Modified PMMA bone cement powder and preparation method thereof, modified PMMA bone cement and preparation method and application thereof

Abstract

The invention provides modified PMMA bone cement powder and a preparation method thereof, modified PMMA bone cement and a preparation method and application thereof, and relates to the technical field of biomedical materials. The modified PMMA bone cement powder comprises 5-20 wt% of a modified magnesium-containing material, 3-7 wt% of an initiator and the balance of PMMA powder; the modified magnesium-containing material comprises a magnesium-containing material (magnesium or magnesium-zinc alloy powder) and an MgF2 layer coated on the surface of the magnesium-containing material. Bone cement added with the modified PMMA bone cement powder is used as a skull defect repair material, after implantation and solidification, through slow release of magnesium ions (which can contain zinc ions) in modified magnesium or magnesium-zinc alloy powder, on the basis of ensuring safety and effective skull repair, through multi-channel anti-inflammation (Mg < 2 + > (which can comprise Zn < 2 + >), hydroxyl and hydrogen synergistic anti-inflammation), the anti-inflammation effect is remarkable, and the anti-inflammation effect is good. And long-term stability of the structure can be guaranteed, and remarkable mechanical attenuation or structural failure is avoided.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biomedical materials, and particularly relates to a modified PMMA bone cement powder, a preparation method thereof, a modified PMMA bone cement and a preparation method and application thereof. BACKGROUND

[0002] The development of skull defect repair materials has experienced evolution from inert materials (such as titanium mesh and PEEK) to bioactive materials (such as hydroxyapatite and calcium phosphate cement). Traditional materials (such as titanium alloy and PEEK) have excellent mechanical properties, but lack bioactivity, easily causing postoperative inflammation or infection, and affecting medical imaging examination. Calcium phosphate cement (CPC) has bone conduction, but has high brittleness, insufficient compressive strength, uncontrollable degradation, and cannot inhibit postoperative inflammation. In recent years, degradable magnesium-based PMMA (polymethyl methacrylate) bone cement materials have attracted widespread attention due to their biocompatibility and osteogenic ability. Studies have shown that magnesium ions (Mg 2+ ) can reduce the release of inflammatory factors by inhibiting the NF-κB pathway and promote bone regeneration. However, pure magnesium degrades too quickly in a physiological environment, leading to rapid decline in mechanical properties and possible adverse reactions caused by local pH increase and hydrogen accumulation; and existing magnesium-based materials rely on single Mg 2+ release for anti-inflammatory, lack of synergistic anti-inflammatory strategies, and are difficult to cope with complex postoperative microenvironments. SUMMARY

[0003] Therefore, the present application aims to provide a modified PMMA bone cement powder, a preparation method thereof, a modified PMMA bone cement and a preparation method and application thereof. The modified PMMA bone cement powder provided by the present application can enable PMMA bone cement to have excellent anti-inflammatory and bone integration functions, while having good mechanical properties.

[0004] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions: The present application provides a modified PMMA bone cement powder, comprising the following components by mass percentage: 5-20% of a modified magnesium-containing material, 3-7% of an initiator, and the balance of PMMA powder; the modified magnesium-containing material comprises a magnesium-containing material and a MgF2 layer coated on the surface of the magnesium-containing material, and the magnesium-containing material is magnesium or magnesium-zinc alloy powder.

[0005] Preferably, the mass fraction of zinc in the magnesium-zinc alloy powder is 0-6%, and is not 0.

[0006] Preferably, the particle size of the magnesium-containing material is 1-50 μm.

[0007] Preferably, the initiator comprises benzoyl peroxide.

[0008] The application provides a preparation method of the modified PMMA bone cement powder, and comprises the following steps: The magnesium-containing material is mixed with the aqueous HF solution to perform modification treatment, so that the modified magnesium-containing material is obtained; The modified magnesium-containing material, the initiator and the PMMA powder are mixed to obtain the modified PMMA bone cement powder.

[0009] Preferably, the mass fraction of the aqueous HF solution is 5-10%, the use ratio of the magnesium-containing material to the aqueous HF solution is 1g:10mL, the modification treatment is performed at a temperature of 25-30℃ for 30-60min.

