Bone filler material

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a two-phase bone filler material of calcium phosphate / hydroxyapatite (CAP/HAP) containing a sintered CAP nucleus and at least one uniform and closed epitaxial growing layer of nanocrystalline HAP coating the sintered CAP nucleus from above; the epitaxial growing nanocrystals have a size and a morphology identical to a human bone mineral, i.e. the length of 30 to 46 nm and the width of 14 to 22 nm. What is described is a method for preparing the bone filler material of CAP/HAP involving the stages as follows: a) making the sintered CAP nucleus, b) immersing the sintered CAP nucleus into an aqueous solution at 10°C to 50°C to initiate the process of CAP to HAP transformation to form the uniform and closed epitaxial growing nanocrystalline hydroxyapatite on the surface of the sintered CAP nucleus with the epitaxial growing nanocrystals have the size and morphology identical to the human bone mineral, c) terminating the transformation by separating the solid material from the aqueous solution in the presence of the uniform and closed coating of at least one HAP nanocrystalline layer, until the comprehensive completion of the transfomraiton process, d) optionally sterilising the material separated at the stage c), and using the above bone filler material as an implant or a prosthesis for osteogenesis, bone regeneration, bone repair and/or replantation at the site of injury in a human or animal.

EFFECT: preparing method for preparing bone filler material of CAP/HAP.

15 cl, 3 tbl, 6 ex

 

The invention relates to a new two-phase material of bone substitutes with a two-layer structure on the basis of calcium phosphate/hydroxyapatite (cap/NAR), the method of obtaining of such material and its use as an implant or prosthesis to support osteogenesis, bone regeneration, recovery of the bones and/or replantation bones to damage a person or animal.

Defects in bone structure arise in various circumstances, such as injury, illness and surgery, and there is still a need for effective removal of bone defects in various fields of surgery.

Numerous natural and synthetic materials and compositions are used to stimulate healing in the damaged bone. Well-known natural osteoconductive material bone tissue substitute, promoting growth of bone in periodontal and maxillofacial bone damage is Geistlich Bio-Oss®, marketed by the company Geistlich Pharma AG. This material is made from natural bone, using the method described in U.S. Patent No. 5167961, you can save the trabecular architecture and nanocrystalline structure of natural bone and as a result providing excellent osteoconductive matrix, which is not difficult or very slowly under the W resorption.

System tricalcium phosphate/hydroxyapatite (TCP/NAR) and their use as materials of bone substitutes are described, for example, in patent US-6,338,752, in which is disclosed a method of obtaining a biphasic cement of α-TCP/NAR by heating a powder mixture of ammonium phosphate and NAR at 1200-1500°C.

In the European patent EP-285826 describes a method of obtaining a layer NAR on metallic and non-metallic bodies for implants by applying a layer of α-TCP and full conversion layer of α-TCP DRUG by reaction with water at pH from 2 to 7 at 80-100°Poluchennym product is metallic or non-metallic body, covered with a layer of NAR.

In document WO 97/41273 describes a method of coating substrates, in particular hydroxyapatite (NAR) or other calcium phosphates (CAP), a layer of carbonated hydroxyapatite, i.e. hydroxyapatite, in which phosphate and/or hydroxyl ions are partially replaced by bicarbonate ions by a process comprising (a) immersing the substrate in a solution with a pH from 6.8 to 8.0, containing calcium ions, phosphate ions and bicarbonate ions at a temperature below 50°C, (b) the heated part of the solution in contact with the substrate, to a temperature of from 50 to 80°C to achieve pH greater than 8, (C) maintaining the substrate in contact with the alkaline solution obtained in step (b) for education carbons is one of hydroxyapatite coating and (d) removing the substrate from the solution and drying the coating. In the specified source describes that bicarbonate ions act as inhibitors of the growth of hydroxyapatite crystals, and the result is the formation of non-stoichiometric crystals, defects and rather small dimensions, i.e. length of 10-40 nm and a width of 3-10 nm (see page 7, lines 1-7).

System components of the calcium phosphate/hydroxyapatite (cap/NAR), in particular systems TCP/NAR, different thermodynamic stability.

Because of this, differences in implantation systems RAA/NAR in the body of a mammal, in particular humans, the solubility of TCP and other phosphates of calcium in body fluids is higher than the solubility of the DRUG. The difference in solubility between the phosphates of calcium and NAR causes destruction of a disordered superstructure SAR systems/NAR because the more soluble the connection CAP (e.g., TCP) is removed faster than NAR. Sintered relationship between CAP and NAR that occur at high temperatures, also contributes significantly increase the solubility of the device in the physiological environment. In the accelerated in-vivo disintegration of such ceramic compounds is dominated by two different types of reactions: chemical dissolution and biological resorption cells. Both processes cause the dissolution of the ceramic material, which also causes local oversaturation of calcium ions, in which visvobodit the greater number of calcium ions, than the number of adsorbed calcium ions. Disappears natural balance of calcium ions, as in the extracellular matrix and tissue surrounding the implant. Local disturbances of the natural calcium balance in terms of the oversaturation of calcium ions leads to increased activity of osteoclasts and thus to rapid uncontrolled resorption of the ceramic material and the risk of adverse inflammatory reactions, in particular, when using a large number of synthetic material bone tissue substitute.

When the material bone tissue substitute Geistlich Bio-Oss® is implanted in the human body, it has virtually no effect on natural calcium balance, and concentration of calcium ions on the surface of the material and within its local environment remains almost unchanged. Thus, biological resorption of the material does not occur or occurs with a very low speed without risk of adverse inflammatory reactions.

