Post-loading of zeolite-covered plastics with antimicrobial metal ions

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine. A method of post-loading of ceramic particles with antimicrobial metal cations is described. The post-loaded particles represent zeolites, where the zeolites are includes into resin, and a combination is used as an implanted device. The polymer represents a thermoplastic polymer such as polyaryletheretherketone (PEEK). A source of antimicrobial activity includes ion-exchange cations, contained in zeolite. Described is the method of adding antimicrobial activity to devices by regulating the delivery of certain cations by ionic exchange via zeolite, included into the device.

EFFECT: device makes it possible to reduce bacteria growth and infection risk.

14 cl, 2 ex

 

The present application claims the priority of provisional patent application U.S. under serial No. 61/264289, filed November 25, 2009, and provisional patent application U.S. under serial No. 61/300631, filed February 2, 2010, the disclosures of which are incorporated in this application.

Background of the INVENTION

Implantable medical devices are implanted in the body for a variety of reasons, including orthopedic indications (e.g., hip replacement, procedures on the spine, knee replacement, repair of bone fractures, etc.). Because of the demands of the structural integrity of such devices, the material used for their production is limited and usually include metal, plastic and composite materials.

The benefits gained by using these devices, often wipe out the infection, which can lead to sepsis and death. The most common organisms causing infection areStaphylococcus epidermidisandStaphylococcus aureus. Problems also cause other gram-positive bacteria, gram-negative bacteria and fungal organisms. Of particular concern is methicillin resistantStaphylococcus aureus(MRSA), a type of staph bacteria that is resistant to many antibiotics. As a result, MRSA infection more difficult to treat than ordinary staph infection, � they have become a serious problem.

Many pathogenic bacteria can form on bioengineered implants multicellular coating called a biofilm. Biofilms can promote the proliferation and transfer of microorganisms to ensure a sustainable protective environment. These biofilms, with sufficient development, can disseminate planktonic bacterial threads that may lead to a widespread systemic infection.

Bioengineered materials act as excellent hosts for the formation of bacterial biofilms. Sometimes (the implant itself carries the infective organism) on implants develop very tenacious biofilms formed by colonization of the infecting microorganisms. When this happens, usually the implant must be removed, the patient should be treated by a long course of one or more antibiotics to cure the infection, and then re-implantation of a new implant. Obviously, this exposes the patient to additional trauma and pain and is a very costly procedure.

Accordingly, much research has been devoted to the prevention of colonization of bacterial and fungal organisms on the surfaces of orthopedic implants by application of antimicrobial agents such as antibiotics, associated with surface materials used in such devices. For example,�edge is a powerful, natural antibiotic and preventative against infections. Acting as a catalyst, it will inactivate the enzyme, in which single-celled bacteria, viruses and fungi need for their oxygen metabolism. They suffocate without corresponding harm to human enzymes or parts of the biochemical systems of the human body. The result is the destruction of pathogenic organism in the body. Silver destroys the bacterial membrane, the intermembrane enzymes and transcription of DNA.

Ceramics such as zeolite, functions as a cationic cage, not able to boot with silver and other cations with antimicrobial properties. Zeolites modified by metal cations, can be used as an antimicrobial agent, for example, by mixing the resins used as thermoplastic materials for the manufacture of implantable devices, or as coatings to be applied to the device; see, e.g., U.S. patent No. 6582715, the description of which is incorporated in this patent application by reference. Antimicrobial zeolites metals can be obtained by substitution of all or part ionoobmennihe ions in the zeolite ions, ammonium ions and antimicrobial metal. Preferably, they are substituted, not all ionoobmennaya ions.

�ne specific thermoplastic resin, which, as observed, can be used as an implant, is polyetheretherketone (PEEK). PEEK is suitable, because its module closely matches the modulus of the bone. In conditions of high temperature and high shear forces may include zeolite, such as zeolite containing silver atoms, PEEK, for example, by mixing the coated metal zeolites with molten PEEK (melting point from 300 to 400°C), followed by molding and processing the composite mixture. Pure PEEK very light brown, and silver zeolite white. However, the heated melt after treatment is a dark brown color. The reasons for the existence of colors can include oxidation of some part of the silver to silver oxide, which may be less soluble and less effective than the pure silver cation coupled to a cell of the zeolite. Metallic silver can have catalytic properties and can cause collapse and partial destruction of the polymer PEEK. Grade PEEK approved for implantation are very clean and inert and must undergo rigorous testing cytotoxicity before their implantation in mammals.