[0010] The application provides a modified PMMA bone cement, which comprises a modified PMMA bone cement powder and a curing liquid, wherein the modified PMMA bone cement powder is the modified PMMA bone cement powder in the above technical solution or the modified PMMA bone cement powder prepared by the preparation method in the above technical solution.

[0011] Preferably, the curing liquid comprises methyl methacrylate.

[0012] The application provides a preparation method of the modified PMMA bone cement in the above technical solution, and comprises the following steps: The modified PMMA bone cement powder and the curing liquid are mixed to obtain the modified PMMA bone cement.

[0013] The application provides an application of the modified PMMA bone cement in the above technical solution or the modified PMMA bone cement prepared by the preparation method in the above technical solution as a skull repair material.

[0014] The application provides a modified PMMA bone cement powder, which comprises the following components in mass percentage: 5-20% of a modified magnesium-containing material, 3-7% of an initiator and the rest of PMMA powder; the modified magnesium-containing material comprises a magnesium-containing material and a MgF2 layer coated on the surface of the magnesium-containing material, and the magnesium-containing material is magnesium or magnesium-zinc alloy powder. Compared with the prior art, the application has the following beneficial effects: the MgF2 layer is coated on the surface of the magnesium or magnesium-zinc alloy powder as a passivation layer, the passivation layer can significantly delay the degradation of magnesium, the degradation period is prolonged from less than 14 days to more than 28 days, and the period is matched with the natural regeneration time window of the skull; the magnesium or magnesium-zinc alloy coated with the MgF2 layer is combined with the PMMA bone cement, Mg 2+ (magnesium-zinc alloy also comprises Zn 2+The synergistic anti-inflammatory effects of hydroxyl (a magnesium degradation product) and hydrogen (a magnesium degradation product) form a multi-pathway anti-inflammatory system. The slow degradation of modified magnesium or magnesium-zinc alloy powder, and its dispersion reinforcement within a high-strength PMMA bone cement matrix, also contribute to the excellent mechanical properties of PMMA bone cement. The modified PMMA bone cement powder provided by this invention enables PMMA bone cement to possess excellent anti-inflammatory and osteointegration-promoting functions, while also exhibiting good mechanical properties.

[0015] This invention provides a modified PMMA bone cement, comprising modified PMMA bone cement powder and a curing liquid. The modified PMMA bone cement powder is the modified PMMA bone cement powder described in the above technical solutions or the modified PMMA bone cement powder prepared by the preparation method described in the above technical solutions. As a cranial defect repair material, the modified PMMA bone cement provided by this invention, after implantation and curing, through the sustained release of magnesium ions (or potentially zinc ions) from surface-modified magnesium powder or magnesium-zinc alloy powder, significantly inhibits inflammation while ensuring safety and effective cranial repair, and guarantees long-term structural stability without significant mechanical attenuation or structural failure. Attached Figure Description

[0016] Figure 1 The anti-inflammatory effect of the modified PMMA bone cement prepared in Examples 1 and 2; Figure 2 The results of the biocompatibility test of the modified PMMA bone cement prepared in Example 1 are shown. Detailed Implementation

[0017] This invention provides a modified PMMA bone cement powder, comprising the following components in weight percentage: The modified magnesium-containing material comprises 5-20%, an initiator comprising 3-7%, and the remainder being PMMA powder; the modified magnesium-containing material comprises a magnesium-containing material and a MgF2 layer coating the surface of the magnesium-containing material, wherein the magnesium-containing material is magnesium or magnesium-zinc alloy powder.

[0018] The modified PMMA bone cement powder provided by this invention comprises 5-20% modified magnesium-containing material, which can be 5%, 10%, 15%, or 20%. In this invention, the modified magnesium-containing material comprises a magnesium-containing material and a MgF2 layer coating the surface of the magnesium-containing material. In this invention, the magnesium-containing material is magnesium or magnesium-zinc alloy powder, preferably with a purity greater than 99.9%; the mass fraction of zinc in the magnesium-zinc alloy powder is preferably 0-6% (and not 0), which can be 2% (i.e., Mg-2Zn alloy), 4%, or 6%. This invention does not have special requirements regarding the source of the magnesium-zinc alloy powder; magnesium-zinc alloy powder with a corresponding zinc content well known to those skilled in the art can be used. In this invention, the particle size of the magnesium-containing material is preferably 1-50 μm. In the embodiments of this invention, the particle size of the magnesium powder is 1-10 μm, and the particle size of the magnesium-zinc alloy powder is 10-50 μm.

