阅读说明：本技术 羟基磷灰石/明胶复合材料及其用途，特别是作为人工象牙的用途,及其制备方法 (Hydroxyapatite/gelatin composite material and use thereof, in particular as artificial ivory, and method for the production thereof ) 是由 D·菲舍尔 J·曼哈特 于 2018-07-05 设计创作，主要内容包括：本发明涉及一种生产多用途的各向同性羟基磷灰石/明胶复合材料的方法,所述方法至少包括以下步骤：a)提供粉状羟基磷灰石在液体介质中的悬浮液,所述液体介质选自C<Sub>1</Sub>-C<Sub>10</Sub>醇、特别是乙醇,另一种水可混溶的分散剂,水及其混合物；b)向所述悬浮液中加入优选浓度为5-25重量％的明胶的明胶水溶液；c)在预定温度下搅动/搅拌所述混合物预定时间段,优选1-10小时,直到所述液体介质部分或完全蒸发；d)任选地干燥步骤c)中获得的产物。在一个特定的实施方案中,所述方法的特征在于在另外的步骤e1)中将在步骤c)或d)中获得的产物进一步用至少一种脂族聚醚渗入。在另一个实施方案中,所述方法的特征在于在步骤e2)中使步骤c)、d)或e1)中获得的产物进一步与至少一种用于交联所述明胶链的试剂接触。本发明的另一方面涉及使用上述方法生产的复合材料,以及其用途,特别是作为人造象牙的用途。(The invention relates to a method for producing a versatile isotropic hydroxyapatite/gelatin composite material, comprising at least the following steps: a) providing a suspension of powdered hydroxyapatite in a liquid medium selected from C 1 ‑C 10 An alcohol, particularly ethanol, another water-miscible dispersant, water and mixtures thereof; b) adding to the suspension a mineral acidSelecting gelatin water solution with gelatin concentration of 5-25 wt%; c) agitating/stirring said mixture at a predetermined temperature for a predetermined period of time, preferably 1-10 hours, until said liquid medium is partially or completely evaporated; d) optionally drying the product obtained in step c). In a particular embodiment, the process is characterized in that the product obtained in step c) or d) is further infiltrated with at least one aliphatic polyether in a further step e 1). In another embodiment, the process is characterized in that the product obtained in step c), d) or e1) is further contacted in step e2) with at least one agent for crosslinking the gelatin chains. Another aspect of the invention relates to a composite material produced using the above method, and its use, in particular as an artificial ivory.)

1. A method of producing an isotropic hydroxyapatite/gelatin composite material, the method comprising at least the steps of:

a) providing a suspension of powdered hydroxyapatite in a liquid medium selected from C₁-C₁₀An alcohol, particularly ethanol, another water-miscible dispersant, water and mixtures thereof;

b) adding an aqueous gelatin solution, preferably having a concentration of 1-40 wt% gelatin, more preferably 5-25 wt% gelatin, to the suspension;

c) agitating/stirring said mixture at a predetermined temperature for a predetermined period of time, preferably 1-10 hours, until said liquid medium is partially or completely evaporated;

d) optionally drying the product obtained in step c).

2. The process according to claim 1, characterized in that step c) is carried out at a temperature lower than the boiling point of the aqueous/organic liquid medium obtained after step b).

3. The process according to claim 1 or 2, characterized in that the product obtained in step c) or d) is further infiltrated with at least one aliphatic polyether in a further step e 1).

4. The method according to any one of claims 1 to 3, characterized in that the product obtained in step c), d) or e1) is further contacted in step e2) with at least one agent for cross-linking the gelatin chains.

5. The method according to claim 4, characterized in that the at least one crosslinking agent is selected from the group consisting of complex-forming metal salts, aldehydes, ketones, epoxides, isocyanates, carbodiimides and enzymes.

6. The method according to claim 5, wherein the complex metal salt is selected from the group consisting of salts of aluminum, chromium, iron, titanium, zirconium, molybdenum, in particular alum, such as potassium alum, chromium alum.