Set 10993 ISO (International standards organization) includes a series of standards for evaluating the biocompatibility of medical devices prior to clinical study. These documents preds�contributed to a tripartite agreement, and they are part of a harmonized assessment of the safe use of medical devices. These standards include:

ISO 10993-1:2003 biological evaluation of medical devices part 1: evaluation and testing

ISO 10993-2:2006 biological evaluation of medical devices part 2: animal welfare requirements

ISO 10993-3:2003 biological evaluation of medical devices part 3: tests for genotoxicity, Carcinogenicity and toxic effect on the reproductive function

- ISO 10993-4:2002/amended 1:2006 biological evaluation of medical devices part 4: selection of tests for interactions with blood

- ISO 10993-5:2009 biological evaluation of medical devices part 5: tests for cytotoxicity in vitro

- ISO 10993-6:2007 biological evaluation of medical devices part 6: tests for local effects after implantation

- ISO 10993-7:1995 biological evaluation of medical devices part 7: the remains of pathogens after sterilization by ethylene oxide

- ISO 10993-8:2001 biological evaluation of medical devices part 8: section of the reference material

- ISO 10993-9:1999 biological evaluation of medical devices part 9: criteria for identification and kolichestvennogo identify possible degradation products

- ISO 10993-10: 2002/amended 1:2006 biological evaluation of medical devices part 10: tests for irritation and hypersensitivity �medlenno type

- ISO 10993-11:2006 biological evaluation of medical devices part 11: tests for systemic toxicity

- ISO 10993-12:2007 biological evaluation of medical devices part 12: sample and reference materials (available in English only)

- ISO 10993-13:1998 biological evaluation of medical devices part 13: identification and quantification of degradation products from polymeric medical devices

- ISO 10993-14:2001 biological evaluation of medical devices part 14: identification and quantification of degradation products from ceramics

- ISO 10993-15:2000 biological evaluation of medical devices part 15: identification and quantification of degradation products from metals and alloys

- ISO 10993-16:1997 biological evaluation of medical devices part 16: the structure toxicokinetic studies to identify degradation products and leachables

- ISO 10993-17:2002 biological evaluation of medical devices part 17: establishment of allowable limits for leachable substances

ISO 10993-18:2005 biological evaluation of medical devices part 18: chemical characterization of materials

- ISO/TS 10993-19:2006 biological evaluation of medical devices part 19: physico-chemical, morphological and topographical characterization of materials

- ISO/TS 10993-20:2006 biological about�assessment of medical devices part 20: principles and methods immunotoxicological testing of medical devices

There is a possibility that the reaction catalyzed by silver when including silver zeolite in PEEK, at high temperature may generate toxic materials that can cause the failure of the product to pass these tests. In addition, at these high processing temperatures, zeolite with incorporated metal can release moisture, unless it is extremely dry. This moisture can cause the formation of voids in the polymer melt and can contribute to the destruction of PEEK polymer and oxidation of metals, such as silver, copper and/or zinc that is included in the antimicrobial zeolite material. Although the presence of voids may not be critical, the absence of voids is crucial for applications involving impact loads, such as repair of the spine.

If the process of incorporating the zeolite with incorporated metal is held in the air, can occur pronounced oxidation, with the rise of temperature, and moisture and oxygen come into contact with metal ions. Silver will darken quickly, getting a dark brown or black color. Also, the inclusion in the polymer PEEK of significant amounts of zeolites entered into them with metals can affect the viscosity and rheology �oppozitsii.

Accordingly, to reduce the growth of bacteria and risk of infection, it would be desirable to provide a medical device with high antimicrobial activity, which do not have the above disadvantages.

A BRIEF SUMMARY of the INVENTION

The disadvantages of the prior art were overcome are described in the present application implementation options, which refer to devices such as surgical implants with antimicrobial properties that provide an inorganic antimicrobial agent, and to methods of post-loading of ceramic particles of the antimicrobial metal ions after the ceramic material included in plastic, and it is preferably given the opportunity to cool off and be cured in its final form, which can be achieved by injection molding or cutting and machining processing. In certain embodiments, the devices are orthopedic implants. In certain embodiments, the antimicrobial agent is a kind of ceramic material, preferably a zeolite with incorporated metal. In certain embodiments, the device includes a polymer. In certain embodiments, the polymer is polyaryletheretherketone (PEK). In certain embodiments, the source of antimicrobial activity includes ionoobmennaya cations contained in the zeolite. In certain embodiments, the described methods of imparting antimicrobial activity to the devices by controlling the delivery of certain cations by ion exchange using zeolite included in the device introduced into the patient. In certain embodiments, the metal cation is present at a level below the capacity of ion exchange, at least part of the zeolite particles.

In certain embodiments, the zeolite included in the device, and the zeolite with the affected environment surface charge of the metal ions of one or more aqueous solutions as a source of one or more metal ions. The device is inserted into the body surgically. The rate of release is governed by the degree of download PEEK a zeolite and the degree to which the exposed environment of the zeolite charged metal ions. The concentration of electrolytes in blood and biological fluids is relatively constant and causes the exchange of ions, such as silver, copper and zinc etc. with the implant surface, which will inactivate or destroy gram-positive and gram-negative organisms, includingE. coliandStaphylococcus aureus. The effect�VNOM fight against microbes (e.g., reducing the level of microorganisms on six logarithms) can be achieved even at low concentrations of metal, equal to 40 mg/ton. X-ray examination remained radiopacity.

DETAILED DESCRIPTION

The variants of the implementation described in this application relate to the use of ceramics, preferably zeolites, cationic cells in combination with medical implants for the delivery and dosing of one or more antimicrobial cations. Suitable cations include ions of silver, copper, zinc, mercury, tin, lead, gold, bismuth, cadmium, chromium, and thallium, preferably silver, zinc and/or copper, and especially preferably silver.

