JP2001079080A - Bioactive inorganic-organic hybrid material and its preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an inorg.-org. hybrid material with excellent flexibility and being useful as a bone substitution material. SOLUTION: The material is provided with a hydrolysate A of an alkoxy silane-terminated polyalkylene oxide of the formula: (R1O)3-xR3xSiR2NHCO- O-[(CH2)mO]n-NHCOR2SiR3x(OR1)3-x (wherein R1 and R3 are each the same or different alkyl group and R2 is an alkylene group and x is 0 or an integer of at most 2 and m is an integer of at least 1 and n is 0 or an integer at least 2), a hydrolysate B of an organoalkoxy silane SiR4y(OR5)4-y bonded with A (wherein R4 and R5 are each an alkyl group being the same or different each other and y is 0 or an integer of at most 3), and calcium ions being ionically bonded oxygens positioned at cleaving points of either one of the hydrolysates.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an inorganic / organic hybrid material having an inorganic skeleton modified with an organic substance and a method for producing the same. This inorganic-organic hybrid material
It can be suitably used as a bone replacement material.

[0002]

2. Description of the Related Art If an organic substance can be introduced into an inorganic material such as ceramics or glass at a molecular level, the resulting material will have both the properties of an inorganic material and that of an organic material, and a new material that is neither an inorganic material nor an organic material. It can be expected that it has excellent properties. For example, bone is an inorganic-organic composite in which apatite particles, which are inorganic components, are precipitated on collagen fibers, which are organic polymers. From this, if it is possible to synthesize a complex combining a flexible organic polymer component and a bioactive inorganic component, it is rich in flexibility,
Moreover, it is expected that a material that can be combined with bone can be obtained.

To meet this expectation, Schmidt has published an organic-inorganic hybrid material called ORMOSILS, obtained by the reaction of tetraethoxysilane with silanol-terminated polydimethylsiloxane (PDMS). Crystallin Solid 1985 7th
3, 681). Omosil is composed of an inorganic component (alkoxysilane: Si (OR) ₄ , R is an alkyl group) and an organic component (P
It is an excellent material in that the elasticity can be adjusted by changing the ratio with DMS). Further, the present inventors, the PDMS
The adjustment range of Young's modulus is wider than Omosil using
Moreover, a material containing a plurality of inorganic components has been disclosed (Japanese Unexamined Patent Publication No.
1-1172109).

[0004]

The above PDMS-based composite material is useful as a material for replacing hard tissue such as cancellous bone.
As bone replacement materials such as skulls and jawbones, more flexible and bioactive replacement materials are required. Therefore, an object of the present invention is to provide an inorganic / organic hybrid material which is useful as a bone replacement material having excellent flexibility.

[0005]

In order to achieve the object, a bioactive inorganic / organic hybrid material of the present invention has a general formula

Embedded image (R¹O)_3-xR^Three _xSiR^TwoNHCO-O-[(CH_Two)_mO]_n-NHCOR^TwoSiR
^Three _x(OR¹)_3-x  [Where R¹And R^Three _xAre the same or different alkyl groups, R^TwoIs
Alkylene group, x is an integer of 0 or 2 or less, m is 1 or more
An integer, n represents an integer of 2 or more. Alkoki]
Hydrolyzate of polysilane oxide terminated with silane
(A); an organoalkoxy bonded to (A)
Run SiR^Four _y(OR^Five)_4-y[R^FourAnd R^FiveAre the same or different from each other
The alkyl group, y represents 0 or an integer of 3 or less. ] Water
Cleavage (B); and cleavage of any hydrolyzate
Calcium ion ionically bonded to oxygen located at the point
It is characterized by having.

[0006] A suitable method for producing the material of the present invention is represented by the general formula:

Embedded image (R¹O)_3-xR^Three _xSiR^TwoNHCO-O-[(CH_Two)_mO]_n-NHCOR^TwoSiR
^Three _x(OR¹)_3-x  [Where R¹And R^Three _xAre the same or different alkyl groups, R^TwoIs
Alkylene group, x is an integer of 0 or 2 or less, m is 1 or more
An integer, n represents an integer of 2 or more. Alkoki]
Sisilane-terminated polyalkylene oxide and organoa
Lucoxysilane SiR^Four _y(OR^Five)_4-y[R^FourAnd R^FiveAre identical to each other
Or a different alkyl group, y represents an integer of 3 or less. ]
Add hydrolyzable calcium compound to solution containing
It is characterized by doing.

