MATERIAL FOR A BONE IMPLANT

Abstract

A material for a bone implant includes a surface which contains a metal-based material, a metal alloy, an oxide ceramics material, a polymer material, a composite material or combinations thereof. An organic polymer matrix is covalently bonded to the surface. A substance is linked with the organic polymer matrix for binding embedded metal ions or nanoparticles. A calcium phosphate is embedded in the organic polymer matrix. As a result, the material for the bone implant is biocompatible and corrosion can be slowed down or even prevented.

Claims

1-15. (canceled)

16. A material for a bone implant, the material comprising: a surface having a substance selected from the group consisting of metal-based materials, metal alloys, oxide ceramic materials, polymer materials, composite materials, and combinations thereof; an organic-polymeric matrix bonded covalently to said surface; a further substance incorporated or attached to said organic-polymeric matrix for binding metal ions or nanoparticles; and calcium phosphate incorporated into said organic-polymeric matrix.

17. The material for the bone implant according to claim 16, wherein said further substance for binding the metal ions or the nanoparticles is a pyrocatechol.

18. The material for the bone implant according to claim 16, wherein said organic-polymeric matrix bonded covalently to said surface contains at least one of a collagen, a gelatin, a polysaccharide, a modified polysaccharide or a polycatechol.

19. The material for the bone implant according to claim 18, wherein said polysaccharide is selected from the group consisting of chitosan, alginate, hyaluronic acid, alginic acid, hyaluronate, pectin, carrageenan, agarose, amylose, heparin/heparan sulfate, chondroitin sulfate/dermatan sulfate, keratan sulfate, xylans or mannans after a carboxy-functionalization, xanthan, gellan, fucogalactan, and welan gum.

20. The material for the bone implant according to claim 18, wherein: said polycatechol has a pyrocatechol main structure; and said pyrocatechol being selected from the group consisting of dopamine, norepinephrine and L3,4-dihydroxyphenylalanine.

21. The material for the bone implant according to claim 18, wherein said calcium phosphate is selected from the group consisting of calcium orthophosphate in all mineral forms.

22. The material for the bone implant according to claim 21, wherein said calcium phosphate is selected from the group consisting of amorphous calcium orthophosphate, dicalcium phosphate dihydrate (DCPD; brushite), octacalcium phosphate, and hydroxylapatite, including with partial fluoride, chloride, strontium or carbonate substitution, and combinations thereof.

23. The material for the bone implant according to claim 16, further comprising a linker selected from the group consisting of pyrocatechol, phosphonic acid, phosphoric acid, and organosilane molecules, wherein said organic-polymeric matrix is bonded to said surface via said linker.

24. The material for the bone implant according to claim 16, wherein said organic-polymeric matrix has a layer thickness of between 0.5 micrometers and 50 μm.

25. The material for the bone implant according to claim 16, wherein said organic-polymeric matrix covers said surface entirely with said substance.

26. The material for the bone implant according to claim 16, wherein: said substance covering said surface is titanium; said organic-polymeric matrix bonded covalently to said surface contains pyrocatechol-modified gelatin, pyrocatechol-modified chitosan, and polydopamine; said further substance includes pyrocatechol molecules incorporated or attached to said organic-polymeric matrix and binds the metal ions or the nanoparticles; and said organic-polymeric matrix contains or incorporates hydroxylapatite.

27. The material for the bone implant according to claim 17, wherein said pyrocatechol is selected from the group consisting of protocatechuic alcohol, protocatechualdehyde, protocatechuic acid, 3-(3,4-dihydroxy¬phen¬yl)propionic acid, and 3,4-dihydroxyphenylacetic acid.

28. The material for the bone implant according to claim 24, wherein said organic-polymeric matrix has a layer thickness of between 1 μm and 20 μm.

29. The material for the bone implant according to claim 24, wherein said organic-polymeric matrix has a layer thickness of 10 μm.

30. A method for producing a material for a bone implant, which comprises the steps of: a) providing a surface with a substance selected from the group consisting of metal-based materials, metal alloys, oxide ceramic materials, polymer materials, composite materials, and combinations thereof; b) covalently coupling an organic-polymeric matrix to the surface; c) introducing and/or coupling a further substance which binds metal ions or nanoparticles into/to the organic-polymeric matrix; and d) mineralizing the organic-polymeric matrix with calcium phosphate.

