JP7560406B2 - Medical Materials - Google Patents

Description

This disclosure relates to medical devices and their manufacturing methods, as well as cell culture carriers.

Conventionally, ceramic structures with pores have been used as biological tissue fillers or cell culture carriers for cell culture or to fill bone defects caused by bone tumor removal or trauma. Although porous bodies have multidirectional pores, it is difficult to control the size and distribution in manufacturing. As a result, cells often do not invade smoothly, and cell growth is not promoted. Honeycomb structures, in which all the through holes are oriented in the same direction, make it difficult for cells to invade from other directions, and are prone to unevenness depending on the location.

For example, Patent Document 1 describes a ceramic structure that is a combination of a honeycomb structure in which the through holes are oriented in one direction, and a random structure that is an aggregate of micromolded objects having at least one through hole, in which the through holes are oriented randomly in three dimensions.

However, when manufacturing the honeycomb structure described in Patent Document 1, even if the honeycomb-shaped extrusion molded body is fired, it is not possible to sufficiently densify it. This results in poor mechanical strength. Furthermore, if there are many large recesses on the inner wall surface that forms the through holes of the honeycomb structure, the cells cultured on the inner wall surface cannot be easily peeled off.

JP 2010-173906 A

The objective of this disclosure is to provide a medical component that has excellent mechanical strength and allows cultured cells to be easily detached.

The medical device according to the present disclosure includes a honeycomb structure made of dense ceramics having a plurality of through holes in the axial direction. The number of recesses having a depth of 10 μm to 20 μm, starting from the ridge between the inner peripheral surface forming the through holes and the observation surface obtained by polishing from the outer peripheral surface of the honeycomb structure toward the axis of the through holes, is 2 or less per 1 mm of the length of the ridge.

The method for manufacturing a medical device according to the present disclosure includes the steps of: placing a powder, wax, a dispersant, and a plasticizer, the main components of which are at least one of aluminum oxide and zirconium oxide, the cumulative 95% by volume of which has a particle size of 6.5 μm or less in a cumulative distribution curve, in a container, and stirring the powder to obtain a slurry; preheating the slurry; degassing the preheated slurry; injecting the slurry into a mold surrounded on the outer periphery by a heating means to obtain a molded body; and firing the molded body.

The cell culture carrier according to the present disclosure includes the above-mentioned medical device.

The medical component according to the present disclosure includes a honeycomb structure of dense ceramics having a plurality of through holes in the axial direction, as described above, and the number of specific recesses is 2 or less per 1 mm of ridge length. Therefore, the medical component according to the present disclosure has excellent mechanical strength and allows cultured cells to be easily peeled off. Furthermore, according to the manufacturing method for a medical component according to the present disclosure, it is possible to provide a medical component that has excellent mechanical strength and allows cultured cells to be easily peeled off.

FIG. 1 is a schematic diagram showing a medical device according to an embodiment of the present disclosure. FIG. 2 is a plan view of the medical device shown in FIG. 1 . FIG. 2A is a partially cutaway perspective view showing a through-hole formed in a medical component according to an embodiment of the present disclosure, and FIG. 2B is an enlarged explanatory view of an area X shown in FIG.

As described above, the medical device according to the present disclosure includes a honeycomb structure made of dense ceramics having a plurality of through holes in the axial direction. The medical device according to the present disclosure will be described with reference to FIG. 1.

As shown in Fig. 1, a medical device according to an embodiment of the present disclosure includes a honeycomb structure 1a. The honeycomb structure 1a is formed of dense ceramics, and is not limited as long as it is dense ceramics. Examples of raw materials for such dense ceramics include aluminum oxide ( _Al2O3 ) and zirconium oxide ( _ZrO2 ). These _raw materials may be used alone or in combination of two or more.

When the dense ceramics is formed from a raw material mainly composed of aluminum oxide, for example, at least one element selected from the group consisting of iron, silicon, calcium, and magnesium may be further contained. The content of these elements is not limited. In this case, the content of iron is preferably 50 mass _ppm or less in terms of _Fe2O3 , the content of silicon is preferably 300 mass ppm or less in terms of _SiO2 , and the content of calcium and magnesium is preferably 350 mass ppm or less in terms of CaO and MgO in total. When the dense ceramics is formed from a raw material mainly composed of _zirconium oxide, for example, at least one of yttrium oxide ( _Y2O3 ), cerium oxide ( _CeO2 ), dysprosium oxide ( _Dy2O3 ), magnesium oxide (MgO), and calcium oxide (CaO) may be contained as a stabilizer. The content of the stabilizer _contained in the dense ceramics is, for example, 2 mol% or more and 5 mol% or less.

