JPH1133106A - Biological implant member - Google Patents

Abstract

PURPOSE: To provide a biological implant member having a hydroxyapatite membrance which has a similar structure and composition to those of a bone over an organic high molecular substrate. CONSTITUTION: This implant member 11 has a hydroxyapatite membrance similar to a bone in an implanting area including the upper adaptor 1, a flange part 3, and the lower adaptor 2 of an organic high molecular substrate, which has an ester bond at a main chain and/or side chain constituting the implant member or has hydroxyl groups at the side chain and/or at the end. With such a structure, the implant member has a biological adaptability and enough strength, and in addition, a larger degree of freedom in designing.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to diseases and disasters,
When administering a drug solution for life support and treatment from outside the living body using a catheter or the like, when injecting a drug solution deeply inside the body, or a member located at the connection part connecting the inside and outside the body or completely inside the living body The present invention also relates to a biological implant member that serves as an injection port, and a biological implant member that substitutes and repairs a defective portion of hard tissue such as bone.

[0002]

2. Description of the Related Art Recent research and development on implant members is remarkable, and new materials are being developed for not only artificial organs but also orthopedic members, artificial roots, and the like. Among them, hydroxyapatite is known to have a high bioactivity and is a specific material to be integrated with bone, and has attracted attention. Accordingly, many inventions relating to implant materials using this material have been published,
No. 86272 discloses a member for implanting a bone material by coating a ceramic material such as alumina or zirconia, pure titanium or a titanium alloy with a calcium phosphate material such as hydroxyapatite.

In Japanese Patent Publication No. Hei 2-13580,
A technique is disclosed in which a living body terminal made of a hydroxyapatite sintered body is used for a portion connecting the inside and outside of a body when extracting in-vivo information to the outside. Japanese Utility Model Publication No. 3-19884 also discloses a technique related to a biological terminal made of hydroxyapatite made from biological bone.

JP-A-3-32676 discloses a technique relating to zirconia or a composite of alumina and hydroxyapatite in order to improve the point that the strength of hydroxyapatite is low and hinders practical application. ing.

Japanese Patent Publication No. 13580/1990 also discloses a sintering method for producing hydroxyapatite, and Japanese Patent Publication No. 50-50737 discloses a plasma spraying method for metal implants. Regarding the plasma spraying method for the core material, see JP-B-59-4691.
No. 1, JP-A-63-34559, JP-A-63-34559
No. 57548, JP-A-63-46165 and the like.

[0006] With respect to the sputtering method, see
The flame spraying method is disclosed in Japanese Ceramics Association 1988, First Autumn Symposium, Proceedings of P.S. There is disclosure in P401-402. The baking method using glass frit is disclosed in Proceedings of the 9th Annual Meeting of the Society of Biomaterials (1987, P6).

Further, regarding the electrophoresis method, see the Ceramic Society of Japan 1988, There is disclosure in P417-418.

A method for depositing hydroxyapatite from an artificial body fluid in which the type and concentration of ions are the same as that of human plasma is disclosed in Japanese Patent Publication No. 62-10939, Japanese Patent Publication No. 1-54290, and Japanese Patent Application Laid-open No. Hei. This is disclosed in Japanese Patent Application Laid-Open No. 2-255515.

[0009]

Conventionally, many techniques have been disclosed as described above with respect to a biological implant member, particularly a biological implant member coated with a bioactive apatite film and a method for producing the same. There are many problems as shown in FIG.

(A) The plasma spraying method requires complicated and expensive equipment, it is difficult to form a dense film, and since the raw material hydroxyapatite is once melted at a high temperature, it is of a type different from apatite in a living body. An apatite film may be formed.

(B) The sputtering method requires a complicated and expensive apparatus, and since the raw material hydroxyapatite is once melted at a high temperature, an apatite film different from apatite in a living body is formed. Is mentioned.

(C) The crystallization method or the glass frit method has a
Since it is necessary to heat-treat at 0 ° C or higher, it can be used only for substrates with high heat resistance. Since the raw material hydroxyapatite is once treated at high temperature, apatite film different from apatite in vivo can be used. Generated. Also,
When the terminal was made of a sintered body, the strength of the hydroxyapatite was low, so that the structure and shape were greatly restricted.

