Composite bone wax material as well as preparation method and application thereof

Abstract

The invention provides a composite bone wax material as well as a preparation method and application thereof, and relates to the technical field of medical filling materials. The composite bone wax material provided by the invention is prepared from the following components in parts by mass: 1 to 10 parts of magnesium oxide, 1 to 10 parts of monopotassium phosphate, 1 to 5 parts of pregelatinized starch and 1 to 10 parts of polyethylene glycol, the mass ratio of the magnesium oxide to the monopotassium phosphate is (1-5): 1. In the composite bone wax material disclosed by the invention, magnesium oxide and monopotassium phosphate can react in a body fluid environment to realize rapid self-curing, so that the adhesion capability is favorably improved; by limiting the mass ratio of magnesium oxide to monopotassium phosphate, an alkaline environment can be formed, and formation of new bones can be induced; the pre-gelatinized starch provides thickening and gelling effects, and polyethylene glycol is used as a reaction medium to endow flexibility, so that the composite bone wax material can show better adhesion capacity in a continuous bleeding environment.

Description

Technical Field

[0001] This invention belongs to the field of medical filler materials technology, specifically relating to a composite bone wax material, its preparation method, and its application. Background Technology

[0002] Traditional bone wax, as a type of hemostatic material for bone cutting, is mainly composed of inert wax materials, such as paraffin softened sterile beeswax. It has a certain physical pressure hemostatic effect, but it does not have the ability to self-curing and cannot be absorbed by the human body. It interferes with the bone healing process, is not conducive to the formation of new bone, and is easily separated by blood when in contact with a moist bone wound surface, resulting in poor adhesion.

[0003] To address the problems of traditional bone wax, existing technologies have introduced inorganic salt materials, such as calcium sulfate, which can undergo a dissolution-recrystallization reaction with body fluids, transforming from a malleable state into a hard solid and achieving self-curing. However, calcium sulfate tends to create a localized acidic environment during curing, which is detrimental to new bone formation, and it has poor adhesion in continuous bleeding environments, making it prone to detachment.

[0004] Another approach involves incorporating high-molecular-weight polymers, such as polyethylene glycol, chitosan, and gelatin, to enhance adhesion. While this can improve the contact stability between the material and tissue to some extent, the adhesion effect remains unsatisfactory in continuous bleeding environments. Summary of the Invention

[0005] The purpose of this invention is to provide a composite bone wax material, its preparation method, and its application. The composite bone wax material provided by this invention has good adhesion and is beneficial to the formation of new bone.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: The present invention provides a composite bone wax material, comprising the following components by mass: 1-10 parts of magnesium oxide, 1-10 parts of potassium dihydrogen phosphate, 1-5 parts of pregelatinized starch and 1-10 parts of polyethylene glycol; wherein the mass ratio of magnesium oxide to potassium dihydrogen phosphate is (1-5):1.

[0007] Preferably, by mass parts, it includes the following components: 1-10 parts magnesium oxide, 1-5 parts potassium dihydrogen phosphate, 1-5 parts pregelatinized starch, and 1-10 parts polyethylene glycol.

[0008] Preferably, by mass parts, it includes the following components: 1-10 parts magnesium oxide, 1-5 parts potassium dihydrogen phosphate, 2-5 parts pregelatinized starch, and 1-10 parts polyethylene glycol.

[0009] Preferably, the composite bone wax material further includes the following components: 0.004 to 0.175 parts of surfactant and / or pH buffer.

[0010] Preferably, the polyethylene glycol is one or more polyethylene glycols with a number average molecular weight of 300 to 5000.

[0011] Preferably, the magnesium oxide is lightly calcined magnesium oxide and / or active magnesium oxide.

[0012] Preferably, the pregelatinized starch is obtained by heating and gelatinizing starch and then drying it.

[0013] Preferably, the starch is one or more of corn starch, tapioca starch, and sorghum starch.

[0014] The present invention also provides a method for preparing the composite bone wax material described in the above technical solution, comprising the following steps: after mixing all raw materials evenly, pressing them into a mold and sealing them for storage.

[0015] The present invention also provides the application of the composite bone wax material described in the above technical solution or the composite bone wax material prepared according to the preparation method described in the above technical solution in the preparation of medical filler materials.

