RU2617252C2 - Method of calcium-phosphate coatings processing on implants - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Method involving introduction of calcium phosphate into 5–20 % solution of orthophosphoric acid till saturation is described; then implant is placed in this solution and galvanic application of calcium-phosphate coating is made at 80–400 V, pulse frequency 50–150 Hz, current density 0.2–1.0 A/mm², during 10–60 minutes, pulse time of 50–300 mcs, pH of electrolyte 6.5–8.0 and electrolyte temperature of 25–40 °C, and product is washed with distilled water, annealed at temperature of 400–1,200 °C during 30–60 minutes until formation of coral-like branched structure of coating with thickness of 5–80 mcm, then product is put into solution with metabolites of lactic bacteria or colibacteria for 10–30 minutes at temperature of 18–25 °C.

EFFECT: method enables to obtain coatings of various thickness, porosity, density, roughness, elasticity depending on purpose of article and eliminates possibility of bacteria replication in near-implantation zone.

1 cl, 1 tbl, 2 ex

Description

The invention relates to the field of medical equipment, namely to coating implants with biologically active compounds, and can be used in traumatology, orthopedics and dental practice.

One of the urgent problems of traumatology, orthopedics and dentistry is the creation of new bone-plastic materials and the use of various implants for osteosynthesis.

In the Russian Federation annually about 6 million cases of various injuries and diseases of bone tissue are recorded. More than 1 million patients require implant surgery for osteosynthesis. Currently, these implants are mainly supplied from foreign countries made of ceramic or titanium. The severity of traumatic injuries is complicated by the development of a specific infection, in particular post-traumatic osteomyelitis, which entails the need for repeated operations, increases the cost of rehabilitation treatment and rehabilitation aimed at restoring the support ability of damaged limbs and the production of medical devices, including endoprostheses, implants, etc. deforming osteo- and spondylarthrosis and pathological bone fractures develop in old and senile age, arising primarily due to developing systemic metabolic disorders and osteoporosis [Corresponding Member of the Russian Academy of Sciences, V. Shevtsov et al. Carbon - new facets of its use in medicine. Medical newspaper, No. 86 dated 11/19/2014].

In recent years, titanium implants have been widely used, which make it possible to form a bioactive surface due to the content of calcium phosphate compounds on the surface. The surface on the implants has a multi-level porous structure with a rough surface with adhesive and osteosynthetic properties.

Several methods for applying calcium phosphate coatings to implants are described. Methods are proposed: microarc oxidation [Patent RU No. 2385740 of 04/10/2010], in a vacuum chamber in an argon atmosphere [Patent RU No. 2400423 of 09/27/2010; RU patent No. 2372101 dated 10.11.2009], in vacuum using a spark or arc discharge [Patent RU No. 2507316 from 02.20.2014], in a plasma of a high-frequency magnetron discharge in an argon atmosphere [Patent RU No. 2523410 from 07.20.2014 ], under conditions of a pulsed current with a spark discharge [Patent RU No. 2291918 dated January 20, 2007], in an electrolyte solution with microarc discharges [Patent RU No. 2206642 dated June 20, 2003]. With the aim of heterogeneous formation of crystallization centers of calcium phosphate, it is proposed to add a number of chemical elements to the coating [Patent RU No. 2124329 of January 10, 1999], in the mode of spark or vacuum-arc discharge it is proposed to apply a two-layer coating [Patent RU No. 2423150 of July 10, 2011 .]. A method for producing a calcium phosphate coating on titanium alloys from a model solution of human synovial fluid is described [Patent RU No. 2532350 of 11/10/2014].

One of the significant drawbacks of the technical solutions proposed above is the impossibility of regulating the physicomechanical characteristics of calcium phosphate coatings depending on the purpose of the implant and the physiological requirements for the implant when used in traumatology, orthopedics and dentistry. The proposed methods do not provide antimicrobial protection of the implants from opportunistic and pathogenic microflora (microbiota) of the patient's body in the postoperative period.

As a prototype, the method of galvanic deposition of biocompatible coatings based on hydroxyapatite on implants was chosen [Patent RU No. 2394501 of 10.20.2010], which allows to obtain a developed surface structure of the coating with a thickness of 14 ± 2 μm and a porosity of 15 ± 3% with a predetermined microhardness of in the range from 150 to 300 MPa, depending on the change in the concentration of the bioactive additive of hydroxyapatite in an alkaline electrolyte when coating by the microarc oxidation method for 15 minutes. In the proposed method, the coating on the implant is carried out in a certain galvanostatic mode at certain current values, the duration of the anode and cathode pulses, the frequency and pauses between pulses, which limits the widespread use of implants depending on their purpose in traumatology, orthopedics, dentistry and the requirements for implants . The method does not provide for the protection of the implant from the conditionally pathogenic and pathogenic microbiota of the patient's body. The sterility of the implant does not prevent the penetration of microbes that persist in the patient’s body into the implant.

