Bone cement

Abstract

The invention relates to bone cements for vertebroplasty. Proposed is a bone cement containing a biocompatible polyurethane polymer and consisting of two components which produce a curable composition when mixed, wherein the first component is a synthesized viscous prepolymer which has a free isocyanate group (NCO) content of 8-10 wt% and is produced from polypropylene glycol with an average molecular mass of 1000 and 4,4'-diisocyanate diphenylmethane, with the addition of an effective amount of zirconium oxide in an amount of 15-40 wt% of the total mass of the first component, in the presence of a synthesis catalyst, namely dibutyltin dilaurate, and the second component is glycerine with a curing catalyst dissolved therein, namely diazabicyclooctane or a mixture of diazabicyclooctane and triethanolamine.

Description

[0001] BONE CEMENT

[0002] AREA OF TECHNOLOGY

[0003] The invention relates to medicine, namely to bone cements for vertebroplasty, used in reconstructive surgery of the spine. The present invention relates to a curable composition consisting of two components, which is stable when stored as separate components and when combined forms a highly viscous bone cement that hardens over a certain period of time.

[0004] PRIOR ART

[0005] Currently, in case of bone density disorders, the technique of bone augmentation is used to increase the strength of transpedicular fixation and to restore the support capacity in case of pathological compression fractures caused by osteoporosis, as well as in case of vertebral neoplasms that impair the support capacity. The most common method used for this purpose is the injection of intraosseous cement based on polymethyl methacrylate. Polymethyl methacrylate has pronounced toxicity, and during polymerization it heats up to more than 70 degrees Celsius, which leads to thermal damage to adjacent tissues and their subsequent necrosis. After polymerization, the Young's modulus for PMM is 2.16 GPa, which significantly exceeds this parameter of bone tissue, especially in patients with osteoporosis. Due to the heterogeneity of the mechanical properties of bone tissue at the adjacent level and augmented, the risk of a pathological fracture at the adjacent level increases.The systemic toxic effect of methyl methacrylate monomer is also known, which may be the basis of the so-called "cement implantation syndrome", manifested by acute cardiovascular failure after surgery. The use of PMMA in bone tissue augmentation during metal fixation is also unsafe due to the disappearance of plastic properties after polymerization, which does not allow changing the trajectory of screw insertion if its position is not optimal. Given the above disadvantages, it is necessary to develop new biocompatible materials suitable for bone tissue augmentation. PREVIOUS LEVEL OF TECHNOLOGY.

[0006] A bone substitute material known from the prior art is patent RU 2518753 (published 10.06.2014, A61L27 / 14, A61F2 / 00). The known bone substitute material contains a biodegradable and biocompatible polymer and as an osteoconductive and biocompatible polymer it contains a polyurethane series polymer with a pore size of 50-400 μm, a compressive strength of 50-60 MPa, adhesion to metal and bone of 60-65 kg / cm2, obtained in two stages, wherein at the first stage a prepolymer is obtained from polyoxypropylene glycol with an average molecular weight of 1000 and 4,4'-diisocyanatodiphenylmethane in the presence of catalysts such as tertiary amines, organotin compounds, with heating in a stream of dry argon or nitrogen and a content of free isocyanate NCO groups in the prepolymer of 11-13% by weight, at the second stage the obtained prepolymer is cured with glycerin with a curing catalyst dissolved therein, such as dibutyl tin dilaurate, wherein the amount of water in glycerin is 0.1-0.5% by weight.

[0007] The well-known bone-substituting material has biocompatibility and osteoconductivity in the absence of pathological reactions during osseous (intraosseous) implantation, high adhesion to metal and bone tissue, which ensures the gluing of bone fragments, and is also plastic, which determines the possibility of modeling complex surfaces.

[0008] The disadvantage of the known material is its radiolucency, which does not allow for proper monitoring and evaluation of the spread of bone cement during bone tissue augmentation, as well as for analyzing postoperative changes in both the surrounding bone tissue and the bone cement.

