JP6579516B2 - Method for coating plastic substrate with apatite and method for producing implant - Google Patents

Description

  The present invention relates to a method for coating various plastic substrates with apatite and a method for producing an implant.

  Hydroxyapatite, a kind of calcium phosphate, has a high biocompatibility and plays an important role as a major component of bone in vertebrate organisms. Utilizing these desirable properties, it can be used as artificial bone using artificially synthesized hydroxyapatite, or by coating it on the surface of titanium metal, etc., and used for various metal implants with excellent biocompatibility. ing.

  On the other hand, various plastic materials having a low affinity with a living body are often used as various implants in the living body. For example, an artificial ligament used to deal with ligament damage is composed of a ribbon-like member in which polyester fibers are bundled. Alternatively, a member using PEEK (polyetheretherketone) material may be used as a spinal cage that may be used for partial replacement of the spine. Furthermore, ultra high molecular weight polyethylene is used for the sliding portion (sliding portion) of the artificial hip joint. Any of these synthetic polymers is recognized as a foreign substance in the living body, and when it exists in the living body in a finely divided state like a friction powder, it is known that an immune reaction is caused and various adverse effects are caused. Furthermore, since biological reactions to the surfaces of these various plastic materials often have undesirable effects, there is a need for a method of imparting high affinity to the surfaces of these plastic materials to the surfaces of these plastic materials. As a specific measure, if hydroxyapatite can be fixed to the surface of these plastic materials, it is possible to impart favorable biocompatibility to the surface, and further, utilizing bone conductivity of hydroxyapatite, living bone and these plastics Since it becomes possible to enhance the adhesion of the material, for example, the adhesion between the artificial ligament and the inner surface of the bone hole into which the artificial ligament is introduced can be strengthened, and the durability and usable life in the living body can be greatly improved. Be expected.

  As a method for coating hydroxyapatite on the surface of titanium metal or the like, a method such as a flame welding method or a plasma welding method in which hydroxyapatite that has been melted at a high temperature is used. However, such a welding method requires high thermal stability for the base material since high-temperature hydroxyapatite is brought into contact with the base material surface to be coated. Therefore, in various plastic materials such as the above-mentioned polyester fiber and PEEK material, since the heat resistance is relatively weak, it has not been possible to coat hydroxyapatite using a conventional welding method.

  Conventionally, a method has been studied in which hydroxyapatite is atomized and used as a coating liquid in a state of being dispersed in a solution, and various plastic materials are coated to form a layer containing hydroxyapatite on the surface. In this case, various binders have been used for the purpose of bonding hydroxyapatite and the surface of a plastic material as a base material. For example, Patent Document 1 discloses a method of forming a layer on the surface of a plastic substrate using calcium apatite fine particles together with an aqueous urethane resin and a self-emulsifiable isocyanate compound. However, the adhesiveness at the interface between the coating layer containing apatite and the plastic substrate provided by this method is still not sufficient, and there is a problem that the adhesiveness gradually decreases immediately after coating. In particular, when it is left in a living body for a long time, the layer containing apatite may be peeled off due to the strength of the layer gradually decreasing due to deterioration of the urethane resin or the like.

  Non-Patent Document 1 describes an attempt to weld calcium phosphate to a titanium alloy surface using a carbon dioxide laser. Since the oscillation wavelength of the carbon dioxide laser is exactly the same as the infrared absorption region of calcium phosphate (near 10 μm), the calcium phosphate is heated by the irradiation of the carbon dioxide laser, and when the laser irradiation intensity is set high, it is heated to near the melting point of calcium phosphate. It has been shown that it can be sintered. However, in this method, calcium phosphate cannot be bonded to the titanium alloy by sintering the calcium phosphate itself. By using sodium phosphate as a binder, the calcium phosphate crystal is bonded to the titanium alloy surface with a certain degree of adhesive strength. It shows what you can do. However, in this method, since it is necessary to heat the sodium phosphate to the extent that it melts, it is impossible to use a plastic material lacking thermal stability as a base material instead of a titanium alloy.

  Non-Patent Document 2 tries to weld a system in which glass (cordierite) is added to hydroxyapatite as a binder, using carbon dioxide gas laser. It is necessary to add up to about 60% with respect to hydroxyapatite, and the properties of hydroxyapatite as a biocompatible material may be lost by the addition of cordierite. In addition, in this case as well, it is necessary to heat the cordierite to a melting level, and a high heat load is applied to the base material. Therefore, application to a plastic material is impossible.

JP 2014-193272 A

Toshihiro Kasuga et al., “The Journal of the Japan Institute of Metals” Volume 70, No. 4, 322-329 (2006) Tadashi Hida, "The Transactions of the Japan Society of Mechanical Engineers" (C) Volume 77, Number 774, 537-544 (2011-2)

  The present invention relates to an improved method for coating various plastic substrates with apatite, and in particular, a coating layer having excellent adhesion at the interface between the apatite and the plastic substrate can be formed on the substrate. Another object of the present invention is to provide a method for coating a plastic substrate with apatite. Another object of the present invention is to provide a method for producing an implant having a coating layer containing apatite on a plastic substrate and having good adhesion at the interface between the substrate and the coating layer containing apatite. To do.

The above-described problems of the present invention are essentially solved by using a method of coating apatite on a plastic substrate as shown below.
1. Apatite or a composition containing apatite is placed on a plastic substrate, and a wavelength region of 9 to 11 μm using a carbon dioxide gas laser is applied to the apatite or the composition containing apatite from the side of the apatite or the composition containing apatite. A method of coating apatite with a plastic substrate, which is irradiated with infrared light.
2. 2. The method of coating apatite on the plastic substrate according to 1 above, wherein the composition containing apatite contains a thermoplastic resin.
3. Apatite or a composition containing apatite is placed on a plastic substrate, and a wavelength region of 9 to 11 μm using a carbon dioxide gas laser is applied to the apatite or the composition containing apatite from the side of the apatite or the composition containing apatite. The manufacturing method of the implant which performs infrared light irradiation.
4). 4. The method for producing an implant according to 3 above, wherein the composition containing apatite contains a thermoplastic resin.

