Preparation method of porous hydroxyapatite microsphere modified PMMA bone cement, product and application thereof
By preparing PMMA bone cement modified with porous hydroxyapatite microspheres, the problem of mismatch between PMMA bone cement and adjacent vertebral bodies was solved, achieving regulation of mechanical properties and improvement of bioactivity, reducing the risk of recurrent compression fractures, and promoting the repair and fusion of fracture sites.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANGHAI NAT ENG RES CENT FORNANOTECH
- Filing Date
- 2023-12-18
- Publication Date
- 2026-07-24
AI Technical Summary
Existing PMMA bone cement, when used to treat osteoporotic vertebral compression fractures, has a mismatch between its mechanical strength and that of adjacent vertebrae, and lacks bioactivity, resulting in a high risk of recurrent compression fractures.
PMMA bone cement modified with porous hydroxyapatite microspheres was prepared by mixing porous hydroxyapatite microspheres with PMMA powder, thereby regulating mechanical properties and increasing bioactivity to promote bone tissue fusion.
Modified PMMA bone cement is adapted to the bone characteristics of the fractured or adjacent vertebral body, reducing the risk of recurrent compression fractures and promoting bone repair and fusion.
Smart Images
Figure CN117653793B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method in the field of biomedical materials technology, specifically a method for preparing PMMA bone cement modified with porous hydroxyapatite microspheres, its products, and applications. Background Technology
[0002] Osteoporosis (OP) is a common systemic metabolic bone disease characterized by low bone mass and damage to bone microstructure, easily leading to non-traumatic fractures. Osteoporotic vertebral compression fractures (OVCFs) are the most common type of osteoporotic fracture, accounting for approximately 45% of all osteoporotic fractures. Percutaneous vertebroplasty (PVP) is the most commonly used minimally invasive technique for treating OVCFs. However, studies report that approximately 8%-52% of OVCF patients undergoing PVP will experience adjacent vertebral compression fractures (AVFs). This is because PMMA bone cement is commonly used in PVP, which has high mechanical strength but a high elastic modulus, resulting in a mismatch with the stiffness of adjacent vertebrae; furthermore, it lacks osteogenic bioactivity, cannot promote bone self-repair, and has poor fusion with surrounding bone tissue. Some scholars have focused on researching bone cement materials and methods for locally improving osteoporosis after PVP (percutaneous transluminal vertebral osmosis) surgery. For example, they have incorporated strontium into calcium phosphate bone cement, utilizing strontium's role in promoting osteoblast proliferation and osteogenic activity to locally improve vertebral osteoporosis after PVP / PKP [Lode, Acta Biomaterialia, 2018]. Another example is incorporating mineralized adhesive raw materials into PMMA (polymethyl methacrylate) bone cement to construct a bioactive MC-PMMA bone cement that simultaneously possesses high mechanical strength and osteogenic effects [Zhu, Theranostics, 2020]. Regulating the mechanical properties of PMMA bone cement to adapt it to the bone characteristics of fractured or adjacent vertebrae, while simultaneously increasing its biocompatibility and osteogenic bioactivity, is a key direction for improving the clinical deficiencies of PMMA.
[0003] Hydroxyapatite is a major inorganic component of human bones and teeth, possessing excellent bioactivity, biocompatibility, and osteoconductivity. It does not cause inflammatory reactions after implantation, is biodegradable, and is widely used in clinical tissue engineering repair in orthopedics, dentistry, and plastic surgery. Based on this research background, this invention uses an emulsion method and high-temperature calcination to prepare porous hydroxyapatite microspheres. The micropores facilitate bone cell growth, nutrient transport, and metabolic waste removal. These microspheres are then mixed with PMMA powder as a filler to prepare PMMA bone cement with high bone-promoting bioactivity and well-matched mechanical properties. Summary of the Invention
[0004] The purpose of this invention is to provide a method for preparing PMMA bone cement modified with porous hydroxyapatite microspheres.
[0005] Another objective of this invention is to provide a PMMA bone cement product modified with porous hydroxyapatite microspheres prepared by the above method.
[0006] Another object of the present invention is to provide an application of the above-mentioned product.
