Biocompatible composite material useful for making bone or tooth prostheses, for coating metal, ceramic, silicon or polymer implants, or for coating textile fabrics

The invention relates to a biocompatible composite material on the basis of an inorganic gel. The composite material is bioactive and as material for the bone or Zahner set, for coating implants made of metals, ceramics, Silicon or polymers and for coating textile fabrics suitable.

It is generally known that load-bearing implants (speci ell hip replacements) are equipped with coatings to the Biocompatibility of prostheses to improve. Important Forde ments for the coatings are that these non-absorbable, physiologically harmless and bioactive, ie that a Growing together with surrounding tissue is possible. It is further it is necessary that the coatings on the load situation in several years are abrasion resistant and in its mechanical Ver hold between bone and implant are. These receivables gen are of recent coating materials only Unzu fulfilled reaching.

It is currently possible to implant surfaces by electrostatic chemical processes or vacuum process to coat. Elek -chemical methods require conductive substrates are substance-specific and do not allow integration of Biopoly mers (DE 44 31 862 C2, DE 195 04 386 A1). Vacuum process ge equip any embedding of biopolymers and require high equipment-related and energy expenditure (EP 0029787 B1).

A known alternative is the coating by the sol- Gel process with subsequent sintering. Thus, calcium phosphate phases (WO 95/13101 A1), TiO₂- (WO 93/21969 A1), ZrO₂- and SiO₂Gel layers (JP 09-122223 A) on Implantatwerkstof fen be deposited. The creation of metal oxide with the sol-gel method is bioinert on training Materials, ie materials without biologically active ingredients parts limited, because for a sufficient substrate adhesion necessary sintering biologically active components or orga American radicals from the layers casts. In addition to providing Stel development of adequate adhesion is the sintering of the conventional metal oxide also sterility of Coatings sought.

A critical disadvantage of the previously known method is that due to the high excitation energies (CVD and PVD proceedings ren), sintering temperatures (sol-gel method) or high Fabric specificity (electrochemical process) integration of biopolymers is not possible and thus the bioactivity of the layers is insufficient. Moreover, due to the pure inorganic character of the layers e in to brittle material behavior and observed a decreased strength.

Other composites based on organic matrix materials or organic gels are known from US 4,172,128 A, DE 94 00 138 U1; US Patent No. 5,429,821 A, DE 27 56 256 A1, DE 41 03 876 C2, US 5,116,824 A, DE-OS 35 26 320 A1 and DE-OS 36 08 158 A1 known.

The object of the invention is to provide an improved compos material indicate that be an integration of biopolymers riding trips and as a bone or tooth replacement material or Implant coating is suitable. The object of the invention it is further to provide a method for producing such specify composite.

These objects are achieved by a composite material and a Ver drive for its production having the characteristics of the Claims 1 and 11 is released. Advantageous execution embodiments of the invention will be apparent from the dependent Claims.

Surprisingly, it was the task with simple means in particular be achieved in that Scleroproteins or their hydrolysis and / or glycosaminoglycans Ver application of the sol-gel technique as a bioactive component in Metalloxidgele be embedded. If suitable co compositions and technologies emerge stable composites with high hardness, wear resistance and adhesion, the bio are active and non-resorbable. In a heat treatment to improve the physical and mechanical properties can be completely or at least partially eliminated. A be Sonderer advantage of the invention is that by the Embedding of biopolymers in an organic matrix of egg nem material similar to natural bone material a Mate material with high mechanical stability and high bioactivity provided.

Deviating from the previous sol-gel process were the Invention first achieved the following specific benefits will. The interest biocompatible materials are relatively poorly soluble. Nevertheless, according to the invention an excellent coating quality with a homogeneous Distribution of biocompatible materials can be achieved. The biocompatible materials meet simultaneously several func NEN. First, they provide the particular desired bioactive Properties. Moreover, the formation becomes clearer, trans ent coatings of high hardness and uniformity in ge wrestle thickness ranges allows. Finally, promote bioactive materials, the liability of an inventive Composite material on each substrate.