  According to the present invention, an improved method for coating various plastic substrates with apatite suitable for the production of a member that can be suitably used for medical applications is provided, and in particular, the interface between the apatite and the plastic substrate. A coating method for obtaining a coating layer and the like having excellent adhesion is provided. Further, according to the present invention, it is possible to produce an implant having a coating layer containing apatite on a plastic substrate and having good adhesion at the interface between the substrate and the coating layer containing apatite.

The temperature change in the irradiation part surface during the laser irradiation in Example 1. FIG. The scanning electron micrograph of the layer of the composition containing the hydroxyapatite formed in the polyester film surface by the laser drawing obtained in Example 1. FIG. The scanning electron micrograph of the layer of the composition containing the hydroxyapatite formed in the polyester film surface by the laser drawing obtained in Example 2. FIG. Sectional photography of the layer of the composition containing the hydroxyapatite formed in the polyester film surface by the laser drawing obtained in Example 2. FIG. The temperature change in the irradiation part surface during the laser irradiation in Example 3. FIG. The scanning electron micrograph of the layer of the composition containing the strontium apatite formed on the PEEK resin film surface by the laser drawing obtained in Example 3. The temperature change in the irradiation part surface during the laser irradiation in Example 4. FIG. The scanning electron micrograph of the layer of the composition containing strontium apatite formed on the surface of the UHMWPE film by laser drawing obtained in Example 4. The temperature change in the irradiation part surface during the laser irradiation in Example 6. FIG. The scanning electron micrograph of the layer of the composition containing strontium apatite formed on the artificial ligament surface by laser drawing obtained in Example 6.

  In the method of coating an apatite on the plastic substrate of the present invention, a composition comprising apatite or apatite is placed on the plastic substrate, and the composition comprising the apatite or apatite from the side of the apatite or the composition comprising apatite. The object is irradiated with infrared light in a wavelength region of 9 to 11 μm using a carbon dioxide laser. The method of coating the plastic substrate of the present invention with apatite is also simply referred to as the coating method of the present invention.

  The carbon dioxide laser that can be used in the present invention uses carbon dioxide gas as a laser medium and a laser that can oscillate laser light with an oscillation wavelength of 10.6 μm or 9.3 μm in the infrared region. Can do. As such a carbon dioxide laser, various types of laser devices that perform continuous or pulse oscillation with a laser output of several watts to several tens of watts are commercially available, and are frequently used for medical applications, particularly dental applications. In the infrared wavelength region 9 to 11 μm, there are many examples showing strong absorption in functional groups containing oxygen of various organic and inorganic compounds. As organic compounds, compounds having various carbon-oxygen bonds such as alcohols exhibit strong absorption due to C—O stretching vibration, and inorganic compounds such as P═O stretching vibration of phosphorus compounds and Si—O stretching vibration of silicate compounds. Thus, it is known that a strong absorption band due to stretching vibration of various inorganic elements bonded to oxygen atoms exists in this wavelength range. Therefore, when a compound having absorption in the infrared wavelength region 9 to 11 μm is irradiated with infrared light in this wavelength region using a carbon dioxide laser, the absorbed light energy is converted into heat by photothermal conversion. It becomes possible to heat itself. In the present invention, apatite, which is a phosphate, is used to directly heat the apatite by irradiating the laser light in the infrared wavelength region (infrared light in the wavelength region of 9 to 11 μm). can do.

  An apparatus that can be used as a carbon dioxide laser is generally intended to use high-power laser light, and the high-power laser light is focused on a minute area of the object and instantaneously several hundred to 1000 ° C or higher. It is possible to heat the surface temperature of the object up to this temperature. In dental use, the apatite constituting the tooth itself absorbs the laser beam in the infrared wavelength region, and is used to remove the tooth due to the evaporation of the apatite due to the generated high heat.

  Non-Patent Document 1 described above was an attempt to perform high-temperature sintering of calcium phosphate (including apatite) itself by irradiation with a carbon dioxide laser. However, since calcium phosphate itself is hard and brittle, It was impossible to form a layer by welding them to a metal surface such as molding or a titanium alloy. Similarly, in Non-Patent Document 2, an attempt was made to join apatites together by carbon dioxide laser irradiation, but it was difficult to join them firmly.

  In the present invention, apatite or a composition containing apatite is installed on a plastic substrate, and the apatite itself is irradiated by irradiating infrared light in a wavelength region of 9 to 11 μm with a carbon dioxide gas laser onto the composition containing apatite or apatite. Is heated, and the surface portion of the plastic substrate on which the apatite or the composition containing apatite is installed is also heated, and both are integrated at the interface by heating, thereby realizing extremely strong adhesiveness. Is found. In addition, since only the surface of the plastic substrate and its vicinity can be heated by controlling the laser irradiation, it is possible to avoid undesirable thermal deformation of the entire substrate.

  As a carbon dioxide laser that can be used in the present invention, a laser device that has an output in the range of several watts to several tens of watts and has a wavelength of 10.6 μm or 9.3 μm and capable of continuous oscillation or pulse oscillation is most preferable. Can be used. The spot diameter when the laser beam is focused is preferably in the range of several μm to several hundreds of μm, but by intentionally shifting the focus, local concentration of heat on the irradiated object is avoided. It may be preferable to heat the irradiated object with a more average temperature distribution.

