Bone strength-customized bone cement composition

Abstract

The present invention relates to a bone cement composition comprising polymethylmethacrylate (PMMA) and microbeads, wherein the polymethylmethacrylate and the microbeads satisfy the following conditions: 0.0014x2-0.0221x+0.1816 ≤ P / M ≤ 0.0014x2-0.0165x+2.243 (P is the weight (g) of the polymethylmethacrylate, M is the weight (g) of the microbeads, and x is the bone strength value and in the range of 1.5 to 45). According to the present invention, it is possible to determine a mixing ratio of polymethylmethacrylate and microbeads for providing a bone strength-customized bone cement composition having mechanical properties (strength) similar to the bone strength of a subject to whom bone cement is to be applied. Accordingly, the prepared bone cement composition and bone cement can provide immediate treatment effects when applied to a subject to whom bone cement is to be applied.

Description

Customized bone cement composition for bone strength

[0001] The present invention relates to a bone strength customized bone cement composition, and more specifically, to a bone cement composition comprising polymethyl methacrylate (PMMA) and microbeads, wherein the polymethyl methacrylate and microbeads have a weight average molecular weight of 0.0014x 2 -0.0221x+0.1816 ≤ P / M ≤ 0.0014x 2 -0.0165x+2.243 (where P is the weight (g) of polymethyl methacrylate, M is the weight (g) of microbeads, and x is a bone strength value, the range of which is 1.5 to 45).

[0002]

[0003] Osteoporosis is defined as a skeletal disease characterized by impaired bone strength and an increased risk of fracture. The prevalence of osteoporosis has been increasing recently due to the aging population and declining birth rates. This rise in prevalence is alarming because it also increases the risk of fracture. With one in ten femoral fractures, a common osteoporotic fracture, known to cause death within a year, fractures are recognized as a serious public health problem.

[0004] Bone cement is a bio-adhesive used in orthopedic surgery for complex fracture restoration and artificial joint surgery, as well as in dentistry for restoring dentin that has not yet been regenerated. Surgical bone cement fills the gap between damaged bone or bone and implant, fixing and stabilizing the two. Bone cement has the advantage of being widely used due to its rapid mixing, application, and hardening process, as well as its ease of application. However, bone cement lacking biocompatibility can cause bone cell necrosis and dissociation, necessitating revision surgery. Therefore, since bone cement is applied to the patient and becomes an integral part of the actual bone, it must induce bone formation, exhibit excellent stability and adhesiveness, be permanent, and have strength similar to that of bone.

[0005] Poly(methyl methacrylate) (PMMA) bone cement, first proposed as an adhesive between bone and implants in the 1960s, has been the most widely used bioadhesive and is one of the most durable materials in orthopedic surgery. However, due to the properties of PMMA, bone union is impossible and complications such as cracks at the interface and rupture of adjacent areas are often accompanied, limiting its clinical application. Therefore, research is continuously being conducted to complement the shortcomings of PMMA bone cement. Technologies to overcome the limitations of existing bone cements include: technology that induces bone regeneration through the formation of pores and canal structures during the biodegradation process using biopolysaccharides; technology that reduces tissue necrosis by minimizing the effect of heat generated during polymerization of MMA monomers on cells; and technology that prevents additional fractures by implementing a low elastic modulus. Despite the research and development of various technologies, various clinical problems still arise, and therefore, there is a need to develop bone cement with excellent bone regeneration ability and no side effects.

[0006] Meanwhile, bone strength is determined by 70% bone quantity and 30% bone quality, and bone quality is determined by bone turnover rate, structure, microdamage, and mineralization, but it is difficult to measure at present, while bone strength depends on 70% bone quantity, that is, bone density, so bone density measurement is known to be a useful method for diagnosing osteoporosis, and the current definition of osteoporosis depends on bone density.

[0007] Bone mineral density (BMD) can be measured at the midshaft of the spine, femur, and other extremities using the most common method, dual-energy X-ray absorptiometry (DXA). The T-score of BMD measured at the midshaft using DXA serves as the WHO standard for diagnosing osteoporosis, and this standard is applied only to postmenopausal women and men over 50 years of age. However, many fractures occur outside the T-score range of the osteoporosis diagnostic criteria, so even following this standard misses a large proportion of fractures.