7. The method according to any one of claims 3-6, comprising at least the steps of:

e1a) contacting the product obtained in step c) or d) of claim 1 with a medium containing a polyether/water mixture for a predetermined period of time, preferably 1 hour to 1 week, and

e1b) subsequently exchanging the medium for an anhydrous medium comprising or consisting of an aliphatic polyether and contacting the product obtained after step e1a) with the anhydrous polyether for a predetermined period of time, preferably 1 hour to several weeks.

8. The process according to claim 3 or 7, characterized in that the contact with the polyether is carried out under reduced pressure or vacuum.

9. The process according to any one of claims 4 to 8, characterized in that the product obtained in step c), d) or e1) is contacted with a solution of a cross-linking agent, in particular a complexing metal salt, for a predetermined period of time, preferably 1 hour to 1 week, and then optionally after removing the cross-linking agent, in particular the metal salt solution, and washing, the product is dried.

10. The method according to any one of claims 4 to 6 or 9, characterized in that only a partial region of the product obtained in step c), d) or e1) is contacted with the cross-linking agent and the gelatine matrix is cross-linked only in this partial region.

11. The method according to claim 10, characterized in that the surface contact is achieved by repeated application of the cross-linking agent on the surface of the composite material, for example with a brush or cloth.

12. The process according to any one of claims 1 to 11, characterized in that the aliphatic polyether has a molecular weight of 100-.

13. The method according to any one of claims 1 to 12, wherein the aliphatic polyether is polyethylene glycol.

14. An isotropic hydroxyapatite/gelatin composite material obtainable by the method according to any one of claims 1 to 13 and comprising hydroxyapatite particles of size in the nanometer range randomly embedded in an amorphous gelatin matrix.

15. A composite material according to claim 14, characterised in that the hydroxyapatite particles represent or comprise needle-like crystals of hydroxyapatite having a size in the nanometer range, typically about 10 x 50 nm.

16. An isotropic hydroxyapatite/gelatin composite material obtainable by the method of any one of claims 1 to 13 and comprising an aliphatic polyether embedded in a hydroxyapatite/gelatin matrix, and/or cross-linked gelatin chains, in particular acid groups of amino acids in said gelatin chains cross-linked by metal complexes.

17. Composite according to claim 16, characterized in that the aliphatic polyether has a molar mass of 100-10,000,000g/mol, preferably 400-4000 g/mol.

18. Composite according to claim 16 or 17, characterized in that the aliphatic polyether is polyethylene glycol.

19. The composite material according to any one of claims 14 to 18, having the following composition:

50 to 100% by weight of a hydroxyapatite/gelatin matrix, wherein the hydroxyapatite/gelatin ratio is from 1:1 to 10:1, preferably from 2:1 to 4:1, in particular about 3:1,

0 to 30% by weight, preferably 1 to 10% by weight, of residual liquid medium, and

optionally from 0.5 to 50% by weight, preferably from 1 to 25% by weight, of a polyether.

20. Composite material according to any one of claims 14 to 19, further comprising one or more additives selected in particular from pigments, dyes and phosphors, materials for marking materials, salts, metal particles, polymers, for example derivatives of polyethylene glycol, in particular UV-curable derivatives, glass, fibers, for example cellulose, hemp, polypropylene, carbon, hollow glass fibers, ZnO nanofibers, or antimicrobial components, for example TiO₂And Ag nanoparticles.

21. The composite of any of claims 14-20, which is ivory in color.

22. Use of a composite material according to any one of claims 14 to 21 as an artificial ivory.

23. Use of a composite material according to any one of claims 14 to 21 for the production of key cladding materials for keyboards, grip/handle inserts, for example for sports equipment, tools and knives, watches, model parts, toys, office equipment, writing utensils, tableware, kitchen utensils, clothing accessories, hygiene products, pharmaceuticals, electronic components, building materials, lamps, automotive interiors, jewelry articles, coatings, for example on wood and other materials, such as glass, plastics or metals, for example for interior trim, spectacle frames or as humidity regulating materials and plastic substitutes.