  When irradiating laser light in the above infrared wavelength region, the irradiation conditions are not particularly limited, and it is possible to control the state of temperature rise in the irradiation part in various patterns by a combination of laser power and irradiation time. is there. That is, when the laser power is set high and the laser light is irradiated, the temperature is raised in a short time by shortening the irradiation time at one place during the laser light irradiation, and the heat is immediately dissipated and cooled. It is also preferable to complete the temperature change in the irradiation section within a short time. In this case, the temperature of the irradiated part will be dissipated to the surroundings within a short time due to thermal diffusion, so the influence of heat in the depth direction of the irradiated part and the peripheral (plane) direction surrounding the irradiated part should be minimized. Is possible. Therefore, by selectively heating a specific part, it is possible to preferably use the apatite or the composition containing apatite as the object of the present invention only in this part for the purpose of adhering to the plastic substrate. In such a case, the pulse irradiation time (pulse width) at one spot of the laser beam is preferably in the range of 1 to 1000 microseconds. In order to process a certain range with a laser beam having a pulse width in this range, it is preferable to irradiate the irradiated object with the laser beam at a laser scanning speed of 3000 to 15000 mm / sec.

  Or it can utilize preferably also when performing irradiation for a comparatively long time using a comparatively low power laser beam. That is, the pulse width of the laser light is the same as that described above, or when laser light irradiation is performed at a relatively slow scanning speed in a continuous oscillation state, a large number of laser light pulses are continuously or repeatedly repeated in the irradiation section. Since it is irradiated twice, heat accumulates in the irradiation part and diffuses around the irradiation part, so that a relatively large area can be uniformly heated. Such irradiation conditions can also be preferably used for the purpose of adhering the target apatite or the composition containing apatite to a plastic substrate. In such a case, the irradiation time at one spot of the laser beam is preferably in the range of 0.001 to 100 milliseconds. In order to treat a certain range with a laser beam having a pulse width in this range, it is preferable to irradiate the irradiated object with the laser beam at a laser scanning speed of 100 to 3000 mm / second.

  Furthermore, it is also possible to heat the irradiated object with various laser irradiation patterns, such as a method of repeatedly irradiating the same spot a plurality of times under the above short-time irradiation or long-time irradiation conditions. In this case, by adjusting the temperature change rate of the irradiated object due to thermal diffusion and the timing of irradiation, it is possible to appropriately adjust the temperature profile of the surface of the irradiated object and the inside by repeated irradiation. In addition, the temperature at which the following plastic substrate is heated and the surface temperature of the laser light irradiation part, which is also the heating temperature of the apatite, can be easily measured using a digital radiation thermometer or the like.

  Examples of the plastic substrate that can be used in the present invention include polyester resin (PET), polyamide resin, polyether resin, polyether ketone resin, polyether ether ketone resin (PEEK), polyethylene resin (PE), and ultrahigh molecular weight polyethylene. Plastic resins having various thermoplastic properties such as a resin (UHMWPE), a polypropylene resin (PP), an acrylic resin, and a polystyrene resin can be preferably used. In the present invention, when these various plastic resins are heated by heat from apatite or a composition containing apatite by laser irradiation, it is preferably heated at a temperature lower than the temperature that induces thermal decomposition. For this reason, the upper limit of the temperature to be heated is usually less than 400 ° C, preferably less than 300 ° C, and more preferably heated at a temperature of less than 280 ° C.

  There is also a preferred range for the lower limit of the temperature at which the plastic substrate is heated. When the apatite or the composition containing apatite provided adjacent to the plastic substrate is heated by carbon dioxide laser irradiation, the plastic substrate is heated by heat conduction, and the surface is softened. It is a feature of the present invention that adhesion proceeds at an interface with apatite or a composition containing apatite, and an extremely strong adhesive force can be realized by integration at the interface where both are in contact. Accordingly, the surface of the plastic substrate is preferably heated to a temperature at or above its glass transition temperature, and more preferably at least 10 ° C. higher than the glass transition temperature. Heating to the vicinity of the melting point of the plastic substrate to be used can be preferably performed, but in this case, the plastic substrate may be thermally deformed by heating. It is preferable to adjust the heating temperature within an appropriate temperature range above the glass transition temperature.

In the present invention, as described above, the apatite is directly heated using a carbon dioxide laser, but there is a preferable temperature range for the heating temperature of the apatite. When the temperature of the apatite exceeds 400 ° C., the temperature of the apatite or the composition containing the apatite and / or the temperature of the adjacent plastic substrate reaches the heat denaturation temperature or the decomposition temperature, and the physical properties of the plastic substrate change. It may not be preferable to do so. A preferred temperature range for the heating temperature of the apatite is in the range of 70 to 400 ° C, more preferably in the range of 80 to 300 ° C, and still more preferably in the range of 90 to 280 ° C. When the apatite is heated in this temperature range, the adhesiveness at the interface between the apatite or the composition containing the apatite and the plastic substrate on which the apatite is installed is improved, and the thermal denaturation, thermal decomposition, and heat of the plastic substrate are improved. This is extremely preferable in avoiding undesirable adverse effects such as deformation.
In the present invention, it is preferable to appropriately set the conditions of the laser beam irradiation by the carbon dioxide laser so that the heating temperature of the plastic substrate and the apatite or the composition containing apatite falls within the above preferable temperature range.

  As the apatite that can be used in the present invention, hydroxyapatite that is a calcium phosphate salt is most representative, and carbonate apatite that contains carbonate ions in its composition and fluorine apatite that contains fluorine ions are also preferably used. it can. Preferable synthesis methods for obtaining these include the synthesis method of carbonate apatite disclosed in JP-A-2015-084814 and the synthesis method of fluorapatite disclosed in JP-A-2014-181160. Various apatites obtained can be preferably used in the present invention. Furthermore, various apatites in which some or all of calcium ions of these various apatites are substituted with metal ions other than calcium can also be preferably used. Examples of metals other than calcium include magnesium, strontium, barium, sodium, potassium, cesium, zinc, silver, and the like. Various apatites containing these metal ions in the composition can also be preferably used. As a method for producing apatite containing metal ions other than calcium, for example, for apatite containing magnesium ions, the method described in JP-A-2015-048266 can be preferably used. Alternatively, examples of apatite containing strontium include the examples described in JP-A-2014-180491, JP-A-2015-060881, JP-A-2015-060882, JP-A-2015-086084, The strontium carbonate apatite containing carbonate ions described in JP-A-2015-086097 can also be preferably used. Furthermore, it is also preferable to use fluorapatite containing strontium as described in JP-A-2015-093825. Only one type of apatite may be used, or a plurality of types may be used in combination.

