JP6621824B2 - Method for manufacturing biological tube model and method for manufacturing biological organ model - Google Patents

Description

  The present invention relates to a method for manufacturing a biological tube model and a method for manufacturing a biological organ model.

  Conventionally, a living organ model resembling a real living organ has been used for surgical training of a surgeon. For example, [Claim 1] of Patent Document 1 includes “an aqueous gel composed of polyvinyl alcohol having an average polymerization degree of 300 to 3500 and a saponification degree of 90 mol% or more and silica particles. A molding material for an organ model is disclosed.

JP 2010-277003 A

In recent years, development is desired not only for living organ models resembling living organs such as the liver, but also for living body tube models resembling living vessels such as blood vessels.
For example, living tubes such as hepatic veins, hepatic arteries, portal veins, and bile ducts are stretched around the actual liver. For this reason, it is more practical to use a living organ model that imitates a living body tube model that imitates a living body tube. In addition, pre-operative conferences and the like are possible.

  Therefore, an object of the present invention is to provide a method for manufacturing a biological tube model in which a biological tube model can be easily obtained, and a method for manufacturing a biological organ model using the biological tube model obtained by the above method.

As a result of intensive studies, the present inventors have found that the above object is achieved by the following configuration. That is, the present invention provides the following [1] to [6].
[1] A male composition having a shape corresponding to the shape of a biological tube is brought into contact with a precursor composition containing a water-soluble polymer and water, and the male mold is formed by a gel film containing the water-soluble polymer and water. A method of manufacturing a biological tube model comprising: a step of covering the surface of the tube; and a step of releasing the male mold from the gel film to obtain a hollow biological tube model made of the gel film.
[2] The step of coating the surface of the male mold with the gel coating is a step of depositing the gel coating on the surface of the male mold by immersing the male mold cooled in advance in the precursor composition. A method for producing a biological tube model according to [1] above.
[3] The method for manufacturing a biological tube model according to [1] or [2], wherein the male material is a material having flexibility.
[4] The method for manufacturing a biological tube model according to any one of [1] to [3], wherein the biological tube model is a blood vessel model.
[5] The method for manufacturing a biological tube model according to any one of [1] to [4], further including a step of injecting a simulated body fluid into the hollow biological tube model.
[6] The biological tube model obtained by the method for manufacturing a biological tube model according to any one of [1] to [5] is disposed in a female internal space having an inner surface shape corresponding to the shape of the biological organ. Injecting a precursor composition containing a water-soluble polymer and water into the internal space to produce a gel body containing the water-soluble polymer and water, and separating the female mold from the gel body. And obtaining a living organ model made of the gel body containing a part or all of the living body tube model.

  ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of the biological tube model from which the biological tube model can be obtained simply, and the manufacturing method of the biological organ model using the biological tube model obtained by the said method can be provided.

FIG. 1A is a cross-sectional view showing an example of a preferred embodiment of the method for producing a biological tube model of the present invention, showing a state in which a male mold and a precursor composition are prepared. FIG. 1B is a cross-sectional view showing an example of a preferred embodiment of the method for producing a biological tube model of the present invention, and shows a state in which a precursor composition is brought into contact with a male mold. FIG. 1C is a cross-sectional view showing an example of a preferred embodiment of the method for manufacturing a biological tube model of the present invention, and shows a state in which a male surface is covered with a gel film. FIG. 1D is a cross-sectional view showing an example of a preferred embodiment of the method for manufacturing a biological tube model of the present invention, and shows a state where the male mold is released from the gel film. FIG. 2 is a cross-sectional view showing an example of a preferred embodiment of a biological tube model into which a simulated body fluid is injected. FIG. 3A is a cross-sectional view showing an example of a preferred embodiment of the method for manufacturing a biological organ model of the present invention, and shows a state in which the biological tube model is arranged in a female internal space. FIG. 3B is a cross-sectional view showing an example of a preferred embodiment of the method for producing a living organ model of the present invention, and shows a state in which a precursor composition is injected into the female internal space. FIG. 3C is a cross-sectional view showing an example of a preferred embodiment of the method for producing a living organ model of the present invention, and shows a state where the female mold is released from the gel body.

