Composite material for bone hemostasis and bone repair promotion, preparation method and application thereof

Abstract

The present invention relates to a composite material for bone hemostasis and bone repair promotion, and a preparation method and application thereof. The composite material comprises a collagen-calcium magnesium phosphate mineralized skeleton with a porous micro-space structure, and a skeleton filler, wherein the skeleton filler comprises polyethylene glycol 2000 and polyethylene glycol 400. The present invention improves the material structure, introduces fillers into the collagen-calcium magnesium phosphate mineralized skeleton with a porous micro-space structure, provides viscosity and plasticity, can be molded into any desired shape, and is tightly adhered to the bone wound surface to stop bleeding by compression. At the same time, the micro-space structure of the skeleton is conducive to the growth, proliferation and differentiation of bone healing cells, thereby effectively promoting bone healing, and improving the limitation of the single function of traditional bone repair materials.

Description

Technical Field

[0001] The invention relates to the technical field of medical biomaterials, and in particular to a composite material for bone hemostasis and bone repair promotion, and a preparation method and application thereof. Background Art

[0002] Clinical treatment of orthopedic trauma will definitely face two problems: bone bleeding and bone healing after trauma. Therefore, clinical treatment of orthopedic trauma will definitely use orthopedic hemostasis and bone healing promotion medical products. At present, there are separate bone hemostasis and bone healing promotion medical products in clinical practice, but there is no product solution that has both good bone hemostasis and bone healing promotion.

[0003] Clinically, bone hemostasis products are mainly non-absorbable bone hemostatic wax represented by Johnson & Johnson, which has good shaping ability, can be filled into bone wounds and provide good hemostasis through physical compression. However, non-absorbable bone wax will be permanently filled into the bone wound, hindering bone healing and causing bone deformities. In addition, absorbable hemostatic bone wax has also appeared. After being filled into the wound surface for compression and hemostasis, although it will be absorbed and will not hinder bone healing, it has no ability to promote bone healing. Clinically, bone healing-promoting products are mainly composite materials with hydroxyapatite and β-tricalcium phosphate as the main components, but they have no bone hemostasis ability. Therefore, there is a lack of product solutions in clinical practice that can simultaneously have good bone hemostasis and promote bone healing.

[0004] There are also related inventions showing materials that have both bone hemostasis and bone repair capabilities. For example, patent document CN117244111A discloses an absorbable bone wax and its preparation method and application. It is mainly achieved by physically blending bone wax with materials that promote bone healing. It has certain clinical value, but the closed structure of bone wax will affect the growth of bone cells, resulting in the bone healing function not being prominent enough, and the bone healing promoting ability needs to be improved. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides a composite material having the functions of bone hemostasis and bone repair promotion and a preparation method thereof.

[0006] One aspect of the present invention provides a composite material for bone hemostasis and bone repair promotion, the composite material comprising a collagen-calcium magnesium phosphate mineralized skeleton with a porous micro-space structure, and a skeleton filler, wherein the skeleton filler comprises polyethylene glycol 2000 and polyethylene glycol 400.

[0007] The composite material of the present invention uses a collagen-calcium magnesium phosphate mineralized skeleton with a micro-space structure as the main structure, and polyethylene glycol 2000 and polyethylene glycol 400 as fillers, which can give the skeleton good viscosity and plasticity, can be molded into a required shape, and tightly adhere to the bone wound surface to stop bleeding by compression. At the same time, the natural structure of collagen in the skeleton is conducive to the adhesion and migration of cells, the in-situ mineralized calcium magnesium phosphate provides a nutritional environment for bone healing, and the micro-space structure is conducive to the growth and differentiation of bone healing cells, thereby effectively combining hemostasis and repair, and effectively promoting bone healing.

[0008] The collagen-calcium-magnesium phosphate mineralized skeleton can be deposited by mineralizing bone components such as phosphate, calcium, and magnesium on the surface of collagen to provide corresponding nutrients for bone repair.

[0009] Preferably, the micro-space pore size of the composite material is 20-200 μm, which is conducive to the growth, proliferation and differentiation of bone healing cells.