[0019] This invention modifies magnesium or magnesium-zinc alloy powder by forming a MgF2 layer on the surface. The MgF2 layer acts as a passivation protective layer, significantly delaying magnesium degradation. Combining the modified magnesium or magnesium-zinc alloy powder with PMMA bone cement achieves the desired magnesium degradation. 2+ (For magnesium-zinc alloys, Zn is also included) 2+ The modified magnesium or magnesium-zinc alloy powder exhibits synergistic anti-inflammatory effects with hydroxide ions (magnesium degradation products) and hydrogen (magnesium degradation products); and the modified magnesium or magnesium-zinc alloy powder has uniform dispersion and stability in the PMMA system. The slow degradation of the modified magnesium or magnesium-zinc alloy powder, as well as its dispersion reinforcement in the high-strength PMMA bone cement matrix, also gives the PMMA bone cement good mechanical properties.

[0020] The modified PMMA bone cement powder provided by this invention includes 3-7% initiator, which can be 5%. In this invention, the initiator preferably includes benzoyl peroxide (BPO).

[0021] The modified PMMA bone cement powder provided by this invention includes PMMA (polymethyl methacrylate) powder as the remainder. This invention does not have special requirements for the PMMA powder; commonly used PMMA powder in PMMA bone cement can be used. In the embodiments of this invention, the PMMA powder used is designated Palacos® R (powder).

[0022] This invention provides a method for preparing the modified PMMA bone cement powder described in the above technical solution, comprising the following steps: The magnesium-containing material was mixed with an HF aqueous solution for modification treatment to obtain a modified magnesium-containing material; The modified magnesium-containing material, initiator, and PMMA powder are mixed to obtain the modified PMMA bone cement powder.

[0023] Unless otherwise specified, all raw materials involved in this invention are commercially available products well known in the art.

[0024] This invention modifies magnesium-containing materials (magnesium or magnesium-zinc alloy powder) by mixing them with an HF aqueous solution to obtain modified magnesium-containing materials.

[0025] In this invention, the magnesium or magnesium-zinc alloy powder is preferably pretreated before use. The pretreatment preferably includes sequentially performing a first cleaning, a second cleaning, and drying on the magnesium or magnesium-zinc alloy powder. In this invention, the first cleaning preferably uses anhydrous ethanol for ultrasonic cleaning, and the ultrasonic cleaning time is preferably 10 minutes; the ultrasonic cleaning removes grease and oxides from the surface of the magnesium or magnesium-zinc alloy powder. In this invention, the second cleaning preferably uses deionized water for washing, and the washing is preferably performed three times. In this invention, the drying is preferably vacuum drying, and the vacuum drying temperature is preferably 50°C, and the time is preferably 2 hours.

[0026] In this invention, the mass fraction of the HF aqueous solution is preferably 5-10%, which can be 5%, 6%, 7%, 8%, 9%, or 10%. The ratio of the magnesium-containing material to the HF aqueous solution (i.e., the solid-liquid ratio) is preferably 1g:10mL. Preferably, the magnesium-containing material (magnesium or magnesium-zinc alloy powder) is immersed in the HF aqueous solution. In this invention, the temperature of the modification treatment is preferably 25-30℃, and the time is preferably 30-60 min, which can be 30, 40, 50, or 60 min. The temperature of the modification treatment can be achieved through a water bath. Through the modification treatment, a dense MgF2 layer is formed on the surface of the magnesium or magnesium-zinc alloy powder, achieving passivation of the magnesium or magnesium-zinc alloy powder.

[0027] After the modification treatment is completed, the modified material is preferably immediately rinsed with deionized water, dehydrated with anhydrous ethanol, and vacuum dried to obtain the modified magnesium-containing material. In this invention, the deionized water rinsing is continued until neutral; the vacuum drying temperature is preferably 60°C, and the time is preferably 4 hours, as vacuum drying can avoid oxidation.

[0028] After obtaining the modified magnesium-containing material, the present invention mixes the modified magnesium-containing material, initiator and PMMA powder to obtain the modified PMMA bone cement powder.