  Hereinafter, the numerical range expressed using “to” in this specification means a range including numerical values described before and after “to” as a lower limit value and an upper limit value.

[Production method of biological tube model]
In the method for producing a biological tube model of the present invention, a water-soluble polymer and water are brought into contact with a male composition surface having a shape corresponding to the shape of the biological tube by bringing a precursor composition containing the water-soluble polymer and water into contact therewith. A step of covering the surface of the male mold with a gel film containing, and a step of releasing the male mold from the gel film to obtain a hollow biological tube model made of the gel film. It is a manufacturing method.
In this way, a hollow living body model made of a gel film to which the shape of the male mold is transferred can be easily obtained simply by forming the gel film on the surface of the male mold and then releasing the mold.

[Preferred embodiment of manufacturing method of biological tube model]
Hereinafter, based on FIG. 1A-FIG. 1D and FIG. 2, the suitable aspect of the manufacturing method of the biological pipe model of this invention is demonstrated roughly.
Drawing 1A-Drawing 1D are sectional views showing an example of the suitable mode of the manufacturing method of the living body model of the present invention. 1A shows a state in which a male mold and a precursor composition are prepared, FIG. 1B shows a state in which the precursor composition is brought into contact with the male mold, and FIG. 1C shows that the surface of the male mold is coated with a gel film. FIG. 1D shows a state in which the male mold is released from the gel film.

First, as shown in FIG. 1A, a male mold 11 is prepared.
The male mold 11 is a mold (core) for obtaining a biological tube model simulating a biological tube. Here, the biological duct is not particularly limited as long as it is an organ having a tubular structure in a living body, and examples thereof include a bile duct and a ureter in addition to blood vessels such as veins, arteries, and portal veins. FIG. 1A shows a male mold 11 having a shape corresponding to a dendritic hepatic vein form as an example.
The material of the male mold 11 is not particularly limited, but for reasons described later, a material having flexibility such as a soft rubbery polymer substance is preferable.
Further, the manufacturing method of the male mold 11 is not particularly limited, but it is preferable to manufacture the male mold 11 using a 3D (three-dimensional) printer because a shape conforming to the actual product can be obtained. The 3D printer uses 3D data of a biological tube such as a blood vessel. At this time, a more precise biological tube model can be obtained by using patient-specific data (after being appropriately processed).

Moreover, as shown to FIG. 1A, the precursor composition 21 is also prepared.
The precursor composition 21 contains at least a water-soluble polymer and water. Examples of the water-soluble polymer include polyvinyl alcohol (PVA).
Polyvinyl alcohol (PVA) is generally obtained by saponifying polyvinyl acetate obtained by polymerizing vinyl acetate monomers.
It does not specifically limit as polyvinyl alcohol used for this invention, A conventionally well-known polyvinyl alcohol can be used suitably.
For example, the average polymerization degree (viscosity average polymerization degree) determined by the viscosity method of polyvinyl alcohol is preferably 300 to 3,500, more preferably 500 to 3000, and still more preferably 1000 to 2500.
The saponification degree of polyvinyl alcohol is preferably 90 mol% or more, more preferably 95 mol% or more, and still more preferably 98 mol% or more. The upper limit of the saponification degree is not limited, and it is preferably as high as possible. Particularly preferred is completely saponified polyvinyl alcohol.
Polyvinyl alcohol may be used alone or in combination of two or more.
As for the density | concentration of water-soluble polymers, such as polyvinyl alcohol, 4-20 mass% is mentioned with respect to the whole mass of the precursor composition 21, for example, 5-20 mass% is preferable, and 5-15 mass% is more. preferable.
In addition, the precursor composition 21 may contain an arbitrary additive as necessary.

  Next, as shown in FIG. 1B, the precursor composition 21 is brought into contact with the surface of the male mold 11. In addition, in FIG. 1B, although the aspect which immerses the male type | mold 11 in the precursor composition 21 put into the container as an example is shown, it is not limited to this, For example, the precursor composition 21 is a brush, You may apply | coat to the surface of the male type | mold 11 using apparatuses, such as a spray.

