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WO2005084581A1 - Structure tridimensionnelle medicale, procede de production de cette structure et appareil de production correspondant - Google Patents

Structure tridimensionnelle medicale, procede de production de cette structure et appareil de production correspondant Download PDF

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Publication number
WO2005084581A1
WO2005084581A1 PCT/JP2004/013096 JP2004013096W WO2005084581A1 WO 2005084581 A1 WO2005084581 A1 WO 2005084581A1 JP 2004013096 W JP2004013096 W JP 2004013096W WO 2005084581 A1 WO2005084581 A1 WO 2005084581A1
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WO
WIPO (PCT)
Prior art keywords
dimensional structure
medical
dimensional
syringe
discharge
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2004/013096
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English (en)
Japanese (ja)
Inventor
Koji Ikuta
Akira Yamada
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Japan Science and Technology Agency
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Japan Science and Technology Agency
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Filing date
Publication date
Application filed by Japan Science and Technology Agency filed Critical Japan Science and Technology Agency
Priority to JP2006510610A priority Critical patent/JPWO2005084581A1/ja
Publication of WO2005084581A1 publication Critical patent/WO2005084581A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C99/00—Subject matter not provided for in other groups of this subclass
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C67/00—Shaping techniques not covered by groups B29C39/00 - B29C65/00, B29C70/00 or B29C73/00

Definitions

  • 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
  • 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.
  • 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.
  • 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.
  • a technology to accurately process extremely fine and three-dimensionally complex members that is, a three-dimensional microfabrication technology, will be used. Required.
  • heat-melt additive manufacturing 3 ⁇ 4 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.
  • Synthetic bioabsorbable polymers for implants STP 1396, American
  • 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.
  • 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).
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • this medical three-dimensional structure requires extremely fine processing, and its forming requires a resolution of 50 ⁇ m or less.
  • three-dimensional medical structures are 50 Even if the size is less than W 200 ⁇ 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.
  • 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.
  • biocompatible biodegradable resin examples 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.
  • 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.
  • DDS drug delivery system
  • the 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.
  • DDS Drug delivery devices
  • 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.
  • the scaffold for regenerating blood vessels or regenerating capillaries according to the fourth invention is very useful in the field of regenerative medicine.
  • 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).
  • 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.
  • 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.
  • the plane direction X-Y direction
  • one of a number of two-dimensional slice layers X-Y slice layers
  • 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.
  • 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.
  • a biotoxic solvent such as a conventional heat-melt additive manufacturing method, an ink-jet binder method, a sheet laminating method, etc.
  • the biodegradable resin melted by heat is discharged from a fine nozzle in the form of a fine line.
  • 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.
  • the diameter of the fine linear discharge from the nozzle is 200 ⁇ or less.
  • the discharge amount of the fine linear discharge material from the nozzle is 1.5 ⁇ L / min or less.
  • 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.
  • resin molding is performed in combination with a molding die.
  • 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.
  • the manufacturing method of the fifth invention 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).
  • 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.
  • An eighth invention of the present application is a medical three-dimensional structure manufacturing apparatus including the following elements (a) to (e).
  • 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.
  • Discharge control means for controlling discharge of syringe contents from the nozzle.
  • 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).
  • 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.
  • the medical three-dimensional structure manufacturing apparatus 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.
  • 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.
  • 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.
  • the control method of the discharge unit and the Z or the molding stage by the movement control means can be arbitrarily selected.
  • 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.
  • 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).
  • 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
  • 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.
  • 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.
  • copolymers obtained by polymerizing any two or more of the above monomers can also be exemplified.
  • 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.
  • 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 ⁇ 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.
  • 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).
  • 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.
  • the hot-melt raw material angle ⁇ '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).
  • the second step 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.
  • 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).
  • 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.
  • the diameter of the fine linear discharge from the nozzle is 200 ⁇ m or less, more preferably 20 ⁇ or less, and particularly preferably 5 ⁇ or less.
  • the discharge amount of the fine linear discharge material from the nozzle is 1.5 ⁇ L / min or less, more preferably 0.1 ⁇ LZmin or less, and particularly preferably 3.8 nL / min. It is as follows.
  • 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.
  • the three-dimensional structure is a hollow tubular body having a branch
  • 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.
  • 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 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 ⁇ or less, more preferably 20 ⁇ or less, and particularly preferably 5 ⁇ 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 ⁇ or less.
  • 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.
  • 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.
  • 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.
  • a molding stage located opposite the nozzle at the lower end of the syringe is located opposite the shaping 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG. 1 schematically shows a medical three-dimensional structure manufacturing apparatus 1 according to an embodiment of the present invention.
  • 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 ⁇ .
  • 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.
  • 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.
  • 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.
  • 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.
  • a biodegradable resin such as polylactic acid
  • 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.
  • 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.
  • a micropipe (outside diameter: 500 ⁇ , inside diameter: 400 ⁇ m) 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.
  • 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 ⁇ L / min or less.
  • the biocompatibility was evaluated by using the box shown in FIG. 7 as a container for cell culture.
  • 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.
  • 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.
  • 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”.
  • the graph “Non-biodegradable well plate for comparison” shows the average value in the comparative example of the above number ⁇ ].
  • 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 ⁇ m or less, but has a branch portion 14.
  • 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.
  • 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 ⁇ L / min or less.
  • the temperature on the molding stage 10 was cooled to a temperature of 20 ° C. or less using a cooling device.
  • 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 ⁇ ⁇ 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.
  • the temperature on the molding stage 10 was cooled to 20 ° C. or lower using a cooling device.
  • a scaffold for regenerating capillary blood vessels having a size almost the same as that shown in FIG. 9 (a) could be produced.

