RU2554819C1 - Method for producing bioactive coating on titanium implant implanted into human bone tissue - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: coating contains layers of at least one metal oxide specified in titanium oxide, zirconium oxide, hafnium oxide, tantalum oxide, niobium oxide. The method involves applying a multiple-layer or multicomponent coating by low-pressure atomic layer deposition at a temperature of 200-300°C, blowing a reaction zone with nitrogen and with the use of precursors containing organometallic compounds of the above metals and water. The precursors are applied on the surface by the pulsed delivery to the surface of a titanium substrate at a supply pulse length of 0.2-0.6 s and the intermediate blowing of the reaction zone with nitrogen for 6 s. A deposition cycle number makes 100-1000 cycles.

EFFECT: method provides coating homogeneity, good bioactive properties, low toxicity and corrosive resistance.

6 ex, 5 tbl, 7 dwg

Description

The invention relates to medicine and specifically relates to the production of titanium implants with a bioactive coating intended for insertion into bone tissue to eliminate bone defects with the restoration of bone tissue, in particular, for the manufacture of various titanium orthopedic and dental implants.

As is known in the art, some metals or metal alloys, such as titanium, zirconium, hafnium, tantalum, niobium or their alloys, are used to form relatively strong bonds with bone tissue. In particular, metal implants made of titanium and its alloys, starting around 1950, are known for their ability to bind well to bone tissue. Branemark called this kind of connection osseointegration (see Branemark et al., “Osseointegrated implants in the treatment of the edentulous jaw. Experience from a 10-year period (Osteointegrated implants in the treatment of toothless jaw. 10-year experience”), Scand. J. Plast. Reconstr., II, suppl 16 (1977)).

Currently, titanium, due to a combination of good strength characteristics, high corrosion resistance and non-toxicity, is one of the main materials in the manufacture of various devices (dental, orthopedic implants) for implantation in bone tissue. Under ordinary conditions, titanium is easily oxidized and a thin film of amorphous titanium dioxide (~ 5 nm) appears on its surface, which provides high corrosion resistance of titanium, but at the same time is characterized by a rather long integration time with bone tissue.

Thus, titanium and its alloys are widely used in reconstructive surgery as both dental and orthopedic implants due to their excellent biocompatibility with bone tissue (PJ Branemark, J. Prosthetik Dent 50: 399-410, 1983; DJ Bardos, D. Williams (ed), Concise Encyelopedia of Medical je Dental Materials, Pergamon Press, Ox for 1990, pp 360-365; R. van Noork, J. Mater. Sci 22: 3801-3811, 1987). This can be explained by the unique characteristics of the titanium-bone interface. However, to enhance the bonding or bonding processes and improve bonding or bonding strengths, plasma coatings of apatite, in particular hydroxyapatite, have been developed and approved for clinical use (K. De Groot, J. Ceram. Soc Japan 99: 943-953, 1991).

Although the bond between this metal and bone tissue is relatively strong, it is desirable to strengthen this bond. Currently, many methods have been developed for processing such metal implants in order to obtain them on a suitable surface to improve their osseointegration. A method for manufacturing intraosseous implants is known from RU 2074674 A1, 03/10/1997, which consists in applying a coating system of four layers — two layers of titanium or titanium hydride of different dispersion and thickness — and a third layer from a mechanical mixture on the titanium base of the implant by plasma spraying. titanium or titanium hydride or hydroxyapatite with a ratio of 60-80 wt. % and 20-40 wt. % and the outer layer is hydroxyapatite. To increase the mechanical strength of the implant, the deposition is carried out layer by layer under various conditions, providing a smooth transition from the structure of compact titanium to the structure of the bioactive layer.

The desire to accelerate the osseointegration of titanium implants has stimulated the development of the so-called bioactive coatings in the scientific community. Bioactivity in implantology is understood as the ability of a material to faster osseointegration in comparison with some reference material, most often with titanium. The traditional bioactive coating is hydroxyapatite (HA), which is applied to the implant surface by plasma spraying.

Lyasnikov V.N. et al. (Lyasnikov V.N., Seryanov Yu.V., Protasova N.V., Mazanov K.V. Formation of a uniform porous structure of titanium and hydroxyapatite coatings on dental implants with ultrasonic plasma spraying. Clin. implant. and dent., 2000, No. ¾ (13/14), pp. 114-118) suggest using three intermediate layers to obtain a reliable coating containing hydroxyapatite: the 1st layer is porous titanium, the dispersion is 3-10 microns, the 2nd layer is porous titanium , dispersion 50-100 microns, 3rd layer - porous composition, titanium particles with hydroxyapatite (60% Ti, 40% g droksiapatit). The creation of an additional branched surface leads to the most durable fixation of particles of plasma sprayed hydroxyapatite on it. To increase the uniformity and porosity of the coating, a technology is proposed for activating ultrasonic vibrations of the substrate during the deposition process.