The alkoxysilane-terminated polyalkylene oxide and the organoalkoxysilane are hydrolyzed and polycondensed by the action of distilled water catalyzed by an inorganic acid such as hydrochloric acid or an alkali such as ammonia. Polycondensate obtained is, Si-O ^- having multiple cleavage points negatively charged as. Therefore, when a hydrolyzable calcium compound is added thereto, calcium ions bind to the cleavage point and exhibit biological activity. Examples of the hydrolyzable calcium compounds include calcium chloride (CaCl ₂ ), calcium acetate (
(CH ₃ COO) ₂ Ca), calcium carbonate (CaCO ₃ ) and the like.

[0008] The structure of the obtained reaction product is represented by polytetramethylene oxide (PTM)
O) is shown in FIG. According to the production method of the present invention, a material that is more flexible than the PDMS-based composite material can be obtained, and can be obtained by changing the content of the alkoxysilane-terminated polyalkylene oxide and the amount of the calcium compound added. The breaking strain and Young's modulus of the material can be adjusted. The reason is probably as follows.

In PDMS, a methyl group is bonded to both sides of silicon, which is the trunk of a polymer chain, so that the polymer chain is hardly bent due to steric hindrance. On the other hand, in the case of alkoxysilane-terminated polyalkylene oxide, FIG. This is because the trunk of the polymer chain is carbon as shown in (1) and only hydrogen is bonded to both sides thereof, so that there is almost no steric hindrance and it is easy to bend. The calcium ions need not be present at all cleavage points, but may be present in an appropriate amount depending on the application. Further, it is not necessary that all the hydrolyzate (B) is bonded to (A), and (B) may be further bonded to (B) bonded to (A).

[0010] The inorganic-organic hybrid material of the present invention comprises:
When implanted in a living body, it naturally forms an apatite layer on its surface and binds to the bone through this layer.
It may be soaked in an aqueous solution containing a and phosphorus P to form a bioactive layer containing apatite as a main component on the surface thereof. An example of such an aqueous solution is a simulated body fluid.

The alkoxysilane-terminated polyalkylene oxide is preferably triethoxysilane-terminated polytetramethylene oxide (Si-PTMO). First
For polyalkylene oxide, PT
This is because MO is easy to synthesize and is sold at a low price.
Secondly, at the trialkoxysilane terminal, a hydrolysis rate is appropriate and a uniform product can be easily obtained as compared with the trimethoxysilane terminal or tributoxysilane terminal.
Si-PTMO is synthesized, for example, from PTMO and isocyanatopropyltriethoxysilane (hereinafter, referred to as IPTS) in a dry atmosphere such as a nitrogen atmosphere.

If a hydrolyzable titanium compound is added to the solution before adding the calcium compound, the ability to generate apatite and mechanical properties on the surface can be drastically improved. This is considered to be because bioactive titania is formed on the surface and a strong network of titania is formed inside.

[0013]

EXAMPLES [Synthesis Example of Si-PTMO] PTMO (average molecular weight: 1000) manufactured by Aldrich Chemical Co., Ltd. and IPTS manufactured by Aldrich Chemical were mixed at a molar ratio of 1: 2, and reacted at 70 ° C. for 5 days in a nitrogen atmosphere. . After the reaction, it was confirmed by IR that the peak of the isocyanate group (2250 cm ^-1 ) had disappeared and the peak of the carbonyl group (1700 cm ^-1 ) had occurred. Therefore, NHCO is added between the propylene group to which the ethoxysilyl group is bonded and the tetramethylene chain.
It is recognized that Si-PTMO having a bond has been formed.

[Example 1] This is PTMO-CaO-S
It is a manufacturing example of iO ₂ . The reagents were adjusted to the compositions shown in Table 1 by the following procedure. X in the table is Si-PTM
O and tetraethoxysilane Si (OEt) ₄ (hereinafter T
EOS. ) And the total weight of
Indicates the weight percentage.

TEOS manufactured by Nacalai Tesque, tetrahydrofuran (hereinafter, referred to as THF), isopropyl alcohol (hereinafter, referred to as IPA), and Si-
After stirring the PTMO in a 100 ml Erlenmeyer flask for 15 minutes, the mixed solution (first solution) was mixed with distilled water and hydrochloric acid (HC).
(135%) and the mixture was further stirred for 24 hours. THF and IPA are solvents, and hydrochloric acid is a catalyst for hydrolysis and polycondensation reactions.

Next, a mixed solution (second liquid) of Ca (NO ₃ ) ₂ , H ₂ O and IPA is added, stirred for 1 to 2 minutes, and then poured into a cylindrical plastic container having an opening area of about 50 cm ^2. However, the opening of the container was covered with a paraffin film, and five holes having a diameter of about 2 mm were formed in the film to gel the solution at room temperature while regulating the evaporation rate of the solvent. 1
After a week, the film was taken out and dried as it was at room temperature for 3 weeks.

