WO2005084581A1

WO2005084581A1 - Medical three-dimensional structure, process for producing the same and production apparatus

Info

Publication number: WO2005084581A1
Application number: PCT/JP2004/013096
Authority: WO
Inventors: Koji Ikuta; Akira Yamada
Original assignee: Japan Science And Technology Agency
Priority date: 2004-03-03
Filing date: 2004-09-02
Publication date: 2005-09-15
Also published as: JPWO2005084581A1; JP2010099494A; JP4641047B2

Abstract

A medical three-dimensional structure comprised of a biocompatible biodegradable resin, which requires a resolution of 50 μm or less in molding. There is provided a process comprising filling a minute syringe with fine granules of a biocompatible biodegradable resin and melting the resin; forming one of two-dimensional slice layers by controlling the discharge of molten biodegradable resin through a nozzle and the plane-direction move of molding stage disposed opposite to the nozzle in accordance with the plane configuration data of a multiplicity of two-dimensional slice layers constituting a three-dimensional structure; effecting spacing movement of the molding stage in the longitudinal direction as much as the thickness of one of the two-dimensional slice layers; and thereafter repeating similar operations, thereby forming a three-dimensional structure. By this process, there can be provided an extremely fine medical three-dimensional structure comprised of a biocompatible biodegradable resin, which can be used as a body implant type therapeutic tool or therapeutic auxiliary tool.

Description

Description Title of the invention Medical three-dimensional structure, manufacturing method and manufacturing apparatus

The present invention relates to a medical three-dimensional structure, and a method and apparatus for manufacturing the same. More specifically, the present invention relates to a fine medical three-dimensional structure made of a biodegradable resin having biocompatibility and having an arbitrary complex shape as an implantable treatment tool or treatment aid. TECHNICAL FIELD The present invention relates to a manufacturing method capable of accurately manufacturing a medical three-dimensional structure without admixing harmful substances, and a manufacturing apparatus capable of performing such a manufacturing method. Background art

Of the so-called biodegradable resins, those that are polymers of biocompatible monomers, such as lactic acid and glycolic acid, are completely degraded in the body over time, and degradation products are harmful to living organisms. Is discharged without any effect.

For this reason, biocompatible biodegradable resins have long been used as sutures that do not need to be removed after surgery, or as temporary implantable treatment tools or treatment aids after surgery. Recently, it has also been used as a scaffold for tissue regeneration in the field of regenerative medical engineering, and as a material for skeletal construction.

However, the form of this type of conventional member is limited to a simple form such as a thread, a sheet, a sponge, and the like, and it is not required that the form be precisely finished. In the future, in order to expand the medical applications of the above materials and to realize innovative medical devices, a technology to accurately process extremely fine and three-dimensionally complex members, that is, a three-dimensional microfabrication technology, will be used. Required.

One of the typical three-dimensional microfabrication technologies up to now is Mike Mouth Stereolithography. With the current two-photon microphone stereolithography, several micron gears and tweezers have been developed. Reference 1 below shows such a A W stereolithography method is disclosed.

Reference 1: K. Ikuta & K. Hirowatari: Real Three Dimensional Micro Fabrication Using Stereo Lithography and Metal Molding. Proc. Of IEEE International Workshop on Micro Electro Mechanical System (MEMS-93), 42/47 (1993)

—On the other hand, as conventional three-dimensional processing methods for biodegradable resins, a heat-melt lamination molding method, an ink-jet binder method, a sheet lamination method, etc. have been developed. Of these, “heat-melt additive manufacturing ¾” generally refers to a method in which a resin melted by heating is supplied in the form of a fine rod by any method, and the resin is run through a fine rod-like forming section or stage to form a two-dimensional slice layer. This is a method of obtaining a three-dimensional structure by forming a three-dimensional structure, and this is disclosed in the following document 2, for example.

Reference 2: D. W. Hutmacher, S. H. Teoh, I. Zein, K. W. Ng, J. T.

S chant z & J. C. Leahy: Design and fabrication of a 3D scafold for tissue engineering bone, In: Agra al CM, Parr JE, Lin ST.Editors.

Synthetic bioabsorbable polymers for implants, STP 1396, American

Society for Testing and Materials, West Conshohocken, PA, 152/167 (2000) Also, the “ink-jet binder method” is a two-dimensional slice for the purpose of forming a binder (adhesive) on a thin layer formed by fine powder. This is a method of producing a three-dimensional structure by spraying according to the layers and repeating this process. Further, the “sheet-to-layer method” is a method in which an arbitrary three-dimensional shape is produced by laminating one sheet at a time according to the cross-sectional shape (two-dimensional slice layer).

