JP2007151805A - Medical device and surface modification method for medical device - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medical device excellent in connectivity with living tissue by being able to join a metallic porous body in which a metallic porous thin plate is multilayered as a medical device surface modification member with excellent connectivity with the living tissue to the surface of a medical device main body with high joining strength, and to provide a surface modification method for the medical device by which the metallic porous body can be easily joined to the surface of the medical device main body having various surface shapes. <P>SOLUTION: In the medical device, the metallic porous body 32 is joined to at least a part of the surface of the medical device body 31, and the metallic porous body 32 has multiple layers. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a medical device and a surface modification method for a medical device.

Medical devices such as artificial tooth roots and hip joints that are used by being implanted in a living body are required to have excellent affinity and high binding properties with surrounding living tissues in the living body.
Since the surface properties of medical devices have a great influence on these properties, various surface modification treatment methods for imparting desirable shapes and properties to the surfaces of medical devices have been proposed.

For example, in Patent Document 1, there are innumerable fine voids, and the metal powder is sintered in a porous state that allows the voids to communicate with the surface, and the medical device itself is formed of a porous metal body, and the medical device is used. Medical devices have been proposed in which the device surface is made of porous metal powder. Patent Document 2 proposes a surface modification treatment method in which a porous layer formed by bonding metallic spherical particles by sintering is attached to the surface of a medical device body.
In addition, a medical device surface modification member having a high binding property with a pre-formed biological tissue is bonded to the surface of the medical device main body, and does not impair the original characteristics of the medical device and is high with the surrounding biological tissue. Various surface modification methods that achieve both binding properties have been studied. Such medical device surface modifying members include those shown in Patent Documents 3 to 8.
JP 2002-320667 A JP 2004-141234 A JP-A-6-7388 JP-A-7-184987 Japanese Patent Laid-Open No. 10-155823 JP 2003-94109 A Special Table 2002-541984 Japanese Patent No. 3445301

However, according to studies by the present inventors, it is difficult to obtain sufficiently high connectivity between the medical device and the surrounding biological tissue by the method of directly modifying the medical device surface. Further, even when a conventionally proposed method for joining a medical device surface modifying member to a medical device body is used, the connectivity between the medical device and the surrounding biological tissue, the medical device body, and the The joint strength with the surface modifying member cannot be satisfied at the same time.
In order to obtain a high binding property with the biological tissue, the surface modifying member should be sufficiently disposed so that cells forming the biological tissue around the implantation portion of the medical device can easily enter the surface modifying member. It is necessary to make a porous body having a high void volume (high porosity).
On the other hand, in order to obtain a high bonding strength with the medical device body, it is important to ensure a sufficient bonding area on the bonding surface between the surface modifying member and the medical device body.

Therefore, in the method of sintering a material such as metal powder described in Patent Documents 1 and 2, it is difficult to control the pore diameter and the porosity of a metal porous body formed by sintering. The invasion of cells into the body is low, and the connectivity between the medical device and the living tissue is insufficient.
In addition, in the methods described in Patent Documents 3 to 8, when the porosity of the metal porous body is increased in order to improve the bondability with living tissue, the bonding strength between the metal porous body and the medical device body is increased. Both of these requirements cannot be fully satisfied because of the decrease.

  In addition, there are various types of medical device bodies according to product standards, individual differences, and the like. Therefore, the medical device surface modification member itself is highly deformable in order to accommodate these various surface shape medical device bodies, and the surface modification member is required for the medical device body. A method of joining with sufficient strength is required.

  The present invention has been made in view of the above problems, and is a metal porous body in which a metallic porous thin plate, which is a medical device surface modifying member having excellent binding properties to living tissue, is multilayered. An object of the present invention is to provide a medical device that is excellent in binding property to a living tissue because it can be bonded to the surface of the medical device body with high bonding strength. It is another object of the present invention to provide a surface modification method for a medical device that can easily join the metal porous body to the surface of a medical device body having various surface shapes.

As a result of intensive studies, the present inventors have found that the above problem can be solved by joining a specific metal porous body to the surface of a medical device body, and have completed the present invention.
That is, the first aspect of the present invention is a medical device in which a metal porous body is bonded to at least a part of the surface of the medical device main body, and the metal porous body is multilayered. It is a medical device characterized by.
Further, in the present invention, the metal porous body is formed of a metal porous thin plate produced by forming a slurry containing metal powder into a sheet shape, degreasing and sintering the dried formed body. It is preferable that Further, the metal porous thin plate is made of a metal manufactured by forming a slurry containing metal powder and a foaming agent into a sheet shape, passing through a foaming process, and then degreasing and sintering the dried molded body. It is preferable to include a porous thin plate.
In the present invention, the porosity of the metal porous thin plate is preferably 40 to 97%. Furthermore, it is preferable that the porosity of the metal porous thin plate joined to the medical device body is lower than the porosity of the metal porous thin plate in contact with the living tissue.
In the present invention, the metal of the metal powder preferably contains at least one selected from pure titanium, titanium alloy, stainless steel, cobalt chromium alloy, tantalum, niobium, and alloys thereof. Further, the metal of the metal powder is preferably the same type of metal as the medical device body.
Moreover, in this invention, the frame | skeleton surface which consists of a sintered compact of the metal powder of the said metal porous thin plate may be coat | covered with the inorganic compound which has biocompatibility.

In the second aspect of the present invention, a metal porous thin plate is produced by molding a slurry containing metal powder into a sheet, and degreasing and sintering the dried molded body. A metal porous body is produced by multilayering a thin plate, and the metal porous body is deformed and joined so as to conform to the surface shape of at least a part of the medical device body. This is a method for surface modification of a device. Further, the metal porous thin plate is made of a metal manufactured by forming a slurry containing metal powder and a foaming agent into a sheet shape, passing through a foaming process, and then degreasing and sintering the dried molded body. It is preferable to include a porous thin plate.
Moreover, in this invention, it is preferable to shape | mold the said slurry in a sheet form with a doctor blade method.
In the present invention, the bonding is preferably diffusion bonding.

In the claims and specification, the term “medical device” refers to a metallic porous body in which a medical device main body and a metallic porous thin plate that is a medical device surface modifying member are multilayered. A bone having a portion to be joined to a hard tissue such as a bone of a human body such as an artificial tooth root or a hip joint, or a joint, for example. It includes artificial prosthetic members that are widely used in the body, such as prosthetic members.
“Surface modification of medical device” means that the characteristics of the surface of the medical device main body change when the metallic porous body is bonded.

  ADVANTAGE OF THE INVENTION According to this invention, the metallic porous body by which the metallic porous thin plate which is a member for medical device surface modification | reformation which has the outstanding bond property with a biological tissue was multilayered was made into a medical device with high joint strength. By being able to be joined to the surface of the main body, a medical device having excellent binding properties with a living tissue can be provided. Moreover, the surface modification method of the medical device which can join the said metal porous body easily to the surface of the medical device main body which has various surface shapes can be provided.

≪Medical device≫
The medical device of the present invention is a medical device in which a metal porous body is bonded to at least a part of the surface of the medical device main body, and the metal porous body is multilayered.
Preferably, the metal porous body is a multilayered metal porous thin plate produced by forming a slurry containing metal powder into a sheet, and degreasing and sintering the dried formed body. It is. More preferably, the metal porous thin plate is produced by forming a slurry containing metal powder and a foaming agent into a sheet, passing through a foaming process, and then degreasing and sintering the dried formed body. It includes a metal porous thin plate.