[0017]

[Table 1]

The obtained dried gel body is 10 × 10 × 2 mm
³ cut to size, polished with # 400 diamond paste, simulated body fluid was adjusted to pH = 7.4,36.5 ℃ (inorganic ion concentration ^{[mM]: Na + 142,} K + 5.0,
Mg ²⁺ 1.5, Ca ²⁺ 2.5, Cl ⁻ 148, HCO ₃ ⁻
4.2, HPO ₄ ² -1.0, SO ₄ ² -0.5) (hereinafter S
(Referred to as BF) in 30 ml for various periods. The change in the surface structure of the sample in SBF was measured by thin film X-ray diffraction (TF-XR
Table 2 shows the number of days required for the formation of apatite to be observed, as analyzed in D).

Separately, a dumbbell-shaped test piece was prepared from the dried gel obtained above using a No. 1 punching die of JIS-K7113. The test piece was placed at a distance between marked lines l ₀ = 1.
The sample was attached to an Instron type tester (DSS-500, manufactured by Shimadzu Corporation) so that the thickness was 5 mm, the crosshead speed was 2 mm / min, and a tensile stress was applied at room temperature until breakage occurred. The maximum tensile stress σ = P / A ₀ is determined from the load value P at the time of fracture and the initial sectional area A ₀ of the test piece,
Distortion ε = Δl / l from moving distance Δl of crosshead
₀ and Young's modulus E were determined from the slope of the stress-strain curve. The number of test pieces was 7 each. Table 2 shows the measurement results. FIG. 2 shows a stress-strain curve when the amount of calcium is changed while keeping the amount of Si-PTMO constant, and FIG. 3 shows a stress-strain curve when the amount of Si-PTMO is changed while keeping the amount of calcium constant.

[0020]

[Table 2]

As can be seen in Table 2, the days required for apatite formation decreased with increasing calcium content and with decreasing Si-PTMO content.
Also, as can be seen in Table 2, FIGS. 2 and 3, when the calcium content was changed, the maximum tensile stress and the breaking strain hardly changed with the calcium content, and the Young's modulus increased as the calcium content increased. Diminished. Si-P
Varying the TMO content increased the breaking strain and decreased the maximum tensile stress and Young's modulus as the Si-PTMO content increased. From the above results, it was found that by changing the calcium content and the Si-PTMO content according to the method of the present invention, bioactive flexible inorganic / organic hybrids having different mechanical properties can be obtained. Further, since the material of the present invention generates apatite on the surface in SBF, it is apparent that apatite is also generated in vivo and bonded to bone via the apatite.

For comparison, a dried gel was prepared under the same conditions as above except that PDMS was used instead of the Si-PTMO. From the dried gel body for comparison, JIS-K71
When a dumbbell-shaped test piece was prepared using the No. 13 type 1 punching die, the dried gel body was poor in flexibility, and thus cracks occurred and the test piece could not be prepared.

Example 2 This is PTMO-CaO-S
This is a production example of iO ₂ —TiO ₂ . The reagents were adjusted to the compositions shown in Table 3 by the following procedure. Y in the table is Si
-Si- based on the total weight of PTMO, TEOS and tetraisopropyl titanate (hereinafter referred to as TiPT)
Shows the percentage of PTMO weight. Unless otherwise noted,
The same reagent as in Example 1 was used. TEOS, TH
F, IPA and Si-PTMO were stirred under the same conditions as in Example 1 to obtain a first liquid. Then, the same operation as in Example 1 was performed, except that TiPT was added to the first liquid and stirred for 24 hours, and then the second liquid was added.

[0024]

[Table 3]

Table 4 shows the number of days of apatite formation of the obtained dried gel body measured under the same conditions as in Example 1. Further, a test piece for measuring mechanical properties was prepared in the same manner as in Example 1, and the results of measuring the mechanical properties are shown in Table 4 and FIG.

[0026]

[Table 4]

As is evident from Table 4, the addition of a small amount of titanium significantly reduced the number of days required for apatite formation and increased the breaking strain of the material. From this result, according to the method of the present invention, by adding an appropriate amount of titanium, bone repair in vivo can be rapidly performed,
Moreover, it is clear that excellent flexibility can be exhibited.

Comparative Example As a starting material, TEOS manufactured by Nacalai Tesque, Ca (NO ₃ ) ₂ , and hydrochloric acid (35%) were used. PDMS (average molecular weight 1100) manufactured by Aldrich Chemical Co., Ltd. was used as an organic component.
Assuming that TEOS is 1, the mixing ratio of the raw materials is 0.109 for PDMS, 0.15 for Ca (NO ₃ ) ₂ , and 2 for water.