However, such coatings exhibit low crystallinity and poor adhesion to the titanium implant. Low crystallinity is the reason for the rapid dissolution of the hydroxyapatite coating in the tissue fluid and leads to a decrease in the service life of the coating, while poor adhesion can lead to delamination. Therefore, the question of finding new bioactive coatings becomes important.

A method for manufacturing an intraosseous implant is known from RU 2458707, C1, 08.20.2012, which includes sandblasting the implant surface with alumina particles, plasma spray coating on the basis of the implant of a system of biocompatible coatings of different dispersion and thickness, consisting of five layers: the first two are titanium or titanium hydride, the following two layers of a mixture of titanium or titanium hydride with calcium hydroxyapatite, differing in the content of components in the layers, and the fifth layer of calcium hydroxyapatite, after whereby a multilayer system of biocompatible coatings is irradiated in a rarefied hydrocarbon gas medium with high-energy inert gas ions with an energy of 40-130 keV and an irradiation dose of 2000-5000 μC / cm ² . The method provides an increase in bioactivity and mechanical strength of the implant.

From RU 2124329, C1, 01/10/1999, a coating material for biomedical applications is known, in particular on biomedical implants made of a titanium or titanium alloy substrate and which contains mainly a gel-based titanium oxide material that is processed at a temperature of 350 ° C-750 ° C, while the said material is capable of causing the formation of calcium phosphate on its surface under in vitro conditions, for example, in a simulator of body fluid and / or under in vivo conditions.

The coating material is applied to the step by dipping a substance into the ash solution, followed by removal from the solution and drying, characterized in that the material used is a gel-based titanium oxide material treated at a temperature of 350 ° C-750 ° C, or by the galvanic method.

From US 2009005880 A1, 01/01/2009 an intraosseous implant made of titanium, in particular with a high degree of osseointegration, and a method for producing such implants coated with a thin film of titanium dioxide in crystalline anatase form are known.

An implant is obtained by applying to the substrate by immersion, dipping, spraying or roller application of a gel-like and stable reagent (hereinafter referred to as the precursor) made of inorganic or organometallic titanium (IV) compounds, followed by heat treatment to achieve compaction, as a result, on the surface of the substrate are formed Thin films of TiO ₂ coating in crystalline anatase form.

The liquid precursor contains a titanium compound, water, an organic solvent, an organic or inorganic acid, a cationic or nonionic surfactant.

As the titanium compound, either an inorganic titanium compound, for example, titanium tetrachloride (TiCl ₄ ), or an organometallic titanium compound is used.

The method is quite complicated and does not allow to obtain very thin multilayer coating films with the required properties on the surface of a titanium implant in this way.

From US Pat. No. 2010159118, A1, June 24, 2010, a method is known for producing a biocompatible titanium implant coated on a substrate, for example, from titanium or a titanium alloy, by the sol-gel technique of a film of titanium oxide, for example, anatase modification, which has excellent hydroxyapatite formation ability , which allows the use of an implant to eliminate bone defects and bone formation. Coatings from titanium oxide by sol-gel technology are formed by applying a titanium fluid containing a titanium compound, such as titanium alkoxide, for example ethoxy titanium [Ti (OC ₂ H ₅ ) ₄ ], an organic solvent, preferably a monohydric alcohol, a catalyst onto a substrate hydrolysis (acid or alkali, for example, inorganic acid). The liquid is applied to the substrate, for example, by dipping. Next, heat treatment is carried out from 250 ° C to 790 ° C, preferably 350 ° C and above. Next, ultraviolet irradiation and treatment of the implant are carried out in a body fluid simulator to generate hydroxyapatite crystals on its surface. Note that the described method is a liquid-phase coating method, and it is not applicable to implants with a large surface area containing deep pores of small diameter.

The prior art technology for the deposition of thin films on substrates, which is based on sequential chemical reactions between a gaseous regent and a solid, the so-called atomic layer deposition (ASO) method. Most ASO reactions use two chemical compounds that are commonly called precursors. Such precursors react in turn with the surface. As a result of the repeated influence of precursors, a thin film grows, [V. B. Aleskovsky, Journal of Applied Chemistry, 47, 2145, (1974)].

The atomic layer deposition method is widely used in microelectronics. So, for example, in the monograph (Kireev V.Yu., Stolyarov A.A. Microelectronics Technologies. Chemical Deposition from the Gas Phase - M .: Tekhnosfera, 2006. - 192 pp.), A method of atomic layer deposition of films of complex chemical compounds by layered, divided into cycles of the process of deposition of material, monoatomic per cycle thickness. At the end of each cycle, the chemical reaction self-stops. The total film thickness is set and controlled by the number of deposition cycles. The atoms of the subsequent layer form chemical bonds with the atoms of the previous one so that an ordered structure of the spatial arrangement of the atoms of the entire multilayer precipitate is created. The technology is implemented by discrete alternating supply of reagents to the surface of the substrate with intermediate purging of the reaction zone with an inert gas.