(Metal porous body)
The metal porous body in the present invention is multi-layered.
The layer is not particularly limited as long as the effects of the present invention can be obtained. Among them, a sheet-shaped one is preferable, and a metal porous thin plate is more preferable.
The metal porous thin plate is manufactured by forming a slurry containing metal powder into a sheet shape, and degreasing and sintering the dried molded body, since the bondability with the medical device body is improved. In addition, since the binding property to living tissue is improved, a slurry containing metal powder and a foaming agent is formed into a sheet, and after the foaming process, the dried molded body is degreased, What contains the metal porous thin plate manufactured by sintering is more preferable.
Hereinafter, the metal porous thin plate suitably used in the present invention will be described.

The metal porous thin plate in the present invention is produced by molding and processing a slurry containing metal powder.
The slurry (hereinafter also referred to as slurry S) contains at least a metal powder, preferably contains a foaming agent, a water-soluble resin binder, and water, and other components such as a plasticizer and an organic solvent as necessary. Containing.

The metal porous thin plate to be produced has a three-dimensional network cell structure, and the metal powder constitutes its skeleton.
As the metal powder, powders such as metals that are not harmful to living organisms and oxides thereof are preferably used.
As the metal of the metal powder, at least one selected from pure titanium, titanium alloy, stainless steel, cobalt chromium alloy, tantalum, niobium and alloys thereof is preferable, and pure titanium and stainless steel are more preferable. These metals are particularly preferably used alone from the viewpoint of galvanic corrosion described later.
The metal powder is a main raw material of the slurry S, and the content thereof is preferably 30 to 80% by mass in the slurry S. More preferably, in the step of producing a metal porous thin plate to be described later, the amount is 50 to 80% by mass when there is no foaming process, and 40 to 70% by mass when there is a foaming process. Within this range, it is easy to control the final shape (opening diameter, porosity, thickness, etc.) of the metal porous thin plate, and the metal type and other components in the slurry S (foaming agent, etc.) Balance can be taken.
The average particle size of the metal powder is preferably 0.5 to 50 μm. By being in this range, the desired porosity and average pore diameter of the metal porous thin plate can be easily obtained. The average particle size of the metal powder can be measured by a laser diffraction method or the like.

  Moreover, it is preferable that the metal of a metal powder is the same kind of metal as a medical device main body. Thereby, the joining strength of a metal porous thin plate and a medical device main body becomes higher. Furthermore, galvanic corrosion (metal ion elution), which becomes a problem when different metals come into contact with each other in the living body, is suppressed, and the corrosion resistance is improved. In the case of a conventional metal porous body manufactured by plating or the like, there is a risk of always destroying the surface layer of the metal porous body due to galvanic corrosion or foreign body reaction (inflammatory reaction, immune reaction, etc.) It is considered a thing. In the present invention, the metal porous thin plate and the medical device main body can be made of the same kind of metal, and the above-described fears are eliminated. As a specific example, for a medical device body made of SUS316L, a porous thin plate made of SUS316L, for a medical device body made of pure titanium, a porous thin plate made of pure titanium, for medical use made of Ti-6Al-4V For the device body, a Ti-6Al-4V porous thin plate may be mentioned.

The slurry S preferably contains a foaming agent. By containing a foaming agent, a metal porous thin plate having a high porosity is easily obtained.
Examples of the foaming agent include surfactants and volatile organic solvents. Among these, a water-insoluble hydrocarbon organic solvent having 5 to 8 carbon atoms is preferable, and neopentane, hexane, heptane, and cyclohexane are more preferable. These foaming agents may be used individually by 1 type, or may use 2 or more types together.

The slurry S preferably contains a water-soluble resin binder. By containing the water-soluble resin binder, the skeleton of the metal porous thin plate is formed better.
As the water-soluble resin binder, for example, methylcellulose, hydroxypropylmethylcellulose, polyvinyl butyral, polyvinyl alcohol and the like are preferably used. These water-soluble resin binders may be used alone or in combination of two or more.
The slurry S preferably contains water.
As other components, for example, plasticizers such as glycerin, ethylene glycol, and polyethylene glycol; organic solvents such as methanol, ethanol, and isopropanol can be used as necessary.
In the case where the slurry S (paste) does not contain a foaming agent, commercially available acrylic beads such as acrylic, polyethylene, and polystyrene prepared for each particle size may be used for adjusting the porosity and average pore diameter.

FIG. 1 shows an embodiment of a metal porous thin plate according to the present invention. FIG. 1 (a) is an enlarged plan view, and FIG. 1 (b) is a side view of a metal porous thin plate produced when there is a foaming process (containing a foaming agent in the slurry S). FIG.
The metal porous thin plate shown in FIG. 1 is in the form of a sheet, and as shown in FIG. 1A, innumerable pores 25a are opened in the front and back surfaces and side surfaces of the metal porous thin plate 21. It is formed in the state.
That is, the metal porous thin plate has a three-dimensional mesh-like structure while the same pores 25 a are opened on the front and back surfaces of the metal porous thin plate 21.
Further, as shown in FIG. 1B, the front and back surfaces of the metal porous thin plate 21 are a surface (front surface) 23 in which foamed holes swelled three-dimensionally by a foaming process are formed, and a carrier sheet to be described later. 12 is a back surface 24 which is a contact surface with 12.
The thickness of the metallic porous thin plate 21 is preferably 150 to 2000 μm.
In the metal porous thin plate 21, the raw material metal to be used can be appropriately selected as described above. Further, by adjusting the average particle diameter and paste composition of the metal powder, or controlling the foaming process, the average pore diameter and porosity of the metal porous thin plate 21 can be controlled. Furthermore, for the purpose of accurately controlling the thickness, porosity, and surface flatness of the metallic porous thin plate 21 to predetermined targets, the sintered metal porous thin plate 21 is subjected to rolling, pressing, or the like. It is desirable to do.

The average pore diameter of the metal porous thin plate in the present invention is preferably 20 to 800 μm, and more preferably 100 to 600 μm. By being equal to or more than the lower limit of the range, the size becomes suitable for invasion and proliferation of living tissue, and the invasion rate and proliferation rate of cells are improved. On the other hand, by being below the upper limit of the range, the positional relationship (interval) between the skeletons where cells grow is improved, and the cell penetration rate and the growth rate are improved.
The average pore diameter of the metal porous thin plate is measured by direct observation with an optical microscope or an electron microscope, a bubble point method, a mercury porosimeter method, or the like.

The specific surface area of the metallic porous thin plate in the present invention is preferably from 0.01 to 0.5M ² / g, more preferably 0.02~0.2m ² / g. As for the specific surface area, the larger the specific surface area, the larger the surface area on which cells can be implanted and proliferated. However, if it is larger than 0.5 m ² / g, it becomes ineffective for cell implantation and proliferation.
The specific surface area of the metal porous thin plate is measured by a gas adsorption / desorption method (BET method) using krypton gas or nitrogen gas.

Further, the porosity of the metal porous thin plate in the present invention is preferably 40 to 97%, and more preferably 50 to 95%. When the porosity is less than 40%, the volume of the pore portion of the porous structure is reduced, and the invasion and proliferation rate of cells from the living tissue is reduced. On the other hand, when it exceeds 97%, the skeleton portion of the metallic porous thin plate is reduced, and the strength of the metallic porous thin plate and the bonding strength between the metallic porous thin plate and the medical device body are insufficient.
Here, in the present specification and claims, “porosity” refers to pores with respect to the volume of the entire metal porous thin plate (single layer) (corresponding to reference numeral 25a shown in FIG. 1A). Means the proportion of
The porosity of the metal porous thin plate is calculated from the weight per unit area (g / cm ² ), the thickness of the thin plate, and the theoretical specific gravity of the constituent materials.

