RU2132702C1 - Osteoplastic glass ceramic composition material for making porous implants as granules and method of their making - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: glass ceramic material for making medicinal articles made of biodevitrified glass has hydroxylapatite at the following ratio of components, wt.-%: SiO₂ 26.0-33.4; P₂O₅ 10.5-13.5; Al₂O₃ 4.3-5.5; CaO 23.6-30.4; MgO 2.1-2.7; ZnO 3.5-4.5 and hydroxylapatite 10.0-30.0. Method involves glass synthesis, mixing finely dispersed glass powders and hydroxylapatite according the claimed composition, preparing plastic mass, making granulate, removal of binding substances, caking granules and isolation of monocrystalline hydroxylapatite (at dallite phase) in 30-60 vol.%. Caking stage is combined with a single-step regime of the directed crystallization. Invention provides producing the new material exhibiting the enhanced mechanical strength and resistant to thermocycling regime and articles made on said as granules of optimal porosity 100-120 mcm which exhibit the enhanced exploitation properties. Composition material can be used as osteosubtituting biomaterial in stomatology, maxillo-facial and reconstructive surgery. EFFECT: improved, simplified method, decreased cost, high quality of the new material, broadened range of using. 2 cl, 4 tbl, 6 ex

Description

 The invention relates to the field of biomaterial science, technology for the synthesis of glass crystal materials, manufacturing technology for medical devices implanted in bone tissue when filling its defects.

 The technological aspect of the problem is that for porous microimplants in the form of microgranules, which expand the possible areas of use of these materials in medicine, for example, in the treatment of bone microdefects in narrow periodontal cavities, wedge-shaped defects, etc., there is no simple and economical technologies for their production from materials containing calcium phosphates and fully meeting the requirements of application, storage, sterilization.

Although biomaterials based on calcium phosphates to replace inert tissue have been known since the 20s. of our century [Albez FH, // Ann.Surg., 1920, 71, h.321], there is still no optimal material science solution for obtaining the most suitable for implantation of granular porous microimplants containing calcium phosphate (in particular, hydroxylapatite) with a complex of properties : osteocompatibility, biodegradation time (correspondence with the time of bone tissue replacement), optimal porosity and mechanical strength, providing stability during implantation without sterilization, storage. The best known osteoplastic materials obtained in granular form (Recho firm Interpor, CFS) based on natural corals [Ray DY, Linneham SA // Natiire, 1974, 247, p.220]. The production method includes the preparation of seafood in an environmentally safe region of the oceans, the removal of the organic matrix, hydrothermal substitution in solutions of ammonium phosphate of a part of coral skeletal calcium carbonate with hydroxylapatite, drying, sintering according to a regime that preserves the texture and strength of the coral exoskeleton: channels, through pores (with a diameter of 150-500 μm) with a total porosity of up to 50-70% of the volume [Ohomiro M., 0hgusci H. // Biometrics, 1991, 12, h. 4] . Moreover, the composition of the material is represented not by stoichiometric Ca ₁₀ (PO ₄ ) ₂ OH, but by defective carbonatapatite with the inclusion of Mg-vitlokite, that is, an X-ray structural analogue of bone biomineral [McConnell D. // In Sat. Phosphorus in the environment M .: Mir, 1977, p.462]. The indicated materials have an osteosubstitution rate: a layer of 1.5 mm is replaced by bone tissue from 6 to 24 weeks, which is associated with the presence of osteoconductor properties of carbonatapatite. However, Interpor materials are not available for large-scale use in domestic practice (for example, 3-5 times grams of material are implanted in the segment of the jaw bone during periodontal surgery to treat periodontal disease, its cost is 2-3 million rubles).

Radical attempts to reduce the cost of osteosubstitution to the utmost with the help of a stoichiometric HAP - Ca ₁₀ (PO ₄ ) ₂ (OH) ₂ , using it as a semi-product of bioceramics - a fine crystalline powder, could not achieve the goal, since, undergoing hydrolysis in aqueous media of the body, hydroxylapatite is physiologically incompatible with bone and connective tissue cells, because the balance pH of hydrolysis = 12.8 [Altshuller Z.S. On Sat "Phosphorus in the environment." Yu-M: Mir, 1977, p.268]. In the manufacture of HAP ceramic materials by heat treatment, the hydrolytic cleavage of Ca-OP bonds in the HAP crystal is eliminated. However, the structural and chemical properties of HAP can be preserved only up to 1100 deg C, and limiting the temperature of real processes to 1150-1200 deg C determines methods such as sintering under pressure in argon, vacuum, etc., in methods for producing dense granular forms of HAP materials. d. [Shtrief H., Musse P. // Brit.Cer. Res., 1990, 45, p. 59].