In particular, in patent US 2006/0251875 A1, 09/09/2006, a biocompatible and bioinert implant (in the form of a chip), biocompatible with warm-blooded animals, and a method for its preparation by deposition of a biocompatible and bio-inert coating on the silicon substrate by atomic-layer deposition consisting of from one or more layers of one or more of the following materials: aluminum oxide or titanium oxide, or zirconium oxide, or vanadium oxide, or silicon nitride, or silicon carbide, or titanium. The coating is precipitated using gaseous precursors, for example, from titanium tetrachloride and water, at a deposition temperature of 100-900 ° C.

However, the resulting coating is not bioactive and the resulting material, as a device such as a chip, is not intended to be used as an implant to eliminate bone defects. In addition, metal gallides TiCl ₄ , TiI ₄ , ZrCl ₄ are used as precursors to the metal, which can lead to the introduction of halogens into the coating, and also, when using these precursors, one of the main reaction products is corrosive substances such as HCl, capable of interact with the reactor material (usually chromium-nickel stainless steel), the coating can be saturated with elements such as Ni, Cr, Fe, which is highly undesirable in biomedical applications due to their toxicity. Note that the use of organometallic compounds Ti (OC ₂ H ₅ ) ₄ , Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ , Ta (OS ₂ H ₅ ) ₅ as precursors on Ti, Zr, and Ta, respectively , should not lead to saturation of the coating with toxic elements.

The technical task of the claimed invention and the technical result achieved by this is to obtain a bioactive coating of a titanium implant, including a multilayer coating, with high uniformity covering a three-dimensional implant, including a very developed surface relief, with good bioactive properties, low toxicity, high corrosion resistance, expanding the arsenal of technical means - titanium implants to eliminate various bone defects, restore osteal tissue.

The stated technical problem and the technical result achieved in this case are achieved by a method for producing a bioactive coating on a titanium implant implanted in human bone tissue, which is a multicomponent or multilayer bioactive coating of at least layers of one transition metal oxide from the group of titanium oxide, zirconia, hafnium oxide, tantalum oxide, niobium oxide, including the subsequent application of layers of a bioactive coating, by growing thin films of these metal oxides the method of atomic layer deposition under reduced pressure, the temperature in the reaction zone of the device used for atomic layer deposition of 200-300 ° C and when the reaction zone is purged with nitrogen at a pressure of 0.5-5 mbar and with a pulsed chemical implant applied to the surface of the metal substrate reagents - precursors, including organometallic compounds and water, with a pulse duration period of supply of metal-containing precursors of 0.2-0.6 seconds and with an inter-pulse purge of the reaction zone with nitrogen for about 6 seconds, with m deposition cycles determine the required thickness of the bioactive coating, which varies from 100 to 1000 cycles, and chemical reagents are used as precursors, including at least one corresponding organometallic compound and water selected from the group including chemical precursors, which includes ethoxy titanium (tetraethoxy titanium Ti (OC ₂ H ₅ ) ₄ ) and water, ethyl methyl amid zirconium Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ and water, ethyl methyl amid hafnium Hf [N (CH ₃ ) (C ₂ H ₅ )] ₄ and water, pentaethoxytantalum Ta (OS ₂ H ₅ ) ₅ , pentaethoxyniobium Nb (OC ₂ H ₅ ) ₅ and water.

As a result of the implementation of this method according to the invention, a multicomponent or multilayer bioactive coating is grown on the surface of a titanium implant grown from precursor reaction products and, in particular, is a coating of at least one transition metal oxide selected from the group comprising a coating of layers titanium oxide TiO ₂ with crystalline anatase modification, a coating of ZrO ₂ layers, HfO ₂ with a polycrystalline structure with a tetragonal lattice, a coating of Ta ₂ O ₅ layers with amorphous th structure, Nb ₂ O ₅ with an amorphous structure, a coating of layers of a multicomponent oxide (TiO ₂ ) _x (Ta ₂ O ₅ ) _1-x , where x is 0.8-0.95 with a structure of a solid solution based on a tetragonal crystal lattice (anatase type) or (ZrO ₂ ) _x (Ta ₂ O ₅ ) _1-x , where x is 0.8-0.95 with the structure of a solid solution based on a tetragonal crystal lattice, with a controlled coating thickness determined by the number of repeated deposition cycles relevant precursors.

A characteristic of about 6 seconds indicated for an intermediate purge of the reaction zone with nitrogen between feed pulses should be understood, such as, for example, 5.4 seconds, 5.7 seconds, 6.1 seconds, 6.25 seconds.

In all the examples cited, the reaction zone was purged with nitrogen at a pressure of 0.5-5.0 mbar.