Generally, in a metal sintered body, the smaller the porosity, the more the metal part increases, so the strength improves. Also, the joint strength when joining with other metals also improves, while the higher the porosity, the stronger the strength. Decreases, and the bonding strength in the case of bonding with other metals also decreases.
In the case of a general metal powder molded body that does not go through a slurry molding method, when the porosity is 50% or more, the bonding strength between adjacent metal powders is weak, and when it is 70% or more, it is difficult to exist as a self-supported molded body. It is.
In contrast, the metal porous thin plate used in the present invention has a high porosity as described above, but has a high strength. This is because, as shown in FIG. 1, the metal porous thin plate is formed by solidly sintering metal powders on the surface of the pores 25a, thereby forming a solid metal skeleton. It is believed that there is. In addition, the metal porous thin plate has high strength and good deformability. Thereby, this metal porous thin board can be easily joined so that it may be easily deformed along the surface shape of the medical device body, and the adhesiveness with the medical device body is increased, so that it can be firmly bonded. In addition, after the medical device to which the metallic porous thin plate is bonded is embedded in the body, when the medical device is deformed under a load, the metallic porous thin plate is also easily deformed accordingly. Therefore, an effect of preventing peeling of the metal porous thin plate from the medical device body is brought about. These effects can also be obtained when the metal porous thin plate is multilayered.

The metal porous body in the present invention is multi-layered, and is produced, for example, when a metal sintered body formed into a sheet shape and a foaming process are present (the slurry S contains a foaming agent). The metal porous thin plate is formed by appropriately combining the metal porous thin plates produced when there is no foaming process (the slurry S does not contain a foaming agent) and the like. can get. Among them, those including a metal porous thin plate produced when there is a foaming process (containing a foaming agent in the slurry S) are preferable. Specifically, there is a foaming process (foaming in the slurry S). Metal porous thin plate produced in the case of containing an agent), metal porous thin plate produced in the absence of a foaming process, and metal porous produced in the presence of a foaming process A preferable example is a multilayered thin plate. More preferably, a plurality of metal porous thin plates having different porosity are multilayered. Since the metal porous body is multi-layered, it is possible to more easily control the characteristics (such as the porosity) of the surfaces of the metal porous body on the medical device main body side and the living tissue side.
In this case, in the metal porous body, the porosity of the metal porous thin plate joined to the medical device body is preferably lower than the porosity of the metal porous thin plate in contact with the living tissue.
In order to increase the bonding strength between the metal porous body and the medical device body, the bonding surface with the medical device body is preferably a metal porous thin plate with a low porosity, while the contact surface with the living tissue. It is preferable that the porosity is high in order to control the invasion of cells from the living tissue and the living tissue structure. Therefore, by controlling the porosity of the metal porous body as described above during multi-layering, the cell penetration from the biological tissue or the controllability of the structure of the biological tissue formed around the metal porous body A member for surface modification of a medical device that is excellent in (bondability between a medical device and a biological tissue), and that the metal porous body and the medical device main body are firmly bonded and the metal porous body is difficult to peel off. Can be obtained.

FIG. 2 shows an embodiment of a metal porous body in which metal porous thin plates are multilayered.
In FIG. 2, a metallic porous body 32 composed of three layers of metallic porous thin plates 21 a, 21 b, and 21 c with different porosity is joined to the surface of the medical device body 31.
2, the metal porous thin plates 21a, 21b, and 21c are in the thickness direction from the medical device main body 31 side to the living tissue side, that is, the metal porous thin plate 21c, the metal porous thin plate 21b, The porosity increases in the order of the metal porous thin plate 21a.

In the metal porous body, the average pore diameter of the metal porous thin plate joined to the medical device body is preferably 20 to 150 μm, and the average pore diameter of the metal porous thin plate in contact with the living tissue is 100 to 600 μm. It is preferable that
Moreover, it is preferable that the porosity of the metal porous thin plate joined to a medical device main body is 50 to 85%, and the porosity of the metal porous thin plate in contact with a living tissue is 80 to 95%. preferable.
The “contact surface with living tissue” refers to the outermost surface of the metallic porous thin plate on the living tissue side.

The skeleton surface made of a sintered metal powder of the metal porous thin plate may be coated with an inorganic compound having biocompatibility.
Thereby, the affinity with respect to the biological tissue of the metallic porous thin plate and the metallic porous body obtained by multilayering the metallic porous thin plate is increased, and the invasion rate and the proliferation rate of cells from the biological tissue are improved.
Examples of the inorganic compound having biocompatibility include metal oxides such as titanium oxide, calcium phosphate, and hydroxyapatite. These inorganic compounds having biocompatibility may be used alone or in combination of two or more.
As a coating method, a physical coating method such as coating of a slurry containing a biocompatible inorganic compound powder or thermal spraying, a deposition method from an aqueous solution, a method involving a chemical reaction such as a chemical vapor deposition (CVD) method, etc. It is possible to select.
The coating treatment with the inorganic compound may be performed before or after the metal porous body is bonded to the surface of the medical device body. Note that firing may be required when the inorganic compound is coated on the surface of the skeleton made of a sintered metal powder of a metal porous thin plate (in the case of a chemical precipitation method). In the case where the firing temperature is lower than the joining temperature and there is a concern that the function of improving the affinity to living tissue may be impaired by heating after firing, the coating treatment is preferably performed after joining.
In the present invention, the skeleton surface of the metal porous thin plate may be entirely covered or partially covered with a biocompatible inorganic compound.

In addition, the metal porous body or a part of the metal porous thin plate constituting the metal porous body includes a drug in the pores by controlling the pore diameter, and if necessary, polylactic acid on the pore surface A biodegradable polymer such as can also be coated. Thereby, after implanting in the body, the drug is gradually released from the surface of the medical device, whereby the treatment of the disease and the repair of the living tissue around the medical device can be promoted. Furthermore, not only drugs but also cells that have been seeded and cultured outside the body in advance are included in the metal porous body or a part of the metal porous thin plate constituting the metal porous body, thereby allowing medical treatment after implantation in the body. It is also possible to promote the regeneration of living tissue around the medical device and the treatment of diseases.
In addition, as for what comprises the metal porous body in this invention, although the above-mentioned metal porous thin plate is used preferably, it is not limited to this, The conventionally well-known medical device surface modification member can also be used. .

(Medical device body)
Examples of the medical device main body include artificial prosthetic members made of a material that is not harmful to living organisms, such as metals such as stainless steel, cobalt chromium alloy, titanium, and titanium alloy;
In the present invention, the “medical device body” refers to an artificial prosthetic member to which the metal porous body of the present invention is not joined, and other medical device surface modifying members and the like are provided. Including things.
In the medical device of the present invention, the metallic porous body is bonded to at least a part of the surface of the medical device main body, and may be bonded to a part of the surface of the medical device main body depending on the purpose, or may be bonded to the entire surface. May be.

(Production method)
The medical device of the present invention can be manufactured by manufacturing a sheet-like molded body that constitutes a metal porous body, for example, and appropriately stacking the molded body with a medical device body.
Hereinafter, regarding a method for manufacturing a medical device using a metal porous thin plate suitably used in the present invention described above, a step of manufacturing a metal porous body, and joining the metal porous body and the medical device body The process will be described in detail by showing preferred specific examples.

<Process for producing metal porous body>
In this step, the slurry S is formed into a sheet, and the dried compact is degreased and sintered to produce a metal porous thin plate, and the metal porous thin plate is multilayered. A metal porous body is produced.
Preferably, the metal porous thin plate is manufactured by forming a slurry S containing metal powder and a foaming agent into a sheet, passing through a foaming process, and then degreasing and sintering the dried formed body. Including metal porous sheet.
Preferably, the slurry S is formed into a sheet shape by a doctor blade method.
Hereinafter, this process will be described with reference to the drawings.

