A biodegradable, injectable bone cement and its preparation method and application

Abstract

The present invention provides a biodegradable, injectable bone cement and a preparation method and application thereof. The composition for preparing the injectable bone cement comprises a liquid phase component and a solid phase component, wherein the liquid phase component is a polyester polymer or a mixture of a polyester polymer and a catalyst; the solid phase component is a calcium phosphate salt or a mixture of a calcium phosphate salt and a developer. The injectable bone cement is formed by cross-linking reaction of polyester polymer, calcium phosphate salt and developer, and is injectable and biodegradable. The biosafe bone cement of the present invention can be highly conformed to complex tissue defect sites, has no obvious exothermic phenomenon during the curing process, has a good development effect, and the porous structure formed by it can promote bone tissue repair and improve the repair quality. It is a bone tissue repair material with clinical application prospects.

Description

Technical Field

[0001] The present invention relates to the fields of material science and medicine, and specifically to a bone cement that can be injected and has self-crosslinking and hydration enhancement in an in vivo environment, and a preparation method and application thereof, in particular, a filling material for repairing bone tissue defects of complex structures. Background Art

[0002] The increasing number of bone defects caused by diseases, accidental injuries, natural disasters, etc. not only leads to a huge market demand for bone tissue repair materials, but also places increasingly high requirements on the surgical operation, mechanical properties and biological activity of existing repair materials. Among them, injectable materials such as polymethyl methacrylate (PMMA) bone cement and calcium phosphate (CPC) bone cement are the most widely used in clinical practice. However, they generally have their own problems in actual clinical applications that need to be solved. Among them, the high temperature (about 70°C) caused by the heat release during the reaction of PMMA bone cement, the toxicity of free monomers, the biological inertness of the bone cement itself, and the excessively high modulus greatly affect its tissue repair effect. Although CPC bone cement has good tissue compatibility and osteoconductivity, its mechanical properties are too poor and it is easy to disintegrate when exposed to water, so it can only be used independently in the field of dental and maxillary bone repair, and most of them are mixed with PMMA. In view of the tight network structure and mechanical strength of calcium-phosphorus inorganic substances and organic collagen in natural bones, the introduction of active organic polymers is of great significance for the design of bone repair materials. On the other hand, injectable bone cement meets the needs of minimally invasive treatment for complex bone defect repair. Based on the above, it is of great clinical significance to design a high-elasticity, high-strength organic-inorganic composite injectable bone cement through biomimetic biomanufacturing strategy to meet the needs of repairing different complex bone defects in an all-round way. Summary of the invention

[0003] The purpose of the present invention is to provide a bone cement which has bioaffinity, in-situ hydration and pore formation in vivo, high biological activity and can be formed in the form of injection.

[0004] In a first aspect of the present invention, there is provided an injectable bone cement composition, the injectable bone cement composition comprising:

[0005] A liquid phase component, wherein the liquid phase component is a polyester polymer or a mixture of a polyester polymer and a catalyst;

[0006] The solid phase component is a calcium phosphate salt or a mixture of a calcium phosphate salt and a developer.

[0007] In another preferred embodiment, the mass ratio of the polyester polymer to the catalyst is 1:0.00001-0.5, preferably 1:0.00005-0.002 or 0.0001-0.0005, and more preferably 1:0.0001-0.001.

[0008] In another preferred embodiment, the mass ratio of the calcium phosphate salt to the developer is 1:9 to 9:1, preferably 2:8 to 8:2, 3:7 to 7:3, 3:7 to 5:5 or 4:6 to 6:4.

[0009] In another preferred embodiment, the developer and the PEGS-OH are bonded via a chemical bond.

[0010] In another preferred embodiment, the injectable bone cement composition further comprises a cross-linking agent, and the cross-linking agent is a diisocyanate cross-linking agent.

[0011] In another preferred embodiment, the cross-linking agent is L-lysine diisocyanate LDI, hexamethylene diisocyanate, or toluene diisocyanate.

[0012] In another preferred embodiment, the mass ratio of the polyester polymer to the cross-linking agent is 1:0.25-2, preferably 1:0.25-0.5, more preferably 1:0.3-0.4, and preferably 1:0.365.

[0013] In another preferred embodiment, the polyester polymer is polyhydroxy polyethylene glycol polyglycerol sebacate PEGS-OH, and the amount of isocyanate groups in LDI is 0.5-2 times the amount of hydroxyl groups in PEGS-OH.

[0014] In another preferred embodiment, the amount of the isocyanate group in LDI is 1-1.5 times, preferably 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4 times, of the hydroxyl group in PEGS-OH.

[0015] In another preferred embodiment, the mass ratio of the liquid phase component to the solid phase component is 0.5:9.5-5:5.

[0016] In another preferred embodiment, the mass ratio of the liquid phase component to the solid phase component is 1:9-9:1, preferably 2:8.

[0017] In another preferred embodiment, the polyester polymer is selected from: polyglyceryl sebacate, polyethylene glycol polyglyceryl sebacate, polyhydroxy polyethylene glycol, polyhydroxy polyethylene glycol polyglyceryl sebacate PEGS-OH,

[0018] Wherein, the structural unit of polyhydroxy polyethylene glycol polyglycerol sebacate PEGS-OH is as shown in Formula Ia or Formula Ib:

[0019]

[0020] Wherein, in Formula Ia, m 1 An integer from 1 to 20, n 1 An integer from 5 to 60;

[0021] In Formula Ib, m 2 An integer from 1 to 20, n 2 An integer from 5 to 60.

[0022] In another preferred embodiment, in Formula Ia, m 1 is an integer of 2-18, an integer of 5-15, an integer of 2-8, or an integer of 8-10. In another preferred embodiment, n 1 It is an integer of 10-50, an integer of 20-40, an integer of 30-50, or an integer of 8-35.

[0023] In another preferred embodiment, in Formula Ib, m 2 is an integer of 2-18, an integer of 5-15, an integer of 2-8, or an integer of 8-10. In another preferred embodiment, n 2 It is an integer of 10-50, an integer of 20-40, an integer of 30-50, or an integer of 8-35.

[0024] In another preferred embodiment, the number average molecular weight of the polyester polymer is 3.0-100.0 kDa, preferably 6.0-50.0 kDa, and more preferably 7.0-20.0 kDa.

[0025] In another preferred embodiment, the dispersion coefficient of the polyester polymer is 1.1-2.0, preferably 1.2-1.7;

[0026] In another preferred embodiment, the polyester polymer contains at least 2 -OH groups on average in one structural unit.

[0027] In another preferred embodiment, the catalyst is an organometallic catalyst.