[0010] Preferably, the composite material comprises the following components in parts by weight: purified water: 30-40 parts, collagen: 10-20 parts, magnesium chloride: 3-5 parts, calcium chloride: 3-5 parts, disodium hydrogen phosphate: 1-3 parts, sodium dihydrogen phosphate: 1-3 parts, polyethylene glycol 2000: 14-42 parts, and polyethylene glycol 400: 5-15 parts.

[0011] Further preferably, the composite material comprises the following raw material components in weight fractions: purified water: 30 parts, collagen: 20 parts, magnesium chloride: 4 parts, calcium chloride: 4 parts, disodium hydrogen phosphate: 2 parts, sodium dihydrogen phosphate: 2 parts, polyethylene glycol 2000: 28 parts, and polyethylene glycol 400: 10 parts.

[0012] Another aspect of the present invention further provides a method for preparing the composite material, comprising the following steps:

[0013] The structure of S1 collagen and calcium magnesium phosphate main structure;

[0014] S11: collagen, magnesium chloride, calcium chloride, disodium hydrogen phosphate, and sodium dihydrogen phosphate are fully mixed and dispersed in purified water according to the material ratio to obtain a uniform solution;

[0015] S12: repeatedly freeze-thaw the obtained homogeneous solution several times to finally obtain a suspension;

[0016] S2 Preparation of composite materials with micro spaces;

[0017] S21: adding polyethylene glycol 2000 and polyethylene glycol 400 to the suspension obtained in step S12 according to the material ratio, stirring, mixing and dispersing to form a uniform colloid;

[0018] S22: freezing the obtained jelly, and then freeze-drying it to obtain the composite material for bone hemostasis and bone repair promotion.

[0019] Preferably, in step S12, the obtained homogenous solution is kept at a constant temperature of 4°C for 2 hours, then frozen at -20°C and kept at a constant temperature for 2 hours, and then transferred to 20°C for natural thawing after the freezing is completed; the above steps are repeated several times to finally obtain a suspension. Repeated low-temperature-room temperature treatment can better mineralize calcium and magnesium ions along the collagen in situ to form calcium magnesium phosphate precipitation, and obtain the collagen-calcium magnesium phosphate main structure.

[0020] Preferably, in step S22, the obtained jelly is kept at a constant temperature of 4°C for 2 hours, and then kept at a constant temperature of -80°C for 4 hours after being frozen. After the freezing is completed, it is transferred to a freeze dryer for freeze drying, thereby obtaining a composite material with a micro-space structure.

[0021] In another aspect of the present invention, the above-mentioned composite material and the use of the composite material prepared by the above-mentioned preparation method in the preparation of orthopedic repair materials are provided.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The present invention improves the material structure by introducing a filler compounded with polyethylene glycol 2000 and polyethylene glycol 400 into a collagen-calcium magnesium phosphate mineralized skeleton with a porous micro-space structure, thereby providing viscosity and plasticity, being able to be molded into any desired shape, and tightly adhering to the bone wound surface to stop bleeding through compression. At the same time, the micro-space structure of the skeleton is conducive to the growth, proliferation and differentiation of bone healing cells, thereby effectively promoting bone healing and improving the limitation of the single function of traditional bone repair materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a schematic diagram of the SEM micro-space structure of a composite material according to an embodiment of the present invention;

[0025] Figure 2 This is a picture of plasticity evaluation of a composite material sample according to an embodiment of the present invention;

[0026] Figure 3 Schematic diagram of the viscosity test of composite material samples according to an embodiment of the present invention. DETAILED DESCRIPTION

[0027] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. The preferred embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0028] In the description of the present invention, unless otherwise clearly defined, terms such as heating, cleaning, weighing, freezing, etc. should be understood in a broad sense, and technicians in the relevant technical field can reasonably determine the specific meanings of the above terms in the present invention in combination with the specific content of the technical solution.