[0008] Another way to measure bone density is to observe bone resorption parameters (eroded surface and number of osteoclasts) in bone tissue morphology. Bone tissue accumulates both living and dead osteoclasts. This method can be used to diagnose osteoporosis risk as low because bone density is observed high even when dead osteoclasts, which cannot function properly, accumulate more than living ones. In other words, even when there are many dead osteoclasts, the bone density value is calculated as high, overlooking the risk of fracture. For various reasons mentioned above, the focus has recently shifted from bone density to bone strength as the cause of osteoporotic fractures. Therefore, it is necessary to provide bone cement with a strength similar to bone strength through accurate bone strength measurement.

[0009] Accordingly, the inventors of the present invention have made extensive research efforts to overcome the problems of the above-mentioned conventional technologies, and as a result, have developed a bone cement composition comprising polymethyl methacrylate and microbeads, wherein the polymethyl methacrylate and microbeads are mixed at a concentration of 0.0014x. 2 -0.0221x+0.1816 ≤ P / M ≤ 0.0014x 2-0.0165x+2.243 (where P is the weight (g) of polymethyl methacrylate, M is the weight (g) of microbeads, and x is the bone strength value, the range being 1.5 to 45), it was confirmed that a bone cement composition having similar bone strength and mechanical properties (strength) to a subject of bone cement application can be provided, thereby providing an immediate treatment effect, and thus completing the present invention.

[0010]

[0011] Accordingly, the main purpose of the present invention is to provide a bone strength customized bone cement composition that has similar bone strength and mechanical properties (strength) to a bone cement application target and can provide an immediate treatment effect.

[0012] Another object of the present invention is to provide a method for determining a bone cement composition ratio for determining a mixing ratio of polymethyl methacrylate and microbeads in the bone strength customized bone cement composition.

[0013] Another object of the present invention is to provide a method for manufacturing bone cement using a method for determining a composition ratio of bone cement to determine a mixing ratio of polymethyl methacrylate and microbeads.

[0014]

[0015] According to one aspect of the present invention, the present invention provides a bone cement composition comprising polymethyl methacrylate (PMMA) and microbeads, wherein the polymethyl methacrylate and microbeads are contained in a ratio represented by the following formula 1.

[0016] [Formula 1]

[0017] 0.0014x 2 -0.0221x+0.1816 ≤ P / M ≤ 0.0014x 2 -0.0165x+2.243

[0018] In the above equation 1,

[0019] P is the weight of polymethyl methacrylate (g),

[0020] M is the weight of the microbead (g),

[0021] x is the bone strength value, which ranges from 1.5 to 45.

[0022] Surgical bone cement fills the empty space between damaged bones or between bones and implants to fix and stabilize the two. Since the bone cement applied to the patient exists as a part of the actual bone, its own strength must be similar to that of the bone. Therefore, it is necessary to provide bone cement that has characteristics similar to the bone strength of a person, especially the bone strength of the person to whom the bone cement is applied.

[0023] Accordingly, the inventors of the present invention have investigated factors affecting strength in a bone cement composition containing polymethyl methacrylate (PMMA) and microbeads in order to provide bone cement suitable for various bone strengths of each person, and confirmed that the mixing ratio of polymethyl methacrylate and microbeads is a major factor affecting the strength of bone cement, and have derived an equation (Equation 1) for estimating the mixing ratio of polymethyl methacrylate and microbeads in order to prepare a bone cement composition having various bone strengths between 1.5 and 45 MPa, which is the range of human cancellous bone strength, thereby completing the present invention.

[0024] In the above formula 1, if the ratio of polymethyl methacrylate and microbeads is below the range, it is possible to derive a mixing ratio of polymethyl methacrylate and microbeads capable of producing a bone cement composition having a strength similar to that of human bone. However, the bone cement has poor formability, making it difficult to apply to the human body. In addition, if the ratio is above the above range, the composition has a strength exceeding that of human bone. Therefore, in order to provide a bone cement having a strength similar to that of human bone, it is preferable to include polymethyl methacrylate and microbeads in a ratio according to formula 1.