FIG. 3 shows an example of a method for producing a metal porous thin plate. In this figure, the doctor blade method is used and an example with a foaming process is shown.
The slurry S is a slurry containing at least metal powder, and preferably contains a foaming agent, a water-soluble resin binder, and water, and contains other components such as a plasticizer and an organic solvent as necessary.
Then, the slurry S is formed into a thin sheet. The forming method is not particularly limited as long as it can be formed into a desired sheet shape, and it is preferable to use the doctor blade method. For example, the slurry S can be formed into a thin sheet by using the green sheet manufacturing apparatus 10 shown in FIG.

In the green sheet manufacturing apparatus 10, first, the slurry S is supplied onto the carrier sheet 12 from the hopper 11 in which the slurry S is stored. The carrier sheet 12 is conveyed by a roller 13, and the slurry S on the carrier sheet 12 is extended between the moving carrier sheet 12 and the doctor blade 14 and formed into a required thickness.
The gap between the carrier sheet 12 and the doctor blade 14 is preferably set to 100 to 1500 μm.

Here, in order to obtain a multilayered metal porous thin plate (metal porous body), molding by the doctor blade method may be performed a plurality of times. As this method, for example, a method as shown in FIG. 4 can be used.
FIG. 4 is a diagram showing an example of a method for forming a metal porous body composed of two layers of metal porous thin plates.
In the green sheet manufacturing apparatus 10, first, the slurry S is supplied onto the carrier sheet 12 from the hopper 11 in which the slurry S is stored, and is extended between the moving carrier sheet 12 and the doctor blade 14. Layer S1 is formed.
Next, on the first slurry layer S1, slurry Sa having a different blending ratio and the like is supplied from the hopper 11a. Then, the second slurry layer S2 having a required thickness is formed on the first slurry layer S1 by the doctor blade 14a.
In the case of forming a metal porous thin plate having three or more layers, the third slurry layer S3 is formed on the second slurry layer S2, and the fourth slurry layer S4 is formed on the third slurry layer S3 in this order. Thereby, the porosity and average pore diameter are controlled in the thickness direction, and the metal porous body from which the porosity and average pore diameter of both outermost surfaces differ can be manufactured.

Next, the formed slurry S is further conveyed by the carrier sheet 12 and subjected to heat treatment. In FIG. 3, it passes through the foaming tank 15 and the heating furnace 16 sequentially.
In the foaming tank 15, by controlling the temperature conditions in a high-humidity atmosphere with a humidity of 80% or more, the pore diameters of innumerable foaming holes formed by the function of the foaming agent are uniformly controlled over the entire slurry S, A three-dimensional network skeleton composed of a slurry component containing metal powder (a skeleton of a metal porous thin plate) is formed.
At this time, flat foaming holes are formed on the contact surface (back surface) of the slurry S with the carrier sheet 12. On the other hand, on the surface (surface) opposite to the contact surface of the slurry S with the carrier sheet 12, foamed holes that are expanded three-dimensionally by free foaming are formed. Therefore, the back surface and the front surface have an asymmetric foam structure. For example, a back surface 24 that is a contact surface between the surface 23 formed with the three-dimensionally expanded foam holes as shown in FIG. 1B and the carrier sheet 12 formed with the flat foam holes is provided. The metal porous thin plate 21 which has is mentioned as an example of embodiment.
In this way, the foam formed on the carrier sheet 12 is dried in the heating furnace 16 as it is in the atmosphere or in an inert gas atmosphere at a temperature of 100 ° C. or lower to form a molded body (hereinafter referred to as a molded body). , Sometimes referred to as a green sheet G).

The green sheet G is peeled off from the carrier sheet 12 and held in a temperature range of 350 to 600 ° C. for about 1 to 10 hours, and the components other than the metal powder contained in the slurry S while maintaining the foamed pore structure. By decomposing and degreasing the metal, a porous metal degreased body formed from a skeleton in which metal powder is aggregated, and holding in a non-oxidizing atmosphere at a temperature range of 1100 to 1350 ° C. for about 1 to 10 hours, A metal porous sintered sheet in which the powders are sintered is obtained. A metal porous thin plate is manufactured by cutting the obtained metal porous sintered sheet into an arbitrary size.
A plurality of metal porous thin plates are manufactured in advance, and the metal porous thin plates are multilayered by joining or the like to manufacture a metal porous body.

  In the present invention, the metal porous thin plates may be multi-layered by, for example, laminating metal porous thin plates that have been produced in advance as described above, and performing molding by the doctor blade method a plurality of times. Alternatively, a plurality of metal porous thin plates may be stacked on the medical device main body and joined in a single process in the process described later. For example, when a metal porous thin plate that does not require a foaming process and a metal porous thin plate that requires a foaming process are multi-layered, the metal porous that does not require a foaming process by the doctor blade method first. Forming a thin plate, and then forming a metal porous thin plate that requires a foaming process by the doctor blade method, and then laminating the two, the high bonding force between them and the simple manufacturing process It is preferable from the viewpoint of conversion.

In the present invention, the doctor blade method is not essential, but it is preferable to use the doctor blade method because a thin plate shape which is a shape suitable as a surface modifying member of a medical device can be easily formed. .
In addition, although a foaming process is not essential, it has a foaming process because it is easy to control the porosity and average pore diameter and it is easy to obtain a metal porous thin plate having a high porosity and high strength. preferable. In particular, the metal porous thin plate constituting the contact surface with the living tissue in the metal porous body is preferably molded through a foaming process.

<Step of joining metal porous body and medical device body>
In this step, the metal porous body manufactured in the above step is deformed and joined so as to conform to the surface shape of at least a part of the medical device body. Preferably, the bonding is a diffusion bonding. Thereby, the characteristic of the medical device main body surface changes.
Hereinafter, this step will be described in detail.

The metal porous body manufactured by the above process is cut in accordance with the surface shape that is the joining target portion of the medical device body.
As a cutting method, a general thin piece cutting method such as a cutter such as a cutter, laser cutting, water jet, electric discharge wire processing, or ultrasonic cutting can be applied.
Next, the metal porous body cut into a predetermined shape is brought into close contact with the surface of the joining target portion of the medical device body, and the metal porous body is plastically deformed so as to follow the surface shape.
Thereafter, the metal porous body is joined to and integrated with the surface of the medical device body to produce a medical device.
At this time, in order to improve the adhesion between the metal porous body 32 and the surface of the medical device main body 31, it is preferable to use a “mold” 41 that matches the surface shape of the joining target portion as shown in FIG.

  As for the bonding method, from the viewpoint of the bonding strength between the metal porous body 32 and the medical device body 31, the die 41 in which both are fixed under pressure is placed in a non-oxidizing atmosphere such as in a vacuum or in an inert gas. Diffusion bonding in which the temperature is raised and maintained is preferable. At this time, in order to ensure the bonding strength between the metallic porous body 32 and the medical device body 31, it is preferable to apply a pressure of 0.01 to 10 MPa to the bonding surface. By being more than the lower limit of the range, better bonding strength can be obtained. On the other hand, by being below an upper limit, the metal porous body 32 can be prevented from being deformed more than necessary, and a desired thickness can be easily obtained.

Further, it is possible to use a method of applying pressure and heating using a joining mold having a gap matched to a desired thickness by utilizing deformation during joining. In this case, it is preferable to apply a pressure of 0.1 to 10 MPa to the joint surface. As for the pressure, it is preferable to select an optimum value as appropriate depending on the material of the metal porous body 32, the porosity, and the surface treatment method (form, treatment temperature, plastic deformation, etc.).
Note that the use of the mold 41 is also effective in preventing foreign matter from being mixed during bonding.