[0016] This invention provides a composite bone wax material, comprising the following components by mass: 1-10 parts magnesium oxide, 1-10 parts potassium dihydrogen phosphate, 1-5 parts pregelatinized starch, and 1-10 parts polyethylene glycol; wherein the mass ratio of magnesium oxide to potassium dihydrogen phosphate is (1-5):1. In the composite bone wax material provided by this invention, magnesium oxide and potassium dihydrogen phosphate react in a body fluid environment to generate stable magnesium phosphate and potassium magnesium phosphate hydrate crystals, achieving rapid self-curing and improving adhesion. By limiting the mass ratio of magnesium oxide to potassium dihydrogen phosphate, an alkaline environment can be formed while achieving rapid self-curing and ensuring mechanical strength, which is beneficial for inducing new bone formation. Pregelatinized starch provides thickening and gelling effects, improving the material's handling properties and adhesion. Polyethylene glycol, as a reaction medium, imparts flexibility, can adjust the self-curing rate, and further improves adhesion. Experimental results show that when the composite bone wax material prepared in this invention is applied to the surface of cortical bone and subjected to in vitro adhesion experiments under simulated body fluid flow conditions, the adhesion state of the material remains unchanged after 5 minutes. When the composite bone wax material prepared in this invention is immersed in simulated body fluid and subjected to shaking treatment on a shaker for 12 hours, it still maintains its original shape and has good adhesion properties. The composite bone wax material prepared in this invention can immediately stop bleeding in the humeral defect area of ​​rats. After 4 and 8 weeks of treatment for filling skull defects in rats, the area of ​​new bone formation in rats increased, demonstrating good osteogenic capacity. Attached Figure Description

[0017] Figure 1 These are photographs of the composite bone wax material during the preparation process in Example 1 of this invention. Figure 2These are photographs showing the plasticity and handling properties of the composite bone wax material prepared in Example 1 of this invention. Figure 3 These are underwater self-curing performance test photos of the composite bone wax material prepared in Example 1 of this invention; Figure 4 Photographs showing the adhesion test of traditional bone wax materials and the composite bone wax material prepared in Example 1 of this invention under simulated body fluid environment; Figure 5 This is a graph showing the change in pH value over time of the immersion solution obtained by immersing the composite bone wax material prepared in Example 1 of the present invention in simulated body fluid. Figure 6 These are photographs of the composite bone wax materials prepared in Examples 1-5 and Comparative Examples 1-2 of the present invention before and after 12 hours of shaking treatment in simulated body fluid; Figure 7 Photographs showing the use of a blank control group, traditional bone wax material, and the composite bone wax material prepared in Example 1 of this invention for hemostasis in the femoral defect area of ​​rats; Figure 8 The graph shows the blood loss of the blank control group, traditional bone wax material, and the composite bone wax material prepared in Example 1 of this invention when used for hemostasis in the femoral defect area of ​​rats. Figure 9 Photos showing the use of a blank control group, traditional bone wax material, and the composite bone wax material prepared in Example 1 of this invention for filling rat skull defects; Figure 10 Micro-CT scan 3D reconstruction ROI (5mm in diameter) images of rat skull defects 4 and 8 weeks after filling treatment with blank control group, traditional bone wax material and composite bone wax material prepared in Example 1 of this invention; Figure 11 for Figure 10 BV / TV quantitative analysis chart; Figure 12 for Figure 10 Quantitative analysis chart of Tb.Th; Figure 13 for Figure 10 Quantitative analysis chromatogram of Tb.N; Figure 14 Histological HE staining and Masson staining images of rats at 4 and 8 weeks after the treatment of filling skull defects with the blank control group, traditional bone wax material, and composite bone wax material prepared in Example 1 of this invention. Detailed Implementation

[0018] The present invention provides a composite bone wax material, comprising the following components by mass: 1-10 parts of magnesium oxide, 1-10 parts of potassium dihydrogen phosphate, 1-5 parts of pregelatinized starch and 1-10 parts of polyethylene glycol; wherein the mass ratio of magnesium oxide to potassium dihydrogen phosphate is (1-5):1.

