JP2023023663A - Medical tissue reconstruction material and method of producing same - Google Patents

Abstract

To provide a medical tissue reconstruction material having both antibacterial properties and bone conductivity.SOLUTION: Provided is a medical tissue reconstruction material that is a calcium-based material having silver carbonate and silver phosphate on its surface, with the total content of the silver carbonate and the silver phosphate being 5.0×10-4 to 3.3×10-2 mass% of the total material.SELECTED DRAWING: Figure 10

Description

TECHNICAL FIELD The present invention relates to a medical tissue reconstruction material having both antibacterial properties and osteoconductivity (bone replacement properties).

In Japan, which has become a super-aged society, the number of bone diseases is increasing, and along with this, the number of surgeries using bone regeneration materials is increasing. In surgery using this bone regeneration material, surgical site infections frequently occur. It has a great impact on various aspects such as increase.

Surgery in which surgical site infections frequently occur includes, for example, high tibial osteotomy for medial knee osteoarthritis (infection rate 5.1%) (see Non-Patent Document 1). Since the prevalence of knee osteoarthritis increases with age, the number of infected people is expected to increase further in the future. In addition, tibial plateau fracture surgery (infection rate of 12.3%) and calcaneus fracture surgery (infection rate of about 4%), which frequently occur among young people, also have high infection rates (see Non-Patent Documents 2 and 3).
Therefore, prevention of postoperative infection is an urgent issue.

Under such circumstances, imparting antibacterial properties to bone regeneration materials used in many surgeries is considered effective in preventing surgical site infections. As means for imparting antibacterial properties to bone regeneration materials, for example, the use of silver compounds having an antibacterial effect has been proposed (see Patent Documents 1 and 2).

JP 2019-210251 A International publication WO2017/150539

Miyazaki et al., Orthopedics and disasters, 66, 509-512, 2017 Henkelmann et al. BMC Musculoskeletal Disorders, 18, 481, 2017 Suzuki et al., Fracture, 42, 232-235, 2020

An object of the present invention is to provide a medical tissue reconstruction material having both antibacterial properties and osteoconductivity.

As described above, silver compounds are used to impart antibacterial properties to bone regeneration materials, but the effects on cytotoxicity and osteoconductivity (bone replacement) are not always considered. I couldn't say That is, the present inventors have found that the presence of excessive silver compounds may cause cytotoxicity and bone formation inhibition, and the silver compounds should be kept at the minimum concentration required to effectively exert antibacterial effects. We found that it is important to localize the silver compound on the material surface for this purpose. In addition, they have found that a sustained antibacterial effect can be expected at the minimum required concentration when silver compounds exhibiting antibacterial effects at different timings are localized on the surface, leading to the completion of the present invention.

That is, the present invention is as follows.
[1] A calcium-based material having silver carbonate and silver phosphate on its surface,
A medical tissue reconstruction material having a total content of silver carbonate and silver phosphate of 5.0×10 ⁻⁴ to 3.3×10 ⁻² mass %.
[2] The medical product according to [1] above, wherein the total content of silver carbonate and silver phosphate is 1.5×10 ⁻³ to 1.0×10 ⁻² mass % (less than). tissue reconstruction material.
[3] The medical tissue reconstruction material according to [1] or [2] above, which contains at least one inorganic compound selected from carbonate-containing calcium phosphate, a mixture of calcium phosphate and a carbonate-containing compound, and bone.
[4] The medical tissue reconstruction material according to any one of [1] to [3], which is a porous material.

[5] A method for producing a tissue reconstruction material for medical use according to any one of [1] to [4] above,
A method for producing a medical tissue reconstruction material, comprising exposing a calcium-based material to a solution containing silver ions.
[6] The method for producing a medical tissue reconstruction material according to [5] above, wherein the calcium-based material is immersed in a solution containing silver ions.
[7] The method for producing a medical tissue reconstruction material according to [5] or [6] above, wherein the solution containing silver ions is an aqueous solution of silver nitrate.