[0028] In another preferred embodiment, the calcium phosphate salt is selected from: tetracalcium phosphate, monocalcium phosphate, tricalcium phosphate, or a mixture of two or more thereof.

[0029] In another preferred embodiment, the developer is selected from iodine-containing contrast agents.

[0030] The second aspect of the present invention provides an injectable bone cement, which is obtained by mixing the liquid phase component and the solid phase component of the injectable bone cement composition described in the first aspect and an optional cross-linking agent.

[0031] In another preferred embodiment, the liquid phase component and the solid phase component are fully and evenly mixed to obtain a white dough-like slurry; the cross-linking agent is evenly mixed with the above slurry to obtain the injectable bone cement.

[0032] In another preferred embodiment, the bone cement is filled into a syringe and injected into a relevant part, thereby solidifying to form bone cement.

[0033] In another preferred embodiment, the storage modulus of the injectable bone cement during injection is 10 3 -4×10 4 Pa, preferably 10 4 In another preferred embodiment, the loss modulus of the injectable bone cement during injection is 2×10 3 -4×10 5 Pa, preferably 10 4 Pa. The storage modulus is not higher than the loss modulus, meeting the injectability requirement.

[0034] In another preferred embodiment, after the liquid phase component and the solid phase component are mixed, they are mixed with a cross-linking agent at 25°C-40°C, more preferably 35°C-37°C, and most preferably 37°C.

[0035] The liquid phase component, solid phase component and cross-linking agent are the same as described above.

[0036] In another preferred embodiment, the curing time of the bone cement is 15 to 120 min, preferably 15 to 30 min, such as 17 min, 20 min, or 26 min.

[0037] In another preferred embodiment, the curing time of the bone cement can be adjusted by the amount of the catalyst.

[0038] In another preferred embodiment, the bone cement is solidified at 25-40° C., preferably 37° C. The bone cement of the present invention has the characteristics of bioaffinity, in-situ hydration and pore formation in vivo, high biological activity, and can be formed by injection.

[0039] The third aspect of the present invention provides a kit for preparing the injectable bone cement according to the second aspect, the kit comprising:

[0040] (a) a first container, and a liquid component located in the container;

[0041] (b) a second container, and a solid phase component located in the container.

[0042] (c) a third container, and a cross-linking agent located in the container.

[0043] In the first container, the liquid phase component exists in the form of a viscous liquid; in the second container, the solid phase component exists in the form of a powder; and in the third container, the cross-linking agent exists in the form of a liquid.

[0044] The liquid phase component, solid phase component and cross-linking agent are the same as described above.

[0045] The fourth aspect of the present invention provides the use of the injectable bone cement described in the third aspect for:

[0046] (i) preparing tissue defect filling materials;

[0047] (ii) preparing materials for guiding tissue regeneration;

[0048] (iii) preparing medical cosmetic materials;

[0049] (iv) 3D printing matrix materials;

[0050] (v) A loading matrix or carrier for growth factors or drugs.

[0051] In another preferred embodiment, the material is used to prepare a material for treating spinal fusion fractures.

[0052] In a fifth aspect of the present invention, a method for filling a tissue defect and / or guiding tissue regeneration is provided, the method comprising applying the injectable bone cement described in the second aspect of the present invention to a site to be treated.

[0053] In the sixth aspect of the present invention, a method for loading growth factors and / or drugs and / or cells is provided, the method comprising mixing the injectable bone cement described in the second aspect of the present invention with the growth factors and / or drugs and / or cells to be loaded.

[0054] In a seventh aspect of the present invention, a method for 3D printing a composite scaffold is provided, the method comprising using the injectable bone cement described in the second aspect of the present invention as a 3D printing matrix material.

[0055] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1The present invention shows the synthesis route of the polyhydroxy PEGS polymer (A); the H NMR spectrum of the polyhydroxy PEGS polymer (B); the Fourier transform infrared spectrum of the polyhydroxy PEGS polymer (PEGS-OH, bottom) and the branched PEGS polymer (PEGS, top) prepared by polycondensation (C); and the molecular weight variation of the polyhydroxy PEGS polymer with different PEG block molecular weights as a function of reaction time (D).

[0057] Figure 2 The figures show the mixing state of the organic phase and the inorganic phase in different proportions in the present invention (A); the Fourier transform infrared spectra after the organic-inorganic mixture in different proportions (B); the rheological curves after the organic-inorganic mixture in different proportions (C); and the thermogravimetric spectra after the organic-inorganic mixture in different proportions (D).

[0058] Figure 3 The present invention shows compression curves of different crosslinking agent contents (A); compression curves of different crosslinking agent contents under the first 60% strain (B); Fourier transform infrared spectra of different crosslinking agent contents (C); rheological curves of different crosslinking agent contents at 37°C (D); rheological curves of different catalyst contents at 37°C (E); and rheological curves of catalyst contents at 0.01% at 25°C (F).

[0059] Figure 4 The figures show the cytotoxicity bar graph of the injectable bone cement of the present invention (A); the compression curve graph of different hydration times (B); the cyclic compression curve graph of different crosslinking agent contents (C); and the microscopic morphology schematic diagram of the bone cement of the present invention (D).

[0060] Figure 5 The figure shows the change of temperature over time after bone cement injection in the present invention (A); a line graph of the change of temperature over time within 10 minutes after bone cement injection (B); bone cement can be formed into complex shapes after extrusion (C); and bone cement does not disintegrate under the impact of water flow (D).

[0061] Figure 6 The present invention shows the development effect of bone cement with different developer contents under X-ray (A); the development effect of bone cement with different developer contents in an isolated sheep spine (B); the comparison of mechanical properties of bone cement under different conditions (C); the rheological curve after adding 60% iohexol as a developer (D); and the curing time after adding 60% iohexol as a developer (E).

[0062] Figure 7The present invention shows the tissue repair CT images of bone cement versus PMMA (A); bone morphology after bone defect repair by bone cement versus PMMA (B); bone area after bone cement repair (C); bone volume ratio after bone cement repair (D); and trabecular separation after bone cement repair (E). DETAILED DESCRIPTION

[0063] After extensive and in-depth research, the inventors unexpectedly discovered for the first time a bone cement that has excellent mechanical properties, quickly solidifies in vivo, and forms a porous structure while hydrating and can be formed by injection.

[0064] Specifically, the bone cement introduces biodegradable polyhydroxy polyethylene glycol polysebacic acid glyceride (PEGS-OH) as the organic phase of the bone cement, and uses calcium phosphate as the inorganic phase to construct an organic-inorganic composite injectable bone cement system based on isocyanate and hydroxyl crosslinking. The bone cement has excellent injection performance, can be quickly solidified and formed in an in vivo environment, and the crosslinking process is mild, without obvious heat release, and has no obvious toxicity to the host organism, which provides the possibility for filling bone defects and guiding regeneration of bone tissue.