In the present invention, when installing apatite or a composition containing apatite on a plastic substrate, it is preferable to use apatite as fine particles. Regarding the size of the fine particles, there is an upper limit of a preferable range, and it is preferable that the volume average particle diameter is 10 μm or less. When using apatite with an average particle size larger than this, the apatite or apatite on the plastic substrate is included due to problems such as scattering of carbon dioxide laser light and heating by laser light irradiation not proceeding uniformly in the irradiated part. The adhesiveness of the composition may decrease. The lower limit of the preferable range of the size of the fine particles is preferably 50 nm or more in the volume average particle diameter. The volume average particle diameter can be measured using a laser diffraction / scattering particle size distribution measuring apparatus.
Moreover, in this invention, it is preferable to install the composition containing apatite on a plastic base material.

In the present invention, the method for installing apatite or a composition containing apatite on a plastic substrate is not particularly limited as long as it can provide a composition containing apatite or apatite on the substrate (substrate surface). Not.
In the present invention, examples of a method for installing apatite or a composition containing apatite on a plastic substrate include, for example, a method of directly placing apatite fine particles on a plastic substrate, A method of adhering, a method of adhering a composition obtained by mixing apatite fine particles and an adhesive or a pressure-sensitive adhesive to a plastic substrate, a method of applying a coating liquid containing apatite fine particles to a plastic substrate, etc. Although various methods can be used, it is preferable to use a method in which coating is performed using a coating solution containing apatite fine particles because uniform installation of a composition containing apatite can be easily performed.

The composition containing apatite in the present invention preferably contains a thermoplastic resin.
In the present invention, by using a thermoplastic resin together with a composition containing apatite, the adhesiveness of the composition containing apatite to the plastic substrate is improved after irradiation with infrared rays of the above wavelength by a carbon dioxide laser (after heating). Therefore, it can be preferably used. Examples of thermoplastic resins that can be used for such purposes include biocompatible polymers such as polylactic acid, polyglycolic acid, poly-ε-caprolactone, and polytrimethylene carbonate, or living organisms such as polymethyl methacrylate and polydimethylsiloxane. Inactive polymers and various other thermoplastic resins such as various acrylic resins, vinyl acetate resins, polyester resins, polyurethane resins, acetal resins, polyamide resins, polystyrene resins, polyolefin resins, etc. are very preferably used. Can do. Only one type of thermoplastic resin may be used, or a plurality of types may be used in combination.

In the above, when a thermoplastic resin is added and used in a composition containing apatite, there is a preferred range for the ratio of the thermoplastic resin to the apatite. When the ratio of the thermoplastic resin to the apatite is less than 10% by mass, the effect of using the thermoplastic resin may be difficult to appear. Alternatively, when the ratio of the thermoplastic resin to the apatite exceeds 100% in mass ratio, the surface of the apatite is coated with the thermoplastic resin after the coating treatment of the present invention using a carbon dioxide laser. Therefore, the characteristics of apatite such as biocompatibility may be difficult to appear in combination with a plastic substrate.
The composition containing apatite may contain components other than apatite and the above-described thermoplastic resin, and may contain, for example, an organic solvent, a surfactant, and the like described later.

In the present invention, the apatite contained in the composition is preferably used as fine particles having a volume average particle diameter of 1 μm or less. In the present specification, fine particles having a volume average particle diameter of more than 1 μm and 10 μm or less are also referred to as fine powder.
The apatite obtained by the various synthesis methods as described above is subjected to a dry pulverization treatment using a ball mill or the like, so that a fine powder having a volume average particle diameter of more than 1 μm and not more than 10 μm, and further a volume average particle diameter. Can be processed into fine particles having a thickness of 1 μm or less. Alternatively, by performing wet dispersion treatment using various media mill apparatuses in water or in various organic solvents, the apatite is a fine powder having a volume average particle diameter of more than 1 μm and not more than 10 μm, and a volume average particle diameter of 1 μm. Processing into the following fine particles can also be preferably used. Further, by such wet dispersion treatment, apatite fine powder having a volume average particle diameter of more than 1 μm and not more than 10 μm or a dispersion of apatite fine particles having a volume average particle diameter of not more than 1 μm (hereinafter also referred to as apatite dispersion). Can be obtained. Such an apatite dispersion is preferably used for a coating liquid containing apatite.

  In the present invention, as the above-mentioned wet dispersion treatment using a media mill apparatus, specifically, apatite is added to water or various organic solvents as a dispersion medium, and glass beads are used as a dispersion treatment medium. A method in which the apatite and the ceramic beads are shaken or stirred, and the apatite and the beads mechanically collide and finely pulverize to perform a wet dispersion treatment of the apatite is preferable.

  To give a specific example of a media mill device, when a small amount is wet-dispersed in a batch system, the wet-dispersed processing is performed by shaking for several hours using a paint conditioner as a media mill device. Can do. In addition, as a media mill device, a device capable of wet dispersion processing in a continuous manner, such as a horizontal bead mill represented by Dino Mill (manufactured by WAB), is used in series with a plurality of units, and one pass. The wet dispersion treatment may be carried out at the same time, or the treatment may be preferably repeated a plurality of times using one media mill. By performing such a wet dispersion treatment, fine powder or fine particles of apatite can be produced in water or various organic solvents. In addition to these, various shapes and types of devices are commercially available as media mill devices. In any case, the device can perform wet dispersion processing in water or various organic solvents using media. Basically, it can be used.