The purpose of this invention is to provide material of bone substitutes based on calcium phosphate/hydroxyapatite (cap/NAR), which, like the material of bone substitutes Geistlich Bio-Oss®, after installation in vivo enables the concentration of calcium ions on the surface of the material and within its local neighborhood is Oia, to remain almost unchanged and, therefore, not lead to increased activity of osteoclasts.

Indeed, natural calcium balance required for optimal bone regeneration must not be violated and destroyed. In addition, the natural balance calcium concentration must be maintained for a long period of material bone tissue substitute to complete the regeneration process. When these conditions are met, does not increase the activity of osteoclasts, and thus there is no risk of adverse inflammatory reactions.

It was found that the above purpose is achieved thanks to a new two-phase nanocrystalline material of bone substitutes based on SAR/NAR with a precisely defined biomimetic two-layer structure provided with described by authors of specific conditions.

Indeed, as the observations using fluorescence light microscopy of this new two-phase nanocrystalline material of bone substitutes based on SAR/NAR implanted in the body of a mammal, not markedly increase the activity of osteoclasts in the vicinity of the implant, which indicates the absence of increasing concentrations of calcium ions on the surface of the material and within its locale the CSO environment.

A new two-phase nanocrystalline material of bone substitutes based on SAR/NAR shows very interesting properties in vivo.

Thus, the invention relates to a two-phase material of bone substitutes based on calcium phosphate/hydroxyapatite (cap/NAR), which includes a core of sintered CAP and at least one of a uniform and closed epitaxies growing a layer of nanocrystalline DRUG deposited on top of the core of the sintered CAP, and epitaxies growing nanocrystals have the same size and morphology as the mineral bone man, that is, the length from 30 to 46 nm and a width of from 14 to 22 nm.

The core of the sintered CAP may include tricalcium phosphate (TCP), in particular α-TCP (α-CA3(RHO4)2) or β-TCP (β-CA3(RHO4)2), and/or phate calcium (TSR) CA4(RHO4)2O.

According to a commonly used variant of implementation of the core of the sintered CAP essentially consists of TCP, and preference is given to α-TCP.

Epitaxies growing a layer of nanocrystalline DRUG structurally and chemically almost identical to natural bone mineral man.

Epitaxies growing a layer of nanocrystalline DRUG usually has a thickness of at least about 15 to 50 nm, preferably at least 20 to 40 nm, more preferably at least 25 d is 35 nm. This minimum thickness corresponds to one layer of DRUG nanocrystals in epitaxially orientation.

Epitaxies growing a layer of nanocrystalline DRUG may include one or more layers of nanocrystals NAR epitaxially orientation. The thickness epitaxies growing a layer of nanocrystalline DRUG, which deals with several layers of DRUG nanocrystals in epitaxially orientation, chosen in accordance with the intended use of the material substitute bone tissue as the implant or prosthesis is subjected to different load parts of the body. Material bone tissue substitute according to the invention really is designed to function in vivo as a replacement for the live system, gradually transforming the core of sintered CAP in hydroxyapatite, similar in size and morphology of the mineral bone man, and the speed of this transformation depends on the rate of calcium release by the kernel of the sintered CAP, which is largely controlled by the thickness epitaxies growing a layer of nanocrystalline DRUG.

Material properties of bone substitutes based on SAR/NAR largely governed by the thickness epitaxies growing a layer of crystalline DRUG. The term "property" includes the ability of bone substitutes based on SA IS/NAR to the release of a constant concentration of calcium ions in the local environment in vitro and in vivo.

The thickness epitaxies growing a layer of nanocrystalline NAR concerns the correlation kernel of the sintered material CAP with NAR, and the aforementioned ratio typically ranges from 5:95 to 95:5, preferably from 10:90 to 90:10.

The material of bone substitutes based on SAR/NAR may be lumpy or granular, with particles or granules having a desired size and shape. Typically, the particles or pellets are approximately spherical and have a diameter of from 250 to 5000 microns.

The material of bone substitutes based on SAR/NAR can also be molded product, for example in the form of a screw, nail, pin or design with the profile part of the bone of the body, such as thighs, collarbone, ribs, lower jaw or skull. Such a screw, nail or pin can be used in the rehabilitation of orthopedic surgery for the insertion of the ligament to a bone, such as the knee or elbow. This design, with the profile part of the bone of the body, can be used in orthopedic surgery as a prosthesis to replace missing or damaged bones or parts of bones.

The invention also concerns a method for obtaining defined above material bone substitutes based on SAR/NAR, and the method includes the following steps:

a) manufacturing a core of sintered material CAP,

b) tap the angling kernel of the sintered material of the CAP in an aqueous solution at temperatures from 10°C to 50°C) to start the conversion process CAP in NAR, with which the surface of the nucleus of the sintered material of the CAP is formed a uniform and closed epitaxies growing a layer of nanocrystalline hydroxyapatite, and epitaxies growing nanocrystals have the same size and morphology as the mineral bone of a man,

c) the termination of the conversion by separating solid material from the aqueous solution in the presence of uniform and closed coating of at least one of the nanocrystalline layer NAR, but to complete the conversion process,

d) optional sterilization separated material from step (C).

The core of the sintered material of the CAP may include tricalcium phosphate (TCP), in particular α-TCP (α-CA3(RHO4)2) or β-TCP (β-CA3(RHO4)2), and/or phate calcium (TSR) CA4(RHO4)2O.

According to a commonly used variant of implementation of the core of the sintered CAP material essentially consists of TCP, and preference is given to α-TCP.