  Next, as shown in FIG. 1C, the surface of the male mold 11 is covered with a gel film 22. The gel film 22 is a film in which the precursor composition 21 is gelled. For this reason, the gel film 22 contains at least a water-soluble polymer and water, like the precursor composition 21.

In the process described based on FIGS. 1A to 1C, a mode in which the gel film 22 is deposited on the surface of the male mold 11 by immersing the male mold 11 cooled in advance in the precursor composition 21 is preferable.
More specifically, for example, first, the male mold 11 is previously cooled to, for example, about −10 ° C. or less, and as the precursor composition 21, as described above, a PVA aqueous solution containing polyvinyl alcohol and water. Is prepared (see FIG. 1A). Next, the cooled male mold 11 is immersed in the precursor composition 21 that is a PVA aqueous solution for about 10 to 60 seconds (see FIG. 1B). Then, the precursor composition 21 near the surface of the male mold 11 is cooled, frozen, and gelled. Then, the gel film 22 is formed on the surface of the male mold 11 by pulling up the male mold 11 from the precursor composition 21 and thawing (see FIG. 1C).
In this way, if the pre-cooled male mold 11 is immersed in the precursor composition 21 to deposit the gel film 22, the gel film 22 can be formed uniformly on the surface of the male mold 11 in a short time. Therefore, it is preferable.
In particular, when the male mold 11 has a complicated shape such as a dendritic shape, it is easy to generate unpainted parts and the like when the precursor composition 21 is applied by brush coating or the like. On the surface, it is difficult for unpainted parts to occur, and it can be applied uniformly and in a short time.
And, since the gel film 22 is formed simply by immersing and pulling up the cooled male mold 11, the gel film 22 can be easily formed into a uniform film thickness without complicated processes such as heat treatment. Can be formed in a short time.

  In addition, it is not limited to the said aspect, For example, as the precursor composition 21, in addition to polyvinyl alcohol and water, you may use the aqueous solution containing a borate ion further. In this case, the gel film 22 is formed by bringing the aqueous solution into contact with the surface of the male mold 11 without cooling the male mold 11 in advance, and then performing an effect treatment such as heating.

  Next, as shown in FIG. 1D, the male mold 11 is released (desorbed) from the gel film 22 to obtain a hollow biological tube model 31 made of the gel film 22. Here, since the male mold 11 having a shape corresponding to the form of the hepatic vein is used, a blood vessel model simulating the hepatic vein is obtained as the biological tube model 31.

The method for releasing the male mold 11 is not particularly limited. For example, as shown in FIG. 1C, a through-hole 33 in which the gel film 22 is not closed is formed on the surface of the male mold 11, and the process shown in FIG. 1D is performed. Thus, a method of pulling out the male mold 11 from the through-hole 33 can be mentioned. With this method, the male mold 11 can be easily detached from the gel film 22.
At this time, the male mold 11 is preferably made of a soft material having flexibility. If the male mold 11 having flexibility is used, the gel film 22 is easily deformed along the shape of the gel film 22 when pulled out from the gel film 22, and the gel film 22 is hardly damaged.
Note that “having flexibility” means deformation without being broken or damaged when an external force such as pushing, bending, or twisting is applied.

FIG. 2 is a cross-sectional view showing an example of a preferred embodiment of a biological tube model into which a simulated body fluid has been injected.
The hollow biological tube model 31 (see FIG. 1D) may be used as it is. However, as shown in FIG. 2, a simulated body fluid 32 simulating body fluid is injected into the biological tube model 31 from, for example, the through-hole 33. May be. As a result, the biological tube model 31 becomes a more realistic model. Examples of the simulated body fluid 32 include simulated blood that simulates blood.

For example, as will be described later, the biological tube model 31 is included in a biological organ model formed using a female mold. At this time, the biological tube model 31 in a state where the simulated body fluid 32 that is a liquid is injected may be inferior in handling property when placed in the female internal space. After the hole 33 is sealed and the shape is appropriately adjusted, it is used in a cooled and solidified state.
It should be noted that the hollow body model 31 in which the simulated body fluid 32 is not injected may be cooled and solidified.