  When the wet dispersion process of apatite is performed using the above-described media, it is preferable to use ceramic beads as the media to be used. In particular, it is preferable to prevent the bead-derived impurities from being mixed into the dispersion liquid by polishing the beads. Even if finely pulverized bead-derived components are mixed, It is preferable that safety is confirmed in vivo. Specifically, ceramic beads containing zirconia such as ZrO, cubic zirconia, yttrium-stabilized zirconia, and zirconia-reinforced alumina can be most preferably used as the ceramic beads that can be used for such purposes. Moreover, it is preferable that the average diameter of a medium exists in the range of 0.01-10 mm, More preferably, it is 0.1-5 mm. The conditions for the wet dispersion treatment using a media mill using such media are treatments at room temperature that are usually performed, and there are no particular restrictions on treatment time, temperature, and the like. In addition, there may be cases where one pass is sufficient as the number of passes, but by performing the treatment with about 2 to 7 passes, a dispersion of apatite with a narrower particle size distribution and excellent dispersion stability. Can be manufactured.

  In the wet dispersion treatment, the amount of water or organic solvent used as the dispersion medium is preferably in the range of apatite: dispersion medium = 1: 1000 to 1: 2 in terms of mass ratio. When the ratio of the dispersion medium with respect to apatite exceeds 1000 in mass ratio, the solid content concentration of the obtained apatite dispersion liquid is not preferable because it is lower than the preferable range of the solid content concentration in the coating liquid described later. In addition, when the ratio of the dispersion medium to the apatite is less than 2 in mass ratio, the viscosity of the dispersion increases during the wet dispersion process, the dispersion process does not proceed, and coarse particles may be mixed in the prepared dispersion. is there.

  When producing a dispersion of apatite in water or an organic solvent using the above method, it is also preferable to perform wet dispersion treatment by adding various surfactants or polymers as a dispersant. In this case, as an example that can be preferably used as a polymer, an apatite dispersion excellent in dispersion stability can be produced by adding various thermoplastic resins as described above and performing wet dispersion treatment. .

An example of a thermoplastic resin that can be most preferably used as a dispersant in the present invention is polylactic acid. The polylactic acid that can be used in the present invention is preferably poly-D, L-lactic acid, which is a polylactic acid containing both D-lactic acid and L-lactic acid in repeating units in the polylactic acid. In this case, the ratio of D-form and L-form contained in the repeating unit is more preferably in the range of 2: 8 to 8: 2 in terms of molar ratio, and the ratio of D-form and L-form is further contained in an equimolar ratio. The case is most preferable. Alternatively, as an example of another preferable polylactic acid, a polylactic acid copolymer containing a repeating unit of glycolic acid, ε-caprolactone, trimethylene carbonate or the like in addition to L- or D-lactic acid in the repeating unit of polylactic acid. The case where the ratio of repeating units other than these lactic acids is less than 80 mol% is preferable.
As the thermoplastic resin contained in the composition containing apatite in the present invention, the above-mentioned polylactic acid is preferable.

  When the polylactic acid is used as an apatite dispersant in the present invention, it is preferable to use an organic solvent as a dispersion medium in the wet dispersion treatment. Preferred organic solvents used in the present invention include cyclic ether compounds such as 1,4-dioxane, 1,3-dioxolane and tetrahydrofuran, various ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and aromatics such as toluene and xylene. Group solvents, and polar solvents such as acetonitrile and dimethylformamide, and these organic solvents may be used alone or in combination.

  The ratio of the dispersant to the apatite when the wet dispersion treatment of the apatite is performed using the dispersant is preferably included in the range of 5 to 100% by mass with respect to the apatite, and 5 to 50% by mass. The case where it falls within the range is more preferable. When a dispersant is used exceeding this ratio, the surface of the apatite is coated with the dispersant. Therefore, after the coating treatment of the present invention using a carbon dioxide gas laser, the characteristics of the apatite such as biocompatibility are plastic substrates. May not be allowed in combination with. Further, the dispersant is preferably contained in a ratio of 5% by mass or more with respect to apatite, and the dispersion stability of the apatite dispersion obtained in this case is good and can be preferably used.

  There is a preferred range for the molecular weight of the polymer used as the dispersant, and the weight average molecular weight is preferably in the range of 1 to 1,000,000, and more preferably in the range of 3 to 300,000. When the weight average molecular weight of the polymer is less than 10,000, the dispersion stability of the apatite dispersion obtained using the polymer may be insufficient, and the apatite may settle over time, and a uniform dispersion may not be produced. is there. Alternatively, when the weight average molecular weight of the polymer exceeds 1,000,000, the viscosity of the dispersion increases, and the apatite is formed by coating using a coating liquid containing an apatite dispersion on the plastic substrate surface. When installing the composition containing, a uniform coating may not be performed. The weight average molecular weight of the polymer can be measured by gel filtration chromatography or a light scattering method.

The coating liquid containing apatite that can be used when a composition containing apatite is placed on a plastic substrate preferably contains a dispersion of apatite obtained by the above wet dispersion treatment. The use of a coating solution containing such an apatite dispersion is preferable because a composition containing apatite having a uniform composition can be placed on a plastic substrate.
The method for preparing the coating solution containing apatite is not particularly limited, and the above-mentioned apatite dispersion may be used as it is as the coating solution containing apatite. The apatite dispersion may contain the above thermoplastic resin, organic A coating solution may be prepared by adding a solvent or the like.

  Various suitable methods can be used as a method for coating a plastic base material using a coating liquid containing apatite according to the size and shape of the plastic base material. For example, as one method, a method of forming a composition layer containing apatite by immersing and lifting a plastic substrate in a coating solution, removing the excess coating solution, and drying the coating solution Alternatively, the coating solution is applied by uniformly adhering the coating solution to a plastic substrate by a method such as spraying or curtain coating, followed by drying and then installing a composition containing apatite, etc. Various known coating methods can be used.

  There is a preferred range for the solid content concentration of the apatite contained in the coating solution, and it is preferably contained in the range of 0.1 to 20% by mass. When a composition containing apatite is installed on a plastic substrate using a coating solution containing apatite at a concentration lower than this range, the coating solution may not be uniformly applied to the surface of the plastic substrate. .