[0019] The composite bone wax material provided by this invention comprises 1 to 10 parts, preferably 3 to 7 parts, of polyethylene glycol by weight. In one embodiment of this invention, the polyethylene glycol may specifically be 1 part, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, or 10 parts. In this invention, polyethylene glycol serves as the reaction medium for magnesium oxide and potassium dihydrogen phosphate, which can adjust the self-curing rate and impart suitable flexibility to the composite bone wax material, improving its handling performance. In a continuously bleeding body fluid environment, it is beneficial to improve the adhesion of the composite bone wax material.

[0020] In this invention, the polyethylene glycol is preferably one or more polyethylene glycols with a number average molecular weight of 300 to 5000. In embodiments of this invention, the polyethylene glycol may specifically be polyethylene glycol with a molecular weight of 400 and 1500 in a mass ratio of 1:4, polyethylene glycol with a molecular weight of 400 and polyethylene glycol with a molecular weight of 1500, or polyethylene glycol with a molecular weight of 400 and 5000 in a mass ratio of 1:4. In this invention, selecting polyethylene glycol with a number average molecular weight within the above-mentioned range allows for the formation of a flexible yet stable matrix structure, enabling the bone wax to maintain good adhesion and sealing effects underwater, while simultaneously achieving suitable biodegradability, creating a favorable microenvironment for subsequent bone healing.

[0021] The composite bone wax material provided by this invention comprises 1 to 10 parts magnesium oxide, preferably 3 to 10 parts, based on a mass fraction of 1 to 10 parts of polyethylene glycol. In one embodiment of this invention, the magnesium oxide may specifically be 1 part, 3 parts, 5 parts, 6 parts, 7 parts, or 10 parts. In this invention, by controlling the amount of magnesium oxide within the above range, the self-curing reaction rate and acidity / alkalinity can be regulated. Insufficient magnesium oxide will result in a slow self-curing rate and acidity, while excessive magnesium oxide will excessively increase the alkalinity of the composite bone wax material. Both insufficient and excessive amounts are detrimental to biocompatibility.

[0022] In this invention, the magnesium oxide is preferably lightly calcined magnesium oxide and / or activated magnesium oxide, more preferably activated magnesium oxide. Activated magnesium oxide has a high specific surface area and high reactivity, which facilitates a thorough self-curing reaction after contact with potassium dihydrogen phosphate, achieving rapid self-curing.

[0023] Based on 1 to 10 parts by mass of polyethylene glycol, the raw materials of the composite bone wax material provided by the present invention include 1 to 10 parts of potassium dihydrogen phosphate, more preferably 1 to 5 parts. As one embodiment of the present invention, the potassium dihydrogen phosphate can specifically be 1 part, 3 parts, 4 parts, 5 parts, or 7 parts. In the present invention, controlling the amount of potassium dihydrogen phosphate within the above range can regulate the self-curing reaction rate and acidity / alkalinity. Potassium dihydrogen phosphate can increase the crystal network density, increase the hardness of the composite bone wax material, and ensure mechanical strength. However, excessive use will lead to acidity, which is detrimental to biocompatibility and reduces plasticity; insufficient use will result in a slow self-curing rate and insufficient mechanical strength after curing.

[0024] In this invention, the mass ratio of magnesium oxide to potassium dihydrogen phosphate is (1~5):1, preferably (1~3):1. In this invention, magnesium oxide and potassium dihydrogen phosphate undergo a self-curing reaction to generate MgKPO4·6H2O and / or Mg3(PO4)2 crystal structures. By controlling the mass ratio of magnesium oxide to potassium dihydrogen phosphate within the above range, it is beneficial to increase the rate of the self-curing reaction. The alkalinity of the composite bone wax material is mainly contributed by magnesium oxide. By controlling the mass ratio of magnesium oxide to potassium dihydrogen phosphate within the above range, an alkaline environment can be formed while achieving rapid self-curing, thereby improving the biocompatibility of the material and promoting the formation of new bone.

[0025] The composite bone wax material provided by this invention comprises 1 to 5 parts, preferably 2 to 5 parts, of pregelatinized starch, based on 1 to 10 parts by weight of polyethylene glycol. In one embodiment of this invention, the pregelatinized starch may specifically be 2, 3, 4, or 5 parts. In this invention, the pregelatinized starch provides thickening and gelling effects, improving the handling properties of the composite bone wax material, enhancing its plasticity, and increasing its adhesion.