[0007] The objective of this invention is achieved through the following method: a method for preparing porous hydroxyapatite microsphere-modified PMMA bone cement, comprising the following steps:
[0008] (1) Preparation of porous hydroxyapatite microspheres: A mixed aqueous solution containing gelatin, α-TCP and hydroxyapatite was used as an aqueous phase solution and added to vegetable oil containing surfactant at 60℃ at a volume ratio of 1:10-1:100 to obtain an O / W type emulsion. The mixture was stirred until α-TCP solidified. The emulsion was then transferred to an ice bath and physiological saline containing 0.1% triton-X was added as a demulsifier. At the same time, glutaraldehyde solution was added to further crosslink the gelatin. The mixture was stirred for 2 hours and the microspheres were extracted by centrifugation. The microspheres were washed three times with ethanol and water respectively and freeze-dried for more than 48 hours. The product was calcined in a muffle furnace at 1200℃ for 4 hours at a heating rate of 5℃ / min to obtain porous hydroxyapatite microspheres.
[0009] (2) Preparation of modified PMMA bone cement
[0010] PMMA bone cement solid powder consists of 50-90% PMMA prepolymer powder, 0.1-44% porous hydroxyapatite microspheres, 5% barium sulfate developer, and 1-5% benzoyl peroxide initiator; the curing liquid consists of 90-95% MMA monomer, 4.9%-9.9% N,N-dimethyl-p-toluidine accelerator, and 0.1% hydroquinone stabilizer. The percentages are by mass, and the total is 100%. The PMMA bone cement solid powder and the curing liquid are mixed at a solid-liquid ratio of 1-1.5 g / mL to obtain PMMA bone cement modified with porous hydroxyapatite microspheres.
[0011] The method for preparing the aqueous solution in step (1) involves adding α-TCP mixed powder containing 1-5% hydroxyapatite by mass to a gelatin solution with a concentration of 5-15% (w / v) at a solid-liquid ratio of 1.2-1.5 mL / g, and then magnetically stirring at 60°C to aid dissolution.
[0012] The surfactant mentioned in step (1) is one or more of Tween 20, Tween 60, Tween 80, and Span 80.
[0013] This invention provides a porous hydroxyapatite microsphere-modified PMMA bone cement, prepared according to any of the methods described above.
[0014] This invention provides the application of porous hydroxyapatite microsphere-modified PMMA bone cement in the preparation of materials required for highly active and mechanically controllable PMMA bone cement.
[0015] A mixed aqueous solution containing gelatin, α-TCP, and hydroxyapatite was used as the aqueous phase solution and added to vegetable oil to obtain an O / W emulsion. Physiological saline containing 0.1% triton-X was added as a demulsifier, and glutaraldehyde solution was added to further crosslink the gelatin. The microspheres were extracted by centrifugation, washed three times with ethanol and water respectively, and freeze-dried. The product was then calcined at 1200℃ for 4 hours to obtain porous hydroxyapatite microspheres. The microspheres were added to PMMA powder to prepare PMMA bone cement modified with porous hydroxyapatite microspheres.
[0016] This invention includes the following steps:
[0017] 1. Prepare a gelatin aqueous solution with a concentration of 5-15% (w / v) at 60℃.
[0018] 2. Add α-TCP mixed powder containing 1-5% hydroxyapatite by mass to the above gelatin solution at a solid-liquid ratio of 1.2-1.5 mL / g to form an aqueous phase solution.
[0019] 3. Add the above aqueous solution to vegetable oil containing surfactant at a volume ratio of 1:10-1:100 to obtain an O / W type emulsion, and continue stirring until α-TCP solidifies.
[0020] 4. Transfer the above emulsion to an ice bath, add physiological saline containing 0.1% triton-X as a demulsifier, and add glutaraldehyde solution to further crosslink the gelatin. Stir continuously for 2 hours.
[0021] 5. Centrifuge to extract microspheres, wash three times with ethanol and water respectively, and freeze-dry for more than 48 hours.
[0022] 6. The product was calcined in a muffle furnace at 1200℃ for 4 hours at a heating rate of 5℃ / min to obtain porous hydroxyapatite microspheres.
[0023] 7. The PMMA bone cement solid powder consists of 50-90% PMMA prepolymer powder, 0.1-44% porous hydroxyapatite microspheres, 5% barium sulfate developer, and 1-5% benzoyl peroxide initiator; the curing liquid consists of 90-95% MMA monomer, 4.9%-9.9% N,N-dimethyl-p-toluidine accelerator, and 0.1% hydroquinone stabilizer. All percentages are by mass, and the total is 100%.