 The densely sintered granulated Allotropat, Durapatit and other products do not have the properties of osteoconductors and protectors, are not biodegradable and therefore are used as materials for contour plastics with problematic effectiveness. Implantation requires precautionary measures. At low strength, in order to prevent fragmentation of the granules (in order to avoid vascular embolism by microparticles, explantation of the material, etc.), the entire volume of material from the applicator is discarded. It cannot be re-sterilized.

Obtaining porous biodegradable calcium phosphate sintered materials with the claimed stoichiometric composition of Ca ₁₀ (PO ₄ ) ₂ (OH ₂ ) has not been implemented in practice.

 All industrial products (porous granules "Apokeram", "Ostegen") are either a biphasic mixture of HAP with TCP, or a mixture of HAP thermolysis products, more soluble in aqueous media than HAP, degrading in cell-mediated reactions with bone cells [De Groot // Proc. 10th Europ. Conf. in biomot. Davos, 1993, p.80].

Known methods for producing crack resistant HAP containing composite materials. For example [Japanese application 264007 MKI C 04 B 35/80. E. Agiro, I. Mauura, N. Nakamara, N 63-212545, decl. 29.08.88, op.05.03.90 // Kokhoy Tokke, ser. 1, 1990, 15, p.331], during which the GAP mixed with whiskers of silicon carbide, impregnated with solutions of Ca (CO ₃ ) ₂ , H ₃ PO ₄ , dried, calcined, get a porous product - a framework of a certain shape, in the final stage impregnated with a molten glass in a system Ca-Al ₂ O ₃ -P ₂ O ₅ .

All implants that have found application in medicine, based on developed composites using oxides ZrO ₂ , TiO ₂ , SiC, BN glass [Dushtyt P. // Biomtd. Mat. Res., 1987, 21, p. 219] are massive products. An arbitrary choice of composition, ignoring the difference in the thermal expansion coefficient of glass and HAP, melt stability, and the nature of the interaction leading to the production of secondary crystalline products make the production of microproducts with a given porosity impossible. At the same time, reliably obtained [Hulbert SY et al. // J. Ctr. Lnst. 1982, 8.4, p. 13] that the optimal pore size (150-100 μm) and the distance between them, that is, the surface of the implant, is one of the main parameters that affect bone replacement, especially with static loads on the implant.

Attempts are known to obtain microimplants from bio-metals in which the necessary manifestation of osteocompatibility is the presence of a HAP layer in the surface destruction products. The presence of CaO and P ₂ O ₅ in the composition of these materials is [Sarkisov L.Yu., Mikhailenko L.Yu., Stroganova O.S. // Technique and technology of sitalls, 1994, 1, N 2, p. 5] a prerequisite for the manifestation of these properties.

The closest in technical essence to the achieved result is bio-metal, including, wt.%:
SiO ₂ - 37.2-38.5
P ₂ O ₅ - 15.5-13.2
Al ₂ O ₃ - 6.2-6.5
CaO - 33.5-35.0
MgO - 3.1-1.8
ZnO - 4.5-5.0
[(decision of VNIIGPE on the grant of a patent of the Russian Federation for an invention dated 03/27/97 on application 05028466/14 (020049) dated 02/26/92), which is part of the "Composition for filling bone cavities"].

 One of the authors of the composition of B-metal M-31 is a co-author of the claimed invention, which allows you to have information about the properties, structural and chemical features of obtaining from the original composite M-31 a bio-metal having osteocompatibility and properties of an osteoprotector having a single-crystal HAPa corbonate phase.

 Porous microimplants were made from this bio-glass, which was adopted by the authors as a prototype — granules, which also had insufficient strength, were not resistant to thermal cycling.

 Crystallization in the biositall prototype has a surface character and goes from the surface of the granules inward, that is, unevenly in volume.

 The minimum fraction of the single-crystal phase did not exceed 30% by volume in the glass-crystalline material and could not be increased due to a change in the dispersion of the glass powder. This did not allow changing the biodegradation time interval (upward) of such implants, which also did not allow increasing the efficiency of the material for a long period of osteosubstitution.