However, although the micro-stereolithography described in the above reference 1 is an excellent processing technique, it is not biodegradable and cannot be expected to be biocompatible because the target material is a photocurable polymer. Therefore, it is suitable for manufacturing implantable treatment tools and treatment aids.

On the other hand, the heat-melt additive manufacturing method described in the above-mentioned reference 2, the other ink-jet binder method, the sheet laminating method, and the like have insufficient processing resolution or manufacturing efficiency. It is difficult to accurately and quickly form fine three-dimensional structures due to insufficient ratio. In addition, there is a problem that the solvent (having biotoxicity) used in the preprocessing of the timber remains in the material of the three-dimensional structure. Therefore, even if a biocompatible biodegradable resin such as polylactic acid is used, there is a problem that the obtained product has low biocompatibility. Disclosure of the invention

For the purpose of the present invention, the material itself is an extremely fine structure made of a biodegradable resin that is biocompatible in the sense that no toxic substance is mixed, It is an object of the present invention to provide a three-dimensional structure having a complicated shape as a treatment aid, and to provide an effective method and apparatus for manufacturing such a three-dimensional structure.

The first invention of the present application is a three-dimensional structure made of a biodegradable resin having biocompatibility and having an arbitrary shape as an implantable treatment tool or treatment assisting tool. This is a medical three-dimensional structure that requires a resolution of less than m.

The medical three-dimensional structure according to the first invention is a structure having an arbitrary shape as an implantable treatment tool or a treatment auxiliary tool, for example, a surgical treatment tool temporarily required during surgery, a scaffold for tissue regeneration And materials for constituting the skeleton. In other words, it is a very useful structural material in the medical field.

Next, the medical three-dimensional structure is made of a biocompatible biodegradable resin. Therefore, after it has been buried in the body to perform its intended function, it is completely degraded over time in the body, and the degradation products are excreted without harmful effects on the living body. Therefore, there is no need to remove the structure after surgery. It is not necessary to perform an extirpative surgery after a certain period, even if the structure is expected to be buried for a certain period of time. In addition, since the constituent materials of the three-dimensional structure do not contain substances harmful to living organisms, biocompatibility is high in this sense.

Furthermore, this medical three-dimensional structure requires extremely fine processing, and its forming requires a resolution of 50 μm or less. In other words, three-dimensional medical structures are 50 Even if the size is less than W 200 μπι or larger, it is necessary to process the structure with a resolution of 50 or less to form all or a part of the structure. Therefore, the possibility of providing a new category of fine treatment tools or treatment aids that were difficult to conceive and provide with conventional manufacturing techniques has been opened.

In the second invention of the present application, the biodegradable resin having biocompatibility according to the first invention is a homopolymer composed of any one of lactic acid, glycolic acid, and ^ prolatatone, or two or more of these homopolymers. It is a medical three-dimensional structure that is a copolymer composed of monomers.

Examples of the “biocompatible biodegradable resin” in the first invention include well-known homopolymers of lactic acid and dalicholic acid, homopolymers of force prolactone, and any two or more of the above. Preferable examples include copolymers composed of monomers.

In the third invention of the present application, the implantable treatment tool or treatment aid according to the first invention or the second invention is a surgical or medical tool, a scaffold for tissue regeneration, a material for skeleton, a drug It is a medical 3D structure that is a delivery system (DDS) or a device for gene transfer. Here, the drug delivery system (DDS: drug delivery system) refers to an entire device constituting a so-called drug delivery system, or an individual member constituting a drug delivery system.

Examples of the `` implantable treatment tool or treatment aid '' in the first invention or the second invention include surgical treatment tools, scaffolds for tissue regeneration, constituent materials for skeleton, Drug delivery devices (DDS) and devices for gene transfer can be mentioned.

In addition, since the medical three-dimensional structure according to the invention of the present application can be provided, it is conventionally difficult to conceive and to provide various treatment tools or treatment aids in a new category. Could be conceived, invented, and provided. Since these treatment tools, members or devices function within the body for a certain period of time, they are disassembled and absorbed, so that re-operation for removal is unnecessary. A fourth invention of the present application is the medical three-dimensional structure, wherein the scaffold for tissue regeneration according to the third invention is a hollow tubular body having a branch portion as a scaffold for blood vessel regeneration or capillary regeneration. Things.