Disclosure of Invention

The components of natural ivory are used in the synthesis method of the present invention. Hydroxyapatite (Ca)₅[PO₄]₃OH) and gelatin were reacted directly in the solvent and concentrated under stirring/agitation. Gelatin is a product of the thermal hydrolysis of collagen and is therefore very similar to collagen, but is more chemically prone toAnd (5) implementing. In this synthesis, a swellable gelatin matrix is formed, which is stabilized by hydroxyapatite and whose properties can be adjusted.

More specifically, the manufacturing method according to claim 1 comprises at least the following steps:

a) providing a suspension of powdered hydroxyapatite in a (preferably polar) liquid medium selected from C₁-C₁₀An alcohol, particularly ethanol, another water-miscible dispersant, water and mixtures thereof;

b) adding an aqueous gelatin solution, preferably having a concentration of 1-40 wt% gelatin, more preferably 5-25 wt% gelatin, to the suspension;

c) agitating/stirring the mixture at a predetermined temperature for a predetermined time, generally in the range of 10 minutes to 24 hours (preferably 1 to 10 hours), until the liquid medium is partially or completely evaporated;

d) optionally drying the product obtained in step c).

The (polar) liquid medium is preferably not water but a water-miscible dispersant, preferably C₁-C₁₀Alcohols, in particular ethanol, or mixtures of such dispersants with water. In a particularly preferred embodiment, this is an azeotropic mixture.

The aqueous gelatin solution added in step b) preferably has a gelatin concentration of 1-40%, more preferably 5-25%, particularly preferably about 15%.

In principle, there is no particular restriction on the choice of gelatin used according to the invention. However, the gelatin preferably has a high Bloom value of typically 50-350, preferably 200-350, a viscosity of typically 1-500, preferably 10-150mps, and a pH of typically 3-9, preferably 4-7.

In step b), the heated gelatin solution (typically in the temperature range of 40-70 ℃) is preferably added to the heated hydroxyapatite suspension (typically in the temperature range of 40-70 ℃).

In step c), the reaction mixture is stirred/stirred, typically at a temperature of 40-200 ℃, preferably 50-60 ℃, for 10 minutes to 24 hours, preferably 2-10 hours.

In one particular embodiment of the process, step c) is carried out at a temperature lower than the boiling point of the aqueous/organic liquid medium obtained after step b) (and, where applicable, also lower than the boiling point of the azeotropic mixture).

The drying in step d) is influenced by temperature, water vapour content and ambient pressure in addition to the amount of material. Preferably, it is carried out in air (1bar), at 25 ℃ and a relative humidity of about 45%. Vacuum drying is also possible.

The drying in step d) can be carried out completely (without further weight loss under standard conditions (1bar, 25 ℃, 45% relative atmospheric humidity)) or only partly. For example, partial drying may be advantageous if the product is further processed, e.g. infiltrated.

The synthesis of calcium phosphate/gelatin composites from solution is described in the literature (e.g.t.kollmann, p.simon, w.carrillo-Cabrera, c.branbarth, t.poth, e.v.rosseeva, r.kniep, chem.mater.22(2010), 5137-.

However, in all publications known to the inventors, calcium phosphate/gelatin composites have not been used as ivory substitutes.

This may be because the known composite materials are often used as bone substitute materials. Although the extracellular matrix of bone and natural ivory have similar major components, namely hydroxyapatite and collagen, their structural arrangement, and thus the basic physical properties, differ significantly from each other. For example, the spatial arrangement of the extracellular matrix is adapted to the corresponding function of bone, and it can also embed functional bone cells. Artificial materials with this structure or these properties are often anisotropic and, for commercial use, are hardly suitable or not suitable at all as ivory replacement materials.

Furthermore, in all publications known to the inventors, the calcium phosphate component is generated in situ. The Ca solution reacts with the phosphate solution and mineralizes the gelatin. In contrast, according to the present invention, powdered hydroxyapatite is directly used. The use of powdered hydroxyapatite has the following advantages in addition to being easier to perform: there are no side reactions to other calcium phases, the components are relatively variable and interchangeable, and other components are easily integrated. Chinese patent CN 101239202B exhibits a similar reaction procedure as shown here, but uses (explicitly produced) layered hydroxyapatite to produce a layered structure (bone substitute material). However, the object of the method according to the invention is the opposite. A random arrangement of components is intentionally created in the product.