In this disclosure, the term "main component" refers to a component that accounts for 60% by mass or more of the total 100% by mass of the components that make up the dense ceramic. Each component can be identified and confirmed using an X-ray diffraction device that uses CuKα radiation. The content of each component can be determined, for example, using an ICP (Inductively Coupled Plasma) emission spectrometer or an X-ray fluorescence analyzer.

In the present disclosure, dense ceramics refers to ceramics having a relative density of 96% or more. The relative density is a value obtained by calculating the apparent density of a dense ceramic in accordance with JIS R 1634-1998, dividing the apparent density by the theoretical density of the dense ceramic, and multiplying the result by 100, and is calculated by the following formula (I):
Relative density (%) = {(apparent density of dense ceramics) / (theoretical density of dense ceramics)} × 100 (I)

When determining the theoretical density of a dense ceramic, if the components of the dense ceramic identified by an X-ray diffraction apparatus using CuKα radiation are, for example, α-Al ₂ O ₃ , SiO ₂ , CaO and MgO, the contents of each of the above metal elements determined by an ICP optical emission spectrometer or the like are used to convert them into α-Al ₂ O ₃ , SiO ₂ , CaO and MgO, respectively.

If the contents of α-Al ₂ O ₃ , SiO ₂ , CaO and MgO are a %, b %, c %, and d %, respectively, the theoretical density values of these oxides (α
Using the above values (α-Al ₂ O ₃ =3.987 g/cm ³ , SiO ₂ =2.648 g/cm ³ , CaO=3.340 g/cm ³ , MgO=3.585 g/cm ³ ), the theoretical density (T.D.) of the dense ceramics can be calculated using the following formula (II).
T. D=1/(0.01×(a/3.987+b/2.648+c/3.340+d/3.585)) (II)

The medical device 1 according to one embodiment has excellent mechanical strength by including a honeycomb structure 1a made of dense ceramics. The shape of the honeycomb structure 1a is not limited as long as it has a shape that allows multiple through holes 2 to be present in the axial direction, as described below. The honeycomb structure 1a may have a cylindrical shape as shown in FIG. 1, or may have other shapes such as a rectangular column shape.

As shown in FIG. 2, the honeycomb structure 1a has a plurality of through holes 2 in the axial direction. FIG. 2 is a plan view of the medical member shown in FIG. 1. The diameter of the through holes 2 is not limited, and is, for example, 50 μm or more and 500 μm or less. When the cross section of the through hole 2 perpendicular to the axial direction is elliptical, the diameter of the through hole 2 is the average value of the major axis and the minor axis. When the cross section of the through hole 2 perpendicular to the axial direction is angular, such as hexagonal, the diameter of the through hole 2 is the equivalent circle diameter.

Figure 3(A) is a partially cutaway perspective view showing a through hole 2 formed in a medical component according to one embodiment, and Figure 3(B) is an enlarged explanatory view of region X shown in Figure 3(A). Figures 3(A) and (B) show the state in which the honeycomb structure 1a formed in the medical component 1 according to one embodiment has been polished from the outer peripheral surface toward the axis C of the through hole 2.

In the medical device 1 according to one embodiment, when the obtained polished surface is the observation surface 2b, the number of recesses 2d having a depth d of 10 μm or more and 20 μm or less, starting from the ridge line 2c between the inner circumferential surface 2a of the through hole 2 and the observation surface 2b, is 2 or less per 1 mm of the length of the ridge line 2c. Thus, with 2 or less recesses 2d, there are few recesses 2d into which cells can enter. Therefore, the cultured cells can be easily peeled off. It is preferable that the number of recesses 2d is 1 or less.

The recess 2d has, for example, a sunken shape. The reason for polishing from the outer peripheral surface of the honeycomb structure 1a toward the axis C is to make it easier to measure the depth d of the recess 2d. The direction of the depth d is the direction within the observation surface 2b, starting from the ridge 2c toward the outer edge 2e, which is the boundary between the outer peripheral surface of the honeycomb structure 1a and the observation surface 2b.

The straightness of the ridgeline 2c on the observation surface 2b may be, for example, 20 μm or less. Straightness refers to the degree of deviation of the ridgeline 2c from a geometrically correct straight line. The straightness of the ridgeline 2c can be measured, for example, using free software called "Pinch Ruler" on an image (e.g., 1.2 mm horizontally and 1.4 mm vertically) of the observation surface 2b photographed with an optical microscope. The axial direction of the through hole 2 is aligned with the vertical direction of the image, and at least one of the left and right ridgelines 2c sandwiching the inner surface 2a is included in the image, and the length of the geometrically correct straight line is set to 1.4 mm.