 The purpose of the invention is the increase in mechanical strength, resistance to thermal cycling and synchronization of the processes of destruction and bone replacement of bone tissue with porous microimplants in the form of granules obtained by the proposed method of manufacturing from the inventive osteoplastic fiberglass composite material.

This goal is achieved in that the osteoplastic glass crystal composite material for the manufacture of porous microimplants in the form of granules containing SiO ₂ ; P ₂ O ₅ ; Al ₂ O ₃ ; CaO; MgO; ZnO additionally contains hydroxylapatite (HAP) in the following ratio of components, wt. %:
SiO ₂ - 26.0-33.4
P ₂ O ₅ - 10.5-13.5
Al ₂ O ₃ - 4.3-5.5
CaO - 23.6-30.4
MgO - 2.1-2.7
ZnO - 3.5-4.5
Hydroxylapatite (HAP) - 10.00-30.00
and can be obtained by a method including mixing finely divided glass and HAP powders in proportions according to the claimed composition, preparing a plastic mass, producing granulate, removing binders, sintering granules and sintering.

 Of the available patent and scientific literature, the authors are not aware of composite osteoplastic glass-crystal materials of this composition for the manufacture of porous microimplants in the form of granules. Due to the achieved structural and chemical properties, the proposed composite material ensures high operational properties of osteo-substituting microimplants in the form of granules and allows us to state that the claimed technical solution meets the requirements of the criteria of “novelty” and “significant differences”.

 The literature available to us does not provide information on the use of volume crystallization as an effective nucleator in the process of obtaining a glass-crystalline material - HAP, and for initiating the process in the phosphate phase - a liquid of the initial bioglass containing latent HAP nuclei.

The synthesis of the proposed osteoplastic glass crystal composite material was carried out as follows:
1. The synthesis of glass composition was carried out, wt.%:
SiO ₂ - 26.0-33.4
P ₂ O ₅ - 10.5-13.5
Al ₂ O ₃ - 4.3-5.5
CaO - 23.6-30.4
MgO - 2.1-2.7
ZnO - 3.5-4.5
in a furnace with heating at t = 1450 degrees C for 3 hours. Charge materials and reagents were used of the “chda” and “kch” grades with a limitation of the content of heavy elements within 10-3 ... 10-4%.

 The finished glass melt was produced by casting into cold water with orientation of the ratio of phase-liquid and matrix. Then the glass was dried at t = 90.. . 100 degrees C and ground in a porcelain mill with dry grinding with uralite bodies. Ground glass was screened to obtain a powder with a particle size of less than 60 microns.

The initial HAP - a small-crystalline industrial product with a glassometric formula (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ with a crystal size of 1 ... 3 μm (according to TU 118-095-56-91 manufactured by AO Kaskor) contained impurities of heavy elements less than 10-4%.

 The content of the proposed starting components of the new osteoplastic glass crystal material are presented in table. 1 (tab. 1-4 see at the end of the description).

 2. A method for producing a composite material in the form of porous microgranules from glass crystalline components includes the following steps.

 1) Weighing the required quantities of glass powders and HAP according to the claimed composition (table. 1) and mixing them.

 2) Moisturizing a mixture of powders with a solution of a plasticizing substance.

 3) Rubbing the resulting mass through a sieve with holes of 1500 microns or in special cleaning machines - granulators.

 4) Drying of the pellet blanks.

 5) Billet granules are sintered in a muffle furnace according to a special regime combining sintering and sinterization.

 6) Cooling with the muffle turned off.

The composition of the glass composite and the modes of crystallization are selected so that the composite material has a fine crystalline structure uniformly crystallized in the entire volume. The uniform development of crystallization centers throughout the volume is predetermined by careful mixing of finely dispersed powders of glass and HAP, that is, the creation of conditions where HAP (dallite) crystals from the volume of the glass-liquid phase grow on numerous surfaces of crystallization nuclei (crystallization seeds), which are not the initial powdered synthetic hydroxyapatite, and dallite, which is obtained by exchange reactions during heat treatment combined with the thermolysis of carbon-containing porophore-plasticizer and the replacement of part of the PO4 group in the lattice of Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ with Ca ₃ , which is a priority novelty of the method. The precipitated crystalline phase, R-graphically identified as HAP carbonate (dallite), gives the composite enhanced performance. The cellular structure of the granules is fixed by a glass phase, which plays the role of a stabilizing structure at the sintering stage.