What is necessary is just to set suitably the site | part and range of the plastic base material which installs the composition containing apatite or apatite according to the shape, use, etc. of a base material. For example, apatite or a composition containing apatite may be installed on the entire surface of the substrate, or a composition containing apatite or apatite may be installed on a part of the surface of the substrate.
In addition, the shape of the apatite or the composition containing apatite placed on the plastic substrate is not particularly limited, and may be any shape such as a particle shape, a lump shape, or a layer shape, for example, but it should be a layer shape. Is preferred. In the present invention, as a preferred embodiment of installing apatite or a composition containing apatite on a plastic substrate, forming a layer of apatite or a composition containing apatite on the substrate can be mentioned.

  In this invention, there exists a preferable range regarding the thickness or quantity of the composition containing apatite or apatite installed on a plastic substrate. When expressed as apatite solid mass (dry solid mass) in apatite or a composition containing apatite per unit area of the plastic substrate, it is preferably in the range of 0.1 to 50 grams per square meter. More preferably, it is in the range of 0.5 to 40 grams. When apatite is used in an amount below this range, characteristics such as biocompatibility, which is a preferable property of apatite, may not appear on the surface of the plastic substrate. Moreover, when apatite is used exceeding the above range, the adhesiveness of apatite or a composition containing apatite to a plastic substrate may be inferior.

  With respect to apatite or a composition containing apatite placed on a plastic substrate by the method described above, infrared light irradiation in a wavelength region of 9 to 11 μm is performed using a carbon dioxide gas laser from the side of the apatite or the composition containing apatite. By performing, the apatite or the composition containing apatite and the substrate can be firmly bonded. Therefore, according to the coating method of the present invention, it is possible to form a coating layer containing apatite and the like having good adhesion at the interface between the plastic substrate and the apatite. Thus, the plastic base material on which the surface is coated with apatite or a composition containing apatite is suitable as an implant used for medical use and the like.

The coating method of the present invention is suitably used for the production of implants used for medical purposes and the like.
In the present invention, apatite or a composition containing apatite is placed on a plastic substrate, and the wavelength of the apatite or the composition containing apatite from the side of the apatite or the apatite-containing composition using a carbon dioxide laser. The manufacturing method of the implant which performs infrared light irradiation of a region 9-11 micrometers is also included.
The production method of the present invention and preferred embodiments thereof are the same as the above-described coating method of the present invention. For example, the composition containing apatite preferably contains a thermoplastic resin. By the production method of the present invention, an implant having a coating layer containing apatite on a plastic substrate and having good adhesion at the interface between the substrate and apatite can be produced. In the implant obtained by the production method of the present invention, since the plastic base material and the apatite are firmly bonded, the apatite is hardly peeled off from the base material. Moreover, since the obtained implant has apatite on the surface of a plastic base material, biocompatibility is favorable and it can be used suitably as an implant for medical uses.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. In addition, the percentage in an Example is a mass reference | standard unless there is a notice.

Example 1
0.5 L of polypropylene with 20 g of hydroxyapatite (manufactured by Taihei Chemical Industrial Co., Ltd., HAP-100, medical grade product) and 2 g of poly-D, L-lactic acid (D / L = 1/1: weight average molecular weight 120,000) The mixture was put in a container, and 118 g of acetonitrile and 160 g of zirconia beads having a particle diameter of 0.3 mm were added thereto and sealed, and wet dispersion treatment was performed for 6 hours while shaking vigorously (shaking) continuously using a paint conditioner. Thereafter, zirconia beads were separated from the dispersion using a filter cloth to obtain a dispersion. The obtained dispersion is diluted with acetonitrile and placed in a batch cell, and the size of the dispersed apatite fine particles is measured using a laser diffraction / scattering particle size distribution analyzer (LA-910, manufactured by Horiba, Ltd.). As a result, the volume average particle diameter was 195 nm.

  Acetonitrile was added to the dispersion obtained above so that the solid content concentration of the dispersed hydroxyapatite was 5% by mass to prepare a coating solution. The obtained coating solution was applied on a 175 μm thick polyester (PET) film (glass transition temperature of about 80 ° C., melting point of about 260 ° C.) using a doctor bar so that the dry solid mass was 20 g per square meter. And dried. Drying was performed at a temperature of about 70 ° C. using a warm air dryer. When the obtained coated surface was rubbed with a finger, the composition containing hydroxyapatite was easily peeled off from the film surface.

  Using the polyester film provided with the composition containing hydroxyapatite prepared above, infrared light irradiation with a laser was performed as follows. Using a carbon dioxide laser (Keyence Corporation, Laser Marker ML-Z9510, wavelength 10.6 μm, maximum output 80 W), the following drawing conditions are applied to the coated surface of the film from the top 18.9 cm away from the polyester film surface. Laser light irradiation was performed. In order to measure the surface temperature of the laser beam irradiation unit, a digital radiation thermometer (LumaSense Technologies Inc., IGA6 / 23) is used, and the diameter of the measurement beam is 0.6 mm at the center point of the laser beam irradiation unit. The change in surface temperature in area was measured. The drawing conditions include the above-mentioned hydroxyapatite while drawing a concentric circle with a line interval of 140 μm from the center point at a laser beam irradiation scanning speed of 12000 mm / sec, a laser power (duty ratio) of 60% and a spot diameter of 70 μm. Drawing was performed on the polyester film surface on which the composition was installed. The oscillation frequency of the laser was 25 kHz, and the pulse width of the laser light was 24 microseconds. At this time, the result shown in FIG. 1 was obtained by measuring the surface temperature of the laser irradiation portion using the above-mentioned radiation thermometer immediately after the start of drawing with laser light.