Or natural zeolites or synthetic zeolites can be used to obtain the zeolites used in the embodiments described in the present application. "Zeolite" is an aluminosilicate having a two-dimensional skeletal structure that is represented by the formula: ΧΜ2/nΟ·Al2O3·YSiO2·ZH2O, where M represents ionoobmennaya ion, in General, the ion of a monovalent or divalent metal, n represents the atomic valency of the ion (metal), X and Y represent coefficients respectively of metal oxide and silicon dioxide, and Z represents the number of centers of crystallization water. Primerica zeolites include zeolites of type A, the zeolite type X, zeolite type Y, zeolite T, zeolite with a high silica content, sodalite, mordenite, analytic, clinoptilolite, habasit and erionite.

Zeolites can be included in the main component with an ingredients elevated concentrations of a range of polymers. For final inclusion in PEEK, the main component with an ingredients in high concentrations must be obtained by the inclusion of typically about 20% zeolite. Upon receipt in this form, the granules of a main component with an ingredients high concentrations of PEEK containing particles of the zeolite can be further restored by mixing with more raw PEEK at a higher temperature and under high shear forces. If the metal present in the zeolite, it would have led even to the second exposure to conditions that may cause damage to the product.

Other suitable resins include low density polyethylene, polypropylene or polystyrene, polyvinyl chloride, styrene ABS resin, silicones, rubber and mixtures thereof, and reinforced resins, such as ceramic or reinforced carbon fiber resin, in particular a reinforced carbon fiber PEEK. The latter can be obtained by dispersing a reinforcing material or materials (e.g., carbon fibers) polyester�world matrix for example, by compounding in a twin-screw extruder implantable PEEK polymer with carbon fibers. The resulting product, which is reinforced by carbon fibres can be used for end-devices of the injection molding and an almost pure form, or it can be subjected to extrusion in the original form for machining. The inclusion of fibers or other suitable reinforcing material provides high resistance to shear, young's modulus of 12 GPA (corresponding to the modulus of cortical bone) and provides sufficient strength to allow its use in very thin implants, which are more effectively distribute the stress on the bone. The amount of reinforcing material, such as carbon fiber, is included in a resin such as PEEK, may vary in order to modify the young's modulus and Flexural strength. One appropriate amount is 30% of the mass. carbon fibers. Resin can also be made porous, such as porous PEEK, PAEK (polyaryletherketone) and PEKK (polyetherketone), with suitable values of porosity, including porosity from 50% to 85% by volume. The average pore size generally greater than 180 microns in diameter, probably from about 300 to about 700 microns. Porosity can be given using a form of polyagents, such as sodium chloride, to create a porous polymer comprising a plurality of interconnected pores, by methods known in this field. Each of the above resins may be made for the maintenance of suitable amounts of zeolite particles, typically, about 20% of the mass. For devices implants preferred UHMWPE (ultrahigh-molecular weight polyethylene).

The typical number of particles of the zeolite included in the resin of the implant is in the range from 0.01 to 50 wt.%, preferably, from 0.01 to 8.0 wt.%, most preferably, from 0.1 to 5.0 wt%. If the implant is covered with a coating or resin that is loaded with zeolite, the coating must be applied and dried or subjected to curing prior to infusion. The method used for coating of the implant is not specifically limited and may include spraying, painting or dipping. By compounding, for example, in the main component with an ingredients in high concentrations, representing a PEEK, PEEK must be protected from moisture and dirt before you restore the raw resin. The compounding may be carried out by mixing in the molten core component with an ingredients in high concentrations and the diluted resin under high temperature and high� shear forces.

The main component with an ingredients in high concentrations is a concentrated encapsulated during the process of heating in a resin carrier, a mixture of pigments and/or additives (for example, zeolite powder, which is then cooled and cut to a granular form. The use of the main component with an ingredients high concentration enables the processor is economical and simple to introduce additives to the raw polymer (diluted resin during the manufacturing process of plastics.

In accordance with certain embodiments of the implementation, cleaner and more sustainable product can be obtained by loading the polymer with pure zeolite (e.g. zeolite, which has not yet uploaded an antimicrobial metal ions or which are only partially loaded), such as zeolite type X, manufactured by W. R. Grace & Co.-Conn., which is able to bear such a burden cationic metal ion, Ag+, Cu++, Cu+ or Zn+, and subsequent load (for example, cooled to a temperature from about 0 to 100°C, preferably to about room temperature) surface containing zeolite metal ions from a source of metal ions, such as aqueous solution of metal ions, such as silver nitrate, copper nitrate and zinc nitrate, alone or in combination. Cooling �about lower temperatures provides a slower download speeds but higher resistance. Download even at higher temperatures can be performed with higher speed by maintaining the system under pressure, for example, in a pressure cooker or autoclave. The content of ions can be controlled by adjusting the concentration of each species of ions (or salts) in solution.

By inclusion of the metal cation in the zeolite after inclusion of zeolite in a polymer resin, the oxidation of metal ions is reduced or eliminated. Specialists in this field it is clear that instead of or in addition to nitrate, can be used saline solutions of other metal ions, such as acetates, benzoates, carbonates, oxides, etc. Adding nitric acid to the solution for infusion may also be advantageous in that it can treat the surface of the implant, providing additional surface area for ion exchange.

