Two-component modified bone cement composition, modified bone cement material and use thereof

Abstract

The application provides a two-component modified bone cement composition, a modified bone cement material and application thereof, and belongs to the technical field of biomedical materials. The two-component modified bone cement composition comprises a bone cement powder and a modified bone cement liquid. The bone cement powder comprises, in percentage by mass, 98.5-99.99% of an acrylate polymer and 0.01-1.5% of an initiator. The modified bone cement liquid comprises a modifier and a bone cement liquid in a volume ratio of 1:1-20. The bone cement liquid comprises, in percentage by mass, 94.5-99.98% of an acrylate monomer, 0.01-5% of a stabilizer and 0.01-1.5% of an accelerator. The modifier is polyethylene glycol.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biomedical materials, in particular to a two-component modified bone cement composition, a modified bone cement material and application thereof. BACKGROUND

[0002] Osteoporotic vertebral compression fractures (OVCF) are common diseases in the elderly population. To treat this orthopedic disease, two minimally invasive surgical techniques, percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP), are widely used in clinical practice. The core of these two techniques is to inject bone cement into the damaged or collapsed vertebral body to quickly stabilize the fractured vertebral body, relieve pain and restore vertebral height.

[0003] Among them, poly(methyl methacrylate) (PMMA) bone cement has become the most widely used vertebral augmentation filling material in clinical practice due to its excellent injectability, rapid curing ability, high mechanical strength, good biocompatibility and relatively low cost. However, PMMA bone cement has inherent defects in long-term clinical application, which limits the treatment effect and may cause serious postoperative complications and long-term risks.

[0004] In terms of mechanical properties, as a filling and fixing material, the mechanical property matching degree of PMMA bone cement with the surrounding bone tissue is the key to the long-term success of the operation. The current commercial PMMA bone cement has a structure that is too dense and hard, and its mechanical properties differ greatly from human cancellous bone. The overall mechanical properties are 1-2 orders of magnitude higher than human cancellous bone, resulting in a sudden change in stiffness between the augmented vertebral body and the adjacent untreated vertebral body, and abnormal stress distribution greatly increases the risk of secondary fracture of adjacent vertebral bodies (AVF). Many studies have shown that the incidence of secondary fracture of adjacent vertebral bodies after PVP / PKP is as high as 7-27.7%, and such secondary fractures can cause patients to suffer severe pain again, aggravate spinal deformity, and even require complex revision surgery.

[0005] Therefore, reducing the mechanical strength of PMMA bone cement and developing low-modulus bone cement that matches the mechanical properties of human cancellous bone is a key direction to improve its clinical defects. Currently, methods such as adding pore-forming agents, changing the powder-liquid ratio or adding plasticizers have been tried to reduce the elastic modulus of PMMA bone cement, but these methods generally have problems such as complex process, excessive loss of mechanical properties or poor biocompatibility. SUMMARY

[0006] To solve the above technical problems, the present application provides a two-component modified bone cement composition, a modified bone cement material and its application, so as to at least partially solve the above technical problems, and the specific technical solutions provided by the present application are as follows.

[0007] As a first aspect of the present application, a two-component modified bone cement composition is provided, comprising a bone cement powder and a modified bone cement liquid. The bone cement powder comprises, in terms of mass percentage: an acrylate polymer, 98.5-99.99%; an initiator, 0.01-1.5%. The modified bone cement liquid comprises a modifier and a bone cement liquid in a volume ratio of 1:1-20. The bone cement liquid comprises, in terms of mass percentage: an acrylate monomer, 94.5-99.98%; a stabilizer, 0.01-5%; an accelerator, 0.01-1.5%. The modifier is polyethylene glycol.

[0008] As a second aspect of the present application, a modified bone cement material is provided, which is obtained by mixing and polymerizing the modified bone cement liquid and the bone cement powder in the two-component modified bone cement composition described above at a water-to-powder ratio of 0.4 mL / g-0.6 mL / g.

[0009] As a third aspect of the present application, the application of a modified bone cement material is provided, including at least one of the following: application in bone filling materials for treating osteoporotic fractures; application in bone filling materials for repairing maxillofacial bone defects; application in bone filling materials for repairing dental bone defects; application in bone filling materials for orthopedic filling; application in bone filling materials for treating infectious arthritis; application in bone filling materials for repairing bone defects in joint replacement surgery; application in bone filling materials for treating infectious diabetic foot.

[0010] In the embodiments of the present application, polyethylene glycol (PEG) is selected as the modifier, which is first added to the bone cement liquid component containing an acrylate monomer, a stabilizer and an accelerator to obtain a modified bone cement liquid, and then the modified bone cement liquid is uniformly mixed with the bone cement powder to finally obtain a modified polymethyl methacrylate (PMMA) bone cement material. The modified bone cement material not only has mechanical properties matching human cancellous bone and good biocompatibility, but also has a rich micro-porous structure on the surface and inside of the modified bone cement material, which is beneficial to the growth of bone cells, nutrient transport and metabolic waste discharge. At the same time, by adjusting the amount of PEG added, the mechanical properties of the modified bone cement material can be precisely controlled to meet different clinical application requirements. BRIEF DESCRIPTION OF DRAWINGS

[0011] Figure 1 Scanning electron microscope image of the surface of the bone cement material prepared in Comparative Example 1 of the present application;

[0012] Figure 2 Scanning electron microscope image of the cross section of the bone cement material prepared in Inventive Example 1 of the present application;

[0013] Figure 3 Scanning electron microscope image of the surface of the modified bone cement material prepared in Inventive Example 1 of the present application;

[0014] Figure 4 Scanning electron microscope image of the cross section of the modified bone cement material prepared in Inventive Example 1 of the present application;

[0015] Figure 5 Infrared spectrogram of the bone cement material in Inventive Example 1 and Comparative Example 1 of the present application;

