NL9301941A - Method of applying a coating of a bioactive material to implants. - Google Patents

Description

Title: Method for applying a coating of a bioactive material to implants.

The invention relates to a method of applying a coating of a bioactive material to implants to be attached to skeletal parts.

The method according to the invention furthermore relates to a new coating material.

Surgical implants that contain a bioactive material are known for repairing or strengthening skeletal parts, such as bones, joints and teeth. In this context, a bioactive material is a material that processes a specific biological response at the interface between an implant and a skeletal part. More specifically, a bond between the skeletal tissue and the implant material is obtained. It goes without saying that the growth of an implant on skeletal tissue is of great advantage. It is of great importance in terms of the increase in clinical function.

For example, it is known that silicate glass, specific ceramic glass compositions, as well as silica, titania, and zirconia layers prepared by the sol-gel method are capable of chemically bonding to bone tissue. More specifically, in a physiological environment, an apatite layer grows on surfaces of these materials. This process takes place both in vivo and in test systems using simulated body fluids. Apatite is a bioactive compound that provides a connection between the aforementioned glassy materials and living skeletal tissue. Another is described in detail in Panjian Li, In vitro and In vivo Calcium Phosphate Induction on Gel Oxides, PhD Thesis Leiden University, Offset Drukkerij Haveka B.V., Alblasserdam, The Netherlands (1993) and in Panjian Li et al., J. Am.Ceram.Soc. 15 (1992), 2094-2097.

. Furthermore, it is known from the review article "Medical Applications of Calcium Phosphate Bioceramics" by K. de Grootin Ceramics International 12. (1993), 363-366, that ceramic articles made from calcium phosphate salts can be used successfully to replace and strengthen bone tissue. It is known to both manufacture implants of completely different ceramic materials and to apply a coating of such a material to a substrate which is used as an implant, for example stainless steel.

Implants made from bioceramics and bioglass only, for example implants from calcium phosphate salts, have strong compression properties, but are weak under-tension and have a low fatigue strength.

Such solid implants can therefore only be used clinically in places where no high tensile strengths occur. An example of a clinical application of an implant from calcium phosphates only is the replacement of middle ossicles.

Implants of a strong material coated with methyl hydroxyapatite or other bioactive calcium phosphate-related compounds do have a high strength. Coatings of calcium phosphate salts, and especially of hydroxyapatite, can be applied to substrates in various ways. In the contribution of Paul Serekian in Hydroxylapatite Coatings in Orthopedic Surgery, edited by R.G.T. Gees ink and M.T. Manley, Raven Press, Ltd., New York (1993), 81-87 discusses the advantages and disadvantages of plasma spraying, flame spraying, dip coating, electrophoresis and microwave sputtering, among others. The most common coating method is plasma spraying. An important drawback of all these known methods is that the methods are laborious and complicated. Therefore, there is a need for a simple method of coating suitable implant substrates.

Bioactive compounds bind to skeletal parts, because these compounds are very similar in structure to the mineral phase of skeletal tissue. In recent years, the calcium-phosphate system, and especially hydroxyapatite, has been extensively studied. Hydroxyapatxet xs a naturally occurring mineral that forms the main mineral component in bone and in tandem enamel. In addition, the calcium carbonate system and carbonate-containing hydroxyapatxet have also been studied in this context.

Bone minerals mainly consist of a complex mixture of calcium, phosphate, carbonate and hydroxyl ions, while potassium and sodium ions are also present. It is believed that a series of salts with the general formula

Cap (PO4) q (C03) r (OH) s where p 2 l and q, r and s 2 0, and where 2p = 3q + 2r + s, can bind to skeletal parts when these salts are present in the form of a solid implant or as a coating material for other, for example, metal implants. When p = 10, q = 6, r = 0 and s = 2, the above formula gives the hydroxyapatxet structural formula; if p = 1, q = 0, r = i ens = 0, calcium carbonate is represented; and when for example p = 9, q = 5, r = 1 and s = 1, a carbonate-containing hydroxyapatxet is obtained.

A simple method has now been found which solves the problem of the known coating methods. This simple method is based on the well-known fact that hard water often forms precipitates. These blows are usually a problem. The deposits formed are difficult to remove due to the excellent adhesion to the materials on which they precipitate. In particular, reference is made to scale formation in kettles and pans, the occurrence of limescale in washing machines, etc. The precipitates mainly consist of calcium carbonate complexes. According to the invention, use is generally made of this generally disadvantageous phenomenon.

The invention relates to a method of coating an implant substrate with a bioactive material represented by the general formula (I)

Cap (PO4) q (CO 3) r (OH) s, where p 2 1 and q, r and s 2 0, and where 2p = 3q + 2r + s, wherein said substrate is brought into a solution in which at least calcium, preferably carbonate ions and optionally phosphate ions and / or a source of hydroxyl ions are present, after which the bioactive material is deposited from the solution on the substrate.