  FIG. 1 shows a temperature change on the surface of the irradiated part during laser irradiation in Example 1. It was found that the surface temperature of the irradiated part reached the softening point temperature (about 120 ° C.) of the polyester film in a short time by laser light irradiation. After drawing, the surface of the film was repeatedly rubbed strongly with cut cotton moistened with acetone. As a result, the layer of the composition containing hydroxyapatite at the laser-irradiated portion remained fused and remained on the polyester film surface. It was found that the part that was not irradiated was wiped with cut cotton. FIG. 2 shows a scanning electron micrograph (magnification 50 times) of a layer of a composition containing hydroxyapatite formed on the surface of a polyester film by laser drawing obtained in Example 1. In FIG. 2, the black part is a polyester film and the gray part is a layer of a composition containing hydroxyapatite. From this result, it was found that a concentric drawing pattern by the layer of the composition containing hydroxyapatite was formed by firmly adhering to the polyester film surface. Moreover, thermal deformation was not seen as the whole polyester film.

(Example 2)
Drawing was performed with a laser beam on the surface of the polyester film on which the composition containing hydroxyapatite was placed in the same manner as in Example 1 except that the line spacing of the concentric circle pattern was set to 35 μm. The change in the measured surface temperature was the same as in Example 1. After drawing, the surface of the film was repeatedly rubbed strongly with cut cotton moistened with acetone, and all the layers of the composition containing hydroxyapatite in the laser-irradiated portion remained fused to the polyester film surface, In Example 2, as a result of irradiating the film surface with laser light without gaps, it was found that the surface was uniformly and firmly covered with a layer of a composition containing hydroxyapatite adhered firmly. FIG. 3 shows a scanning electron micrograph (magnification 200 times) of a layer of a composition containing hydroxyapatite formed on the surface of a polyester film by laser drawing obtained in Example 2. From this result, it was found that the layer of the composition containing hydroxyapatite was formed by firmly adhering to the polyester surface. Moreover, when the cross section of the film was similarly observed with the scanning electron microscope, the result shown in FIG. 4 was obtained. FIG. 4 shows a cross-sectional photograph (magnification 130 times) of a layer of a composition containing hydroxyapatite formed on the surface of a polyester film by laser drawing obtained in Example 2. The arrow in FIG. 4 shows the thickness of the layer of the composition containing hydroxyapatite. From this figure, it was confirmed that the layer of the composition containing hydroxyapatite was uniformly formed on the surface of the polyester film with a thickness of about 20 μm. In order to further evaluate the adhesion between the obtained hydroxyapatite-containing composition layer and the polyester film, the polyester film having the hydroxyapatite-containing composition layer was repeatedly used with a cloth moistened with acetone. The surface appearance was observed by rubbing, but no change in appearance was observed, and it was confirmed that the surface was firmly adhered. Moreover, thermal deformation was not seen as the whole polyester film.

(Example 3)
Strontium apatite was synthesized according to the method described in JP-A No. 2014-180491. That is, strontium chloride hexahydrate 267 g (1 mol) and diammonium hydrogen phosphate 132 g (1 mol) were synthesized with strontium hydrogen phosphate (α-SrHPO ₄ ), and 35 g of sodium hydroxide was added thereto. Strontium apatite (Sr ₁₀ (PO ₄ ) ₆ (OH) ₂ ) was synthesized by heating and stirring at 0 ° C. for 3 hours. The produced strontium apatite was recovered by filtration, thoroughly washed with distilled water, dried in a vacuum dryer at 70 ° C. for 24 hours, and used for the following wet dispersion treatment.

  10 g of the strontium apatite obtained above is introduced into a 200 mL polypropylene container, and 1 g of poly-D, L-lactic acid (D / L = 1/1: weight average molecular weight 120,000) is added, and acetonitrile is used as a dispersion medium. 60 g of was added. To this, 100 g of zirconia beads having a particle size of 0.3 mm was added and sealed, and wet dispersion treatment was performed for 6 hours while vigorously shaking (shaking) continuously using a paint conditioner. Thereafter, zirconia beads were separated from the dispersion using a filter cloth to obtain a dispersion. The obtained dispersion had a solid content concentration of 15.5% by mass.

  Acetonitrile was added to the dispersion obtained above so that the total solid content concentration was 5% by mass to prepare a coating solution. The obtained coating solution was applied to a polyether ether ketone (PEEK) resin film (glass transition temperature 143 ° C., melting point 343 ° C.) using a wire bar so that the dry solid mass was 36 g per square meter. Drying was performed using hot air from When the obtained coated surface was rubbed with a finger, the composition containing strontium apatite was easily peeled off from the film surface.

  Using a carbon dioxide laser (Laser Marker ML-Z9510) in the same manner as in Example 1, laser light irradiation (wavelength under the following drawing conditions on the coated surface of the film from the upper part 18.9 cm away from the surface of the PEEK resin film) 10.6 μm). The surface temperature of the laser beam irradiation part was measured in the same manner as in Example 1. As a drawing condition, a composition containing the above strontium apatite is set while drawing a concentric circle with a scanning speed of 6000 mm / sec, a laser power (duty ratio) of 40%, a spot diameter of 70 μm, and a line interval of 70 μm from the center point. Drawing was performed on an area of 1.4 mm in diameter on the surface of the PEEK resin film. The oscillation frequency of the laser was 25 kHz, and the pulse width of the laser beam was 16 microseconds.

  FIG. 5 shows temperature changes on the surface of the irradiated part during laser irradiation in Example 3. It was found that the surface temperature of the irradiated part rose to around 200 ° C. in a short time by laser light irradiation. When the surface of the film was repeatedly rubbed repeatedly with a cut cotton moistened with acetone after drawing, the layer of the composition containing strontium apatite in the portion irradiated with the laser remained fused to the surface of the PEEK resin film, It was found that the part not irradiated with the laser was wiped with cut cotton. 6 shows a scanning electron micrograph (magnification 2500 times) of a layer of a composition containing strontium apatite formed on the surface of a PEEK resin film by laser drawing obtained in Example 3. FIG. From this result, it was found that the layer of the composition containing strontium apatite was formed by firmly adhering to the surface of the PEEK resin film. Further, no thermal deformation was observed as a whole of the PEEK resin film.

Example 4
The coating liquid prepared in Example 3 was coated on an ultrahigh molecular weight polyethylene resin (UHMWPE) film (softening point of about 80 ° C., melting point 136 ° C.) using a wire bar so that the dry solid mass was 36 g per square meter. And it dried using the hot air from a dryer. When the obtained coated surface was rubbed with a finger, the composition containing strontium apatite was easily peeled off from the film surface.