[0029] In the description of the present invention, the description with reference to the terms "some embodiments", "examples", etc. means that the specific methods and materials described in conjunction with the embodiments or examples are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific methods and materials described can be combined in any one or more embodiments or examples in a suitable manner.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0031] In the following examples and comparative examples, the experimental methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are all commercially available unless otherwise specified.

[0032] Examples 1-4

[0033] The formula of each embodiment is shown in Table 1, and the specific preparation method is as follows:

[0034] The structure of S1 collagen and calcium magnesium phosphate main structure.

[0035] S11 Stir collagen, magnesium chloride, calcium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate in purified water according to the material ratio and mix thoroughly to form a uniform solution.

[0036] S12: The obtained homogenous solution is transferred to 4°C and kept at a constant temperature for 2 hours, and then transferred to -20°C, and kept at a constant temperature for 2 hours after freezing. After the freezing is completed, it is transferred to 20°C and thawed naturally. The above operation is repeated 3 times to finally obtain a suspension.

[0037] S2 Preparation of composite materials with microspaces.

[0038] S21: adding polyethylene glycol 2000 and polyethylene glycol 400 to the suspension obtained in step S12 according to the material ratio, stirring, mixing and dispersing to form a uniform colloid;

[0039] S22: The obtained jelly is transferred to 4°C for 2 hours, and then transferred to -80°C, and kept at the constant temperature for 4 hours after freezing. After freezing, it is transferred to a freeze dryer for freeze drying to obtain a composite material for bone hemostasis and bone repair promotion.

[0040] Table 1: Examples and Comparative Examples

[0041]

[0042] Comparative Example 1

[0043] The same as Example 1, the only difference is that the amount of purified water used is 15g, and the other components and preparation method are the same as Example 1.

[0044] Comparative Example 2

[0045] The same as Example 1, the only difference is that the amount of purified water used is 50g, and the other components and preparation method are the same as Example 1.

[0046] Comparative Example 3

[0047] The same as Example 1, the only difference is that the amount of polyethylene glycol 2000 is 10g, the amount of polyethylene glycol 400 is 3g, and the other components and preparation method are the same as Example 1.

[0048] Comparative Example 4

[0049] The same as Example 1, the only difference is that the amount of polyethylene glycol 2000 is 45g, the amount of polyethylene glycol 400 is 20g, and the other components and preparation method are the same as Example 1.

[0050] Comparative Example 5

[0051] The same as Example 1, the only difference is that an equal amount of propylene glycol is used to replace polyethylene glycol 400 therein, and the other components and preparation method are the same as Example 1.

[0052] Comparative Example 6

[0053] The same as Example 1, the only difference is that the polyethylene glycol 2000 is replaced by an equal amount of polyvinyl alcohol, and the other components and preparation method are the same as Example 1.

[0054] Performance testing and trial

[0055] The samples of Examples 1-4 and Comparative Examples 1-6 were selected to evaluate the pore size, plasticity, viscosity, hemostatic ability, and bone healing promoting ability.

[0056] The specific evaluation methods and standards are as follows:

[0057] Pore ​​size: The pore size of the composite material was observed and measured by SEM. The pore diameter should be between 20 μm and 200 μm, which is suitable for osteoblast growth. Figure 1 Schematic diagram of the SEM micro-space structure of the obtained composite material sample.

[0058] Plasticity: The composite material should have good plasticity when kneaded by hand. Figure 2 This is a picture of the plasticity evaluation of the composite material sample obtained.

[0059] Adhesion: Bond the composite material to two plastic sheets, and use a universal testing machine to pull the two plastic sheets apart. The measured separation force should be no less than 2N. Figure 3 Schematic diagram of viscosity test for composite materials samples.

[0060] Hemostasis ability: Prepare a hollow plastic tube with a diameter of 3mm and a length of 1.91m, seal one end with the composite material, and add purified water from the other end to simulate the effect of sealing medullary bleeding. The sealing time of the composite stent should be no less than 5min.

[0061] Bone healing ability: The activity of osteoblasts is an important indicator for evaluating bone healing ability. Osteoblasts were inoculated on the composite material and cultured for 72 hours. Compared with the blank control (ordinary culture dish), the activity of osteoblasts in the experimental group should be no less than 1.5 times.