If the straightness of the ridge 2c is 20 μm or less, there are almost no large depressions 2d on the inner surface 2a. Therefore, the cells cultured on the inner surface 2a of the through-hole 2 can be more easily peeled off.

The inner surface 2a of the through hole 2 may be a fired surface with a root mean square slope (RΔqi) of 1.3 or less. With this configuration, the inner surface 2a has no crushed layer and the root mean square slope (RΔqi) is controlled. As a result, there are almost no particles that fall off. Therefore, the risk of such particles becoming contaminants and interfering with cell culture is reduced. In particular, the inner surface 2a may be a fired surface with a root mean square slope (RΔqi) of 1 or less.

The inner surface 2a of the through hole 2 may be a fired surface with a cut level difference (Rδci) of 1.7 μm or less, which represents the difference between the cut level at a load length ratio of 25% on the roughness curve and the cut level at a load length ratio of 75% on the roughness curve. With this configuration, the inner surface 2a has no crushed layer and the cut level difference (Rδci) is in a controlled state. As a result, there are almost no particles that fall off. Therefore, the risk of such particles becoming contamination and interfering with cell culture is reduced. In particular, the cut level difference (Rδci) of the inner surface 2a may be a fired surface of 1.4 μm or less.

The outer peripheral surface of the honeycomb structure 1a may be a fired surface having a root-mean-square slope (RΔqo) of 0.04 or more. With this configuration, the outer peripheral surface of the honeycomb structure 1a has no crushed layer and has moderate hydrophilicity. As a result, when the outer peripheral surface of the honeycomb structure 1a is also used for cell culture, the adhesion of cells after seeding is improved. In particular, the root-mean-square slope (RΔqo) of the outer peripheral surface of the honeycomb structure 1a may be a fired surface having a root-mean-square slope (RΔqo) of 0.2 or more.

The outer peripheral surface of the honeycomb structure 1a may be a fired surface having a cut level difference (Rδco) of 0.04 μm or more, which represents the difference between the cut level at a load length ratio of 25% on the roughness curve and the cut level at a load length ratio of 75% on the roughness curve. With this configuration, the outer peripheral surface of the honeycomb structure 1a has no crushed layer and has moderate hydrophilicity. As a result, when the outer peripheral surface of the honeycomb structure 1a is also used for cell culture, the fixation of cells after seeding is improved. In particular, the cut level difference (Rδco) of the outer peripheral surface may be 0.25 μm or more on the fired surface.

The root mean square slope (RΔqi, RΔqo) and the cut level difference (Rδci, Rδco) can be measured in accordance with JIS B 0601:2001 using a shape analysis laser microscope (Keyence Corporation, VK-X1100 or its successor). The measurement conditions are as follows: first, the illumination method is a coaxial epi-illumination method; the magnification is 480x, there is no cutoff value λs, the cutoff value λc is 0.08mm, there is no cutoff value λf, there is end effect correction, and the measurement range per point from the inner surface 2a and the outer surface to be measured is set to, for example, 710μm×533μm. For each measurement range, four lines to be measured are drawn at approximately equal intervals along the longitudinal direction of the measurement range, and line roughness measurement is performed. The measurement range is two points in total, one in the center of the axial direction, and the length to be measured is, for example, 560 μm.

Next, a method for producing a medical device according to the present disclosure will be described. The method for producing a medical device according to an embodiment of the present disclosure includes the following steps (a) to (e).
Step (a): A step of placing a powder containing as a main component at least one of aluminum oxide and zirconium oxide, having a cumulative 95 volume % particle size of 6.5 μm or less in a cumulative distribution curve, a wax, a dispersant, and a plasticizer in a container, and stirring to obtain a slurry.
Step (b): Preheating the slurry.
Step (c): A step of subjecting the preheated slurry to a defoaming treatment.
Step (d): A step of injecting the slurry into a mold the outer periphery of which is surrounded by a heating means to obtain a molded body.
Step (e): A step of firing the molded body.

Step (a) is a step of placing the raw materials in a container and stirring them to obtain a slurry. The raw materials are a powder mainly composed of at least one of aluminum oxide and zirconium oxide, wax, a dispersant, and a plasticizer.

The powder containing at least one of aluminum oxide and zirconium oxide as the main component has a cumulative 95% by volume particle size of 6.5 μm or less in the cumulative distribution curve. By using such a powder, for example, a dense ceramic having a relative density of 96% or more can be obtained, and the formation of recesses 2d on the inner surface 2a of the through hole 2 can be reduced. In particular, the recesses 2d can be further reduced by reducing the average particle size of the powder used. The purity of the main component powder is not limited, and for example, a powder having a purity of 99.5% by mass or more may be used.