The present invention is the creation of biologically resistant to microbial contamination of the coating of implants that meet the requirements for implants in traumatology, orthopedics, dentistry, depending on their purpose.

The purpose of the technical solution is to change the technology for the manufacture of calcium phosphate coatings by creating conditions that prevent the growth of bacteria in the implant and expanding the conditions for galvanic deposition of calcium phosphate on the implant, allowing the product to be used in traumatology, orthopedics and dentistry, depending on the purpose of the manufactured product.

The technical result is simple, not requiring large material costs and is based on creating conditions that prevent contamination and reproduction of bacteria in the implant as a result of processing the coating on medical devices with metabolites of eubiotics (probiotics), which are able to exclude the possibility of propagation of pathogenic and conditionally pathogenic microflora in implants in the postoperative period, as well as the expansion of the conditions for the galvanic deposition of calcium phosphate coatings on implants that allow sex chat coating of varying thickness, porosity, density, roughness, flexibility, and the expected load on the product depending on the product destination in traumatology, orthopedics and dentistry.

The technical result of our proposed method for treating implants with bacterial metabolites is based on the use of a general biological pattern of bacterial growth in a liquid nutrient medium, including the initial - lag phase, exponential, stationary and the dying phase. In the stationary phase and the dying phase, the largest number of bacterial metabolites is released that impede the propagation of microbiota. It was established that these metabolites do not have species specificity and actually act on various types of opportunistic microorganisms [Bukharin OV, Perunova NB, Ivanova EV Bifidoflora in associative human symbiosis. - Yekaterinburg: Ural Branch of the Russian Academy of Sciences, 2014. - 212 p.]. To exclude the possibility of penetration of pathogenic microbes into the macroorganism - producers of metabolites and their pathogenic effects on the macroorganism, bacteria that are representatives of the normal microflora of the human body (probiotics) were used as producers of metabolites. In the stationary phase or in the phase of the death of bacteria, the liquid nutrient medium with bacteria was passed through a bacterial filter to remove bacterial microbial cells and to obtain a sterile suspension of metabolites of lactobacilli and colibacteria.

The technical result is achieved by the fact that according to the invention, calcium phosphate is introduced into a 5-20% phosphoric acid solution until saturation, the implant is placed in this solution and galvanic deposition of calcium phosphate coating is carried out at a voltage of 80-400 V, pulse frequency of 50-150 Hz, density current 0.2-1.0 A / mm ² , for 10-60 minutes, pulse time 50-300 μs, pH of the electrolyte 6.5-8.0 and the temperature of the electrolyte 25-40 ° C, the product is washed with distilled water, firing the product at a temperature of 400-1200 ° C for 30-60 minutes until the formation of a coral p branched coating structure with a thickness of 5-80 μm, then the product is placed in a solution with metabolites of lactobacilli (or colibacilli) for 10-30 minutes at a temperature of 18-25 ° C, and a solution with metabolites of lactobacilli (or colibacilli) is obtained as follows: liquid nutrient medium with lactobacilli (or colibacilli) in the stationary phase and / or phase of the death of bacteria is passed through a bacterial filter to obtain sterile bacterial metabolites.

The proposed method is carried out in the following ways.

Calcium phosphate was added to saturation in a 5-20% phosphoric acid solution. The implant was placed in this solution and galvanic deposition of calcium phosphate coating was carried out at a voltage of 80-400 V, pulse frequency 50-150 Hz, current density 0.2-1.0 A / mm ² , for 10-60 min, pulse time 50-300 μs, the pH of the electrolyte is 6.5-8.0 and the electrolyte temperature is 25-40 ° C. The product was washed with distilled water, and then fired at a temperature of 400-1200 ° C for 30-60 minutes until a coral branched structure of the coating with a thickness of 5-80 microns was formed. The finished product was placed in a solution with metabolites of lactobacilli (or colibacteria) for 10-30 minutes at a temperature of 18-25 ° C, which was obtained as follows: a liquid nutrient medium with bacteria in a stationary and / or phase of the death of bacteria was passed through a bacterial filter to obtain sterile bacteria metabolites.

Examples of practical use of the proposed method

Preclinical tests of the application of the method of processing calcium-phosphate coatings on the implant on rabbits of the breed "chinchilla" weighing 2000-3000 grams. Healthy rabbits were kept in cages in accordance with the requirements of sanitary rules (Approved by the Chief State Sanitary Doctor No. 1045-73). In the vivarium, the air temperature was maintained at 24-26 ° С in accordance with the order of the Ministry of Health of the Russian Federation No. 267 of 06/19/2003 and the requirements of the European Convention (Strasbourg, 1986) on keeping, feeding and caring for experimental animals, removing them from the experiment and subsequent disposal. The operations were performed under general anesthesia.