  In addition, a bonding method other than diffusion bonding, such as a bonding shape, may be applied as appropriate, for example, a spot or seam welding method using laser, resistance heating or ultrasonic waves, a brazing method, or the like.

When joining several types of metallic porous thin plates to the medical device body 31, by using the method shown in FIG. 4 and the like, the metallic porous thin plates are joined together in a desired property (pore size distribution) in advance. The formed metal porous body 32 can be joined to the medical device main body 31, and this is preferably used particularly in the case of a complicated shape.
Note that a plurality of metal porous thin plates can be stacked on the medical device body 31 and bonded together by a single treatment.

Specific examples of the bonding conditions between the metal porous body 32 and the medical device body 31 include graphite, alumina, zirconia, silica, high-purity quartz, and boron nitride as the material of the mold 41. Of these, graphite is preferable because it is excellent in workability, and high-purity quartz is preferable because it is excellent in cleanliness.
In addition, when using graphite for a type | mold, since it may react with the metal of joining object, you may provide a barrier layer in the part which contacts the metal porous bodies 32 as needed. As this barrier layer, for example, a sprayed layer such as a ceramic member such as zirconia or alumina is suitable.
The degree of vacuum is preferably 5.0 × 10 ⁻² Pa or less. It is also possible in an Ar atmosphere.
The joining time is preferably maintained for about 1 to 5 hours after reaching a predetermined temperature.
The bonding method is preferably diffusion bonding. Due to the diffusion bonding, higher bonding strength can be obtained.
It is preferable that joining temperature is 700-1200 degreeC, More preferably, it is 800-1100 degreeC. By being 700 ° C. or higher, better bonding strength can be obtained. On the other hand, when the temperature is 1200 ° C. or lower, the progress of sintering of the metal porous body 32 is suppressed, the desired porosity can be stably obtained, and the thermal influence on the medical device body 31 can be kept low. And mechanical properties are improved. It is preferable that the bonding temperature is appropriately selected in accordance with the material, porosity, etc. of the metal porous thin plate and the metal porous body 32 in which the metal porous thin plate is multilayered.
Further, the metal porous body 32 is bonded to at least a part of the surface of the medical device main body 31, and may be bonded to a part of the surface of the medical device main body 31 or may be bonded to the entire surface depending on the purpose. .

In addition, the metal porous body has a smaller deformation resistance than a normal bulk metal material, and the bonding between the metal porous body and the medical device body is substantially a part of the contact surface. Since the bonding area is small, it is possible to bond at a lower stress and temperature than the bulk metal material having the same shape.
Therefore, even if the medical device body has a highly curved surface shape, it is possible to deform the metal porous body in advance along the surface shape of the medical device body and join them together.

Examples of the medical device provided by the present invention include a prosthesis for hard tissues such as an artificial hip joint, an artificial elbow joint, an artificial knee joint, an artificial shoulder joint, an artificial tooth root, an artificial vertebral body, and a bone prosthetic member; soft tissue such as a ligament Alternatively, those that simultaneously prosthetic both soft tissue and hard tissue; those that promote tissue regeneration after implantation in the body by previously seeding and culturing cells in vitro.
FIG. 6 shows an example embodiment of a medical device.
FIG. 6A is a schematic view showing a state where the artificial hip joint 51 in which the metal porous body 32 according to the present invention is joined to the surface of the femoral stem 52 is inserted into the medullary cavity of the femur 53 and fixed to the pelvis 54. FIG.
FIG. 6B is a schematic view showing a state in which the artificial tooth root 55 in which the metal porous body 32 according to the present invention is bonded to the surface of the core material 56 is inserted into the alveolar bone 57. In the figure, 58 is a connective tissue and 59 is an epithelium.
FIG. 6C is a schematic view showing a state in which the artificial elbow joint in which the metal porous body 32 according to the present invention is joined to the surfaces of the humeral stem 71 and the ulnar stem 72 is inserted and fixed in the humerus and ulna. It is.
FIG. 6D is a schematic view showing a state in which the artificial knee joint in which the metal porous body 32 according to the present invention is joined to the surface of the tibial stem 73 is inserted and fixed in the tibia. In the figure, 74 is an artificial femoral head (knee joint side), 75 is a joint sliding portion, 76 is a base plate, and 77 is a femur.
FIG. 6E shows a state in which the artificial shoulder joint in which the metal porous body 32 according to the present invention is joined to the surface of the humeral stem 78 is inserted and fixed in the humerus while being connected to the artificial humeral head. It is a schematic diagram shown. In the figure, 79 is an artificial humeral head, and 80 is an artificial joint bulk.

≪Method for surface modification of medical device≫
The surface modification method for a medical device of the present invention is a method for forming a metal porous thin plate by molding a slurry containing metal powder into a sheet, and degreasing and sintering the dried molded body, A metal porous body is manufactured by multilayering the metal porous thin plate, and the metal porous body is deformed and joined so as to conform to the surface shape of at least a part of the medical device body. is there. Preferably, the metal porous thin plate is a metal produced by forming a slurry containing metal powder and a foaming agent into a sheet, passing through a foaming process, and then degreasing and sintering the dried compact. Includes porous sheet metal.
In the medical device surface modification method of the present invention, the slurry is preferably formed into a sheet by a doctor blade method. Further, the bonding is preferably diffusion bonding.
About each processing method, it is the same as that of the case of the manufacturing method of the above-mentioned medical device, and abbreviate | omits description.

  ADVANTAGE OF THE INVENTION According to this invention, the metallic porous body by which the metallic porous thin plate which is a member for medical device surface modification | reformation which has the outstanding bond property with a biological tissue was multilayered was made into a medical device with high joint strength. By being able to be joined to the surface of the main body, a medical device having excellent binding properties with a living tissue can be provided. Moreover, the surface modification method of the medical device which can join the said metal porous body easily to the surface of the medical device main body which has various surface shapes can be provided.

In addition, the medical device provided by the present invention can use a metal porous thin plate having a higher porosity than a similar metal porous body manufactured by a conventional sintering method, etching / punching, or the like. In addition, it has excellent connectivity with living tissue, and has a high cell penetration / proliferation rate, and has excellent connectivity not only in hard tissue but also in soft tissue.
In addition, the medical device provided by the present invention is superior in bonding strength to the medical device body than before and can be manufactured at low cost.
Moreover, the medical device surface modification method of the present invention can provide a medical device having a high porosity.
In the medical device surface modification method of the present invention, the metal porous body, which is a medical device surface modification member, can be easily joined to an existing medical device body having various surface shapes. it can.

Further, the medical device provided by the present invention is a medical device surface modification member (metal porous body) that occurs after the medical device is embedded in the body, peeling from the medical device body, or a living body. Problems caused by lack of tissue connectivity are reduced, and it can be used in the body for a longer period of time than before.
Furthermore, the metal porous body used in the present invention can be applied to medical device bodies at various sites.
As described above, the present invention can be expected to improve the patient's QOL (Quality of Life) and to reduce medical expenses.

Hereinafter, the present invention will be described in more detail using examples, but the present invention is not limited to these examples.
The bonding strength of the bonding test piece (Example 1) obtained by bonding the metal porous body in which the metal porous thin plate was multilayered according to the present invention was evaluated.
Moreover, the binding property of a biological tissue was evaluated with respect to the multilayer joined body (Examples 2-3) which joined the metal porous body by which the metal porous thin plate was multilayered concerning this invention.

