Premixed bone putty material and preparation method thereof

Abstract

The invention provides a premixed bone putty material and a preparation method thereof, and belongs to the field of bone repair. The invention provides a premixed bone putty material which comprises the following components in parts by mass: 1-5 parts of starch; 5-10 parts of biological ceramic powder; 1 to 12 parts of glycerol; 0.01 to 1 part of a shaping agent; and 0-10 parts of water. By adjusting the proportion of the starch, the glycerol and the biological ceramic powder, the pre-mixed bone putty material can reach expected curing strength, the tissue bonding strength of the pre-mixed bone putty material is greatly enhanced, and the adverse effects such as separation after filling of the pre-mixed bone putty material can be effectively prevented; and the long-term storage and instant use of the premixed bone putty material can be realized and the use hand feeling can be regulated and controlled by changing the content of the shaping agent and the water, so that the material can adapt to more operation scenes and the operation requirements of technicians.

Description

Technical Field

[0001] The invention relates to the field of bone repair, and in particular to a premixed bone putty material and a preparation method thereof. Background Art

[0002] Bone defects caused by diseases or high-energy trauma are very common in clinical practice. Affected by the patient's own health status and the limitation of bone self-healing ability, patients with bone defects often suffer from serious consequences such as delayed bone healing or bone nonunion if no human intervention is taken. The use of tissue engineering materials to achieve regenerative repair of patients' bone defects is of great significance for restoring the physiological structure of patients' bone tissue and improving patients' motor function. Therefore, the selection of artificial bone repair materials is one of the key issues in current clinical bone repair surgery.

[0003] Premixed bone putty materials are one of the most widely used bone repair material formulations. This type of material is mostly composed of artificially synthesized bioceramics, allogeneic bone or xenogeneic bone and other osteogenic active components, compounded with glycerol, cellulose, water or collagen and water, and can be used to fill the defect during surgery to adapt to the shape of the bone defect and play a role in inducing bone repair after surgery. OsteoCove TM Putty and Medtronic The BoneGraft series of products have been used extensively in clinical practice and have demonstrated good bone filling effects. However, due to the limitations of the materials selected, this type of premixed bone putty has long-term problems such as insufficient tissue adhesion strength and easy dislocation after implantation. There are still certain risks in its clinical use, which affects the patient's postoperative recovery. At the same time, because these materials contain a high proportion of water, there is a problem of continuous hydrolysis of bone repair materials and added materials such as cellulose and collagen during the storage of the product. In addition, the excess water phase limits the use of self-curing artificial bone material powders such as calcium sulfate, calcium phosphate and magnesium phosphate bone cement in premixed bone putty materials, because these materials will react and solidify quickly when exposed to water, making it impossible to achieve long-term storage and immediate use of the materials. Summary of the invention

[0004] The invention provides a premixed bone putty material and a preparation method thereof. The premixed bone putty material has high bonding strength and can be stored for a long time and used immediately.

[0005] The present invention provides a premixed bone putty material, which comprises the following components in parts by mass:

[0006]

[0007] Preferably, the starch comprises one or more of sulfonated starch, hydroxypropyl distarch phosphate, corn starch, waxy starch, tapioca starch, sorghum starch, sweet potato starch, taro starch, yam starch, broad bean starch, lentil starch and pea starch.

[0008] Preferably, the plasticizer includes one or more of polyethylene glycol, borax solution, polyphosphate and poloxamer solution;

[0009] The mass fraction of borax in the borax solution is 1-10%, and the mass fraction of poloxamer in the poloxamer solution is 1-10%.

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

[0011] Preferably, the polyethylene glycol comprises a mixture of polyethylene glycol 400 and polyethylene glycol 1500 or a mixture of polyethylene glycol 600 and polyethylene glycol 1500.

[0012] Preferably, the bioceramic powder includes one or more of allogeneic bone, xenogeneic bone, hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate, biphasic calcium phosphate, calcium sulfate, magnesium phosphate, polycalcium phosphate, tetracalcium phosphate, phosphoserine-modified calcium phosphate, magnesium polyphosphate and bioactive glass.

[0013] Preferably, the particle size of the bioceramic powder is less than 200 μm.

[0014] The present invention also provides a method for preparing the premixed bone putty material described in the above technical solution, comprising the following steps:

[0015] Performing a first mixing of starch and bioceramic powder to obtain a first mixture;

[0016] The first mixture is mixed with glycerol and water to obtain a second mixture;

[0017] The second mixture is mixed with the plasticizer for a third time to obtain the premixed bone putty material.