Manufacturing a core of sintered material CAP by prominent specialists of ways, including first mixing powders of dicalcium phosphate (Sanro4), calcium carbonate and/or calcium hydroxide, then roasting and sintering the mixture in an appropriate temperature range, obtaining, thus, the bulk material poison is and sintered CAP (see, for example, Mathew M. et al, 1977, Acta. Cryst. B33:1325; Century Dickens et al., 1974, J. Solid State Chemistry 10, 232; and Durucan .et al., 2002, J. Mat. Sci., 37:963).

Lumpy the core material of the sintered TCP, thus, can be obtained by mixing powders of dicalcium phosphate (Sanro4), calcium carbonate and/or calcium hydroxide in stoichiometric ratio, calcining, and sintering the mixture at a temperature in the range of 1200-1450°C, preferably about 1400°C.

Lumpy the core material of the sintered TDR can also be obtained using the process described above.

Lumpy material of the sintered CAP, obtained by such methods may be porous with a porosity of from 2 to about 80. % and a wide pore distribution. The porosity of choice, in accordance with the intended use of the material of bone substitutes based on SAR/NAR.

The core of the sintered material of the CAP used in step b), may be

- lump core material of the sintered CAP, obtained as described above,

the particles or granules of the kernel of the sintered material of the CAP obtained from the bulk core material of the sintered CAP, made as described above, by applying traditional methods, such as crushing, shredding and/or grinding and sieving, or

- harvesting core of sintered material CAP having a desired shape and size, for example in the form of a screw, nail, pin or design, with the profile part of the bone of the body.

Such a workpiece, having any desired shape and size, can be obtained from the bulk sintered core material obtained as described above, by applying well-known methods, prototyping, such as CNC milling or stereoscopic printing (see, for example, P. Bartolo et al., 2008, Bio-Materials and Prototyping Applications in Medicine, Springer Science, New York, ISBN 978-0-387-47682-7; R. Landers et al., 2002, Biomaterials 23(23), 4437; Yeong W. - Y. et al., 2004, Trends in Biotechnology, 22 (12), 643; and H. Seitz et al., 2005, Biomed. Mater. Res. 74B (2), 782).

The aqueous solution from step (b) may be pure water, the simulated liquid body or buffer. It is important that the pH of the solution is to dive from step b) was almost neutral and remained stable during the whole conversion process, preferably in the range of pH from 5.5 to 9.0.

The buffer can be any buffer in the above pH range, but I prefer phosphate buffer with calcium, magnesium and/or sodium or without it.

The term "simulated body fluids" refers to any solution that mimics the fluid body. Preferably simulated body fluids is the concentration of ions close to the index of blood plasma.

The temperature range in step (b) is usually from 10°C to 50°C, preferably from 25 to 45°C., more preferably from 35°C to 40°C.

Phase is gryzenia b) in the first phase causes a phase transition of the first kind of material CAP core and thus, the formation of crystallization centers precursors of DRUG nanocrystals. During the second phase of the resulting precursor DRUG of first phase grow and form a closed (i.e. cover) epitaxialy nanocrystalline composite layer. The first layer of nanocrystals NAR should be uniform and closed and epitaxies connected to the core of the sintered material CAP.

During the third phase, the phase transition of the first kind may occur within the newly formed two-layer composite for further transformation kernel of the sintered material CAP (TCP or TSR) in nanocrystalline DRUG. During this third stage of the transition phase calcium ions are released during the controlled period of time during controlled slow process of diffusion, while the core part of the sintered material of the CAP is not converted to nanocrystalline DRUG.

The conversion time and, consequently, the rate of calcium release can be regulated by changing the thickness of NAR.

Epitaxies growing a layer of nanocrystalline NAR corresponding thickness receive in-vitro, and the conversion CAP in NAR is terminated before completion.

As soon as the material of bone substitutes based on SAR/NAR placed in vivo, the conversion process CAP in NAR CH the VA is activated due to contact with body fluids, and material bone tissue substitute functions as a replacement of a living system, forming a new hydroxyapatite, similar in size and morphology of the material human bones. During the conversion process in vivo phase displaced calcium ions are released into the local environment, supporting the local calcium balance, which is important and favorable for the regeneration of bones.

Due to the difference in time of regeneration when damaged bones at different load areas of the body is important to control the rate of calcium release. This can be achieved by changing the thickness epitaxies growing a layer of hydroxyapatite.

Thus, step (C) is a key step. The exposure time of an aqueous solution in step b) is based on the required layer thickness of the NAR. Need at least one layer of nanocrystalline DRUG in epitaxially orientation. It is essential that the conversion CAP in NAR is incomplete.

The proper exposure time in accordance with the required thickness can be calculated using several thermodynamic differential equations, well known to experts in the field of chemistry related calcium phosphates and cement production and concrete.

See, for example: Pommersheim, J.C.; Clifton, J.R. (1979) Cem. Cone. Res.; :765; Pommersheim, J.C.; Clifton, J.R. (1982) Cem. Cone. Res.; 12:765; and Schlussler, K.H. Mcedlov-Petrosjan, O.P.; (1990): Der Baustoff beton, VEB Verlag Bauwesen, Berlin.

Transfer the solution to the above differential equations to a system of cap/NAR allows to predict the phase transition from CAP to NAR and the thickness of the layer, so that epitaxialy layer NAR could be formed in a stable and repeatable manner.

The separation of the solid material from the aqueous solution usually performed by filtering and drying, using methods well-known among specialists in this field.

Optional sterilization d) perform the methods well-known among specialists in this field, such as gamma radiation.