Even if the blood vessels and capillaries are regenerated using scaffolds, there is no point unless the scaffolds subsequently disappear. Therefore, the scaffold for regenerating blood vessels or regenerating capillaries according to the fourth invention is very useful in the field of regenerative medicine. In addition, in this scaffold, it is also preferable that the tube is closed at each end of the hollow tubular body.

The fifth invention of the present application is a method for manufacturing a medical three-dimensional structure, including the following processes (1) to (3).

(1) A nozzle at the lower end of a small syringe provided with a heating means is brought close to and opposed to a modeling stage, and the syringe is filled with fine particles of a biodegradable resin having biocompatibility, and the heating means is used. Heat melt.

(2) Based on the planar shape data of a large number of two-dimensional slice layers constituting a three-dimensional structure, the biodegradable resin that is melted by heat is discharged from the nozzle in the form of a thin line, and the syringe or the molding stage is discharged. By moving in the plane direction (X-Y direction), one of a number of two-dimensional slice layers (X-Y slice layers) is formed.

(3) The second step is repeated after moving the syringe or the molding stage in the vertical direction (Z direction) by the thickness of one layer of the two-dimensional slice layer, and repeating the three-dimensional process. It forms all of the many 2D slice layers that make up the structure.

In the fifth invention, W: The syringe is filled with fine particles of a biodegradable resin, melted by heat, and discharged as it is from the nozzle into a fine I shape, thereby providing a medical three-dimensional structure. That is, since the raw material is filled into a syringe in a batch system, and then heated and melted for use in molding, a biotoxic solvent such as a conventional heat-melt additive manufacturing method, an ink-jet binder method, a sheet laminating method, etc. No need to preprocess biodegradable resin. That is, there is no possibility that the toxic solvent remains in the constituent material of the structure.

In addition, based on the planar shape data of a large number of two-dimensional slice layers constituting a three-dimensional structure, the biodegradable resin melted by heat is discharged from a fine nozzle in the form of a fine line. By moving the syringe or modeling stage in the plane direction to form a large number of two-dimensional slice layers sequentially, applying a well-known mechanism to perform these operations precisely and cooperatively, it is very fine and complicated 3D structures with shapes can be manufactured accurately.

A sixth invention of the present application is the medical three-dimensional structure, wherein each of the processes (1) to (3) in the fifth invention is performed according to at least one of the following conditions (4) to (6). It is a method of manufacturing a product.

(4) The diameter of the fine linear discharge from the nozzle is 200 μππ or less.

(5) The discharge amount of the fine linear discharge material from the nozzle is 1.5 μL / min or less.

(6) The temperature on the modeling stage is 30 ° C. or lower than the thermal melting point temperature of the biodegradable resin.

The method itself of molding a target object by melting the resin by heat and discharging it from a nozzle is a general method. Usually, such resin molding is performed in combination with a molding die. However, it is virtually impossible to mold a medical three-dimensional structure that requires a resolution of 5 or less, because it is difficult to manufacture a mold. For this reason, there has been no proposal to manufacture an extremely fine object by discharge molding by thermal melting.

The inventor of the present application has already presented one solution for that by the micro stereolithography method according to the above-mentioned Document 1. However, since micro-stereolithography is intended for photocurable polymers, it cannot be applied to the manufacture of bio-implantable treatment tools or treatment aids using biodegradable polymers. Therefore, the inventor of the present application paid attention to the fact that the ejected matter from the nozzle is in a fine line shape. In the case where the manufacturing method of the fifth invention is used, by setting certain conditions for rapidly cooling and solidifying the discharged material, the molded body can be rapidly cooled and solidified without using a molding die. We have determined that a high-precision compact can be obtained. The condition is at least one or more of the conditions (4) to (6) of the sixth invention, specifically the conditions of (4) and / or (5).

According to a seventh aspect of the present invention, in the case where the three-dimensional structure according to the fifth or sixth aspect is a hollow tubular body having a branch portion, a plurality of two-dimensional structures corresponding to the branch portion are provided. By changing the shape of each layer of the rice layer from one circular shape to an elliptical shape, an oval shape with a constriction at the center, an “8” shape, and two circular shapes, This is a method for manufacturing a medical three-dimensional structure that forms a branch.

An efficient method of forming a hollow tubular body having a very small branching portion, such as a scaffold for revascularization or capillary regeneration, has not yet been proposed. The inventor of the present application has found that, based on the premise that the fifth production method is used, the production method of the seventh invention enables an extremely fine hollow tubular body having a branch portion to be efficiently formed. .

An eighth invention of the present application is a medical three-dimensional structure manufacturing apparatus including the following elements (a) to (e).