[0016] Figure 6 Differential scanning calorimetry graph of the bone cement material in Inventive Example 1 and Comparative Example 1 of the present application;

[0017] Figure 7 Thermal stability test graph of the bone cement material in Inventive Example 1 and Comparative Example 1 of the present application;

[0018] Figure 8 Elastic modulus comparison graph of the bone cement material in Inventive Example 1-3 and Comparative Example 1 of the present application;

[0019] Figure 9 Compressive strength comparison graph of the bone cement material in Inventive Example 1-3 and Comparative Example 1 of the present application;

[0020] Figure 10 Flexural strength comparison graph of the bone cement material in Inventive Example 1-3 and Comparative Example 1 of the present application;

[0021] Figure 11 Flexural modulus comparison graph of the bone cement material in Inventive Example 1-3 and Comparative Example 1 of the present application;

[0022] Figure 12 1-day result graph of in vitro cell compatibility test of the bone cement material in Inventive Example 1-3 and Comparative Example 1 of the present application;

[0023] Figure 13 3-day result graph of in vitro cell compatibility test of the bone cement material in Inventive Example 1-3 and Comparative Example 1 of the present application;

[0024] Figure 14 Flexural strength comparison graph of the bone cement material in Inventive Example 7 and Comparative Example 2 of the present application;

[0025] Figure 15 Flexural modulus comparison graph of the bone cement material in Inventive Example 7 and Comparative Example 2 of the present application;

[0026] Figure 16 Figure 1 is a bending strength comparison chart of the bone cement materials in the present application comparative example 1, comparative example 4 and example 1;

[0027] Figure 17 Figure 2 is a bending modulus comparison chart of the bone cement materials in the present application comparative example 1, comparative example 4 and example 1;

[0028] Figure 18 Figure 3 is an infrared spectrum chart of the bone cement materials in the present application comparative example 1, comparative example 4 and example 1. DETAILED DESCRIPTION

[0029] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to specific embodiments and drawings.

[0030] In the process of realizing the concept of the present application, it is found that polyethylene glycol (PEG) is widely used in the fields of drug manufacturing, material modification, chemical synthesis, etc. as a water-soluble, non-toxic and biocompatible polyether polymer, but there is currently little research on using it to improve the mechanical properties of PMMA bone cement. The existing PMMA bone cement is not matched with human cancellous bone in terms of elastic modulus, which easily causes secondary vertebral fracture after surgery, and the existing modification methods have many defects.

[0031] Based on this, the present application provides a two-component modified bone cement composition, a modified bone cement material and its application, aiming to obtain a modified bone cement material with suitable elastic modulus, good biocompatibility and simple preparation by PEG modification, so as to reduce the risk of secondary vertebral fracture after PVP / PKP surgery.

[0032] As a first aspect of the present application, a two-component modified bone cement composition is provided, comprising a bone cement powder and a modified bone cement liquid. The bone cement powder comprises, in terms of mass percentage: an acrylate polymer, 98.5-99.99%; an initiator, 0.01-1.5%. The modified bone cement liquid comprises a modifier and a bone cement liquid in a volume ratio of 1:1-20. The bone cement liquid comprises, in terms of mass percentage: an acrylate monomer, 94.5-99.98%; a stabilizer, 0.01-5%; a promoter, 0.01-1.5%. The modifier is polyethylene glycol.

[0033] In the embodiments of the present application, polyethylene glycol is used as a modifier to be compounded with the liquid component of bone cement in a specific volume ratio (1:1-20), and then mixed with the powder component containing acrylate polymer and initiator. On the one hand, the excellent biocompatibility of polyethylene glycol improves the overall biological safety of the modified bone cement material and reduces the risk of inflammation in clinical application. On the other hand, the modification of PMMA bone cement material by polyethylene glycol makes the mechanical properties (such as elastic modulus) of the modified bone cement material well matched with human cancellous bone, effectively reducing the stress shielding effect and the risk of secondary fracture of adjacent vertebral bodies after operation. At the same time, the two-component design retains the original injectability and rapid curing characteristics of the modified bone cement material, and the preparation process is simple, which meets the needs of clinical operation.

[0034] In some embodiments, the molecular weight of polyethylene glycol is 200-800. PEG with this molecular weight range is in liquid state at room temperature, has excellent compatibility with the liquid component of bone cement, and can be quickly and uniformly dispersed in the system to avoid local aggregation affecting the modification effect. The length of its molecular chain is moderate, which can effectively weaken the intermolecular force of modified PMMA and accurately control the elastic modulus of the modified bone cement material to match the range of human cancellous bone, and can also avoid excessive decay of mechanical properties due to excessive molecular weight, ensuring the core bearing strength of the modified bone cement material. At the same time, the biocompatibility of this molecular weight PEG has been clinically verified, and the synergistic effect with bone cement material can reduce the risk of inflammation without affecting the injectability and curing rate of the modified bone cement material.

[0035] In some embodiments, the acrylate monomer is at least one selected from the group consisting of methyl methacrylate, ethyl methacrylate, butyl methacrylate, hydroxyethyl methacrylate, methyl acrylate, ethyl acrylate, n-butyl acrylate, isobutyl acrylate, 2-ethylhexyl acrylate, n-octyl acrylate, isooctyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, isopropyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, hexyl methacrylate, 2-hydroxyethyl methacrylate, and 2-hydroxypropyl methacrylate. In addition to the above-mentioned acrylate monomers, other acrylate monomers that can be used in medical treatment can also be used.

[0036] In some embodiments, the acrylate-based polymer is selected from polymethyl methacrylate, or a copolymer of methyl methacrylate with one or more of the acrylate-based monomers and / or styrene described above. Among them, the polymethyl methacrylate is a homopolymer of methyl methacrylate. By copolymerizing methyl methacrylate with one or more of the acrylate-based monomers and / or styrene, other groups are introduced compared with polymethyl methacrylate, and the amount of acrylate-based monomers and / or styrene is adjusted to adjust the strength and rigidity of the acrylate-based polymer. At the same time, it can also give more excellent properties such as toughness, processability, weather resistance, etc. on the basis of maintaining rigidity and strength.