The invention also relates to the use specified above material bone substitutes based on SAR/NAR, usually in the form of a lump or molded products, as an implant or prosthesis to support osteogenesis, bone regeneration, recovery of the bones and/or replantation bones to damage a person or animal.

The invention also relates to a method of promoting osteogenesis, bone regeneration and/or restoration of bones where damage to a person or an animal by implanting defined above material bone substitutes based on SAR/NAR, usually in the form of a lump or fo is ovannogo products.

The material advantages of bone substitutes based on SAR/NAR according to the invention

Epitaxies growing nanocrystals NAR, surrounding a core of sintered material CAP, identical in size and morphology of the Apatite crystals constituting the natural mineral human bones, as shown below in Table 1. Thus, the material of bone substitutes based on SAR/NAR according to the invention successfully simulates the composition or microstructure of the bone and is a biomimetic material mineral bones.

Table 1
Comparison of the size and morphology of crystals of the DRUG for bone substitutes based on SAR/NAR according to the invention and mineral bone man
Crystallographic axis (hexagonal space group P63/m)RAA/NAR according to the invention, obtained at physiological temperature. The size of the crystals+[nm]Natural mineral bone man. The size of the crystals+[nm]
and (1,0,0)18 (±4)15-21
b (0,1,0) 18 (±4)15-21
with (0,0,1)38 (±8)34-45
+ Analysis of the size of the crystals was performed by applying THE (transmission electron microscopy), SPM (scanning probe microscopy), as well as data processing x-ray diffraction using the method of Bragg.

Constant concentration of calcium ions resulting in better adhesion of osteoblasts and osteoclasts to the surface of the DRUG in the correct ratio for osteogenesis and, thus, for steady state regeneration of bones. Provides a surface to which osteoblasts and osteoclasts is easily attached in the correct ratio for the regeneration of bones.

In addition, thanks to a well-controlled surface, the material properties of bone substitutes based on SAR/NAR according to the invention can function as a matrix for biologically active molecules, such as proteins of the extracellular matrix, in particular growth factors for regeneration of bones.

The following examples explain the invention without limiting its scope.

Example 1. Preparation of bulk sintered material α-TCP

To a mixture of 500 g (dry weight) 360 g of anhydrous powder di is antifolate, 144 g of powdered calcium carbonate and 220 ml of deionized water were mixed for 7 minutes at 500 rpm using a laboratory stirrer. The suspension after the mixing process immediately transferred in a high-temperature resistant platinum Cup. Filled in a platinum Cup was placed in a cold furnace. The furnace was heated up to 1400°C with a heating rate of 60°C per hour. The heating process was stopped after 72 hours by turning off the furnace. The sample was cooled to room temperature, remove from oven. Lumpy sintered material (cystopathy α-CA3(RHO4)2) were removed from the furnace and platinum cups. Lumpy product after the sintering process weighed in at 420 grams (mass loss of 16.7%. Control over the purity of the phases was carried out using analysis by powder x-ray diffraction.

Example 2. Fabrication of porous pellets sintered α-TCP with a particle size of from 0.25 to 2 mm

Lumpy product from Example 1 was crushed using a jaw crusher (the size of a gap of 4 mm). Coarse granules were screened using the screen mesh installation and removable sieve with cells of 2 mm and 0.25 mm After sieving fraction pellet was twice washed with purified water to separate fine powder residue adsorbed into pellets. Porous granules were dried for 10 hours at 120°C in a drying chamber. Control over particle size distribution was carried out is by using the technology of laser diffraction. Clean the surface of the particles after washing was controlled by surface observation using scanning electron microscopy.

Example 3. Fabrication of porous cylinders (length 10 mm, diameter 6 mm) made of sintered α-TCP by CNC-milling

Lumpy product from Example 1 was reduced to a cube-shaped workpieces with a length of edges a=3 cm, b=2 cm, c=2 cm using a grinding machine. The workpiece was placed and fixed in four-axis CNC milling machine equipped with a semicircular cutter for hard metals with a diameter of 3 mm Cylinders were cut using the path milling with a radius of 3 mm and a slope of 0.25 mm Main speed of the workpiece during the process CNC-milling was 1700 rpm, the maximum speed of the road milling was calculated by the integral process within CNC equipment, and it is 10 revolutions per minute. After milling a cylindrical billet was twice washed with purified water to separate fine powder residue adsorbed in cylindrical surface. Porous cylinders were dried for 10 hours at 120°C in a drying chamber. The purity of the surface of the workpiece after washing was controlled by surface observation using scanning electron microscopy. The correctness of the workpiece controlled with the help of the personnel is of encircle.

Example 4. Getting epitaxies increasing coverage of nanocrystalline DRUG in pellets of sintered α-TCP with Example 2

Buffer solution (1000 ml), sufficient to cover and phase transformation were prepared using 1.82 mol/l sodium, and 4.68 mol/l hydrogen, 0.96 mol/l of phosphorus, 5,64 mol/l of oxygen, 0.01 mol/l calcium and 0.71 mol/l of chlorine. The solution is brought to pH 7.4 at 40°C. the Granules obtained according to examples 1 and 2, was immersed in the prepared solution and kept in a water bath with a stable temperature (40°C) over time, calculated in accordance with the thickness of the layer has an average of 250 nm (10 hours), which corresponds to the phase composition (mass/mass) 75% alpha-TCP and 25% hydroxyapatite. After immersing the pellets washed three times with purified water to remove residue from the buffer solution. Porous granules were dried for 4 hours at 120°C in a drying chamber. Phase composition pellets were analyzed using ravendusk data analysis powder x-ray diffraction, the crystal size of the crystalline phases obtained in the process of the coatings was analyzed by size-strain data of x-ray diffraction in accordance with the method of Bragg. The porosity of the pellets was controlled by using Parametrii with the intrusion of mercury, the morphology of the surface after coating control Aravali using scanning electron microscopy.