The invention thus relates to a biocompatible compo sitmaterial which a metal oxide gel and one or more homo gen embedded Scleroproteins or glycosaminoglycans includes and / or hydrolysis products of these proteins, and the Use of such a composite material. The composite material favors the deposition of basic calcium phosphate Stages and is as a material for bone or tooth replacement or for the coating of implants made of metals, ceramics, Silicon or polymers and for coating textile fabrics suitable. The invention is also a process for the Producing such a biocompatible composite material.

The Scleroproteins used comprise a group of Pro proteins consisting in biological organisms support functions to practice. The Scleroproteins be as fibrillar proteins or linear fiber proteins referred. Examples of scleral proteins are the keratins of the hair, nails, feathers, wool and like the silk fibroin, collagens support and Bin degewebes, skin, bone and cartilage, which in connective tissue occurring elastin and chitin-protein compounds such. as the conchagens.

As the inorganic metal oxides can gel of elements of II.-IV. Main group and subgroup of the periodic table such as SiO₂. Al₂O₃, ZrO₂, TiO₂, B₂O₃, ZnO, CaO, P₂O₅ or mixtures thereof ver be used by the one by a sol-gel process, z. B., Hydrolysis of the corresponding metal alkoxides in accordance Eq. (1), to the corresponding metal oxide sols and subsequently quent gelation by neutralization, heating or Aufkon centering, replaced. See JC Brinker, GW Scherer, Sol-Gel Science, Academic Press, London 1990. For the modification the sol-gel coating properties, the hydrolysis of Metal alkoxides in the presence of admixed alkyl trialkoxysilanes R-Si (OR ')₃ and / or R Dialkoxysilanes₂-Si (OR ')₂ accomplished are thereby modified Metalloxidgele be formed, the relative to 1 weight metal oxide from 0 to 1 Parts by weight of R-SiO_3/2 and / or R₂-SiO Included. R is organic alkyl radical, the amino, hydroxyl or alkoxy may contain. R 'is an alkyl radical having 1-4 primarily Carbon atoms. This modification may, for. Example, the Elasticity and adhesion behavior of the gel layers targeted be improved.

The preparation of the biocompatible composite material in the following steps:

(1) sol preparation

Preparation of metal oxide sol by acidic or basic Hydrolysis of metal alkoxides (including Siliciumverbin tions) or metal halides to the corresponding sols.

M (OR)_n + N / 2H₂O → (MO_{n / 2})_Sol + NROH (1)

M = z. As Si, Al, Ti, Zr, Ti, B, Zn, Ca, P, or mixtures thereofR '= alkyl radical having 1-4 carbon atoms

For the modification of the metal oxide can before solation Alkyl trialkoxysilanes R-Si (OR ')₃ and / or Dialkoxysilanes R₂-Si (OR ')₂ be added. The hydrolysis of the corresponding Metal alkoxides is preferably effected in an aqueous, organic rule or mixed solvent, optionally with the addition of dilute mineral acid, aqueous alkali, fluoride or tertiary amines as hydrolysis. As the organic Solvent is preferably ethanol, acetone or dioxane used. The resulting metal oxide are water-clear Solutions with a solids content of 3-20 wt .-%.

(2) formation of Biokompositsolen

Addition of bio-component (one or more homogeneously Embedded Scleroproteins or their hydrolysis and / or Glycosaminoglycans) in dissolved or solid form to the metal oxide sol. The biocomponent may also before or during the hydro lytic formation of the metal oxide are mixed, when stable to the hydrolysis conditions (pH and Lö solvent milieu) is.

(MO_{n / 2})_Sol + Biocomponent → (MO_{n / 2} + Biocomponent)_Sol (2)

For proteinaceous components, it is recommended to share to keep organic solvents in metal oxide low to Denaturing to avoid. This can easily be z. B. by distillative removal of the organic solvent at simultaneous addition of the equivalent volume quantities achieve water. In this way, sufficiently stable, purely aqueous modified metal oxide, with the proteinaceous bio homogeneous Biokompositsole corre accordingly (2) arise. The proportion of bio-component can vary depending on intended use 1-50 .-% based on the total Kompositmenge be. For many applications, about 20 wt .-% proved Biocomponent in the composite to be particularly advantageous.