[8] Medical tissue reconstruction according to any one of [5] to [7] above, wherein the calcium-based material is immersed in an aqueous solution of silver nitrate in an amount of 0.6 to 41.3 equivalents to the calcium-based material. How the material is made.
[9] Medical tissue reconstruction according to any one of [5] to [8] above, wherein the calcium-based material is immersed in an aqueous silver nitrate solution of 1.9 to 12.5 equivalents to the calcium-based material. How the material is made.
[10] The method for producing a medical tissue reconstruction material according to [8] above, wherein a total of 5.0×10 ⁻⁴ to 3.3×10 ⁻² mass % of silver carbonate and silver phosphate is produced.
[11] The medical tissue reconstruction material according to [9] above, characterized in that a total of 1.5×10 ⁻³ to 1.0×10 ⁻² mass % (less than) of silver carbonate and silver phosphate is produced. Production method.
[12] Any one of the above [5] to [11], wherein the calcium-based material is at least one inorganic compound selected from carbonate-containing calcium phosphate, a mixture of calcium phosphate and a carbonate-containing compound, and bone. method for producing a tissue reconstruction material for medical use.

The medical tissue reconstruction material of the present invention is an excellent medical tissue reconstruction material having both antibacterial properties and osteoconductivity.

FIG. 4 is a diagram showing the concentrations of silver compounds (silver phosphate and silver carbonate) in a carbonate apatite porous body when the carbonate apatite porous body is immersed in an aqueous silver nitrate solution of 5×10 ⁻² to 5×10 ³ equivalents for 60 minutes. Fig. 2 shows scanning electron microscope images and silver mapping images of carbonated apatite porous bodies obtained by immersing the carbonated apatite porous bodies in aqueous solutions of 0.5 and 50 equivalents of silver nitrate for 60 minutes. White arrowheads in the images indicate silver compounds. 1 is a powder X-ray diffraction pattern of a carbonate apatite porous material after being immersed in 5 to 500 equivalents of silver nitrate for 60 minutes. In the figure, black arrowheads indicate diffraction lines of silver phosphate. 1 is a powder X-ray diffraction pattern of a carbonate apatite porous material after being immersed in 500 equivalents of silver nitrate for 7 days. In the figure, the white circle indicates the diffraction line of silver phosphate, the white arrowhead indicates the diffraction line of silver carbonate, and the black arrowhead indicates the diffraction line of carbonate apatite. FIG. 3 is a diagram showing silver concentrations in carbonate apatite discs and hydroxyapatite discs after immersing the discs in a silver nitrate aqueous solution of 5 to 5000 equivalents for 24 hours; FIG. 2 shows the antibacterial effect of carbonated apatite porous bodies against methicillin-resistant Staphylococcus aureus (MRSA) after the carbonated apatite porous bodies were immersed in an aqueous silver nitrate solution of 0.5 to 5000 equivalents for 60 minutes. FIG. 2 is a diagram showing the antibacterial effect of a carbonated apatite porous material against Staphylococcus epidermidis after the carbonated apatite porous material has been immersed in an aqueous silver nitrate solution of 0.5 to 500 equivalents for 60 minutes. FIG. 3 is a diagram showing the cytotoxicity of a carbonate apatite porous material after immersing the carbonate apatite porous material in an aqueous silver nitrate solution of 0.5 to 5000 equivalents for 60 minutes. FIG. 2 shows the antibacterial effect against MRSA of carbonate apatite and hydroxyapatite that have not been immersed in a silver nitrate aqueous solution, and carbonate apatite and hydroxyapatite that have been immersed in a silver nitrate aqueous solution of 5 to 5000 equivalents for 24 hours. A carbonated apatite porous material that had been immersed in 5 equivalents of silver nitrate for 60 minutes and a carbonated apatite porous material that had not been immersed were immersed in the MRSA bacterial solution for 10 minutes. It is a figure which shows viable count. A carbonated apatite porous material that had been immersed in 5 equivalents of silver nitrate for 60 minutes and a carbonated apatite porous material that had not been immersed were immersed in the MRSA bacterial solution for 10 minutes. It is a figure which shows a histopathological finding.