Since PEEK is susceptible to dissolution in a strong oxidizing acid, you should take precautions to avoid the use of too high a concentration of acid that can lead to release of metal with the zeolite particles from the surface. PEEK is very resistant and impervious to water and biological fluids. As a result, it is expected that dispersed in PEEK metal ions incorporated into the zeolite cage, alumroots only when the TC�TKA is exposed to the environment on the surface of the polymer. For this reason, you can postglucose at least such amount of available metal ions by post-processing from solution, which would be accessible from the metal in the zeolite included in the hot mixture. Indeed, it is expected that the availability of metal ions from postclosing system will be much higher, because the metal ions are clean and not subjected to thermal oxidation or reactions with the polymer at a high temperature.

The number of metal ions in the zeolite should be sufficient to ensure that they are present in an antimicrobial effective amount. For example, suitable amounts may range from about 0.1 to about 20 or 30% open to environmental influence of zeolite (wt./mass. %). These levels can be defined with full extraction and determination of the concentration of metal ions in an extraction solution by atomic absorption.

Preferably, obtained by ion exchange antimicrobial metal cations is present at a level less than the capacity of the ion exchange ceramic particles. The amount of ammonium ions is preferably limited to education from about 0.5 to about 15 wt.%, preferably, from 1.5 to 5 wt%. For applications where strength is not critical, may be accepted by the loading of the zeolite, dost�offering 50%. Under such downloads, metal ions can penetrate the surface layer due to contact between particles, and possible much large load of metal ions.

The amount of zeolite included in the resin should also be an amount, effective to promote antimicrobial activity; for example, a sufficient amount to prevent or inhibit the growth of bacterial and/or fungal organisms or, preferably, to destroy them. Suitable amounts of zeolite in the resin are in the range of approximately from 0.01 to 50.0 wt.%, preferably, about 0.01 to 8.0 wt.%, most preferably, from about 0.1 to about 5.0% of the mass.

Absorption of metal ions in synthetic zeolites and natural zeolites in aqueous dispersion or loaded in the polymer, can be carried out from solutions of metal salts. The rate of absorption is proportional to the available surface area, concentration of metal ions in solution and temperature. With increasing concentration of metal adsorbed in the zeolite, the speed will decrease. When the absorption rate reaches release rate, equilibrium is reached when the concentration of the solution. Higher concentration in the solution can stimulate higher loading. Loaded zeolite may promyvat�Xia deionized water rinse to remove concatenated with the zeolite solution of metal ions. The goal is only subjected to ion exchange of the cations of metal, attached to the cage, and they can only be removed by ion exchange, and not deionized water.

The most useful ions for inclusion to release in orthopedic implants are ions of silver, copper and zinc. All three ions have antimicrobial properties, and the most active is silver. There may also be synergies between the metals from the standpoint of antimicrobial activity. For example, if a microorganism develops resistance to one kind of metal, it may well be destroyed one of the other metal ions. Ions of copper and zinc also perform other functions during wound healing and repair and bone growth.

For example, the composite zeolite PEEK can be loaded to ensure contact of the material with an aqueous mixed solution containing ammonium ions and antimicrobial metal ions, such as silver, copper, zinc etc. the Most suitable temperature at which can be the infusion is in the range from 5°C to 75°C, but can also be used at higher temperatures, even above 100°C, if the reaction vessels held under pressure. Higher temperatures show the increased speed of insisting, but lower temperatures can ultimately create bol�e homogeneous and higher load. the pH of the solution for infusion may be in the range of from about 2 to about 11, but preferably is from about 4 to about 7.

Suitable sources of ammonium ions include ammonium nitrate, ammonium sulfate and ammonium acetate. Suitable sources of antimicrobial metal ions include: a source of silver ions, such as silver nitrate, silver sulfate, silver perchlorate, silver acetate, diamine silver nitrate; a source of copper ions, such as copper nitrate(II), copper sulfate, copper perchlorate, copper acetate, tetracaine-copper-potassium; zinc ion source, such as zinc nitrate(II), zinc sulfate, zinc perchlorate, zinc acetate and zinc thiocyanate.

Below are illustrative examples of solutions for insisting, but effective wide range of concentrations and ratios.

Solution for infusion A
ComponentComposition (wt./mass.)
Ammonium hydroxide2,0
Silver nitrate1,2
Purified water96,8
the pH may be brought acid such as lemon to�slot or nitric acid
Total100

Solution for infusion B
ComponentComposition (wt./mass.)
Ammonium hydroxide2,0
Copper nitrate5,0
Purified water93,0
the pH may be brought acid such as citric acid or nitric acid
Total100

Solution for infusion C
ComponentComposition (wt./mass.)
Ammonium hydroxide2,0
Nitrate zinc7,0
Purified water91,0
the pH may be brought acid such as citric acid or nitric� acid
Total100

Solution for infusion D
ComponentComposition (wt./mass.)
Ammonium hydroxide2,0
Silver nitrate0,5
Copper nitrate2,0
Nitrate zinc2,5
Purified water93,0
the pH may be brought acid such as citric acid or nitric acid
Total100

Since there is a delicate balance between the concentrations of silver, zinc and copper in the metabolism for optimal healing, the advantage of this method is that it provides an easy way to precisely control the relative concentrations of the ions of certain metals. The optimum ratio can be achieved by varying the concentrations of salt ions by various�to link metals for download in the appropriate proportions and subsequent release in the appropriate proportions and speeds.