Example 5. Getting epitaxies increasing coverage of nanocrystalline NAR cylinders of sintered α-TCP with Example 3

Buffer solution (1000 ml), sufficient to cover and phase transformation were prepared using 1.82 mol/l sodium, and 4.68 mol/l hydrogen, 0.96 mol/l of phosphorus, 5,64 mol/l of oxygen, 0.01 mol/l calcium and 0.71 mol/l of chlorine. The solution was brought to pH 7.4 at 40°C. the Porous cylinders, obtained according to examples 1 and 3, was immersed in the prepared solution and kept in a water bath with a stable temperature (40°C) over time, calculated in accordance with the thickness of about 20 μm (60 hours), which corresponds to the phase composition of approximately 85% (weight/weight) of alpha-TCP and 15% (weight/weight) of hydroxyapatite. After diving cylinders washed three times with purified water to remove residue from the buffer solution. Porous cylinders were dried for 10 hours at 120°C in a drying chamber. The phase composition of the cylinders were analyzed using ravendusk data analysis powder x-ray diffraction, the crystal size of the crystalline phases obtained in the process of the coatings was analyzed by size-strain data of x-ray diffraction in accordance with the method of Bragg. Epitaxialy growth was analyzed by reflective difference (RD) spec is roscopy. The porosity of the cylinder controlled by using Parametrii with the intrusion of mercury, the morphology of the surface after the coating was controlled by scanning electron microscopy. The layer thickness was controlled by applying a reflective diffraction of high energy electrons (RHEED) and/or photoelectron spectroscopy (XPS).

Example 6. The influence of dive time on the layer thickness and phase composition

In Tables 2 and 3 shows experimental data for an example that shows the effect of dive time on the layer thickness and phase composition, respectively, for porous particles of α-TCP nearly spherical geometrical shape and size of from 10 to 20 μm, a porosity of 25 to 40 vol.%, specific (internal) surface area of 50-60 m /g and a bulk density 0.6-0.8 g/ml

Table 2
The influence of dive time on the thickness of the layer
The immersion time [min]The thickness of the layer*
[nm]
0-
1537(±10)
30112 (±4)
60121 (±9)
600238(±8)
* Analysis of epitaxy, chemical composition of the layer and the layer thickness was carried out using RHEED (reflective diffraction of high energy electrons) and XPS (photoelectron spectroscopy)

Table 3
The influence of dive time on the phase composition
The immersion time [h]TCP** [wt.%]NAR** [wt.%]
0100-
0,586,6 (±1)the 13.4 (±2)
1to 85.8 (±1)of 14.2 (±3)
2to 83.5 (±1)to 16.4 (±3)
578,1 (±1)of 21.9 (±3)
7,575,3 (±1)of 24.7 (±3)
10 74,2 (±5)the 25.8 (±2)
12to 58.8 (±6)41,2 (±7)
2444,8 (±9)55,2 (±6)
48a 35.8 (±6)64,2 (±3)
72-100
** Quantitative phase analysis was carried out using ravendusk data analysis powder x-ray diffraction.
*** These experiments were evaluated on a system with the following parameters: liquid phase: phosphate-saline buffer solution, 20x, 40°C.

1. A two-phase material of bone substitutes based on calcium phosphate / hydroxyapatite (cap/NAR), comprising a core of sintered CAP and at least one of a uniform and closed epitaxies growing a layer of nanocrystalline DRUG deposited on top of the core of the sintered CAP, and epitaxies growing nanocrystals have the same size and morphology as the bone mineral rights, that is the length from 30 to 46 nm and a width of 14 is about 22 nm.

2. The material of bone substitutes based on SAR/NAR according to claim 1, characterized in that epitaxies growing a layer of nanocrystalline DRUG, typically has a thickness of at least about 15 to 50 nm.

3. The material of bone substitutes based on SAR/NAR according to claim 1, characterized in that epitaxies growing a layer of nanocrystalline DRUG, typically has a thickness of at least 20 to 40 nm.

4. The material of bone substitutes based on SAR/NAR according to any one of claims 1 to 3, characterized in that the ratio of material from the bed ranges from 5:95 to 95:5.

5. The material of bone substitutes based on SAR/NAR according to any one of claims 1 to 3, characterized in that the ratio of the kernel of the sintered material CAP DRUG ranges from 10:90 to 90:10.

6. The material of bone substitutes based on SAR/NAR according to any one of claims 1 to 3, characterized in that the core of the sintered CAP essentially consists of α-TCP.

7. The material of bone substitutes based on SAR/NAR according to any one of claims 1 to 3, characterized in that provided in the form of particles or granules.

8. The material of bone substitutes based on SAR/NAR according to any one of claims 1 to 3, characterized in that it is molded product.

9. The material of bone substitutes based on SAR/NAR of claim 8, characterized in that it has the form of a screw, nail or pin.

10. The material of bone substitutes based on SAR/NAR n is 8, characterized in that it is a structure having a profile portion of a bone of the body.