[0026] In this invention, the pregelatinized starch is preferably obtained by heating and gelatinizing starch followed by drying. Before heating, the starch is preferably mixed with water at a mass ratio of 1:5. The gelatinization condition is preferably boiling, and after gelatinization, it is preferably cooled to room temperature. The starch is preferably one or more of corn starch, tapioca starch, and sorghum starch. Pregelatinized starch has good hydrophilicity and gelatinization properties, and can quickly form a viscous system upon contact with water or body fluids, which can improve the plasticity, molding stability, and adhesion of composite bone wax materials. The porous structure and water-absorbing swelling properties of pregelatinized starch can absorb water from the blood, concentrate platelets and clotting factors, and accelerate the coagulation process. Pregelatinized starch has excellent biocompatibility, which can reduce the irritation of bone wax to surrounding tissues and reduce inflammatory responses.

[0027] Based on 1-10 parts by weight of polyethylene glycol, the raw materials of the composite bone wax material provided by the present invention preferably further include 0.004-0.175 parts of surfactant and / or pH buffer, more preferably 0.004-0.175 parts of surfactant and pH buffer. The surfactant is preferably Tween-80, Pluronic F68, or lecithin; the pH buffer is preferably Na2HPO4 (0.5-2 wt%), Tris (0.05-0.5 M), or sodium citrate (0.1-1 wt%). The surfactant can effectively reduce surface tension and improve powder dispersion and paste uniformity; the pH buffer can regulate the pH of the system (maintaining it within the range of 7.0-7.4) and slow down the acid-base reaction rate, thereby improving the controllability of the self-curing process and the biocompatibility of the material, further improving the operational performance and biocompatibility of the composite bone wax material.

[0028] The composite bone wax material provided by this invention can quickly achieve self-curing, has good handling performance and plasticity, good molding stability, and good adhesion in a continuously bleeding body fluid environment; it forms an alkaline environment, which improves the biocompatibility of the material and is conducive to the formation of new bone.

[0029] The present invention also provides a method for preparing the composite bone wax material described in the above technical solution, comprising the following steps: after mixing all raw materials evenly, pressing them into a mold and sealing them for storage.

[0030] The present invention does not have any particular limitation on the source of the raw materials used; they can be commercially available or prepared according to methods known in the art.

[0031] This invention involves uniformly mixing all raw materials. There are no particular limitations on the mixing method for all raw materials; uniform mixing is sufficient. In one embodiment, the mixing can be performed using a shaker or a ball mill. In another embodiment, the mixing is carried out in a mortar and pestle until no noticeable particles remain. In yet another embodiment, the mixing can be performed at room temperature or at a temperature below 60°C. In a third embodiment, the mixing is first performed at room temperature and then heated to 60°C.

[0032] In this invention, all raw materials are mixed evenly, then pressed into a mold and sealed for storage. The mold is preferably an aluminum foil tube or a plastic tube.

[0033] The composite bone wax material prepared by the above preparation method can quickly achieve self-curing, has good handling performance and plasticity, good molding stability, and good adhesion in a continuously bleeding body fluid environment; it forms an alkaline environment, which improves the biocompatibility of the material and is conducive to the formation of new bone.

[0034] The present invention also provides the application of the composite bone wax material described in the above technical solution or the composite bone wax material prepared according to the preparation method described in the above technical solution in the preparation of medical filler materials.

[0035] The medical filler material prepared from the composite bone wax material of the present invention can quickly stop bleeding, has self-curing ability, good adhesion, and is conducive to the formation of new bone.

[0036] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0037] Example 1 Composite bone wax material: by mass fraction, it consists of 5 parts magnesium oxide, 5 parts potassium dihydrogen phosphate, 3 parts pregelatinized starch and 5 parts polyethylene glycol. The magnesium oxide is active magnesium oxide and the polyethylene glycol is a mixture of polyethylene glycols with a mass ratio of 1:4 and a molecular weight of 400 and 1500.

[0038] Preparation method of composite bone wax material: All raw materials are stirred evenly in a mortar at room temperature, heated to 60°C and stirred evenly, then pressed into an aluminum foil tube mold and sealed for storage.