[0037] In some embodiments, the stabilizer is selected from at least one of hydroquinone, 2,6-di-tert-butyl-p-cresol. The main role of the stabilizer is to prevent the acrylate-based monomer from premature polymerization during mixing and curing, maintain plasticity and flowability, and facilitate surgical operation.

[0038] In some embodiments, the accelerator is selected from at least one of p-methyl methacrylate, N,N-dimethyl-p-toluidine. The main role of the accelerator is to improve the polymerization reaction rate of the modified bone cement material after the modified bone cement liquid is mixed with the bone cement powder.

[0039] In some embodiments, the initiator is selected from at least one of benzoyl peroxide, sodium persulfate, ammonium persulfate. The main role of the initiator is to provide active radicals in the initial stage before the polymerization reaction occurs after the bone cement powder and the modified bone cement liquid are mixed, causing the polymerization reaction to occur and promoting the formation of modified PMMA molecular chains.

[0040] In some embodiments, the bone cement powder further comprises a developing agent. The content of the developing agent in the bone cement powder is 10-30% by mass percentage. Among them, the developing agent is selected from any one of barium sulfate, zirconium oxide, sodium diatrizoate. Adding a developing agent can enhance the visibility of the modified bone cement material in medical images such as X-rays, CT, etc. By adding a developing agent, the distribution of the modified bone cement material, whether it is uniformly filled, and whether there are leaks and other problems can be more accurately observed, thereby ensuring the surgical effect. After the operation, the curing of the modified bone cement material, the degree of combination with the surrounding tissue, and whether there are complications, etc. can be evaluated through medical images.

[0041] As a second aspect of the present application, a modified bone cement material is provided, which is obtained by mixing and polymerizing the modified bone cement liquid and the bone cement powder in the two-component modified bone cement composition described above at a water-powder ratio of 0.4 mL / g-0.6 mL / g.

[0042] In some embodiments, the modified bone cement material surface and interior form a rich microporous structure, and the elastic modulus thereof is ≤0.6 GPa, which is highly matched with the mechanical properties of human cancellous bone, and can effectively reduce the stress shielding effect after surgery.

[0043] In the embodiments of the present application, the microporous structure of the modified bone cement material is realized by regulating the polymerization and curing process of the modified bone cement material by PEG. The core mechanism is based on the difference in thermodynamic compatibility of PEG in different systems. When PEG is introduced into the modified bone cement material, due to the thermodynamic incompatibility between PEG and the modified PMMA, as the acrylate monomers gradually polymerize to form long-chain modified PMMA macromolecules, the PEG in the system presents two forms: part of the PEG will be embedded in the modified PMMA crosslinked network and connected to the modified PMMA macromolecules through physical bonding, playing a softening and plasticizing effect; the other part will gradually separate from the modified PMMA phase due to the increasing polarity difference, causing the two-phase separation of PEG and modified PMMA, i.e., from homogeneous to heterogeneous structure, forming a large number of PEG-rich microzones. These PEG microzones distributed on the surface and in the matrix of the modified bone cement material constitute the core forming sites of the pores. During the polymerization reaction, the synergistic effect of free radical action and reaction heat release in the modified bone cement material promotes the gradual degradation and volatilization of PEG in the microzones; after the modified bone cement material is completely cured, pores are formed at the positions of the original PEG microzones, and finally the modified bone cement material presents a microporous structure. The whole micropore formation process makes full use of the difference in thermodynamic compatibility of PEG in the acrylate monomer solution and in the modified PMMA phase.

[0044] The two processes of molecular chain plasticization and phase structure transformation together cause changes in the chemical environment of PMMA molecular chains, increase the free volume of the environment in which PMMA molecular chains exist, reduce the degree of constraint between chains, and enhance the activity of PMMA molecular chains, which directly lays the foundation for the softening of the macroscopic mechanical properties.

[0045] Specifically, the present application provides a preparation method of a modified bone cement material, and the specific process is as follows.

[0046] Polyethylene glycol (PEG) with good fluidity at room temperature is selected as a modifier; the PEG is added to the bone cement liquid containing acrylate monomers, stabilizers and accelerators in a certain proportion, and a modified bone cement liquid is obtained after mixing uniformly; the modified bone cement liquid is mixed with bone cement powder containing acrylate polymers, developing agents and initiators in a certain proportion, and is fully stirred to occur polymerization and curing reaction, and a modified bone cement material is obtained.

[0047] As a third aspect of the present application, there is provided an application of a modified bone cement material, including at least one of the following: an application in a bone filling material for treating osteoporotic fractures; an application in a bone filling material for repairing maxillofacial bone defects; an application in a bone filling material for repairing dental bone defects; an application in a bone filling material for orthopedic filling; an application in a bone filling material for treating infectious arthritis; an application in a bone filling material for repairing bone defects in joint replacement surgery; an application in a bone filling material for treating infectious diabetic foot.

[0048] The present application significantly reduces the elastic modulus of the modified bone cement material (which can be reduced to below 0.6 GPa) by adding liquid PEG as a modifier, so that it matches the mechanical properties of human cancellous bone, reduces the stress shielding effect, and further reduces the risk of secondary fracture of adjacent vertebral bodies caused by vertebral body strengthening with bone cement. PEG, as a biocompatible polymer material, effectively improves the overall biocompatibility of the modified bone cement material and reduces inflammation. At the same time, PEG plays a pore-forming role in the curing process of the modified bone cement material, forming a rich microporous structure on the surface and inside of the modified bone cement material, which is conducive to bone cell growth, nutrient transport and metabolic waste discharge, and promotes bone integration. In addition, by adjusting the amount of PEG added, the distribution density of micropores in the modified bone cement material can be changed, allowing precise control of the mechanical properties of the modified bone cement material to meet different clinical application requirements. The preparation method of the modified bone cement material is simple and easy to implement, does not require complex equipment and rich experience, and is suitable for industrial production.