11. The method of obtaining material of bone substitutes based on SAR/NAR according to any one of claims 1 to 10, comprising the following steps
a) manufacturing a core of sintered material CAP,
b) immersing a core of sintered material CAP in aqueous solution at temperatures from 10°C to 50°C to start the conversion process CAP in NAR, with which the surface of the nucleus of the sintered material of the CAP is formed a uniform and closed epitaxies growing a layer of nanocrystalline hydroxyapatite, and epitaxies growing nanocrystals have the same size and morphology as the mineral bone of a man,
c) the termination of the conversion by separating solid material from the aqueous solution in the presence of uniform and closed coating of at least one of the nanocrystalline layer NAR, but to complete the conversion process, and
d) optional sterilization separated material from step c).

12. The method according to claim 11, characterized in that in step b) the pH of the aqueous solution remains in the range from 5.5 to 9.0.

13. The method according to claim 11 or 12, characterized in that the temperature in step b) is from 25 to 45°C, preferably from 35°C to 40°C.

14. The use of the material of bone substitutes based on SAR/NAR p is any of claims 1 to 10 as an implant or prosthesis for osteogenesis, regeneration of bone repair bone and/or replantation bones to damage a person or animal.

15. A method of promoting osteogenesis, bone regeneration and/or restoration of bones where damage to a person or an animal by implanting material of bone substitutes based on SAR/NAR according to any one of claims 1 to 10.



 

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4 cl, 1 tbl, 6 ex

FIELD: nanotechnology.

SUBSTANCE: invention relates to the field of evaluation of properties of dispersed materials and can be used for development of energy nanotechnologies in different fields of industry and fields of knowledge, as well as for development and management of self-organising systems, offers the opportunities to learn new principles of making technical devices. To determine the range of movement of moving objects, the direction of their movement, determining the number and size of particles in the sectors of the restrictive circle the object-preparation is used made of paper coated with a restrictive line with width of 5-6 mm in the form of a circle with a marked centre, the direction of the video camera location and divided into sectors with thin lines of the circle of the hydrophobic material. And in the marked centre of the restrictive circle a template is placed into which the particulate material is placed. Then in the restrictive circle the liquid under study is placed in an amount providing the thickness of the liquid layer over the material under study. Then a capillary is brought to its centre at a height of 1-6 mm, containing the surfactant, the video camera is switched on, which records of the changes on the surface. After completion of the process of moving the self-organising objects on the surface of the material under study the video camera is switched off, the plate with the object-preparation and the material under study in the template is left for drying without draining the water from the surface of the object-preparation. Then, using a microscope the number of the particles and their sizes near the restrictive circle is determined in each sector, according to which the direction is determined, in which the objects are predominantly moved, and an approximate combination of moving objects.

EFFECT: providing the ability to determine the range of movement of moving objects, the direction of their movement, determining the number and size of particles in the sectors of the restrictive circle.

9 dwg, 4 ex

FIELD: nanotechnology.

SUBSTANCE: method of forming nanoscale structures is designed to produce strips of thin films of nanoscale width with the purpose of their study and formation of elements of nanoelectromechanical systems (NEMS). In the method of forming the nanoscale structures comprising obtaining the preforms of thin films and selection of strips of thin films from them, at least one thin film preform is fixed inside the filled volume, which is mounted in a microtome holder so that the plane of the thin film preform is not parallel to the plane of cutting, after that cutting of the filled volume is carried out with the knife of at least one thin film preform and a flat fragment with a thin film strip is obtained. There are embodiments in which the filled volume is set in a microtome holder so that the plane of the thin film preform is perpendicular to the plane of cutting and perpendicular to the direction of cutting; or the filled volume is set in the microtome holder so that the plane of the thin film preform is perpendicular to the plane of cutting and parallel to the direction of cutting. There are also embodiments in which after the cutting is carried out the investigation is carried out with the probe of a scanning probe microscope of the surface of the filled volume with at least one thin film preform; or modification is carried out of the thin film preform located inside the filled volume. There are also embodiments in which the modification of the thin film preform is the mechanical exposure with a probe to it; or the electric exposure with a probe to it; or electrochemical exposure with a probe to it; or exposure to it with an electron beam; or exposure to it with an ion beam; or exposure to it with an X-ray beam; or exposure to it with a beam of alpha-particles; or exposure to it with a beam of protons; or exposure to it with beam of neutrons. There is also an embodiment in which the inside filled volume a set of thin film preforms is fixed; and the thin film preforms are located parallel to each other. There is also an embodiment in which the thin film is used as graphene.

EFFECT: all of the above embodiments of the method extend its functional capabilities.

17 cl, 5 dwg

FIELD: electricity.

SUBSTANCE: dark characteristic of tunnel emission current is measured with increase of voltage on the anode and the value of voltage V is determined, the measured surface of the emitter is eradiated with a laser beam of ultraviolet or visible band with a fixed value of optical power and wavelength λ1, the value of tunnel photoemissive current at increase of voltage on the anode is measured, and the value of voltage V∞λ1 is fixed, the value of work function A and value of amplification of local electric field β In a spatial area of the emitter irradiation from the given relation are determined, or the measured surface of the emitter is eradiated additionally with a laser beam at another wavelength λ2 of ultraviolet or visual band with maximum difference with reference to the first wavelength, the value of voltage V∞λ2 is determined, and also the value of amplification of a local electric field in a spatial area of the emitter irradiation and value of the work function A from the given relation are determined.

EFFECT: possibility for determination of local electric field at simultaneous determination of work function of electrons from the emitter.

4 dwg

FIELD: electricity.