The medical tissue reconstruction material of the present invention is a calcium-based material having silver carbonate and silver phosphate on its surface, and the total content of silver carbonate and silver phosphate is 5.0×10 ⁻⁴ to 3.0×10 −4 . .3×10 ⁻² mass %.

Since the medical tissue reconstruction material of the present invention comprises different kinds of silver compounds such as silver carbonate and silver phosphate, it can maintain its antibacterial properties. That is, when the medical tissue reconstruction material is first applied to body tissue, silver carbonate shows antibacterial action, and then silver phosphate shows antibacterial action, so that antibacterial activity can be maintained over a long period of time. In addition, since the silver compound exists only on the surface of the reconstruction material, sufficient antibacterial properties can be exhibited by applying the minimum amount of silver compound. Furthermore, since the content of the silver compound is within a specific range, it is possible to prevent cytotoxicity and osteogenesis inhibition as well as antibacterial properties and effectively perform tissue reconstruction.

INDUSTRIAL APPLICABILITY The medical tissue reconstruction material of the present invention can be used in the medical field or in fields related to medicine, such as tissue reconstruction procedures for bones and the like, regenerative medicine scaffolds, and the like.

The total content of silver carbonate and silver phosphate (hereinafter sometimes simply referred to as silver compounds when referring to both) in the medical tissue reconstruction material of the present invention is, as described above, 5.0×10 ^-4 to 3.3×10 ^-2 % by mass, but from the viewpoint of antibacterial properties, it is preferably 1.5×10 ^-3 % by mass or more, and is 2.0×10 ^-3 % by mass or more. is more preferably 3.0×10 ⁻³ mass% or more, more preferably 4.0×10 ^{−3 mass% or more, particularly preferably 4.0×10 −3} mass% or more, and 5.0×10 ⁻³ mass% or more Most preferably there is. In addition, considering the effects of cytotoxicity, etc., it is preferably 2.8×10 ⁻² mass% or less, more preferably less than 1.0×10 ⁻² mass%, and 9.0×10 ⁻ It is more preferably ³ % by mass or less.

The medical tissue reconstruction material (calcium-based material) of the present invention contains an inorganic compound as a main component. Such an inorganic compound is not particularly limited as long as it produces both silver carbonate and silver phosphate when exposed to a solution containing silver ions, that is, as long as it contains a phosphoric acid component and a carbonic acid component. Specific examples thereof include carbonate-containing calcium phosphate, a mixture of calcium phosphate and a carbonate-containing compound, and bones, with carbonate-containing calcium phosphate being preferred. As the carbonate-containing calcium phosphate, carbonate apatite is particularly preferred because it is an inorganic component of human bones, has high osteoconductivity, and eventually replaces bones. For example, hydroxyapatite, which does not form silver carbonate, has insufficient antibacterial effect and is not included in the scope of the present invention.

The content of inorganic compounds in the medical tissue reconstruction material (calcium-based material excluding silver compounds) of the present invention is preferably 70% by mass or more, more preferably 80% by mass or more, and more preferably 90% by mass or more. is more preferable, 95% by mass or more is particularly preferable, and substantially 100% by mass is most preferable. Materials other than the above inorganic compounds include, for example, collagen, chitosan, polymers such as lactic acid, glycolic acid, polylactic acid, caprolactone, glycerol sebacic acid, hydroxybutyric acid, dioxanone, and copolymers thereof.

The shape and size of the medical tissue reconstruction material of the present invention are not particularly limited, but a porous material is preferable to a dense material in terms of imparting a silver compound to the surface of the material and tissue reconstruction. Examples of the porous body include a honeycomb structure having through holes extending in one direction, and a porous body having a large number of pores at random, such as a foam, which enables tissue reconstruction to be performed more effectively. Therefore, the former honeycomb structure is preferable.