[0049] The present application is further illustrated by the following examples and related test experiments. In the following detailed description, many specific details are set forth in order to provide a thorough understanding of the embodiments of the present application. However, it is apparent that one or more embodiments can be practiced without these specific details. In addition, the details in each of the following embodiments can be combined with each other to form other feasible embodiments without conflict. All instruments, consumables and reagents, etc. in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0050] Comparative Example 1

[0051] A PMMA bone cement material was prepared in this comparative example, and the specific preparation method was as follows:

[0052] 98.49 wt% methyl methacrylate (MMA), 0.01 wt% hydroquinone (stabilizer) and 1.5 wt% N,N-dimethyl-p-toluidine (accelerator) were thoroughly mixed and uniformly mixed to obtain a bone cement liquid.

[0053] The above-mentioned bone cement liquid was mixed with bone cement powder containing 68.5 wt% PMMA (molecular weight 800,000) powder microspheres, 30 wt% sodium diatrizoate (developer) and 1.5 wt% benzoyl peroxide (initiator) at a water-to-powder ratio of 0.5 mL / g. After stirring for 4 min, the mixture was poured into a mold and polymerized and cured at room temperature for 1 h to obtain PMMA bone cement material.

[0054] Example 1

[0055] In Example 1, a modified bone cement material was prepared. The specific preparation method is as follows:

[0056] Liquid PEG with a molecular weight of 400 was added to bone cement liquid containing 98.49 wt% methyl methacrylate (MMA), 0.01 wt% hydroquinone (stabilizer), and 1.5 wt% N,N-dimethyl-p-toluidine (accelerator) at a volume ratio of 1:3, and the mixture was thoroughly mixed to obtain modified bone cement liquid.

[0057] The modified bone cement liquid was mixed with bone cement powder containing 68.5 wt% polymethyl methacrylate (PMMA, molecular weight 800,000) powder microspheres, 30 wt% BaSO4 (developer) and 1.5 wt% benzoyl peroxide (initiator) at a water-to-powder ratio of 0.5 mL / g. After stirring for 4 min, the mixture was poured into a mold and polymerized and cured at room temperature for 1 h to obtain the modified bone cement material.

[0058] The structures of the bone cement material in Comparative Example 1 and the modified bone cement material in Example 1 were characterized as follows.

[0059] Figure 1 This is a scanning electron microscope image of the surface of the bone cement material prepared in Comparative Example 1 of the present invention; Figure 2 This is a scanning electron microscope image of the cross-section of the bone cement material prepared in Comparative Example 1 of the present invention; Figure 3 This is a scanning electron microscope image of the surface of the modified bone cement material prepared in Example 1 of the present invention; Figure 4 This is a scanning electron microscope image of the cross-section of the modified bone cement material prepared in Example 1 of the present invention.

[0060] from Figures 1-4 As can be seen from this, the bone cement material in Comparative Example 1 ( Figure 1 surface, Figure 2 The cross-section has a dense structure: the surface is relatively flat with no obvious pores, and the cross-section exhibits a uniform and dense morphology; while the modified bone cement material of Example 1 ( Figure 3 surface, Figure 4The cross-section forms a porous structure: the surface is covered with a large number of dispersed micropores, the cross-section presents a rich porous network, and the interior has a uniformly distributed microporous structure with a pore size range of 1-4μm. This indicates that PEG modification effectively transforms PMMA bone cement material from a dense structure to a porous structure, and there is a significant difference in morphology compared with unmodified bone cement material.

[0061] Figure 5 The infrared spectra of the bone cement materials in Comparative Example 1 and Example 1 of this invention are shown.

[0062] from Figure 5 It can be seen that the unmodified bone cement material exhibits characteristic absorption peaks such as CH and C=O; while the modified bone cement material, in addition to retaining the above characteristic peaks of PMMA, also shows the addition of characteristic absorption peaks of OH (corresponding to the hydroxyl group of PEG) and COC (corresponding to the ether bond of PEG). This result indicates that PEG has been successfully introduced into the PMMA bone cement system, confirming that the modified bone cement material incorporates PEG components in its structure, showing a significant difference from the structure of the unmodified bone cement material.

[0063] Figure 6 Differential scanning calorimetry (DSC) images of bone cement materials in Comparative Example 1 and Example 1 of this invention are shown.

[0064] from Figure 6 It can be seen that the glass transition temperature (T) of unmodified bone cement materials g The temperature of the modified bone cement material is 102.9℃, while the temperature of the modified bone cement material is 102.9℃. g The temperature dropped to 69.8℃. This change is due to the introduction of PEG: on the one hand, PEG is embedded in the PMMA crosslinking network, reducing the packing density between molecular chains and increasing the free volume of the system, making it easier for chain segments to begin moving at lower temperatures; on the other hand, the polymerization reaction induces phase separation and phase structure transformation, forming PEG microregions in the PMMA system (consistent with the results shown by scanning electron microscopy). After phase separation, the PMMA-PEG phase interface becomes the "active region" for chain segment movement. Compared with the high rigidity constraint of PMMA-PMMA chain segments in the pure PMMA system, the PMMA chain segments at the interface are subjected to lower constraint due to the low modulus environment of the surrounding PEG phase, and their relaxation activation energy is significantly reduced, allowing PMMA chain segments to achieve cooperative movement at lower temperatures. Therefore, the glass transition temperature drops significantly. The decrease in glass transition temperature means that at physiological temperatures (37℃), the glass transition temperature can be lowered. oC) Down, the shift of the material bulk from rigid glassy state to flexible high-elastic state, the modified PMMA cement material is in a state closer to high-elastic state, and the molecular chains and segments have higher activity. The elastic modulus and strength of the cement material reach the highest in the glassy state, and when the modified cement material is "softer" and "tougher" due to the decrease of the glass transition temperature, its resistance to deformation (modulus) and resistance to damage (strength) will decrease. Therefore, the decrease of the glass transition temperature is one of the fundamental reasons for the decrease of the macro modulus and strength of the modified cement material.