The aim of the synthesis is to produce homogeneous composite materials of suitable strength, which have isotropic properties and, in addition, whose swellability is particularly adjustable. This can generally be achieved by the method according to the invention. The following aspects are particularly important for the synthesis.

On the one hand, the properties can be influenced by the ratio of the components, and on the other hand, the use of gelatin with a high Bloom value (corresponding to a high mechanical strength in the gel) and a highly concentrated gelatin solution increases the strength of the product. Furthermore, it is advantageous to keep the duration of the chemical reaction short or the temperature low, since the chain length of the gelatin molecules gradually degrades by hydrolysis with increasing duration/temperature. In addition, the pH should preferably be around the neutral point (pH 6-7).

This can be done, for example, by using azeotropic mixtures. For example, a mixture of water (4.4%) and ethanol (95.6%) boils azeotropically at 78.1 ℃. Thus, if for example hydroxyapatite suspended in ethanol is reacted with a gelatin solution instead of hydroxyapatite suspended in water, concentration of the suspension can be carried out more quickly at lower temperatures. Furthermore, gelatin (insoluble in ethanol) is not further diluted, but the water content is continuously reduced. The low water content, high Bloom values and fast reaction at low temperatures maintain longer gelatin molecular chains and thus produce a more stable product. Hydroxyapatite crystals are embedded in a gelatin matrix without preferred orientation, which results in isotropic product properties.

A product synthesized by the method according to claim 1 shows increased water absorption compared to natural ivory. This is undesirable for some applications. The swellability can be reduced by heat treatment, but at the same time the gelatin matrix also decomposes, which already leads to a brown color in the product at temperatures >150 ℃.

A preferred embodiment of the synthesis method according to the invention therefore comprises a further process step by which the water absorption of the product is reduced or the already absorbed water is removed again.

One possibility is to impregnate with aliphatic polyethers, preferably polyethylene glycol (PEG). PEG (HO (CH)₂CH₂O)_n-H) is available in a variety of molecular weights, is water soluble, non-toxic, and has an antibacterial effect.

The crude product of the invention can be readily impregnated with a PEG/water mixture or PEG. The material initially stores water which is then exchanged for PEG, resulting in a durable infusion product. This penetration can also be used to adjust the water absorption by the different molecular weights of the PEG polymers used.

For this purpose, completely dry (no further weight loss under standard conditions) or only incompletely dry materials can be used, whereby the infiltration also simultaneously cures the material.

The material also remains dimensionally stable when infiltrated with a PEG/water mixture, since water absorption is also significantly reduced. On the other hand, infiltration with pure water produces a soft plastic (soft rubbery) product.

In general, the aliphatic polyethers used, in particular PEG, have a molar mass of 100-10,000,000g/mol, preferably 400-4000 g/mol.

The infiltration treatment according to the invention generally comprises at least one of the following steps:

contacting the product obtained in step c) or d) of claim 1 with a medium containing a polyether/water mixture for a predetermined period of time, preferably 1 hour to 1 week, and optionally subsequently drying; or

Contacting the product obtained in step c) or d) of claim 1 with an anhydrous medium comprising or consisting of an aliphatic polyether for a predetermined period of time, preferably 1 hour to several weeks.

A particular process variant is characterized in that the contact with the polyether takes place under reduced pressure or vacuum. The specific process conditions are not particularly critical and can be readily optimized by one skilled in the art in routine experimentation. For example, the contacting may be carried out at a pressure of from 10 to 500mbar or from 20 to 200mbar for from 1 to 48 hours, preferably from 1 to 24 hours.

A preferred embodiment of the method comprises at least the following steps:

e1a) contacting the product obtained in step c) or d) of claim 1 with a medium containing a polyether/water mixture for a predetermined period of time, preferably 1 hour to 1 week, and

e1b) subsequently exchanging the medium for an anhydrous medium comprising or consisting of an aliphatic polyether and contacting the product obtained after step e1a) with the anhydrous polyether for a predetermined period of time, preferably 1 hour to several weeks.