[0065] The bone cement of the present invention not only has excellent mechanical properties and biological activity, as well as good cell compatibility and osteoconductivity, but also has ideal tissue repair effect and clinical applicability, so that the implantation of the material does not require open surgery, which is convenient for doctors to operate and reduces the pain of patients, and provides new optional materials and design ideas for minimally invasive tissue regeneration technology. On this basis, the present invention was completed.

[0066] the term

[0067] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0068] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0069] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0070] As used herein, the terms "PEG", "polyethylene glycol" are used interchangeably.

[0071] As used herein, the terms "PGS", "polyglycerol sebacate" are used interchangeably.

[0072] As used herein, the terms "PEGS", "PEGylated polyglyceryl sebacate", "polyethylene glycolated polyglyceryl sebacate", and "PEGS polymer" are used interchangeably.

[0073] As used herein, the terms "CPC," "calcium phosphate salt," and "calcium phosphate salt" are used interchangeably.

[0074] As used herein, the terms "LDI", "L-lysine diisocyanate" are used interchangeably.

[0075] As used herein, the terms "PEGS-OH", "polyhydroxy PEGS" are used interchangeably.

[0076] As used herein, the terms "T-9," "stannous octoate," and "stannous 2-ethylhexanoate" are used interchangeably.

[0077] As used in this article, in the terms "C7P3", "C8P2" and "C9P1", C stands for CPC, 7, 8, and 9 mean that the mass of CPC is 70%, 80%, and 90% of the total mass of bone cement, and P stands for PEGS-OH, and 3, 2, and 1 mean that the mass of PEGS-OH is 30%, 20%, and 10% of the total mass of bone cement.

[0078] As used herein, the terms "L1.5", "L1.25" and "L1.0" wherein L represents L-lysine diisocyanate LDI, and 1.5, 1.25 and 1 mean that the amount of isocyanate in LDI is 1.5 times, 1.25 times and 1.0 times the amount of hydroxyl in PEGS.

[0079] Polyhydroxylated polyglyceryl sebacate (PEGS-OH)

[0080] In the present invention, polyhydroxy polyethylene glycol polysebacic acid glyceride (PEGS-OH) has a structure shown in Formula Ia or Formula Ib:

[0081]

[0082] In Formula Ia, m 1 An integer from 1 to 20, n 1 An integer from 5 to 60;

[0083] In Formula Ib, m 2 An integer from 1 to 20, n 2 An integer from 5 to 60.

[0084] In the present invention, Figure 1 The preparation of polyhydroxy PEGylated polysebacic acid glyceride (PEGS-OH) is shown in A. Wherein, the left figure shows the synthesis of PEGS-OH shown in formula Ia.

[0085] Specifically, the preparation method of the polyhydroxy polyethylene glycol polyglycerol sebacate comprises the following steps:

[0086] (a1) under the protection of argon atmosphere, a diacid and a diglycidyl ester in a molar ratio of 1:1 are dissolved in a solvent (wherein the diacid can be sebacic acid, carboxylated PEG with a molecular weight of 250Da, or carboxylated PEG with a molecular weight of 600Da; the diglycidyl ester can be diglycidyl sebacic acid ester or polyethylene glycol diglycidyl ester with a molecular weight of 500Da), and a 0.6mol% ditetra-n-butylammonium hydroxide catalyst (wherein the carboxylic acid part of the ammonium salt can be sebacic acid, carboxylated PEG with a molecular weight of 250Da, or carboxylated PEG with a molecular weight of 600Da) is added, and the mixture is reacted at 90-120°C (preferably 100°C) for 1-3 days;

[0087] (b1) After the product of step (a1) is precipitated in diethyl ether, it is dried under vacuum at room temperature for 6-12 hours (preferably 10-12 hours) to obtain a polyhydroxy polyethylene glycol polysebacic acid glycerol polymer PEGS-OH.

[0088] In another preferred embodiment, the preparation method further comprises the steps of:

[0089] (c1) dialysis purification of the PEGS-OH obtained in step (b1) to obtain purified PEGS-OH.

[0090] Bone cement of the present invention

[0091] Bone cement is a kind of biomedical material that can play a supporting role in tissue defect sites. The present invention provides a bone cement that is biocompatible, hydrated and porous in vivo, and can be formed by injection.

[0092] As used herein, the terms "injectable bone cement", "bone cement of the present invention", "PEGS / CPC bone cement", and "organic-inorganic composite bone cement" are used interchangeably.

[0093] The bone cement of the present invention is formed by mixing a liquid phase component, a solid phase component and an optional cross-linking agent; the liquid phase component is a polyester polymer or a mixture of a polyester polymer and a catalyst; the solid phase component is a calcium phosphate salt or a mixture of a calcium phosphate salt and a developer.

[0094] In another preferred embodiment, the liquid phase component includes polyhydroxy polyethylene glycol polysebacic acid glyceride and stannous 2-ethylhexanoate;

[0095] The solid phase components include tetracalcium phosphate and anhydrous calcium phosphate;

[0096] The cross-linking agent includes L-lysine diisocyanate.

[0097] The developer includes iohexol.

[0098] In a preferred embodiment, polyhydroxy polyethylene glycol polysebacic acid glyceride (PEGS-OH) is used as the organic phase, calcium phosphate (CPC) is used as the inorganic phase, and iohexol is used as the developer. Under the catalytic action of stannous 2-ethylhexanoate (T-9), it is cross-linked and cured by L-lysine diisocyanate (LDI) and injected into the relevant part by syringe injection to obtain a bone cement material with certain mechanical properties.

[0099] The mass ratio of the liquid phase component to the solid phase component is 1-3:9-7, preferably 2:8.

[0100] In another preferred embodiment, the calcium phosphate salt and the PEGS-OH are combined by physical mixing.

[0101] The PEGS-OH of the present invention and the cross-linking agent are combined through an addition reaction between the hydroxyl group of PEGS-OH and the isocyanate group of LDI.

[0102] The mechanical properties and rheological properties of the bone cement of the present invention can be adjusted and optimized by the mass ratio of polyhydroxy polyethylene glycol polysebacic acid glyceride to calcium phosphate.

[0103] The gel time and cytotoxicity of the bone cement of the present invention can be optimized by regulating the catalyst content.

[0104] In another preferred embodiment, the mass ratio of the polyester polymer and the cross-linking agent can be used to adjust the modulus, rheological properties and pore content of the bone cement.

[0105] In another preferred embodiment, the mass ratio of the polyester polymer and the catalyst can be used to adjust the rheological properties, curing time and cytotoxicity of the bone cement.