[0018] Preferably, before the first mixing, the method further comprises: pre-gelatinizing the starch;

[0019] The pregelatinization comprises the following steps:

[0020] The starch is dispersed in water and then boiled, and then the obtained solution is cooled and dried to obtain the pregelatinized starch.

[0021] Preferably, after the third mixing, the method further comprises: allowing the obtained third mixture to stand and extrude.

[0022] By adjusting the ratio of starch, glycerol and bioceramic powder, the present invention can make the premixed bone putty material reach the expected curing strength, greatly enhance the tissue bonding strength of the premixed bone putty material, and effectively prevent the premixed bone putty material from falling out after filling, and other adverse consequences; the change of the plasticizer and the water content can realize the long-term storage and immediate use of the premixed bone putty material (it can be used in various application forms such as mixing the raw materials during surgery and pre-shaping in advance), and can adjust the feel of use, so that the material can adapt to more operation scenarios and the operation requirements of technicians. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The actual picture of the premixed bone putty material in Example 1 before and after extrusion;

[0024] Figure 2 It is a diagram of kneading and shaping the premixed bone putty material;

[0025] Figure 3 This is the bone adhesion diagram of the premixed bone putty material of Example 2;

[0026] Figure 4 The results of the bonding strength test of the premixed bone putty materials of Example 8 and Comparative Example 1 on bone chips;

[0027] Figure 5 These are actual photos of the samples prepared in Example 8 and Comparative Examples 1 and 2 being immersed in water for 10 minutes. DETAILED DESCRIPTION

[0028] The present invention provides a premixed bone putty material, comprising the following components:

[0029]

[0030] In terms of weight percentage, the components of the premixed bone putty material include 1 to 5 parts of starch. In a specific embodiment of the present invention, the weight percentage of the starch can be 1 part, 2 parts, 3 parts, 4 parts or 5 parts.

[0031] In the present invention, the starch preferably includes one or more of sulfonated starch, hydroxypropyl distarch phosphate, corn starch, waxy starch, tapioca starch, sorghum starch, sweet potato starch, taro starch, yam starch, broad bean starch, lentil starch and pea starch.

[0032] Based on the unit mass fraction of the starch, the components of the premixed bone putty material include 5 to 10 parts of bioceramic powder. In a specific embodiment of the present invention, the mass fraction of the bioceramic powder can be 5, 6, 7, 8, 9 or 10 parts; the bioceramic powder preferably includes one or more of allogeneic bone, xenogeneic bone, hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate, biphasic calcium phosphate, calcium sulfate, magnesium phosphate, polycalcium phosphate, tetracalcium phosphate, phosphoserine-modified calcium phosphate, magnesium polyphosphate and bioactive glass; the calcium sulfate preferably includes calcium sulfate hemihydrate and / or anhydrous calcium sulfate.

[0033] In the present invention, the particle size of the bioceramic powder is preferably less than 200 μm. In a specific embodiment of the present invention, the particle size of the bioceramic powder can be 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 160 μm, 170 μm, 180 μm, 190 μm or 200 μm.

[0034] Based on the unit mass fraction of the starch, the components of the premixed bone putty material include 1 to 12 parts of glycerol. In a specific embodiment of the present invention, the mass fraction of the glycerol can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts or 12 parts.

[0035] Based on the unit mass fraction of the starch, the components of the premixed bone putty material include 0.01 to 1 part of a plasticizer. In a specific embodiment of the present invention, the mass fraction of the plasticizer can be 0.01 part, 0.1 part, 0.3 part, 0.5 part, 0.7 part or 1 part.

[0036] In the present invention, the plasticizer preferably includes one or more of polyethylene glycol, borax solution, polyphosphate and poloxamer solution;

[0037] The mass fraction of borax in the borax solution is preferably 1-10%. In a specific embodiment of the present invention, the mass fraction of borax in the borax solution may be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%. The mass fraction of poloxamer in the poloxamer solution is preferably 1-10%. In a specific embodiment of the present invention, the mass fraction of poloxamer in the poloxamer solution may be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.

[0038] In the present invention, the polyethylene glycol is one or more polyethylene glycols with a molecular weight of 300 to 5000.

[0039] In the present invention, the polyethylene glycol preferably includes a mixture of polyethylene glycol 400 and polyethylene glycol 1500 or a mixture of polyethylene glycol 600 and polyethylene glycol 1500.

[0040] The mass ratio of polyethylene glycol 400 to polyethylene glycol 1500 in the mixture of polyethylene glycol 400 and polyethylene glycol 1500 is preferably 1:1; the mass ratio of polyethylene glycol 600 to polyethylene glycol 1500 in the mixture of polyethylene glycol 600 and polyethylene glycol 1500 is preferably 1:1-2.

