RU2448741C1 - Method of forming nanostructured biocompatible coating on implants - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine. Described is method of biocompatible coating on implant surface which lies in precipitation on implant surface of polysilicon film in reactor. Obtained polysilicon film is subjected to chemical etching to form nanostructured superficial layer of porous polysilicon. Etching of polysilicon film nis carried out submerging implant into mixture which contains 50-55% water solution of tetrafluoroboric acid (HBF₄), 70-90% water solution of nitric acid (HNO₃) and anionic surface active substance on the basis of ammonium salt of perfluorsulfonic acid R_fSO₃NH₄ in amount 5·10^-3-10^-2 (wt %), where R_f - C₈F₁₇ or C₂F₅OC₃F₆OC₂F₄, or C₆F₁₃CH₂CH₂. Used are water solution of acids with ratio of their volume parts: HBF₄:HNC₃, as (100-800):(1:1.1), with further washing of implant with deionised water and drying.

EFFECT: extension of technological possibilities of the method irrespective of materials used and constructive abilities of implants.

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Description

Technical field

The invention relates to the field of medicine and medical technology, and in particular to methods of forming a biocompatible coating on the surfaces of implants used in reconstructive operations with the replacement of bone tissue with implants.

Such operations are characteristic of traumatology, orthopedics, dentistry.

Dozens of companies are involved in the development and production of implants in the world.

For the reliability of osseointegration, i.e. biological implant growth into the bone without inflammatory reactions, to reduce implant rejection, the contact surfaces of the implants are modified by applying macroscopic-notching elements, recesses to connect the implant with bone tissue and form special biocompatible coatings for bone tissue to grow on the surface of the implant.

State of the art

Various technological processes for the formation of biocompatible coatings on implant surfaces are known.

The most common biocompatible coatings for implants are coatings based on calcium phosphate compounds - hydroxyapatites, which are similar to bone composition.

So, for example, in technical solutions (see patents RU No. 2291918, publ. 2007; No. 2221904, publ. 2004; No. 2154463, publ. 2000), the process of forming bio-coatings containing calcium phosphate compounds is carried out when an implant made of titanium or its alloys is placed in an aqueous solution of an acid electrolyte based on phosphoric acid and hydroxyapatite powder and upon excitation of microarc discharges, a coating is formed.

A common disadvantage of these methods is that phosphoric acid, which is an aggressive medium, is used as the basis for the electrolyte.

In the technical solution according to patent RU No. 2206642, the process of forming biocoatings containing calcium phosphate compounds is carried out when the product (implant) is placed in an aqueous electrolyte solution and microarc discharges are excited on the surface of the product by applying current pulses at a voltage of up to 1000 V. Pulse duration 30- 400 μs and a pause between them of at least 100 μs. In the embodiment described in example 12 of the patent, the coating on titanium BT 1-00 is carried out for 10 minutes in an aqueous electrolyte solution with a pH of 12-14, containing KOH, hydroxyapatite and Al ₃ O ₃ , with an anode and cathode current ratio equal to value of 6.7. According to the given data, the thickness of the obtained coating is approximately 41 microns, porosity - 24%. However, a significant coating thickness reduces strength, which can lead to osteoporosis and other complications.

The possibility of using this solution to obtain microcoatings on miniature implants that do not allow a significant coating thickness on the surface is technologically limited.

From the prior art it follows that the required physical and mechanical properties of calcium phosphate coatings on titanium implants (thickness, microhardness, porosity, roughness) in traumatology, orthopedics or dentistry differ significantly and depend on many conditions, such as:

- the purpose of the implant (for implantation in the body or in the role of prostheses - substitutes for missing organs);

- the duration of stay in the body, the need for extraction after a certain time as a result of the restoration of natural organs or the need for replacement, estimated loads, etc.