[0106] In another preferred embodiment, the mass ratio of the developer to the inorganic calcium phosphate salt can be used to adjust the in vivo development effect and modulus of the bone cement.

[0107] The imaging effect of the bone cement of the present invention can be optimized by adjusting the content of the developer.

[0108] The bone cement has one or more of the following characteristics:

[0109] (1) The compression modulus is between 10 and 280 MPa, preferably between 80 and 100 MPa;

[0110] (2) At 37°C, the curing time is between 15 and 120 minutes, preferably between 15 and 30 minutes;

[0111] (3) At 25°C, the operating period is greater than 120 minutes.

[0112] The cytotoxicity of the injectable bone cement was 85% of that of the blank group.

[0113] The injectable bone cement does not break or slag under a pressure of 5000N.

[0114] The surface of the injectable bone cement has porous structures of varying sizes.

[0115] The injectable bone cement does not disintegrate under the impact of water flow.

[0116] The curing process of the injectable bone cement has no obvious exothermic phenomenon.

[0117] Preparation method of bone cement of the present invention

[0118] The present invention provides a method for preparing a PEGS-OH / CPC composite bone cement, comprising the following steps:

[0119] (i) providing polyhydroxy polyethylene glycol polysebacic acid glyceryl ester (PEGS-OH), calcium phosphate (CPC), iohexol, stannous 2-ethylhexanoate (T-9), and L-lysine diisocyanate (LDI);

[0120] (ii) adding T-9 catalyst to the PEGS-OH polymer and mixing uniformly to obtain a liquid phase;

[0121] (iii) CPC powder and iohexol are mixed uniformly to obtain a solid phase;

[0122] (iv) mixing the solid phase and the liquid phase uniformly, adding LDI cross-linking agent, and mixing uniformly to obtain bone cement slurry.

[0123] The bone cement slurry is transferred into a syringe barrel and then injected into the defect site to solidify in vivo to form bone cement.

[0124] In the step (i), the molecular weight of PEGS-OH (polymer) is 12000 Da, the molecular weight of stannous 2-ethylhexanoate (T-9) is 405.12 g / mol, and the molecular weight of L-lysine diisocyanate (LDI) is 226.23 g / mol.

[0125] In the step (ii), the amount of catalyst T-9 used is 0.1-0.01%.

[0126] In the step (iii), the mass ratio of CPC to iohexol is 3-9:1-7.

[0127] In the step (iv), the mass ratio of liquid to solid is 1-3:9-7; the amount of isocyanate group in LDI is 1.5 times, 1.25 times, and 1.0 times the amount of PEGS-OH hydroxyl group; the reaction temperature is 37° C., and the reaction time is 15 to 30 min.

[0128] The curing time of the injectable bone cement is shortened with the increase of the catalyst content, and the curing time is adjustable within the range of 15 to 120 minutes. The compression modulus of the bone cement is enhanced with the increase of the CPC content, and the initial compression modulus is adjustable within the range of 10 to 35 MPa.

[0129] The main advantages of the present invention include:

[0130] 1) The bone cement of the present invention has excellent injectability and mechanical strength;

[0131] 2) The bone cement mixture of the present invention can be cured in situ by injection into the desired part, and the curing time can be adjusted between 15-120 minutes;

[0132] 3) The rheological properties, injection properties, mechanical properties and cell behavior of the bone cement of the present invention can be regulated and optimized by changing the content of its components;

[0133] 4) The bone cement of the present invention can freely fill the defect and can fit the defect highly;

[0134] 5) The bone cement of the present invention is biodegradable;

[0135] 6) The bone cement of the present invention has good imaging effect;

[0136] 7) The cross-linking process of the bone cement of the present invention is gentle and has no obvious heat release;

[0137] 8) The inorganic CPC in the bone cement of the present invention provides the possibility for guided regeneration of bone tissue;

[0138] 9) The minimally invasive properties of the bone cement described in the present invention give it a promising prospect in clinical application.

[0139] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0140] Example 1. Synthesis of polyhydroxy PEGS

[0141] (a) Dissolve 4.68 mL of glycidol and 18.9 mL of triethylamine in 100 mL of toluene. Add the mixture into a three-necked flask under argon atmosphere and stir at room temperature to mix well.

[0142] (b) 6.08 mL of sebacyl chloride was dissolved in 8 mL of toluene and added to a constant pressure funnel under an argon atmosphere;

[0143] (c) The reaction apparatus is transferred to a -15°C ethanol bath, and the piston of the constant pressure funnel is opened to allow the sebacic acid chloride solution in (b) to be added dropwise to the mixed solution in (a). The molar content of sebacic acid chloride relative to glycidol in the reaction is 50%, that is, the molar ratio of the acyl chloride to the hydroxyl group in the reaction is 1:1.

[0144] (d) After reacting for 6 hours, the triethylamine hydrochloride was removed by suction filtration, and the solvent was removed by rotary evaporation. Diglycidyl sebacate was purified by column chromatography to obtain diglycidyl sebacate.

[0145] (e) In a glove box filled with argon atmosphere, 2.39 g of diglycidyl sebacate and 2.5 g of carboxylated PEG were weighed, dissolved in DMF, and heated and stirred at 100° C. for 1-3 days.

[0146] (f) The prepolymer product is purified by ethanol dissolution-ultrapure water dialysis operation to remove unreacted monomers and small molecules to obtain a purified polyhydroxy PEGS polymer.

[0147] Different polyhydroxy PEGS polymers were obtained by using carboxylated PEGs of different molecular weights (number average molecular weights were 250Da, 500Da, and 600Da, respectively), and were named PEGS 250 -OH、PEGS 500 -OH、PEGS 600 At the same time, PGS-OH without PEG component and PEG-OH without sebacic acid component were prepared using the same method.

[0148] Among them, PEGS obtained by using carboxylated PEG with a number average molecular weight of 250Da 250 The number average molecular weight of -OH is 12175 Da, and the dispersity coefficient is 1.61.

[0149] The H NMR spectrum of the obtained polyhydroxy PEGS polymer is as follows: Figure 1 As shown in B, the peak position is consistent with the theoretical structure of PEGS hydrogen atoms. No peak of epoxy functional groups was observed at the chemical shift of 3.00 ppm, indicating that all epoxy functional groups were completely consumed by the reaction and the reaction was thorough.

[0150] The Fourier transform infrared spectrum of the obtained polyhydroxy PEGS polymer is as follows: Figure 1As shown in C, it is at 3500cm -1 The hydroxyl peak intensity at is significantly enhanced compared to that of PEGS obtained by direct polycondensation of polyethylene glycol, sebacic acid and glycerol, indicating that the hydroxyl content of the polyhydroxy PEGS polymer of the present invention is significantly higher than that of the PEGS obtained by polycondensation.