[Evaluation of bonding strength]
The bonding strength of the bonding test piece (Example 1) obtained by bonding the metal porous body in which the metal porous thin plate was multilayered according to the present invention was evaluated.
In addition, as a test example, the same joint strength evaluation as in Example 1 (Test Examples 1 and 2) was performed on the test piece obtained by bonding the metal porous thin plate (single layer) used in the present invention. . Moreover, as a comparative test with respect to Test Examples 1 and 2, comparative evaluations (Test Examples 3 to 4) using the same single porous metal thin plate were performed.

(Test Example 1)
SUS316L porous thin plate 61 (average pore diameter 150 μm, porosity 87%, thickness 0.31 mm) having a three-dimensional communication hole structure each cut into a shape of 20 mm × 50 mm, and a SUS316L foil body 62 (thickness) 0.5mm), as shown in FIG. 7 (a), 10mm each is overlapped and fixed, and in a state where it is pressure-bonded and pressurized at 1.5MPa, it is heated to 1050 ° C in Ar to perform diffusion bonding, Five joining test pieces having a width of 20 mm and a length of 90 mm were produced.

Using the autograph precision universal testing machine (load cell capacity: 5 kN) manufactured by Shimadzu, the 10 mm each of the both ends of the bonding test piece is fixed to the five bonding test pieces prepared above, and the tensile speed is 0.5 mm. / Min. The tensile test was carried out under the following conditions.
The tensile test was performed until the joining test piece broke, and the fracture process and the site where the fracture occurred were evaluated. The average tensile strength at which the joining test piece started to break was 7.4 MPa.

(Test Example 2)
A pure Ti porous thin plate (average opening diameter 50 μm, porosity 79%, thickness 0.30 mm) and a pure Ti foil body (thickness 0.5 mm) were pressed and pressed at 2.0 MPa. In the state, a bonded test piece was prepared and evaluated in the same manner as in Test Example 1 except that diffusion bonding was performed by heating to 950 ° C. in vacuum. The average tensile strength at which the fracture of the joining test piece started was 12.4 MPa.

Example 1
SUS316 porous thin plate A (average pore diameter 300 μm, porosity 89.5%, thickness 0.42 mm) having a three-dimensional communication hole structure each cut into a shape of 20 mm × 50 mm, and a SUS316L foil body (thickness) 0.1mm), as shown in FIG. 7A, in a state where 10 mm is overlapped and pressed and pressed at 1.5 MPa, diffusion bonding is performed by heating to 1050 ° C. in a vacuum, and the width is 20 mm. X Five joining test pieces A having a length of 90 mm were produced.

Next, the SUS316 porous thin plate A cut into a shape of 120 mm × 70 mm and a SUS316L porous thin plate B having a three-dimensional communication hole structure (average pore diameter 50 μm, porosity 65.3%, thickness 0) .27 mm) were laminated so as to be completely overlapped, and in a state of being pressure-bonded and pressurized at 1.5 MPa, diffusion bonding was carried out by heating to 1050 ° C. in a vacuum to produce a metal porous body C.
Cut out 5 samples of width 20mm x length 50mm from this metal porous body C (thickness 0.66mm), and cut this metal porous body C into a shape of width 20mm x length 50mm. The five SUS316L foil bodies (thickness 0.1 mm) were joined in the same manner as the joining test piece A, thereby producing five joining test pieces B.

Furthermore, a porous thin plate D-1 made of SUS316 (average pore diameter of 30 μm, porosity of about 53%) produced using a slurry (paste) containing no foaming agent as the first layer by a multiple molding process as shown in FIG. SUS316L porous thin plate D-2 (average pore diameter: 300 μm, porosity: approx. 0.15 mm) and a slurry (paste) containing a foaming agent as the second layer and produced through a foaming process. 85%, thickness of about 0.3 mm) was laminated and the multilayered sheet was dried, degreased, and sintered to prepare a metal porous sheet E (thickness 0.45 mm). From the obtained metal porous sheet E, a sample having a width of 20 mm × 50 mm was cut out, and the metal porous sheet E thus cut out and a SUS316L foil body (thickness cut into a shape of 20 mm wide × 50 mm in length). 5 mm) were joined in the same manner as the above-mentioned joining test piece A, and five joining test pieces C were produced.
About the obtained joining test piece A, B, and C, it carried out similarly to Test Example 1, and implemented tensile test evaluation, respectively. The average tensile strength at which the fracture of the joining test piece started was 6.5 MPa for the joining test piece A, 13.6 MPa for the joining test piece B, and 20.8 MPa for the joining test piece C.

(Test Example 3)
Five test pieces were prepared by cutting a SUS316L porous thin plate (average pore diameter 150 μm, porosity 87%, thickness 0.31 mm) into a width of 20 mm and a length of 90 mm, and evaluated in the same manner as in Test Example 1. went. The average tensile strength at which the SUS316L porous thin plate started to break was 7.5 MPa.

(Test Example 4)
Five test pieces obtained by cutting a pure Ti porous thin plate (average pore diameter 50 μm, porosity 79%, thickness 0.30 mm) into a width of 20 mm and a length of 90 mm were prepared and evaluated in the same manner as in Test Example 1. Went. The average tensile strength at which rupture of the pure Ti porous thin plate started was 12.6 MPa.

<Results of evaluation of bonding strength>
(Test Examples 1 to 4)
In any of the tensile tests of Test Examples 1 to 4, the fracture of the test piece proceeded after the yielding starting from a crack generated at one location of the test piece.
Moreover, as shown in FIG.7 (b), in the joining test piece of Test Examples 1-2, all the fracture | rupture parts 64 were located in the metal porous thin plate 61 side from the junction part 63. FIG. In addition, peeling with the foil body 62 and the metal porous thin plate 61 did not arise.
As for the tensile strength at which the test piece started to break, the average tensile strength between the bonded test piece of Test Examples 1 and 2 and the metal porous thin plate of Test Examples 3 to 4 was only about 5% maximum. It was confirmed that they had almost the same level of strength.
From the above results, it was confirmed that the metal porous thin plate 61 used in the present invention can be easily joined along the surface shape of the foil body 62. Furthermore, it was confirmed that the joint strength between the foil body 62 and the metal porous thin plate 61 is at least higher than that of the metal porous thin plate 61 and has sufficient strength for diffusion bonding.

Example 1
Moreover, in Example 1, the fracture | rupture part 64 was located in the metal porous thin plate (metal porous body) side instead of the junction part 63 in any joining test piece.
Moreover, when the cross section of the fracture | rupture part 64 of the joining test piece B and the joining test piece C was observed, the remarkable peeling in the joining (lamination | stacking) surface of metal porous thin plates was not observed.
From the above results, the metal porous body C and the metal porous body sheet E in which the metal porous thin plate having a lower porosity are multilayered are compared with the metal porous thin sheet A having a high porosity. It was confirmed that the material strength was high.
In addition, the bonding strength between the two metal porous thin plates and the bonding strength between the metal porous thin plate and the metal foil body are both the strength of the metal porous thin plate alone or the metal porous body itself. It was confirmed that it was higher than the strength.
From the above results, it was confirmed that the metal porous thin plates can be easily and firmly joined together, and the high porosity metal porous thin plate and the lower porosity metal porous thin plate are multilayered. As a result, it was confirmed that the substantial strength (bonding strength with the metal foil) was improved.

[Evaluation of biological tissue connectivity]
The binding property of living tissue was evaluated for the multilayer joined body (Examples 2 to 3) obtained by joining the metal porous bodies in which the metal porous thin plates were multilayered according to the present invention.
In addition, as a test example, the same evaluation of the binding property of biological tissue was performed on the metal porous thin plates (Test Examples 5 to 9) used in the present invention. In the test examples, the evaluation in the medical device in which the metal porous thin plate is bonded to the surface of the medical device main body and the evaluation in the metal porous thin plate alone have the same tendency. A simple evaluation was performed on a single porous thin plate.
In addition, as a medium for cell culture, Dulbecco's modified Eagle's minimum essential medium (D-MEM
) To which 10% by volume fetal bovine serum (FBS) was added.