(3) Formation of biocomposite gels

The preparation of volume products (so-called. "Bulk" products) he followed by gelling the Biokompositsole after heating or Neutralization and subsequent drying. The production dün ner coatings are by concentrating during a Be interleaving process on a support. By Gelierungspro process carried out a homogeneous embedding of the biological component in the inorganic gel and an effective immobilization:(MO_{n / 2} + Biocomponent)_Sol → (MO_{n / 2} + Biocomponent)_gel (3)

The production of layered composites can be prepared by conventional Coating techniques such as dipping ( "dip coating"), spraying ( "Spray coating"), spinning ( "spin-coating"), brushing or Baste done. The layer thicknesses are typically in a range of 0.08. , , 2 microns. As the support can all customary in medical substrates of metals, Kera mik, silicon or polymers are used. It should also the impregnation of textile fabrics such. B. of medical Ver band stuff, no problem.

must finally to stabilize the composite material the Solvent from the solidified by a Biogel be removed and drying process is called gets. xerogels in the form of volume products or films. The aging at room temperature, heat treatment or chemical curing can lead further improvement of material properties.

For the production of biocompatible composite materials as Skleroprotein component preferably collagen I, elastin, Fibroins or mixtures thereof are used. Alternatively, or be sliding the addition of glycosaminoglycan component is pos Lich. Except hyaluronic acid, derivatives thereof, and hydrolysis products may chondroitin sulfate, keratan sulfate or other Representatives of the class of substances or mixtures are added. As Hydrolysates are preferred gelatin solutions, collagen Hydro lysate, or mixtures thereof. The recovery of the Pro teinkomponente can from natural sources or by gentechni cal preparation done.

The protein additive causes the decisive improvement of Biocompatibility and mechanical properties of the resulting biocompatible composite material. Cell adhesion is improved. Furthermore, the mechanical behav improved th over known coating materials for implant tate, since by varying the composition of Kompositsols Fracture toughness, modulus, flexural strength, compressive strength, Substrate adhesion and wear parameters of the resulting bio compatible composite can be optimized.

A modification of the biocompatible composite material can carried out using chemical curing agent. These are bi- or polyfunctional compounds which react with the side chains the amino acids of scleroproteins react, so that a intermolecular crosslinking. Typically, the Proportion of the crosslinking agent used is less than 1 wt .-% of the biocompatible composite material. It can anor ganic crosslinking (z. B. chromium and aluminum salts) organic crosslinking agents (eg. as diimides, diisocyanates, Epoxides, formaldehyde or dialdehydes) are used. The chemical curing leads to an increased stability of the Kom posits in physiological media, improved mechanical Properties and prevents the metabolism of compo sits. Additional property modifications of biocompatible Composite can through the addition of special bioactive get drugs or drug mixtures to composite sol will. Usual additives are to 5 wt .-% (based on the solids content of the composite). Among bioactive action materials are preferably broad-spectrum antibiotics (eg. as gentamicin, Erythromycin or colistin) to understand. By antimicrobial bielle effect of antibiotics is the risk of infection in Associated with reduced implantation. Among bioactive Agents are also substances to be understood that the A can grow the implant in bone tissue accelerate. These can include, for. Example, hormones, growth factors, cytokines, or Signal peptide sequences are used. Among the best known Active ingredients of the substance classes include TGF β, BMP-2, RGD Peptides or calcitonin. Included are simple Verbin compounds, such as O-phosphoserine, aspartic acid, glycine, arginine or derivatives thereof. The improved ingrowth favors Healing process and leads to earlier with Rehabilitation measures can be started after the operation.

The addition of calcium salts, phosphates or basic Calcium phosphate suspensions in concentrations of 30 wt .-% to can be further modified, the biocompatible composite material will. In this way, mechanical properties can ver improved and the bioactivity of the composite material further he be increased.