[Production method of biological organ model]
Next, the manufacturing method of the biological organ model of this invention is demonstrated.
The biological organ model manufacturing method of the present invention includes a step of arranging the biological tube model obtained by the biological tube model manufacturing method of the present invention in a female internal space having an inner surface shape corresponding to the form of the biological organ. A step of injecting a water-soluble polymer and water-containing precursor composition into the internal space to form a water-soluble polymer and water-containing gel body, and releasing the female mold from the gel body. And a step of obtaining a living organ model composed of the gel body containing part or all of the living body tube model.
Since the biological organ model obtained in this way includes the biological tube model, it is possible to perform surgical training or the like that is more realistic.

[Preferred embodiment of manufacturing method of biological organ model]
Hereinafter, based on FIG. 3A-FIG. 3C, the suitable aspect of the manufacturing method of the biological organ model of this invention is demonstrated roughly.
3A to 3C are cross-sectional views showing an example of a preferred embodiment of the method for manufacturing a biological organ model of the present invention. FIG. 3A shows a state in which the biological tube model is disposed in the female internal space, FIG. 3B shows a state in which the precursor composition is injected into the female internal space, and FIG. The state where is released.

First, as shown in FIG. 3A, the biological tube model 31 is placed in the internal space 52 formed by the female mold 51. The female mold 51 is a mold for obtaining a living organ model imitating a living organ such as a liver, and is made of, for example, a hard material. The female mold 51 is also preferably manufactured using a 3D (three-dimensional) printer for the same reason as the male mold 11.
Here, as an example, a female mold 51 having an inner surface shape corresponding to the form of the liver is shown. That is, the internal space 52 imitating the shape of the liver is formed by the inner surface shape of the female mold 51. The female mold 51 is formed with an injection hole 53 through which the precursor composition 41 (see FIG. 3B) is injected into the internal space 52.
As an example, the biological tube model 31 is disposed in the internal space 52 in a state of being cooled and solidified as described above.

  Next, as shown in FIG. 3B, the precursor composition 41 is injected from the injection hole 53 to fill the internal space 52, and a gel body 42 (see FIG. 3C) reflecting the shape of the internal space 52 is generated. .

Here, as the precursor composition 41, the same composition as the precursor composition 21 described above (an aqueous solution containing PVA as a water-soluble polymer) can be suitably used.
The precursor composition 41 preferably contains gelatin. Thereby, in the obtained gel body 42, a structure in which two or more kinds of gels are phase-separated is formed, and unique fragility in a real living organ (particularly the liver) is reproduced. The concentration of gelatin is preferably 0.1 to 8.0% by mass and more preferably 0.3 to 5.0% by mass with respect to the total mass of the precursor composition 41.
Furthermore, the precursor composition 41 preferably contains an electrolyte such as sodium chloride. Thereby, since the gel body 42 has a certain electric conductivity, the similarity with a real thing becomes high regarding the touch which isolate | separates while coagulating the protein of a structure | tissue using a high frequency electric knife. The concentration of the electrolyte is preferably 0.15 to 2.00% by mass and more preferably 0.15 to 1.90% by mass with respect to the total mass of the precursor composition 41.
In addition, the precursor composition 41 may contain an arbitrary additive as necessary.

The gel body 42 is a gel body in which the precursor composition 41 is gelled. For this reason, the gel body 42 contains at least a water-soluble polymer and water, like the precursor composition 41.
Although it does not specifically limit as a method of producing | generating the gel body 42, For example, PVA aqueous solution containing polyvinyl alcohol (PVA) which is a water-soluble polymer, and water is used as the precursor composition 41, This precursor composition 41 The gel mold 42 is obtained by cooling the female mold 51 in a state of being injected at, for example, about −10 ° C. or less for about 1 to 10 hours and then thawing. The PVA aqueous solution is frozen by the cooling, but at this time, it gels.