(Test Example 5)
A pure titanium porous thin plate (average pore diameter: 150 μm, porosity: 89%, thickness: 0.5 mm, 11 mm square) having a three-dimensional communication pore structure is left standing in a 12-well tissue culture microplate, and the cells About 100,000 human osteosarcoma-derived cells Saos-2 were seeded in 2 mL of culture medium (D-MEM + 10% by volume FBS).
Next, after culturing for 1,4,7 days in an incubator at a temperature of 37 ° C, 95% air + 5% carbon dioxide, fix with 4% formalin buffer and stain with fluorescent dye (Texas Red). The cells were observed with a confocal microscope. The evaluation results are shown in FIG.
In the confocal microscope image, the bright part is the cell, and the brighter the cell, the more the cell is proliferating.

(Example 2)
Pure titanium porous thin plate 91 (average aperture diameter 600 μm, porosity 75.3%, thickness 0.32 mm) having a three-dimensional communication hole structure and another pure titanium porous thin plate 91 (average aperture diameter) having different pore diameters 50 μm, porosity 79.8%, thickness 0.30 mm), and a pure titanium foil body (thickness 0.03 mm) are stacked and pressed and pressurized at 2.0 MPa in a vacuum. Diffusion bonding was performed by heating to 950 ° C. The resulting multi-layer joined body obtained by joining pure titanium porous bodies is cut into 11 mm squares, washed with acetone and sterilized, and is shown in FIG. 9 in a 12-well tissue culture microplate (without cell adhesion treatment). Thus, about 100,000 human osteosarcoma-derived cells Saos-2 were seeded in 2 mL of cell culture medium (D-MEM + 10 vol% FBS).
Next, after culturing for 1, 4 and 7 days in an incubator under an environment of temperature 37 ° C., air 95% + carbon dioxide 5%, the number of viable cells was measured by the WST-1 method (color detection method). The evaluation results are shown in FIG.

(Test Example 6)
SUS316L porous thin plate 91 (average pore diameter 50, 150, 300, 600 μm; porosity 85.3, 84.9, 84.7, 85.3%; thickness) having four different three-dimensional communication hole structures 0.31, 0.63, 0.43, 0.46 mm; 11 mm square) in a 12-well tissue culture microplate (without cell adhesion treatment) using a silicon tube 92 as shown in FIG. Each of them was placed vertically, and about 100,000 pieces of Saos-2 were seeded in 2 mL of cell culture medium (D-MEM + 10% by volume FBS).
Next, after culturing for 1, 4 and 7 days in an incubator at a temperature of 37 ° C., 95% air + 5% carbon dioxide, the number of viable cells was measured by the WST-1 method. The evaluation results are shown in FIG.

(Test Example 7)
Using a 12-well tissue culture microplate, seed 100,000 cells of Saos-2 in 2 mL of cell culture medium (D-MEM + 10% FBS), temperature 37 ° C, air 95% + carbon dioxide 5% Was pre-cultured for 1 day in an incubator under the above environment.
Then, a pure titanium porous thin plate (average pore diameter 150 μm, porosity 89%, thickness 0.5 mm, 11 mm square) having a three-dimensional communicating hole structure was allowed to stand from above the cells, and the temperature was 37 ° C. and the atmosphere. After further culturing for 5, 10, and 15 days in an incubator with 95% + carbon dioxide 5%, fix with 4% formalin buffer, stain with fluorescent dye (Texas Red), and use confocal microscope Was observed, and the distance from the surface of the porous thin plate of the most invading cells was measured. The evaluation results are shown in FIG.

(Test Example 8)
Using a 12-well tissue culture microplate, seed 100,000 cells of Saos-2 in 2 mL of cell culture medium (D-MEM + 10% FBS), temperature 37 ° C, air 95% + carbon dioxide 5% Was pre-cultured for 1 day in an incubator under the above environment.
Thereto, three types of porous thin plates made of pure titanium having a three-dimensional communication hole structure (average pore diameter 50 μm, 11 mm square; porosity 87.5%, 84.0%, 78.7%) 71.9%; the thickness is 0.34mm, 0.29mm, 0.22mm, 0.20mm) in order from the highest porosity, and left at the top of the cell, temperature 37 ° C, air 95% + carbonic acid Incubate for 10 days in an incubator under 5% gas environment, fix with 4% formalin buffer, stain with fluorescent dye (Texas Red), observe the cells with a confocal microscope, The distance of the cells that had invaded from the surface of the porous thin plate was measured. The evaluation results are shown in FIG.

(Example 3)
Using a 12-well tissue culture microplate, about 100,000 human osteosarcoma-derived cells Saos-2 are seeded in 2 mL of cell culture medium (D-MEM + 10% by volume FBS) at a temperature of 37 ° C. and 95% of the atmosphere. + Pre-cultured in an incubator under an environment of 5% carbon dioxide for 1 day.
Thereto, a multilayer joined body obtained by joining pure titanium porous bodies prepared in the same manner as in Example 2, and a pure titanium porous thin plate prepared by the same method (average pore diameter 50 μm, porosity 79.8%, thickness 0.3 mm) was prepared by subjecting a pure titanium foil (thickness: 0.03 mm) to pressure bonding / diffusion bonding (hereinafter referred to as a single layer bonded body), cut into 11 mm squares, and then washed with acetone.・ Leave the sterilized cell from the top of the cell with the foil-joined side up, and culture it in an incubator at 37 ° C, 95% air + 5% carbon dioxide for an additional 5 or 10 days. did. After the completion of the culture, fixation with 4% by volume formalin buffer, staining with a fluorescent dye (Texas Red), observing the cells with a confocal microscope, and the multilayer zygote and single-layer zygote of the most invaded cells The distance from the body surface was measured. The evaluation results are shown in FIG.

(Test Example 9)
A pure titanium porous thin plate (average pore diameter 150 μm, porosity 89%, thickness 0.5 mm, 11 mm square) having a three-dimensional communicating hole structure is made of silicone rubber placed on the bottom of a 12-well tissue culture microplate It left still on an O-ring, and about 100,000 human osteosarcoma-derived cells Saos-2 were seeded in 2 mL of a cell culture medium (D-MEM + 10 vol% FBS).
Next, after pre-culturing for 1 day in an incubator at a temperature of 37 ° C. and 95% air + 5% carbon dioxide, cell culture medium was mixed with 0.5 mM β-glycophosphate and 50 μg / mL L-ascorbic. It exchanged for the thing containing acid.
Thereafter, after further culturing for 7, 14, 21, 28 days, the cell culture medium was changed to one containing 1 μg / mL calcein, and calcium was labeled by culturing for 4 hours, and then with 4% by volume formalin buffer. The calcification state was observed with a fixed and confocal microscope. The evaluation results are shown in FIG.

