JP2008307180A - Laminated structure three-dimensional scaffold and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a scaffold which is a porous structure of through-holes through which blood or a body fluids can pass, has compression strength applicable to a fracture site of a joint or a spine, and can be easily shaped to a complex shape of the fracture site, and to provide its manufacturing method. <P>SOLUTION: The scaffold is composed of any biodegradable resin sheet chosen from a group composed of a polylactic acid, polyglycolic acid, a copolymer of the lactic acid and a glycolic acid, a polycaprolactone, a copolymer of lactic acid and caprolactone and is made by stacking flat scaffold fragments having supports vertically and horizontally arranged in the form of a lattice on the obverse and concavities vertically and horizontally arranged in the form of a lattice on the reverse into which the heads of the supports can be fitted by fitting the heads of the supports into the concavities of the upper scaffold fragments. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to a scaffold for medical tissue regeneration, and more particularly to a scaffold made of a composite material made of a biodegradable resin and a method for producing the same. Bone tissue and nerve tissue are regenerated by injecting stem cells, osteoblasts, and the like into the scaffold structure and performing treatment on the tissue defect.

When a defect occurs in the human body, it is often cured naturally. However, when the defect grows larger, there are cases where it cannot be repaired by natural healing power. Regenerative medical technology that regenerates tissue with stem cells that are undifferentiated cells at such times is spreading its application to all parts of the human body. In this case, what is required is a scaffold for inducing tissue regeneration, and a biodegradable resin that is decomposed in the body according to tissue regeneration is used for this scaffold.

  Since this biodegradable resin decomposes itself in vivo or in a normal environment, it occupies an important position in regenerative medicine. Examples of biodegradable resins used for medical purposes include polylactic acid (PLA) resin and polycaprolactone (PCL) resin. In particular, PLA resin is excellent in biodegradability and absorbability, and is expected as a new medical material having both high strength, biocompatibility, and self-degradability.

The present inventor has already developed a scaffold made of a biodegradable resin (Patent Document 1). Such a scaffold has an opening structurally, can be seeded by injection at the time of clinical use, and is excellent in rigidity by combining a fiber made of PLA resin and a PCL resin used as a binder, and can support a load due to human activity. It is possible.
In addition, a structure that prevents epithelial entry into the defect and accumulation of bacterial plaque is provided, or a structure that immediately biodegrades at the interface with the defect after the treatment is performed, so that body fluid is quickly circulated in the scaffold, It has many functions such as a better environment for playback.

  3D printer (3DP: 3D-printer), photopolymerization molding method (SLA: Stereo-lithography), laser sintering method (SLS: Selective laser sintering), impact particle molding method (BPM: Ballistic particle manufacturing), melting The biodegradable resin can be directly molded into the shape of the target defect by methods such as FDM (Fusion Deposition Modeling), and it is possible to produce a scaffold according to the individual patient's condition ( For example, see Patent Literature 2 to Patent Literature 4).

  The production of a scaffold according to the condition of each individual patient is an important process in the advancement of tailor-made advanced medicine for the affected / defected part of the individual tissue of the patient, particularly in regenerative medicine. In other words, as a scaffold, it is necessary to produce a scaffold having a porous structure in order to accurately three-dimensionally repair the shape and size of a tissue such as a joint or spine, or a defect caused by injury or surgical excision. Yes.

JP 2003-169845 A Japanese Patent No. 2930420 US Pat. No. 5,518,680 US Pat. No. 6,730,252

  The problem to be solved by the present invention is a porous structure having a communication hole through which blood and body fluid can pass, and has a compressive strength that can be applied to a defect in a joint or spine. It is an object of the present invention to provide a scaffold that can be easily formed into a shape and a method for manufacturing the same.