First, TEOS was placed in a mixed solvent of IPA and THF, and distilled water was added with vigorous stirring using hydrochloric acid as a catalyst. After a 2 hour hydrolysis reaction, PDMS was added. The stirring was continued for as long as 15 hours or more. Continue to mix for 1.5 hours, then Ca (NO ₃ ) ₂ , distilled water and I
The mixture of PA was added and stirred for 1 hour. At this time, the pH of the reaction solution was 3.0 to 4.0. The reaction solution was put in a plastic container and left in the atmosphere at 40 ° C. for 1 day to ripen. A part of the solvent was evaporated and the reaction solution became a gel. By heating this gel at 150 ° C. for 1 day, a disk having a diameter of 70 mm and a thickness of 7 mm was obtained.

Next, a dumbbell-shaped test piece was prepared from the dried gel obtained above using a No. 1 punching die of JIS-K7113. The test piece was placed at a distance between marked lines l ₀ = 2.
It was attached to an Instron type tester (AGS-10KNG, manufactured by Shimadzu Corporation) so that the distance became 0 mm. Then, the crosshead speed was set to 0.5 mm / min, and a tensile stress was applied until breakage occurred at room temperature. As in Example 1, σ, breaking strain and Young's modulus E were determined. As a result, σ
= 12.16 ± 2.64, strain at break = 23.27%, E
= 151 ± 44. The number of test pieces was eight.

[0031]

As described above, according to the present invention, it is possible to easily obtain a material having desired mechanical properties, for example, excellent flexibility and excellent bone forming ability on the surface. Beneficial for treatment.

[Brief description of the drawings]

FIG. 1 is a diagram showing a chemical structure of a material of an embodiment.

FIG. 2 is a graph showing a stress-strain curve when the calcium content is changed.

FIG. 3 is a graph showing a stress-strain curve when the content of Si-PTMO is changed.

FIG. 4 is a graph showing a stress-strain curve when the titanium content is changed.

Claims (8)

[Claims] (1) A compound represented by the general formula:¹O)_3-xR^Three _xSiR^TwoNHCO-O-[(CH_Two)_mO]_n-NHCOR^TwoSiR
^Three _x(OR¹)_3-x  [Where R¹And R^ThreeAre the same or different alkyl groups, R^TwoIs
A alkylene group, x is an integer of 0 or 2 or less, and m is an integer of 1 or more.
The number and n represent an integer of 2 or more. An alkoxy represented by the formula:
Hydrolyzate of silane-terminated polyalkylene oxide
(A); an organoalkoxy bonded to (A)
Run SiR^Four _y(OR^Five)_4-y[R^FourAnd R^FiveAre the same or different from each other
The alkyl group, y represents 0 or an integer of 3 or less. ] Water
Cleavage (B); and cleavage of any hydrolyzate
Calcium ion ionically bonded to oxygen located at the point
Bioactive inorganic and organic hive characterized by comprising
Lid material. 2. The material according to claim 1, further comprising a hydrolyzate (C) of a titanium compound bonded to either (A) or (B). 3. The material according to claim 1, wherein a layer mainly composed of apatite is formed on the surface. (4) a compound represented by the general formula:¹O)_3-xR^Three _xSiR^TwoNHCO-O-[(CH_Two)_mO]_n-NHCOR^TwoSiR
^Three _x(OR¹)_3-x  [Where R¹And R^Three _xAre the same or different alkyl groups, R^TwoIs
Alkylene group, x is an integer of 0 or 2 or less, m is 1 or more
An integer, n represents an integer of 2 or more. Alkoki]
Sisilane-terminated polyalkylene oxide and organoa
Lucoxysilane SiR^Four _y(OR^Five)_4-y[R^FourAnd R^FiveAre identical to each other
Or a different alkyl group, y represents 0 or an integer of 3 or less.
You. ] With a hydrolyzable calcium compound
Bioactive inorganic / organic high, characterized by adding and mixing
Manufacturing method of brid material. 5. The method of claim 4 wherein said alkoxysilane terminated polyalkylene oxide is triethoxysilane terminated polytetramethylene oxide (Si-PTMO). 6. The method according to claim 5, wherein said Si-PTMO is synthesized from polytetramethylene oxide and isocyanatopropyltriethoxysilane. 7. The method according to claim 4, wherein a hydrolyzable titanium compound is added to the solution before adding the calcium compound. 8. A layer comprising apatite as a main component on the surface by immersing the mixture in an aqueous solution containing calcium Ca and phosphorus P having a solubility equal to or higher than the solubility of apatite. The method described in Crab.