[0039] Example 2 The difference between this composite bone wax material and that of Example 1 is that, by mass fraction, it consists of 6 parts magnesium oxide, 4 parts potassium dihydrogen phosphate, 2 parts pregelatinized starch, and 6 parts polyethylene glycol. The magnesium oxide is lightly calcined magnesium oxide, and the polyethylene glycol is a mixture of polyethylene glycols with a mass ratio of 1:4 and a molecular weight of 400 and 1500.

[0040] The preparation method of the composite bone wax material is the same as that in Example 1.

[0041] Example 3 The difference between this composite bone wax material and that of Example 1 is that, by mass fraction, it consists of 7 parts magnesium oxide, 3 parts potassium dihydrogen phosphate, 4 parts pregelatinized starch, and 4 parts polyethylene glycol. The magnesium oxide is active magnesium oxide, and the polyethylene glycol is a single polyethylene glycol with a molecular weight of 400.

[0042] The preparation method of the composite bone wax material is the same as that in Example 1.

[0043] Example 4 The difference between this composite bone wax material and that of Example 1 is that, by mass fraction, it consists of 10 parts magnesium oxide, 5 parts potassium dihydrogen phosphate, 3 parts pregelatinized starch, and 7 parts polyethylene glycol. The magnesium oxide is active magnesium oxide, and the polyethylene glycol is a single polyethylene glycol with a molecular weight of 1500.

[0044] The preparation method of the composite bone wax material is the same as that in Example 1.

[0045] Example 5 The difference between this composite bone wax material and that of Example 1 is that, by mass fraction, it consists of 7 parts magnesium oxide, 5 parts potassium dihydrogen phosphate, 5 parts pregelatinized starch, and 3 parts polyethylene glycol. The magnesium oxide is lightly calcined magnesium oxide, and the polyethylene glycol is a mixture of polyethylene glycols with a mass ratio of 1:4 and a molecular weight of 400 and 5000.

[0046] The preparation method of the composite bone wax material is the same as that in Example 1.

[0047] Comparative Example 1 Calcium phosphate bone cement material: by mass fraction, it consists of 2.5 parts pregelatinized starch, 5 parts α-tricalcium phosphate, and 7.5 parts polyethylene glycol. The polyethylene glycol is a mixture of polyethylene glycols with a molecular weight of 400 and 1500 in a mass ratio of 1:4.

[0048] Preparation method of calcium phosphate bone cement material: All raw materials are stirred evenly in a mortar at room temperature, heated to 60°C and stirred evenly again, then pressed into an aluminum foil tube mold and sealed for storage.

[0049] Comparative Example 2 Calcium sulfate bone cement material: by mass fraction, it consists of 2.5 parts pregelatinized starch, 5 parts calcium sulfate, and 7.5 parts polyethylene glycol. The polyethylene glycol is a mixture of polyethylene glycols with a mass ratio of 1:4 and a molecular weight of 400 and 1500.

[0050] The preparation method of calcium sulfate bone cement material is the same as that of Comparative Example 1.

[0051] Take 2g of the composite bone wax material prepared in Example 1 and knead it manually for 30s at room temperature (22~25℃) to simulate the preoperative softening process. Record the plasticity, operability and adhesion of the sample to the surface of the surgical glove during the kneading process.

[0052] Figure 1 The images shown are actual photos of the composite bone wax material preparation process in Example 1. The left image is a photo of all the raw materials mixed together, and the right image is a photo of the composite bone wax material after it has been manually kneaded.

[0053] Figure 2 These are photographs showing the plasticity and handling properties of the composite bone wax material prepared in Example 1, from left to right: sphere, cube, cuboid, and sheet. Figure 2 It can be seen that the composite bone wax material of this application has good workability and strong plasticity.

[0054] Take 2g of the composite bone wax material prepared in Example 1, knead it by hand for 30s at room temperature (22~25℃) until it becomes spherical, and observe its morphology after soaking in deionized water for 12h.

[0055] Figure 3 These are photographs showing the underwater self-curing performance test of the composite bone wax material prepared in Example 1 of this invention. The left image is a photograph taken after immersion in water for 0 hours, the middle image is a photograph taken after immersion in water for 12 hours, and the right image shows the state after self-curing. Figure 3 It can be seen that the composite bone wax material of this application retains its complete shape and remains as hard particles after being immersed in water for 12 hours, indicating that it has completed self-curing.