[0024] 8. PMMA bone cement solid powder and curing liquid are mixed at a solid-liquid ratio of 1-1.5 g / mL to obtain porous hydroxyapatite microsphere modified PMMA bone cement.
[0025] The porous hydroxyapatite microspheres prepared in this invention exhibit good bioactivity, biocompatibility, and osteoconductivity. Their micropores facilitate osteoblast growth, nutrient transport, and metabolic waste removal. Modified PMMA bone cement can regulate the mechanical properties of PMMA bone cement to adapt to the bone characteristics of fractured or adjacent vertebrae, while simultaneously increasing its biocompatibility and osteopromoting bioactivity, promoting the fusion of the implant with bone tissue, and reducing the risk of recurrent compression fractures in adjacent vertebrae.
[0026] The advantages of this invention are:
[0027] Porous hydroxyapatite microspheres have good bioactivity, biocompatibility and osteoconductivity. Their micropores are conducive to osteoblast growth, nutrient transport and metabolic product excretion.
[0028] Porous hydroxyapatite microspheres modified PMMA bone cement can regulate the mechanical properties of PMMA bone cement to adapt it to the bone characteristics of fractures or adjacent vertebrae, while increasing its biocompatibility and osteopromoting bioactivity, promoting the fusion of implants with bone tissue, and reducing the risk of recurrent compression fractures of adjacent vertebrae. Attached Figure Description
[0029] Appendix Figure 1 The compressive strength mechanical curve of the PMMA bone cement modified with porous hydroxyapatite microspheres prepared in Example 1 is shown. Detailed Implementation
[0030] The following embodiments are implemented based on the technical solution of the invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.
[0031] Example 1
[0032] A porous hydroxyapatite microsphere-modified PMMA bone cement is prepared according to the following steps:
[0033] (1) Preparation of porous hydroxyapatite microspheres:
[0034] Dissolve 0.5g of gelatin in 10mL of pure water, add 7.68g of α-TCP and 0.32g of hydroxyapatite to the gelatin solution and mix well to form an aqueous solution. Add the aqueous solution to 300mL of olive oil containing 3g of Span-80 to obtain an O / W type emulsion. Continue stirring until α-TCP solidifies.
[0035] The above emulsion was transferred to an ice bath, and 300 mL of physiological saline containing 0.1% triton-X was added as a demulsifier. At the same time, 500 μL of 1% (w / v) glutaraldehyde solution was added to further crosslink the gelatin. The mixture was stirred continuously for 2 h. After the reaction was completed, the microspheres were extracted by centrifugation, washed three times with ethanol and water respectively, and freeze-dried for more than 48 h. The product was calcined in a muffle furnace at 1200 °C for 4 h at a heating rate of 5 °C / min to obtain porous hydroxyapatite microspheres.
[0036] (2) Preparation of modified PMMA bone cement, wherein the percentage of each component is by mass:
[0037] PMMA bone cement solid powder is composed of 60% PMMA prepolymer powder, 30% porous hydroxyapatite microspheres, 5% barium sulfate as a developer, and 5% benzoyl peroxide as an initiator.
[0038] The curing solution consists of 95% MMA monomer, 4.9% N,N-dimethyl-p-toluidine accelerator, and 0.1% hydroquinone stabilizer;
[0039] PMMA bone cement solid powder and curing liquid were mixed at a solid-liquid ratio of 1 g / mL to obtain porous hydroxyapatite microsphere modified PMMA bone cement.
[0040] Appendix Figure 1 The compressive strength mechanical curve of the porous hydroxyapatite microsphere-modified PMMA bone cement prepared in this embodiment shows that its elastic modulus reaches 590 MPa.
[0041] Example 2
[0042] A porous hydroxyapatite microsphere-modified PMMA bone cement, step (2) of which involves the preparation of the modified PMMA bone cement is the same as in Example 1, prepared according to the following steps: In step (1),
[0043] First, dissolve 0.5g of gelatin in 10mL of pure water and add the mixed powder of 0.14g of hydroxyapatite and 6.86g of α-TCP to the above gelatin solution. After mixing evenly, add it to 100mL of olive oil containing 1g of span-80 to obtain an O / W type emulsion. Continue stirring until α-TCP solidifies.