Although the method used is called atomic layer deposition (ASO), in fact, the fraction of a monolayer of a substance grows in one deposition cycle. In particular, in a coating of the type (TiO ₂ ) _x (Ta ₂ O ₅ ) ₁ cycles are selected so that as a result, not alternating layers of titanium oxide and tantalum oxide are obtained, namely, a mixture that has new properties, which leads to accelerate osseointegration.

Obtained by the claimed method is implanted in human bone tissue a titanium implant contains a bioactive coating. The bioactivity of the coating is controlled by the formation of an in vitro layer of hydroxyapatite in a solution that mimics the tissue fluid of the human body.

It is known that crystalline modifications of TiO ₂ , such as anatase and rutile, have bioactive properties, which are manifested in their accelerated (as compared with amorphous natural titanium oxide) osseointegration, with preference being given to titanium oxide with anatase crystal structure.

Indeed, it was found that anatase primarily satisfies the crystallographic criterion when choosing materials for bioactive coatings. [Masaki Uchida, Hyun-Min Kim, Tadashi Kokubo, Shunsuke Fujibayashi, Takashi Nakamura. Structural dependence of apatite formation on titania gels in a simulated body fluid // Journal of Biomedical Materials Research Part A Volume 64A, Issue 1, pages 164-170, 1 (2003)].

Since the basis of human bone tissue is hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ) in a hexagonal crystallographic modification, materials in a crystalline modification with interplanar distances similar to hydroxyapatite (primarily transition metal oxides), especially tetragonal modifications, are potential candidates for rapid osteointegration with human bone tissue.

The invention is illustrated by drawings and examples.

In FIG. 1 shows the relative position of the OH groups of hydroxyapatite with respect to oxygen atoms in TiO ₂ with the anatase structure;

In FIG. 2 shows the relative position of the OH groups of hydroxyapatite with respect to oxygen atoms in TiO ₂ with the structure of rutile;

In FIG. 3 shows X-ray diffraction patterns from TiO ₂ coatings deposited on a titanium substrate for a specified number of reaction cycles;

In FIG. 4 shows X-ray diffraction from a TiO ₂ coating deposited on a titanium substrate for a specified number of reaction cycles after exposure to a solution simulating tissue fluid;

In FIG. 5 shows X-ray diffraction spectra measured from samples with TiO ₂ obtained with the following pulse widths of tetraethoxy titanium: t = 0.06 sec, t = 0.2 sec and t = 0.6 sec;

In FIG. Figure 6 shows the diffraction patterns of samples with ZrO ₂ obtained with the following pulse durations of zirconium ethylmethylamide: t = 0.06 sec. and t = 0.5 sec.

In FIG. 7 shows the X-ray diffraction spectra measured from samples with multicomponent oxides (TiO ₂ ) _x (Ta ₂ O ₅ ) _{1 x} , with a concentration of TiO ₂ x = 0.7 and x = 0.9.

In FIG. 1 and FIG. Figure 2 shows the relative position of the OH groups of hydroxyapatite with respect to oxygen atoms in TiO ₂ with the anatase structure (Fig. 1) and in TiO ₂ with the rutile structure (Fig. 2).

Indeed, in FIG. 1 shows the position of the O anatase O atoms in the crystallographic plane (101) with respect to the positions of the OH groups of hydroxyapatite in the (0001) plane, and in FIG. 2, the position of the rutile O atoms in the (110) plane with respect to the positions of the OH groups of hydroxyapatite in the (0001) plane. It can be seen from the figure that in the case of anatase the coincidence of the position of oxygen atoms with the position of OH groups is almost complete, and in the case of rutile there is a discrepancy of ~ 3%. This circumstance is often taken into account when explaining the higher anatase bioactivity compared to rutile.

Bioactive characteristics are also possessed by coatings of zirconium oxide and hafnium oxide in tetragonal crystalline modification.

1. When choosing coating materials - candidates for high bioactivity, in addition to the crystallographic approach described above when choosing materials, it seems interesting to consider the following circumstances. According to [Kim NM, Himeno T, Kokubo T, Nakamura T, Process and kinetics of bonelike apatite formation on sintered hydroxyapatite in a simulated body fluid, Biomaterials 26 (2005) 4366-4373], a key factor for enhancing bioactive properties is formation active influx of calcium ions on the surface of the implant, since the process of osseointegration begins with the formation of a calcium-containing layer. The isoelectric potential is a value that is actually the pH value of the liquid, when placed in which there is no potential difference between the surface of the implant and the liquid. It is known that the pH of human blood varies between 7.2-7.4. Then materials with an isoelectric potential of the surface <7.2-7.4 will provide a potential difference with the tissue fluid, providing a flow of Ca ⁺ ions to their surface. In the table. 1 from [M. Textor, S. Sittig, V. Frauchiger, S. Tosatti, DM Brunette. Properties and Biological Significance of Natural Oxide Films, on Titanium and Its Alloys in “Titanium in Medicine: Material Science, Surface Science, Engineering, Biological Responses and Medical Applications”, Springer Verlag, Heidelberg and Berlin; 2001; pp. 171-230] provides data on the isoelectric potential and cytotoxicity of some simple transition metal oxides. Oxides possessing both low isoelectric potential and not showing cytotoxicity are highlighted in gray. Among these materials, Ta ₂ O ₅ has the lowest isoelectric potential.