[0062] The results are shown in Table 2.

[0063] Table 2: Evaluation results of composite materials of examples and comparative examples

[0064]

[0065]

[0066] From the above, it can be seen that the preparation method of the present invention first obtains a collagen-calcium magnesium phosphate mineralized skeleton with a porous microspace structure by repeated freezing and thawing, and then introduces polyethylene glycol 2000 and polyethylene glycol 400 as fillers to shape and provide adhesion, and the obtained conforming material has good viscosity and plasticity, hemostasis ability and bone healing ability. Among them, the amount of purified water used will affect the size of the microspace aperture, and the appropriate amount of addition can be made into a material with a suitable aperture. Polyethylene glycol 2000 and polyethylene glycol 400 will affect the plasticity and viscosity of the composite material, and then affect the hemostasis ability. Too much will make the texture soft, too little will make it hard, and no matter too much or too little will lead to insufficient bonding force, so as not to achieve good hemostasis and bone healing effects. And it was found in the experiment that compared with other combinations, the combination of polyethylene glycol 2000 and polyethylene glycol 400 is more likely to provide suitable plasticity and viscosity.

[0067] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0068] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A composite material for bone hemostasis and bone repair, characterized in that: The composite material comprises a collagen having a porous micro-space structure - calcium magnesium phosphate mineralized skeleton, and a skeleton filler, the skeleton filler comprises polyethylene glycol 2000 and polyethylene glycol 400; The raw materials of the composite material include the following components in parts by weight: purified water: 20-40 parts, collagen: 10-30 parts, magnesium chloride: 3-5 parts, calcium chloride: 3-5 parts, disodium hydrogen phosphate: 1-3 parts, sodium dihydrogen phosphate: 1-3 parts, polyethylene glycol 2000: 14-42 parts, polyethylene glycol 400: 5-15 parts; The method for preparing the composite material comprises the following steps: S1 Construction of collagen-calcium magnesium phosphate main structure; S11: collagen, magnesium chloride, calcium chloride, disodium hydrogen phosphate, and sodium dihydrogen phosphate are fully mixed and dispersed in purified water according to the material ratio to obtain a uniform solution; S12 The obtained uniform solution is kept at 4°C for 2 hours, then frozen at -20°C and kept at a constant temperature for 2 hours, and after the freezing is completed, it is transferred to 20°C for natural thawing; the above steps are repeated several times to finally obtain a suspension; S2 Preparation of composite materials with porous microspaces; S21 adding polyethylene glycol 2000 and polyethylene glycol 400 to the suspension obtained in step S12 according to the material ratio, stirring, mixing and dispersing to form a uniform colloid; S22 The obtained jelly is frozen and then freeze-dried to obtain the composite material.

2. The composite material according to claim 1, characterized in that The pore size of the porous micro space is 20-200 μm.

3. The composite material according to claim 1, characterized in that The raw materials include the following components in parts by weight: purified water: 30-40 parts, collagen: 10-20 parts, magnesium chloride: 3-5 parts, calcium chloride: 3-5 parts, disodium hydrogen phosphate: 1-3 parts, sodium dihydrogen phosphate: 1-3 parts, polyethylene glycol 2000: 14-42 parts, and polyethylene glycol 400: 5-15 parts.

4. The composite material according to claim 3, characterized in that The raw materials include the following components in weight fractions: purified water: 30 parts, collagen: 20 parts, magnesium chloride: 4 parts, calcium chloride: 4 parts, disodium hydrogen phosphate: 2 parts, sodium dihydrogen phosphate: 2 parts, polyethylene glycol 2000: 28 parts, and polyethylene glycol 400: 10 parts.

5. The composite material according to claim 1, characterized in that In the step S22, the obtained jelly is kept at a constant temperature of 4°C for 2 hours, and then kept at a constant temperature of -80°C for 4 hours after being frozen. After the freezing is completed, it is transferred to a freeze dryer for freeze drying.

6. Use of the composite material according to any one of claims 1 to 5 in the preparation of orthopedic repair materials.

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