  To achieve the above object, the laminated three-dimensional scaffold of the present invention is any one of biodegradation selected from the group consisting of polylactic acid, polyglycolic acid, a copolymer of lactic acid and glycolic acid, polycaprolactone, and a copolymer of lactic acid and caprolactone. A plate-like scaffold fragment comprising a support resin resin sheet and arranged on the front surface in the form of a vertical and horizontal grid and a recess on the back surface that can fit the heads of the columns arranged in a vertical and horizontal grid pattern. Each of the column heads is stacked by being fitted into the recesses of the upper scaffold fragment.

Here, it is preferable that the scaffold fragment is shaped based on tomographic imaging data of a tissue defect portion. This is because a scaffold that conforms to the shape of the defect can be formed simply by stacking the scaffold fragments.
Also, the stacking process is facilitated by making the heads of the pillars have a loose taper shape and the recesses have an inverted taber shape with a slightly wider opening than the bottom.

  Since blood and body fluid can pass through the gap formed in the gap between the adjacent struts and the layer gap of the adjacent scaffold fragment, it is possible to provide a favorable environment for the cells. From a biodegradable resin sheet, such as polylactic acid, which is a bioabsorbable material, a single-layer plate-like scaffold fragment is produced with a microstructure mold, and the scaffold fragment is cut based on tomographic data of a patient's defect. The fragments are stacked like blocks to produce a three-dimensional scaffold for tissue regeneration.

  The laminated three-dimensional scaffold according to the present invention includes a porous structure with a communication hole through which blood and body fluid can pass by being produced by laminating scaffold fragments having support columns like a block. Moreover, it can apply to the defect part of a joint or a spine by selecting the resin which has compressive strength which can be applied to the defect part of a joint or the spine for a biodegradable resin sheet. Furthermore, by shaping and stacking the scaffold fragments individually, it is possible to easily construct a three-dimensional shape that matches the complex shape of the defect.

  Moreover, it is preferable that the uppermost scaffold fragment is not provided with a support. This is to protect the surrounding tissue in contact with the uppermost scaffold fragment.

In addition to the above-described structure, the laminated three-dimensional scaffold of the present invention is coated with a polycaprolactone resin, a copolymer of lactic acid and glycolic acid, or polyglycolic acid on the concave portion and / or the column head of the laminated three-dimensional scaffold. In addition, it is preferable to use it as a binder for the support and the recess. The reason for providing the support and the concave binder is to increase the strength of the scaffold having a three-dimensional structure against the vertical extension by bonding.
In addition to the binder described above, polylactic acid dissolved in acetone may be applied to the concave portions and / or the column heads of the laminated three-dimensional scaffold.

In addition, from the viewpoint of the method for producing the laminated three-dimensional scaffold of the present invention, a mold shape for molding the above-mentioned laminated three-dimensional scaffold support or recess is formed on the surface of the round bar, and a rolling method using a roll. A mold capable of molding the biodegradable resin sheet is provided.
A round bar with a mold for support molding formed on the surface and a round bar with a mold for recess molding formed on the surface are reciprocally rotated in parallel and sandwiched with a biodegradable resin sheet and pressed. By feeding it out, it is possible to produce a plate-like scaffold fragment having struts arranged in a vertical and horizontal grid pattern on the front surface and recesses arranged in a vertical and horizontal grid pattern on the back surface.

In addition, from the viewpoint of the method for producing a laminated three-dimensional scaffold of the present invention, a method for producing a laminated three-dimensional scaffold in the following steps (1) to (5) is provided.
(1) A polylactic acid resin pellet is melted at a predetermined temperature, hot-pressed and then cooled immediately to produce a biodegradable resin sheet.
(2) The first mold to be molded with the support and the second mold to mold the recess are heated to a predetermined temperature, the biodegradable resin sheet is sandwiched and pressed, and press-molded. A plate-like scaffold fragment is prepared, which is provided with struts arranged on the back surface and recesses into which the heads of the struts arranged in the vertical and horizontal grids can be fitted.
(3) The scaffold fragment is shaped based on tomographic imaging data of a tissue defect portion.
(4) A solution of polylactic acid dissolved in acetone is applied to the recess and / or the column head.
(5) The shaped scaffold fragments are stacked by fitting the heads of the columns to the recesses of the upper scaffold fragments, respectively.