Nevertheless, thin films of tantalum oxide obtained by various methods have a significant drawback from the point of view of the crystallographic bioactivity criterion presented above - they are amorphous in a fairly wide range of thicknesses. Therefore, in this regard, it seems promising to develop a multicomponent coating that includes a component that meets the crystallographic criterion (TiO ₂ in the tetragonal modification of anatase or ZrO ₂ in the tetragonal modification) and a component with a low isoelectric potential (Ta ₂ O ₅ ). In order to maximize compliance with the crystallographic criterion, the coating in its phase composition should be a solid solution of the type (TiO ₂ ) _x (Ta ₂ O ₅ ) _1-x or (ZrO ₂ ) _x (Ta ₂ O ₅ ) _1-x with a tetragonal lattice . We note that the use of Ti, Zr, Hf, and Ta organometallic compounds as precursors is Ti (OC ₂ H ₅ ) ₄ , Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ , Hf [N (CH ₃ ) (C ₂ H ₅ )] ₄ , Ta (OC ₂ H ₅ ) ₅ , respectively, should not lead to saturation of the coating with toxic elements.

Below are examples illustrating the claimed invention, but not limiting it.

Example 1

Directly before ASO, Grade 4 titanium plates were washed in an ultrasonic bath at 50 ° C, first in acetone (ChP) (10 min), then in ethanol (96%, ChP) (10 min), then in deionized water (10 min). ASO TiO ₂ on titanium plates was carried out in a vertical-type atomic layer deposition reactor operating under reduced pressure (~ 2 mbar) at a reactor temperature of 300 ° C in a nitrogen pumping mode. Due to the low vapor pressure of ethoxy titanium (Ti (OC ₂ H ₅ ) ₄ ), it was fed into the reactor from a heated source at a temperature of 150 ° C. The duration of the feed pulses of Ti (OC ₂ H ₅ ) ₄ and H ₂ O was 0.2 and 0.2 s, respectively. The nitrogen purge time after each precursor feed pulse was 6 s after each reagent feed pulse. The number of reaction cycles "n" ranged from 100 to 1000, which corresponded to the thickness of the obtained TiO ₂ from 4 to 40 nm.

The crystal structure of the obtained TiO ₂ coatings was studied by x-ray diffractometry. In this and other examples of the invention, the bioactivity of the coatings was evaluated by their ability to form a hydroxyapatite layer on the surface after they were soaked in a solution simulating tissue fluid (BCL) for 9 days according to the method described in [Tas A.S., Bhaduri SB // Biomaterials. 2000. V. 21. P. 1429]. The presence of hydroxyapatite was monitored by x-ray diffractometry and / or by gravity.

In FIG. 3 and FIG. 4 shows diffraction patterns of titanium samples coated with TiO _{2 of} 100, 300, 600 and 1000 cycles. Measurements were made in the region of the most intense peak of anatase (101) 2θ ~ 24.6 ° -26.2 °. It has been observed that while the number of cycles is less than 300, X-ray diffraction has not revealed any diffraction peaks. Scanning in a wide range (2θ ~ 10-70 °, not shown in Fig. 3) also did not reveal diffraction peaks except for the peak from the titanium substrate. While with the number of cycles n≥300, a peak from anatase (101) 2θ ~ 25.4 ° appears (ICDD: No. 01-070-6826). It is also worth noting that the peak intensity increases with the number of “n” cycles (Fig. 3).

While the number of reaction cycles is less than 600, X-ray diffraction reveals only one peak at 25.4 °, corresponding to the crystalline phase of anatase (101). With an increase in the number of cycles n> 600, a second peak from anatase appears at 48.2 ° (200). Thus, the polycrystalline structure of the film and the ratio of the relative intensities of peaks (101) and (200) corresponding to the tabular data indicate the absence of strong texturing of TiO ₂ films created by atomic layer deposition.

So in FIG. 3 and FIG. 4 presents x-ray diffraction from: FIG. 3 TiO ₂ coatings deposited on a titanium substrate in 100, 300, 600, 1000 reaction cycles; FIG. 4 TiO ₂ coatings deposited on a titanium substrate in 100, 300, 600, 1000 reaction cycles after exposure to a solution simulating tissue fluid depending on the number of reaction cycles.