(a) A discharge unit composed of a small syringe with a lip at the lower end and heating means provided on the outer periphery of the syringe.

(b) Discharge control means for controlling discharge of syringe contents from the nozzle.

(c) a molding stage located opposite the nozzle at the lower end of the syringe;

(d) Movement control means for controlling the movement of the discharge section and / or the molding stage in a plane direction (X-Y direction) and a vertical direction (Z direction).

(e) A controller to which planar shape data of a large number of two-dimensional slice layers constituting a three-dimensional structure is input, and which operates the movement control means and the discharge control means in cooperation based on the data.

Since the medical three-dimensional structure manufacturing apparatus according to the eighth invention includes the elements (a) to (e) necessary to execute the manufacturing method according to the fifth to seventh inventions, the first The medical three-dimensional structures according to the inventions to the fourth invention can be effectively manufactured.

The size of each of the elements (a) to (e) may be determined arbitrarily, but the invention of the present application already has a plane size of 30 cm or less in the vertical direction of the entire device. We are prototyping an effective device that is less than 50 cm in width and less than 50 cm in height. Also, the size of the syringe and nozzle, which directly affects the size setting of the medical three-dimensional structure, can be designed extremely fine as needed. According to a ninth aspect of the present invention, the control method by the movement control means according to the eighth aspect is such that a control method is performed in a plane direction (X-Y direction) and a vertical direction (Z direction) of one of the discharge unit and the molding stage. Either the movement is controlled, or the movement of one of the discharge unit and the molding stage in the plane direction (X-Y direction) is controlled and the movement of the other in the vertical direction (Z direction) is controlled. This is a system for manufacturing medical three-dimensional structures.

In the apparatus for manufacturing a medical three-dimensional structure according to the eighth aspect described above, the control method of the discharge unit and the Z or the molding stage by the movement control means can be arbitrarily selected. Among them, as a representative first control method, a method of controlling the movement of either the discharge part or the molding stage in the plane direction (X-Y direction) and the vertical direction (Z direction) is used. Can be illustrated. A typical second control method is to control the movement of either the discharge section or the molding stage in the plane direction (X-Y direction) and the movement of the other in the vertical direction (Z direction). Can be exemplified. Brief Description of Drawings

FIG. 1 is a simplified view of a medical three-dimensional structure manufacturing apparatus. FIG. 2 is a diagram showing a process of acquiring slice data of a medical three-dimensional structure. FIG. 3 is a diagram showing a manufacturing process of a medical three-dimensional structure. 4 to 7 are diagrams each showing an example of manufacturing a three-dimensional structure. FIG. 8 is a graph showing the biocompatibility of the medical three-dimensional structure. FIG. 9 is a view for explaining a production example of a hollow tubular body having a branch portion. BEST MODE FOR CARRYING OUT THE INVENTION

Next, embodiments for carrying out the first to ninth inventions of the present application will be described, including the best mode. In the following, when the present invention is simply referred to, each invention of the present application is referred to collectively.

(Biocompatible biodegradable resin)

The material used in the present invention is a biocompatible biodegradable resin. Doctor In industrial fields other than medical treatment, biodegradable resins composed of non-biocompatible monomers are often used, but such non-biocompatible biodegradable resins are not used in the present invention.

In the present invention, “having biocompatibility” means that the biodegradable resin itself has biocompatibility as a characteristic, and that the biodegradable resin does not include additives or inclusions that are toxic to living organisms. It also means that.

A typical example of a biodegradable resin having biocompatibility is polylactic acid, which is a polyester polymer (homopolymer) of lactic acid. Further, polyglyconic acid, which is a polyester polymer (homopolymer) of glycolic acid, is also included. Other examples include homopolymers of force prolactone. The degree of polymerization or molecular weight of these homopolymers is not particularly limited.

Furthermore, various copolymers (copolymers) obtained by polymerizing any two or more of the above monomers can also be exemplified. In copolymers, the molar ratio of two or more monomers is not limited, and not only those in which two or more monomers are polymerized exactly alternately, but also so-called block copolymers and random copolymers can be used. . The degree of polymerization or molecular weight of these copolymers is not particularly limited.

(Medical 3D structures)

In the present invention, the “medical three-dimensional structure” is a three-dimensional structure made of the above-mentioned biodegradable resin and having an arbitrary shape as an implantable treatment tool or treatment aid. It refers to one that requires a resolution of 50 μπι or less for its forming. That is, a structure with a size of 50 im or less, or at least a part of a three-dimensional structure having a part to be accurately formed with a size of 50 or less even when the overall size exceeds 50 m. Things.