[0044] The emulsion was transferred to an ice bath, and 100 mL of physiological saline containing 0.1% Triton-X was added as a demulsifier. Simultaneously, 500 μL of 1% (w / v) glutaraldehyde solution was added, and stirring continued for 2 h. After the reaction, the microspheres were extracted by centrifugation, washed three times each with ethanol and water, and then freeze-dried. The product was calcined in a muffle furnace at 1200 °C for 4 h at a heating rate of 5 °C / min to obtain porous hydroxyapatite microspheres.
[0045] Example 3
[0046] A porous hydroxyapatite microsphere-modified PMMA bone cement, step (1) of which involves the preparation of the porous hydroxyapatite microspheres is the same as in Example 1, prepared according to the following steps: In step (2),
[0047] PMMA bone cement solid powder is composed of 70% PMMA prepolymer powder, 20% porous hydroxyapatite microspheres, 5% barium sulfate as a developer, and 5% benzoyl peroxide as an initiator.
[0048] The curing solution consists of 97% MMA monomer, 2.9% N,N-dimethyl-p-toluidine accelerator, and 0.1% hydroquinone stabilizer;
[0049] PMMA bone cement solid powder and curing liquid were mixed at a solid-liquid ratio of 1 g / mL to obtain porous hydroxyapatite microsphere modified PMMA bone cement.
[0050] Example 4
[0051] A porous hydroxyapatite microsphere-modified PMMA bone cement, step (1) of which involves the preparation of the porous hydroxyapatite microspheres is the same as in Example 1, prepared according to the following steps: In step (2),
[0052] PMMA bone cement solid powder is composed of 50% PMMA prepolymer powder, 40% porous hydroxyapatite microspheres, 5% barium sulfate as a developer, and 5% benzoyl peroxide as an initiator.
[0053] The curing solution consists of 95% MMA monomer, 4.9% N,N-dimethyl-p-toluidine accelerator, and 0.1% hydroquinone stabilizer;
[0054] PMMA bone cement solid powder and curing liquid were mixed at a solid-liquid ratio of 1 g / mL to obtain porous hydroxyapatite microsphere modified PMMA bone cement.
Claims
1. A method for preparing porous hydroxyapatite microsphere-modified PMMA bone cement, characterized in that, Includes the following steps: (1) Preparation of porous hydroxyapatite microspheres: A mixed aqueous solution containing gelatin, α-TCP and hydroxyapatite was used as an aqueous phase solution and added to vegetable oil containing surfactant at 60℃ at a volume ratio of 1:10-1:100 to obtain an O / W type emulsion. The mixture was stirred until α-TCP solidified. The emulsion was then transferred to an ice bath and physiological saline containing 0.1% triton-X was added as a demulsifier. At the same time, glutaraldehyde solution was added to further crosslink the gelatin. The mixture was stirred for 2 hours and the microspheres were extracted by centrifugation. The microspheres were washed three times with ethanol and water respectively and freeze-dried for more than 48 hours. The product was calcined in a muffle furnace at 1200℃ for 4 hours at a heating rate of 5℃ / min to obtain porous hydroxyapatite microspheres. (2) Preparation of modified PMMA bone cement PMMA bone cement solid powder consists of 50-90% PMMA prepolymer powder, 0.1-44% porous hydroxyapatite microspheres, 5% barium sulfate developer, and 1-5% benzoyl peroxide initiator; the curing liquid consists of 90-95% MMA monomer, 4.9%-9.9% N,N-dimethyl-p-toluidine accelerator, and 0.1% hydroquinone stabilizer. All percentages are by mass, and the total is 100%. The PMMA bone cement solid powder and curing liquid are mixed at a solid-liquid ratio of 1-1.5 g / mL to obtain PMMA bone cement modified with porous hydroxyapatite microspheres. The method for preparing the aqueous solution in step (1) involves adding α-TCP mixed powder containing 1-5% hydroxyapatite by mass to a gelatin solution with a concentration of 5-15% (w / v) at a solid-liquid ratio of 1.2-1.5 mL / g, and then magnetically stirring at 60°C to aid dissolution.
2. The method for preparing PMMA bone cement modified with porous hydroxyapatite microspheres according to claim 1, characterized in that, The surfactant mentioned in step (1) is one or more of Tween 20, Tween 60, Tween 80, and Span 80.