(D) Since the electrophoresis method uses the substrate itself as an electrode, it can be applied only to a metal substrate having good conductivity, and also uses sintered apatite as a raw material. A different apatite film is formed.

(E) The method of precipitating from an artificial body fluid is based on the fact that the base that adheres well to the generated hydroxyapatite is CaO /
There is a problem that it has not been found other than SiO ₂ glass. (F) As a measure for solving some of the above problems, it has been found that an epoch-making implant member can be made by coating an organic polymer with hydroxyapatite having almost the same composition as that of a living body. However, this attempt could not be realized because the problem that hydroxyapatite and the organic polymer could not obtain sufficient adhesive strength was not solved.

The present invention has been intensively studied by the present inventors in order to solve the above-mentioned problems, particularly the problem of item F, and is excellent in compatibility with living bodies and has sufficient strength. It is an object of the present invention to provide a biological implant member that can be designed and has a large degree of freedom in design.

[0016]

According to the present invention, there is provided a biological implant member comprising a hydroxyapatite component aqueous solution having a substantially saturated or supersaturated concentration, preferably having the same type and concentration of ions as human plasma. A hydroxyapatite film is formed on a base material from a simulated body fluid that has been formed. It is composed of selected items.

A more specific configuration of the biological implant member is as follows.

A. Hydroxyapatite film thickness is 3-100μ
m is preferable.

B. It is effective that the organic polymer containing an ester bond in the main chain is selected from allyl resin, oxybenzoyl polyester, polyarylate, polybutylene terephthalate, polycarbonate, and polyethylene terephthalate.

C. Organic polymers containing an ester bond in the side chain include AAS resins (copolymers of acrylates, acrylonitrile and styrene), cellulose plastics such as cellulose acetate, cellulose butyrate and ethylene cellulose, and copolymers of ethylene, vinyl acetate and vinyl chloride. Polymer,
It is effective to use a resin selected from a copolymer of ethylene and vinyl chloride, a copolymer of ethylene and estyl acrylate, a copolymer of estyl acrylate and butadiene and styrene, a methacrylic resin, and a vinyl acetate resin.

D. It is preferable that the organic polymer having a hydroxyl group at a side chain and / or a terminal is a polymer selected from an epoxy resin, a phenol resin, and polyvinyl alcohol.

E. It is particularly effective that the surface of the substrate is non-specular.

F. A phosphate group or a part of the hydroxyl group of hydroxyapatite is substituted by a carbonate group.

G. Glass powder whose main component is CaO and SiO ₂ has a particle size of 100 to 600 μm.
Is preferably 80% or more.

[0025]

In the present invention, the base material of the biological implant member must be selected from a polymer having an ester bond in the main chain and / or the side chain and a polymer having a hydroxyl group in the side chain and / or the terminal. Is necessary to obtain practically sufficient adhesive strength with hydroxyapatite.

Examples of the organic polymer having an ester bond in the main chain include allyl resin, oxybenzoyl polyester, polyarylate, polybutylene terephthalate, polycarbonate, and polyethylene terephthalate, but are not necessarily limited to this organic polymer. Not
If the main chain contains a sufficient ester bond, the object of the present invention can be achieved.

Examples of the organic polymer having an ester bond in the side chain include AAS resin (copolymer of acrylate, acrylonitrile and styrene), cellulose plastics such as cellulose acetate, cellulose butyrate and ethylene cellulose, and ethylene and vinyl acetate. And vinyl chloride copolymers, ethylene and vinyl chloride copolymers, ethylene and estyl acrylate copolymers, estyl acrylate and butadiene and styrene copolymers, methacrylic resins, and resins selected from vinyl acetate resins However, the present invention is not necessarily limited to this organic polymer, and the object of the present invention can be achieved as long as the side chain has a sufficient ester bond.

Examples of the organic polymer having a hydroxyl group at a side chain and / or a terminal include an epoxy resin, a phenol resin,
There is a polymer selected from polyvinyl alcohol, but it is not necessarily limited to this organic polymer, and it is possible to achieve the object of the present invention if there is a sufficient amount of hydroxyl groups on the chain side and / or at the terminal. It is possible.

In the case of polyvinyl alcohol, it must be partially crosslinked and not dissolved in water. Otherwise, the function as a biological implant member cannot be achieved.