The medical three-dimensional structure of the present invention should have a resolution of 50 or less for its molding, and there is no inevitable force. Such an implantable treatment tool or treatment aid has a fine three-dimensional structure. The feature of the present invention that a complicated shape is accurately formed is best exhibited. The type and content of the implantable treatment tool or treatment aid are not limited. Preferred examples include surgical treatment tools, scaffolds for tissue regeneration, skeletal components, drug delivery devices (DDS), and gene transfer devices.

A particularly preferred example of the scaffold for tissue regeneration is a hollow tubular body having a branch portion, as a scaffold for revascularization or capillary regeneration. These hollow tubular bodies may have a shape in which each terminal of the tubular body is open, or a shape in which each terminal of the tubular body is closed. In the latter case, tissue cells grow on the outer periphery of the tubular body but do not grow on the inner periphery. This hollow tubular body is used not only for regenerating blood vessels and knitted blood vessels, but also as a scaffold for regenerating other luminal organs, particularly fine luminal organs such as tubules. can do.

[Method of manufacturing medical three-dimensional structures]

The method for producing a medical three-dimensional structure according to the present invention is a method including at least the following processes (1) to (3).

(1) The nozzle at the lower end of the small syringe provided with the heating means is brought close to and opposed to the modeling stage, and the biodegradable fine particles (micropellet) that are biocompatible with the small syringe. ) And thermally fused by the heating means.

(2) Based on the planar shape data of a large number of two-dimensional slice layers that make up a three-dimensional structure, the hot-melt raw material angle 军 'I' green resin is discharged from the nozzle in a fine line shape, and a syringe or modeling stage is used. Is moved in the plane direction (X-Y direction) to form one of a number of two-dimensional slice layers (X-Y direction slice layers).

(3) After moving the syringe or the molding stage in the vertical direction (Z direction) by the thickness of one layer of the two-dimensional slice layer, the second step is repeated, and this step is repeated. It forms all of the many 2D slice layers that make up the 3D structure.

As a result of the above process, the two-dimensional slice layers formed using the hot-melt resin are fused and integrated with each other, and then cooled and solidified, so that the desired three-dimensional structure can be accurately formed. It is formed. [Rapid solidification by controlling the discharge amount]

Each of the processes (1) to (3) is particularly preferably performed according to at least one of the following conditions (4) to (6). By complying with these conditions, a minute medical three-dimensional structure can be rapidly cooled and solidified, effectively preventing “deformation” after discharging hot-melt resin without using a molding die, and achieving a very accurate purpose. A three-dimensional structure having the following shape can be manufactured.

(4) The diameter of the fine linear discharge from the nozzle is 200 μm or less, more preferably 20 μπι or less, and particularly preferably 5 μπι or less.

(5) The discharge amount of the fine linear discharge material from the nozzle is 1.5 μL / min or less, more preferably 0.1 μLZmin or less, and particularly preferably 3.8 nL / min. It is as follows.

(6) The temperature on the molding stage is 30 ° C. or more lower than the thermal melting point temperature of the biodegradable resin. More preferably, the temperature is 20 ° C. or less on the modeling stage. If necessary, appropriate cooling devices are used.

(Branch pipe manufacturing method)

When the three-dimensional structure is a hollow tubular body having a branch, for example, a hollow tubular body having a branch as a scaffold for a blood vessel or a capillary tube, a plurality of two-dimensional slice layers corresponding to the branch are provided. By changing the shape of each layer from one circular shape to an elliptical shape, an elliptical shape with a constriction at the center, an “8” shape, and two circular shapes, the branch part of the hollow tubular body is changed. Can be freely configured. ,

[Medical 3D structure manufacturing equipment]

An apparatus for manufacturing a medical three-dimensional structure according to the present invention is an apparatus including at least the following elements (a) to (e).

(a) A discharge section comprising a small syringe having a lip at the lower end and a heating means provided on the outer periphery of the syringe. The size of the syringe or nozzle can be appropriately set according to the purpose, but the inner diameter of the nozzle is set, for example, to 200 μπι or less, more preferably 20 μπι or less, and particularly preferably 5 μπι or less. It is preferable to do so. The lower limit of the inner diameter of the nozzle is not limited, as long as the manufacturing technology allows For example, the inner diameter may be set to 1 μπι or less.