  The laminated three-dimensional scaffold according to the present invention comprises a plate-like scaffold fragment having columns arranged on the front surface in a vertical and horizontal grid pattern and concave portions on the back surface that can fit the heads of the columns arranged in the vertical and horizontal grid pattern. Each of the pillar heads is fitted with a recess in the upper scaffold fragment and stacked to form a three-dimensional shape, which is a porous structure with a communication hole through which blood and body fluid can pass. It has a compressive strength that can be applied to the defect portion, and has an effect that it can be easily formed into a complicated shape of the defect portion.

  Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings.

  Hereinafter, a production flow of the laminated three-dimensional scaffold of Example 1 will be described with reference to FIG. Here, FIG. 1 shows a manufacturing process of the laminated three-dimensional scaffold of the first embodiment. FIG. 2 shows a production configuration of a stacked three-dimensional scaffold using a scaffold fragment cut using a CT image.

(1) First, polylactic acid resin pellets are melted at 200 ° C., and a biodegradable resin sheet having a thickness of 0.7 mm is produced by hot pressing. This resin sheet is rapidly cooled with water immediately after production. This is because the resin sheet becomes an amorphous molecular structure by rapid cooling immediately after the production, thereby increasing the strength and toughness of the resin sheet.

(2) Next, a mold for molding is heated to about 180 ° C. in advance, and the resin sheet produced in the above step (1) is sandwiched and pressed to perform press molding.
One embodiment of the mold is shown in FIG. There are two types of molds, one having a vertical column of 5.0 mm and a thickness of 1.0 mm, which molds a support column, and one having a vertical and horizontal column which molds a recess, and having a thickness of 5.0 mm and a thickness of 2.0 mm. Detailed specifications of the mold shapes are shown in FIGS.
When these two types of molds are used to sandwich and press the resin sheet and press mold, a scaffold fragment as shown in the schematic diagram of FIG. 5 can be produced.
An appearance photograph of the actually produced scaffold fragment is shown in FIG.

(3) The produced single-layer scaffold is a cylinder having a diameter of 0.2 mm, and a vertical and horizontal grid with a gap width of 0.5 mm between the cylinders. The height of the grid is 0.7 mm. There is a pillar having a diameter of 0.2 mm, and a circular hole having a diameter of 0.2 mm and a depth of 0.2 mm is formed on the lower side (back side) of the intersection. In the present embodiment, a scaffold fragment having a 0.2 mm diameter column is prepared in order to create a structure close to the cancellous bone structure. The diameter and interval of the cylinders and the height of the cylinders can be arbitrarily changed depending on the site used for regenerative medicine.
It was confirmed that the fabricated one-layer scaffold fragment withstands a compressive force of 300 N / cm ^{2 in} order to deform 0.2 mm in the compression test. Thereby, it turns out that the lamination | stacking three-dimensional scaffold which laminated | stacked this scaffold fragment | piece can be used for the joint of a jaw and knee with a heavy load load.

(4) Here, it is assumed that the load-load direction in the defect part that regenerates the tissue is taken as the Z axis, and the defect space is expressed as the XYZ axis. A sheet-like scaffold fragment is cut in accordance with each XY plane when the pitch is set to about 0.5 mm along the Z axis. At the time of cutting, a tomographic photograph of the affected part based on a CT scan image of the patient may be cut as data.

(5) Then, the cut sheet-like scaffold fragments are stacked by inserting the vertical columns of the respective sheet-like scaffold fragments into the circular holes of the upper sheet-like scaffold fragments so as to stack the blocks, and stacking the three-dimensional scaffolds. Is molded.

(6) At the time of stacking, the strength of the scaffold can be increased by adhesion by applying and laminating a binder in which polylactic acid is dissolved in acetone to the circular holes.
In addition, when a compressive load is applied only in the longitudinal column direction, adhesion with a binder is not essential.