[0029] In this invention, the preferred method of mixing is to add the modified magnesium-containing material to PMMA powder and mix it evenly; then add an initiator thereto.

[0030] This invention provides a modified PMMA bone cement, comprising modified PMMA bone cement powder and a curing liquid, wherein the modified PMMA bone cement powder is the modified PMMA bone cement powder described in the above technical solution or the modified PMMA bone cement powder prepared by the preparation method described in the above technical solution.

[0031] In this invention, the curing liquid preferably includes methyl methacrylate (MMA); this invention does not have any special requirements on the amount of curing liquid used, and the modified PMMA bone cement powder can be fully cured by using the amount of curing liquid known to those skilled in the art.

[0032] The modified PMMA bone cement system provided by this invention solves the core bottleneck of existing bone cement technology. Regarding degradation control, the MgF2 passivation layer extends the magnesium degradation cycle from less than 14 days to more than 28 days, matching the natural regeneration time window of the skull; in terms of function, Mg... 2+ Hydrogen inhibits inflammation, Zn 2+ Enhanced antibacterial and anti-inflammatory properties create a multi-pathway anti-inflammatory system. In clinical applications, PMMA-based materials meet the need for rapid intraoperative curing. The modified PMMA bone cement provided by this invention has three major advantages: controllable degradation, synergistic anti-inflammatory effects, and clinical universality, offering a safer and more efficient solution for skull defect repair.

[0033] This invention provides a method for preparing the modified PMMA bone cement described in the above technical solution, comprising the following steps: The modified PMMA bone cement powder and the curing liquid are mixed to obtain the modified PMMA bone cement.

[0034] In this invention, the preferred method for mixing the modified PMMA bone cement powder and the curing liquid is to inject the modified PMMA bone cement powder into the curing liquid and stir until it becomes a paste.

[0035] This invention provides the application of the modified PMMA bone cement described in the above technical solutions or the modified PMMA bone cement prepared by the preparation method described in the above technical solutions as a cranioplasty material.

[0036] In the application, the modified PMMA bone cement (semi-solid) is implanted into the skull defect and solidifies within 3 minutes.

[0037] In traditional bone cement containing magnesium oxide or magnesium ions, magnesium oxide undergoes direct hydrolysis or magnesium ions are released directly at a relatively fast rate, resulting in a single active product. This invention, however, utilizes surface-modified magnesium powder or magnesium-zinc alloy to passivate the continuous corrosion and slow degradation of magnesium particles during implantation. This process continuously and very slowly generates hydrogen and hydroxide ions (in addition to magnesium ions), eliminating reactive oxygen species (ROS) in surrounding tissues and better suppressing inflammation. This invention addresses the clinical application of cranioplasty, resolving the problems of cranioplasty injury and inflammation in surrounding tissues.

[0038] To further illustrate the present invention, the modified PMMA bone cement powder and its preparation method, as well as the modified PMMA bone cement and its preparation method and application, provided by the present invention are described in detail below with reference to examples. However, these descriptions should not be construed as limiting the scope of protection of the present invention.

[0039] Example 1 Step 1: Magnesium powder modification treatment Raw material: High-purity magnesium powder (purity 99.99%, particle size 1~10μm).

[0040] Preparation of modified magnesium powder: The magnesium powder was ultrasonically cleaned in anhydrous ethanol for 10 min to remove surface grease; washed 3 times with deionized water and vacuum dried at 50℃ for 2 h; an 8wt% HF aqueous solution was prepared in a polytetrafluoroethylene container; the magnesium powder was immersed in the HF aqueous solution at a solid-liquid ratio of 1:10 (g / mL) and reacted in a water bath at 30℃ for 40 min; after passivation, it was immediately rinsed with deionized water until neutral, dehydrated with anhydrous ethanol, and vacuum dried at 60℃ for 4 h.

[0041] Step 2: Bone cement composite (i.e., preparation of modified PMMA bone cement) Formulation: PMMA powder (commercial brand Palacos® R PMMA bone cement (powder)): 80wt%; modified magnesium powder: 15wt%; initiator (benzoyl peroxide, BPO): 5wt%.