Although the configuration of the heating means is not limited, for example, a method of heating with a heating wire such as a -chrome wire through a metal block such as an aluminum alloy surrounding the outer periphery of the syringe is exemplified. The temperature range of the heating by the heating means is appropriately set in consideration of the glass transition point and the melting point of the biodegradable resin. It is more preferable that the heating means be cooperatively controlled by a controller described later together with the movement control means and the discharge control means. This makes it possible to automatically control the entire medical three-dimensional structure manufacturing equipment.

(b) Discharge control means for controlling discharge of syringe contents from the nozzle. The discharge control means controls the ON / OFF of discharge of the thermally degradable biodegradable resin from the nozzle and the discharge amount at the time of discharge. Although the configuration of the discharge control means is not particularly limited, for example, a method in which the operation of a resin extruding biston rod reciprocating in the syringe is controlled by a stepping motor via a feed screw can be used. In this case, the discharge or stop of the biodegradable resin from the nozzle or the control of the discharge amount is performed according to the rotation of the stepping motor or its rotation speed.

(c) A molding stage located opposite the nozzle at the lower end of the syringe. It is preferable that the shaping stage be capable of controlling movement in, for example, a three-dimensional direction (X-Y-Z direction). However, a part or all of such a movement control mechanism is set on the discharge unit side. In that case, part or all of the movement control mechanism of the modeling stage can be dispensed with as long as it is performed.

(d) The discharge section and the noss molding stage are provided on any of them, a means for controlling movement in a plane direction (X-Y direction) and a means for controlling movement in a vertical direction (Z direction). Therefore, it is necessary to control the relative movement in the three-dimensional directions (X-Y-Z directions). Therefore, if one of the discharge unit and the modeling stage can be controlled to move in a three-dimensional direction (X, Y, and Z directions), the other may be a fixed type.

(e) Planar shape data of a number of two-dimensional slice layers constituting a three-dimensional structure is input, and the movement control means and the discharge control means cooperate based on this data. A controller that operates in tune. Here, “planar shape data of a large number of two-dimensional slice layers constituting a three-dimensional structure” is obtained using three-dimensional CAD or CT (Computer Tomography; MR I (Magnetic Resonance Imaging), etc.) Is the shape data of a “ring slice” of a three-dimensional structure.

The “cooperative operation of the movement control means and the discharge control means” means, for example, discharge of biodegradable resin from the discharge control means when the discharge part or the molding stage is moving in a plane direction. And that the discharge of the biodegradable resin from the discharge control means is stopped when the discharge section or the molding stage is moving in the vertical direction.

In the above three-dimensional structure manufacturing equipment, the molding stage is maintained in a low temperature range by using appropriate cooling means to quickly solidify the hot-melt biodegradable resin discharged from the nozzle. Therefore, it is also preferable to ensure the accuracy of forming the three-dimensional structure. For example, the molding stage should be cooled to a temperature lower than the hot melting point temperature of the biodegradable resin by 30 ° C or more, and more preferably to room temperature (20 ° C) or less, by means such as circulation of cold air. Can be. Example

(Example 1: Medical three-dimensional structure manufacturing apparatus)

FIG. 1 schematically shows a medical three-dimensional structure manufacturing apparatus 1 according to an embodiment of the present invention. In this manufacturing apparatus 1, a very thin syringe 2 is provided with a fine nos and a hole 3 at its lower end. The nozzle 3 has a hole diameter of about 50 / m. The diameter of the fine linear discharge from Nozore 3 is about 45 μιη. The outer circumference of the syringe 2 is surrounded by a spirally wound nichrome wire 5 through a cylindrical body 4 made of aluminum. The heating control section 6 controls the ONZO FFF and the heating temperature of the dichrome wire 5.

A piston rod 7 can be inserted from the upper end opening of the syringe 2, and the piston rod 7 is driven up and down inside the syringe 2 by a stepping motor 8. And the stepping motor 8 is sent to the controller 9 which is the central control unit. Therefore, the operation is controlled. The controller 9 may be configured to control the heating control unit 6 as well.

On the other hand, a molding stage 10 is provided immediately below the nose 3 of the syringe 2. The molding stage 10 is capable of performing arbitrary parallel movements in a plane direction (X-Y direction) and a vertical direction (Z direction) with an arbitrary force, and the operation thereof is controlled by the controller 9. .

The controller 9 receives the planar shape data of a large number of two-dimensional slice layers in a state in which the three-dimensional structure, which is the object of modeling, is sliced (round sliced) into a number of layers along the plane direction. 9 operates the stepping motor 8 and the molding stage 10 in cooperation with each other based on the data.

(Example 2: Manufacturing method of medical three-dimensional structure)

A method for manufacturing a medical three-dimensional structure using the above-described manufacturing apparatus 1 will be described with reference to FIGS. 2 and 3.