The thickness of the hydroxyapatite film is 3 to 100
μm is preferred. If the thickness is less than 3 μm, the hydroxyapatite film may be eroded and disappear while being embedded in the living body. If the thickness exceeds 100 μm, the strain due to the difference in expansion coefficient between the base material and the hydroxyapatite with respect to temperature and humidity increases, and as a result, cracks easily enter the hydroxyapatite layer, and the cracks easily break off as nuclei. is there. Further, the time required for forming the hydroxyapatite layer becomes longer, so that the production cost is increased, and the industrial meaning of thickening the film is lost.

Further, it is preferable that the hydroxyapatite has a phosphate group or a part of the hydroxyl group replaced by a carbonate group, since this is closer to the hydroxyapatite of a living body and has a good affinity with the living body. It is.

Further, the glass powder for the main component CaO and SiO _2, CaO in terms of oxides and SiO ₂
In the range of CaO 20 to 60 mol% SiO ₂ 40 to 80 mol%, and the total of CaO and SiO ₂ is 70 mol
% Or more, and the particle size is 100 to 600 μm.
Means a powder having 80% or more of particles in the range.
Japanese Patent Application Laid-Open No. 25515/1990 discloses a composition of glass whose main components are CaO and SiO ₂ .

The particle size of the glass powder is 100 to 600.
If the particle size is less than 100 μm, the particle size is too small, so that the aqueous solution of the hydroxyapatite component having a saturated or supersaturated concentration is not sufficiently supplied between the glass particles and the substrate, and the hydroxyapatite layer does not grow. Otherwise, the growth is extremely slow, and it is industrially meaningless. On the other hand, if the particle size exceeds 600 μm, sufficient growth nuclei are not formed on the surface of the base material, so that the growth rate is extremely slow or the surface becomes non-uniform, which is not practically preferable. In this case, it is preferable that 80% or more of the particles have a particle size in the range of 100 to 600 μm.
If the content is less than 100%, the number of particles not in the range of 100 to 600 μm increases, so that the growth rate of hydroxyapatite is slowed down or the hydroxyapatite does not grow at all.

[0034]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The main components used in the present invention are CaO and SiO _2.
Was prepared as follows.

<Glass Raw Material Components and Amounts><GlassComposition> CaCO ₃ … 28.431 g CaO 49.87 mol% MgO 2.289 g SiO ₂ 35.46 mol% β-Ca ₂ P _{2 O 7 ... 14.517g P 2 O} 5 ... 7.153mol% CaF 2 ...... 0.249g MgO ... 7.111mol% SiO 2 ...... 17.015g CaF 2 ... 0.399mol% i.e., blending of the glass raw material After finely pulverizing the product using a mortar and mixing uniformly, put in a platinum crucible and place at 1450 ° C.
, And the mixture was poured on an iron plate, rapidly cooled, and pulverized using a ball mill. The following various glass powders were prepared using a sieve for classification. Four types of glass samples shown in Table 1 were prepared and used for evaluation.

[0036]

[Table 1]

An aqueous solution of a hydroxyapatite component having a substantially saturated or supersaturated concentration is prepared with the following composition, and the pH value at 36.5 ° C. is controlled to 7.
Adjusted to 4.

[0038] <solution 1 composition in liters> aqueous solution (1) aqueous solution (2) NaCl ...... 7.996g 11.994g NaHCO 3 ...... 0.350g 0.525g KCl ...... 0.224g 0.336g K 2 HPO _{4 · 3H 2 O ...... 0.228g 0.342g} MgCl 2 · 6H 2 O ...... 0.305g 0.458g CaCl 2 ...... 0.278g 0.417g Na 2 SO 4 ...... 0.071g 0.107g 1NHCl Approximately 45 ml Approximately 68 ml Tris (hydroxymethyl) aminomethane 6.057 g 8.086 g And the living body implant member according to the present invention is shown in FIG. 1 showing the shape of an implant member called a skin button, and FIG. The process is explained using the schematic process diagrams of Figs. 2 and 3 in which the surface is coated with hydroxyapatite. To. In FIG. 1, reference numeral 11 denotes an implant member made of polyether sulfone [trade name: PES4100G], 1 is an upper adapter, 2 is connected to the flange portion 3 of the upper adapter 1, and through the through hole 8b. The lower adapter connects the through holes 8 and 8a. 2 and 3, 4 and 4a are containers, 5 is the above-mentioned glass powder, 6 is an aqueous solution (1), and 7 is an aqueous solution (2).