SUBSTANCE: invention relates to lighting engineering, namely the manufacture of light-emitting semiconductor devices with the substrate from amorphous mineral glass. The glassy composition on the basis of mineral glass containing oxides of elements of groups II, and/or III, and/or IV of periodic system, differs by that the surface of the glass is coated with the grown layer of conducting and light-emitting semiconductor compound of the type A2B5, and/or A2B6, and/or A3B5, and/or A4B6. The method of manufacture of glassy composition is also offered on the basis of mineral glass containing oxides of elements of the groups I, I and/or III, and/or IV of periodic system, where for formation on the glass surface of the layer of conductive and light-emitting compound of the type A2B5, and/or A2B6, and/or A3B5, and/or A4B6 the glass is exposed to heat treatment by heating in neutral gas at the temperature 500-5000° C, the glass is doped before or during the heat treatment by the element of the groups V and/or VI, oxygen is removed from the heat treatment zone.

EFFECT: invention provides a possibility of forming of forecasted semiconductor compounds of various compositions.

6 cl

FIELD: heating.

SUBSTANCE: in combined regenerative heat exchanger comprising a heat insulating body, an attachment inside the body, the attachment comprises two parts: at the side of the "warm" end of the regenerative heat exchanger the attachment is made from a woven metal mesh, at the side of the "cold" end of the regenerative heat exchanger is filled with lead nanoballs, between parts of the attachment there is a protection net, which prevents penetration of lead nanoballs into the area of the woven metal mesh.

EFFECT: increased efficiency of a gas microcryogenic machine in general.

1 dwg

FIELD: nanotechnology.

SUBSTANCE: invention relates to a technology of nanomaterials and nanostructures, and can be used to produce thin-film polymeric materials and coatings used in sensing, analytical, diagnostic and other devices, and when creating the protective dielectric coatings. The method of production of thin-film organic coating of cationic polyelectrolyte comprises modification of the substrate, preparing the aqueous solution of cationic polyelectrolyte with the adsorption of polyelectrolyte on the substrate, washing, drying the substrate with the deposited layer. The substrate is used as monocrystalline silicon with roughness less than or comparable with the thickness of the obtained coating. To generate the negative electrostatic charge the substrate is modified in the solution of alkali, hydrogen peroxide and water at 75°C for 15 min. During the adsorption the substrate is illuminated from the side of the solution with light having intensity in the range of 2-8 mW/cm2 and with wavelengths of the range of intrinsic absorption of silicon.

EFFECT: invention enables to reduce the roughness and thickness of the organic coating.

3 cl, 3 dwg, 5 tbl, 6 ex

FIELD: nanotechnology.

SUBSTANCE: invention relates to nanotechnology, namely the material and method of production of spherical conglomerates containing nanoparticles (NP) of metal, particularly copper, in the shell of another substance or organic polymer. At that the NP is obtained in the individual state or in the form of component parts of the nanocomposites, including polymer-containing. The invention relates to a method of production of the polymer copper-bearing composite consisting of homogeneous spherical conglomerates with a diameter of 50-200 nm of the polymer with spherical copper nanoparticles embedded in it with a diameter of 5-10 nm. The invention also relates to a method of production of the polymer copper-bearing composite consisting in thermal decomposition of the precursor of the composite at 450°C in the inert atmosphere.

EFFECT: obtaining the composite of uniform spherical conglomerates comprising a plurality of nanoparticles of copper embedded in the polymer matrix, with a narrow area of distribution in size.

4 cl, 7 dwg

FIELD: chemistry.

SUBSTANCE: venous whole blood is collected from a worker for whom silicon dioxide is a risk factor in the air of the working area and said blood is divided into two samples. The first sample is analysed by X-ray energy-dispersive microanalysis to determine presence of silicon at the detection threshold level in the sample. The second sample, which is mixed in a volume ratio of 1:1 with heparin solution in concentration of 5000 ME/ml, is analysed by dynamic light-diffusion with photon correlation spectroscopy to determine the size of the detected silicon dioxide particles and construct a first histogram of size distribution of said particles. Dynamic light-diffusion with photon correlation spectroscopy is also used to analyse a first control sample, which is an aqueous suspension of nanodispersed silicon dioxide, while constructing a second histogram of particle size distribution, and a second control sample which is the venous whole blood of an individual not exposed to silicon dioxide mixed with heparin solution with concentration of 5000 ME/ml in volume ratio of 1:1, while constructing a third histogram of particle size distribution. The first, second and third histograms are superimposed and a match between at least part of the peaks on the particle distribution of the first histogram with peaks on the second and third histograms, with simultaneous detection of presence of silicon in the blood sample at the detection threshold level with X-ray energy-dispersive microanalysis, proves presence of nanodispersed silicon dioxide particles in the whole blood.

EFFECT: enabling determination of spatial distribution of nanoparticles in a volume and the behaviour of nanoparticles when analysing diffusion or aggregation and settling processes.

2 cl, 1 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely to composite material, including biocompatible and bioabsorbable glass, biocompatible and bioabsorbable matrix polymer and binding agent, capable of formation of covalent bonds. Composite includes compatibiliser, with at least 10% of structural units of compatibiliser being identical to structural units of matrix polymer, and molecular weight of compatibiliser being less than 30000 g/mol. Described is application of claimed composite, medical device, which contains said composite, and method of composite obtaining.

EFFECT: composite has at least as high modulus as modulus of cortical bone layer.

20 cl, 1 dwg, 2 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention relates to macromolecular compound chemistry, to preparing polymeric compositions of fibre materials with the antimicrobial properties. The method consists in immobilising a bioactive polymeric complex of (N-(2-hydroxypropyl)methacrylamide-acrylic acid + gentamicin base) copolymer on phosphorus cellulose or carbon fibre materials. The method involves sorption for 24 hours at temperature 25°C from aqueous solutions of the various (0.06-0.5%) concentrations of the polymeric complex on the phosphorylated cellulose or carbon fibre materials containing the functional phosphorus groups in the acid or salt forms on its surface. The polymeric complex is attached in the structure of the fibre material with additional thermal processing at 90°C for 1.5 hours.