First, a method for acquiring planar shape data of a large number of two-dimensional slice layers of a three-dimensional structure is as shown in FIG. That is, for example, the three-dimensional structure 11 assumed to have the shape shown in FIG. 2 (a) is changed to the second shape according to the principle of a tomographic imaging method such as three-dimensional CAD or CT or MRI. As shown in Fig. 2 (b), processing is performed on data sliced into a number of layers along the plane, and planar shape data of each 2D slice layer is obtained as shown in Fig. 2 (c). These data are input to the controller 9 described above.

Next, an appropriate amount of a micro-pellet of a biodegradable resin such as polylactic acid is filled in the syringe 2 and the nichrome wire 5 is melted by heating. While maintaining such a heat-melted state, the biodegradable resin is ejected from the nozzle 3 in a fine / linear manner, and the molding stage 10 is moved in the plane direction (X-Y direction) as shown in FIG. 3 (a). To the specified point. At this time, the discharge of biodegradability from the horn 3 and the movement of the molding stage 10 are controlled by the controller 9, so that the discharged fine-line-shaped biodegradable resins are fused to each other. Then, a two-dimensional slice layer 12 is formed accurately as a whole.

First, the first stage (lowest layer) of the two-dimensional slice layer 12 is formed, Controlled by the roller 9, the discharge of the biodegradable resin from the blade 3 is temporarily stopped, and the molding stage 10 moves down by one layer of the two-dimensional slice layer 12, and then moves as described above. In the same manner, two-dimensional slice layers 12 of the second and subsequent stages are sequentially laminated and formed as shown in FIG. 3 (b). By this repetition, the three-dimensional structure 11 as originally assumed is formed.

As specific examples of 2 and 3 of the three-dimensional structure 11 actually manufactured by the inventor of the present invention, a micropipe (outside diameter: 500 μιη, inside diameter: 400 μm) whose SEM image is shown in FIG. m, height 1.5 mm), micro-bend pipe (outer diameter 1.5 mm, height 4 mm) shown in Fig. 5, coil spring shown in Fig. 6 (representative diameter 0.5 mm, pitch 0.5) 8 mm), and the like. For example, a box (4.5 mm square and 5 mm deep) with an open top as shown in FIG. 7 can be exemplified. Each of the three-dimensional structures shown in FIGS. 4 to 7 was prepared using polylactic acid as a biodegradable resin, and the biodegradable resin from the nozzle 3 during the production thereof was used. The discharge rate was 0.1 μL / min or less.

(Example 3: Evaluation of biocompatibility)

The biocompatibility was evaluated by using the box shown in FIG. 7 as a container for cell culture. As a container for the comparative experiment, a commercially available 96-hole microphone port and a 7-layer plate for ellipse were used.

The cells subjected to the culture are PC12 cells derived from rat pheochromocytoma. These cells have been used for studies of nerve function because they exert nerve growth factor NGF as a helping factor. If the cells can grow, it is confirmed that the box shown in FIG. 7 has sufficient biocompatibility.

Although the details of the evaluation experiment are omitted, PC12 cells were used so that the number of cells per unit area of the bottom was the same as that of the box of the example and the microwell plate of the comparative example. seeded, same general environment (3 7 ° C, 5% C 0 2) was cultured in, KoTsuta observed and populations of force Unto cells until after sowing 8 9 hours passed.

As a result, no remarkable difference was observed in the shape of cells between the example and the comparative example, and the results of counting the number of individuals were as shown in FIG. Fig. 8 shows cells on the vertical axis. The change in the number of cells (Time [hour]) is plotted on the horizontal axis, and the average force in the above several examples is shown in a graph labeled “3D niicrofabricated PLA vessel”. , And the graph “Non-biodegradable well plate for comparison” shows the average value in the comparative example of the above number ^].

From the results shown in FIG. 8, it was proved that the box as the medical three-dimensional structure according to the present example had sufficient biocompatibility.

(Example 4: Production of hollow tubular body having branch portion)

The scaffold 13 shown in FIG. 9 (a) for regenerating the blood vessels of the knitting field is made of polylactic acid which is a biodegradable resin, and the production apparatus of the first embodiment is used to produce the scaffold 13 of the second embodiment. It is manufactured by the manufacturing method. The scaffold 13 is a hollow tubular body whose tube wall 15 has a substantially circular cross-sectional shape with a diameter of 50 μm or less, but has a branch portion 14.