[0025] According to one experimental example of the present invention, as a result of confirming whether Equation 1 of the present invention derives an appropriate mixing ratio of polymethyl methacrylate and microbeads for providing a bone cement composition having a desired bone strength value, it was confirmed that the bone cement manufactured through the mixing ratio of polymethyl methacrylate and microbeads derived through the Equation of the present invention had a bone strength value at a level similar to the desired bone strength value, but it was confirmed that the desired bone strength value was not exhibited when the mixing ratio was not derived through the Equation of the present invention or was outside the range of the Equation. These results suggest that the bone cement composition according to the present invention can control and include the mixing ratio of polymethyl methacrylate and microbeads for deriving bone strength values ​​in various ranges, and such a characteristic configuration can provide a bone cement composition that matches the desired bone strength value, for example, the bone strength value of a subject of application.

[0026] In the bone cement composition of the present invention, the microbeads may be porous. Since the biodegradation rate of the microbeads should not exceed the rate of new bone tissue growth, the biodegradation rate of the microbeads must be controlled. This biodegradation rate can be controlled through the porous characteristics of the microbeads, and higher porosity, i.e., higher porosity, can increase biodegradability.

[0027] In the bone cement composition of the present invention, a hydrogel may be incorporated into the pores of the microbeads. The hydrogel serves to enhance the adhesion ability of osteoblasts, and the hydrogel may be at least one hydrogel selected from the group consisting of polymer hydrogels such as hyaluronic acid-based hydrogels, collagen-based hydrogels, alginate-based hydrogels, and organic polysaccharide hydrogels, and is preferably a hyaluronic acid-based hydrogel.

[0028] In the bone cement composition of the present invention, the microbeads have biodegradable properties, for example, bioglass microspheres, hydroxyapatite (Ca) of calcium phosphate 10 (PO4)6(OH)2), alpha-tricalcium phosphate (α-TCP), beta-tricalcium phosphate (β-TCP), biphasic calcium phosphate (BCP), BCP (mixture of HA and β-TCP, consisting of mixtures of various HA / β-TCP ratios), potassium dihydrogen phosphate, monocalcium phosphate monohydrate (MCPM), dicalcium phosphate (DCP), calcium pyro phosphate (CPC), dicalcium anhydride (DCPA), dicalcium dehydrade (DCPD), amorphous calcium phosphate, tetracalcium phosphate (TTCP), MCPM (Ca(H2PO4)2·H2O), calcium pyrophosphate (Ca2P2O7), DCPD(CaHPO4·2H2O), DCPA(CaHPO4), HA(Ca 10 (PO4)6(OH)2), tetracalcium phosphate, dicalcium phosphate anhydrous, and dicalcium phosphate dehydrate, and preferably biodegradable bioglass microspheres. The biodegradable property of the microbeads can rapidly provide a bone defect treatment effect by increasing the penetration of osteoblasts through the space formed by biodegradation after implantation, i.e., pores.

[0029] In the bone cement composition of the present invention, the particle size of the biodegradable bioglass microspheres is 20 to 1000 μm, preferably 50 to 700 μm. If the particle size of the biodegradable bioglass microspheres is smaller than the above range, bone cell growth is difficult, and if it is larger than the above range, it is difficult to maintain an appropriate skeleton.

[0030] In the bone cement composition of the present invention, the polymethyl methacrylate is contained in an amount of 30 to 70 wt% based on the total weight of the composition, and the microbeads are contained in an amount of 70 to 30 wt% based on the total weight of the composition. If the content of polymethyl methacrylate is less than the above range, the bone cement formability is poor, and if it exceeds the above range, bone formation is not easy. In addition, if the content of the microbeads is less than the above range, the bone formation ability is poor, and if it exceeds the above range, the bone cement formability is poor.