31. The method according to claim 30, which further comprises forming the organic-polymeric matrix to contain a polycatechol, the polycatechol being prepared in step by means of oxidation of at least one pyrocatechol.

32. A bone implant, comprising: a solid material and/or a solid body having the material for the bone implant according to claim 16 being applied thereto.

33. A method of using a material, which comprises the steps of: providing the material according to claim 16; and using the material as a bone implant material on a bone implant.

Description

IN THE DRAWINGS

[0049] FIG. 1 shows a schematic representation of a construction of a material for a bone implant with an organic-polymeric matrix, with a layer-by-layer construction of the individual substances,

[0050] FIG. 2 shows a schematic representation of the construction of the material for a bone implant from FIG. 1, in mineralized form,

[0051] FIG. 3 shows a schematic representation of an alternative construction of a material for a bone implant with an organic-polymeric matrix, as a mixture of the individual substances, and

[0052] FIG. 4 shows a schematic representation of the construction of the material for a bone implant from FIG. 3, in mineralized form.

[0053] FIG. 1 shows, in a schematic representation, a construction of a material 10 for a bone implant 12 (not shown in detail) with an organic-polymeric matrix 18, with a layer-by-layer construction of individual substances, such as gelatin 26, chitosan 32, and polydopamine 34.

[0054] The material 10 for the bone implant 12, which is formed, for example, of a solid material or of a three-dimensional body 44 (not shown in detail), comprises a surface 14, comprising a material 16 selected from the group consisting of metal-based materials, metal alloys, oxide ceramic materials, polymer materials, composite materials, or combinations thereof, and here specifically titanium 42.

[0055] Applied to the surface 14, as a surface coating, is an organic-polymer matrix 18 bonded covalently to this surface 14, application taking place layer by layer or in at least three layers 46, 48, 50. The organic-polymeric matrix 18 comprises collagen and/or gelatin 26 (layer 50), a polysaccharide 28 or a modified polysaccharide 28 (layer 46), and a polycatechol 30 (layer 48). Moreover, the organic-polymeric matrix 18 covers the entire surface 14 of the material 16.

[0056] In this case the polysaccharide 28 is selected from a group consisting of chitosan 32, alginate, hyaluronic acid, alginic acid, hyaluronate, pectin, carrageenan, agarose, amylose, heparin/heparan sulfate, chondroitic sulfate/dermatan sulfate, keratan sulfate, xylans or mannans after a carboxy-functionalization, xanthan, gellan, fucogalactan, or welan gum, and here by way of example is chitosan 32.

[0057] The polycatechol 30 has a pyrocatechol main structure, the pyrocatechol 24 being selected from a group consisting of dopamine 34, norepinephrine or L-3,4-dihydroxyphenylalanine (L-DOPA). In this exemplary embodiment, shown by way of example, the pyrocatechol main structure is based on dopamine 34, and so the polycatechol 30 is polydopamine 34.

[0058] The organic-polymeric matrix 18 additionally has a layer 50 of gelatin 26. The polycatechol 30 or polydopamine 34 serves here as a connector between the layer 46 of chitosan 32 and the layer 50 of gelatin 26. In this exemplary embodiment, the chitosan 32 is first applied to the surface 14, then the contact mediator polydopamine 34, and subsequently the gelatin 26. In principle, however, it is also possible for the gelatin 26 to be applied first, and the chitosan 32 after the polydopamine 34.

[0059] In order to capture any detaching metal which diffuses away, the organic-polymeric matrix 18 comprises a substance 20 which is incorporated or attached to the organic-polymeric matrix 18 and which is able to bind metal ions or nanoparticles. This substance 20 binding the metal ions or nanoparticles is a pyrocatechol 24, preferably selected from a group consisting of protocatechuic alcohol, protocatechualdehyde, protocatechuic acid, 3-(3,4-dihydroxyphenyl)propionic acid, and 3,4-dihydroxyphenylacetic acid. The polycatechol 30 or polydopamine 34 of the layer 48 is also able to bind metal ions or metal nanoparticles. Pyrocatechol molecules 24 preferably serve as the substance 20 which is incorporated or attached to organic-polymeric matrix 18 and binds metal ions or nanoparticles.