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  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
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  • Heart & Thoracic Surgery (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Mechanical Engineering (AREA)
  • Dermatology (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention se rapporte à une structure tridimensionnelle médicale, composée d'une résine biodégradable biocompatible, qui nécessite une résolution inférieure ou égale à 50νm lors du moulage. On utilise à cet effet un procédé consistant à remplir une petite seringue avec de fines granules d'un résine biodégradable biocompatible et à faire fondre la résine; à former une couche de tranche bidimensionnelle en régulation la décharge de la résine biodégradable fondue à travers une buse et le mouvement dans la direction plane de l'étage de moulage disposé à l'opposé de la buse en fonction des données de configuration plane d'une multitude de couches de tranches bidimensionnelles constituant une structure tridimensionnelle; à effectuer une mouvement dans l'espace de l'étage de moulage dans le sens longitudinal sur une longueur égale à l'épaisseur de l'une des couches de tranches bidimensionnelles, et à répéter ensuite ces même opérations, en vue de former une structure tridimensionnelle. Grâce à ce procédé, on peut produire une structure tridimensionnelle médicale extrêmement fine composée d'une résine biodégradable biocompatbile, qui peut servir d'outil thérapeutique ou d'outil auxiliaire de thérapie du type implant corporel.
PCT/JP2004/013096 2004-03-03 2004-09-02 Structure tridimensionnelle medicale, procede de production de cette structure et appareil de production correspondant Ceased WO2005084581A1 (fr)

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DE102006017595A1 (de) * 2006-04-13 2007-10-18 Friedrich-Baur Gmbh Verfahren zum Herstellen eines biokompatiblen Gerüstes, insbesondere zur Herstellung eines Implantates
JP2011253060A (ja) * 2010-06-02 2011-12-15 Nihon Univ 三次元粘弾性構造体製造装置及び製造方法
CN103302859A (zh) * 2013-05-21 2013-09-18 黄辉 一种彩色三维打印机与打印方法
CN104210108A (zh) * 2014-09-15 2014-12-17 王跃宣 3d打印机的打印缺陷弥补方法和系统
EP3064193A1 (fr) * 2015-03-06 2016-09-07 Coltène/Whaledent AG Cartouche en matériau composite
WO2019077144A1 (fr) * 2017-10-19 2019-04-25 Commissariat A L'energie Atomique Et Aux Energies Alternatives Procede de fabrication d'un dispositif microstructure et dispositifs de mise en œuvre associes

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JP6002954B2 (ja) * 2012-01-20 2016-10-05 兵神装備株式会社 立体構造物造形装置
US10583604B2 (en) 2014-02-25 2020-03-10 Seiichi YUYAMA 3D printer
EP3189959B1 (fr) * 2014-09-05 2019-05-01 MCPP Innovation LLC Filament pour impression 3d et procédé de production d'article moulé en résine cristalline souple
KR101697556B1 (ko) * 2016-08-05 2017-01-18 이상혁 마이크로 구조체 제조장치, 제조방법 및 이로부터 제조된 마이크로 구조체
KR102026635B1 (ko) * 2017-09-19 2019-09-30 원광대학교산학협력단 드래깅 기법으로 제작된 세포지지체 및 제작방법

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Publication number Priority date Publication date Assignee Title
DE102006017595A1 (de) * 2006-04-13 2007-10-18 Friedrich-Baur Gmbh Verfahren zum Herstellen eines biokompatiblen Gerüstes, insbesondere zur Herstellung eines Implantates
JP2011253060A (ja) * 2010-06-02 2011-12-15 Nihon Univ 三次元粘弾性構造体製造装置及び製造方法
CN103302859A (zh) * 2013-05-21 2013-09-18 黄辉 一种彩色三维打印机与打印方法
CN104210108A (zh) * 2014-09-15 2014-12-17 王跃宣 3d打印机的打印缺陷弥补方法和系统
CN104210108B (zh) * 2014-09-15 2017-11-28 宁波高新区乐轩锐蓝智能科技有限公司 3d打印机的打印缺陷弥补方法和系统
EP3064193A1 (fr) * 2015-03-06 2016-09-07 Coltène/Whaledent AG Cartouche en matériau composite
WO2016142323A1 (fr) 2015-03-06 2016-09-15 Coltène/Whaledent Ag Cartouche contenant un matériau composite
US20180111316A1 (en) * 2015-03-06 2018-04-26 Coltène/Whaledent Ag Cartridge having composite material
EP3800051A1 (fr) * 2015-03-06 2021-04-07 Coltène/Whaledent AG Cartouche à matière composite
US11305479B2 (en) 2015-03-06 2022-04-19 Coltène/Whaledent Ag Cartridge having composite material
WO2019077144A1 (fr) * 2017-10-19 2019-04-25 Commissariat A L'energie Atomique Et Aux Energies Alternatives Procede de fabrication d'un dispositif microstructure et dispositifs de mise en œuvre associes

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