[0031] According to another aspect of the present invention, the present invention provides a method for determining a mixing ratio of polymethyl methacrylate (PMMA) and microbeads in a bone cement composition comprising polymethyl methacrylate and microbeads, characterized in that the mixing ratio of the polymethyl methacrylate and microbeads is determined according to the following formula 1.

[0032] [Formula 1]

[0033] 0.0014x 2 -0.0221x+0.1816 ≤ P / M ≤ 0.0014x 2 -0.0165x+2.243

[0034] In the above equation 1,

[0035] P is the weight of polymethyl methacrylate (g),

[0036] M is the weight of the microbead (g),

[0037] x is the bone strength value, which ranges from 1.5 to 45.

[0038] The strength of human cancellous bone is generally known to range from 1.5 to 45 MPa, meaning that bone strength varies from person to person. Since bone cement applied to a person actually exists as part of that person's bone, it is necessary to provide bone cement that matches the bone strength of the individual receiving the cement. To achieve this, it is necessary to predict the subject's bone strength and determine the mixing ratio of polymethyl methacrylate and microbeads to provide bone cement appropriate for that bone strength.

[0039] Before determining the mixing ratio of polymethyl methacrylate and microbeads, a prerequisite is to predict the subject's bone strength. Human bone strength can be estimated using various known methods, including, but not limited to, T-scores derived from dual-energy X-ray absorptiometry (DXA).

[0040] As previously explained, the main factor affecting the strength of bone cement is the mixing ratio of polymethyl methacrylate and microbeads. Therefore, the mixing ratio of polymethyl methacrylate and microbeads can be determined using the equation (Equation 1) derived in the present invention. The detailed information regarding the mixing ratio of polymethyl methacrylate and microbeads has been described in detail previously, and therefore is omitted.

[0041] According to another aspect of the present invention, a method for producing bone cement is provided, comprising the steps of immersing and drying microbeads in a hydrogel to obtain microbeads mixed with hydrogel, and mixing the microbeads mixed with the hydrogel with polymethyl methacrylate (PMMA), wherein the mixing ratio of the polymethyl methacrylate and the microbeads mixed with the hydrogel is determined according to the following formula 1.

[0042] [Formula 1]

[0043] 0.0014x 2 -0.0221x+0.1816 ≤ P / M ≤ 0.0014x 2 -0.0165x+2.243

[0044] In the above equation 1,

[0045] P is the weight of polymethyl methacrylate (g),

[0046] M is the weight of the microbead (g),

[0047] x is the bone strength value, which ranges from 1.5 to 45.

[0048] In the method for manufacturing bone cement of the present invention, the hydrogel may be at least one hydrogel selected from the group consisting of a hyaluronic acid-based hydrogel, a collagen-based hydrogel, an alginate-based hydrogel, and an organic polysaccharide hydrogel, and is preferably a hyaluronic acid-based hydrogel.

[0049] In the method for manufacturing bone cement of the present invention, the polymethyl methacrylate is contained in an amount of 30 to 70 wt% based on the total weight of the composition, and the microbeads containing hydrogel are contained in an amount of 70 to 30 wt% based on the total weight of the composition. If the content of polymethyl methacrylate is less than the above range, the bone cement formability is poor, and if it exceeds the above range, bone formation is not easy. In addition, if the content of the microbead is less than the above range, the bone formation ability is poor, and if it exceeds the above range, the bone cement formability is poor.

[0050]

[0051] As described above, the mixing ratio of polymethyl methacrylate and microbeads can be determined to provide a bone strength customized bone cement composition having similar bone strength and mechanical properties to a subject of bone cement application, and the bone cement composition and bone cement prepared accordingly can provide an immediate treatment effect when applied to a subject of bone cement application.

[0052]

[0053] Hereinafter, the present invention will be described in more detail through examples. These examples are intended merely to illustrate the present invention, and therefore, the scope of the present invention is not to be construed as being limited by these examples.

[0054]

[0055] Example: Preparation of bone cement composition

[0056] First, the mixing ratio of the microbeads containing polymethyl methacrylate and hydrogel was determined when x is 25 in the following equation 1 of the present invention, i.e., when the bone strength value is 25 MPa.