A cumulative distribution curve is a curve that shows the cumulative distribution of particle sizes in a two-dimensional graph with particle size on the horizontal axis and cumulative percentage of particle size on the vertical axis. The cumulative distribution curve can be determined by the laser diffraction scattering method, for example, using a particle size distribution measuring device manufactured by Microtrac-Bell (MT3300 or its successor model).

For 100 parts by mass of the powder, the wax is used in an amount of 13 parts by mass to 14 parts by mass, the dispersant is used in an amount of 0.4 parts by mass to 0.5 parts by mass, and the plasticizer is used in an amount of 1.4 parts by mass to 1.5 parts by mass. Examples of the wax include paraffin wax and beeswax. Examples of the dispersant include higher fatty acids and higher fatty acid esters. Examples of the plasticizer include higher fatty acids and phthalate esters.

The powder, wax, dispersant, and plasticizer are placed in a container that has been heated to, for example, 90°C or higher and 140°C or lower. At this time, the wax, dispersant, and plasticizer are in liquid form. The container is made of, for example, resin. The container is set in a stirrer and rotated for three minutes (rotational kneading process), stirring the powder, wax, dispersant, and plasticizer to obtain a slurry.

In step (b), the slurry obtained in step (a) is preheated. Preheating increases the fluidity of the slurry, thereby enhancing the effect obtained in step (c). Preheating is performed, for example, at a temperature of 120°C or higher and 180°C or lower.

In step (c), the slurry preheated in step (b) is subjected to a degassing treatment. By carrying out the degassing treatment, the number of bubbles contained in the slurry is reduced, and dense ceramics with a higher relative density can be obtained. The degassing treatment is carried out, for example, by filling the obtained slurry into a syringe and rotating the syringe on its axis and revolution for one minute using a degassing tool.

In step (d), the slurry degassed in step (c) is poured into a mold to obtain a molded body. As the mold, a mold whose outer periphery is surrounded by a heating means is used. By using a mold whose outer periphery is surrounded by a heating means in this way, a honeycomb structure as shown in Figures 1 (B) and (C) is obtained. The heating means is not limited, and examples thereof include a heater. It is preferable that the slurry is heated by the heating means so that the difference in temperature between the slurry and the slurry when it is poured into the mold is within 50°C. The shape of the molded body is not limited, and it may be cylindrical as shown in Figure 1 (A), or may be other shapes such as a rectangular column.

In step (e), the molded body obtained in step (c) is fired. For example, firing may be performed in an air atmosphere at 1400°C to 1700°C for 1 hour to 3 hours. In this manner, a medical component according to one embodiment is obtained, including a honeycomb structure of dense ceramics having a plurality of through holes in the axial direction. In the medical component according to one embodiment thus obtained, the number of recesses having a depth of 10 μm to 20 μm, starting from the ridge between the inner peripheral surface forming the through holes and the observation surface obtained by polishing from the outer peripheral surface of the honeycomb structure toward the axis of the through holes, is 2 or less per 1 mm of the ridge length.

The size of the medical component according to one embodiment is not limited, and in the case of a cylindrical shape, for example, the diameter is 10 mm or more and 15 mm or less, and the height (thickness) is 1 mm or more and 5 mm or less. In the case of a prismatic shape, for example, the widest part of the top surface (bottom surface) is 10 mm or more and 15 mm or less, and the height (thickness) is 1 mm or more and 5 mm or less.

The medical component according to the present disclosure is used, for example, as a cell culture carrier. For example, a cell culture carrier including the medical component according to the present disclosure has excellent mechanical strength and allows cultured cells to be easily peeled off.

This disclosure is not limited to the above-described embodiments, and various modifications, improvements, combinations, etc. are possible without departing from the spirit and scope of this disclosure.

The following describes specific examples, but the present disclosure is not limited to these examples.

Example 1
As the raw material powder, aluminum oxide powder with a purity of 99.7% by mass (particle size at cumulative 95% by volume in the cumulative distribution curve: 6.5 μm) was used. The particle size at cumulative 95% by volume in the cumulative distribution curve was measured using a particle size distribution measuring device (MT3300) manufactured by Microtrack Bell. The raw material powder, wax, dispersant and plasticizer were placed in a resin container and heated to 90° C. and mixed. Next, the container was placed at a predetermined position of the stirrer and rotated for 3 minutes (rotational kneading process) to obtain a slurry. The wax was 13.5 parts by mass, the dispersant was 0.45 parts by mass, and the plasticizer was 1.45 parts by mass relative to 100 parts by mass of the raw material powder.