 The crystallization process - the separation of the HAPa monophase (dallite) is combined in the temperature-time regime with the regimes of sintering and fusion of granules. Crystal boundaries are integrated in the glass phase in the conditions of the proposed method. The only crystalline phase corresponding to 60 vol.% Compared with 30 vol.% Of the prototype excludes secondary crystallization from glass.

 The inventive method obtained products (in our case, porous microspheres) from a new composition of glass-crystal composite material with new valuable properties superior to the properties of the starting materials.

 According to the proposed method, porous granules of the most convenient sizes for implantation with a diameter of 100 ... 1500 microns, with the necessary, not vitrified, and partially glazed surface condition, with open porosity, pore diameter of 100 are made. . 120 μm for bone tissue infiltration [Huldert S.F. //cal.J.Am.cer.int/ 1982, 8, 4, p. 131].

 The properties of the obtained porous materials were determined by the methods usually used in determining the properties of materials from bio-metals of the same purpose. To compare the values of the properties, porous granules were made of glass - a prototype and the claimed (boundary compositions) bio-metal.

The study of the properties of the obtained glass-crystal composite materials was determined on a standard model. From literature data it is known that Ca-P materials are unstable to prolonged exposure to physiological solutions. Cylindrical samples of materials of all compositions were made with the same porosity of the material, d = h = 10 mm, and σ _{compress of the} initial samples and samples after exposure to 0.85% NaCl solutions (physiological solution) for 10 days was determined. The results of the determination are presented in table. 2.

Thus, an analysis of the values of the mechanical compressive strength shows that
the prototype is a decrease in σ _sg by 10%;
in foreign trains by 9 - 29%;
the claimed compounds <10% - 8%, 7% and 0, i.e. practically, the changes are not significant, the samples retain their strength.

Resistance to thermal cycling, characterizing how many (in% by weight) granules crumbled without preserving their shape, was determined as follows:
granules with a total weight of 3 g were poured into cuvettes made of heat-resistant glass and placed in a thermostat with t = 120 degrees C and kept for 1 hour (the mode was selected as close as possible to the dry heat sterilization modes). After exposure, the granules spilled onto a metal tray at room temperature 18-20 degrees C.

 After cooling, a sieve analysis of the granules was carried out and the ratio of the number of granules (in g) remaining on the sieve with a mesh size of 1000 μm was determined in%.

g0 is the weight of the granules before the test = 3 g (sample), passed through a sieve of 1500 μm and remaining on a sieve of 1000 μm;
g1 is the weight of the granules passing through a 1500 μm sieve and remaining on a 1000 μm sieve after testing in a thermostat.

 Set term. (g0 - g1) / g0 100%.

 The results of the determination are presented in table. 3.

 It can be seen from the data presented that they retain their shape, that is, almost all granules are resistant to thermal cycling (the fraction of fragmented particles does not exceed 7%, which is the necessary tolerance), and the prototype glass and foreign compositions lose from 25% to 40% of all whole granules in the mode re-sterilization.

 The data presented in Table 4 indicate that the destruction rates of porous implants in bench tests under conditions that simulate the effects of body biological media (blood, plasma) in the temperature regime of the duct are correlated with the results of biomedical experiments.

 Analysis of the calculated values of the destruction rates for samples of the same porosity under equal conditions (temperature, reagent composition, flow rate) allows us to establish that with an increase in the content of the crystalline phase, the destruction rate decreases (for the claimed compositions from 30 ... 50% compared to the prototype).

This allows the introduction of a certain amount of HAPa into the glass crystal composite, i.e., by varying the composition, to obtain material either for contour plasty, or for treating patients with osteogenesis problems, when their own osteogenesis is slowed down, or for treating diseases not complicated by systemic lesions of osteogenetic processes, which distinguishes this material and reveals a wide range of its application
Description of specific examples of the manufacture of porous implants in the form of granules from an osteoplastic glass crystal composite material.

Example 1
1. Grind the original glass in a porcelain ball mill with uralite balls for 5 hours. Sift through a sieve with a mesh size of not more than 60 microns.

 2. Weigh 90 g of glass powder and 10 g of HAP, mix.

 3. 10 g of paraffin / grade A / are dissolved in 25 ml of gasoline / GOST 84-53 / purified, aviation B-70, BP-1 GOST 5827-68, add to the powder mixture and mix thoroughly.