[0151] Figure 1 Figure D shows the change in molecular weight of polyhydroxy PEGS polymers with different PEG block molecular weights as a function of reaction time by gel permeation chromatography. The results show that the number average molecular weight of PEGS-OH increases with the extension of reaction time and is not significantly affected by the PEG block molecular weight, all of which are around 12 kDa.

[0152] Example 2. Synthesis of polyhydroxy PEGS

[0153] (a) 1.95 g of sebacic acid (0.01 mol) and 20 g (0.07 mol) of tetrabutylammonium hydroxide (25 wt% aqueous solution) were added to 100 mL of 95% ethanol, stirred at 55° C. for 30 min, then the ethanol was removed by rotary evaporation at 40° C., and finally lyophilized to obtain the product di(tetrabutylammonium hydroxide) sebacic acid ester (TBAS);

[0154] (b) Under nitrogen atmosphere, 20.23 g of sebacic acid (0.1 mol), 50.00 g of polyethylene glycol diglycidyl ether and 0.41 g of the product TBAS of step (a) were weighed, and the above raw materials were mixed and dissolved in 180 mL of anhydrous N,N-dimethylformamide, and stirred at 100° C. for 72 h;

[0155] (c) The product of step (b) was dialyzed using a dialysis bag with a molecular weight cut-off of 3500 Da to obtain purified linear polyhydroxy PEGS.

[0156] Example 3. Exploration and characterization of PEGS-OH / CPC ratio

[0157] Explore the composite properties of polyester polymer PEGS-OH and calcium phosphate CPC in different proportions.

[0158] PEGS-OH was prepared by the method of Example 2. PEGS-OH and CPC were weighed to a mass ratio of 1:9, 2:8, and 3:7, respectively, and mixed evenly to form bone cement slurries (C7P3, C8P2, and C9P1).

[0159] like Figure 2 As shown in A, with the increase of inorganic phase content, the bone cement slurry gradually thickens. When CPC:PEGS-OH is 9:1, it has become a powder and loses liquid fluidity. When CPC:PEGS-OH is 8:2, it is injectable but does not flow freely, which is the best state.

[0160] The above slurry was tested by Fourier transform infrared spectroscopy using potassium bromide tablet method. Figure 2 As can be seen in Figure B, the phosphate groups of the inorganic phase have corresponding peaks to the hydroxyl, methylene, carbonyl and ether bonds of PEGS-OH.

[0161] The change of its rheological properties with frequency is tested by a rotational rheometer. The use of the rotational rheometer includes the following steps:

[0162] (a1) Turn on the rotational rheometer (Thermo Hakke, USA), set different temperatures (37°C, 25°C) and control the temperature, set the frequency at 10 Hz, and set the strain at 1.0%;

[0163] (b1) bone cement slurries with different compound ratios (C7P3, C8P2, C9P1);

[0164] (c1) filling the bone cement slurry in (b1) into the syringe barrel for standby use;

[0165] (d1) Use the syringe in (c1) to quickly inject into the 20 mm diameter steel parallel plate and start the test immediately;

[0166] (e1) Record the changes of storage modulus (G') and loss modulus (G") over time.

[0167] from Figure 2 It can be seen from C that the loss modulus is greater than the storage modulus, indicating fluidity. The storage modulus and loss modulus of the C8P2 group are equivalent, indicating that it is between liquid and solid and is a suitable injectable state.

[0168] After preparing C7P3, C8P2, and C9P1 bone cement slurries using the same method as above, 56 μL of crosslinker LDI was added to each group. After stirring evenly, the mixture was placed in a 37°C oven overnight to solidify. After the bone cement solidified, a thermogravimetric analysis was performed using a thermobalance. Figure 2 As can be seen from Figure D, the organic and inorganic content of bone cement conforms to the theoretical feed ratio, and the extra organic matter mass of about 6% is the cross-linking agent LDI.

[0169] The results showed that bone cement had the most suitable injectability when the mass ratio of CPC:PEGS-OH was 8:2.

[0170] Example 4. Investigation and characterization of crosslinking agent and catalyst content

[0171] In order to investigate the mechanical properties of bone cement under compression, this study investigated the compression properties of bone cement with different cross-linking agent contents.

[0172] Weigh 200 mg of PEGS-OH and 800 mg of CPC, mix them evenly, and then add 56 μL (L1.0 group), 70 μL (L1.25 group), and 84 μL (L1.5 group) of cross-linking agent LDI to the above slurry respectively. After thorough stirring, fill it into a polytetrafluoroethylene cylindrical female mold with a diameter of 10 mm and a depth of 6 mm. After it is cured overnight in a 37°C oven, a universal testing machine is used to perform a compression test on the cylindrical bone cement sample. Five parallel samples are set for each group of samples to be tested. During the compression test, the compression rate is 10 mm / min until the force reaches 5000 N, and the stress-strain curve is recorded. The results are as follows. Figure 3 As shown. Figure 3 As can be seen from Figure A, as the cross-linking agent content increases, the mechanical properties of bone cement decrease. This is because the excess cross-linking agent reacts with the surrounding water to form a porous structure. However, the difference between L1.25 and L1.0 is not too large. Both have mechanical properties and a porous structure that is beneficial to tissue repair. Figure 3 B is Figure 3 The compression curve of A in the first 60% strain represents the initial modulus of bone cement, and its trend is similar to Figure 3 A is consistent with the middle one.

[0173] In addition, the cylindrical bone cement samples prepared by the above method were subjected to infrared detection by potassium bromide tableting method. Figure 3 As can be seen in C, at wave number 2200cm -1 There is no infrared peak of isocyanate, indicating that the isocyanate has reacted completely to form polyurethane or polyurea.

[0174] Three groups of bone cement slurries, L1.0, L1.25, and L1.5, with a PEGS-OH:CPC mass ratio of 2:8 were prepared in the same manner as above. After the slurries were stirred evenly, they were immediately placed in a rotational rheometer controlled at 37°C for rheological testing. Figure 3 The rheological diagram over time in D shows that at 37°C, without adding a catalyst, the bone cement curing time is about 120 minutes, and the cross-linking agent content has little effect on it.