[0065] Figure 7 The thermal stability test graph of the cement material in Comparative Example 1 and Example 1 of the present application.

[0066] From Figure 7 It can be seen that there is a difference in the thermal weight loss behavior between the unmodified cement material and the modified cement material: the modified cement material has a slight weight loss at a lower temperature range (before about 200°C), and the initial weight loss temperature of the unmodified cement material is relatively higher; in the subsequent high temperature section, the weight loss trends of the two gradually approach, but the introduction of PEG slightly reduces the initial thermal stability of the modified cement material, which is related to the thermal decomposition characteristics of PEG itself, and reflects the influence of PEG modification on the thermal stability of the modified cement material.

[0067] Example 2

[0068] In this Example 2, a modified cement material is prepared, and the specific preparation method is as follows:

[0069] Liquid PEG with a molecular weight of 400 is added to the cement liquid containing 98.49wt% MMA, 0.01wt% hydroquinone (stabilizer) and 1.5wt% N,N-dimethyl-p-toluidine (accelerator) at a volume ratio of 1:4, and is fully mixed and uniform, to obtain a modified cement liquid.

[0070] The above modified cement liquid is mixed with the cement powder containing 68.5wt% PMMA (molecular weight 800,000) powder microspheres, 30wt% BaSO4 (developer) and 1.5wt% benzoyl peroxide (initiator) at a water-powder ratio of 0.5mL / g, and after stirring for 4min, it is injected into a mold, and is polymerized and cured at room temperature for 1h to obtain a modified cement material.

[0071] Example 3

[0072] In this Example 3, a modified cement material is prepared, and the specific preparation method is as follows:

[0073] The liquid PEG with a molecular weight of 400 was added into the cement liquid containing 98.49 wt% MMA, 0.01 wt% hydroquinone (stabilizer) and 1.5 wt% N,N-dimethyl-p-toluidine (accelerator) at a volume ratio of 1:5, and was mixed uniformly to obtain a modified cement liquid.

[0074] The modified cement liquid was mixed with the cement powder containing 68.5 wt% PMMA (molecular weight 800,000) powder microspheres, 30 wt% BaSO4 (developer) and 1.5 wt% benzoyl peroxide (initiator) at a water / powder ratio of 0.5 mL / g, and was injected into a mold after stirring for 4 min, and was polymerized and cured at room temperature for 1 h to obtain a modified cement material.

[0075] Further, the mechanical properties of the cement materials obtained in Example 1-Example 3 and Comparative Example 1 were tested. The test method is as follows:

[0076] Bending strength and bending modulus: determined according to the standard test method ISO-5833-2002 using a universal electronic testing machine (WDW-20, China). A cuboid sample with a length of 75 mm, a width of 10 mm and a thickness of 3.5±0.2 mm was placed on the universal electronic testing machine, and a three-point bending test was performed at a speed of 5 mm / min until the sample failed, and the bending strength and bending modulus of the sample were calculated according to formula (1) and formula (2).

[0077] Formula (1).

[0078] Formula (2).

[0079] Wherein, B is the bending strength, F is the force at which the sample fails, a is the distance between the inner and outer load points, b is the sample width, h is the sample height; E is the bending modulus, Δ is the load range, l is the distance between the outer loads, and f is the difference between the corresponding deflections at a load of 15 N and 50 N.

[0080] Compressive strength and elastic modulus: a cylindrical sample with a diameter of 6 mm and a height of 12 mm was placed on a universal electronic testing machine, and the compressive strength and elastic modulus were tested at a speed of 20 mm / min until the upper yield point or the sample failed. The compressive strength was obtained by dividing the pressure corresponding to the upper yield point by the original cross-sectional area, and the elastic modulus was obtained from the slope of the elastic phase in the stress-strain curve.

[0081] Figure 8 Figure 1 is a comparison chart of the elastic modulus of the cement materials in Example 1-Example 3 and Comparative Example 1 of the present application; Figure 9 Figure 2 is a comparison chart of the compressive strength of the cement materials in Example 1-Example 3 and Comparative Example 1 of the present application;Figure 10 Figure 1 is a graph showing the comparison of the bending strength of the bone cement materials in Example 1-3 and Comparative Example 1 of the present application; Figure 11 Figure 2 is a graph showing the comparison of the bending modulus of the bone cement materials in Example 1-3 and Comparative Example 1 of the present application.

[0082] From Figures 8-11 It can be seen that with the increase of the PEG addition amount, the mechanical properties of the modified bone cement materials gradually decrease: the elastic modulus (0.833 GPa), compressive strength (76.961 MPa), bending strength (48.416 MPa), and bending modulus (2.038 GPa) of the bone cement material in Comparative Example 1 are the highest; with the PEG proportion rising to 15% (Example 3), 20% (Example 2), and 25% (Example 1), the properties gradually decrease, and the elastic modulus and bending modulus of Example 1 (25% PEG) have significantly decreased, and are more close to the mechanical properties of human cancellous bone.