The composite material according to the invention is as a material for the bone or tooth replacement suited. The xerogel can to Grinding be compressed as granules for moldings, as in implants suitable for repair of bone and tooth defects are.

Moreover, the biocompatible composite material is advantageous exemplified for the coating of implants made of metals or other materials suitable. Typically, the use is as Coating on load bearing implants made of titanium and is NEN alloys such. as hip prostheses, orthodontic In implants or prosthetic knee. It is characteristic that the United use of the material as a coating, the bioactivity of the metallic material greatly improved. The biokompa tible composite induced in vitro or in vivo the Ab divorce basic calcium phosphates. The high proportion protein component, the adhesion improves on the Material. Due to good substrate adhesion on different union substrates (eg., glass, titanium, silicon) the suitability of the biocompatible composite material as a coating on walls ren nonabsorbable implants.

In addition, the biocompatible composite material is suitable for Impregnation of textile fabrics, z. B. by medical Ver band stuff. The impregnation leads with good skin treaty sensitivity to an improved mechanical stability and a controllable depending on protein content of the water absorption Tissue.

The advantages of the invention biocompatible compos terials made over previous coatings

<ul><li>1. in the combination of a high biocompatibility with good mechanical properties at both volume-products as well as in coatings,</li><li>2. in the improved mechanical adjustment of load-bearing Implants (z. B. hip prosthesis) by applying the material as an intermediate layer between the prosthesis and bone tissue,</li><li>3. in lower thermal pretreatment of the material, which embed thermo unstable Scleroproteins and associated high biocompatibility of the composite material allows</li><li>4. the possibility of formulation by change proteins and Agents (eg., Antibiotics or interleukins) in the Be To embed coating,</li><li>5. in good adhesion to different implant Mate materials and high wear resistance of the modified top tracts,</li><li>6. the ability, by varying the quantitative ratios mechanical between inorganic sol and Skleroprotein to adjust properties of the later purpose of use,</li><li>7. in small appliances technical, energy and temporal Expenditure for production of the composite material,</li><li>8 to provide a non-brittle, deformable Kompositmate rials, the occurrence of long-term relaxation phenomena counteracts the bone or tooth replacement, and</li><li>9. in favoring the deposition of basic Calciumphos phatphasen.</li></ul>

The biocompatible composite material is is therefore particularly as a material for bone or tooth alternatively, for the coating of implants made of metals, Kera mik, silicon or polymers and textile impregnation Tissue.

embodiments

example 1

10 ml tetraethoxysilane, 40 ml of 1,4-dioxane and 20 ml of 0.01M Hydrochloric acid are stirred at room temperature for 20 h. You get a stable SiO₂Sol A (solids content approximately 4.2% in 70% 1,4-dioxane, pH ca. 2.0).

7 ml of the sol A are mixed with 7 ml of water, 2.3 ml of a kommer cial aqueous 10% ZrO₂Sol (MERCK KGaA, Darmstadt) and 10 g Collapur solution (1% collagen I solution, Grunau Illertissen GmbH, Illertissen) mixed. The result is a kla res Sol. The dip coating a titanium specimen 1 × 4.4 cm (drawing speed 30 cm / min) gives, after Trock NEN in the air a transparent coating of about 1 micron Thick, containing about 16% by weight collagen.

Mechanical testing of the coating indicated for Vickers hardness HV 0.0008 a value of 44 (nanoindentation SHIMADZU DUH-202, 0:08 p test load, penetration depth: 126-381 nm). The layer wears out at a test load of 122 g self after 2000 Reibcyclen not (Oscillating Kugeltribometer, Ball diameter 5 mm, movement frequency 3 Hz).

The immersion of the coated specimen in a simulated Blood fluid resulted after 12 h, the separation of basic Cal ciumphosphate on the layer surface. (Test by S. Li, Q. Liu, J. de Wijn, K. de Groot, B. Zhou J. Materials Sci. Lett. 15 (1996) 1882 ff.).