[0056] Take 2g of the composite bone wax material prepared in Example 1 and 2g of the traditional bone wax material (Johnson & Johnson W810T bone wax: composed of 86% beeswax, 4% medical petrolatum and 10% soybean oil), and knead them by hand for 30s until they become spherical at room temperature (22~25℃). Apply them to the surface of cortical bone and conduct an in vitro adhesion experiment under simulated body fluid (SBF, pH=7.4±0.1) flow conditions. Record the changes in the adhesion state of the bone wax material within 5 minutes using an electronic timer to analyze its adhesion stability in the simulated body fluid environment.

[0057] Figure 4 Images show the adhesion tests of traditional bone wax materials and the composite bone wax material prepared in Example 1 of this invention under simulated body fluid conditions. The left image shows the in vitro adhesion test process, and the right image shows the adhesion state of the material after 5 minutes. Figure 4 As can be seen, the composite bone wax material prepared in Example 1 of this application was not dispersed by the simulated body fluid. Compared with traditional bone wax materials, the composite bone wax material of this application exhibits good adhesion and structural stability.

[0058] The composite bone wax material prepared in Example 1 was placed in a centrifuge tube at a solid-liquid ratio of 0.05 g / mL, and pre-prepared simulated body fluid (SBF, pH=7.4±0.1) was added. The centrifuge tube was sealed and stored in a 37°C constant temperature oven. After soaking for 1, 3, 5, 7, 10, and 14 days, the centrifuge tube was removed, and the pH value of the soaking solution was measured using a calibrated pH meter. The measurement data were recorded.

[0059] Figure 5 This is a graph showing the change in pH value over time of the immersion solution obtained by immersing the composite bone wax material prepared in Example 1 of the present invention in simulated body fluid. Figure 5The pH values ​​corresponding to days 1, 3, 5, 7, 10, and 14 were 8.55±0.21, 9.06±0.17, 9.68±0.17, 8.20±0.17, 7.74±0.25, and 7.67±0.21, respectively. Figure 5 It can be seen that the composite bone wax material prepared in Example 1 of the present invention can cause a short-term increase in local pH during the dissolution and release process, indicating that the composite bone wax material can form an alkaline environment in simulated body fluid.

[0060] Take 1g of the composite bone wax material prepared in Examples 1-5 and Comparative Examples 1-2 respectively, place them in petri dishes, add simulated body fluid (SBF, pH=7.4±0.1) to completely immerse the samples, and store the petri dishes at a constant temperature of 37℃. Take photographs of each sample before shaking treatment. Then, place the petri dishes on a shaker and shake at 50rpm for 12h. After treatment, take photographs of the samples to compare the appearance changes of each sample under simulated body fluid shaking conditions.

[0061] Figure 6 The images show photographs of the composite bone wax materials prepared in Examples 1-5 and Comparative Examples 1-2 of this invention before and after 12 hours of shaking treatment in simulated body fluid. The top image is the photograph before shaking treatment, and the bottom image is the photograph after 12 hours of shaking treatment. Figure 6 It can be seen that the composite bone wax material prepared in the embodiment of the present invention still maintains its original shape after being shaken on a shaker for 12 hours, and has good adhesion properties; the composite bone wax material prepared in the comparative example cannot maintain its original shape after being shaken on a shaker for 12 hours, and has poor adhesion properties.

[0062] Rats were randomly divided into three groups: Control group (blank control), Bone wax group (traditional bone wax material), and MPP group (composite bone wax material prepared in Example 1), with 3 rats in each group. Before the experiment, several sterile dry cotton balls were weighed using an electronic balance and their initial mass was recorded as M0. All rats were anesthetized using a portable multi-channel small animal anesthesia machine. After the rats entered a deep anesthesia state, the hair in the femur area was removed, and an incision of about 3 cm was made on the skin of the outer thighs of both sides of the rat. The muscles were bluntly dissected until the femur was completely exposed. Then, a non-penetrating hole with a diameter of 2 mm was made in both femurs using a ball-shaped bone burr to establish a femoral hemorrhage model. The Control group received no treatment. The Bone wax group and MPP group had their respective materials filled into the defects for hemostasis. During the bleeding process, the oozing blood was wiped away with pre-weighed dry cotton balls. When no more blood oozed from the femoral defect, wiping was stopped, and the mass of the cotton balls was weighed again and recorded as M1. The bleeding volume M in each group was calculated according to the formula M=M1-M0. By comparing the bleeding volume M values ​​of each group, the hemostatic effect of the composite bone wax material (MPP) prepared in Example 1 and the traditional bone wax material (Bone wax) in the femoral defect model can be evaluated.