[0083] Further, the compatibility of the bone cement materials obtained in the above examples and comparative examples is tested. The testing method is as follows:

[0084] A cylindrical sample with a diameter of 6 mm and a height of 12 mm is placed in a sterile test tube, 10 mL of cell culture solution is poured into the test tube, and a sample extract is prepared, which is used for subsequent cell experiments. A mouse cell strain (MC3T3-E1) provided by Nankai University (Tianjin, China) is selected to evaluate the cell compatibility of the bone cement material. The composition of the cell culture solution for culturing MC3T3 cells is: 89% (v / v) a minimum essential medium (a-MEM), 10% (v / v) fetal bovine serum, and 1% (v / v) double-antibiotic (penicillin and streptomycin). When culturing the cells, 2.5×10 4 cells are planted on a 96-well transparent cell culture plate, and after 24 hours of culture, the culture medium is removed and replaced with a sample extract. After 1 day and 3 days of culture, the culture solution is replaced with 0.5 mg / mL thiazolyl blue tetrazolium bromide (MTT), and incubated in a cell culture box for 4 h, then the MTT solution is removed, and an equal amount of Formazan is added, and then placed on a constant temperature shaker at 60 rpm for gentle shaking for 20 minutes. After complete dissolution, the absorption at 490 nm is recorded by a microplate reader (Synergy H1, USA). Each sample is in six replicates, and the cell survival rate is calculated according to formula (3). Wherein, OD 提取 is the absorbance value measured at 490 nm after MTT treatment and Formazan dissolution of the cells cultured by the sample extract; OD 对照The absorbance value measured at 490 nm after the same MTT-Formazan procedure was performed on cells cultured in a conventional cell culture medium without sample extract treatment.

[0085] Formula (3).

[0086] Figure 12 Figure for 1-day results of in-vitro cell compatibility test of the bone cement material in Example 1-Example 3 and Comparative Example 1 of the present application; Figure 13 Figure for 3-day results of in-vitro cell compatibility test of the bone cement material in Example 1-Example 3 and Comparative Example 1 of the present application.

[0087] From Figure 12 and Figure 13 It can be seen that the cell survival rate of the bone cement of Comparative Example 1 and each example is at a high level; with the increase of the PEG addition amount, the cell survival rate shows an overall upward trend: the cell survival rate of Example 1 (25% PEG) reaches 116.2% at 1 day, and further increases to 126.24% at 3 days, which is significantly higher than that of Comparative Example 1. This shows that the PEG modification does not reduce the cell compatibility of the bone cement material, but rather improves the in-vitro biocompatibility thereof, and the higher the addition amount, the better the cell proliferation effect.

[0088] To study the influence of the introduction of different molecular weight polyethylene glycol (PEG) and different flexible polymer chains on the performance of the modified bone cement material, the following examples and comparative examples are prepared.

[0089] Example 4

[0090] In this Example 4, a modified bone cement material is prepared, and the specific preparation method is as follows:

[0091] Liquid PEG with a molecular weight of 600 is added to the bone cement liquid containing 98.49wt% MMA, 0.01wt% hydroquinone (stabilizer) and 1.5wt% N,N-dimethyl-p-toluidine (accelerator) at a volume ratio of 1:4, and is fully mixed and uniform, to obtain a modified bone cement liquid.

[0092] The above modified bone cement liquid is mixed with the bone cement powder containing 68.5wt% PMMA (molecular weight 800,000) powder microspheres, 30wt% BaSO4 (developer) and 1.5wt% benzoyl peroxide (initiator) at a water-powder ratio of 0.5mL / g, stirred for 3min, and then injected into a mold, and polymerized and cured at room temperature for 1h to obtain a modified bone cement material.

[0093] The modified bone cement material was prepared according to the following method: The liquid PEG with a molecular weight of 400 was added to the bone cement liquid containing 98.49wt% MMA, 0.01wt% hydroquinone (stabilizer) and 1.5wt% N,N-dimethyl-p-toluidine (accelerator) in a volume ratio of 1:3, and was fully mixed to obtain a modified bone cement liquid.

[0094] Example 5

[0095] The modified bone cement material was prepared according to the following method: The liquid PEG with a molecular weight of 400 was added to the bone cement liquid containing 98.49wt% MMA, 0.01wt% hydroquinone (stabilizer) and 1.5wt% N,N-dimethyl-p-toluidine (accelerator) in a volume ratio of 1:3, and was fully mixed to obtain a modified bone cement liquid.

[0096] The liquid PEG with a molecular weight of 200 and 400 was first mixed in a volume ratio of 1:1, and then added to the bone cement liquid containing 98.49wt% MMA, 0.01wt% hydroquinone (stabilizer) and 1.5wt% N,N-dimethyl-p-toluidine (accelerator) in a volume ratio of 1:4, and was fully mixed to obtain a modified bone cement liquid.

[0097] The modified bone cement liquid was mixed with the bone cement powder containing 68.5wt% PMMA (molecular weight 800,000) powder microspheres, 30wt% BaSO4 (developer) and 1.5wt% benzoyl peroxide (initiator) at a water-powder ratio of 0.5mL / g, stirred for 5min, and then injected into a mold, and was polymerized and cured at room temperature for 1h to obtain a modified bone cement material.

[0098] The modified bone cement material was prepared according to the following method: The liquid PEG with a molecular weight of 400 was added to the bone cement liquid containing 98.49wt% MMA, 0.01wt% hydroquinone (stabilizer) and 1.5wt% N,N-dimethyl-p-toluidine (accelerator) in a volume ratio of 1:3, and was fully mixed to obtain a modified bone cement liquid.

[0099] Example 6

[0100] The modified bone cement material was prepared according to the following method: The liquid PEG with a molecular weight of 400 was added to the bone cement liquid containing 98.49wt% MMA, 0.01wt% hydroquinone (stabilizer) and 1.5wt% N,N-dimethyl-p-toluidine (accelerator) in a volume ratio of 1:3, and was fully mixed to obtain a modified bone cement liquid.

[0101] The liquid PEG with a molecular weight of 400 was added to the bone cement liquid containing 98.49wt% MMA, 0.01wt% hydroquinone (stabilizer) and 1.5wt% N,N-dimethyl-p-toluidine (accelerator) in a volume ratio of 1:3, and was fully mixed to obtain a modified bone cement liquid.

