling mold 1001 is 8.0 mm. The outer wall has a thickness of 1.5 mm and a height of 2.5 mm. The columnar molding mold 1002 has an outer diameter of 1.2 mm and a height of 2.5 mm.

Next, in step B, as the polymer B-1, a solution B-1 in which κ-carrageenan (tricrystal, CSK-01) similar to that in Example 1 was dissolved in water at 70 ° C. at a concentration of 2% by weight was prepared. .. After cooling the prepared solution B-1 to 40 degrees, inject it into space 1003 with a dropper and leave it in an environment of 28 degrees for 30 minutes to gel the solution B-1, having an outer diameter of 8.0 mm and a height of 8.0 mm. A 2.5 mm columnar structure was prepared.

Next, as step C, step A and step B were repeated three times on the upper part of the structure in the same manner as in Example 1. Finally, a columnar structure was formed in which four structures were laminated in the vertical direction, and solution A-1 and solution B-1 were gelled in each of them. The structure has an outer diameter of 8.0 mm and a height of 10.0 mm. A part of the final tubular structure 3010 included in the structure is referred to as a structure 3010.

Next, structures 3020 having different diameters are laminated on the upper part of the structure 3010. The structure including the structure 3010 produced by the steps A to C is used as a base.

In step A, the gel-like solution A-1 is discharged in different shapes and laminated on the upper part of the base structure. In step A, a structure having an outer diameter smaller than the outer diameter of the tubular molding die 1000 is produced on the upper part of the structure. The newly laminated structure has an outer diameter of 6.0 mm for the outer wall of the tubular molding mold 1001, a thickness of 1.5 mm for the outer wall, and an outer diameter of 1.2 mm and a height of 2.5 mm for the columnar molding mold 1002. became. Next, in the same manner as in step B, the solution B-1 was injected into the space 1003 of the structure with a dropper and left in an environment of 28 degrees for 30 minutes to gel the solution B-1. Next, in the same manner as in step C, steps A and B were repeated twice on the upper part of the structure. Finally, a columnar structure was formed in which three structures were laminated in the vertical direction, and solution A-1 and solution B-1 were gelled in each of them. Therefore, as shown in the cross-sectional view of the structure of FIG. 10B, a structure having a shape in which two structures having different outer diameters of cylinders are laminated is formed.

Finally, step D is performed. Steps A to C were performed twice with different diameters, and the produced structure was cooled together with the PET film of the base material 102 in an environment of 4 degrees for 2 hours. Then, since the sol-gel transition temperature of the solution A-1 is lower than 21 ° C., the gel-like solution A-1 is sol-ized and removed from the structure. A schematic view of the modeled object 2000 after cooling is shown in FIG. 10 (a). As for the dimensions of the object to be modeled 2000, the diameter of the central hole is 1.2 mm and the total height is 17.5 mm, and the lower cylinder has an outer diameter of 5.0 mm and an outer wall thickness of 1. It was 9 mm and had a height of 10.0 mm, and the upper cylinder had an outer diameter of 3.0 mm, an outer wall thickness of 0.9 mm, and a height of 7.5 mm.

In the above embodiment, the method of forming the modeling object 3000 by combining two cylindrical shapes having different diameters has been described, but the shape and the size of the diameter are not limited to this, and different shapes can be arbitrarily combined. Is. Further, according to this manufacturing method, the hollow portion 3001 can be manufactured so as to be narrowed.

It is conceivable to divide cylinders with different diameters into multiple members and bond them together to form a single member, but manually bonding members with different diameters and outer wall thicknesses is an adhesion. It was difficult because the area was small. Therefore, as in the present embodiment, if the structures produced up to the previous step are used as a base for laminating and modeling, each structure can be easily bonded.

Further, by using a temperature-responsive gel as the material of the modeling mold 1000, it is possible to remove it by solification at the time of removal. When using a conventional molding of metal or insoluble material, the shape that can be shaped is limited in order to take out the molding without destroying the object to be modeled. However, according to the present invention, it is easy to form a member having a hollow shape having the largest diameter in the center and a narrow end and a wide internal space, or a member having a complicated shape having a narrowing. be.

Although the preferred embodiments and the like have been described in detail above, the embodiments are not limited to the above-described embodiments and the like, and various embodiments and the like described above are used without departing from the scope of the claims. Modifications and substitutions can be added. For example, by using a biomaterial for the polymer B of the above-mentioned example, it is possible to easily model the modeling object 2000 applicable to the healthcare field. Further, the first embodiment and the second embodiment can be combined and implemented as appropriate.

Further, in the embodiment, the method of manufacturing the tubular modeling object 2000 has been described. However, needless to say, if only the tubular modeling mold 1001 is used as the modeling mold and the modeling object is produced in the same manner as the manufacturing method of the present embodiment without providing the columnar modeling mold 1002 in the space 1003, the hollow portion It is possible to produce a columnar object to be modeled without the above.

101 Syringe 102 Base material 103 Drive stage 104 Dispenser 105 Syringe nozzle 1000 Modeling mold 1001 Cylindrical modeling mold 1002 Columnar modeling mold 1003 Space 2000, 3000 Modeling object 2001, 3001 Hollow part 3010, 3020 Structure

Special Table 2013-542728

Claims (6)

A cavity is provided at least in part by using a first gel-like member which is a temperature-responsive hydrogel having a sol-gel transition temperature that sol-gels at a temperature lower than the sol-gel transition temperature and gels at a temperature higher than the sol-gel transition temperature. The first step of making the sol-gel process
A second step of filling the cavity with a second solution and curing it,
A third step of producing a laminated structure by repeating the first step and the second step on the upper part of the structure produced in the first step and the second step.
The atmosphere, the base material that serves as the base of the molding mold, or the molding mold that is the laminated portion of the first gel-like member is removed from the laminated structure by setting the molding mold to the sol-gel transition temperature or lower, and the molding target is removed. The fourth step to make and
A method for manufacturing a three-dimensional structure. The method for manufacturing a three-dimensional structure according to claim 1, wherein the three-dimensional structure has a tubular shape. The modeling mold is
Cylindrical molding with a cavity penetrating in one direction,
The method for manufacturing a three-dimensional structure according to claim 1 or 2, wherein the cavity is provided with a columnar molding. The temperature-responsive hydrogel is
The method for producing a three-dimensional structure according to any one of claims 1, 2 and 3, characterized in that it is any one of methyl cellulose, 8-arms PEG-block-PLLA-cholesterol / conjugate, and poloxamer. The second solution is
The method for producing a three-dimensional structure according to any one of claims 1, 2, 3, and 4, wherein gelation is possible in a temperature region equal to or higher than the sol-gel transition temperature. The method for producing a three-dimensional structure according to any one of claims 1, 2 , 3, 4, and 5, wherein the second solution contains particles.

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