 4. Wipe the resulting mass through a sieve with a mesh size of 1500 microns.

 5. We place the granules on a porous tray and dry in air until the smell of gasoline disappears.

 6. Transfer the granules to a quartz tray and place in a cold muffle furnace, the heating of which to t = 500 deg C is carried out at a speed of 8-10 deg / min.

 7. After reaching this temperature, the pan with granules is transferred to another muffle, heated to t = 970 ± 10 degrees C, and held for 30 minutes.

 8. The muffle furnace is switched off, and the granules are spontaneously cooled together with the furnace.

Example 2
1. From example 1.

 2. Weigh 80 g of glass powder into 20 g of HAP, mix.

 3, 4, 5, 6. From example 1.

 7. Exposure in a muffle furnace for 35 minutes at t = 970 ± 10 degrees C.

 8. From example 1.

Example 3
1. From example 1.

 2. Weigh 70 g of glass powder and 30 g of HAP, mix.

 3, 4, 5, 6. From example 1.

 7. Exposure in the oven for 40 minutes at t = 970 ± 10 degrees C.

 8. From example 1.

Example 4
1. From example 1.

 2. Weigh 95 g of glass powder and 5 g of HAP, mix.

 3, 4, 5, 6. From example 1.

 7. Extract in a muffle furnace for 30 minutes at a temperature of 970 ± 10 degrees C.

 8. From example 1.

Example 5
1. From example 1.

 2. Weigh 65 g of glass powder and 35 g of HAP.

 3, 4, 5, 6. From example 1.

 7. Exposure in a muffle furnace for 50 minutes at 970 ± 10 degrees C.

 8. From example 1.

Example 6
The glass prototype undergoes preliminary crystallization to isolate the HAP phase.

 1. From example 1.

 2. Weigh 100 g of glass powder.

 3, 4, 5, 6. From example 1.

 7. Exposure in a muffle furnace for 20 minutes at ± 10 degrees C.

 8. From example 1.

 Technical appraisal and economic benefits of the claimed compositions of the new osteoplastic biomaterial.

 1. The compositions and the technology for creating glass-crystalline material developed by the authors for the first time effectively and economically solve the problem of obtaining durable porous granular microimplants to replace bone defects. The main area of application of the new material may be the treatment in dentistry of the most common periodontium, filling in small defects of bone tissue without fear of fragmentation and explantation of the material. Biosital can be applied both independently and in combination with biopolymers, saline solutions, and drugs used in the treatment of diseases.

 2. Achieved in comparison with the prototype, the expansion of the range of time of replacement of the material allows us to recommend the use of the material in the treatment of complex diseases with a change in the rate of osteogenesis.

 The biological activity of the material, its osteocompatibility is preserved both in the claimed compositions and in the prototype, the main single-crystal phase is represented by HAPa carbonate - dallite - an analogue of biomineral. The maximum content of impurities of heavy elements does not exceed 10-4% and meets the requirements of ISO-4045.

 3. An economical and simplified method for producing porous granules, as well as non-deficient and affordable raw materials produced in the Russian Federation, make it possible to offer domestic medicine a material that meets international standards, but is much cheaper.

 4. Improved characteristics of mechanical strength, thermal cycling conditions provide ease of packaging, storage, re-sterilization when using the material, which is important when conducting operations in outpatient conditions.

Claims (1)

1. Osteoplastic glass-crystal composite material for the manufacture of porous implants in the form of granules containing SiO ₂ , P ₂ O ₅ , Al ₂ O ₃ , CaO, MgO, ZnO and hydroxyapatite (HAP), characterized in that the components are in the following ratio, wt .%:
SiO ₂ - 26.0 - 33.4
P ₂ O ₅ - 10.5 - 13.5
Al ₂ O ₃ - 4.3 - 5.5
CaO - 23.6 - 30.4
MgO - 2.1 - 2.7
ZnO - 3.5 - 4.5
Hydroxyapatite (HAP) - 10.0 - 30.0
2. A method of manufacturing porous implants in the form of granules, including the synthesis of glass, the mixing of glass and hydroxyapatite (HAP), the preparation of plastic mass, the manufacture of granulate, the removal of binders, the sintering of granules, characterized in that the mixing of glass and HAP is carried out in the ratio according to paragraph 1, and the sintering process is combined with a single-stage mode of directional crystallization, as a result of which a single-crystal HAP in the dallite phase of 30-60 vol.% Is released.

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