In the process of the invention, the presence of calcium ions in a solvent is essential, and in a number of preferred embodiments, the presence of carbonate or hydrogen carbonate ions will furthermore be used for the precipitation reaction.

The solvent must be subject to the requirement that it may contain calcium, carbonate and phosphate ions. In a preferred embodiment of the method according to the invention, an aqueous solution, preferably water, is used as the solution.

The method according to the invention will normally start from a solution in which calcium ions are present. Hydrogen carbonate ions can be added to this solution in the form of a soluble hydrogen carbonate salt or formed in situ from a soluble carbonate salt or from CC> 2 gas being passed through.

As is well known, the scale discussed above is formed when hard water containing calcium ions is boiled in the presence of carbon dioxide. Carbon dioxide in water forms hydrogen carbonate ions. Boiling of the water causes decomposition of (a part of) these hydrogen carbonate ions, after which the poorly soluble calcium carbonate is formed.

In the form of a form, this reaction takes place as follows in water, for example:

Ca (HC03) 2 - (elevated temperature) - »CaCO3 (4) + CO2 (T) + H2O Hydrogen carbonate ions give a weakly acidic pH in water. By escaping (part of) the carbon dioxide gas, the pH of the remaining solution will rise, or, in other words, the concentration of OH ions will rise.

If phosphate ions are also present in a solution with calcium and (hydrogen) carbonate ions, they will also precipitate with a rise in pH. This can be represented by the following (incomplete) reaction equation:

Ca2 + + HPO42- + H2PO4- + HCO3-— C02 (t) + Cap (PO4) q (C03) r (OH) g (4)

Depending on the ion concentrations and pH of the solution, a precipitate of a compound of formula (I) can be obtained with any desired value for p, g, r and s.

One skilled in the art can easily determine the process conditions for precipitating a desired coating composition by trial and error. Preferably a bioactive material is deposited in which the ratio p / q is between 1 and 2.

More specifically, the solubility products of the various calcium carbonate phosphate salts are known in the literature as a function of temperature and pH (see, for example, F. CM Driessens, Formation and Stability of CalciumPhosphates in relation to the Phase Composition of the Mineralin Calcified Tissues , In Bioceramics of Calcium Phosphate, K. de Groot editor, CRC Press, 1984). In addition, it is well known that as the concentration of ions in a solution increases, the following conditions may arise: unsaturation; supersaturation or the formation of a metastable state; and precipitation. These three stages can also be created by, for example, increasing the temperature and / or the pH.

The manner in which the coating is deposited from a solution containing at least calcium and carbonate ions according to the invention is not critical. However, using the method according to the invention it is most effective when the starting solution is in the metastable state. The simulated body fluid described in the above publications of Panjian Li is very satisfactory. This simulated body fluid has an ionic composition that is similar to the ionic composition of liquids present in the body, such as blood and tissue fluid. In essence, from such a metastable liquid, a suitable precipitate can be deposited on a substrate by introducing the substrate into this solution and maintaining it therein for some time, for example a few days. Preference is, however, given to methods in which a precipitate on a substrate deposited in the metastable solution is obtained by means of a temperature change or a pH change. Such methods can be better controlled, regulated.

In one preferred embodiment, the solution is heated to precipitate the bioactive material on the substrate. Although this is dependent on deion concentrations in the (metastable) solution, a temperature increase of 50 ° C will usually suffice to precipitate the desired calcium salt. This method can be compared to the formation of scale in a kettle.

In another embodiment, the substrate that is (partially) immersed in the solution is heated to precipitate the bioactive material thereon. This method can be compared to the formation of limescale on a heating element in, for example, a washing machine. Depending on the ion concentrations in the solution, a temperature difference between the substrates and the solution of about 50 ° C will generally be sufficient for a desired precipitation.

In yet another embodiment, the solution is added to allow the bioactive material to settle on the substrate. This embodiment can be compared with known methods for the softening of (waste) water. In these softening methods, which are described, for example, in the publication Abscheidung von Calciumphosphaten aus Abwasser durch Kristallisation imwirbelbett reactor of E. Eggers and J.C. van Dijk, which publication was nominated on 28 November 1986 at the Symposium Entfernung von Phosphaten aus Abwassem und

Nutzbahrmachung vom Klarschlammen in Frankfurt / Neu-Isenburg 2, BRD, is injected into a stream of hard water lye. This results in a metastable solution, which is softened after passage through a fluidized bed of, for example, sand grains. In principle, any basic compound can be added as a basic solution in the method according to the invention. For example, a caustic soda solution or a soda solution can be injected. Preferably, however, a lime water solution is added to the solution used in the process of the invention.