[0041] Based on the unit mass fraction of the starch, the components of the premixed bone putty material include 0 to 10 parts of water. In a specific embodiment of the present invention, the mass fraction of the water can be 0, 1, 3, 5, 7, 9 or 1.

[0042] The present invention also provides a method for preparing the premixed bone putty material described in the above technical solution, comprising the following steps:

[0043] Performing a first mixing of starch and bioceramic powder to obtain a first mixture;

[0044] The first mixture is mixed with glycerol and water to obtain a second mixture;

[0045] The second mixture is mixed with the plasticizer for a third time.

[0046] The present invention performs a first mixing of starch and bioceramic powder to obtain a first mixture.

[0047] In the present invention, when the bioceramic powder is magnesium phosphate, the present invention preferably first mixes magnesium oxide and potassium dihydrogen phosphate with starch. Magnesium oxide and potassium dihydrogen phosphate will generate magnesium phosphate after mixing with water.

[0048] In the present invention, when the bioceramic powder is hydroxyapatite, the present invention preferably first mixes α-tricalcium phosphate and dibasic calcium phosphate with starch. Alpha-tricalcium phosphate and dibasic calcium phosphate with water will generate hydroxyapatite.

[0049] Before the first mixing, the present invention preferably further comprises: pre-gelatinizing the starch, wherein the pre-gelatinization comprises the following steps:

[0050] The starch is dispersed in water and then boiled, and then the obtained solution is cooled and dried to obtain the pregelatinized starch.

[0051] In the present invention, the mass ratio of starch to water is preferably 1:1.5-2.

[0052] In the present invention, the first mixing is preferably performed in an oscillator.

[0053] After obtaining the first mixture, the present invention performs a second mixing of the first mixture with glycerol and water to obtain a second mixture.

[0054] In the present invention, the second mixing is preferably performed under grinding conditions.

[0055] After obtaining the second mixture, the present invention performs a third mixing of the second mixture and the plasticizer to obtain the premixed bone putty material.

[0056] In the present invention, the third mixing is preferably performed under grinding conditions.

[0057] In the present invention, after the third mixing, preferably further comprising:

[0058] The resulting third mixture was allowed to stand and was extruded.

[0059] The present invention has no special limitation on the extrusion, and the extrusion may be performed until no obvious particles are left.

[0060] After the extrusion, the method preferably further comprises: shaping the obtained extrudate.

[0061] The premixed bone putty material and the preparation method thereof provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0062] The method of starch pregelatinization in the embodiment is:

[0063] Disperse 1 part of starch in 1.5 parts of water, boil the solution and continue heating for 30 minutes, then cool it to room temperature, dry the solution and collect the solid product, the obtained product is the pregelatinized starch.

[0064] Example 1

[0065] 1. Place 0.9 g of hydroxyapatite with a particle size of 30 μm and 0.1 g of pregelatinized waxy starch in a centrifuge tube, mix them evenly using an oscillator, and pour the evenly mixed powder into a mortar.

[0066] 2. Add 400 μL of glycerol and 100 μL of deionized water to the powder, grinding continuously during the addition process to fully mix the powder and liquid.

[0067] 3. Add 50 μL of a liquid mixture of polyethylene glycol 400 and polyethylene glycol 1500 (the mass ratio of polyethylene glycol 400 to polyethylene glycol 1500 is 1:1) to the mixture, and keep grinding during the process. Let the product stand at room temperature, and fully squeeze the product until there are no obvious particles to obtain a premixed bone putty material.

[0068] Example 2

[0069] 1. Place 0.9 g of α-tricalcium phosphate with a particle size of 20 μm, 0.1 g of dibasic calcium phosphate with a particle size of 10 μm, and 0.5 g of pregelatinized corn starch in a centrifuge tube, mix them evenly using an oscillator, and pour the evenly mixed mixture into a mortar.

[0070] 2. Add 800 μL of glycerol and 50 μL of deionized water to the powder, grinding continuously during the addition process to fully mix the powder and liquid.

[0071] 3. Add 150 μL of a liquid mixture of polyethylene glycol 600 and polyethylene glycol 1500 (the mass ratio of polyethylene glycol 600 and polyethylene glycol 1500 is 1:1) to the ground mixture, and keep grinding. Let the product stand at room temperature, and fully squeeze the product until there are no obvious particles to obtain a premixed bone putty material.