Apatite-forming ability of TiO ₂ coatings was studied depending on the number of reaction cycles n. After exposure to a solution simulating tissue fluid, titanium samples with a TiO ₂ coating were analyzed by x-ray diffraction, a scanning electron microscope with an elemental analysis attachment. In FIG. Figure 3 shows the diffraction pattern of titanium samples coated with TiO ₂ obtained by varying the number of reaction cycles n in the range of 100-1000 cycles after exposure to a solution simulating tissue fluid. At n <300, diffraction reveals only one diffraction peak at 31.7 °, which corresponds to NaCl. At n≥300, a peak appears at 26.1 °, 31.8 °, 32.3 ° and 32.8 °, which corresponds to the peaks (002), (211), (112), (300) hydroxyapatite, respectively. Thus, FIG. 3 and FIG. 4 show that the amorphous TiO ₂ coating (n <300) does not cause the growth of hydroxyapatite upon exposure to a solution simulating tissue fluid. With a further increase in the coating thickness with a change in n in the range of 300–1000 (10–40 nm), hydroxyapatite is present, with no significant change in its amount. As a result, a correlation was established between the structural characteristics of ASO TiO ₂ and its bioactive properties, which manifests itself in the fact that X-ray amorphous TiO ₂ coatings are bio-inert (there is no hydroxyapatite after exposure to samples), while polycrystalline with anatase-type tetragonal structure exhibit bioactive properties ( after exposure of the samples to breast cancer, hydroxyapatite is present on the surface). Thus, it is shown that the thickness of the ASO coating of TiO ₂ can be selected from the condition that the coating exhibits a polycrystalline structure.

Example 2

ASO coatings of TiO ₂ were obtained at three different pulse widths of the titanium precursor feed - Ti (OC ₂ H ₅ ) ₄ , namely t = 0.2 s, t = 0.6 s and t = 0.06 s. All other conditions for the preparation of substrates and ASO process were the same as in example 1.

Below are the X-ray diffraction spectra measured from samples with TiO ₂ obtained at t = 0.06 s, t = 0.2 s and t = 0.6 s (Fig. 5).

X-ray diffraction analysis showed that ASO with short pulses t = 0.2 s of a titanium precursor feed allows a single-phase TiO ₂ coating with anatase structure to be obtained, while the ASO process at t = 0.6 s leads to the appearance of a coating in addition to the anatase phase rutile phase 2Θ ~ 27.5 ° (110). At t = 0.06 s, reflections from crystalline phases were not detected.

Example 1 shows that X-ray amorphous TiO ₂ coatings are bioinert. However, it was known that the bioactivity of the rutile phase of TiO _{2 is} significantly lower than the anatase bioactivity. Thus, the need for the ASO TiO ₂ process at the pulse durations of the titanium precursor specified in the claims is shown.

Example 3

Directly before ASO, Grade 4 titanium plates were washed in an ultrasonic bath at 50 ° C, first in acetone (ChP) (10 min), then in ethanol (96%, ChP) (10 min), then in deionized water (10 min.) . ASO ZrO ₂ was carried out using ethylamidacirconium Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ and water as precursors, and ASO HfO _{2 was} carried out using ethylamidagafnium Hf [N (CH ₃ ) (C ₂ H ₅ )] ₄ and water as precursors in a vertical-type atomic layer deposition reactor at a reactor temperature of 240 ° C operating under reduced pressure (~ 2 mbar) in a nitrogen pumping mode. Due to the low vapor pressure of ethylmethylamidzirconium Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ and ethylamidahafnium Hf [N (CH ₃ ) (C ₂ H ₅ )] ₄ they were fed into the reactor from a heated source at a temperature of 100 ° C. The nitrogen purge time after each precursor feed pulse was 6 s. ASO coatings of ZrO ₂ and HfO ₂ were obtained at three different pulse durations for the supply of metal-containing precursors —Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ in the case of growth of ZrO ₂ and Hf [N (CH ₃ ) (C ₂ H ₅ )] ₄ in the case of an increase in HfO ₂ , namely t = 0.8 s, t = 0.5 s and t = 0.06 s. The number of reaction cycles varied in the range of 100-1000, which corresponded to the thickness of the resulting coatings 8-80 nm.

In FIG. Figure 6 shows the diffraction patterns of samples with a ZrO ₂ coating obtained with a pulse duration of zirconium ethyl methylamide of 0.06 sec and 0.5 sec. The figure shows that the sample with the time of the inlet of the precursor Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ 0.5 sec. possesses crystalline reflections of [110], [101] tetragonal structures, and a sample with 0.06 sec is amorphous.

After that, a bioactivity test was made in a solution simulating tissue fluid. To verify these results, quantitative studies based on RD spectra were presented, during which the area under the peaks was estimated. The simulation was performed in the WinXRD environment; the Pearson and Split Pearson functions were used to simulate the spectra. Data on quantitative x-ray structural studies and weight gain are summarized in table 2.