The implant member 11 shown in FIG.
Is partially buried in a glass powder 5 of glass D and immersed in an aqueous solution (1) 6. After being left for one week in a constant temperature layer of 36.5 ° C., the implant member 11 is taken out and immersed in the aqueous solution (2) 7 as shown in FIG. The implant member 11 is left in a constant temperature layer of 36.5 ° C. for one week, taken out, washed well with distilled water, and then dried at 60 ° C. By the above operation, a bone-like hydroxyapatite film (not shown) of the present invention similar to the bone is formed on the surface of the implant member 11 in the region where the glass powder 5 shown in FIG.

According to the above-described procedure, a total of 22 samples of each of Example 11 and Comparative Example 11 were prepared as samples.
Two were made per condition, one was used for the destructive test and the other one
Individuals were buried in adult dogs to evaluate their compatibility with the living body. The evaluation items are the following three items A to C.

A, Measurement of Hydroxyapatite Film Thickness A part of a flange portion of the above implant material is cut,
Cut the uncorrupted coating with a blade, and use a scanning electron microscope to move the sample
At an angle of 0 °, the thickness of the hydroxyapatite layer at the cut was measured.
The inclination was corrected by calculation, and a list was prepared in the following table.

B, Adhesive strength between base material and hydroxyapatite layer Flange part of the above implant material is partially cut,
A cellophane tape (adhesive tape) was applied to the uncorrupted coating portion, and peeled, and the evaluation was made based on whether or not the hydroxyapatite layer was peeled off.

C. Biocompatibility An implant device as shown in FIG. 4 was prepared using the above implant members not used in the destructive test. After this was sterilized with ethylene oxide gas, it was placed on the chest of an adult dog as shown in FIG.
It was buried as below. 1 day, 3 days, 1 week, 2
The state after one week, three weeks, and one month was observed and the biocompatibility was evaluated. In order to evaluate this biocompatibility with high sensitivity, the implant device is partially outside the body and partially inside the body. The embedding was performed as described above, and the embedding was performed as described above, and the condition of the interface with the skin surface was evaluated. 4 and 5, an upper tube 12 is connected from the through hole 8 of the implant member 11, and a lower tube 13 fixed by a fixing system 14 is connected from the through hole 8a. The distal end of the upper tube 12 has a luer adapter 17 and an intermittent infusion plug 18 attached thereto and is fixed with a fixture 19. On the other hand, the lower adapter 2 including the flange portion 3 of the implant member 11, as shown in FIG.
It is implanted subcutaneously, i.
Is connected to an indwelling catheter 16 via a connector 15 and extends to a required organ (not shown) in the living body.

Hereinafter, Examples 1 to 3, Example 4, and Example 5
The results of the evaluation will be described while selecting Comparative Examples 10 to 10 in comparison with Comparative Examples.

Examples 1-3: In Examples 1-3, it was shown that the implant member of the present invention can strongly attach hydroxyapatite to an organic polymer to such an extent that there is no practical problem and exhibit excellent biocompatibility. Show. The examples were prepared by changing the base material and the glass, and are shown in Table 2 together with the evaluation results. As a comparative example, polyethylene, polystyrene, polypropylene, Teflon, ABS resin, polyvinyl chloride resin, polyurethane resin, and nylon substrate were used for the substrate. Table 3 shows the specifications and evaluation results of Comparative Examples 1 to 9. Of the comparative examples, Comparative Example 1 was based on
The same as polymethyl methacrylate in Table 7 of Example 2 of JP-A-25515, but the glass is made of CaO and SiO ₂
Using a board of the same composition without using a powder whose main component is
It was immersed in the aqueous solution (1) at intervals of 0.5 mm.

In Comparative Example 2, the base was disclosed in JP-A-2-25.
It was prepared under the same conditions as the polyethylene in Table 7 of Example 2 of JP-A-515, and the base material and the main components were CaO and S
A glass plate made of iO ₂ was used and immersed in the aqueous solution (1) at intervals of 0.5 mm.