The magnitude of the release rate of metal ions in the saline solution with phosphate buffer or 0.8% solution of sodium nitrate can be quantified by spectroscopy with inductively coupled plasma ICP, or spectroscopy by atomic absorption in graphite oven.

When the "ladder" study these results can be used to optimize the speed of elution. Because metal ions are never exposed to high temperatures, ions, coupled with the zeolite and the eluting from it, will be a pure metal cations.

Another advantage of this method is that the amount of metal included in the implant will be limited to exactly what is included in the surface layer. From the point of view of cost and safety, it is the best solution.

Method will be effective regardless of whether the implants by injection molding or machining to achieve the final size of the implant.

Although the method is most applicable to polymers with a high melting point, such as PEEK, it can also be used effectively for polymers with lower melting points, which are used in a wide range of applications in orthopedics. For example, HDPE (high density polyethylene) is used at�nnyh elements grafts hip and knee joints.

Method of postnagruzki also suitable for termootdelenii resins, such as polyesters, epoxies and urethanes, etc.

This approach avoids the contact of silver ions with reagents, reaction intermediates and catalysts, which form the finished polymer.

The variants of the implementation described in the present application is applicable to obtain self-sterilizing fabrics and plastic films. Such materials can be used for the production of wound dressing materials for wide applications.

Facial mask, which eluted silver, copper and zinc, used for long-term control of microorganisms that may be inhaled in a medical facility or increasingly, in the event of a possible pandemic. Suitable substrates for such devices include polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), PCT, PETG (PET, type G), copolymer of PET and sobolifera in General, styrene, polytrimethylene (PTT)m3GT, Halar®, polyamide 6 or 6,6, etc., see U.S. patents Nos. 6946196 and 6723428 issued by the company Foss manufacturing, the descriptions of which are incorporated in this application by reference.

Other applications that use self-sterilizing fabrics, included in the scope of the embodiments described in this application.

When the material is exposed to externally� environment or immersed in a liquid medium, the exhausted zeolite can be selected antimicrobial metal ions.

You can download pure polymer zeolite, subjected to polymer extrusion into the fibers and hold postnagruzku material of the antimicrobial metal ions in the same manner as described for surgical implants.

Although variants of the implementation described in this application, focused on orthopedic implants, specialists in this field it is clear that the invention can be applied in a much wider range of applications, such as toothbrushes, door handles, components of a computer mouse and keyboard, pen knives and cutting boards, surgical instruments, components surfaces phones, vessels for casting water, containers for storage of food products and polymers to obtain self-sterilizing clothing and self-sterilizing facial masks.

Example 1

Ion-exchange zeolite, natural or synthetic, such as zeolite type A or type X, commercially available from the company W. R. Grace & Co.-Conn., or equivalent, included in PEEK. The normal amount of zeolite particles included in the resin of the implant is in the range from 0.01 to 10 wt.%, preferably, from 0.01 to 8.0 wt.%, most preferably, from 0.1 to 5.0 wt%. The method used for coating of the implant is not specifically limited and m�can include spraying, staining or dip. For example, by compounding in PEEK, the PEEK composite must be protected from moisture and contamination. The compounding may be carried out by mixing.

Approximately 5% of the mass. zeolite powder is mixed thoroughly with powdered or granular PEEK. The mixture was heated and processed at 400°C, using high shear. Zeolite and PEEK should be dry before processing to minimize the destruction and formation of voids in the product.

This system containing a zeolite without added silver ions, does not show the progressive appearance of discoloration and darkening that occurs in systems containing silver.

Consider that the manifestation of dark color in systems containing silver zeolite due to the formation of silver oxide and the destruction of the polymer.

The material is processed as described above, and it can be formed into pellets for further processing, molded into blocks to be subjected to extrusion into rods or injection molding into the final desired profile.

Materials in the form of blocks and cores can be subjected to machine processing in profiles that are suitable for use as orthopedic implants or other structures, where he finds the use of antimicrobial PEEK. Implants can be designed to ensure uvelichennaya surface by the presence of grooves, carved into the surfaces, or obtain products with the holes in the housing parts. The surface area can also be increased by texturing with sand or sandblasted surfaces.

Example 2

Download of the finished parts of the antimicrobial metal ions

Finished parts produced as described in example 1, immersed in a solution for infusion with the aim of download parts of the antimicrobial metal ions.

A typical solution for infusion prepared by adding 2% silver nitrate, 5% trinitroglycerine copper and 1% nitric acid to purified water.