[0042] Mixing: Premix the modified magnesium powder with PMMA powder, add BPO, and then inject the resulting mixed powder into the methyl methacrylate (MMA) liquid phase (i.e., curing liquid). Stir until a paste is formed. The ratio of the mixed powder to the MMA liquid phase is 40g:20mL.

[0043] Step 3: Implantation and Shaping Semi-solid bone cement was injected into a rat skull defect model (5 mm in diameter) and solidified within 3 minutes.

[0044] Example 2 Step 1: Modification treatment of magnesium-zinc alloy powder Raw material: High-purity magnesium-zinc alloy powder (Mg-2Zn alloy, purity 99.95%, particle size 10~50μm).

[0045] Preparation of modified magnesium-zinc alloy powder: The magnesium-zinc alloy powder was ultrasonically cleaned in anhydrous ethanol for 10 min to remove surface grease; washed 3 times with deionized water and vacuum dried at 50℃ for 2 h; a 10 wt% HF aqueous solution was prepared in a polytetrafluoroethylene container; the magnesium-zinc alloy powder was immersed in the HF aqueous solution at a solid-liquid ratio of 1:10 (g / mL) and reacted in a water bath at 30℃ for 50 min; after passivation, it was immediately rinsed with deionized water until neutral, dehydrated with anhydrous ethanol, and vacuum dried at 60℃ for 4 h.

[0046] Step 2: Bone cement composite (i.e., preparation of modified PMMA bone cement) Formulation: PMMA powder (commercial brand Palacos® R PMMA bone cement (powder)): 85wt%; modified magnesium-zinc alloy powder: 10wt%; initiator (benzoyl peroxide, BPO): 5wt%.

[0047] Mixing: Premix the modified magnesium-zinc alloy powder with PMMA powder, add BPO, and then inject the resulting mixed powder into the methyl methacrylate (MMA) liquid phase (i.e., curing liquid). Stir until a paste is formed. The ratio of the amount of the resulting mixed powder to the amount of MMA liquid phase is 40g:20mL.

[0048] Step 3: Implantation and Shaping Semi-solid bone cement was injected into a rat skull defect model (5 mm in diameter) and solidified within 3 minutes.

[0049] The modified PMMA bone cement prepared in the examples was subjected to performance tests, as detailed below: (a) Anti-inflammatory effect test Test method: Real-time quantitative PCR assay: Total RNA was extracted from treated macrophages and purified using the Qiagen RNeasy Plus kit. Complementary DNA to the reverse transcriptome was synthesized using Takara RT Master Mix (Takara) as recommended by the manufacturer. Primers for RT-qPCR detection were produced by Life Technologies (ThermoFisher scientific) based on sequences obtained from Primer Bank (https: / / pga.mgh.harvard.edu / primerBank / ). cDNA target amplification and detection were performed using the SYBR GreenPremix Ex Taq (Takara) on the StepOne Plus real-time PCR system (Applied Biosystems) to detect the expression of osteogenic pro-inflammatory genes (CCL2, CD11c, TNF-α, and IL-6), anti-inflammatory genes (MRC1, CD301, ARG1, and IL-10), and inflammasome-related genes (NLRP3, Caspase-1, IL-1β, and IL-18). All reactions were performed triplicate and normalized to determine the expression profile of ACTB. Using the ΔΔCt technique, the results are shown as folding changes.

[0050] Figure 1 The anti-inflammatory effect of the modified PMMA bone cement prepared in Examples 1 and 2 is discussed. Figure 1 In this context, "bone cement + magnesium" refers to the modified PMMA bone cement prepared in Example 1, "bone cement + magnesium-zinc alloy" refers to the modified PMMA bone cement prepared in Example 2, "bone cement" is bone cement with the modified magnesium powder omitted in Example 1, and Ti represents titanium alloy.

[0051] Depend on Figure 1 It can be seen that the modified PMMA bone cement prepared in Example 1 has a significant anti-inflammatory effect compared with the Ti group and the bone cement group, which downregulates pro-inflammatory factors and upregulates anti-inflammatory factors in intracranial cells. The modified PMMA bone cement prepared in Example 2 has a better anti-inflammatory effect than that in Example 1.