[0009] DISCLOSURE OF INVENTION

[0010] The technical task of the claimed invention is to create bone cement with the possibility of its puncture introduction during vertebroplasty by injection through a cannula needle into the affected vertebral body or introduction through cannulated fenestrated screws. The created bone cement should have sufficient radiopacity for intraoperative control and obtaining diagnostic information, high viscosity, moderate thermal effect, biocompatibility, sufficient biomechanical strength in the solid phase.

[0011] The technical result is achieved due to the fact that bone cement is proposed in the form of a biocompatible polymer of the polyurethane series, consisting of two components that are stable when stored separately and when mixed, a hardening composition is obtained, wherein:

[0012] - the first component is a synthesized viscous prepolymer with a free isocyanate NCO-group content of 8-10 wt. %, obtained from polyoxypropylene glycol with an average molecular weight of 1000 and 4,4'-diisocyanatodiphenylmethane with the addition of an effective amount of zirconium oxide in an amount of 15-40 wt. % of the total weight of the first component in the presence of a synthesis catalyst such as dibutyl tin dilaurate,

[0013] - the second component is glycerin with a curing catalyst dissolved in it, such as diazobicyclooctane or a mixture of diazobicyclooctane and triethanolamine, in the following ratio, mass %: diazobicyclooctane - 0.2 - 0.6, triethanolamine - 0 - 15, glycerin - the rest,

[0014] - in this case, the first and second components are mixed to obtain a curable composition in a ratio of 0.5-0.9 parts by weight per 10 parts by weight of the first component.

[0015] IMPLEMENTATION OF THE INVENTION

[0016] The proposed bone cement is obtained as follows.

[0017] The first component is synthesized as follows. Polyoxypropylene glycol is placed in a round-bottomed flask with a stirrer, and an X-ray contrast agent is added while stirring. Zirconium oxide is used as an X-ray contrast agent. After obtaining a homogeneous mass, 4,4'-diisocyanatodiphenylmethane and a catalyst, dibutyl tin dilaurate, are added. The synthesis is carried out at a temperature of 45-55 °C in a weak stream of inert gas. Dry argon or nitrogen is used as an inert gas. Then, the reaction mass is evacuated and the synthesis process is completed. Then, the reaction mass is allowed to stand in a hermetically sealed flask filled with an inert gas until all gas bubbles are removed from the mass of the first component. Then, an analysis is carried out for the content of free NCO groups. The viscosity of the obtained first component is determined at 45 ° C on a rotational viscometer. The viscosity of the first component should be at least 12 Pa*s.

[0018] The second component is obtained as follows. Glycerin and a curing catalyst in the form of diazobicyclooctane (DABCO) or a mixture of diazobicyclooctane with a tertiary amine (triethanolamine) are placed in an Erlenmeyer flask. A magnetic anchor is placed in the flask and placed on a heated magnetic stirrer platform. Mixing is then carried out at a temperature of 45-55 °C for a time sufficient for complete dissolution of the curing catalyst. After this time, the flask is removed from the magnetic stirrer platform and left to stand at room temperature for a time sufficient to remove gas bubbles from the mass of the second component.

[0019] When stored separately, the first and second components of the proposed bone cement are stable, therefore the proposed bone cement is supplied to the consumer (surgeon) in the form of two components. In order to form a curable working composition, the second component is taken in an amount of 0.5-0.9 parts by weight per 10 parts by weight of the first component.

[0020] The components are mixed by the surgeon in the operating room immediately before the injection of the proposed bone cement. The first and second components are combined in a single container and mixed manually or automatically for a certain period of time. Mixing can be done using a special mixer. As a result of mixing, the components of the system enter into a chemical reaction, during which the viscosity of the system increases. The process can be divided into the following phases:

[0021] Mixing phase - from 0 to 2 min;

[0022] Fluidity phase - from 2 to 8 minutes;

[0023] “Paste” phase - from 8 to 13 minutes;

[0024] Phase “plasticine” - from 13 to 17 minutes;

[0025] The “rubber” phase – from 17 to 50 minutes;