As described above, the medical tissue reconstruction material of the present invention contains an inorganic compound as a main component and has silver carbonate and silver phosphate on its surface. It can also be regarded as a structure having a shell portion containing silver carbonate and silver phosphate on the surface.

The medical tissue reconstruction material of the present invention can be produced by exposing a calcium-based material to a solution containing silver ions. The calcium-based material is a material containing an inorganic compound as a main component, as described in the medical tissue reconstruction material of the present invention.

When the calcium-based material is exposed to a solution containing silver ions, the anions and silver ions in the calcium-based material react with each other to produce silver carbonate and silver phosphate on the surface of the calcium-based material. Examples of the method of exposing the calcium-based material to the solution containing silver ions include a method of immersing the calcium-based material in the solution and a method of applying the solution to the calcium-based material by spraying or the like. The former immersion method is preferable because the silver compound can be applied efficiently. As the solution containing silver ions, an aqueous solution of silver nitrate is preferable.

The concentration of silver nitrate in the silver nitrate aqueous solution is preferably 0.6 to 41.3 equivalents with respect to the raw material calcium-based material. The lower limit is preferably 1.9 equivalents or more, more preferably 2.5 equivalents or more, even more preferably 3.8 equivalents or more, and 5.0 equivalents relative to the calcium-based material. It is particularly preferably 6.3 equivalents or more, and most preferably 6.3 equivalents or more. As for the upper limit, it is preferably 35 equivalents or less, more preferably less than 12.5 equivalents, and even more preferably 11.3 equivalents or less with respect to the calcium-based material.

Specifically, in the immersion method, the calcium-based material is immersed in an aqueous silver nitrate solution of 0.6 to 41.3 equivalents to the calcium-based material, and the total amount of silver carbonate and silver phosphate is 5.0×10 ⁻ It is preferable to generate ⁴ to 3.3×10 ⁻² mass %. Further, the calcium-based material is immersed in an aqueous silver nitrate solution of 1.9 to 12.5 equivalents to the calcium-based material, and the total amount of silver carbonate and silver phosphate is 1.5×10 ⁻³ to 1.0×10. It is more preferable to generate ^-2 % by mass (less than).

The temperature of the solution is not particularly limited as long as it does not freeze or boil the aqueous solution containing silver ions, and is preferably 10 to 80°C, more preferably 10 to 30°C. The immersion time is not particularly limited as long as the desired amount of silver carbonate and silver phosphate is formed, and is preferably 10 minutes to 7 days, more preferably 60 minutes to 24 hours.

EXAMPLES The present invention will be specifically described below with reference to examples, but the technical scope of the present invention is not limited to the examples.

[Test Example 1]
As the carbonated apatite porous body, a cylindrical honeycomb structure having a diameter of about 10 mm and a height of about 10 mm and having a large number of square prism-shaped through holes extending in one direction was used. The length of one side of the through-hole was about 300 μm. The same applies to the carbonated apatite porous bodies in the examples after Test Example 1.

The carbonated apatite porous material was immersed in an aqueous silver nitrate solution of 5×10 ⁻² to 5×10 ³ equivalents at 20° C. for 60 minutes. The silver concentration in the sample after immersion was measured by high frequency inductively coupled plasma emission spectroscopy. The measurement results are shown in FIG.