[0175] According to the mass ratio of stannous 2-ethylhexanoate to PEGS-OH polymer of 0.1%, 0.05%, and 0.001%, the catalyst stannous 2-ethylhexanoate was added to the PEGS-OH polymer and mixed evenly. Then, C8P2L1.25 bone cement slurry was prepared in the same way as above. After the slurry was stirred evenly, it was immediately placed in a rotational rheometer controlled at 37°C for rheological testing. Figure 3Figure E shows that at 37°C, once the catalyst is added, the curing time of bone cement is reduced to 15-30 minutes, which is a significant shortening of the curing time. Considering that the effect of the catalyst addition amount from 0.01% to 0.1% on the curing time is not too large, and the catalyst may cause toxicity, 0.01% is selected as the optimal amount.

[0176] In addition, a rotational rheometer was used to test the rheological properties of C8P2L1.25 bone cement slurry containing 0.1%, 0.05%, and 0.001% of the catalyst 2-ethylhexanoate. Figure 3 It can be seen in Figure F that even with the addition of a catalyst, the bone cement can still remain in a slurry state for more than 120 minutes without solidifying. The extended operation period makes it easier for doctors to deal with emergencies during surgery, which is conducive to the expansion of the application of this bone cement in the market.

[0177] The results showed that when the amount of isocyanate substance was 1.25 times the amount of hydroxyl substance and the mass of catalyst was 0.01% of the mass of bone cement, bone cement could solidify within 30 minutes at 37°C and had good injectability and mechanical properties.

[0178] Example 5. Characterization of cytotoxicity, mechanical properties and surface morphology of the bone cement of the present invention

[0179] In order to evaluate the cell compatibility of bone cement, this study used mouse fibroblasts (L929) co-cultured with bone cement to investigate its cytotoxicity at 1d (day), 3d, and 7d.

[0180] Weigh 200 mg of PEGS-OH containing 0.01% (mass ratio) catalyst T-9 and 800 mg of CPC, mix well, and add 70 μL (L1.25) of crosslinker LDI to the above slurry. After sufficient stirring, fill it into a polytetrafluoroethylene cylindrical female mold with a diameter of 10 mm and a depth of 6 mm. After it is fully cured at 37°C, sterilize it by ultraviolet radiation, and inoculate L929 cells for co-culture. On the 1st, 3rd, and 7th days, refer to the national standard GB / T 16886.5-2017, and perform MTT experiments on the samples to detect the cytotoxicity of bone cement. Figure 4 The cytotoxicity results of A show that when the T-9 content is 0.01% of the total mass of bone cement, the cytotoxicity of bone cement is 85% of the blank group, which is greater than the national standard requirement of 70%. And the negative control and positive control composite theoretical results.

[0181] C8P2L1.25 bone cement cylindrical samples were prepared according to the above method and immersed in ultrapure water at 37°C for 1, 3, 6, and 12 hours. The samples were then dried and subjected to compression tests using a universal testing machine. The compression rate during the compression test was 10 mm / min until the force reached 5000 N, and the stress-strain curve was recorded. Figure 4 It can be seen from B that at 37°C, the mechanical properties of bone cement are enhanced as the hydration time increases (the initial modulus increases from the original 5MPa as the hydration time increases, and after 12 hours of hydration, the initial modulus reaches 15MPa), indicating that the bone cement of the present invention will be further enhanced in the presence of water in the human body after being injected into the human body, thereby achieving the hydration of the CPC component. C8P2L1.0, C8P2L1.25, and C8P2L1.5 bone cement cylindrical samples were prepared respectively, and their cyclic compression performance was tested by a universal testing machine. During the compression test, the compression rate was 10mm / min until the stress reached 12MPa, and then the stress was released to 0MPa at a rate of 10mm / min, which was considered a cycle, and the cycle was repeated 10 times. Figure 4 Figure C shows that, unlike the existing rigid bone cement materials (PMMA and CPC), the bone cement of the present invention has excellent elasticity due to the PEGS-OH component being an elastic polymer. Under 10 cycles of compression, the bone cement has good recovery performance, which is not available in rigid materials. The rigidity of the filling material is the cause of secondary fractures, while the elastic material can store stress by deformation when the stress is overloaded, thereby avoiding secondary fractures caused by mismatch between the material modulus and the tissue.

[0182] According to the above method, a cylindrical sample of C8P2L1.25 bone cement was prepared and adhered to the SEM sample stage by conductive glue. After gold spraying, the surface morphology of the bone cement was observed by scanning electron microscope. Figure 4 In Figure D, it can be clearly seen that the pore structure on the surface of the bone cement is very obvious. This is because the excess LDI reacts with the surrounding water to form polyurea, thereby releasing CO 2 In addition, CPC can be observed very clearly on the bone cement, and the surface inside the formed pores is relatively smooth, which is the result of the formation of polyurea occurring inside the polymer.

[0183] It can be seen that the bone cement of the present invention has qualified cytotoxicity, can enhance mechanical properties in vivo through hydration, and has certain elasticity and irregular pore structure, and is a good type of biomaterial that is beneficial to tissue repair.

[0184] Example 6. Characterization of the reaction temperature and anti-collapse performance of the bone cement of the present invention

[0185] In order to evaluate the reaction temperature of the bone cement during curing, this study used an infrared thermal camera to investigate the changes in reaction temperature and ambient temperature during the curing process of the bone cement. At the same time, in order to characterize the anti-collapse performance of the bone cement, this study placed the bone cement in a certain shape after curing under water flow impact for observation.

[0186] Specifically, 200 mg of PEGS-OH containing 0.01% (mass ratio) of catalyst T-9 and 800 mg of CPC were weighed and mixed evenly, and then 70 μL (L1.25) of crosslinking agent LDI was added to the slurry. After sufficient stirring, it was filled into a 5 mL syringe, and the bone cement was squeezed out and injected through the syringe, and an infrared thermal camera was used to take pictures and record the temperature changes of the bone cement at different times after injection.

[0187] Figure 5 Figure A shows the reaction temperature of bone cement during curing examined by an infrared thermal imager. It can be seen that when the bone cement of the present invention is just extruded, its temperature is slightly higher than the ambient temperature (27.4°C: 26.4°C) due to the work done by the shear force, and after 10 minutes, its temperature is close to the ambient temperature (26.6°C: 26.3°C) due to heat exchange.

[0188] Figure 5 Figure B shows the temperature change of the bone cement of the present invention and the environment within 10 minutes after injection. The temperature of the bone cement has been decreasing after injection, approaching the ambient temperature, and no heat release phenomenon has been observed. However, the curing heat release of PMMA bone cement, which is currently the most commonly used in clinical practice, has always been a difficult problem to solve. Its curing temperature can be as high as 70°C, which can even burn local tissues in the human body. However, the bone cement of the present invention does not release heat during curing, which is more competitive.