[0026] The "solid substance" phase from 50 min onwards. For the surgeon, the working phases are the "fluidity" phase, the "paste" phase and the "plasticine" phase. During the "fluidity" and "paste" phases at room temperature, the resulting composition has the ability to be pressed through a needle with a diameter of at least 3.2 mm, which is used in vertebroplasty. During the "fluidity" phase, the curable composition has the ability to slowly flow to the sides, evenly distribute over the filled volume and penetrate into the deeper layers of the spongy tissue of the vertebral body. The viscosity of the "fluidity" phase ensures safe filling of the affected vertebral body, allows control over the spread of bone cement in the vertebral body and reduces the likelihood of its exit beyond the body into the epidural space. During the "paste" phase, the curable composition is still squeezed out through the needle, but does not flow, but holds its shape and can be modeled manually.During the next phase, "plasticine", the curing composition is practically not pressed through the needle, but it can be modeled manually and given the necessary shape. During the "rubber" phase, the surgeon usually no longer performs any manipulations with the curing composition, and it gains hardness. The "rubber" phase ends when the hardness of the curing composition reaches 70%.

[0027] Tests have been conducted that have shown that the optimal content of free NCO groups in the first component should be from 8 to 10% by weight. An excess amount of free NCO groups over 10% leads to a significant decrease in its viscosity (less than 12 Pa*s) and increases the fluidity of bone cement in its liquid phase, which can increase the risk of an unfavorable outcome of a surgical operation. With an NCO group content of less than 8%, bone cement in the "solid substance" phase becomes insufficiently rigid and differs from the mechanical strength of bone tissue, which corresponds to a Young's modulus of 400-800 MPa.

[0028] When synthesizing the second component, a curing catalyst such as diazobicyclooctane or a mixture of diazobicyclooctane and triethanolamine is dissolved in glycerin. The components are taken in the following ratio: diazobicyclooctane - 0.2 - 0.6, triethanolamine - 0 - 15, glycerin - the rest.

[0029] Studies have shown that excessive concentration of the curing catalyst, where diazobicyclooctane is more than 0.6% and triethanolamine is more than 15%, leads to a decrease in the working time and brittleness of the material, deterioration of the cytotoxicity indices in the "solid" phase. Insufficient concentration of diazobicyclooctane in the second component less than 0.2 wt. % leads to deterioration of the physical and mechanical properties of the material (increased fluidity in the working time phases, long set of strength characteristics). By changing the content of diazobicyclooctane in the second component in the range of 0.2 - 0.6% and triethanolamine in the range of 0 - 15%, the working time of the cured composition and the strength of the cement in the "solid" phase will change, but the properties of the cement corresponding to the technical result will be unchanged.Namely, the proposed bone cement will have sufficient radiopacity to obtain diagnostic information, high viscosity, moderate thermal effect, biocompatibility, and sufficient biomechanical strength in the solid phase.

[0030] In order to form a curable working composition, the first and second components are mixed, with the second component taken in an amount of 0.5-0.9 mass parts per 10 mass parts of the first component. Studies have shown that an excessive amount of the second component (hardener) over 0.9 mass parts leads to a decrease in the working time and brittleness of the material, and a deterioration in the cytotoxicity indices in the "solid substance" phase. An insufficient amount of the second component less than 0.5 mass parts leads to the fact that NCO groups remain free, which in turn leads to a deterioration in the physical and mechanical properties of the material.

[0031] The proposed bone cement has a moderate thermal effect during polymerization. The hardening process occurs uniformly with heat release and pore formation. The maximum surface temperature of the hardening composition is no more than 41° C, which allows to exclude burning of adjacent tissues and their subsequent necrosis. During the "fluidity" and "paste" phases, the proposed bone cement expands and increases in volume due to the release of carbon dioxide and the formation of pores. The expansion coefficient of bone cement is 1.2-1.4, i.e. the volume of bone cement in the "solid substance" phase is 20-40% greater than the initial volume of the mixture of the first and second components. Despite the porosity, bone cement in the "solid substance" phase is sufficiently rigid and corresponds to the mechanical strength of bone tissue (Young's modulus 400-800 MPa).In addition, the ability to expand within the specified limits allows bone cement to penetrate and fill deeper and more difficult to reach bone voids.