During the infiltration treatment, the color of the product also changes from white to ivory, the respective color intensity depending on the material used and the duration. Therefore, this treatment particularly advantageously uses the artificial ivory according to the present invention as a piano key covering material.

Another possibility for the work-up of the crude product obtained according to the invention is the contact (curing) with at least one agent for crosslinking the gelatin chains. The water absorption can also be reduced in this way.

The at least one crosslinking agent is preferably selected from the group consisting of complex-forming metal salts, aldehydes, ketones, epoxides, isocyanates, carbodiimides and enzymes, particularly preferably complex-forming metal salts.

The complex-forming metal salt is generally not particularly limited. However, it is preferably selected from salts of aluminium, chromium, iron, titanium, zirconium, molybdenum, in particular alum, e.g. potassium alum, chromium alum.

The acid group of the amino acid in the gelatin chain can be crosslinked by treating with a complex-forming metal salt to form a metal complex, and thus the swelling property and water absorption property can also be reduced or adjusted.

Crosslinking may also be combined with the impregnation treatment as described above.

A particular embodiment of the process according to the invention is therefore characterized in that the product obtained in step c), d) or e1) as described above is further contacted in step e2) with at least one agent for crosslinking the gelatin chains.

In a typical embodiment, the product obtained in step c), d) or e1) is contacted with a solution of a cross-linking agent, preferably a complex-forming metal salt, for a predetermined time, preferably 1 hour to 1 week, and then optionally dried after removal of the cross-linking agent, e.g. metal salt solution, and washing.

A further particular embodiment of the process according to the invention is characterized in that only a partial region of the product obtained in step c), d) or e1) is contacted with the crosslinking agent and the gelatin matrix is crosslinked only in this partial region.

This can be achieved, for example, by repeated application of the crosslinking agent to the surface of the composite material for surface contact, for example with a brush or cloth.

A further particular embodiment of the process according to the invention is characterized in that the crude product according to the invention is infiltrated and contacted with the crosslinking agent in one step. In this variant, steps e1) and e2) occur simultaneously. In a preferred process variant, the product is treated with a PEG/aqueous (preferably about 1%) potassium alum solution.

Another aspect of the invention relates to the product obtainable by the method according to the invention, i.e. an isotropic hydroxyapatite/gelatin composite.

After steps a) -d) of the above-described process according to the invention, a white solid product is initially produced which is fracture-resistant, hygroscopic, machinable, temperature-resistant and, under certain conditions, also flexible. By using the same components as in ivory, the product is very close to a natural product and also the choice of synthetic method is changed, e.g. by introduction/embedding or chemical reaction to optimize the desired material properties.

For example, as described above, the aliphatic polyether may be embedded in the material and/or the gelatin chain may be crosslinked. In addition, the incorporation of polyethers and/or treatment with suitable crosslinkers leads to the production of ivory products. Furthermore, the introduction of polyethers and/or treatment with suitable crosslinkers also improves the hand of the products. As already mentioned at the outset, this is very important for certain applications, in particular for piano keys, and in this respect the product according to the invention offers a clear advantage over conventional ivory substitute products for the production of synthetic key cladding materials.

Thus, in some embodiments, the isotropic hydroxyapatite/gelatin composite according to the present invention is characterized in that it contains aliphatic polyethers, in particular PEG, embedded in a hydroxyapatite/gelatin matrix and/or cross-linked gelatin chains, in particular acid groups of amino acids in gelatin chains cross-linked by metal complexes.

The material according to the invention can also be crosslinked or otherwise modified only in partial regions, for example on the surface.

The aliphatic polyethers, in particular PEG, which are optionally incorporated have a molar mass of 100-10,000,000g/mol, preferably 400-4000 g/mol.