As shown in FIG. 1, it was found that the silver content in the samples increased as the silver nitrate concentration increased. As shown in Test Examples 3 and 4 below, these silvers are derived from silver phosphate and silver carbonate. Silver nitrate concentration relative to carbonate apatite is 5×10 ⁻² , 5×10 ⁻¹ , 1.5, 2.5, 3.5, 5, 15, 25, 35, 5×10 ¹ , 5×10 ² , At 5×10 ³ equivalents, about 5.5×10 ⁻⁴ , 9.9×10 ⁻⁴ , 1.2×10 −3 , 2.0×10 ⁻³ , 2.0×10 ⁻³ , respectively, relative to the total mass. 8×10 ⁻³ , 6.1×10 ⁻³ , 1.2×10 ⁻² , 2.0×10 ⁻² , 2.8×10 ⁻² , 3.8×10 ⁻² , 3.6× 10 ⁻¹ , 4.1 mass % of silver phosphate and silver carbonate were produced. In other words, it can be seen that the concentrations of silver phosphate and silver carbonate can be controlled by the concentration of silver nitrate.

Further, as shown in Test Example 5 described later, when hydroxyapatite containing no carbonate ions is immersed in an aqueous solution of silver nitrate under the same conditions as carbonated apatite, hydroxyapatite produces less silver compounds than carbonated apatite. This is because silver carbonate does not form when hydroxyapatite is used.

[Test Example 2]
The carbonated apatite porous material was immersed in aqueous silver nitrate solutions of 0.5 and 50 equivalents at 20° C. for 60 minutes. The microstructure of the sample surface after immersion was observed with a scanning electron microscope, and silver on the sample surface was mapped with an energy dispersive X-ray spectrometer. For comparison, the same analysis was performed on the carbonate apatite porous material before being immersed in the silver nitrate aqueous solution. The analysis results are shown in FIG.

As shown in FIG. 2, silver compounds (white arrowheads) that were not observed before immersion in the aqueous solution of silver nitrate were observed after immersion. It can be seen that the silver compound amount increases as the silver nitrate concentration increases.

[Test Example 3]
The carbonated apatite porous material was immersed in 5 to 500 equivalents of silver nitrate at 20° C. for 60 minutes, and the crystal phase after immersion was evaluated by powder X-ray diffraction method. FIG. 3 shows powder X-ray diffraction patterns of the sample before and after immersion and of silver phosphate (Ag ₃ PO ₄ ).

As shown in FIG. 3, when immersed in 500 equivalents of silver nitrate, the X-ray diffraction line of silver phosphate was confirmed in the sample, but when the silver nitrate was 50 equivalents or less, the diffraction line of silver phosphate was confirmed. I didn't. Considering that the detection limit of this analysis method is 0.1 to 1% by mass, and that the silver concentration is less than 0.1% by mass with respect to the total mass at 50 equivalents or less from Test Example 1, phosphoric acid It is reasonable that no silver diffraction lines were identified. In the X-ray diffraction method, no diffraction line of silver phosphate was confirmed at 50 equivalents or less, but it is clear from Test Example 1 (Fig. 1) and Test Example 2 (Fig. 2) that a silver compound was produced.

[Test Example 4]
The carbonated apatite porous body was immersed in 500 equivalents of silver nitrate at 20° C. for 7 days, and the crystal phase after immersion was evaluated by powder X-ray diffraction method. FIG. 4 shows the powder X-ray diffraction patterns of the sample, silver phosphate (Ag ₃ PO ₄ ) and silver carbonate (Ag ₂ CO ₃ ) before and after immersion.

As shown in FIG. 4, diffraction lines of silver carbonate and silver phosphate were confirmed in the sample after immersion, and it became clear that these crystal phases were formed.

[Test Example 5]
A carbonate apatite disc (φ8 mm×1.5 mm), which is a carbonate-containing calcium phosphate, and a hydroxyapatite disc (φ8 mm×1.5 mm), which is a carbonate-free calcium phosphate, were immersed in an aqueous silver nitrate solution of 5 to 5000 equivalents at 20° C. for 24 hours. The specific surface areas of the used carbonate apatite and hydroxyapatite are the same, 4 m ² g ⁻¹ . The silver concentration in the sample after immersion was measured by high frequency inductively coupled plasma emission spectroscopy. The measurement results are shown in FIG.

As shown in FIG. 5, it was found that carbonate apatite has a higher silver content than hydroxyapatite at all silver nitrate concentrations. This is because, as described above, carbonate apatite produces silver carbonate and silver phosphate, but hydroxyapatite produces only silver phosphate.