As shown in FIG. 9 (b), these branch portions 14 are formed by changing the shape of each layer of the above-described two-dimensional slice layer into one circle with respect to the tube wall portion 15 corresponding to the branch portion 14. It is formed by sequentially changing the shape from an ellipse, an ellipse with a constriction in the center, an “8” shape, and two circles. In the production of the scaffold 13, the heat-melted polylactic acid was discharged from the nozzle 3 having a pore diameter of 20 m at a discharge rate of 1.5 μL / min or less. In addition, in order to rapidly solidify the discharged polylactic acid, the temperature on the molding stage 10 was cooled to a temperature of 20 ° C. or less using a cooling device.

(Example 5: Production of an extremely fine hollow tubular body having a branch portion)

It consists polylactic acid is a biodegradable resin, a scaffold for capillary regeneration of the same shape as that in the example 4, a very fine hollow say tube wall is less than the diameter ₅ μ πι I made a tubular body. The manufacturing method was the same as in Example 4, except that the diameter of the nozzle for discharging the hot-melted polylactic acid was 2 m, and the discharge rate was 0.15 L / min. In addition, in order to rapidly solidify the discharged polylactic acid, the temperature on the molding stage 10 was cooled to 20 ° C. or lower using a cooling device. As a result, a scaffold for regenerating capillary blood vessels having a size almost the same as that shown in FIG. 9 (a) could be produced. Industrial applications

INDUSTRIAL APPLICABILITY As described above, according to the present invention, a fine medical three-dimensional structure made of a biodegradable resin having biocompatibility and having an arbitrary complex shape as an implantable treatment tool or treatment aid Is provided. Further, an advantageous manufacturing method and a manufacturing apparatus capable of executing such a manufacturing method are provided.

Claims

The scope of the claims

1. A three-dimensional structure made of a biodegradable resin having biocompatibility and having an arbitrary shape as an implantable treatment tool or treatment / capture aid, and having a shape of 50 μm or less Medical three-dimensional structure requiring resolution.

2. The biodegradable resin having biocompatibility is a homopolymer composed of any one of lactic acid, glycolic acid, and force prolactone, or a copolymer composed of two or more of these monomers. The medical three-dimensional structure according to item 1.

3. The implantable treatment tool or treatment aid is a surgical treatment tool, a scaffold for tissue regeneration, a material for a skeleton, a drug delivery system, or a gene transfer device. The medical three-dimensional structure according to 1.

4. The medical three-dimensional structure according to claim 3, wherein the scaffold for tissue regeneration is a hollow tubular body having a branch portion as a scaffold for blood vessel regeneration or capillary vessel regeneration.

5. A method for manufacturing a medical three-dimensional structure including the following processes (1) to (3).

(2) Based on the planar shape data of a large number of two-dimensional slice layers constituting a three-dimensional structure, the biodegradable resin that has been melted is discharged from the nozzle in a thin line shape, and the syringe or molding stage is discharged. Is moved in the plane direction (X-Y direction) to form one of a number of two-dimensional slice layers (X-Y direction slice layers).

6. Each of the above processes (1) to (3) is performed in a few of the following (4) to (6). 6. The method for producing a medical three-dimensional structure according to claim 5, wherein the method is performed according to at least one or more conditions.

(4) The diameter of the fine linear discharge from the nozzle is 200 m or less.

7. When the three-dimensional structure is a hollow tubular body having a branch, the shape of each of a plurality of two-dimensional slice layers corresponding to the branch ^ is sequentially changed from one circle to an ellipse, The medical device according to claim 5 or 6, wherein a branch portion of the hollow tubular body is formed by changing the shape into an elliptical shape having a constriction at the center, a figure of "8", and two circular shapes. Manufacturing method for 3D structures.

8. An apparatus for manufacturing a medical three-dimensional structure including the following elements (a) to (e).

(a) A small syringe having a nozzle at the lower end, and a discharge unit composed of caro heating means provided on the outer periphery of the syringe.

(c) A modeling stage located opposite the lip of the lower end of the syringe.

(d) Movement control means for controlling the movement of the discharge unit and the stage or the molding stage in a plane direction (X-Y direction) and a vertical direction (Z direction).

9. The control method by the movement control means is a force that controls the movement of either the discharge unit or the molding stage in the plane direction (X-Y direction) or the vertical direction (Z direction). 9. The method according to claim 8, wherein a movement of one of the discharge unit and the molding stage in a plane direction (X-Y direction) is controlled and a movement of the other in a vertical direction (Z direction) is controlled. 3. The apparatus for manufacturing a medical three-dimensional structure according to claim 1.