The composite material according to the invention may further comprise one or more additives, in particular pigments, dyes and phosphors, materials for marking materials, salts, metal particles, polymers such as polyethylene glycol and derivatives thereof (e.g. UV curable derivatives), glass, fibers (cellulose, polypropylene, carbon, hollow glass fibers, ZnO nanofibers, hemp fibers) or antimicrobial components, such as TiO₂And Ag nanoparticles.

In a typical embodiment, the isotropic hydroxyapatite/gelatin composite according to the present invention is characterized in that it contains hydroxyapatite particles randomly embedded in an amorphous gelatin matrix, the size of the hydroxyapatite particles being in the nanometer range, typically about 5-1000nm, preferably 10-900nm, more preferably 10-500nm, such as 10-100nm or 50-500 nm.

In a preferred embodiment, the isotropic hydroxyapatite/gelatin composite material according to the present invention is characterized in that it contains needle-like crystals of hydroxyapatite with dimensions in the nanometer range, typically about 10 x 50nm, randomly embedded in an amorphous gelatin matrix.

In a particular embodiment, the composite material according to the invention has the following composition:

50 to 100% by weight of a hydroxyapatite/gelatin matrix, wherein the hydroxyapatite/gelatin ratio is from 1:1 to 10:1, preferably from 2:1 to 4:1, in particular about 3: 1; 0 to 30% by weight, preferably 1 to 10% by weight, of residual liquid medium, and

optionally from 0.5 to 50% by weight, preferably from 1 to 25% by weight, of a polyether.

As already mentioned, the composite material according to the invention offers, owing to its advantageous properties, a multiplicity of possible uses, in particular as an artificial ivory, but also in other fields.

According to the invention, it is also possible to produce for the first time a black key coating material by incorporating a black pigment, which coating material also has the advantageous properties of ivory. To date, keys made of black wood, such as ebony, or plastic keys have been used for this purpose.

Thus, another aspect of the invention relates to the preferred use of the material, for example for the production of key covering materials for keyboards, grip/handle inserts, for example for sports equipment, tools and knives, watches, model parts, toys, office equipment, writing instruments, tableware, kitchen utensils, clothing accessories, hygiene articles, pharmaceuticals, electronic components, building materials, lamps, automotive interiors, jewelry articles, coatings, for example on wood, glass, plastics or metals, for example for interior trim, eyeglass frames or more generally as humidity-regulating materials and plastic substitutes.

The embedding of the fibers also provides the possibility to optimize properties such as porosity, surface roughness and stability. In addition, some of the fibers may be removed from the material again with a suitable solvent.

All kinds of plastic articles can thus be produced, which do not require petroleum or plasticizers for their production.

Products having a multilayer structure can also be realized.

Drawings

FIG. 1 shows a photograph of an isotropic composite according to the invention;

figure 1A shows a hydroxyapatite/gelatin composite feedstock after air drying;

fig. 1B shows the material after cutting, polishing and PEG infiltration.

Figure 2 shows an SEM image of the surface of a material with apatite crystals in a gelatin matrix.

FIG. 3 shows TEM images of a composite material at different scales; figures 3A and 3B show embedded needle crystals of hydroxyapatite (typical dimensions about 10 x 50 nm); figure 3C shows embedded non-acicular hydroxyapatite particles (up to 1000nm in size).

Figure 4 shows the IR spectra of feedstock (1) treated with PEG-400/water (2) or with PEG/potassium alum (3).

Figure 5 shows the X-ray powder diffraction pattern of feedstock (1) treated with PEG-400/water (2) or with PEG/potassium alum (3).

Figure 6 shows raman data comparing a natural ivory (1) and a composite material (2) according to the invention.

The following examples are intended to explain the invention in more detail, but without limiting it to the respective specific parameters and conditions.

Example 1

Preparation of hydroxyapatite/gelatin composite material

An aqueous gelatin solution (10g in 75ml of deionized water) was added to 30g of hydroxyapatite suspended in 75ml of ethanol or water and concentrated in a beaker while stirring/stirring at about 50 ℃. The material was then completely dried in air.

Figure 1A shows the hydroxyapatite/gelatin composite feedstock obtained as above after air drying.