The disadvantages of the known technical solutions for the formation on the surfaces of the implants of biocompatible calcium phosphate coatings are:

- the impossibility of regulating their physico-mechanical properties, mainly strength;

- low crack resistance and low fatigue strength in physiological conditions;

- the porous surfaces of the coatings have an irregular structure, pore cells are different in size, completely monolithic zones on the coating are possible, which reduces the efficiency of germination, in particular, of bone tissue on the material and leads to osteoporosis and other complications;

- weak stimulating effect on the growth of new bone tissue;

- a significant amount of phosphorus in the compound Ca _10-x (НРО ₄ ) _x (РО ₄ ) _6-x (ОН) _2-x (0 <x <1) does not reproduce bone morphology (see the journal "Nanotechnologies Ecology Production" , No. 1 (8), January 2011, pp. 102-103).

Currently, the most promising implants with modified surfaces based on coatings of polycrystalline silicon with a porous structure of the surface layer.

The biocompatibility of porous polysilicon was described in 1995 (by Canham et al., “Bioactive Silicon Structure Through Nanoetching Techniques)), Journal ((Advanced Materials)), 1995, Vol 7, No. 12, pp. 1033-1037).

In GB patent No. 2317885, publ. 04/08/1998, a technical solution was proposed for the use of porous polysilicon as a biomaterial compatible with the tissues of a living organism. US patent No. 7186267, publ. 06/03/2007 (application US No. 2004/000313, publ. 15.01.2004) confirmed the possibility of using polycrystalline silicon with a nanostructured layer of porous polysilicon as a coating on the surfaces of implants made mainly of titanium or steel. According to this technical solution, it was confirmed that the presence of a polysilicon coating on the implant surface with a nanostructured layer of porous polysilicon promotes the formation of bone tissues on its surface.

The technical solution according to US patent No. 7186267 is selected as the closest analogue of the present invention.

In the mentioned technical solution, the formation of a biocompatible coating on the surfaces of the implants is carried out by deposition of a polysilicon film on the implant surface in the reactor, followed by its etching with the formation of a layer of a nanostructured surface layer of porous polysilicon.

As follows from this technical solution, the process of forming a biocompatible coating based on porous polysilicon on the surfaces of the implants is carried out using the known technology, according to which a polysilicon film is deposited on the substrate by pyrolysis of monosilane (SiH ₄ ) in reactors operating under reduced pressure and carry out its electrochemical etching using an electrolyte containing hydrofluoric acid (HF) (see US patent No. 5348618, publ. September 20, 1994).

The etching method used is used to nanostructure the surface layer of a polysilicon film deposited on the surface of implants made of electrochemically active materials, which, in particular, include titanium and steel, which are widely used in implantology.

Among the metals used for implantation, the proportion of titanium and its alloys, the best for implantology in biocompatibility and specific strength, is approximately 5%. This is due to the low manufacturability of titanium.

Currently, considerable attention is paid to the creation of implants from dielectrics, in particular, glass ceramics. The use of implants from these materials ensures the reliability of their fixation, speeds up the healing process, reduces the risk of postoperative complications, eliminates threading in the bone, thereby facilitating preparation for implantation. The main technological process for the production of these implants is a relatively cheap casting, which significantly reduces the cost of prosthetics.

However, the dielectric properties of glass-ceramic materials preclude the possibility of implementing a technological process for nanostructuring the surface layer of a polycrystalline silicon film by electrochemical etching.

Technologically, the possibilities of using the well-known technical solution according to US patent No. 7186267 are also limited in the case of etching a polysilicon film on the relief surface of the implant in order to obtain a uniform nanostructured layer of porous polysilicon in thickness, which is explained by the heterogeneity of the current density in different parts of the relief surface of the implant.

SUMMARY OF THE INVENTION

The technical result of the present invention was to expand the technological capabilities of the method of forming a biocompatible coating to obtain a nanostructured layer of porous polysilicon on the surfaces of the implants, regardless of the materials used for their manufacture and design features of the implants.

To solve this technical result, a method for forming a nanostructured biocompatible coating on implants is proposed, which consists in depositing a polysilicon film on the implant surface in the reactor, subsequently etching it with the formation of a nanostructured surface layer of porous polysilicon, while the polysilicon film is etched when the implant is immersed in a mixture containing 50-55% aqueous tetrafluoroboric acid (HBF _4), 70-90% aqueous solution of nitric acid (HNO ₃₎ and on an anionic erhnostno-active substance based on perfluorosulfonic acid R _f SO ₃ NH ₄ ammonium salt in an amount of 5 x 10 ^-3 -10 ^-2 (wt.%), where R _f - C ₈ F ₁₇ or C ₂ F ₅ OC ₃ F ₆ OC ₂ F ₄ , or C ₆ F ₁₃ CH ₂ CH ₂ , using aqueous solutions of acids in the ratio of their volume parts: HBF ₄ : HNO ₃ , as (100-800): (1: 1,1), followed by washing the implant with deionized water and drying.