It is emphasized once again that the method according to the invention makes use of processes which are referred to as undesirable - scale formation or limescale formation - or of processes used to prevent these undesirable processes - softening of water.

From the article Medical Applications of Calcium Phosphate Bioceramics by K. de Groot in Journal of the Ceramic Society of Japan, ££ (1991), 943-953, it appears that the optimal thickness for a coating on an implant at the upper limit is determined by the strength, brittleness of the coating layer and at the lower limit due to the fact that an apatite surface in the body is broken down.

A thicker coating has been shown to be more brittle and less strong than a thinner coating. Furthermore, since thinner coatings adhere better to a substrate, it appears desirable to apply a coating as thin as possible.

On the other hand, however, apatite surfaces degrade in the body. Care must be taken to ensure that the layer is so thick that skeletal tissue can grow. It is known that approximately 20 µm apatite is broken down in the body per year. Moreover, studies have shown that the role of hydroxyapatite coatings is essential, especially in the first year and especially in the first month after implant placement.

In a preferred embodiment of the method according to the invention, a layer of bioactive material with a thickness between 5 and 100, and preferably between 10 and 50 µ, is deposited.

As stated above, it is preferred to start from an aqueous solution of calcium ions, in which at least {hydrogen) carbonate ions and preferably also phosphate ions are present. As a rule, this aqueous solution will be weakly acidic. In a preferred embodiment, fluoride ions are additionally present. Fluorapatite is known to not degrade under physiological conditions. Although traces of other elements may be present, the starting solution is preferably prepared with starting materials which are as pure as possible. For example, aquadest is used as the basis for an aqueous solution.

Finally, the invention relates to a new implant comprising a substrate material coated with a carbonate-containing calcium phosphate layer. Known implants which are coated with bioactive compounds are always subjected to a heat treatment during manufacture (e.g., pias formation or calcination steps). Due to the known heat treatments, all carbonate in the form of CO2 will always escape. According to the method according to the invention, it is now possible to apply carbonate-containing calcium phosphate coatings to implants.

Known implant materials can be used as a substrate. In particular, excellent results are obtained when the bioactive coating is applied to metal implants. Suitable materials include titanium, titanium alloys, stainless steel and chromium-nickel-cobalt alloys. In addition, the concept of the method according to the invention can also be used for the production of bioactive bulk material for the formation of small implants, such as middle ear prostheses, by introducing a seed material into the, preferably metastable, solution.

One of the great advantages of the method of the invention over known methods is the absence of a heating step, reaching temperatures above 100 ° C (plasma formation or calcination step). This makes it possible to also coat plastic substrates with a bioactive calcium salt, which can lead to new possibilities in the use of implants.

Examples.

An aqueous solution with 142 mM Na +, 5 mM K +, 2.5 mM Ca 2+, 147.8 mM Cl ', 4.2 mM HCO3 "and 1 mM HPO42" was prepared by dissolving distilled water "reagent-grade" NaCl , NaHCO3,1 KCl, K2HPO4 * 3H2O and CaCl2. A stainless steel implant was immersed in this solution and the solution was heated to 87 ° C. A carbonate-containing hydroxyapatite layer was deposited with a thickness between 1 and 10 µm.

This can be confirmed with FT-IR reflection analysis; and SEM recordings.

Example 2

A stainless steel implant was introduced into the solution prepared in Example 1. Then a 1 molar lime water solution was continuously added to the solution. It was found that a carbonate-containing hydroxyapatite layer was deposited at a rate of 2-3 µm / h. The deposited salt layer was considerably smoother than the layer obtained using the method of Example 1.

Claims (9)

A method of coating an implant substrate with a bioactive material represented by the general formula Cap (PO4) g (CO3) r (OH) Si where p> 1 and q, r and s> 0, and where 2p = 3q + 2r + s, wherein said substrate is brought into a solution in which at least calcium ions, preferably carbonate ions and optionally phosphate ions are present, after which the bioactive material from the solution is precipitated on the substrate. A method according to claim 1, wherein a bioactive material is precipitated, wherein the ratio p / q is between 1 and 2. A method according to claim 1 or 2, wherein an aqueous solution is used as the solution. The method according to any of the preceding claims, wherein the solution is heated to precipitate the bioactive material on the substrate. A method according to any one of claims 1-3, wherein the substrate is heated to precipitate the bioactive material thereon. The method of any one of claims 1 to 3, wherein a basic compound is added to the solution to precipitate the bioactive material on the substrate. A method according to any one of the preceding claims, wherein a layer of bioactive material with a thickness between 5 and 100 mm is deposited. A method according to any one of the preceding claims, wherein fluoride ions are also present in the solution. Implant comprising a substrate material coated with a carbonate-containing calcium phosphate layer.