[0189] C8P2L1.25 bone cement was prepared in the same way as above, and squeezed out through a syringe to write the word "Hua Li". After it solidified at 37°C, the bone cement with the word "Hua Li" was placed under a tap and impacted with water to observe its anti-collapse performance. Figure 5 C shows that the bone cement of the present invention has good formability and can adapt to complex defects. Figure 5 In Figure D, the text written in Figure C was washed with water, and there was no deformation of the text, indicating that the presence of PEGS-OH provided good cohesion for the CPC component and solved the problem of disintegration of CPC bone cement.

[0190] The results show that the bone cement of the present invention has good injectability and biocompatibility, can achieve hydration in vivo to enhance mechanical properties, does not release heat during solidification, and does not disintegrate when exposed to water, and is an excellent tissue repair material.

[0191] Example 7. Characterization of the imaging effect of the bone cement of the present invention

[0192] In order to evaluate the in vivo imaging effect of bone cement so as to be used in clinical spinal repair surgery, this study used an X-ray apparatus to place the bone cement under X-rays for imaging.

[0193] CPC and iohexol are mixed in advance in a ratio where the mass of iohexol accounts for 20%, 30%, 40%, 50%, 60%, 70% of the total mass of CPC and iohexol. Subsequently, PEGS-OH 200mg containing 0.01% (mass ratio) catalyst T-9 and a mixture of CPC and iohexol 800mg are weighed, and after uniform mixing, 70 μL (L1.25) of crosslinking agent LDI are added to the above-mentioned slurry. After sufficient stirring, it is filled into a 10mm diameter, 6mm deep polytetrafluoroethylene cylindrical female mold. C8P2L1.25 bone cement cylindrical samples with different iohexol contents are prepared. The sample is placed under an X-ray instrument to investigate its development effect. Figure 6 The results in Figure A show that under X-ray, as the iohexol content increases, the bone cement becomes more and more obvious.

[0194] According to the above method, C8P2L1.25 bone cement slurry with iohexol mass accounting for 50%, 60%, and 70% of the total mass of CPC and iohexol solid phase was prepared and injected into the isolated goat spine with defect. The goat spine injected with bone cement was placed under an X-ray machine to simulate the imaging effect of bone cement in vivo. Figure 6 In B, it can be clearly seen that the bone cement can fill the defect of the sheep spine well and has a significant imaging effect under X-ray. The contrast of the imaging deepens with the increase of iohexol content.

[0195] According to the above method, a cylindrical sample of C8P2L1.25 bone cement with 60% iohexol (PEGS-OH / CPC+60% iohexol) was prepared, and the compression performance was compared with that of C8P2L1.25 bone cement hydrated for 12 hours (PEGS-OH / CPC hydrated), unhydrated C8P2L1.25 bone cement (PEGS-OH / CPC) and ordinary CPC bone cement (CPC). The compression rate during the compression test was 10 mm / min until the force reached 5000 N, and the stress-strain curve was recorded. Figure 6 Figure C is a comparison of the mechanical properties of bone cement under different conditions, indicating that the addition of iohexol significantly improves the mechanical properties of bone cement. This is because iohexol not only acts as a developer, but also covalently bonds with the organic phase of bone cement through chemical reactions.

[0196] Figure 6D in the figure is the result of testing the fluidity of bone cement containing 60% iohexol. The method and parameters of the rotational rheometer are set as follows:

[0197] (a1) Turn on the rotational rheometer (Thermo Hakke, USA), set different temperatures to 25 °C and control the temperature, set the frequency to 0.1-10 Hz, and set the strain to 1.0%;

[0198] (b1) preparing bone cement slurry (C8P2L1.25) containing 60% iohexol;

[0199] (c1) filling the bone cement slurry in (b1) into the syringe barrel for standby use;

[0200] (d1) Use the syringe in (c1) to quickly inject into the 20 mm diameter steel parallel plate and start the test immediately;

[0201] (e1) Record the changes of storage modulus (G') and loss modulus (G") with frequency.

[0202] The results show that the loss modulus of the slurry is greater than the storage modulus, it is in a fluid state, and has a certain thickening effect as the frequency increases.

[0203] Figure 6 Figure E is the result of characterizing the curing time of bone cement containing 60% iohexol. The rotational rheometer was used in the same manner as above, with the parameters set as follows: temperature 37°C, frequency 0.1Hz, strain 1.0%, and the changes in storage modulus (G') and loss modulus (G") over time were recorded. The results show that the curing time of bone cement is about 21 minutes, and the addition of iohexol has no significant effect on its curing time.

[0204] Example 8. Characterization of the tissue repair effect of the bone cement of the present invention

[0205] In order to evaluate the in vivo tissue repair effect of bone cement, this study selected a rat femoral defect repair model to compare the bone regeneration promoting abilities of PMMA and the bone cement of the present invention.

[0206] Select SD rats weighing about 500g, after anesthesia, cut the fur at the distal end of the femur, and expose the femoral condyle. Use a circular trephine with a diameter of 5mm to make a defect on the side of the femur and then use it. According to the ratio of iohexol mass accounting for 60% of the total mass of CPC and iohexol, CPC and iohexol are mixed in advance. Subsequently, weigh PEGS-OH 200mg containing 0.01% (mass ratio) catalyst T-9 and a mixture of CPC and iohexol 800mg, after mixing, add cross-linking agent LDI70μL (L1.25) to the slurry. After fully stirring, it is injected into the above-mentioned femoral defect and the skin is sutured subsequently. Wherein, PMMA is selected from commercially available products.

[0207] Three months later, the rats were killed by overdose of anesthesia, and the femur samples were removed and fixed with 4% paraformaldehyde solution for one week, followed by CT examination and photographs of the femurs. Figure 7 Figure A compares the bone repair effects of PMMA and bone cement. Compared with the large number of gaps in the blank group, both PMMA and bone cement can successfully fill the defective areas. PMMA is biologically inert and difficult to degrade, so it exists independently of bone tissue and rarely has tissue ingrowth. The bone cement group has integrated with bone tissue due to its good biocompatibility and has a good bone repair effect. Figure 7 Figure B compares the effects of using bone cement on bone tissue morphology. It can be clearly seen that the blank group that did not use bone cement developed obvious black lesions after surgery, indicating a state of bone necrosis. However, after using PMMA or bone cement, no bone necrosis was observed, proving that the mechanical properties of bone cement can provide good support at the defect site and prevent the occurrence of bone necrosis. Figure 7 Figures C, D, and E are some of the CT quantification results. Whether it is bone area, bone volume ratio or trabecular separation, bone cement can achieve a repair-promoting effect similar to that of PMMA and far superior to that of the blank group. It should be noted that PMMA will be considered as dense bone in CT quantitative analysis due to its high contrast.