[0063] Figure 7 Images showing the use of a blank control group, traditional bone wax material, and the composite bone wax material prepared in Example 1 of this invention for hemostasis in rat femoral defect areas. Figure 8 The graph shows the blood loss of the blank control group, traditional bone wax material, and the composite bone wax material prepared in Example 1 of this invention when used for hemostasis in the femoral defect area of ​​rats. Figure 8 The blood loss in the blank control group, the traditional bone wax material, and the rat defect area hemostasis method of Example 1 of this invention were 0.63±0.07g, 0.05±0.01g, and 0.02±0.01g, respectively. Figure 8 It can be seen that the hemostatic effect of the composite bone wax prepared in Example 1 of the present invention is significantly better than that of traditional bone wax materials.

[0064] Rats were randomly divided into three groups: Control group (blank control), Bone wax group (traditional bone wax material), and MPP group (composite bone wax material prepared in Example 1), with 4 rats in each group. All rats were anesthetized using a portable multi-channel animal anesthesia machine. After hair removal and local disinfection, a longitudinal incision of about 2 cm was made at the midline of the skull, and the skin, flesh, and periosteum were bluntly separated to the surface of the skull. Then, two holes with a diameter of 5 mm were drilled in the skull to establish a rat skull defect model. The defect area in the Control group was not filled, while the defect areas in the Bone wax group and MPP group were filled with the corresponding materials, respectively. After the incision was sutured, penicillin was injected intramuscularly into each rat on the 3rd day after surgery at a concentration of 40,000 to 60,000 units / mL. Four and eight weeks post-surgery, rats were euthanized under anesthesia, and their skulls were removed and fixed with 4% paraformaldehyde. The skull tissue was then scanned on a Micro-CT animal imaging system (Quantum FX; PerkinElmer, United States) with the following imaging parameters: voltage 90 kV, current 180 μA, FOV 40 mm, 360° scan for 4.5 min. After scanning, three-dimensional reconstruction was performed using Caliper Analyze software, and residual tissue other than bone was removed. After three-dimensional reconstruction, the data was imported into the Measure module of Caliper Analyze to measure and record bone mass percentage (BV / TV), trabecular bone thickness (Tb.Th), and trabecular bone number (Tb.N). Subsequently, the specimens were decalcified with EDTA at room temperature for 4 weeks, dehydrated, and embedded in paraffin. Histological sections were cut into 6 μm thick sections and stained with HE and Masson staining to assess bone regeneration.

[0065] Figure 9 Photos of rat skull defect filling treatment using blank control group, traditional bone wax material and composite bone wax material prepared in Example 1 of the present invention (left image is blank control group, right image left is composite bone wax material prepared in Example 1, right image right is traditional bone wax material). Figure 10 The images show 3D reconstructed ROIs (5 mm in diameter) obtained by Micro-CT scanning at 4 and 8 weeks after rat skull defect filling treatment, using a blank control group, traditional bone wax material, and the composite bone wax material prepared in Example 1 of this invention. Figure 11 for Figure 10 BV / TV quantitative analysis chart, Figure 12 for Figure 10 Quantitative analysis chromatogram of Tb.Th Figure 13 for Figure 10 Tb.N quantitative analysis chromatogram, Figure 14 Four weeks after rat skull defect filling treatment, the blank control group, traditional bone wax material, and the composite bone wax material prepared in Example 1 of this invention were used. Figure 14 (a) and 8 weeks ( Figure 14 Histological HE staining and Masson staining (FT: fibrous tissue, Bone wax, MPP: , NB: new bone) in b).