In the present invention, a coating is formed on the surface of the implant in the form of a polysilicon film with a thickness of 0.4-0.6 μm, and with the formation of a nanostructured surface layer of porous polysilicon with a thickness of not more than 200 nm.

When implementing the present invention, the technological capabilities of the method are expanded to form a biocompatible coating on the surfaces of the implants to obtain a nanostructured layer of porous polysilicon:

- regardless of the implant materials used with a polycrystalline silicon film formed on their surfaces, when they are treated with an aqueous solution of concentrated tetrafluoroboric (HBF ₄ ) and nitric (HNO ₃ ) acids, the process of chemical etching of the polycrystalline silicon film is carried out. The process of oxidation of a polycrystalline film in the presence of nitric acid in an aqueous solution is accompanied by the formation of nitrous acid and nitrosonium ions (NO ⁺ ), which is an active oxidizing agent, the point effect of which on the local zones of the polysilicon crystal structure implements the process of selective etching in these zones with the formation of porous silicon. The use of concentrated nitric acid in a chemical solution in the presence of tetrafluoroboric acid (HBF ₄ ) increases the concentration of nitrosonium ions in the solution, which stabilizes the formation of the nanoporous structure of the surface layer of polysilicon;

- the specified acid solution provides the process of forming a homogeneous thickness of the surface layer of nanoporous polysilicon on the surface of the complex implant surface, which is associated with the use of an anionic surfactant based on the ammonium salt of perfluorosulfonic acid in an aqueous solution of acids;

- the use of concentrated tetrafluoroboric acid (HBF ₄ ) in the composition allows the process of chemical formation of a nanostructured layer of porous polysilicon to be realized on the surfaces of implants modified with a polycrystalline silicon film, regardless of the materials used for implants (metal, ceramic).

In the analysis of the prior art, no technical solutions with a combination of features corresponding to the present invention and providing the result described above were found.

The above analysis of the prior art indicates that the claimed technical solution meets the criteria of the invention of “novelty”, “inventive step”.

The present invention can be industrially implemented using known technological processes, equipment and materials, including those intended for the manufacture of implants from titanium, its alloys, steel and dielectric materials, for example, based on glass ceramics.

The implementation of the invention

The invention is illustrated in Figure 1, which shows a fragment of a cross section of a polysilicon film with a nanostructured layer of porous polysilicon obtained by chemical etching of a polycrystalline silicon film formed on a metal (titanium) surface.

To implement the invention using well-known in the industry equipment and materials.

1. A reactor for gas-phase deposition of a film of polycrystalline silicon on the surface of products used, for example, in the electronics industry in the manufacture of semiconductor devices. The process of deposition of a film of polysilicon on the surface of the product in the reactor is carried out in a known manner and, preferably, during the pyrolysis of monosilane (SiH ₄ ) at a temperature of 600-650 ° C and under reduced pressure (25-130 Pa). The chemical reaction proceeding as follows is as follows: SiH ₄ → Si + 2H ₂ . During the process, a polycrystalline silicon film is formed.

For this technological process, implants with different relief surfaces can be used and made both from metals (titanium, titanium alloys, steel), as well as from cermets and glass ceramics.

2. An aqueous solution of 50-55% tetrafluoroboric acid (HBF ₄ ).

To implement the present invention, it is preferable to use a concentrated 50% solution of tetrafluoroboric acid (HBF ₄ ), with a ratio of the mass fraction of fluorine and boron for this acid 3.85-4.05, according to TU 301-14-92, RF.

3. 70-90% aqueous solution of nitric acid (HNO ₃ ) - see the reference book "Aldrich", 2006, p. 1821, [7697-37-2].

To implement the present invention, it is preferable to use a concentrated 70% aqueous solution of nitric acid.