3. The method for preparing porous hydroxyapatite microsphere-modified PMMA bone cement according to any one of claims 1 to 2, characterized in that, Prepare according to the following steps: (1) Preparation of porous hydroxyapatite microspheres: Dissolve 0.5g of gelatin in 10mL of pure water, add 7.68g of α-TCP and 0.32g of hydroxyapatite to the gelatin solution and mix well to form an aqueous solution. Add the aqueous solution to 300mL of olive oil containing 3g of Span-80 to obtain an O / W type emulsion. Continue stirring until α-TCP solidifies. The above emulsion was transferred to an ice bath, and 300 mL of physiological saline containing 0.1% triton-X was added as a demulsifier. At the same time, 500 μL of 1% (w / v) glutaraldehyde solution was added to further crosslink the gelatin. The mixture was stirred continuously for 2 h. After the reaction was completed, the microspheres were extracted by centrifugation, washed three times with ethanol and water respectively, and freeze-dried for more than 48 h. The product was calcined in a muffle furnace at 1200 °C for 4 h at a heating rate of 5 °C / min to obtain porous hydroxyapatite microspheres. (2) Preparation of modified PMMA bone cement, wherein the percentage of each component is by mass: PMMA bone cement solid powder is composed of 60% PMMA prepolymer powder, 30% porous hydroxyapatite microspheres, 5% barium sulfate as a developer, and 5% benzoyl peroxide as an initiator. The curing solution consists of 95% MMA monomer, 4.9% N,N-dimethyl-p-toluidine accelerator, and 0.1% hydroquinone stabilizer; PMMA bone cement solid powder and curing liquid were mixed at a solid-liquid ratio of 1 g / mL to obtain porous hydroxyapatite microsphere modified PMMA bone cement.
4. The method for preparing PMMA bone cement modified with porous hydroxyapatite microspheres according to claim 3, characterized in that, In step (1), First, dissolve 0.5g of gelatin in 10mL of pure water and add the mixed powder of 0.14g of hydroxyapatite and 6.86g of α-TCP to the above gelatin solution. After mixing evenly, add it to 100mL of olive oil containing 1g of span-80 to obtain an O / W type emulsion. Continue stirring until α-TCP solidifies. The emulsion was transferred to an ice bath, and 100 mL of physiological saline containing 0.1% triton-X was added as a demulsifier. At the same time, 500 μL of 1% (w / v) glutaraldehyde solution was added, and stirring was continued for 2 h. After the reaction was completed, the microspheres were extracted by centrifugation, washed three times with ethanol and water respectively, and then freeze-dried. The product was calcined in a muffle furnace at 1200 °C for 4 h at a heating rate of 5 °C / min to obtain porous hydroxyapatite microspheres.
5. The method for preparing PMMA bone cement modified with porous hydroxyapatite microspheres according to claim 3, characterized in that, In step (2), PMMA bone cement solid powder is composed of 70% PMMA prepolymer powder, 20% porous hydroxyapatite microspheres, 5% barium sulfate as a developer, and 5% benzoyl peroxide as an initiator. The curing solution consists of 97% MMA monomer, 2.9% N,N-dimethyl-p-toluidine accelerator, and 0.1% hydroquinone stabilizer; PMMA bone cement solid powder and curing liquid were mixed at a solid-liquid ratio of 1 g / mL to obtain porous hydroxyapatite microsphere modified PMMA bone cement.
6. The method for preparing PMMA bone cement modified with porous hydroxyapatite microspheres according to claim 3, characterized in that, In step (2), PMMA bone cement solid powder is composed of 50% PMMA prepolymer powder, 40% porous hydroxyapatite microspheres, 5% barium sulfate as a developer, and 5% benzoyl peroxide as an initiator. The curing solution consists of 95% MMA monomer, 4.9% N,N-dimethyl-p-toluidine accelerator, and 0.1% hydroquinone stabilizer; PMMA bone cement solid powder and curing liquid were mixed at a solid-liquid ratio of 1 g / mL to obtain porous hydroxyapatite microsphere modified PMMA bone cement.
7. A porous hydroxyapatite microsphere-modified PMMA bone cement, characterized in that, Prepared by the method according to any one of claims 1-6.
8. The application of the porous hydroxyapatite microsphere-modified PMMA bone cement according to claim 7 in the preparation of materials required for highly active and mechanically controllable PMMA bone cement.