[0052] (ii) Biocompatibility testing Test Methods: Histological analysis. To evaluate the biocompatibility of the bone cement material, mice were sacrificed 8 weeks after bone cement injection, and major organs (lung, liver, kidney, skeletal muscle, and spleen) were harvested. All tissues were fixed in 4% paraformaldehyde solution for 24 h, dehydrated by graded ethanol series, embedded in paraffin, and sectioned at a thickness of 4 μm. Hematoxylin and eosin (H&E) staining methods were as follows: dewaxed sections were rehydrated, stained with Mayer's hematoxylin for 5 min, differentiated in 1% acidic alcohol, stained with eosin for 2 min, and then coated with neutral balsam. Pathological evaluation was performed under a light microscope (DM4000, Leica, Germany), including assessment of structural integrity, inflammatory infiltration, and fibrotic changes.

[0053] Figure 2 The biocompatibility test results (scale bar is 100 μm) of the modified PMMA bone cement prepared in Example 1 are shown. Figure 2 In the text, "bone cement + Mg group" refers to the modified PMMA bone cement prepared in Example 1, "bone cement group" refers to bone cement after omitting the modified magnesium powder in Example 1, and "Ti group" refers to titanium alloy. It can be seen that the modified PMMA bone cement, Ti group, and bone cement group prepared in Example 1 all have no toxic side effects and good biocompatibility.

[0054] (III) Mechanical property testing Bone cement samples were subjected to room temperature compression tests using a universal mechanical testing machine. The results showed that the compressive strength of the bone cement sample (bone cement with modified magnesium powder omitted in Example 1) was 77 MPa, the compressive strength of the magnesium-containing bone cement (modified PMMA bone cement prepared in Example 1) was 82 MPa, and the compressive strength of the modified PMMA bone cement prepared in Example 2 was 84 MPa. The mechanical strength of the samples remained above 50 MPa throughout the degradation process.

[0055] As can be seen from the above embodiments, compared with titanium alloys and ordinary bone cement as skull repair materials, the bone cement of the present invention containing modified magnesium or magnesium-zinc alloy powder has a significant effect on inhibiting inflammation while ensuring safety and effective skull repair, and can ensure long-term structural stability without significant mechanical attenuation or structural failure.

[0056] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A modified PMMA bone cement powder characterized in that, Comprise the following components by mass percentage: 5-20% of modified magnesium-containing material, 3-7% of initiator and the rest of PMMA powder; the modified magnesium-containing material comprises a magnesium-containing material and a MgF2 layer coated on the surface of the magnesium-containing material, and the magnesium-containing material is magnesium or magnesium-zinc alloy powder.

2. The modified PMMA bone cement powder according to claim 1, characterized in that The mass fraction of zinc in the magnesium-zinc alloy powder is 0-6%, and is not 0.

3. The modified PMMA bone cement powder according to claim 1 or 2, characterized in that The particle size of the magnesium-containing material is 1-50 μm.

4. The modified PMMA bone cement powder according to claim 1, characterized in that, The initiator comprises benzoyl peroxide.

5. The method for preparing the modified PMMA bone cement powder according to any one of claims 1 to 4, characterized in that, Comprise the following steps: Mix the magnesium-containing material with an aqueous HF solution to perform modification treatment, to obtain a modified magnesium-containing material; Mix the modified magnesium-containing material, initiator and PMMA powder to obtain the modified PMMA bone cement powder.

6. The production method according to claim 5, wherein The mass fraction of the aqueous HF solution is 5-10%, and the usage ratio of the magnesium-containing material to the aqueous HF solution is 1 g:10 mL; the modification treatment is performed at a temperature of 25-30 °C for 30-60 min.

7. A modified PMMA bone cement, characterized in that Comprise modified PMMA bone cement powder and a curing liquid, and the modified PMMA bone cement powder is the modified PMMA bone cement powder according to any one of claims 1-4 or prepared by the preparation method of claim 5 or 6.

8. The modified PMMA bone cement according to claim 7, characterized in that The curing liquid comprises methyl methacrylate.

9. The method of producing the modified PMMA bone cement according to claim 7 or 8, characterized in that, Comprise the following steps: Mix the modified PMMA bone cement powder and the curing liquid to obtain the modified PMMA bone cement.

10. Use of the modified PMMA bone cement according to claim 7 or 8 or prepared by the preparation method of claim 9 as a skull repair material.

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