Next, as shown in FIG. 3C, the female mold 51 is released from the gel body 42. The female mold 51 is configured to be divided as an example. By opening the female mold 51, a living organ model 61 including a gel body 42 including the living tube model 31 can be taken out.
In addition, after the thawing, the simulated body fluid 32 injected into the biological tube model 31 may be liquefied. In this case, the through-hole 33 (see FIG. 2 and the like) of the biological tube model 31 is also present. If covered with the gel body 42, the simulated body fluid 32 is prevented from leaking from the living organ model 61.

  In addition, in order to make the surface of the living organ model 61 more approximate to a real living organ, a surface thin film that looks like a sputum, a sputum, or a blood vessel may be formed as necessary.

  The biological organ model 61 thus obtained is more practical as a biological organ model for practicing surgical procedures because it contains a biological tube model 31 that imitates a biological tube. At this time, if a biological tube model imitating a patient-specific biological tube is used as the biological tube model 31, very precise surgical training, a pre-operative conference, and the like are possible.

  In the above description, a liver model resembling a human liver has been mainly described as an example, but the present invention is not limited to this, and other biological organs include, for example, the brain, heart, esophagus, stomach , Bladder, small intestine, large intestine, kidney, pancreas, spleen, uterus and the like.

  Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to these.

(Manufacture of male mold)
A male mold having a shape corresponding to the shape of liver blood vessels (hepatic vein, hepatic artery and portal vein) was produced using a 3D printer (trade name: Object 260 Connex, manufactured by Stratasys). Liver blood vessel 3D data used in the 3D printer was obtained by processing on a computer 3D data of a certain individual obtained from a 3D image analysis system (trade name: Volume Analyzer SYNAPSE VNCENT, manufactured by FUJIFILM Corporation). For data processing, 3D graphic software (manufactured by E Frontier, trade name: Shade 3D) was used. Rubber-like TangoPlus (manufactured by Stratasys) was used as the ink for the 3D printer, which is a male material.

(Production of blood vessel model)
The produced male mold was immersed in methanol cooled with dry ice and cooled. Next, the cooled male mold was quickly and polyvinyl alcohol having a viscosity average polymerization degree of 1700 and a saponification degree of about 99.3 mol% or more (trade name: Kuraray Poval PVA-117H, manufactured by Kuraray Co., Ltd.) 13 It was immersed in a mass% aqueous solution (precursor composition) for 30 seconds to deposit polyvinyl alcohol gel (gel film) on the male mold surface. In order to further crystallize and solidify the deposited gel film, the male mold covered with the gel film was pulled up from the precursor composition and then immersed in methanol cooled with dry ice for 10 minutes. Then, the male mold coated with the gel film is left at room temperature (25 ° C.). When the gel film becomes soft and stretchable, the rubber-like male mold is pulled out to obtain a hollow blood vessel model composed of the gel film. It was.
Thus, a blood vessel model simulating the hepatic vein, hepatic artery and portal vein was prepared.

(Production of simulated blood vessel model)
First, 0.61 g of food dye red (manufactured by Kyoritsu Foods) and 0.06 g of food dye green (manufactured by Kyoritsu Foods) were added to 1 L of water to prepare simulated blood. Next, this simulated blood was injected from the through-hole of the previously prepared hollow blood vessel model to obtain a blood vessel model with simulated blood.
For the prepared blood vessel model with simulated blood, after injecting simulated blood, the through hole was sealed with a clip, and the shape was adjusted in methanol, and then dry ice was immersed in this methanol and solidified on ice. .

(Production of bile duct model)
A bile duct model was prepared in the same manner as the blood vessel model. The bile duct model was solidified with ice in the same manner as the vascular model.