[0102] The modified bone cement liquid was mixed with the bone cement powder containing 68.5wt% PMMA (molecular weight 800,000) powder microspheres, 30wt% BaSO4 (developer) and 1.5wt% benzoyl peroxide (initiator) at a water-powder ratio of 0.5mL / g, stirred for 5min, and then injected into a mold, and was polymerized and cured at room temperature for 1h to obtain a modified bone cement material.

[0103] The modified bone cement material of Example 6 was tested according to the above-mentioned mechanical property testing method, and the results showed that the elastic modulus of the modified bone cement material was 0.50 GPa, the compressive strength was 38.65 MPa, the bending strength was 19.78 MPa, and the bending modulus was 0.39 MPa.

[0104] Example 7

[0105] A modified bone cement material was prepared in this Example 7, and the specific preparation method was as follows:

[0106] Liquid PEG with a molecular weight of 400 was added to the bone cement liquid containing 98.49 wt% MMA, 0.01 wt% hydroquinone (stabilizer), and 1.5 wt% N,N-dimethyl-p-toluidine (accelerator) at a volume ratio of 3:7, and was fully mixed and uniform to obtain a modified bone cement liquid.

[0107] The above-mentioned modified bone cement liquid was mixed with the bone cement powder containing 98.5 wt% PMMA (molecular weight 800,000) powder microspheres and 1.5 wt% benzoyl peroxide (initiator) at a water-powder ratio of 0.5 mL / g, and was injected into a mold after stirring for 4 min, and was polymerized and cured at room temperature for 1 h to obtain a modified bone cement material.

[0108] Comparative Example 2

[0109] In this Comparative Example 2, a bone cement material was modified by another flexible long-chain polymer poly(ethylene glycol) methacrylate (PEGMA) which was liquid at room temperature, and the specific preparation method was as follows:

[0110] Liquid PEGMA at room temperature was added to the bone cement liquid containing 98.49 wt% MMA, 0.01 wt% hydroquinone (stabilizer), and 1.5 wt% N,N-dimethyl-p-toluidine (accelerator) at a volume ratio of 3:7, and was fully mixed and uniform to obtain a modified bone cement liquid.

[0111] The above-mentioned modified bone cement liquid was mixed with the bone cement powder containing 98.5 wt% PMMA (molecular weight 800,000) powder microspheres and 1.5 wt% benzoyl peroxide (initiator) at a water-powder ratio of 0.6 mL / g, and was injected into a mold after stirring for 5 min, and was polymerized and cured at room temperature for 1 h to obtain a modified bone cement material.

[0112] The bending strength and bending modulus of the bone cement materials in Example 7 and Comparative Example 2 were tested according to the above-mentioned mechanical property testing method.

[0113] Figure 14 The bending strength comparison chart of the bone cement materials in Example 7 and Comparative Example 2 of the present application is shown in Figure 1. Figure 15 The bending modulus comparison chart of the bone cement materials in Example 7 and Comparative Example 2 of the present application is shown in Figure 2.

[0114] From Figure 14 and Figure 15 It can be seen that the flexural strength (43.131 MPa) and flexural modulus (1.256 GPa) of the bone cement material in Comparative Example 2 are significantly higher than those in Example 7 at the same addition amount; the flexural strength of the bone cement material in Example 7 is reduced to 20.449 MPa, and the flexural modulus is reduced to 0.682 GPa. This shows that at an addition amount of 30%, using PEG instead of PEGMA can more effectively reduce the mechanical properties of the PMMA bone cement material, making the flexural modulus more close to the characteristics of human cancellous bone, and more suitable for clinical needs.

[0115] Comparative Example 3

[0116] Comparative Example 3 modifies the bone cement material by another flexible long-chain polymer triethylene glycol dimethacrylate (TEGDMA) which is liquid at room temperature. The specific preparation method is as follows:

[0117] The TEGDMA which is liquid at room temperature is added to the bone cement liquid containing 98.49wt% MMA, 0.01wt% hydroquinone (stabilizer) and 1.5wt% N,N-dimethyl-p-toluidine (accelerator) in a volume ratio of 3:7, and is fully mixed and uniform, to obtain a modified bone cement liquid.

[0118] The above modified bone cement liquid is mixed with the bone cement powder containing 98.5wt% PMMA (molecular weight 800,000) powder microspheres and 1.5wt% benzoyl peroxide (initiator) at a water-powder ratio of 0.6mL / g, and after stirring for 5min, it is injected into a mold, and is polymerized and cured at room temperature for 1h to obtain a modified bone cement material.

[0119] According to the above test method of mechanical properties, the results show that the flexural strength of the modified bone cement material in Comparative Example 3 is 61.96Mpa, and the flexural modulus is 2.29Gpa, which does not achieve the effect of effectively reducing the modulus of the PMMA bone cement material.

[0120] Although the modified substances added in Comparative Example 2 and Comparative Example 3 are both flexible long-chain polymers, they do not have the effect of softening and plasticizing PMMA. The reason is that flexible long-chain polymers cannot embed into the PMMA cross-linked network like low molecular weight PEG molecules to increase the free volume of the molecular chain, and the compatibility of the two modified substances in Comparative Example 2 and Comparative Example 3 with PMMA is good, and cannot cause obvious phase separation during the polymerization process, so it is difficult to reduce the high rigidity constraint of the PMMA molecular chain, and thus cannot achieve the effect of reducing the modulus.

[0121] Comparative Example 4

[0122] Comparative Example 4 modifies the bone cement material by another solid-state PEG at room temperature with high molecular weight (2000 molecular weight), and the specific preparation method is as follows:

[0123] A certain amount of solid-state PEG at room temperature with 2000 molecular weight is put into a mortar and ground thoroughly until the PEG is ground into a uniform powder form, and then added to the bone cement powder containing 68.5wt% PMMA (80 million molecular weight) powder microspheres, 30wt% BaSO4 (developer), and 1.5wt% benzoyl peroxide (initiator) at a mass ratio of 1:3, and mixed uniformly to obtain a modified bone cement powder.