The base of Comparative Example 3 is disclosed in JP-A-2-25.
No. 515, prepared under the same conditions as the polyethylene shown in Table 7 of Example 2 was prepared using the same CaO and SiO ₂ as in Example 1.
The glass powder was immersed in an aqueous solution (1). In all samples, the surface of the base material was roughened with # 150 sand pepper.

[0048]

[Table 2]

The biological implant member of Example 2 was manufactured as follows. A bioimplant member having the same shape as in Example 1 was injection-molded with Denkastyrol MW, then dipped twice in the following solution, cooled in an atmosphere at -5 ° C, and gelled by crystallizing polyvinyl alcohol. This sample was further annealed in silicone oil to produce a biological implant member coated with a transparent hydrogel having a water content of 20% or less. This biological implant member was coated with hydroxyapatite in the same manner as in Example 1. .

(Method of preparing solution) Degree of saponification: 99.5 mol
1% of Kuraray polyvinyl alcohol was dissolved at a high temperature in a mixed solvent of 30% water and 70% dimethylformamide. Thus, the polyvinyl alcohol concentration is 10%
Was obtained.

[0051]

[Table 3]

The downgrowth shown in Tables 2 and 3 is a phenomenon in which the skin falls down at the interface between the skin and the implant member unless the biocompatibility is good. It is judged that biocompatibility is better as there is no downgrowth. In addition, it is considered that if the biocompatibility is good, the resistance of living tissues to bacteria from the outside does not decrease, so that infection is difficult.

In summary, it can be said that the infection did not occur even if the disinfection was stopped in the implant member of the present invention, which is an epoch-making result.

The brand names of the organic polymer manufacturers used in Examples 1 to 3 and Comparative Examples 1 to 10 are as follows.

<Substance name><Companyname> PBT1401 Toray polyethylene terephthalate Toray Denkastyrol MW Tokaido Kagaku Kogyo Delpet 60N Asahi Kasei Neoxex 45150 Mitsui Petrochemical Dialex HF-77 Mitsubishi Mitsubishi Santo Nobrene EBG… Mitsui Toatsu PTFE… Polyethylene tetrafluoride (this is a scientific name) Stylac 101… Asahi Kasei SR-1158… Riken vinyl industry [medical grade] EG65D… Thermex Co., Ltd. Daiamide 1901… Huls Example 4: In Example 4, the particle size of the glass powder was 1
It is indicated that it is preferable that 80% or more of the particles in the range of 00 to 600 μm are present.

The base material used was polyethersulfone, and only the glass powder was changed to samples A to C.
The conditions were the same as in Example 1. Table 4 shows the evaluation results.

[0057]

[Table 4]

From the results shown in Table 4, it is found that the particle size of the glass powder is 100 to 60 in order to sufficiently grow the hydroxyapatite layer.
This indicates that the content within the range of 0 μm must be 80% or more.

Examples 5 to 10: Only the time during which the substrate was immersed in the aqueous solution (2) was changed.
The same as in Example 1. The thickness of the hydroxyapatite was changed by this method. Table 5 shows specifications and evaluation results of the examples.

[0060]

[Table 5]

In the results shown in Table 5, the surface of the sample of Example 5 was observed after 3 weeks, and it was found that the hydroxyapatite layer had disappeared. When the surface of the sample of Example 10 was observed one month later, it was found that the hydroxyapatite layer partially disappeared.

From the above results, it can be seen that in the present invention, the thickness of the hydroxyapatite layer is preferably 3 to 100 μm, more preferably 10 to 60 μm.

Embodiment 11: In Embodiment 11, the radius is 8 mm.
A 15 μm-thick cylindrical apatite substrate made of polyethylene terephthalate [Toray] was coated with a 14 μm-thick hydroxyapatite in the same manner as in Example 1.
This was implanted in the femur of a rabbit and removed 10 weeks later.
The state of adhesion between the implant member and the living bone tissue was checked. The living tissue had completely adhered to the implant member. This material has a flexural strength of 800 kg / cm ² or more, a breaking elongation of 100% or more, and other implant materials.
For example, it is far superior to bioglass, hydroxyapatite sintered body, and the like, and it can be seen that an implant member that is lightweight and has excellent biocompatibility can be provided.