[0072] Example 3

[0073] 1. Place 0.25 g of magnesium oxide with a particle size of 50 μm, 0.25 g of potassium dihydrogen phosphate with a particle size of 20 μm, and 0.25 g of pregelatinized waxy starch in a centrifuge tube, mix them evenly using an oscillator, and pour the evenly mixed mixture into a mortar.

[0074] 2. Add 400 μL of glycerol and 1000 μL of deionized water to the powder, grinding continuously during the addition process to fully mix the powder and liquid.

[0075] 3. Add 500 μL of 4%wt borax solution to the ground mixture, and keep grinding. Let the product stand at room temperature, and fully squeeze the product until there are no obvious particles to obtain a premixed bone putty material.

[0076] Example 4

[0077] 1. Place 0.5 g of α-TCP (α-tricalcium phosphate) with a particle size of 20 μm and 0.25 g of corn starch in a centrifuge tube, mix them evenly using an oscillator, and pour the evenly mixed mixture into a mortar.

[0078] 2. Add 400 μL of glycerol to the above mixed powder, and continue grinding during the addition process to ensure that the powder and liquid are fully mixed.

[0079] 3. Add 75 μL of a liquid mixture of polyethylene glycol 600 and polyethylene glycol 1500 (the mass ratio of polyethylene glycol 600 to polyethylene glycol 1500 is 1:2) to the ground mixture, and keep grinding during the process. Let the product stand at room temperature, and fully squeeze the product until there are no obvious particles to obtain a premixed bone putty material.

[0080] Example 5

[0081] 1. Place 0.4 g of 45S5 bioactive glass with a particle size of 100 μm and 0.2 g of pregelatinized waxy starch in a centrifuge tube, mix them evenly using an oscillator, and pour the evenly mixed mixture into a mortar.

[0082] 2. Add 400 μL of glycerol and 900 μL of deionized water to the above mixed powder, and continue grinding during the addition process to ensure that the powder and liquid are fully mixed.

[0083] 3. Add 100 μL of a liquid mixture of polyethylene glycol 600 and polyethylene glycol 1500 (the mass ratio of polyethylene glycol 600 to polyethylene glycol 1500 is 1:2) to the ground mixture, and keep grinding during the process. Let the product stand at room temperature, and fully squeeze the product until there are no obvious particles to obtain a premixed bone putty material.

[0084] Example 6

[0085] 1. Place 0.6 g of α-TCP with a particle size of 50 μm and 0.4 g of corn starch in a centrifuge tube, mix them evenly using an oscillator, and pour the evenly mixed mixture into a mortar.

[0086] 2. Add 400 μL of glycerol to the above mixed powder, and continue grinding during the addition process to ensure that the powder and liquid are fully mixed.

[0087] 3. Add 100 μL of 5% poloxamer aqueous solution to the ground mixture, and keep grinding. Let the product stand at room temperature, and fully squeeze the product until there are no obvious particles to obtain a premixed bone putty material.

[0088] Example 7

[0089] 1. Place 0.9 g of human allogeneic bone powder with a particle size of 150 μm and 0.4 g of pregelatinized corn starch in a centrifuge tube, mix them evenly using an oscillator, and pour the evenly mixed mixture into a mortar.

[0090] 2. Add 700 μL of glycerol and 50 μL of deionized water to the powder, grinding continuously during the addition process to fully mix the powder and liquid.

[0091] 3. Add 200 μL of a liquid mixture of polyethylene glycol 600 and polyethylene glycol 1500 (the mass ratio of polyethylene glycol 600 and polyethylene glycol 1500 is 1:1) to the ground mixture, and keep grinding. Let the product stand at room temperature, and fully squeeze the product until there are no obvious particles to obtain a premixed bone putty material.

[0092] Example 8

[0093] 1. Place 0.9 g of α-tricalcium phosphate with a particle size of 30 μm, 0.1 g of dibasic calcium phosphate with a particle size of 20 μm, and 0.5 g of pregelatinized waxy starch in a centrifuge tube, mix them evenly using an oscillator, and pour the evenly mixed mixture into a mortar.

[0094] 2. Add 800 μL of glycerol to the powder, and continue grinding during the addition process to ensure that the powder and liquid are fully mixed.

[0095] 3. Add 150 μL of a liquid mixture of polyethylene glycol 600 and polyethylene glycol 1500 (the mass ratio of polyethylene glycol 600 and polyethylene glycol 1500 is 1:1.5) to the ground powder, and keep grinding. Let the product stand at room temperature, and fully squeeze the product until there are no obvious particles to obtain a premixed bone putty material.

[0096] Comparative Example 1

[0097] The only difference from Example 8 is that no glycerol was added.

[0098] Comparative Example 2

[0099] The only difference from Example 8 is that no starch is added.