[0124] The above modified bone cement powder is mixed with a bone cement liquid containing 98.49wt% MMA, 0.01wt% hydroquinone (stabilizer), and 1.5wt% N,N-dimethyl-p-toluidine (accelerator) at a water-powder ratio of 0.5mL / g, stirred for 5min, and then injected into a mold, and polymerized and cured at room temperature for 1h to obtain a modified bone cement material.

[0125] The bending strength and bending modulus of the bone cement materials in Comparative Example 1, Comparative Example 4, and Example 1 are tested according to the above mechanical property testing method.

[0126] Figure 16 The bending strength comparison chart of the bone cement materials in Comparative Example 1, Comparative Example 4, and Example 1 of the present application is shown in FIG. 1. Figure 17 The bending modulus comparison chart of the bone cement materials in Comparative Example 1, Comparative Example 4, and Example 1 of the present application is shown in FIG. 2.

[0127] From Figure 16 and Figure 17 It can be seen that the bending strength of the bone cement material in Comparative Example 4 (33.932MPa) is lower than that of Comparative Example 1 (48.416MPa) at the same addition amount, but the degree of decrease is significantly less than that of Example 1, and the bending modulus of the bone cement material in Comparative Example 4 (2.025GPa) is very close to that of Comparative Example 1 (2.038GPa), which is much higher than that of Example 1 (0.334GPa), and almost no modification effect is achieved, indicating that the addition of solid-state PEG reduces the load-bearing capacity of the bone cement material to some extent, but does not achieve the effect of softening and plasticizing, and instead easily causes brittle fracture under external force, without achieving the effect of effectively reducing the modulus of the PMMA bone cement material.

[0128] The structure of the bone cement materials in Comparative Example 1, Comparative Example 4, and Example 1 is characterized by infrared spectroscopy.

[0129] Figure 18 The infrared spectrograms of the bone cement materials in Comparative Example 1, Comparative Example 4, and Example 1 of the present application are shown in FIG. 3.

[0130] From Figure 18 It can be seen from the infrared spectrum data of the bone cement material in Comparative Example 4 that the infrared spectrum data is almost the same as that in Comparative Example 1, and compared with Example 1, there is no O-H characteristic peak, indicating that the solid PEG does not enter the PMMA bone cement system, and the PMMA and the solid PEG exist independently, without the desired modification effect.

[0131] Therefore, compared with low molecular weight (molecular weight below 800) PEG, high molecular weight PEG cannot disperse into the PMMA system due to the limitation of its own molecular activity, and thus cannot modify the PMMA bone cement material and reduce the modulus of the PMMA bone cement material. In summary, the use of low molecular weight PEG can more effectively reduce the mechanical properties of the PMMA bone cement material, making the bending modulus more close to the characteristics of human cancellous bone, and more suitable for clinical needs.

[0132] The above specific examples further illustrate the purpose, technical solutions and advantages of the present application. It should be understood that the above description is only a specific embodiment of the present application and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A modified bone cement material, characterized in that, The modified bone cement material is obtained by mixing modified bone cement liquid and bone cement powder at a water-to-powder ratio of 0.4 mL / g-0.6 mL / g and then polymerizing and solidifying them. The bone cement powder comprises, by weight percentage: Acrylic polymers, 68.5%; Initiator, 1.5%; Developer, 30%; The modified bone cement liquid comprises a modifier and bone cement liquid in a volume ratio of 1:1-20, wherein, by mass percentage, the bone cement liquid comprises: Acrylic ester monomers, 94.5-99.98%; Stabilizer, 0.01-5%; Accelerator, 0.01-1.5%; The modifier is polyethylene glycol; The molecular weight of the polyethylene glycol is 400-800; The modified bone cement material has a uniformly distributed microporous structure inside, and the pore size of the microporous structure ranges from 1 to 4 μm.

2. The modified bone cement material according to claim 1, characterized in that, The acrylate monomers are selected from at least one of methyl methacrylate, ethyl methacrylate, butyl methacrylate, hydroxyethyl methacrylate, methyl acrylate, ethyl acrylate, n-butyl acrylate, isobutyl acrylate, 2-ethylhexyl acrylate, n-octyl acrylate, isooctyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, isopropyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, ethyl methacrylate, 2-hydroxyethyl methacrylate, and 2-hydroxypropyl methacrylate.

3. The modified bone cement material according to claim 2, characterized in that, The acrylate polymer is selected from polymethyl methacrylate, or copolymers formed from methyl methacrylate and one or more of the acrylate monomers and / or styrene.

4. The modified bone cement material according to claim 1, characterized in that, The stabilizer is selected from at least one of hydroquinone and 2,6-di-tert-butyl-p-cresol.

5. The modified bone cement material according to claim 1, characterized in that, The accelerator is selected from N,N-dimethyl-p-toluidine.

6. The modified bone cement material according to claim 1, characterized in that, The initiator is selected from at least one of benzoyl peroxide, sodium persulfate, and ammonium persulfate.

7. The modified bone cement material according to claim 1, characterized in that, The developer is selected from any one of barium sulfate, zirconium oxide, and sodium diatrizoate.

8. An application of a modified bone cement material as described in any one of claims 1-7, characterized in that, The application includes at least one of the following: Application in bone filling materials for treating osteoporotic fractures; Application in bone filling materials for maxillofacial bone defect repair; Application in bone filling materials for dental bone defect repair; Application in bone filling materials for surgical plastic surgery; Application in bone filling materials for the treatment of infectious arthritis; Application of bone filling materials in joint replacement surgery for bone defect repair; Application in bone filling materials for the treatment of infectious diabetic foot.

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