Example 1

A 2500 gram gram chinchilla rabbit underwent an operation on the ilium to install a calcium phosphate-coated implant of bacterial metabolite treated with the commercial drug Lactobacterin, based on Lactobacillus plantarum 8P-A3, or L. plantarum38, or L. fermentum 90T -C4, or L. fermentum 39. An implant with a diameter of 6 mm is installed in the formed hole in the rabbit ileum. The calcium phosphate coating on the implant was treated as follows.

Calcium phosphate was added to saturation in a 5-20% phosphoric acid solution. The implant was placed in this solution and galvanic deposition of calcium phosphate coating was carried out at a voltage of 80-400 V, pulse frequency 50-150 Hz, current density 0.2-1.0 A / mm ² , for 10-60 min, pulse time 50-300 μs, the pH of the electrolyte is 6.5-8.0 and the temperature of the electrolyte is 25-40 ° C. The product was washed with distilled water, and then fired at a temperature of 400-1200 ° C for 30-60 minutes until a coral branched structure of the coating with a thickness of 5-80 microns was formed. The finished product was placed in a solution with bacteria metabolites of the commercial drug “Lactobacterin” (H46 series, manufactured by FSUE NPO Mikrogen, Russia, Nizhny Novgorod) for 10-30 min at a temperature of 18-25 ° C. Metabolites were prepared as follows: a liquid nutrient medium with bacteria in the dying stage (after 72 hours of bacterial growth on a thioglycol medium) was passed through a bacterial filter to obtain sterile bacterial metabolites.

The operation went without features. Clinical observation of the animal was performed for 21 days. There are no signs of the development of an infectious process. When opening the animal after 21 days, a study of the peri-implantation zone was performed. No signs of an inflammatory process were found in this zone. During microbiological examination of the peri-implantation zone, it was not possible to isolate pathogenic and conditionally pathogenic microorganisms.

Example 2

The rabbit of the "chinchilla" breed weighing 2800 grams had an operation on the ilium to install an implant with a calcium phosphate coating of bacteria metabolite treated with the metabolite of bacteria, the commercial drug "colibacterin" (Series H 18/0914, IMBIO - Nizhny Novgorod GP for the production of bacterial preparations. Microgen) .

An implant with a diameter of 6 mm is installed in the formed hole in the ileum of the rabbit. The calcium phosphate coating on the implant was treated as follows.

Calcium phosphate was added to saturation in a 5-20% phosphoric acid solution. The implant was placed in this solution and galvanic deposition of calcium phosphate coating was carried out at a voltage of 80-400 V, pulse frequency 50-150 Hz, current density 0.2-1.0 A / mm ² , for 10-60 min, pulse time 50-300 μs, the pH of the electrolyte is 6.5-8.0 and the electrolyte temperature is 25-40 ° C. The product was washed with distilled water, and then fired at a temperature of 400-1200 ° C for 30-60 minutes until a coral branched structure of the coating with a thickness of 5-80 microns was formed. The finished product was placed in a solution with the metabolites of bacteria of a commercial preparation, colibacterin for 10-30 minutes at a temperature of 18-25 ° C, which was obtained as follows: the bacteria were cultured in a liquid nutrient medium for 48 hours (stationary phase of bacterial reproduction). A suspension of bacteria was passed through a bacterial filter to obtain sterile bacterial metabolites.

The operation went without features. Clinical observation of the animal was performed for 21 days. There are no signs of the development of an infectious process. When opening the animal after 21 days, a study of the peri-implantation zone was performed. No signs of an inflammatory process were found in this zone. During microbiological examination of the peri-implantation zone, it was not possible to isolate conditionally pathogenic and pathogenic microflora (microbiota).

The advantages of the proposed method in comparison with the prototype are presented in the table.

The proposed method for processing calcium-phosphate coatings on implants with metabolites of lactobacilli (or colibacteria) was tested on rabbits weighing 2,000 - 3,000 grams of chinchilla breed. Preclinical tests were performed on 12 laboratory animals. Studies have shown that the treatment of calcium phosphate coatings with metabolites of lactobacilli (or colibacteria) excludes the possibility of the development of an infectious process in the postoperative period.

Claims (1)

A method of processing calcium phosphate coatings on implants involves adding calcium phosphate to a 5-20% phosphoric acid solution until saturated, the implant is placed in this solution and galvanic coating of the calcium phosphate coating is performed at a voltage of 80-400 V, pulse frequency of 50-150 Hz, current density 0.2-1.0 A / mm ² , for 10-60 minutes, pulse time 50-300 μs, electrolyte pH 6.5-8.0 and electrolyte temperature 25-40 ° C, the product is washed with distilled water , carry out the firing of the product at a temperature of 400-1200 ° C for 30-60 minutes until the formation of coral the branched structure of the coating is 5-80 μm thick, then the product is placed in a solution with metabolites of lactobacilli or colibacilli for 10-30 minutes at a temperature of 18-25 ° C, and a solution with metabolites of lactobacilli or colibacilli is obtained as follows: a liquid nutrient medium with bacteria in the stationary phase and / or phase of the death of bacteria is passed through a bacterial filter to obtain sterile bacterial metabolites.