It can be seen from the table that the sample obtained with a pulse duration of Zr [N (CH ₃ ) (C ₂ H ₅ )] of ₄ 0.5 s has the highest bioactivity. Similar dependences on the bioactivity of the coatings on the pulse duration of the metal precursor were obtained in the case of the growth of the HfO ₂ coating using ethylmethylamidogafnium as a metal precursor. Thus, the need for an ASO ZrO ₂ and HfO ₂ process at the pulse durations of metal precursors specified in paragraph 1 of the claims is shown.

Example 4

Directly before ASO, Grade 4 titanium plates were washed in an ultrasonic bath at 50 ° C, first in acetone (ChP) (10 min), then in ethanol (96%, ChP) (10 min), then in deionized water (10 min). ASO Ta ₂ O ₅ was carried out using Ta (OS ₂ H ₅ ) ₅ pentaoxitantal and water as precursors, and ASO Nb ₂ O ₅ was used using pentoxyniobium Nb (OC ₂ H ₅ ) ₅ and water, in an atomic vertical-type deposition at a reactor temperature of 300 ° C, operating under reduced pressure (~ 2 mbar) in the mode of nitrogen pumping. The nitrogen purge time after each precursor feed pulse was 6 s. ASO coatings and Nb ₂ O ₅ and were obtained at three different pulse durations for the supply of metal-containing precursors - Ta (OC ₂ H ₅ ) ₅ in the case of growth of Ta ₂ O ₅ and Nb (OC ₂ H ₅ ) ₅ in the case of growth of Nb ₂ O ₅ namely t = 0.8 s, t = 0.5 s and t = 0.06 s. The number of reaction cycles varied in the range of 100-1000, which corresponded to the thickness of the resulting coatings 4-40 nm.

Coated samples were tested for bioactivity in a solution simulating tissue fluid. After X-ray diffraction identification of the formation of hydroxyapatite on samples aged in a solution simulating tissue fluid, the increase in the mass of hydroxyapatite was determined gravitometrically and is shown in Table 3.

The table shows that the highest bioactivity (the largest increase in hydroxyapatite) has a sample with a coating of Ta ₂ O ₅ , obtained with a pulse duration of Ta (OC ₂ H ₅ ) ₅ - 0.5 s. Similar dependences on the bioactivity of coatings on the pulse duration of a metal precursor were obtained in the case of the growth of the Nb ₂ O ₅ coating using Nb (OC ₂ H ₅ ) ₅ as a metal precursor. Thus, the need for the ASO process Ta ₂ O ₅ and Nb ₂ O ₅ at the pulse durations of the metal precursors specified in paragraph 1 of the claims is shown.

Example 5

ASO coatings (TiO ₂ ) _x (Ta ₂ O ₅ ) _1-x on Grade 4 titanium plates were obtained at three different concentrations x, namely x = 0.9, x = 0.7 and x = 0.98. In order to obtain multicomponent coatings of the indicated composition x ASO, the process was carried out in cyclically repeating supecycles including 9 reaction cycles using Ti (OC ₂ H ₅ ) ₄ (pulse duration 0.2 sec) and H ₂ O (pulse duration 0.1 sec) and 1 reaction cycle with using Ta (OC ₂ H ₅ ) ₅ (pulse duration 0.5 sec) and H ₂ O (pulse duration 0.1 sec) to obtain a coating of composition x = 0.9; 7 reaction cycles using Ti (OC ₂ H ₅ ) ₄ (pulse duration 0.2 sec) and H ₂ O (pulse duration 0.1 sec) and 1 reaction cycle using Ta (OC ₂ H ₅ ) ₅ (pulse duration 0.5 sec) and H ₂ O (pulse duration 0.1 sec) - to obtain a coating, composition x = 0.7; 20 reaction cycles using Ti (OC ₂ H ₅ ) ₄ (pulse duration 0.2 sec) and H ₂ O (pulse duration 0.1 sec) and 1 reaction cycle using Ta (OC ₂ H ₅ ) ₅ (pulse duration 0.5 sec) and H ₂ O (pulse duration 0.1 sec) - to obtain a coating of composition x = 0.98. The total number of supercycles was chosen so as to obtain the thickness of the multicomponent (TiO ₂ ) _x (Ta ₂ O ₅ ) _1-x coating in the range of 30-50 nm. All other conditions for the preparation of substrates and the ASO process were the same as in example 1.

In FIG. 7 shows the X-ray diffraction spectra measured from samples with (TiO ₂ ) _x (Ta ₂ O ₅ ) _1-x obtained at concentration numbers x = 0.7 and x = 0.9.