[0032] The content of the radiopaque substance in the proposed material is 15-40 wt. % of the total mass of the first component. Tests have shown that the content of the radiopaque substance less than 15% does not provide sufficient visualization using radiography and computed tomography, and the content of the radiopaque substance more than 40% significantly reduces the physical and mechanical properties of bone cement in the "solid substance" phase due to the formation of a heterophase system. Density indicators according to computed tomography data should be at least 2500 HU.

[0033] The proposed bone cement has acceptable biocompatibility, which was confirmed by cytotoxicity tests conducted jointly with the Federal State Budgetary Educational Institution of Higher Education “Priorhinolaryngological Medical University” of the Ministry of Health of the Russian Federation (Nizhny Novgorod).

[0034] EXAMPLE OF IMPLEMENTATION OF THE INVENTION

[0035] Example No. 1.

[0036] The first component was synthesized as follows. 92.1 g of polyoxypropylene glycol were placed in a round-bottomed flask with a stirrer, 82.5 g of zirconium oxide were added with stirring, after obtaining a homogeneous mass, 125.4 g of 4,4'-diisocyanatodiphenylmethane and 0.05 g of dibutyl tin dilaurate were introduced. The synthesis was carried out at a temperature of 48.5-50 °C for 120 minutes in an argon flow. Then an analysis was carried out for the content of free NCO groups, which was 9.8%. The viscosity of the obtained first component was 12.5 Pa*s at 45 °C, this parameter was determined on a ROTAVISC me-vi rotational viscometer.

[0037] The second component was synthesized as follows. 0.06 g of crystalline diazobicyclooctane (DABCO), 3 g of triethanolamine, and 26.94 g of glycerol were loaded into a 50 ml Erlenmeyer flask, a magnetic anchor was placed in the flask, and it was installed on a magnetic stirrer with heating. Then mixing was carried out at a temperature of 49 °C. Then a sample of the material was taken and quality control was carried out. The first and second components were mixed in the ratio: 0.7 parts by weight of the second component to 10 parts by weight of the first component.

[0038] Table No. 1 shows examples of obtaining bone cement with different curing catalysts.

[0039] Table No. 1

[0040] Example A of Table 1 indicates a bone cement where the second component is glycerol with diazobicyclooctane (DABCO) dissolved therein in an amount of 0.5 wt.%. Example B of Table 1 indicates a bone cement where the second component is glycerol with a mixture of diazobicyclooctane with 10 wt.% of a tertiary amine dissolved therein in an amount of 0.2 wt.%.

[0041] In Table No. 1, the "working time" column indicates the time from the start of mixing the first and second components to the end of the "plasticine" phase, and the "initial hardening time" column indicates the time from the start of mixing the first and second components to the end of the "rubber" phase. The "expansion coefficient" column indicates the coefficient of expansion of the volume in the "solid substance" phase from the initial volume of the mixture of the first and second components.

[0042] The proposed bone cement is mainly used to perform puncture vertebroplasty by injection through a needle-cannula or for bone tissue augmentation during metal fixation by injecting bone cement through fenestrated screws. However, the specified area of ​​application does not limit its use in other nosologies.

Claims

CLAUSE OF INVENTION Bone cement containing a biocompatible polymer of the polyurethane series and consisting of two components, the mixing of which results in a curable composition, characterized in that the first component is a synthesized viscous prepolymer with a content of free isocyanate NCO-groups of 8-10 wt. %, obtained from polyoxypropylene glycol with an average molecular weight of 1000 and 4,4'-diisocyanatodiphenylmethane, with the addition of an effective amount of zirconium oxide in an amount of 15-40 wt. % of the total weight of the first component, in the presence of a synthesis catalyst - dibutyl tin dilaurate, the second component is glycerin with a curing catalyst dissolved in it - diazobicyclooctane or a mixture of diazobicyclooctane and triethanolamine, in the following ratio, wt. %: diazobicyclooctane 0.2-0.6 triethanolamine 0-15 glycerin the rest, while the first and second components are used to obtain a curable composition in a ratio of 0.5-0.9 parts by weight.the second component per 10 parts by weight of the first component. 9 SUBSTITUTE SHEET (RULE 26)

Images