[0066] Figure 11 The bone mass percentages of the blank control group, traditional bone wax material, and composite bone wax material prepared in Example 1 of this invention were 6.01±1.58%, 4.41±1.89%, and 17.29±3.50% at 4 weeks, respectively; and the bone mass percentages of the blank control group, traditional bone wax material, and composite bone wax material prepared in Example 1 of this invention were 15.05±3.53%, 11.57±1.38%, and 27.80±6.85% at 8 weeks, respectively. Figure 12 The trabecular bone thicknesses of the blank control group, traditional bone wax material, and composite bone wax material prepared in Example 1 of this invention were 0.07±0.02 mm, 0.07±0.01 mm, and 0.12±0.03 mm, respectively, after 4 weeks. The trabecular bone thicknesses of the blank control group, traditional bone wax material, and composite bone wax material prepared in Example 1 of this invention were 0.11±0.01 mm, 0.10±0.03 mm, and 0.16±0.02 mm, respectively, after 8 weeks. Figure 13 The number of trabeculae (expressed as the number of trabecular intercepts per millimeter) in the 4-week blank control group, traditional bone wax material, and the composite bone wax material prepared in Example 1 of this invention were 0.73±0.08 1 / mm, 0.63±0.29 1 / mm, and 1.48±0.13 1 / mm, respectively. The number of trabeculae in the 8-week blank control group, traditional bone wax material, and the composite bone wax material prepared in Example 1 of this invention were 1.11±0.16 1 / mm, 1.10±0.34 1 / mm, and 2.05±0.41 1 / mm, respectively. Figures 11-13 It can be seen that the composite bone wax material prepared in Example 1 at 4 and 8 weeks post-surgery showed significantly higher percentage of bone volume (BV / TV), trabecular thickness (Tb.Th), and number of trabecular bones (Tb.N) after filling rat skull defects, indicating that it has better osteogenic capacity.

[0067] Figure 14 Four weeks after rat skull defect filling treatment, the blank control group, traditional bone wax material, and the composite bone wax material prepared in Example 1 of this invention were used. Figure 14 (a) and 8 weeks ( Figure 14 Histological HE staining and Masson staining images (FT: fibrous tissue, Bone wax: traditional bone wax material, MPP: composite bone wax material, NB: new bone) from b) Figure 14 It can be seen that the composite bone wax material prepared in Example 1, after 4 and 8 weeks post-surgery, significantly increased the area of ​​new bone formation after being used to fill skull defects in rats, indicating that it has good osteogenic capacity.

[0068] As can be seen from the above examples and comparative examples, the composite bone wax material prepared by the present invention has good operability and strong plasticity; it has good stability in simulated body fluids and good adhesion properties; it has good hemostatic effect and good osteogenic ability.

[0069] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle 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 composite bone wax material comprising, by mass fraction, 1-10 parts of magnesium oxide, 1-10 parts of potassium dihydrogen phosphate, 1-5 parts of pregelatinized starch, and 1-10 parts of polyethylene glycol. The mass ratio of the magnesium oxide to the potassium dihydrogen phosphate is (1-5) :

1.

2. The composite bone wax material of claim 1, wherein, comprising, by mass fraction, 1-10 parts of magnesium oxide, 1-5 parts of potassium dihydrogen phosphate, 1-5 parts of pregelatinized starch, and 1-10 parts of polyethylene glycol.

3. The composite bone wax material of claim 2, wherein, comprising, by mass fraction, 1-10 parts of magnesium oxide, 1-5 parts of potassium dihydrogen phosphate, 2-5 parts of pregelatinized starch, and 1-10 parts of polyethylene glycol.

4. The composite bone wax material according to any one of claims 1 to 3, wherein The composite bone wax material further comprises 0.004-0.175 parts of a surfactant and / or a pH buffer.

5. The composite bone wax material according to any one of claims 1 to 3, wherein The polyethylene glycol is one or more of polyethylene glycols with a number average molecular weight of 300-5000.

6. The composite bone wax material according to any one of claims 1 to 3, wherein The magnesium oxide is light-burned magnesium oxide and / or active magnesium oxide.

7. The composite bone wax material according to any one of claims 1 to 3, wherein The pregelatinized starch is prepared by heating and gelatinizing starch and then drying.

8. The composite bone wax material of claim 7, wherein, The starch is one or more of corn starch, cassava starch, and sorghum starch.

9. A method of preparing the composite bone wax material according to any one of claims 1 to 8, comprising the steps of: After mixing all the raw materials uniformly, the mixture is pressed into a mold and sealed for storage. 10.Use of the composite bone wax material according to any one of claims 1-8 or prepared according to the method of claim 9 in the preparation of a medical filling material.

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