EFFECT: invention provides the biological compatibility of the material that exhibit the haemostatic, thromboresistant, antibacterial properties.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to a method for preparing a biocompatible nanostructured conducting composite. The method involves preparing an ultra-disperse suspension of carboxymethyl cellulose and carbon nanotubes with the mechanical system of carbon nanotube structuring wherein nanostructuring is enabled by exposing the suspension to laser light in a continuous mode at generation wave lengths 0.81÷0.97 mcm and light intensity 0.5÷5 Wt/cm2.

EFFECT: invention provides preparing the high-conductivity bio-composite.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to fibre-reinforced composite materials, in particular to oriented in application composite materials, used in dental and medical fields/devices. Solidified fibre-reinforced composite material includes compounded with each other: system of monomers, containing, at least, one solidified monomer, system of filling agents and initiator(s) of polymerisation, and/or polymerisation accelerator(s). System of filling agents contains, at least, one prepreg, containing 0.5-100 mm long fibres, and polymer matrix, and optionally, at least, one powder filling agent, prepreg being located in form of parts, which are 0.5-100 mm long. As fibre, preferably fibre glass is used. Powder filler is selected from common powder filling agents and nanomeric powder filling agents. Claimed is method of said material obtaining and its application in dental and medical field and corresponding devices, in particular, for filling in dental cavities, as filling composites, temporary and semi-permanent composite material for crowns and bridges, filling and binding materials.

EFFECT: composite materials according to invention are stable product, can be applied in requires form and solidified, improved mechanical properties are provided.

26 cl, 3 tbl, 8 ex, 11 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Described is patch for application in surgery, produced by method, which includes stages of selection of animals tissue, which contains substrate, diametrical linking and fixation of substrate, minimisation of substrate agents activity, substrate tanning and binding of active layer to substrate.

EFFECT: biological patch for surgery does not induce immune rejection and has good biological compatibility.

17 cl, 1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and follow-up care (medical rehabilitation), and can be used for antiseptic surface preparation of medical devices made of polymeric materials used in minor orthopaedics. A method consists in forming on a device surface an antiseptic coating of a preparation containing biocide based on a nanodispersed powder of bentonite intercalated by silver or/and copper ions in a plastic binder solution. The particle size of the bentonite powder is no more than 150 nm. The antiseptic coating process is executed in two stages. At the first stage, a surface of the device made of a polymeric material based on silicon rubbers of molecular weight 2·105-6·105 is modified in low-temperature oxygen plasma at oxygen (O2) consumption 0.8-7 l/h, working pressure equal to (70-135)±5 Pa, at high-frequency electromagnetic radiation of frequency 13.56 MHz and power 20-40 Wt, during (2-3)±1 minutes. At the second stage, the modified surface of the device is treated with the antiseptic preparation wherein the plastic binder is fluoracrylic polymer in solvent based on perfluoroisobutylmethyl and perfluorobutylmethyl esters in the ratio, wt %: fluoracrylic polymer - 1-3, solvent - the rest, with perfluoroisobutylmethyl ester - 20-80 wt % and perfluorobutylmethyl ester - 20-80 wt %. The antiseptic preparation has the following proportions: biocide: plastic binder in solvent, as 1:(50-100) weight parts.

EFFECT: use of the invention enables forming a coating with antiseptic and service effective properties on the surface of the devices made of organosilicon polymers of molecular weight 2·105-6·105.

2 cl, 3 ex

FIELD: medicine.

SUBSTANCE: hemocompatible material comprises solid and unpenetrable synthetic substrate to which biological tissue is adhered by means of composing agent of specified substrate dispersed in the resolvent.

EFFECT: method simplification.

6 cl

FIELD: chemistry.

SUBSTANCE: method of the polymer surface modification includes processing the polymer surface by a pulsed plasma spraying of graphite target. Spraying is effected with a 0.9-0.9 Hz pulse frequency. In spraying, the surface is subjected to etching by independent ion-beam source in an oxygen-containing mix with inert gas, the oxygen concentration making 10-30 parts by volume.

EFFECT: hydrophilic-hydrophobic nanostructures are obtained on the polymer surfaces, they sizes being comparable to those of biologically-active molecules.

3 tbl, 1 ex

New prepreg // 2207107
The invention relates to a profiled the prepreg comprising fibers and a polymer matrix

The invention relates to medical science, and more specifically to techniques for the preparation of surfaces of medical polymers with improved hemocompatible properties, and can be used in implant surgery with prosthetic various human organs: artificial blood vessels, arteriovenous shunts, heart valves, pacemakers, etc

FIELD: food industry.

SUBSTANCE: what is described is a polymeric composition formulation of poly(hydroxy butyrate-co-hydroxyvalerate) (PHB-co-PHV) with additionally administered poly(D,L-lactide) in a solid ratio of 3:1 and dissolved in chloroform to the concentration of 6-9%; the composition is thereafter mixed for 2 hours and heated to 35°C. What is described is a membrane prepared by electrostatic formation (electrospinning) which involves including biologically active substances of fibronolytic preparations or direct action anticoagulants in the structure of fibres.

EFFECT: membranes possess biocompatible properties, a biodegradation life no more than 60 days, and enable preventing the adhesion formation effectively in experiment.

2 cl, 2 tbl

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