<Results of evaluation of biological tissue connectivity>
(Test Examples 5 to 8)
From FIG. 8, it was confirmed that in the pure titanium porous thin plate, the cells adhered and extended on the surface of the porous thin plate and the internal bridge portion, and that the cells grew smoothly as the number of culture days increased. It was.
From FIG. 11, it was confirmed that the number of viable cells increased as the number of days of culture increased in the porous thin plate made of SUS316L having any pore size. Moreover, in the porous thin plate made of SUS316L having an aperture diameter of 300 μm or less, it was confirmed that the larger the aperture diameter, the larger the number of viable cells.
On the other hand, for the porous thin plate made of SUS316L having an opening diameter of 600 μm, the number of viable cells after one day of culture was the same as that of 300 μm, but the subsequent cell growth rate tends to be lower than that of 300 μm. confirmed.
From FIG. 12, it was confirmed that the cells entered the porous thin plate and grew as the number of culture days increased.
From FIG. 13, it was confirmed that the higher the porosity, the greater the cell penetration distance, and the tendency of promoting cell entry.
As described above, from the results of Test Examples 5 to 8, the metal porous thin plate used in the present invention used for the evaluation has excellent connectivity with living tissue, and the higher the pore diameter or the porosity, the more the cells enter. It was confirmed to promote.

(Test Example 9)
FIG. 15 shows that calcification, which is the first stage of bone formation, has occurred in the pure titanium porous thin plate and the internal bridge portion, and that culturing for 14, 21, 28 days is more lime than 7 days. It was confirmed that the conversion was progressing.
In addition, as a result of high-magnification observation with a confocal microscope for a sample after 28 days of culture in which cells were labeled with a fluorescent dye (Texas Red), the cells adhered to the surface of the pure titanium porous thin plate and the internal bridge portion It was confirmed that calcification occurred in the vicinity.
From the above results, it was confirmed that the invasion / proliferation of cells into the metal porous thin plate used in the present invention is important for calcification and subsequent bone formation.

(Examples 2-3)
From FIG. 10, it was confirmed that the cells grew smoothly with the increase in the number of culture days in the multilayer joined body.
From FIG. 14, it was confirmed that the cell invasion distance increased with an increase in the number of culture days for any sample. In particular, it was confirmed that the cell penetration distance was larger in the multilayer joined body than in the single-layer joined body (sample in which one surface was joined to the foil), and the cells easily entered.

  As described above, from the results of Examples 2 to 3, in the multilayer joined body of the example according to the present invention, the porous thin plate having different pore diameters and void ratios is multilayered, so that the cell structure is more than that of the single layer. It was confirmed that it has the effect of promoting invasion.

An example embodiment of a metal porous thin plate is shown. FIG. 1A is an enlarged plan view thereof, and FIG. 1B is a conceptual diagram showing a side surface of a metal porous thin plate. It is sectional drawing which shows one embodiment of the metal porous body formed in the multilayer. It is a schematic diagram which shows an example of the method of manufacturing a metal porous thin plate. It is a schematic diagram which shows an example of the method of forming the metal porous body which consists of a two-layer metal porous thin plate. It is a schematic diagram which shows the type | mold for joining a metal porous body and a medical device main body. FIG. 6A is a schematic diagram showing an embodiment of a medical device, FIG. 6A is an artificial hip joint, FIG. 6B is an artificial tooth root, FIG. 6C is an artificial elbow joint, and FIG. 6D is an artificial knee. The joint, FIG. 6 (e) is an artificial shoulder joint. FIG. 7A is a plan view of a joining test piece, and FIG. 7B is a plan view showing a state in which the joining test piece after a tensile test is broken. It is. It is the image which culture | cultivated Saos-2 in the porous thin plate made from a pure titanium, and carried out fluorescence dyeing | staining and observed with the confocal microscope (Test Example 5). It is the schematic diagram which showed the method of fixing a metal thin plate vertically using a silicon tube. It is a graph showing the result of having culture | cultivated Saos-2 in the state which left | seated the pure titanium multilayer joined body perpendicularly | vertically, and measured the number of living cells by WST-1 method (Example 2). It is a graph showing the result of having culture | cultivated Saos-2 in the state which left the porous thin plate made from SUS316L from which an average pore diameter differs, respectively, and measuring the number of living cells by WST-1 method (Test Example 6). This shows the result of measuring the cell invasion distance with a confocal microscope after fluorescent staining and concentrating a pure titanium porous thin plate on a cell that is uniformly adhered to and growing on the bottom of the cell culture microplate. It is a graph (Test Example 7). A pure titanium porous thin plate with different porosity is brought into contact with the cells that have been uniformly cultured and proliferated on the bottom of the cell culture microplate, cultured, then fluorescently stained, and the cell penetration distance measured with a confocal microscope It is a graph showing the result obtained (Test Example 8). After contacting and culturing pure titanium multi-layered and single-layered assemblies on the bottom of a cell culture microplate and cultivating them uniformly, the cells are fluorescently stained and the cell penetration distance is measured with a confocal microscope. It is a graph showing the result (Example 3). It is the image which culture | cultivated Saos-2 in the porous thin plate made from a pure titanium, and observed the calcification state with the confocal microscope (Test Example 9).

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Green sheet manufacturing apparatus 11 Hopper 11a Hopper 12 Carrier sheet 13 Roller 14 Doctor blade 14a Doctor blade 15 Foaming tank 16 Heating furnace 21 Metal porous thin plate 21a Metal porous thin plate 21b Metal porous thin plate 21c Metal porous thin plate 22 Skeleton 23 Surface 24 Back 25a Pore 31 Medical Device Body 32 Metal Porous Body 41 Type 51 Artificial Hip Joint 52 Femoral Stem 53 Femur 54 Pelvis 55 Artificial Root 56 Core Material 57 Alveolar Bone 58 Connective Tissue 59 Epithelium 61 Metal Porous Thin plate 62 Foil body 63 Joint part 64 Break part 71 Humeral stem 72 Ulna stem 73 Tibial stem 74 Artificial femoral head 75 Joint sliding part 76 Base plate 77 Femur 78 Humeral stem 79 Artificial humeral head 80 Artificial joint volume 91 Metal Thin 92 silicon tube

Claims (12)

  A medical device in which a metallic porous body is bonded to at least a part of a surface of a medical device main body, wherein the metallic porous body is multilayered.   The metal porous body is formed by multilayering a metal porous thin plate produced by forming a slurry containing metal powder into a sheet, and degreasing and sintering the dried formed body. Item 1. A medical device according to Item 1.   The metal porous thin plate is a metal porous produced by forming a slurry containing metal powder and a foaming agent into a sheet, passing through a foaming process, and then degreasing and sintering the dried molded body. The medical device according to claim 2, comprising a thin plate.   The medical device according to claim 2 or 3, wherein the porosity of the metal porous thin plate is 40 to 97%.   The medical device according to claim 4, wherein the porosity of the metallic porous thin plate joined to the medical device main body is lower than the porosity of the metallic porous thin plate contacting the living tissue.   The medical metal according to any one of claims 2 to 5, wherein the metal of the metal powder includes at least one selected from pure titanium, titanium alloy, stainless steel, cobalt chromium alloy, tantalum, niobium, and alloys thereof. device.   The medical device according to claim 6, wherein the metal of the metal powder is the same type of metal as the medical device body.   The medical device according to any one of claims 2 to 7, wherein a skeleton surface made of a sintered metal powder of the metal porous thin plate is coated with an inorganic compound having biocompatibility.   A metal porous thin plate is manufactured by forming a slurry containing metal powder into a sheet, degreasing and sintering the dried molded body, and then forming the metal porous thin plate into a multilayer A method for modifying the surface of a medical device, comprising: producing a porous body, and deforming and joining the metallic porous body so as to conform to a surface shape of at least a part of the medical device body.   The metal porous thin plate is a metal porous produced by forming a slurry containing metal powder and a foaming agent into a sheet, passing through a foaming process, and then degreasing and sintering the dried molded body. The medical device surface modification method according to claim 9, comprising a thin plate.   The surface modification method for a medical device according to claim 9 or 10, wherein the slurry is formed into a sheet by a doctor blade method. The surface modification method for a medical device according to any one of claims 9 to 11, wherein the bonding is diffusion bonding.

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