[0060] The substance 20 may act as a crosslinker of the collagen or of the gelatin 26, of the polycatechol 30 or polydopamine 34, and of the polysaccharide 28 or the chitosan 34, and therefore represents modifications of these molecules.

[0061] In the exemplary embodiment shown by example here, the organic-polymeric matrix 18 bonded covalently to the surface 14 of titanium 42 therefore comprises a layer 50 of pyrocatechol-modified gelatin 26, a layer 48 of pyrocatechol-modified polydopamine 34, and a layer 46 of pyrocatechol-modified chitosan 32.

[0062] The organic-polymeric matrix 18 is bonded to the surface 14 via a linker 38, which is selected from the group consisting of pyrocatechol, phosphonic acid, phosphoric acid, and organosilane molecules. It is preferably a silane linker 38.

[0063] As can be seen in FIG. 2, which is a schematic representation of the construction of the material 10 for the bone implant 12, in mineralized form, the organic-polymeric matrix 18 comprises incorporated calcium phosphate 22. The calcium phosphate 22 is selected from the group consisting of calcium orthophosphate 22 in all mineral forms or from the group consisting of amorphous calcium orthophosphate (ACP), dicalcium phosphate dihydrate (DCPD; brushite), octacalcium phosphate, and hydroxylapatite 36, including with partial fluoride, chloride, strontium or carbonate substitution, and combinations thereof. According to the embodiment shown, the calcium orthophosphate 22 is hydroxylapatite 36.

[0064] The organic-polymeric matrix 18 has a layer thickness 40 of between 0.5 micrometers (μm) and 50 μm, preferably between 1 μm and 20 μm, and very preferably of 10 μm.

[0065] A method of the invention for producing the material 10 for a bone implant 12, comprises at least the steps of:

[0066] (a) providing a surface 14 comprising a material 16 selected from the group consisting of metal-based materials, metal alloys, oxide ceramic materials, polymer materials, composite materials, or combinations thereof,

[0067] (b) covalently coupling an organic-polymeric matrix 18 to this surface 14,

[0068] (c) introducing and/or coupling a substance 20 which binds metal ions or nanoparticles into/to the organic-polymeric matrix 18, and

[0069] (d) mineralizing the organic-polymeric matrix 18 with calcium phosphate 22.

[0070] Where the organic-polymeric matrix 18 comprises a polycatechol 30, the polycatechol 30 is prepared in step (b) by means of simple oxidation of at least one pyrocatechol 24.

[0071] The substance 20 which binds metal ions or nanoparticles may be introduced and/or coupled into/to the organic-polymeric matrix 18 by incubation of the organic-polymeric matrix 18 in the corresponding substance solution, with subsequent incubation in a solution of a coupling mediator. The coupling mediator may be EDC, HMDA, ADH, formaldehyde or glutaraldehyde, for example.

[0072] Described below by way of example is the production of the material 10:

[0073] Coating of the titanium-based surface 14 with silane linkers 38:

[0074] The surface 14/substrate used was a substrate coated by vapor deposition with 200 nanometers (nm) of titanium 42, and also metal flakes of titanium 42. The reaction is carried out as represented in scheme 1. In this case, first of all, the (3-aminopropyl)trimethoxysilane (APTS) is hydrolyzed in a slightly acidic medium at a pH of 4 for 15 minutes (min) at room temperature.

[0075] Simultaneously, in parallel, the titanium substrates are cleaned with ethanol and water and then incubated in 2 mol (M) NaOH to activate the surface. The cleaned and dried titanium substrates are then immersed into silane solution and incubated at room temperature for 1 hour (h). The unbound silane linker molecules are washed off subsequently with water.