[0100] Figure 1 The following is a physical picture of the premixed bone putty material in Example 1 before and after extrusion. Figure 1 A in the middle is the photo before mixing; Figure 1 B in the middle is a photo after mixing and extrusion.

[0101] Figure 2 This is a diagram of kneading and shaping the premixed bone putty material.

[0102] Figure 3 This is a bone adhesion diagram of the premixed bone putty material of Example 2. Figure 3 Middle A is a premixed bone putty material adhered to the surface of the bone slice; Figure 3 Figure B in the middle shows the underwater adhesion effect between the premixed bone putty material and the bone slices.

[0103] Depend on Figure 3 It can be seen that the premixed bone putty material has good wet adhesion to bone tissue and is stable in a liquid environment.

[0104] The premixed bone putty materials of Examples 1 to 8 and Comparative Examples 1 to 2 were used to test the bonding strength of bone fragments. The results are as follows: Figure 4 As shown in Table 1. (Test method: Use a fixture to fix two bone blocks up and down on a mechanical testing machine. After the premixed bone putty material is applied to the opposite surfaces of the two bone blocks, the fixture is controlled by the test software to move so that the two bone blocks are in contact with each other at a pressure of 100N and maintained for 60s. The contact area of ​​the two bone blocks is 2cm 2The clamp was then moved up and down to pull the bone block, the maximum pulling force generated was recorded and the adhesion strength was calculated. After several measurements, the average and standard deviation of the adhesion strength were calculated).

[0105] Table 1 Test results of the bonding strength of the premixed bone putty materials of Examples 1 to 8 and Comparative Examples 1 and 2 to bone chips

[0106]

[0107]

[0108] Depend on Figure 4 As shown in Table 1, the adhesion performance of the premixed bone putty material to bone tissue is mainly affected by the starch and glycerol components in the system, and changing the bioceramic powder in the components will not significantly affect the adhesion strength of the premixed bone putty material to bone tissue.

[0109] Figure 5 These are actual photos of the samples prepared in Example 8 and Comparative Examples 1 and 2 being immersed in water for 10 minutes.

[0110] Depend on Figure 5 It can be seen that the combination of starch and glycerol can effectively improve the stability of the material system in water, making it less likely to collapse.

[0111] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A premixed bone putty material, characterized in that: In parts by mass, it includes the following components:

2. The premixed bone putty material according to claim 1, characterized in that: The starch includes one or more of sulfonated starch, hydroxypropyl distarch phosphate, corn starch, waxy starch, tapioca starch, sorghum starch, sweet potato starch, taro starch, yam starch, broad bean starch, lentil starch and pea starch.

3. The premixed bone putty material according to claim 1, characterized in that: The plasticizer includes one or more of polyethylene glycol, borax solution, polyphosphate and poloxamer solution; The mass fraction of borax in the borax solution is 1-10%, and the mass fraction of poloxamer in the poloxamer solution is 1-10%.

4. The premixed bone putty material according to claim 3, characterized in that: The polyethylene glycol is one or more polyethylene glycols with a molecular weight of 300 to 5000.

5. The premixed bone putty material according to claim 3 or 4, characterized in that: The polyethylene glycol includes a mixture of polyethylene glycol 400 and polyethylene glycol 1500 or a mixture of polyethylene glycol 600 and polyethylene glycol 1500.

6. The premixed bone putty material according to claim 1, characterized in that: The bioceramic powder includes one or more of allogeneic bone, xenogeneic bone, hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate, biphasic calcium phosphate, calcium sulfate, magnesium phosphate, polycalcium phosphate, tetracalcium phosphate, phosphoserine-modified calcium phosphate, magnesium polyphosphate and bioactive glass.

7. The premixed bone putty material according to claim 1 or 6, characterized in that: The particle size of the bioceramic powder is less than 200 μm.

8. The method for preparing the premixed bone putty material according to any one of claims 1 to 7, characterized in that: The following steps are involved: Performing a first mixing of starch and bioceramic powder to obtain a first mixture; The first mixture is mixed with glycerol and water to obtain a second mixture; The second mixture is mixed with the plasticizer for a third time to obtain the premixed bone putty material.

9. The preparation method according to claim 8, characterized in that: Before the first mixing, the method further includes: pre-gelatinizing the starch; The pregelatinization comprises the following steps: The starch is dispersed in water and then boiled, and then the obtained solution is cooled and dried to obtain the pregelatinized starch.

10. The preparation method according to claim 8, characterized in that: After the third mixing, the method further includes: allowing the obtained third mixture to stand and extrude.

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