  A carbon dioxide laser (laser marker ML-Z9510) was used in the same manner as in Example 1, and laser light irradiation (wavelength 10) was applied to the coated surface of the film from the upper part 18.9 cm away from the UHMWPE film surface under the following drawing conditions. .6 μm). The surface temperature of the laser beam irradiation part was measured in the same manner as in Example 1. As a drawing condition, a composition containing the above strontium apatite is set while drawing a concentric circle with a scanning speed of 600 mm / sec, a laser power (duty ratio) of 8%, a spot diameter of 70 μm, and a line interval of 70 μm from the center point. Drawing was performed on an area of 1.4 mm in diameter on the surface of the UHMWPE resin film. The oscillation frequency of the laser was 25 kHz, and the pulse width of the laser beam was 3 microseconds.

  FIG. 7 shows temperature changes on the surface of the irradiated part during laser irradiation in Example 4. It was found that the surface temperature of the irradiated portion rose to around 150 ° C. in a short time by laser light irradiation. When the surface of the film was repeatedly rubbed strongly with cut cotton moistened with acetone after drawing, the layer of the composition containing strontium apatite in the portion irradiated with the laser was fused and remained on the surface of the UHMWPE film. It was found that the part that was not irradiated was wiped with cut cotton. FIG. 8 shows a scanning electron micrograph (magnification 2500 times) of a layer of a composition containing strontium apatite formed on the surface of the UHMWPE film by laser drawing obtained in Example 4. From this result, it was found that the layer of the composition containing strontium apatite was formed by firmly adhering to the surface of the UHMWPE film. Further, no thermal deformation was observed as a whole UHMWPE film.

(Example 5)
A spinal cage used for spinal fusion (Medtronic Sofa Moda Neck Co., Ltd., sterilized CAPSTONE PEEK, PEEK resin implant) was used as a base material, and the adhesion of the composition containing strontium apatite to this was examined. The spine with the composition containing strontium apatite on the surface was dried by dipping the spine cage in the coating solution prepared in Example 3, lifting it up and allowing it to stand in a dryer at 70 ° C. for 3 hours. A cage was prepared. In contrast, a carbon dioxide laser (laser marker ML-Z9510) was used to irradiate laser light (wavelength 10.6 μm) from the side where the composition was placed, scanning speed 6000 mm / second, laser power (duty ratio) Drawing was performed in a straight line in parallel at a line interval of 70 μm with a spot diameter of 40% and a line diameter of 70 μm. The oscillation frequency of the laser was 25 kHz, and the pulse width of the laser beam was 16 microseconds. Since the spine cage is a three-dimensional structure having a complicated shape, there is a portion that is not irradiated with laser in one drawing. Therefore, the entire laser irradiation was performed without changing the angle. Using a spinal cage after laser irradiation, this was immersed in simulated body fluid for 30 days, during which time a small amount of fluid was collected and the concentration of eluted strontium ions was measured. An almost constant value of around 5 ppm was measured. During this time, no change such as peeling was observed in the composition layer containing strontium apatite formed on the spinal cage surface. After the test, the spinal cage was taken out and the surface was observed with a scanning electron microscope. As a result, it was confirmed that scaly crystals of calcium apatite derived from simulated body fluid were deposited on the surface of the spinal cage. It became clear to show.

(Example 6)
A composition containing strontium apatite to an artificial ligament (The Leads-Keio Artificial Ligments II, 15 mm × 500 mm) made of polyester fiber, which is one of biological implantable implants, as a base material The adhesion by laser was examined. The artificial ligament was dipped in the coating solution prepared in Example 3, pulled up and left to stand in a drier at 70 ° C. for 3 hours for drying, and an artificial composition in which a composition containing strontium apatite was placed on the surface A ligament was prepared. On the other hand, a carbon dioxide laser (laser marker ML-Z9510) was used, and laser light irradiation (wavelength 10.6 μm) was performed from the side where the composition was placed, scanning speed 12000 mm / second, laser power (duty ratio) Drawing was performed in a straight line in parallel at a line interval of 70 μm with a spot diameter of 40% and a line diameter of 70 μm. The oscillation frequency of the laser was 25 kHz, and the pulse width of the laser beam was 16 microseconds. The surface temperature of the laser beam irradiation part was measured in the same manner as in Example 1. FIG. 9 shows a temperature change on the surface of the irradiated part during laser irradiation in Example 6. It was found that the surface temperature of the irradiated part rose to around 80 ° C. in a short time by laser light irradiation. After drawing, the surface of the artificial ligament was repeatedly rubbed strongly with cut cotton moistened with acetone, and a layer of the composition containing strontium apatite in the portion irradiated with the laser remained fused to the surface of the artificial ligament, It was found that the part not irradiated with the laser was wiped with cut cotton. FIG. 10 shows a scanning electron micrograph of a layer of a composition containing strontium apatite formed on the surface of an artificial ligament by laser drawing obtained in Example 6. The magnifications in FIG. 10 are (a) 500 times and (b) 2500 times. From this result, it was found that the layer of the composition containing strontium apatite was formed by firmly adhering to the surface of the artificial ligament.

  The method for coating a plastic base of the present invention with apatite can be preferably used in the manufacture of medical devices such as various biological implants because it can firmly adhere apatite to the surface of various plastic bases.

Claims (2)

On a plastic substrate having a thermoplastic, established a composition comprising apatite and thermoplastic resin, relative to the composition from the side of the composition, the infrared light in the wavelength region 9~11μm using carbon dioxide laser A method of coating apatite on a plastic substrate that is irradiated. On a plastic substrate having a thermoplastic, established a composition comprising apatite and thermoplastic resin, relative to the composition from the side of the composition, the infrared light in the wavelength region 9~11μm using carbon dioxide laser A method for manufacturing an implant, which performs irradiation.