##STR00001##

[0076] Scheme 1: schematic representations of the reaction pathway of the coating of the titanium-based substrates with silane linkers

[0077] Coupling of a layer 46 of chitosan 32:

[0078] The coupling of chitosan 32 (or alternatively modified chitosan 32) is accomplished using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). This is a widespread and commercially available coupling reagent which is frequently employed for the chemical coupling of, for example, proteins and peptides, oligonucleotides. Together with N-hydroxysuccinimide (NHS), specifically, a reaction of carboxylates and amines is promoted, to form an amide bond. EDC coupling reactions are carried out typically under acidic reaction conditions (pH 4.5 to 5.5). The reaction scheme for the coupling of chitosan 32 to the silane surface is shown in scheme 2.

##STR00002##

[0079] Scheme 2 schematic representations of the reaction pathway of the coupling of chitosan 32 to a silane-modified titanium surface 14

[0080] Coupling of a layer 48 of polydopamine 34:

[0081] The attachment of a layer 48 of polydopamine 34 is accomplished by incubation of the titanium-silane linker-chitosan material in a solution of L-DOPA, which is subsequently polymerized by addition of an oxidizing agent. The surface is subsequently washed thoroughly with water.

[0082] Coupling of a layer 50 of gelatin 26:

[0083] The further attachment of a layer 50 of gelatin 26 (or of modified gelatin 26) is accomplished by incubation of the above-produced material in a solution of gelatin 26 at 40° C. Immediately thereafter a crosslinker is added, such as EDC or hexamethylene diisocyanate, for example. The surface is subsequently washed thoroughly with water.

[0084] Modification of chitosan 34 or gelatin 26:

##STR00003##

[0085] Scheme 3: schematic representation of dopamine 34 bonded via an amide bond to gelatin 26

[0086] The attachment of dopamine 34 is accomplished by the incubation of a gelatin 26 or chitosan solution 32 by addition of a crosslinker such as EDC or hexamethylene diisocyanate. The modified gelatin 26 or the modified chitosan 32 is subsequently subjected to dialysis to remove unreacted substances.

[0087] Mineralization of the organic-polymeric matrix 18:

[0088] The matrix 18 is mineralized by incubation of the coated substrates in a solution containing calcium ions (e.g., CaCl.sub.2) for around 15 minutes at room temperature. The pH is adjusted to 9. Subsequently a phosphate-containing solution (e.g., of Na.sub.2HPO.sub.4) is added dropwise at a controlled rate of around 3 mL/min. It is necessary here for the pH to be kept constant at 9. When addition has been made, the solution is stirred at room temperature for a further 24 h. The substrates are subsequently washed with water.

[0089] FIGS. 3 and 4 show an alternative exemplary embodiment of the organic-polymeric matrix 18. Essentially, substances, features and functions which remain the same are labeled in principle with the same reference numerals. In order to distinguish the exemplary embodiments, however, the letter a has been added to the reference numerals of the alternative exemplary embodiment. The description below is confined essentially to the differences relative to the exemplary embodiment in FIGS. 1 and 2; regarding substances, features and functions which remain the same, reference may be made to the description of the exemplary embodiment in FIGS. 1 and 2.

[0090] FIGS. 3 and 4 show a material 10a for a bone implant 12a, with an alternatively constructed organic-polymeric matrix 18a. In this case the embodiments of the examples of FIGS. 1/2 and FIGS. 3/4 differ in that, rather than the organic-polymeric matrix 18a being constructed in layers, the organic-polymeric matrix 18a is instead constructed as a mixture 52 of the individual substances, collagen/gelatin 26, polycatechol 30/polydopamine 34, polysaccharide 28/chitosan 32.

LIST OF REFERENCE NUMERALS

[0091] 10 Material [0092] 12 Bone implant [0093] 14 Surface [0094] 16 Material [0095] 18 Matrix [0096] 20 Substance [0097] 22 Calcium phosphate [0098] 24 Pyrocatechol [0099] 26 Gelatin [0100] 28 Polysaccharide [0101] 30 Polycatechol [0102] 32 Chitosan [0103] 34 Dopamine [0104] 36 Hydroxylapatite [0105] 38 Linker [0106] 40 Layer thickness [0107] 42 Titanium [0108] 44 Body [0109] 46 Layer [0110] 48 Layer [0111] 50 Layer [0112] 52 Mixture