[0057] [Formula 1]

[0058] 0.0014x 2 -0.0221x+0.1816 ≤ P / M ≤ 0.0014x 2 -0.0165x+2.243

[0059] Specifically, the equation below (Equation 1) included within the range of the equation for the lower limit and the equation for the upper limit in Equation 1 above was arbitrarily derived, and the mixing ratio (P / M) of microbeads containing polymethyl methacrylate and hydrogel when x is 25 was derived from the equation.

[0060] [Equation 1]

[0061] P / M = 0.0014x 2 - 0.0221x + 0.2816

[0062] As a result, P / M was calculated to be approximately 0.6.

[0063] According to the above results, a bone cement composition containing a P / M ratio of 0.6 was prepared. Briefly, hyaluronic acid was dissolved in deionized water to prepare a hydrogel having a concentration of 10 mg / mL, and then 0.5 g of TCP microbeads were immersed in the hydrogel to prepare microbeads in which hydrogel was incorporated into the pores of the microbeads. Then, the microbeads in which polymethyl methacrylate and hydrogel were incorporated were prepared by modifying them so that the mixing ratio (P / M) was 0.6 (PMMA 40 wt%, microbeads in which hydrogel was incorporated 60 wt%), and then mixed to prepare a bone cement composition.

[0064]

[0065] Comparative Example 1: Preparation of bone cement composition

[0066] A bone cement composition was prepared in which the P / M was 9 instead of 0.6 as derived from the above equation 1. Briefly, hyaluronic acid was dissolved in deionized water to prepare a hydrogel having a concentration of 10 mg / mL, and then 0.5 g of TCP microbeads were immersed in the hydrogel to prepare microbeads in which hydrogel was incorporated into the pores of the microbeads. Then, the microbeads in which polymethyl methacrylate and hydrogel were incorporated were prepared by modifying them so that the mixing ratio (P / M) was 9 (90 wt% PMMA, 10 wt% microbeads incorporating hydrogel), and then mixed to prepare a bone cement composition.

[0067]

[0068] Comparative Example 2: Preparation of bone cement composition

[0069] 0.0014x in the above equation 1 2 In the equation -0.0165x+2.243, when x is 25, that is, when the bone strength value is 25 MPa, the mixing ratio of polymethyl methacrylate and microbeads was determined, and P / M was calculated to be approximately 2.7. According to the above results, a bone cement composition containing a P / M ratio of 2.7 was prepared. Briefly, hyaluronic acid was dissolved in deionized water to prepare a hydrogel with a concentration of 10 mg / mL, and then 0.5 g of TCP microbeads were immersed in the hydrogel to prepare microbeads in which hydrogel was incorporated into the pores of the microbeads. Then, the microbeads in which polymethyl methacrylate and hydrogel were incorporated were prepared by improving the mixing ratio (P / M) to 2.7 (PMMA 73 wt%, microbeads in which hydrogel was incorporated 27 wt%), and then mixed to prepare a bone cement composition.

[0070]

[0071] Experimental Example: Bone Strength Measurement

[0072] Using the bone cement prepared in the above examples and comparative examples 1 and 2, the bone was arbitrarily formed into a bone shape, and the strength thereof was measured, and the results are shown in Table 1.

[0073] Strength (Mpa) Example 23.7 Comparative Example 177.4 Comparative Example 249.7

[0074] As a result, as can be confirmed in Table 1 above, in the case of bone cement manufactured through the mixing ratio of microbeads containing polymethyl methacrylate and hydrogel derived through the formula of the present invention, it was confirmed to have a strength similar to the desired bone strength (25 MPa), but in the case of bone cement manufactured through the mixing ratio of microbeads containing polymethyl methacrylate and hydrogel not derived through the formula of the present invention (Comparative Example 1), it was confirmed to have a strength about 3 times higher than the desired bone strength (25 MPa), and when it was out of the range of the formula of the present invention (Comparative Example 2), a mixing ratio of microbeads containing polymethyl methacrylate and hydrogel different from the examples was derived even at the same bone strength, and the strength of the bone cement manufactured with such a mixing ratio showed a strength different from the desired bone strength (25 MPa).