From FIG. Figure 7 shows that a sample with a concentration value of x = 0.9 has a diffraction maximum corresponding to reflection (101) of the anatase crystal structure, while a sample with a concentration value of x = 0.7 does not have diffraction maxima, which means that there is an amorphous coating on the surface. A test was also carried out in a solution simulating tissue fluid, after which an analysis was made on a diffractometer. The results are shown in table 3.

Table 4 shows the integrated intensities and weight gain for samples with a multicomponent coating (TiO ₂ ) _x (Ta ₂ O ₅ ) _1-x with different concentration numbers x, after exposure to a solution simulating tissue fluid.

It can be seen from the table that the sample with the multicomponent coating (TiO ₂ ) _x (Ta ₂ O ₅ ) _1-x with the concentration number x = 0.9 has the highest bioactivity. Thus, the necessity of using a concentration number in the range from 0.8 to 0.95 was shown.

Example 6

ASO coatings (ZrO ₂ ) _x (Ta ₂ O ₅ ) _1-x on Grade 4 titanium plates were obtained at three different concentrations x, namely x = 0.9, x = 0.7 and x = 0.97. In order to obtain multicomponent coatings of the specified composition x ASO, the process was carried out in cyclically repeated supercycles, including 5 reaction cycles using Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ (pulse duration 0.5 sec) and H ₂ O (duration pulse 0.1 s) and 1 reaction cycle using Ta (OC ₂ H ₅ ) ₅ (pulse duration 0.5 s) and H ₂ O (pulse duration 0.1 s) - to obtain a coating composition x = 0.9 ; 3 reaction cycles using Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ (pulse duration 0.5 sec) and H ₂ O (pulse duration 0.1 sec) and 1 reaction cycle using Ta (OC ₂ H ₅ ) ₅ (pulse duration 0.5 sec) and H ₂ O (pulse duration 0.1 sec) - to obtain a coating composition x = 0.7; 10 reaction cycles using Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ (pulse duration 0.5 sec) and H ₂ O (pulse duration 0.1 sec) and 1 reaction cycle using Ta (OC ₂ H ₅ ) ₅ (pulse duration 0.5 sec) and H ₂ O (pulse duration 0.1 sec) - to obtain a coating composition x = 0.97. The total number of supercycles was chosen so as to obtain the thickness of the multicomponent (ZrO ₂ ) _x (Ta ₂ O ₅ ) _1-x coating in the range of 30-50 nm. All other conditions for the preparation of substrates and the ASO process were the same as in example 1.

Coated samples were tested for bioactivity in a solution simulating tissue fluid. After X-ray diffraction identification of the formation of hydroxyapatite on samples aged in a solution simulating tissue fluid, the increase in the mass of hydroxyapatite was determined gravitometrically and is shown in Table 5.

Table 5. Samples coated with (ZrO ₂ ) _x (Ta ₂ O ₅ ) _1-x with concentration numbers x: The weight gain of hydroxyapatite, mg X = 0.7 6.0 ± 0.4 X = 0.9 9.0 ± 0.4 X = 0.97 8.2 ± 0.4

It can be seen from the table that the sample with the multicomponent coating (ZrO ₂ ) _x (Ta ₂ O ₅ ) _1-x with the concentration number x = 0.9 has the highest bioactivity. Thus, the necessity of using a concentration number in the range from 0.8 to 0.95 was shown.

Thus, the claimed invention allows to obtain a bioactive coating on a titanium implant with bioactivity, non-toxicity and not susceptible to corrosion damage.

Claims (1)

A method of obtaining a bioactive coating on a titanium implant implanted in human bone tissue, which is a multilayer or multicomponent bioactive coating of at least layers of one transition metal oxide from the group of titanium oxide, zirconium oxide, tantalum oxide, hafnium oxide, niobium oxide, by growing thin films of these metal oxides by atomic layer deposition under reduced pressure, temperature in the reaction zone of the device used for atomic layer deposition of 200-300 C during the purging of the reaction zone with nitrogen, and during the pulsed supply of precursor chemicals to the surface of the titanium implant, including organometallic compounds of these metals and water, with a pulse duration of supply of metal precursors of 0.2-0.6 sec and with an intermediate purging of the reaction zone with nitrogen about 6 seconds, with the number of deposition cycles determine the required thickness of the coating, which is from 100 to 1000 cycles, and chemical reagents are used as precursors, including at least one organometallic compound and water, organometallic compounds selected from the group consisting of ethoxy titanium (tetraethoxy titanium Ti (OC ₂ H ₅ ) ₄ ), ethyl methyl amid zirconium Zr [N (CH ₃ ) (C ₂ H ₅ )] ₄ , ethylmethylamidhafnium Hf [N (CH ₃ ) (C ₂ H ₅ )] ₄ , pentaethoxytantalum Ta (OS ₂ H ₅ ) ₅ , pentaethoxyniobium Nb (OC ₂ H ₅ ) ₅ .

Images