[Example 1]
The antibacterial effect against methicillin-resistant Staphylococcus aureus (MRSA) was evaluated in accordance with JIS Z 2801:2010 by immersing the carbonated apatite porous material in an aqueous silver nitrate solution of 0.5 to 5000 equivalents for 60 minutes at 20°C. For comparison, the antibacterial effect of a sample not immersed in silver nitrate was also evaluated in the same manner. FIG. 6 shows the relationship between silver nitrate concentration and MRSA survival rate.

As shown in FIG. 6, when the carbonate apatite porous material was immersed in silver nitrate solutions of 0.5 equivalent and 1.5 equivalent, the survival rate of MRSA was 7.7% and 7.3%, respectively. When immersed in the above silver nitrate solution, the survival rate of MRSA was 0%. From Test Example 1, when immersed in a 2.5 equivalent silver nitrate solution, 2.0×10 ⁻³ mass % of silver phosphate and silver carbonate are generated, and when immersed in a 1.5 equivalent silver nitrate solution, , 1.2×10 ⁻³ wt. is present between 1.2×10 ⁻³ and 2.0×10 ⁻³ mass %. In addition, when the concentration of silver phosphate and silver carbonate is 9.9 × 10 ^-4 to 1.2 × 10 ^-3 mass%, the number of bacteria can be reduced to about 7.5%, so sterilization It can be seen that even silver phosphate and silver carbonate concentrations of 9.9×10 ⁻⁴ mass % exhibit bactericidal effects.

[Example 2]
A carbonated apatite porous material was immersed in an aqueous solution of silver nitrate of 0.5 to 500 equivalents at 20° C. for 60 minutes, and the antibacterial effect against Staphylococcus epidermidis was evaluated according to JIS Z 2801:2010. For comparison, the antibacterial effect against Staphylococcus epidermidis of a sample that had not been immersed in the aqueous solution of silver nitrate was evaluated in the same manner. The results are shown in FIG.

As shown in FIG. 7, when the silver nitrate concentration was 0.5 equivalent, the number of colonies of Staphylococcus epidermidis was 7×10 ⁷ /mL. When the silver nitrate concentration was 5 equivalents or more, the number of colonies of Staphylococcus epidermidis was 0/mL. It was found that the threshold concentration of silver phosphate and silver carbonate relative to the total mass for complete killing of Staphylococcus epidermidis lies between 9.9×10 ⁻⁴ and 6.1×10 ⁻³ wt %. The results are similar to the antibacterial test using MRSA described in Example 1.

[Example 3]
The cytotoxicity of a sample obtained by immersing the porous carbonate apatite in 5 to 5000 equivalents of silver nitrate at 20° C. for 60 minutes against mouse calvaria-derived osteoblast-like cells (MC3T3-E1) was evaluated. As a comparison, the cytotoxicity of samples not soaked in silver nitrate was also evaluated. The cytotoxicity test results are shown in FIG.

As shown in FIG. 8, when the carbonated apatite porous material was immersed in a silver nitrate solution of 35 equivalents or less, no cytotoxicity was observed. When immersed in a silver nitrate solution of 50 equivalents or more, cell viability decreased dramatically, confirming cytotoxicity. From Test Example 1, the concentration of silver phosphate and silver carbonate when immersed in a 50-equivalent silver nitrate solution was 3.8×10 ⁻² mass % of the total mass, and the silver phosphate when immersed in a 35-equivalent silver nitrate solution and the silver carbonate concentration is 2.8×10 ⁻² mass % of the total mass. That is, the threshold concentration of silver phosphate and silver carbonate indicating cytotoxicity exists between 2.8×10 ⁻² and 3.8×10 ⁻² mass % of the total mass.