Furthermore, the specimen in cell culture studies was Cell line L 929 (mouse lung fibroblasts) on cell adhesion tested within 24 h. The quantitative comparison was made after MTT-test, that is, synthesis of a formazan dye by Akti tivity of cellular succinate dehydrogenase (see. E. Winter coat, S. Ha "Biocompatible Materials Science and Engineering", Sprin ger-Verlag 1996, pp 68-80.). The evaluation of the cell growth resulted in an increase to 111% (for comparison without schichtes Glass 100%).

example 2

100 ml of tetraethoxysilane, 400 ml of ethanol and 200 ml of 00:25% strength Ammonia solution are stirred at room temperature for 20 h. one A stable SiO₂Sol B (solids content 4.2% in 70% Ethanol, pH = 9.2).

To 200 ml of the sol B is a solution of 1.3 g of collagen hydrolyzate Nutrilan® I-50 (Grunau Illertissen GmbH, Iller Tissen) in 5 ml 0.1 M NH₄Cl / NH₃Buffer carefully added dropwise. The result is a clear, slightly yellowish Sol (viscosity at 20 C = 3.5 mPas). The dip-coating a 2.5 × 7.5 cm² Glass plate (drawing speed 30 cm / min) obtained by Trock NEN in the air a transparent coating of about 0.4 microns Thickness, containing approximately 7.1 wt .-% biopolymer.

Mechanical testing of the coating indicated for Vickers hardness HV 0.0008 a value of 21st

The immersion of the coated specimen in a simulated Blood fluid resulted after 12 h, the separation of basic Cal ciumphosphate on the layer surface.

example 3

80 ml of tetraethoxysilane, 20 ml 3-Glycidyloxypropyl trimethoxysilane (GLYMO), 400 ml 1,4-dioxane and 200 ml 0.01N Hydrochloric acid are mixed and stirred at room temperature for 20 h. This gives a stable SiO₂Sol C (about 5.0% solids content).

4 g of inert gelatin (FEW Wolfen) are in 96 ml 0.01N HCl dissolved solution and adjusted with 1N HCl solution to pH 4.0. To 120 ml Sol C. 80 ml of the gelatin solution are added dropwise. It A clear composite sol.

The dip-coating a 2.5 × 7.5 cm² Glass plate (Ziehge speed 30 cm / min) gives, after drying in air, a transparent coating of about 1 .mu.m thickness of ca. 35 wt .-% biopolymer contains.

The immersion of the coated specimen in a simulated Blood fluid resulted after 12 h, the separation of basic Cal ciumphosphate on the layer surface.

Furthermore, it was the Biokompositsol described above, the obtained by mixing the sol C with 4% gelatin solution was, for coating a technical polyamide fabric ver turns (two-roll, 0.5 m / min rolling speed). After drying the samples at 4 h / 60 ° C were at 2 × 6 cm² Strip tensile strength tests performed with the Strips were stretched longitudinally to the breaking point. There following values ​​were obtained for the maximum tensile strength: 1170 N for untreated strips, 1320 N for with Biokompositsol impregnated strips.

example 4

100 ml of tetraethoxysilane, 400 ml of ethanol and 200 ml of 0.01M Hydrochloric acid are stirred at room temperature for 20 h. 600 ml of thus obtained sol are mixed with 420 ml of water. The GE is mixed in a distillation apparatus at the boiling water heated and 420 ml of ethanol distilled off. After cooling, a stable aqueous SiO₂sol D (Solids content 4.2% in water, pH = 2.3).

25 ml Sol D with 1,357 g of 1% solution of hyaluronic acid (GfN, production of natural extracts GmbH, Wald-Michelbach) mixed. The resulting clear viscous sol (viscosity = 51.7 mPas at 20 ° C).

The dip-coating a 2.5 × 7.5 cm² Glass plate (Ziehge speed 15 cm / min) results in egg after drying in air, nen transparent coating of about 1 micron thickness.

Mechanical testing of the coating indicated for Vickers hardness HV 0.0008 ver a value of 76. The layer wears out at a test load of 222 g after 2000 Friction not cyclen.

The immersion of the coated specimen in a simulated Blood fluid resulted after 12 h, the separation of basic Calcium phosphates on the layer surface.