4. Anionic surfactant based on ammonium salt of perfluorosulfonic acid R _f SO ₃ ^- NH ₄ ⁺ , where R _f - C ₈ F ₁₇ , or C ₂ F ₅ OC ₃ F ₆ OC ₂ F ₄ , or C ₆ F ₁₃ CH ₂ CH ₂ . Anionic organofluorine surfactants are manufactured by DuPont (US), 3M (US). 3M (US) anionic fluorine-containing surfactants are trademarks of Novec 4300.

The anionic organofluorine surfactant (SAS) selected for the implementation of the present invention has high resistance to aggressive media, increases wetting of surfaces and stabilizes diffusion oxidation processes during the formation of a nanostructured layer of porous polysilicon.

The concentration of the indicated anionic organofluorine surfactant specified in the present invention in an aqueous solution of the aforementioned acids is most optimal according to the conditions of wetting the surfaces, the effect on the oxidation processes, and the costly part when using it.

For the implementation of the present invention, an anionic fluorine-containing surfactant of the FS-62 brand was selected, the formula C ₆ F ₁₃ CH ₂ CH ₂ SO ₃ ^- NH ₄ ⁺ , a preparation from DuPont (see http://www.dupont.com/).

The process of forming a biocompatible coating on the surfaces of the implants was carried out during the implementation of the following steps.

Stage 1.

For the implementation of the present invention, 3 pcs of steel disks were used as samples, 3 pcs of titanium and 1 pc of glass-ceramic plate. The diameter of the discs is 10 cm, the thickness is 4 mm, the size of the plate is 2 × 3 cm, and the thickness is 4 mm.

Polycrystalline silicon films were formed on the disks and plate by gas-phase deposition. The process of forming a film of polycrystalline silicon on steel disks was carried out to obtain a film with a thickness of 0.5 μm, on titanium disks and a plate, the film thickness was 0.4 μm.

The minimum value (0.4 μm) of the polycrystalline silicon film thickness specified by the invention is most optimal for the formation of biocompatible coatings on the surfaces of implants and, preferably, miniature implants used in dentistry. The possibility of obtaining a polycrystalline silicon film on implant surfaces of less than 0.4 μm using known methods for their preparation is technologically complicated.

2 stage.

To implement the present invention, a concentrated aqueous acid solution was prepared. To prepare the solution used:

an aqueous solution of 50% tetrafluoroboric acid (HBF ₄ ), with a ratio of the mass fraction of fluorine and boron for a given acid of 3.85-4.05, and a 70% aqueous solution of nitric acid (HNO ₃ ).

The ratio of the volume parts of the acids used as defined by the present invention is optimal.

With an increase in the composition of the ratio of the volume parts of nitric acid (HNO ₃ ) and tetrafluoroboric acid (HBF ₄ ), the polishing effect of the solution on polysilicon crystals takes place, and with a decrease, the efficiency of the process of selective etching of the local zones of the polycrystalline silicon film decreases. In general, a change in the ratio of the volume parts of nitric acid (HNO ₃ ) and tetrafluoroboric acid (HBF ₄ ) in solution worsens the process of nanostructure of a polysilicon film.

To implement the invention, aqueous acid solutions were prepared according to the following examples.

Example 1

100 ml [700 (v / v)] - 50% tetrafluoroboric acid solution;

0.15 ml [~ 1 part by volume] - 70% nitric acid solution. The mixture was mixed with the addition of 0.008 mg of anionic fluorine-containing surfactant grade FS-62.

Example 2 (control).

100 ml [700 (v / v)] - 50% tetrafluoroboric acid solution;

0.15 ml [~ 1 part by volume] - 70% nitric acid solution. The mixture was stirred.

3 stage.

Steel and titanium disks were lowered into the aqueous solution obtained in Example 1. In total, 2 disks from each material and a glass-ceramic plate were used.

Steel and titanium disks were lowered into the aqueous solution obtained in Example 2. Used one disk from each material.

In case of liquid etching of disks, the treatment time was determined by visual assessment of the color change of the modified surfaces of the disks from the color characteristic of a polycrystalline silicon film to bluish-violet during liquid etching.