The obtained slurry was then preheated at 150°C. The preheated slurry was filled into a syringe, and the syringe was rotated and revolved for 1 minute using a defoaming tool to defoam the slurry. The defoamed slurry was then injected into a mold whose outer periphery was surrounded by a heating means. The slurry was injected from the mold while being heated to 100°C by the heating means to obtain a molded body.

The resulting molded body was degreased and sintered to obtain a medical component. Firing was performed in an air atmosphere at 1600°C for 2 hours. When the structure of the surface of the resulting medical component was observed under a microscope, it was found to have a honeycomb structure as shown in Figures 1(B) and (C), with multiple through holes formed. Furthermore, the resulting medical component had a relative density of 96%, and was found to be made of dense ceramics.

Furthermore, the number of recesses 2d shown in FIG. 2(B) was counted for the obtained medical component using the following procedure. First, the outer peripheral surface of the honeycomb structure 1a (medical component 1) was polished toward the axis C of the through hole 2 to obtain an observation surface 2b with an arithmetic mean roughness Ra of 0.01 μm or more and 0.1 μm or less.

Then, the observation surface 2b was photographed with a scanning electron microscope. The depth of the existing recesses was measured for the photographed image (2.3 mm horizontally, 1.7 mm vertically) using the free software "Pinch Ruler." The number of recesses 2d with a depth d of 10 μm to 20 μm was counted, and the number was 2 per 1 mm of the length of the ridge line 2c.

Reference Signs List 1 Medical member 1a Honeycomb structure 2 Through hole 2a Inner peripheral surface 2b Observation target surface 2c Ridge line 2d Recess 2e Outer edge

Claims (8)

The honeycomb structure includes a dense ceramic honeycomb structure having a plurality of through holes in an axial direction,
the number of recesses having a depth of 10 μm or more and 20 μm or less, which start from a ridge line between an inner circumferential surface forming the through hole and an observation surface obtained by polishing from the outer circumferential surface of the honeycomb structure toward the axis of the through hole, is 2 or less per 1 mm of the length of the ridge line;
In the observation surface, the straightness of the ridge is 20 μm or less.
Medical parts. The honeycomb structure includes a dense ceramic honeycomb structure having a plurality of through holes in an axial direction,
the number of recesses having a depth of 10 μm or more and 20 μm or less, which start from a ridge line between an inner circumferential surface forming the through hole and an observation surface obtained by polishing from the outer circumferential surface of the honeycomb structure toward the axis of the through hole, is 2 or less per 1 mm of the length of the ridge line;
The inner circumferential surface is a fired surface having a root mean square slope (RΔqi) of 1.3 or less ;
Medical parts. The honeycomb structure includes a dense ceramic honeycomb structure having a plurality of through holes in an axial direction,
the number of recesses having a depth of 10 μm or more and 20 μm or less, which start from a ridge line between an inner circumferential surface forming the through hole and an observation surface obtained by polishing from the outer circumferential surface of the honeycomb structure toward the axis of the through hole, is 2 or less per 1 mm of the length of the ridge line;
The inner circumferential surface is a fired surface having a cut level difference (Rδci) of 1.7 μm or less, which represents the difference between the cut level at a load length ratio of 25% in a roughness curve and the cut level at a load length ratio of 75% in the roughness curve ;
Medical parts. The medical device according to claim 2 or 3, wherein the straightness of the ridgeline on the observation surface is 20 μm or less. The medical device according to any one of claims 1 to 4, wherein the outer peripheral surface is a fired surface having a root mean square slope (RΔqo) of 0.04 or more. The medical device according to any one of claims 1 to 5, wherein the outer peripheral surface is a fired surface having a cut level difference (Rδco) of 0.04 μm or more, which represents the difference between the cut level at a load length ratio of 25% on the roughness curve and the cut level at a load length ratio of 75% on the roughness curve. A method for producing a medical device according to any one of claims 1 to 6,
A step of placing a powder containing at least one of aluminum oxide and zirconium oxide as a main component, the powder having a cumulative 95% by volume particle size of 6.5 μm or less in a cumulative distribution curve, a wax, a dispersant, and a plasticizer in a container and stirring the powder to obtain a slurry;
preheating the slurry;
A step of degassing the preheated slurry;
A step of injecting the slurry into a mold the outer periphery of which is surrounded by a heating means to obtain a molded body;
and firing the molded body.
A manufacturing method for medical components. A cell culture carrier comprising the medical device according to any one of claims 1 to 6.

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