ComponentComposition (wt./mass.)
Silver nitrate2
Trinitroglycerin copper5
Nitric acid1
Purified water92
Total100

Finished parts support or give the opportunity to move freely in the solution for infusion. The mortar should be mixed to enhance diffusion of ions to the surface of the composite and from it. Desi�individual to a process of maceration in the dark to minimize photo-oxidation of silver in the solution. This can be carried out on a laboratory scale placing an opaque cover, such as a tin can, a beaker in which the infusion details.

The rate of infusion depends on several variables. At normal temperatures, 90 minutes is sufficient time for efficient loading of surface metal ions. The brewing process can be allowed to occur over a period of 24 hours or more to maximize the load of antimicrobial metal. The speed and degree of loading depends on several variables, including the concentration of the solution, composition of the solution (the ratio of metal ions), temperature of solution and mixing speed.

It must be possible to download metal ions exposed to the environment of the zeolite to the level of 40% of the mass.

When the maceration is completed or to desirable levels, the items are removed from the solution for infusion and washed three times with purified water. They can then be dried in a stream of hot air or in an oven or desiccator, etc.

Measure the antimicrobial activity of the product is the release of antimicrobial metal (e.g., silver) from the outer surface of the product. The release of metal can be measured as the amount of antimicrobial metal released �W outer surface of the sample size 2 inch by 2 inch (0.05×0.05 m or 5×5 cm). Provided the contact you want to test the outer surface of the sample with a solution of sodium nitrate (40 ml of 0.8% sodium nitrate) within 24 hours at room temperature (i.e. 25°C) for formation of the test solution. Then the test solution is analyzed to measure the amount of antimicrobial metal in the test solution in parts per billion and, thus, exposure to inorganic antimicrobial agent on the surface of the product. The amount of antimicrobial metal in the test solution can then be measured using a spectrophotometer to determine the atomic absorption or graphite furnace ICP. For products comprising 2.0 percent by weight (% wt.) inorganic antimicrobial agent based on the weight of the product layer or multi-layer products, and where inorganic antimicrobial agent contains 2.0 wt%. antimicrobial metal based on the total weight of the inorganic antimicrobial agent, the outer surface is the release of antimicrobial metal is more than or equal to about 10 parts per billion (bn) is preferably more than or equal to about 20 billion hours, preferably more than or equal to about 30 billion hours, and most preferably, more than or equal to about 40 billion hours

1. Method post-loading of ceramic particles antimicrobial cations of metals, including�by the inclusion of empty ceramic particles in a thermoplastic polymer and then load the specified ceramic particles of one or more cations of metals, moreover, the content of ceramic particles is 0.01-50 wt.%, and the number of metal ions is 0.1-30 wt./mass%.

2. A method according to claim 1, where said ceramic particles contain zeolite.

3. A method according to claim 1 or 2, where said one or more cations of metals selected from the group consisting of silver, zinc and copper.

4. A method according to claim 1, where said ceramic particles do not contain cations antimicrobial metals for inclusion in the specified thermoplastic polymer.

5. A method according to claim 1 or 2, where the specified thermoplastic polymer contains REEK.

6. A method according to claim 1, further comprising forming these ceramic particles and a thermoplastic polymer in the implant having a surface that is in contact with tissue or biological fluid of the body, and where at least some of the ceramic particles are present at said surface and are capable of releasing these metal cations in antimicrobe effective amount.

7. A method according to claim 1, where said cations of metals are present at levels less than the ion exchange capacity of the ceramic particles.

8. Method of imparting antimicrobial activity to the device by regulating the release of antimicrobial ions from said device through ion exchange containing the incorporation of ceramic particles in the�moplastic polymer and subsequent loading of these ceramic particles of one or more cations of metals, where said cations of metals can be released from these particles in antimicrobe effective quantity by ionic exchange.

9. A method according to claim 8, where said ceramic particles include zeolite and these metal cations contain silver.

10. A method according to claims. 1, 2 or 8, where the specified thermoplastic polymer contains reinforced RAILS.

11. A method according to claim 10, where the specified reinforced RAILS is a RAILS reinforced with carbon fibers.

12. A method according to claims. 1, 2 or 8, where the specified thermoplastic polymer contains a porous REEK.

13. A method according to claim 11, where the specified porous REEK has a porosity of from 50% to 85% by volume.

14. A method according to claim 2 or 9, where zeolite particles are particles of zeolite Α-type, having a two-dimensional skeletal structure that is represented by the formula: XM2/nO·Al2O3·YSiO2·ZH2O, where M represents ionoobmennaya ion, n represents the atomic valency of the ion (metal), X and Υ represent the coefficients respectively of metal oxide and silicon dioxide and Ζ represents the number of centers of crystallization water.



 

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20 cl, 3 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a method for measuring antimicrobial-coated tubular polyurethane products, including multiple-lumen polyurethane catheters consisting in the three-staged chlorhexidine and/or its salts modification. Chlorhexidine and/or its salts are impregnated on the product surface by processing the products in aqueous-alcohol solutions of chlorhexidine and/or its salts, removing excessive chlorhexidine and/or its salts from the product surface, applying a solution of polyurethane in tetrahydrofurane containing chlorhexidine and/or its salts, and evaporating tetrahydrofurane.