As described in Examples 1 and 2, the concentration of silver phosphate and silver carbonate exhibiting a bactericidal effect of 90% or more is 9.9 × 10 ^-4 mass% or more of the total mass, and the silver phosphate that completely kills bacteria and silver carbonate concentration threshold exists between 1.2×10 ⁻³ and 2.0×10 ⁻³ mass %. If it is 9×10 ⁻⁴ to 2.8×10 ⁻² % by mass, it certainly does not show cytotoxicity, shows a bactericidal effect of 90% or more, and 2.0×10 ⁻³ to 2.8×10 ⁻² It can be seen that if it is mass %, it does not exhibit cytotoxicity and can completely kill bacteria. However, since inflammation that occurs in vivo is a complex reaction of the immune system involving various cells and factors, unexpected cytotoxicity may occur. Considering the above, the upper limit concentration is preferably lower, and for example, a concentration lower than 1.0×10 ⁻² mass % is considered good. Even at such a low concentration, the antibacterial properties are sufficiently exhibited (see Examples 4 and 5).

[Test Example 6]
A carbonate apatite disc (φ8 mm×1.5 mm), which is a carbonate-containing calcium phosphate, and a hydroxyapatite disc (φ8 mm×1.5 mm), which is a carbonate-free calcium phosphate, were immersed in an aqueous silver nitrate solution of 5 to 5000 equivalents at 20° C. for 24 hours. The specific surface areas of the used carbonate apatite and hydroxyapatite are the same, 4 m ² g ⁻¹ . The antibacterial effect against MRSA was evaluated according to JIS Z 2801:2010. For comparison, the antibacterial effect of a sample not immersed in the silver nitrate aqueous solution was also evaluated in the same manner. FIG. 9 shows the measurement results.

As shown in FIG. 9, in carbonate apatite, the antibacterial effect was not confirmed in the sample not immersed in the silver nitrate aqueous solution, but the sample immersed in the silver nitrate aqueous solution of 0.5 equivalent or more did not detect MRSA, and the antibacterial effect was observed. was confirmed. On the other hand, for hydroxyapatite, no antibacterial effect was observed in samples immersed in silver nitrate aqueous solution of 50 equivalents or less, and the number of MRSA colonies could not be reduced to zero unless the silver nitrate concentration was increased to 5000 equivalents. According to Test Example 5, the silver compound concentration in carbonate apatite immersed in 5 equivalents of silver nitrate aqueous solution is equivalent to the silver compound concentration in hydroxyapatite immersed in 50 equivalents of silver nitrate aqueous solution. The concentration of the silver compound in the hydroxyapatite thus obtained is ten times higher than that in the carbonate apatite immersed in a 5-equivalent aqueous solution of silver nitrate. From the above, it has been clarified that the use of carbonate apatite as a raw material inorganic compound has a higher antibacterial effect than the use of hydroxyapatite as a raw material inorganic compound. This is because when carbonate apatite is immersed in an aqueous solution of silver nitrate, both silver carbonate and silver phosphate are produced, whereas hydroxyapatite produces only silver phosphate, and both silver carbonate and silver phosphate are produced. was shown to increase the antibacterial effect.

[Example 4]
A sample obtained by immersing a carbonated apatite porous material in 5 equivalents of silver nitrate at 20°C for 60 minutes and an unimmersed sample were immersed in an MRSA bacterial solution of 1 × 10 ⁷ CFU/mL for 10 minutes. 3 mm). FIG. 10 shows the results of measuring the number of viable bacteria in the vicinity of the implantation site after 2 weeks.

As shown in FIG. 10, about 22400 colonies per 1 g of the unimmersed sample were detected, but no viable bacteria were detected from the sample immersed in 5 equivalents of silver nitrate at 20° C. for 60 minutes. That is, in the in vitro tests of Examples 1, 2, and 3, when the silver phosphate and silver carbonate concentrations on the surface of the material were 6.1×10 ⁻³ mass % of the total mass, no cytotoxicity was exhibited, and antibacterial activity was exhibited. However, animal experiments have also demonstrated that the antibacterial effect is exhibited when the concentration of silver phosphate and silver carbonate on the surface of the material is 6.1×10 ⁻³ mass % of the total mass.