(7) Further, by using the uppermost sheet-like scaffold fragment without a support, it is possible to avoid excessively stimulating the surrounding tissue adjacent to the uppermost scaffold fragment.

(8) Generally, the scaffold is sterilized with gamma rays, etc., and then seeded with the patient's own stem cells cultured in advance, and then transplanted to the affected area after adhering and proliferating in the seeded state. If there is a large defect and the cell cannot be proliferated in advance, the scaffold is divided into several blocks during transplantation, and the stem cells grown there are seeded on each block. Then, it can be transplanted after being combined and laminated and molded.

The laminated three-dimensional scaffold of the present invention is a scaffold that can be used for a joint of a jaw or knee having a large load, that is, a stem cell, an osteoblast, or the like is injected into the scaffold structure of the present invention to form a tissue defect. The treatment is expected to be used as a regenerative material for jaw and knee joint tissues.
It is also useful as a bioreactor for culturing cells.

Production flow diagram of laminated three-dimensional scaffold of Example 1 Production flow diagram of stacked 3D scaffolds using scaffold fragments cut using CT images Drawing of an embodiment of a mold (mold drawing for casting a support) Drawing of an embodiment of a mold (mold drawing for molding a recess) Schematic diagram of a single-layer scaffold fragment Appearance photograph of the actually produced scaffold fragment

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Stacked three-dimensional scaffold 2 Scaffold fragment 3 Prop 4 Recess 10 Mold for molding prop 11 Mold for molding recess

Claims (7)

  Polylactic acid, polyglycolic acid, a copolymer of lactic acid and glycolic acid, polycaprolactone, a support made of any biodegradable resin sheet selected from the group consisting of a copolymer of lactic acid and caprolactone and arranged on the surface in a matrix pattern A plate-like scaffold fragment having a recess that can fit the heads of the columns arranged in a vertical and horizontal lattice on the back surface, and the heads of the columns are fitted into the recesses of the upper scaffold fragment, respectively. Laminated three-dimensional scaffold characterized by layering.   The stacked three-dimensional scaffold according to claim 1, wherein the scaffold fragment is shaped based on tomographic imaging data of a tissue defect portion.   The stacked three-dimensional scaffold according to claim 1 or 2, wherein the uppermost scaffold fragment is not provided with the support column.   The polycaprolactone resin, a copolymer of lactic acid and glycolic acid, or polyglycolic acid is applied to the recess and / or the head of the column, and used as a binder for the column and the recess. The laminated three-dimensional scaffold according to any one of 3.   The laminated tertiary according to any one of claims 1 to 3, wherein polylactic acid dissolved in acetone is applied to the recess and / or the column head and used as a binder for the column and the recess. Former scaffold.   It is a metal mold | die for shape | molding the lamination | stacking three-dimensional scaffold of Claim 1, Comprising: The metal mold | die shape for shape | molding the said support | pillar or the said recessed part is formed on the surface of a round bar, The said rolling method by a roll A mold characterized by molding a biodegradable resin sheet. The manufacturing method of the lamination three-dimensional scaffold characterized by including the following process.
(1) A polylactic acid resin pellet is melted at a predetermined temperature, hot-pressed and then cooled immediately to produce a biodegradable resin sheet.
(2) The first mold to be molded with the support and the second mold to mold the recess are heated to a predetermined temperature, the biodegradable resin sheet is sandwiched and pressed, and press-molded. A plate-like scaffold fragment is prepared, which is provided with struts arranged on the back surface and recesses into which the heads of the struts arranged in the vertical and horizontal grids can be fitted.
(3) The scaffold fragment is shaped based on tomographic imaging data of a tissue defect portion.
(4) A solution of polylactic acid dissolved in acetone is applied to the recess and / or the column head.
(5) The shaped scaffold fragments are stacked by fitting the heads of the columns to the recesses of the upper scaffold fragments, respectively.