EFFECT: preparing the polyurethane products, eg catheters possessing the prolonged antimicrobial activity being in full accord with the multifunctionality of the multiple-lumen catheters.

9 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: antimicrobial composition for coating a medical device includes a material, which forms a polymer film, and an antimicrobial preparation from the traditional Chinese medicine, selected from a group: extract of Houttuynia cordata, sodium houttuyfonat and sodium new houttuyfonat or their mixtures. The medical device, covered with an antimicrobial composition, is made in the form of an implanted device.

EFFECT: invention provides the antimicrobial effectiveness with respect to microorganisms - causative agents of surgical infections.

19 cl, 2 dwg, 7 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a bioresorbable hydrogel polymer composition for cardiovascular surgery in the form of a film prepared by a reaction of natural polymers, biologically active substances, a solvent and a softening agent wherein the polymers are presented by cross-linked bioresorbable polymers - gelatin, chitosan or a mixture of chitosan and gelatin, chitosan and polyhydroxybutyrate; the biologically active substance or mixtures thereof are presented by the antioxidant L-carnosine, the anticoagulant heparin, the antiaggregant dipyridamole, acetylsalicylic acid, the non-steroid anti-inflammatory preparation acetylsalicylic acid, the antimicrobial preparations - ciprofloxacin, metronidazole; mechanical strength of the film is not less than 1.2 MPa, the relative elongation is no more than 160%, and the elasticity modulus is 0.4-5 MPa.

EFFECT: there are used hydrogel polymer compositions with the control bioresorption period, prolonged length of biologically active substance release, having biocompatible and thrombus-resistant properties and improved mechanical characteristics - higher softness and elasticity.

7 cl, 12 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and tissue engineering, and may be used in cardiovascular surgery for small-vessel bypasses. A vascular graft is made by two-phase electrospinning with the staged introduction of the ingredients into the polymer composition.

EFFECT: making the bioresorbed small-diameter vascular graft possessing the improved biocompatibility ensured by using the polymer composition of polyhydroxybutyrate (PHBV) with oxyvalerate, and epsilon-polycaprolactone with type IV collagen, human fibronectin and human fibroblast growth factor (hFGF) additionally introduced into the composition.

2 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is described is a biomaterial on the basis of calcium phosphate, preferentially on the basis of hydroxyapatite, or on the basis of a material containing hydroxyapatite, such as diphase calcium phosphates and calcium phosphate cements, and using it for making an implant or for positioning prosthesis for the purpose of osteoanagenesis.

EFFECT: biomaterial provides the excellent properties of biological compatibility and fast osteoneogenesis.

17 cl, 4 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and represents artificial dura mater, produced from electrospinning layers by technology of electorspinning, with electrospinning layer, consisting of, at least, hydrophobic electrospining layer, which is produced from one or several hydrophobic polymers, selected from polylatic acid and polycaprolactone.

EFFECT: invention ensures creation of artificial dura mater, which has good tissue compatibility, anti-adhesiveness and possibility of introducing medications, preventing cerebrospinal fluid outflow during regeneration of person's own dura mater.

30 cl, 7 ex, 11 dwg

FIELD: medicine.

SUBSTANCE: there are described new reinforced biodegradable frames for soft tissue regeneration; there are also described methods for living tissue support, extension and regeneration, wherein the reinforced biodegradable frame is applied for relieving the symptoms requiring high durability and stability apart from patient's soft tissue regeneration. What is described is using the frames together with cells or tissue explants for soft tissue regeneration in treating medical prolapsed, e.g. rectal or pelvic prolapse, or hernia.

EFFECT: frames are adequately durable to be applicable for implantation accompanying the medical conditions requiring the structural support of the injured tissues.

14 cl, 19 dwg, 2 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a method for measuring antimicrobial-coated tubular polyurethane products, including multiple-lumen polyurethane catheters consisting in the three-staged chlorhexidine and/or its salts modification. Chlorhexidine and/or its salts are impregnated on the product surface by processing the products in aqueous-alcohol solutions of chlorhexidine and/or its salts, removing excessive chlorhexidine and/or its salts from the product surface, applying a solution of polyurethane in tetrahydrofurane containing chlorhexidine and/or its salts, and evaporating tetrahydrofurane.

EFFECT: preparing the polyurethane products, eg catheters possessing the prolonged antimicrobial activity being in full accord with the multifunctionality of the multiple-lumen catheters.

9 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to an orthopaedic product and an orthopaedic pad, particularly an amputation stump pad, a contact pad, a prosthesis cover, an orthesis cover, a prosthesis collar, a shoe sole or orthopaedic socks, i.e. polymer materials used in direct skin contact. The polymer material is applicable for direct skin contact and contains a fine-distributed silver as an antibacterial agent and is additionally provided with fine-dispersed particles of other metal. The metals of the group containing aluminium or aluminium alloy, magnesium, bronze, titanium and/or platinum are applicable.

EFFECT: invention enables concealing the discoloration when using the orthopaedic pad on the skin, and hence when using the orthopaedic product provided with this pad, also including for masking the discoloration in the pigmented or coloured polymer materials applicable in air or skin contact.