[0208] The above results show that bone cement provides effective support at the bone defect site and prevents the occurrence of bone necrosis. At the same time, its good biocompatibility is also conducive to bone tissue regeneration, and ultimately can achieve a bone repair effect that is no less than that of PMMA.

[0209] In summary, the injectable, biodegradable high-strength porous bone cement of the present invention has good injection performance, a long operation period, can be quickly cured at 37°C, and the curing process is not exothermic. At the same time, the bone cement has high strength and elasticity after curing, does not disintegrate when exposed to water, and the in vivo development effect can meet the needs of clinical surgery. In addition, the bone cement can also regulate the rheological properties of the bone cement slurry by adjusting the ratio of PEGS-OH to CPC, and adjust the mechanical properties after curing by adjusting iohexol. Among them, the sample with a ratio of PEGS-OH:CPC:iohexol of 2:3.2:4.8 has suitable injectability and the highest modulus. Therefore, the bone cement of the present invention can be used for irregular bone defects, and it promotes bone regeneration while playing a filling and supporting role. It is an injectable bone cement material with clinical application prospects.

[0210] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. An injectable bone cement composition, It is characterized in that The injectable bone cement composition comprises: A liquid phase component, wherein the liquid phase component is a polyester polymer or a mixture of a polyester polymer and a catalyst; A solid phase component, wherein the solid phase component is a mixture of a calcium phosphate salt and a developer; wherein the calcium phosphate salt is selected from one or a mixture of two or more of tetracalcium phosphate, monocalcium phosphate, and tricalcium phosphate; The developer is selected from: iohexol and iopamidol; The mass ratio of the liquid phase component to the solid phase component is 0.5:9.5-5:5; The mass ratio of the calcium phosphate salt to the developer is 1:9 to 9:1; The injectable bone cement composition further comprises a cross-linking agent; Wherein, the polyester polymer is polyhydroxy polyethylene glycol polyglycerol sebacate PEGS-OH, The structural unit of polyhydroxy polyethylene glycol polysebacic acid glycerol PEGS-OH is shown in Formula Ia or Formula Ib: Wherein, in Formula Ia, m 1 An integer from 1 to 20, n 1 An integer from 5 to 60; In Formula Ib, m 2 An integer from 1 to 20, n 2 An integer from 5 to 60.

2. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the polyester polymer to the catalyst is 1:0.00001-0.

5.

3. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the polyester polymer to the catalyst is 1:0.00005-0.

002.

4. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the polyester polymer to the catalyst is 0.0001-0.0005.

5. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the calcium phosphate salt to the developer is 2:8 to 8:

2.

6. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the calcium phosphate salt to the developer is 3:7 to 7:

3.

7. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the calcium phosphate salt to the developer is 3:7 to 5:

5.

8. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the calcium phosphate salt to the developer is 4:6 to 6:

4.

9. The injectable bone cement composition according to claim 1, It is characterized in that The developer and the PEGS-OH are combined through chemical bonds.

10. The injectable bone cement composition according to claim 1, It is characterized in that In Formula Ia, m 1 An integer between 2 and 18, n 1 An integer between 10 and 50; In Formula Ib, m 2 An integer between 2 and 18, n 2 An integer from 10 to 50.

11. The injectable bone cement composition according to claim 1, It is characterized in that In formula Ia, m 1 is an integer from 5 to 15, and n 1 is an integer from 20 to 40; In Formula Ib, m 2 An integer between 5 and 15, n 2 An integer between 20 and 40.

12. The injectable bone cement composition according to claim 1, It is characterized in that In Formula Ia, m 1 An integer between 2 and 8, n 1 An integer between 30 and 50; In Formula Ib, m 2 An integer between 2 and 8, n 2 An integer between 30 and 50.

13. The injectable bone cement composition according to claim 1, It is characterized in that The dispersion coefficient of the polyester polymer is 1.1-2.

0.

14. The injectable bone cement composition according to claim 1, It is characterized in that The catalyst is an organic metal catalyst.

15. The injectable bone cement composition according to claim 1, It is characterized in that In Formula Ia, m 1 is an integer between 8 and 10, n 1 An integer between 8 and 35; In Formula Ib, m 2 is an integer between 8 and 10, n 2 An integer from 8 to 35.

16. The injectable bone cement composition according to claim 1, It is characterized in that The cross-linking agent is a diisocyanate cross-linking agent.

17. The injectable bone cement composition according to claim 16, It is characterized in that The cross-linking agent is L-lysine diisocyanate LDI, hexamethylene diisocyanate, toluene diisocyanate.

18. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the polyester polymer to the cross-linking agent is 1:0.25-2.

19. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the polyester polymer to the cross-linking agent is 1:0.25-0.

5.

20. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the polyester polymer to the cross-linking agent is 1:0.3-0.

4.

21. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the polyester polymer to the cross-linking agent is 1:0.

365.

22. The injectable bone cement composition of claim 16, It is characterized in that The polyester polymer is polyhydroxy polyethylene glycol polysebacic acid glycerol PEGS-OH, and the amount of isocyanate groups in the cross-linking agent is 0.5-2 times the amount of hydroxyl groups in the PEGS-OH.

23. The injectable bone cement composition of claim 16, It is characterized in that The amount of isocyanate groups in LDI is 1-1.5 times the amount of hydroxyl groups in PEGS-OH.

24. The injectable bone cement composition according to claim 1, It is characterized in that The mass ratio of the liquid phase component to the solid phase component is 2:

8.

25. An injectable bone cement, It is characterized in that The injectable bone cement is obtained by mixing the liquid phase component and the solid phase component of the injectable bone cement composition according to any one of claims 1 to 24 and a cross-linking agent.

26. The injectable bone cement according to claim 25, It is characterized in that The storage modulus of the injectable bone cement during injection is 10 3 -4×10 4 Pa; The loss modulus of the injectable bone cement during injection is 2×10 3 -4×10 5 Pa.

27. The injectable bone cement according to claim 25, It is characterized in that The curing time of the injectable bone cement is 15 to 30 minutes.

28. A kit for preparing the injectable bone cement according to any one of claims 25 to 27, wherein the kit include: (a) a first container, and a liquid component located in the container; (b) a second container, and a solid phase component located in the container; (c) a third container, and a cross-linking agent located in the container; In the first container, the liquid phase component exists in the form of a viscous liquid; in the second container, the solid phase component exists in the form of a powder; In the third container, the cross-linking agent is present in liquid form.

29. Use of the injectable bone cement according to any one of claims 25 to 27, It is characterized in that Used for: (i) preparing tissue defect filling materials; (ii) preparing materials for guiding tissue regeneration; (iii) preparing medical cosmetic materials; (iv) 3D printing matrix materials; (v) A loading matrix or carrier for growth factors or drugs.

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