In the liquid etchant of Example 1, the surfaces of the samples used with a polycrystalline silicon film deposited on them had a uniform bluish-violet color after 0.5 minutes.

The processing time of implants in an aqueous solution of the composition used according to the invention depends mainly on the thickness of the polycrystalline silicon film on its surface.

At the same time for treating the surface of the disks (with a polycrystalline silicon film deposited on them) during processing in a liquid etchant according to Example 2, an uneven bluish-violet surface color was obtained, which indicates the inefficiency of this solution to obtain a uniform nanosized silicon surface layer of polysilicon.

The samples of porous polysilicon obtained as a result of liquid etching were washed with deionized water and dried.

During the washing of the samples, the surfaces of porous polysilicon underwent oxidation with the predominant formation of surface bonds of the Si – OH type, which are necessary to increase the biocompatibility of the material.

A disk made of titanium treated by liquid etching in an aqueous acid solution of Example 1 was examined using a Solver P-47 atomic force microscope (manufacturer NT-MDT, Moscow, RF) to determine and evaluate a nanostructured surface layer of porous polysilicon, obtained on a film of polycrystalline silicon.

Figure 1 shows an AFM image of a fragment (along the X, Y, Z axes) of a polysilicon film (1) with a nanostructured near-surface layer of porous polysilicon (2) obtained by chemical etching of the film according to the invention.

From the above figure it follows that the polycrystalline silicon film (1) during the implementation of the invention provides the formation of a homogeneous in structure and thickness of the nanostructured surface layer of porous polysilicon (2).

The thickness of the obtained nanostructured near-surface layer of porous polysilicon does not exceed 200 nm.

The biological compatibility of porous polysilicon, the presence of adhesion of bone tissue and the formation of calcium phosphate compounds on its surface, the absence of cytotoxicity is confirmed by a number of research works, including the following:

- Bayliss S.C., Harris P.J. and other. Phosphate and cell growth on nanostructured semiconductors. Jornal of Materials Science Letters. 1997: 16: 737-740;

- Yangyang Lu, Fan Yang, Linto Cai. Osteoblast adhesion on porous silicon. Bulleten of Advanced Technology Research. 2009, Jan., Vol. 3, No. l, 25-28.

In particular, the effect of porous polysilicon on cell viability and proliferation was studied in vitro on cell cultures — osteoblasts, fibroblasts. Previously, cells (culture medium) for their tracking were marked with a CellTracker ™ indicator (probe) (green CMFDA, molecular probe). CellTracker ™ probes are fluorescent chloromethyl derivatives. Labeled cells were examined using a Leica vertical microscope designed for high-contrast epifluorescence and equipped with a program for capturing (capturing) an image.

The research results show that the nanostructured layer of porous polysilicon promotes the adhesion of cell structures on the surface of the material. Studies confirm that porous polysilicon is able to support the growth of osteoblasts and fibroblasts, is non-toxic and biocompatible material.

Claims (2)

1. The method of forming a nanostructured biocompatible coating on the surfaces of the implants, which consists in the deposition of a polysilicon film on the surface of the implant in the reactor, and then etching it with the formation of a nanostructured surface layer of porous polysilicon, while the etching of the polysilicon film is carried out by immersing the implant in a mixture containing 50-55 % aqueous solution of tetrafluoroboric acid (HBF _4), 70-90% aqueous solution of nitric acid (HNO ₃₎ and an anionic surfactant in Snov ammonium salt of perfluorosulfonic acid R _f SO ₃ NH _4, in an amount of 5 x 10 ^-3 -10 ^-2 (wt.%), where R _f -C ₈ F ₁₇ or C ₂ F ₅ OC ₃ F ₆ OC ₂ F _4, or C ₆ F ₁₃ CH ₂ CH ₂ , using aqueous solutions of acids with a ratio of their volume parts HBF ₄ : HNO ₃ , as (100-800) :( 1: 1,1), followed by washing the implant with deionized water and drying. 2. The method according to claim 1, characterized in that on the surface of the implant a coating is formed in the form of a polysilicon film with a thickness of 0.4-0.6 microns, and with the formation of a nanostructured surface layer of porous polysilicon with a thickness of not more than 200 nm.

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