7 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: described is a matrix of a biocompatible non-absorbable spatially linked polymer, obtained by exposure to UV light of a photopolymerised composition, which contains oligomers of a methacryl line, is made in the form of an elastic transparent for light two-layered film, a continuous layer of which is smooth, and the other layer, in the form of a relief pattern, is made with the height, equal to half of the matrix thickness, with forming a ring-shaped element, which does not have any common side with adjacent elements.

EFFECT: matrix possesses an adsorbing ability, contributes to regeneration of tissues, isolates an operation wound from the oral cavity side, has elasticity and shape-stability in case of long exposition on the wound surface with a possibility of visual control of the wound state and a possibility of removal from the post-operation area without destruction of regenerated tissues.

2 cl, 4 dwg, 1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. There are described methods for making implantable medical devices, preferentially of PEEK, having antimicrobial properties. The antimicrobial action is ensured by implantation of ceramic particles containing antimicrobial metal cations into the molten PEEK resin to be cooled and finally shaped by injection moulding, cutting and mechanical treatment or by other processing methods.

EFFECT: implants possess effective antimicrobial action for reducing a bacterial growth and a risk of infection.

12 cl, 1 dwg, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: implant represents a medicated polymer device, e.g. in the form of a rod, designed for release control of a biologically active substance clonidine and derivatives thereof, such as clonidine HCl, for a long period of time, e.g. for 2 months, 3 months, 4 months and even 4.5 months. The above polymer preferentially represents a biodegradable polymer, such as poly(lactide-co-glycolide) or poly(lactic acid). A challenge of using medicated salt forms HCl, such as clonidine consists in release control of the high water-soluble medication up to 4.5 months. It has been found that a particle size distribution control in the medicated powder can provide more uniform medication distribution in a polymer carrier which can be regulated. This enables avoiding formation of aggregates causing faster medication release.

EFFECT: invention refers to medical devices able to release the biologically active substances.

5 cl, 10 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to cell transplantology and tissue engineering, and describes a matrix, a basic element of which is a flat plate made from a spatially cross-linked hydrophobic polymer containing hydrophilic groups and forming on the plate surface a layer of saturated hydrocarbons having a chain length of 8 to 16 carbon atoms and directed preferentially along the normal line to the plate surface. The spatially cross-linked polymer is formed on substrates by exposing a photopolimerisable composition containing oligourethane methacrylate, a methacrylate monomer having a chain length of 8 to 18 carbon atoms, 2,2-dimethoxy-2-phenylacetophenone and 2,4-ditertbutylorthquinone, to light at a wave length of 320-380 nm.

EFFECT: matrix has a good adhesive capacity; it is biocompatible and bioresorbable, preserves progenitor cells, promotes their differentiation and growth, and is mechanically strong.

5 cl, 1 tbl, 5 ex, 8 dwg

Filler material // 2518753

FIELD: medicine.

SUBSTANCE: filler material containing a biodegradable and biocompatible polymer; as osteoconductive and biocompatible polymer, it contains a polyurethane polymer prepared of polyoxypropylene glycol with an average molecular weight of 1000, 4,4'-diisocyanatodiphenyl methane and glycerol.

EFFECT: ensured modelling composite surface by plasticity of the material and adhesion of the bone fragments by high adhesion properties of the material to metal and bone tissue.

3 tbl, 4 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and is used for treating individuals suffering from hormonal diseases.

EFFECT: there are described methods and a device for octreotide delivery to the patients involving the implantation of a controlled release composition for octreotide delivery; the composition avoids the need of pre-implantation hydration and optionally contains a parting agent.

10 cl, 11 ex, 7 tbl, 17 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to ophthalmosurgery, and in particular to scleroplasty. Transplant for scleroplasty has polymeric base, covered with porous layer of the same polymer. As polymer base, transplant includes layer, made from porous stretched polytetrafluoroethylene, which has nodular-fibrillar structure. As porous layer, it includes layer of porous polytetrafluoroethylene, which has volume fraction of void space 15-40%, specific surface of void space 0.25-0.55 mcm2/mcm3, average distance between voids in volume 25-30 mcm and average chord volume 8-25 mcm, with the total width of transplant constituting 0.15-0.35 mm (first version). Transplant for scleroplasty can also include porous layer of polymer, whose surface is processed to add compatibility with sclera tissue. Transplant surface is processed by application of allogenic dermal fibroblasts of 3-5 passages of culturing, with the total width of transplant being 0.15-0.35 mm (second version).

EFFECT: chemically and biologically inert transplant, which ensures effect of invasion of sclera tissues, is obtained.

2 cl

FIELD: medicine.

SUBSTANCE: invention describes a composite ceramic bone graft containing a porous ceramic carrier made of zirconium oxide - aluminium oxide; the carrier is coated with a layer of hydroxyl apatite and platelet-rich plasma; the carrier is made by preparing a mixture ceramic powder and foaming agent Al(OH)3 or Zr(OH)4, adding distilled water to give the moulding properties and caking the end product.

EFFECT: composite ceramic bone graft of the ceramic material of zirconium oxide system is effective and applicable in medicine for synthesis of the anatomic continuity and functions of the bone tissue.

1 ex, 14 dwg

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