[Example 5]
A sample in which a porous carbonate apatite was immersed in 5 equivalents of an aqueous solution of silver nitrate for 60 minutes and a sample not immersed in an aqueous solution of silver nitrate were immersed in an MRSA bacterial solution of 1×10 ⁷ CFU/mL for 10 minutes. × 3 mm). FIG. 11 shows histopathological findings in the vicinity of the implantation site after 2 weeks.

As shown in FIG. 11, in the specimen in which the specimen was immersed in 5 equivalents of silver nitrate for 60 minutes, no infiltration of inflammatory cells or bacterial bone resorption was observed around the implantation site, and new growth was observed in and around the specimen. bone was formed. On the other hand, in specimens implanted with specimens that had not been immersed in silver nitrate aqueous solution, marked infiltration of inflammatory cells and large-scale bone resorption due to bacteria occurred around the implantation site, and new bone formation occurred inside and around the specimen. No formation was confirmed. From the above, it can be concluded that a sample having a surface silver phosphate and silver carbonate concentration of 6.1×10 ⁻³ mass % of the total mass obtained by immersing in a 5-equivalent silver nitrate aqueous solution for 60 minutes has antibacterial effect and osteoconductivity. It was found to have a combination of

INDUSTRIAL APPLICABILITY The medical tissue reconstruction material of the present invention is industrially useful because it can be used for tissue reconstruction procedures for bones and the like, scaffolds for regenerative medicine, and the like in the medical field or fields related to medical care.

Claims (12)

A calcium-based material having silver carbonate and silver phosphate on its surface,
A medical tissue reconstruction material having a total content of silver carbonate and silver phosphate of 5.0×10 ⁻⁴ to 3.3×10 ⁻² mass %. 2. The tissue reconstruction material for medical use according to claim 1, wherein the total content of silver carbonate and silver phosphate is 1.5×10 ⁻³ to 1.0×10 ⁻² mass % (less than). 3. The medical tissue reconstruction material according to claim 1, comprising at least one inorganic compound selected from carbonate-containing calcium phosphate, a mixture of calcium phosphate and a carbonate-containing compound, and bone. The tissue reconstruction material for medical use according to any one of claims 1 to 3, which is a porous body. A method for producing the medical tissue reconstruction material according to any one of claims 1 to 4,
A method for producing a medical tissue reconstruction material, comprising exposing a calcium-based material to a solution containing silver ions. 6. The method for producing a medical tissue reconstruction material according to claim 5, wherein the calcium-based material is immersed in a solution containing silver ions. 7. The method for producing a medical tissue reconstruction material according to claim 5, wherein the solution containing silver ions is an aqueous solution of silver nitrate. 8. The method for producing a medical tissue reconstruction material according to any one of claims 5 to 7, wherein the calcium-based material is immersed in an aqueous silver nitrate solution of 0.6 to 41.3 equivalents to the calcium-based material. 9. The method for producing a medical tissue reconstruction material according to any one of claims 5 to 8, wherein the calcium-based material is immersed in an aqueous silver nitrate solution of 1.9 to 12.5 equivalents to the calcium-based material. 9. The method for producing a medical tissue reconstruction material according to claim 8, wherein a total of 5.0×10 ⁻⁴ to 3.3×10 ⁻² mass % of silver carbonate and silver phosphate is produced. 10. The method for producing a medical tissue reconstruction material according to claim 9, wherein a total of 1.5×10 ⁻³ to 1.0×10 ⁻² mass % (less than) of silver carbonate and silver phosphate is produced. The medical tissue reconstruction material according to any one of claims 5 to 11, wherein the calcium-based material is at least one inorganic compound selected from carbonate-containing calcium phosphate, a mixture of calcium phosphate and a carbonate-containing compound, and bone. Production method.

Images