Claims

1. A bone cement composition comprising polymethyl methacrylate (PMMA) and microbeads, A bone cement composition characterized in that the polymethyl methacrylate and microbeads are included in a ratio of the following formula 1. [Formula 1] 0.0014x 2 -0.0221x+0.1816 ≤ P / M ≤ 0.0014x 2 -0.0165x+2.243 In the above equation 1, P is the weight of polymethyl methacrylate (g), M is the weight of the microbead (g), x is the bone strength value, which ranges from 1.5 to 45.

2. In paragraph 1, A bone cement composition characterized in that the above microbeads are porous.

3. In paragraph 2, A bone cement composition characterized in that a hydrogel is mixed into the pores of the above microbeads.

4. In paragraph 3, A bone cement composition characterized in that the hydrogel is at least one selected from a polymer hydrogel composed of a hyaluronic acid-based hydrogel, a collagen-based hydrogel, an alginate-based hydrogel, and an organic polysaccharide hydrogel.

5. In paragraph 1, The above microbeads are bioglass microspheres, hydroxyapatite (Ca) of calcium phosphate 10 (PO4)6(OH)2), alpha-tricalcium phosphate (α-TCP), beta-tricalcium phosphate (β-TCP), biphasic calcium phosphate (BCP), BCP (mixture of HA and β-TCP, consisting of mixtures of various HA / β-TCP ratios), potassium dihydrogen phosphate, monocalcium phosphate monohydrate (MCPM), dicalcium phosphate (DCP), calcium pyro phosphate (CPC), dicalcium anhydride (DCPA), dicalcium dehydrade (DCPD), amorphous calcium phosphate, tetracalcium phosphate (TTCP), MCPM (Ca(H2PO4)2·H2O), calcium pyrophosphate (Ca2P2O7), DCPD(CaHPO4·2H2O), DCPA(CaHPO4), HA(Ca 10 A bone cement composition characterized by being selected from the group consisting of (PO4)6(OH)2), tetracalcium phosphate, dicalcium phosphate anhydrous, and dicalcium phosphate dehydrate.

6. In paragraph 5, A bone cement composition characterized in that the particle size of the biodegradable bioglass microspheres is 20 to 1000 μm.

7. In paragraph 1, A bone cement composition characterized in that the polymethyl methacrylate is contained in an amount of 30 to 70 wt% based on the total weight of the composition, and the microbeads are contained in an amount of 70 to 30 wt% based on the total weight of the composition.

8. A method for determining the mixing ratio of polymethyl methacrylate (PMMA) and microbeads in a bone cement composition comprising polymethyl methacrylate (PMMA) and microbeads according to Article 1, A method for determining a composition ratio of bone cement, characterized in that the mixing ratio of the above polymethyl methacrylate and microbeads is determined according to the following formula 1. [Formula 1] 0.0014x 2 -0.0221x+0.1816 ≤ P / M ≤ 0.0014x 2 -0.0165x+2.243 In the above equation 1, P is the weight of polymethyl methacrylate (g), M is the weight of the microbead (g), x is the bone strength value, which ranges from 1.5 to 45.

9. A method for manufacturing bone cement, comprising the steps of immersing and drying microbeads in hydrogel to obtain microbeads mixed with hydrogel, and mixing the microbeads mixed with hydrogel with polymethyl methacrylate (PMMA). A method for manufacturing bone cement, characterized in that the mixing ratio of the microbeads containing the polymethyl methacrylate and hydrogel is determined according to claim 8.

10. In paragraph 9, A method for manufacturing bone cement, characterized in that the hydrogel is at least one selected from a polymer hydrogel composed of a hyaluronic acid-based hydrogel, a collagen-based hydrogel, an alginate-based hydrogel, and an organic polysaccharide hydrogel.

11. In paragraph 9, A method for manufacturing bone cement, characterized in that the polymethyl methacrylate is included in an amount of 30 to 70 wt% based on the total weight of the composition, and the microbeads containing hydrogel are included in an amount of 70 to 30 wt% based on the total weight of the composition.