The living body implant member according to the present invention has been described above using several embodiments. Although it is well known that hydroxyapatite has excellent biocompatibility, its strength is low, so its use as a sintered body as an implant member is limited to parts that do not bear a large force. Have been. Metal substrate to improve this,
Alternatively, a method of coating ceramics has been developed, but it has not become a general-purpose implant member because of the high price of the substrate itself and poor moldability. Originally, it is ideal to coat an organic polymer material that has much better moldability than other materials and is relatively inexpensive.However, the adhesion strength with hydroxyapatite is low, and it is realized. I didn't.

Taking these facts into consideration, the present embodiment has achieved a "biological implant member in which an organic polymer material is coated with hydroxyapatite" which has a sufficiently practical level of adhesive strength to an organic polymer. And proved to have excellent performance.

[0066]

As described above, according to the present invention, the surface of the organic polymer base material having an ester bond in the main chain or / and the side chain or having a hydroxyl group in the side chain or / and / or the terminal is substantially formed. Since a biological implant member having a bone-like hydroxyapatite film was developed using a saturated or supersaturated aqueous solution of hydroxyapatite, it is excellent in compatibility with the living body, has sufficient strength, and has a high degree of design freedom. An implant member has been achieved, which is expected to make a significant contribution, especially to the medical field.

[Brief description of the drawings]

FIG. 1 is an explanatory diagram of a shape of a biological implant member according to one embodiment of the present invention.

FIG. 2 is a schematic view showing a first step of coating a hydroxyapatite film according to the present invention.

FIG. 3 is a schematic view showing a second step of coating a hydroxyapatite film according to the present invention.

FIG. 4 is an explanatory view of a configuration of an implant device formed using the living body implant member according to the present invention.

FIG. 5 is an explanatory view showing a state where the living body implant member of FIG. 4 is embedded and placed in a living body.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Upper adapter 2 Lower adapter 3 Flange part 4,4a Container 5 Glass powder 6 Aqueous solution (1) 7 Aqueous solution (2) 8,8a, 8b Through-hole 11 Implant member

Claims (9)

[Claims] 1. A substrate and a glass powder mainly composed of CaO and SiO ₂ are brought into contact with each other in an aqueous solution of a hydroxyapatite component having a substantially saturated or supersaturated concentration. A bio-implant member having a film formed thereon, wherein the substance constituting the base material is an organic polymer having an ester bond in a main chain or / and a side chain, and an organic polymer having a hydroxyl group in a side chain or / and / or a terminal. A biological implant member selected from the group consisting of: 2. The film thickness of the hydroxyapatite is 3 to 100 μm.
The biological implant member according to claim 1, wherein 3. The organic polymer according to claim 1, wherein the organic polymer having an ester bond in the main chain is a resin selected from allyl resin, oxybenzoyl polyester, polyarylate, polybutylene terephthalate, polycarbonate, and polyethylene terephthalate. Biological implant members. 4. An organic polymer containing an ester bond in a side chain is an AAS resin (copolymer of acrylate, acrylonitrile and styrene), cellulose plastic such as cellulose acetate, cellulose butyrate, and ethylene cellulose, and ethylene and vinyl acetate. And vinyl chloride copolymers, ethylene and vinyl chloride copolymers, ethylene and estyl acrylate copolymers, estyl acrylate and butadiene and styrene copolymers, methacrylic resins, and resins selected from vinyl acetate resins 2. The method according to claim 1, wherein
Biological implant members. 5. The bioimplant member according to claim 1, wherein the organic polymer having a hydroxyl group on a side chain and / or a terminal is an organic polymer selected from an epoxy resin, a phenol resin, and polyvinyl alcohol. 6. The biological implant member according to claim 5, wherein the polyvinyl alcohol is a resin which is partially crosslinked and does not dissolve in water. 7. The biological implant member according to claim 1, wherein the surface of the substrate is non-mirror. 8. A phosphate group of hydroxyapatite, or
The living body implant member according to claim 1, wherein a part of the hydroxyl group is substituted by a carbonate group. 9. The living body implant member according to claim 1, wherein 80% or more of the glass powder containing CaO and SiO ₂ as main components has a particle size in a range of 100 to 600 μm.