(Manufacture of female mold)
A female mold having an inner surface shape corresponding to the shape of the human liver was produced using a 3D printer (Stratasys, trade name: Object 260 Connex). The 3D data used in the 3D printer was obtained by processing on a computer 3D data of a certain individual obtained from a three-dimensional image analysis system (trade name: Volume Analyzer SYNAPSE VINCENT, manufactured by Fujifilm Corporation). For data processing, 3D graphic software (manufactured by E Frontier, trade name: Shade 3D) was used. At this time, more specifically, using the data of the surface portion of the liver parenchyma, creating rectangular data that covers the entire liver parenchyma and that is at least 1 cm thicker than the liver parenchyma surface, from this rectangular data The liver parenchyma data was cut out by Boolean calculation. In the female mold, an injection hole with a diameter of 1 cm for injection was formed, and further divided into three so that the solidified gel body could be removed. VeroClear (manufactured by Stratasys) was used as the ink for the 3D printer, which is a female material.

(Production of liver model)
First, polyvinyl alcohol having a viscosity average polymerization degree of 1700 and a saponification degree of about 99.3 mol% or more (made by Kuraray Co., Ltd., trade name: Kuraray Poval PVA-117H) was added at a concentration of 7 mass%, gelatin (Japanese Concentration of 3% by mass (manufactured by Kojun Yakuhin Kogyo Co., Ltd.), concentration of sodium chloride as an electrolyte (manufactured by Wako Pure Chemical Industries, Ltd.) of 0.5% by mass, and sodium benzoate as preservative concentration of 0.1% % Was added to water to prepare 2 L of a PVA / gelatin aqueous solution (precursor composition).
The prepared PVA / gelatin aqueous solution was stirred for 3 hours while heating to 85 ° C., and then allowed to cool to about 60 ° C. Next, for the purpose of bringing the color of human liver closer, 0.60 g of food color red (manufactured by Kyoritsu Foods) and 0.06 g of food color green (manufactured by Kyoritsu Foods) are added and stirred to obtain a uniform composition. And colored.
After the release agent was applied to the inner surface of the female mold, the molds were aligned and the joint surface was sealed. At this time, the blood vessel model and the bile duct model previously prepared and ice-cooled were placed in the female internal space. An appropriate amount (about 1.5 kg) of the colored PVA / gelatin aqueous solution was injected from an injection hole provided in the female mold.
Next, the female mold into which the PVA / gelatin aqueous solution was injected was placed in a freezing room (room temperature: −20 ° C.), cooled for 5 hours, then taken out of the freezing room and left at room temperature until it reached room temperature.
Next, the female mold that was allowed to stand at room temperature was placed in a dryer, heated to 60 ° C., held at that temperature for 1 hour, then removed from the dryer and allowed to cool. Thereafter, the female mold was opened, and the gel body in which the colored PVA / gelatin aqueous solution was gelled was taken out. Thus, a liver model composed of a gel body containing a blood vessel model and a bile duct model was obtained.

11: Male type 21: Precursor composition 22: Gel coating 31: Biological tube model 32: Simulated body fluid 33: Through hole 41: Precursor composition 42: Gel body 51: Female type 52: Internal space 53: Injection hole 61 : Living organ model

Claims (5)

The male surface having a shape corresponding to the form of the natural canal, contacting the precursor composition containing the polyvinyl alcohol and water, to coat the surface of the male by gel coating containing polyvinyl alcohol and water A step of depositing the gel film on the surface of the male mold by immersing the previously cooled male mold in the precursor composition;
And a step of releasing the male mold from the gel film to obtain a hollow biological tube model made of the gel film.   The method for manufacturing a biological tube model according to claim 1, wherein the male material is a material having flexibility.   The method for manufacturing a biological tube model according to claim 1 or 2, wherein the biological tube model is a blood vessel model.   Furthermore, the manufacturing method of the biological tube model of any one of Claims 1-3 provided with the process of inject | pouring a simulated body fluid into the said hollow biological tube model. Arranging the biological tube model obtained by the manufacturing method of the biological tube model according to any one of claims 1 to 4 in an internal space of a female mold having an inner surface shape corresponding to a form of a biological organ;
Injecting a precursor composition containing a water-soluble polymer and water into the internal space to produce a gel body containing the water-soluble polymer and water;
And a step of releasing the female mold from the gel body to obtain a biological organ model made of the gel body including part or all of the biological tube model.